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UNIT 1
INTRODUCATION TO PHARMACOLOGY
Pharmacology: pharmacon (drug), logus (science) is the study of

substances that interact with living systems, by binding to specific
molecules (receptors), and activating or inhibiting normal body
processes.
Branches of Pharmacology:
1) Medical Pharmacology: is the branch of pharmacology associated with

the use of drugs to prevent, diagnose, or to treat disease.
2) Clinical Pharmacology: is a science that deals with drug

administration, the therapeutic and unwanted effects (adverse effects),
and actions produced by the drug on the patient with a cretin pathologic
condition, as well as the interactions between drugs.
3) Toxicology: is defined as a science involved in studying the toxicologic

effects produced by the drug on the living organism from cellular to
complex ecosystems.
4) Pharmacokinetics: refers to the study of actions produced by the body

on the drug or (what the body does to the drug), including drug
administration, absorption, binding, distribution, metabolism and
excretion of the drug, (ADME).
5) Pharmacodynamics: is the study of the mechanism of action (M.O) of

drugs, or the mechanisms by which drugs exert their biologic effects,
(what the drug does to the body).
6) Pharmaceutical Pharmacology: is the branch of pharmacology, deals

with studying of the chemical structure, biosynthesis, and pharmaceutical
forms of the drug (tablets, pills, capsules, suppositories, ointments, gases
and others).
7) Pharmacogenetics: is the study of the genetic variations that cause

differences in drug response among individual or populations, (genetic
activated or inhibited P-450 system (drug metabolism) of the liver.
1 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

8) Experimental Pharmacology: is the branch of pharmacology,
specialized in studying of actions, kinetics, M.O, toxicologic and
mutagenic actions of a candidate drug (preparation) in animals, in order
to be used in human.
The Nature of Drugs:

Drug: may be defined as any substance that brings about a change in
biologic functions, through its interaction with living molecules
(receptors) of organisms.
Identification of The Drugs: the drugs are named according to their:
a. Chemical structure: e.g. N-acetyl Para amino-phenol (paracetamol)
b. International (Generic) name: e.g. aspirin.
c. Trade name: is specific for individual pharmaceutical companies, the

naming of drug differs from one company to another e.g. prazocin
(minipress) and diclofenac sodium (diclofen or rufinal).
Classification of Drugs:
a. Internal: drugs may be synthesized within the body e.g. hormones.
b. External: Xenobiotics or toxins are not synthesized by the body, but

prepared synthetically e.g. antibiotics, antifungals and antivirals.
Interaction of Drugs With The Living Organism:
The physical nature of drugs: drugs may be solid as aspirin and atropine,
liquid as ethanol and nicotine or gaseous such as nitrous oxide. These factors
determine the best route of administration.
Drug Size: determines the ability of the drug to move from site of
administration to site of action as well as its affinity to bind its specific
receptors.
a. The majority of drugs have MW between 100 and 1000 unites.

b. No drugs are completely specific in their actions, increasing the dose of
drug will affect non-target receptors thereby leading to unwanted and
toxicologic effects.
c. Drugs with large MW don't diffuse readily from one compartment to

another, so they should be administered directly into the needed
compartment, e.g. in the case alteplase which is a fibrinolytic (clot
dissolving enzyme), administered directly into the vascular
compartment.
Drug Receptor Bonds: drugs act by 3 main processes:
a. Covalent bonds: are rare, but form very strong and irreversible bonds-
the effects of the drug are longer than its concentration in the blood, due
to its slow dissociation from receptors, e.g. aspirin binds covalently to
cyclooxygnase (COX) - the antiaggregant effect of aspirin lasts long after
aspirin has disappeared from the blood, (about 15 minutes) and is
reversed by synthesis of new enzyme in new platelets, a process takes
about several days.
b. Electrostatic bonds: is much more common, but weaker than covalent,

characterized by binding of charged ions of drug with hydrogen ions.
c. Hydrophobic bonds: the lipid-soluble drugs (lipophilic) readily

penetrate throughout the cell membrane, than non-lipid-soluble (polar
drugs).
Drug Shape: in order to bind to receptors a drug molecule must has a

specific configuration that corresponds with its receptor.
Pharmacodynamic Principles: Drugs bind to their receptors to produce

either:
a. Agonists or (Mimetics): drugs that stimulate the physiologic action of
the cell, by either activation of receptors (direct action), or by increasing
the concentration of a physiologic ligand (e.g. acetylcholine (Ach) or
norepinephrine) (indirect action), e.g. acetylcholinosterase inhibitors
(edrophonium), prolong the action of Ach (parasympathomimetic effect).
b. Antagonists or Lytics (Blockers): drugs that inhibit the physiologic

action of the cell by preventing the binding of specific substances to their
receptors e.g. atropine prevents the interaction between acetylcholine and
cholinoceptors (parasympatholytics) or ranitidine (antihistamine)
prevents the binding of histamine to its receptors.
Duration of Drug Action: termination of drug action differs from one to

another drug, it depends on the occupation of a drug with its receptors, some
drugs are rapidly dissociated from their receptors, whereas others are
slowly dissociated, maintaining long-duration of action.
Inert Binding Site: is defined as the binding of a drug to non regulatory

protein e.g. plasma albumin or α-globulins, without changing functions of
an organism (no pharmacologic effect) but determining the
pharmacokinetic properties of a drug.
Pharmacokinetics Principles: It is important for the drug to reach its

intended site, some medications are administered as prodrugs which
should be metabolized to active drugs, and therefore drug undergoes
absorption, distribution, penetration, metabolism (elimination), and
excretion.
Permeation: drugs diffuse across the plasma membrane by 4 primary

mechanisms:
1) Aqueous diffusion (Passive diffusion): drugs may diffuse passively

through aqueous channels in the intracellular junctions (tight junctions) it
is governed by Ficks low- the passive flux of molecules down a
concentration gradient, thus drug absorption is faster from organs with
large surface (small intestine) than from with smaller absorbing surface
(stomach), furthermore drug absorption is faster from organs with thin
membrane barriers (lung) than from those with thick barriers (brain).
2) Lipid diffusion: is the most important among others, many drugs

permeate plasma membranes, because of their structure, usually
uncharged molecules diffusion is better than charged.
3) Active transport: some drugs are insoluble or with large MW requiring a

specific carrier that needs energy to accomplish this process, e.g.,
transport of sugar and amino acids.

4) Endocytosis and exocytosis: endocytosis occurs when the molecules of
a drug are too large to cross the cell membrane, the molecules are
engulfed by plasma membrane into the cell, e.g. the transport of vit.B12
and iron, specific receptors are required for these processes, exocytosis is
the reverse way by which the substance is released from the intracellular
space into the extracellular space, e.g. the release of neurotransmitters
from vesicles toward the synaptic gap, e.g. noradrenaline or
acetylcholine.
Ionization of Weak Acids and Weak Bases: it is important to note that

drugs are either weak acids or weak bases that are readily absorbed;
non-ionized molecules of drugs best diffuse than ionized molecules,
weak acids are excreted faster in the alkaline urine, and conversely, weak
bases are faster eliminated in the acidic urine, so to accelerate excretion of
the drug (overdose), it is important to prevent its reabsorption from the
tubule, this could be done by adjusting urine pH, when a patient takes an
overdose of a weak acid drug its excretion may be accelerated by giving
bicarbonate and thus alkalinizing urine, this is because weak acid drug
dissociates to its charged (polar) form in alkaline urine and this form cannot by
readily diffuse from the renal tubule back into the blood.
Handerson-Hasselbalch Equation: is the ratio of protonated to

unprotonated weak acid or weak base to the molecules pKa and the pH.
Protonation: is the combination of a drug with proton (H2) ions.
a. For weak acids: combination of weak acid with a proton, results in the
release of H+ and A-, only the uncharged HA can permeate through
membranes, but A- can't. HA= H+ + A-.
b. For weak bases: combination of weak base with a proton, produces

uncharged base (B) and the proton (H+), only the B penetrates through
membranes but H+ can't. BH+ = B + H+.
Drug Receptors and Pharmacodynamics:
Receptor: is a specific cellular component (usually proteins) that interacts

with molecules of drugs through biochemical reactions leading to its
pharmacologic actions.

Types of Receptors: most receptors are regulated proteins and classified
as the following:
1. Enzymes: the drug brings about its effect either by activation or

inactivation of certain enzyme.
2. Ion channels: the drug acts either by activation or inactivation of a

cretin ion channel.
3. Structural proteins: some drugs act by binding to structural protein e.g.

colchesine binds to the structural protein tubulin.
Relation Between Drug Concentration and Response: the relation

between dose of a drug and the clinically observed response may be
complex, increasing dose results in incidence of toxic effects, because all
target receptors are occupied, however increasing the dose to achieve
better therapeutic effect, results in reduced response, because there are no
free receptors.
Spare Receptors: present when the maximal drug response is obtained at

less than maximal occupation (binding) of the receptors, in practice, the
determination usually made by comparing the concentration for 50% of
maximal effect (EC50) with the concentration for 50% of maximal binding
(Kd ), if the EC50 is less than the Kd, spare receptors are said to exit.
Mechanisms of Spare Receptors;

a. The effect of the drug-receptor interaction may persist for a much
longer time than the interaction itself.
b. The actual number of receptors may exceed the number of effector
molecules available.
Sensitivity of Receptors: the decreased concentration of a drug, the more

sensitivity of its receptors (increased their number, namely spare
receptors) and conversely the increased concentration of a drug, the less
sensitivity of its receptors e.g. in insulin dependent diabetes mellitus
(IDDM) hypoinsulinemia is present, with increased number and
sensitivity of insulin's receptors and in NIDDM hyperinsulinemia
reduces sensitivity of insulin's receptors respectively.

Types of Agonists: on the basis of their pharmacologic effects they are
divided into:
a. Full agonists: agents that produce a high affinity and maximal effects
by occupying to all available receptors.
b. Partial agonists: drugs that exert agonist-antagonist property, as in

higher doses they have antagonistic activity. They stimulates receptors
but not enough to produce a full response, e.g. acebutalol (β
adrenoblocker causes less bradycardia in hypertensive patients associated
with bradycardia or less hypoglycemia in hypertensive diabetics).
Types of Antagonists: on the basis of their pharmacologic effects they are

divided into:
a. Competitive antagonists: drugs that compete for binding to their

receptors in the presence of full agonists; the degree of inhibition
produced by a competitive antagonist depends on the concentration of
antagonist and agonist, then higher concentration of antagonists completely
will block receptors and conversely high concentration of agonists prevent the
action of antagonists.
b. Irreversible antagonists: they are not competitive, with agonists for

binding to receptors, they form covalent bonds with receptors and very
slowly dissociate from them, the remaining receptors for agonist are too
low to exert a response, agonist's response will be achieved only if spare
receptors are involved, and if the concentration of irreversible antagonist
is too low.
Others Mechanisms of Drug Antagonism:
a. Chemical antagonism: the ability of drug A to antagonize drug B,

chemically, e.g. protamine sulfate is a positively charged drug can bind a
negatively charged heparin thus reducing its toxicity.
b. Physiologic antagonism: 2 agents opposing physiological effects by

affecting 2 different receptors, e.g. zafirlukast causes bronchodilation by
inhibiting leukotrine receptors, whereas propranolol causes
bronchoconstriction by acting on β receptors.

c. Pharmacologic antagonism: 2 agents opposing physiological effects by
affecting the same receptors, e.g., glucagon stimulates β receptors but
atenolol blocks them.
The Molecular Aspects By Which Drugs Act: Generally there are five
mechanisms:
a. Intracellular receptors: the lipophilic drug crosses plasma membrane
and binds to an intracellular receptor, which may be an enzyme, e.g.
activation of guanylyl cyclase intermediates actions of some hormones.
b. Extracellular receptors: the drug binds to extacellular domain of

transmembrane receptor, which in its turn stimulates cytoplasmic
domain, leading to an alteration in enzymatic activity.
c. Tyrosine kinase receptors: is very similar to the previous but the

external domain binds to the internal domain of tyrosine kinase, which
enzymatically become active and phosphrylates one another, e.g. insulin
and ANP produce their effects by using this system.
d. Ligand-gated channels: the ligands bind to an ion channels and

regulate them either by activation or inactivation e.g. acetylcholine
activates nicotinic receptors by opening Na channels, that results in influx
of Na and the development of depolarization, in contrast Ca antagonists
(blockers) prevent the movement of Ca into the cell thus inhibiting
depolarization.
e. G proteins receptors as a second messenger: some drugs act with the

help of second messengers (G proteins): this process is accomplished by
the following steps:
1. The drug is detected by a transmembrane receptor G protein.
2. The activated G protein changes the activity of an enzyme or ion
channel), two types of G protein present: Gs, (stimulatory) and Gi
(inhibitory).
Purposes of Drug Use:

1. Compensatory therapy: a drug is used for replacement of substances
that either never produced or produced in low concentrations, e.g. the
use of exogenous insulin in IDDM (type I), or the use of thyroid
hormones in hypothyroidism.

2. Supportive therapy: is the use of a drug to enhance the function of the
cell physiologically, e.g. oral hypoglycemic agents are approved for the
management of NIDDM (type II), to enhance or support the release of
insulin.
3. Prophylactic therapy: is the use of a drug to prevent certain diseases,

e.g. isoniazid may be used to prevent the development of tuberculosis.
4. Etiologic therapy: is the use of drugs that affect direct cause of disease,
e.g. antibacterials, antifungals and antivirals.
5. Symptomatic therapy: is the use of a drug that relives symptoms of

disease, but not affecting pathogenic aspects of disease, e.g. aspirin is
used for reducing fever or as analgesic, but not as ant-inflammatory
agent.
6. Pathotropic therapy: in this type the use of a drug can affect

pathogenetic aspects of disease, antihypertensives are used to interfere
with pathophysiologic mechanisms of hypertension, but these drugs can’t
cure essential hypertension, e.g. (enalopril is an angiotensin converting
enzyme inhibitor "ACEI").
7. Diagnostic therapy: a drug may be used for diagnostic purposes, e.g.

histamine is used to examine the ability of the stomach to secrete acid, if
anacidity or hypo-secretion occurs, this may indicate the presence of
pernicious anemia or atrophic gastritis, on the other hand, if
hypersecretion develpos, this reaction may be associated with duodenal
ulcer or gastrinoma.
Second Messengers: many drugs (ligands) act with the help of second
messengers that are regulated by G-proteins, to bring about their
pharmacologic effects; there are 3 types of second messengers:
1. Cyclic Adenosine Monophosphate (cAMP): mediates physiologic and

pharmacologic actions of many drugs:
a. Stimulation of β-adrenoreceptors: located in the heart, blood vessels,
eye and others.
b. Catabolism of carbohydrates and lipids: glycogenolysis and lipolysis.
c. Reabsorption of water via vasopressin (antidiuretic hormone ADH).
d. Ca homeostasis.
Adenylyl cyclase is a transmembrane effecter enzyme for cAMP which is
under the control of G-protein; the enzyme converts the intracellular ATP
to cAMP which is inactivated to 5-AMP by phosphdiesterases, that are
inhibited by caffeine and therefore providing the IC accumulation of
cAMP.
2) Calcium and phosphoinositides: some hormones and

neurotransmitters trigger this pathway by activation of G-proteins or
tyrosine kinase receptors, with stimulation of phospholipase C enzyme
that splits a phospholipid component of plasma membrane
phosphotidylinositol biphosphate (PIP2) into 2 second messengers
diacylglycerol (DAG) and inositol triphosphate (IP3).
DAG: activates protein kinase C which in its turn activates Ca channels,

(increased cytosolic concentration of Ca), its action is terminated by
dephosphorylation into either phospholipids or arachidonic acid.
IP3: acts to increase the intracellular concentration of Ca by enhancing its

release from the EPR, consequently increased its cytoplasmic
concentration, it is also terminated by dephosphorrylation.
Actions of Phosphoinositides:
a. cAMP Antagonism: vaspressor drugs act by increasing the IC
concentration of IP3 that causes contraction of smooth muscles, whereas,
agents acting by increasing concentration of cAMP promote relaxation of
smooth muscles (vasodilation).
b. cAMP Synergism: cAMP and IP3 act together to release glucose from
the liver in response to hypoglycemia, (glycogeolysis and gluconeogenesis).
3. Cyclic Guanosine Monophosphate (cGMP):
cGMP: some drugs act with the help of cGMP e.g. nitric oxide (NO), its
action is similar to cAMP, but the effector enzyme is guanylyl cyclase that
converts GTP to cGMP, which causes dephophsphorylation of enzymes
or ions, mainly inactivation of myosin light chain kinase (MLCK) (is
required for muscle contraction), thus it prevents the interaction of
myosin and actin, maintaining relaxation of vascular smooth muscles,
and therefore vasodilation.

Relation Between Drug Dose and Clinical Response: in order to obtain
a maximum therapeutic effect and minimal toxicity, it is important to
understand the following terms:
a. Efficacy: is the maximal response produced by the drug, and depends

on the number of drug-receptor complexes, however a substance may
bind to receptor and does not elicit a response, thus efficacy is zero e.g.
antagonists.
b. Potency or ED50: is defined as the dose of drug that gives 50% of the
maximal response, or how much drug is required to elicit a given
response, the lower the dose for a given response, the more potent the drug.
c. Median toxic dose TD50: is the dose at which 50% of the experimented
animals will produce toxicity.
d. Median lethal dose LD50: is the dose at which 50% of the experimented
animals will be killed.
e. Therapeutic Index: is the ratio of the dose that produces toxicity to the
dose that produces effective response.
Therapeutic Index = LD50/ED50
NOTE: the higher the therapeutic index the safer the drug and conversely
the lower the therapeutic index the greater toxicity of the drug, it is often
used in experimental pharmacology to determine the toxicity of the drug
before its use in human.
f. Tolerance: is characterized by decreased pharmacologic responses after

repeated doses of a certain drug, a higher dose is required to achieve the
same effect, e.g. morphine tolerance.
g. Tachyphylaxis: differs from tolerance in that decreased pharmacologic

responses occur rapidly after administration of a drug, calcitonin
demonstrates tachyphylaxis in 2–3 days when being used to treat
hypercalcemia of malignancy. This reaction is anticipated and calcitonin
is given along with biphosphonates, which have their maximum effect in
2–3 days.

Causes of Tolerance and Tachyphylaxis:
1. Alterations in pharmacokinetic properties of the drug: including a
decrease in absorption, distribution, binding, metabolism, and excretion.
2. Alterations in number or function of receptors: in myasthenia gravis
there is a decrease in number and function of nicotinic receptors to its
endogenous neurotransmitter (acetylcholine).
h. Therapeutic effect: defined as the beneficial effects produced by the

drug, e.g. aspirin produces analgesic and antipyretic effects.
i. Side effects: are unwanted (adverse) effects that can appear in patients
at therapeutic doses, e.g. penicillin in addition to its antibacterial effect
may produce G.I.T distress or allergic reactions.
j. Toxic effects: effects that are produced when a drug is given in large
toxic doses (over therapeutic doses), e.g. taking large doses of
paracetamol more than 6 g daily can lead to hepatic failure.
k. Mutagenic effects: the ability of drug to change mutation, which is

involved in normal physiologic functions, e.g. alteration of genotype of
DNA can lead to malignancy.
l. Teratogenic effects: refers to the toxicity of drug produced on the fetus

used during pregnancy, e.g. warfarin can cross PBB, and can cause fetal
toxic effects, whereas heparin does not penetrate the PBB.
m. Iatrogenic: drugs that can induce diseases, chlorpromazine can induce

the incidence of parkinsonism.
n. Carcinogenic: drugs which induce the development of tumors e.g.

anticancer drugs and hormones.
o. Cytotoxic: drugs that can cause damage the cell, e.g. chloramphenicol
(bone marrow inhibition) or streptomycin (nerve and renal damage).
Pharmacokinetics: is a very important branch of pharmacology,
specialized in studying of drug administration, absorption, binding,
distribution, metabolism (biotransformation) and elimination, (ADME)
Aim of pharmacokinetics: to determine the following parameters:
a. The route of drug administration. b. Dosage of a drug.
c. Speed of onset of drug action. d. The duration of drug action.

Routes of Drug Administration:
1. The route of administration is determined by the properties of the
drug, (e.g. lipid solubility, shape, size and ionization).
2. The therapeutic objectives, e.g. the rapid onset of action, long-term
therapy, or restriction to local site.
3. There are 2 major routes of administration:
A) Enteral B) Parenteral
A) Enteral Route: the introduction of drugs throughout the G.I.T, it is

subdivided into 3 types:
1. The oral route:

a. Giving a drug by mouth is the most common route of administration;
some drugs are absorbed from the stomach e.g. weak acids, however the
duodenum is the major site of entry to the systemic circulation, because of
its larger absorptive surface due to the presence of villi.
b. Most oral drugs enter the portal system, and encounter the liver (first-
pass metabolism) before their distribution, e.g. some drugs are
extensively metabolized (inactivated) by the liver, intestine and the
stomach, so they are given either at large amounts or by others routes.
2. The sublingual route: is the placement of drug under the tongue, the
drug directly enters the systemic circulation and therefore avoiding first-
pass metabolism of the drug.
3. The rectal route:

a. In this route 50% of drug bypasses the portal circulation, and thus its
metabolism is minimized, another advantage is avoiding of gastric or
intestinal metabolism or ulceration.
b. The rectal rout is useful if the drug induces vomiting, so is commonly

used to administer antiemetic drugs.
B) Parenteral Route:
a. Used for drugs that are poorly absorbed from the G.I.T, e.g. insulin is
unstable in gastric pH.
b. For unconscious patients and circumstances which require a rapid
onset of action.

c. There are 3 major parenteral routes:
1. Intravascular: includes intravenous (I.V) and intra-arterial (IA).

Advantages: I.V injection is the most common parenteral route,
prescribed in order to achieve a rapid effect; it also avoids the first-pass
metabolism, and doses are less than those required for orally prescribed
drugs.
Disadvantages:
a. Contamination through introduction of a drug, HBV, HCV, syphilis
and HIV infection.
b. Allergic reactions such as hemolysis, (rapid catabolism of RBCs).
c. Toxicity: because a drug directly reaches the systemic circulation, so
infusion should be done carefully.
2. Intramuscular (IM): these drugs are aqueous solutions or suspensions,

absorbed (both charged and uncharged molecules) from the muscles
(gluteus maximus, vastus lateralis or deltoid), but slowly reaches the
systemic circulation than IV.
Disadvantages are similar to IV injection.
3. Subcutaneous (SC): it is like IM but absorption is slower than IV, it

minimizes the risks associated with IV, e.g. SC administration of insulin,
norepinephrine and implantation of contraceptives.
Other Routes:
a. The inhalation route: the introduction of drugs via the respiratory
system, this route is used for gaseous drugs (anesthesia) or respiratory
drugs providing a rapid delivery of a drug to the site of action
(bronchodilators in bronchial asthma), another advantage is that their
side effects are minimal.
b. The intranasal route: some drugs are available as drops or spray.
c. The intrathecal / Intraventricular route: is introduction of drugs

directly into the CNS.
d. The topical route: is used when a local effect of the drug is desired, e.g.
dermatologic and ophthalmologic drugs.

e. The transdermal route: this route achieves systemic effects by
application to the skin via tansdermal patchs, most often used for
sustained delivery of drug e.g. the use of the antianginal drug
nitroglycerin.
Absorption of Drugs:
Definition: is the passage of a drug from its site of administration to the
blood stream, before reaching its site of action.
Factors Influencing Drug Absorption:
1. Lipid–solubility: the lipophilic drugs readily and rapidly diffuse across

the plasma membrane; whereas lipophopic can't pass through it.
2. Ionization: usually drugs are either weak acids or weak bases, (strong
acids and bases are not absorbed because they are ionized) existing in un-
ionized and ionized forms in an aqueous environment. The un-ionized
form is usually lipid soluble (lipophilic) and diffuses readily across cell
membranes. The ionized form has low lipid solubility (but high water
solubility—hydrophilic) and high electrical resistance and thus cannot
penetrate cell membranes easily.
3. Effects of pH on drug absorption: the extent of absorption depends on

the ratio between charged and uncharged forms, and determined by its
strength in pH which is represented by the pka, that is a measure of the
strength of interaction of drug with a proton- (acid dissociation constant), The
pKa is the pH at which concentrations of ionized and un-ionized forms
are equal.
When the pH is lower than the pKa, the un-ionized form of a weak acid
predominates, but the ionized form of a weak base predominates. Thus,
in plasma (pH 7.4), the ratio of un-ionized to ionized forms for a weak
acid (e.g., with a pKa of 4.4) is 1:1000; in gastric fluid (pH 1.4), the ratio is
reversed (1000:1). Therefore, when a weak acid is given orally, most of the
drug in the stomach is un-ionized, favoring diffusion through the gastric
mucosa. For a weak base with a pKa of 4.4, the outcome is reversed; most
of the drug in the stomach is ionized. Theoretically, weakly acidic drugs
(e.g., aspirin) are more readily absorbed from an acid medium (stomach)
than are weakly basic drugs (e.g., quinidine). However, whether a drug is
acidic or basic, most absorption occurs in the small intestine namely in
the duodenum.
4. Blood flow to the absorption site and total surface absorptive area: the
blood flow to the intestine is greater than that to the stomach so
absorption here is more than the stomach; in addition, the intestine is rich
in microvilli.
5. Gastrointestinal motility (Contact time at the absorption surface): if a
drug moves through the G.I.T quickly (increased gastric emptying) as in
severe diarrhea (parasympathetic input), its absorption is decreased,
particularly of drugs that require prolonged contact with the absorbing
surface and those that are absorbed only at a particular site along the GI
tract. Similar problems can occur with enteric-coated and sustained-
release formulations. Decreased gastric emptying may either reduce
absorption by retarding dissolution and slowing gastric emptying, or
increase absorption by keeping a drug for a longer period of time in the
area of optimal absorption.
Bioavailability: is defined as the fraction of unchanged drug reaching the
systemic circulation after administration by any route, e.g., if 100 mg is
administered orally, and 70% of this drug is absorbed unchanged its
bioavailability is 70%, thus for I.V used drugs bioavailability is 100%, but
for other routes (oral, IM or S/C) is less than 100% because of:
a. Extent of absorption: ionization and lipophilicity characteristics of
drugs.
b. First-pass hepatic effect or metabolism: it is the fraction of lost drug
during the process of absorption which is generally related to the liver
and gut wall, the concentration of a drug is greatly reduced before it
reaches the systemic circulation.
c. Chemical stability: e.g. penicillin G is unstable in gastric pH
Drug Distribution:
Definition: is the process by which the drug leaves the blood stream and
enters the interstitial, (ECF) and may be the intracellular fluid.
Factors Determining Drug Distribution:
a. Blood flow: the blood flow differs from one site to another, e.g. the
brain; kidney and liver receive more blood than others tissues (skeletal
muscles and skin), the greater blood flow, the more drug's distribution.
b. Capillary permeability: varies from organ to another, tight junctions of

brain capillaries prevent passage of drug to the CNS (BBB), however

lipophilic drugs readily penetrate to the CNS, on the other hand the liver
or spleen have discontinuous capillaries through which the drug can
pass.
c. Binding of drugs to proteins: drugs molecules bind to plasma proteins

reversibly especially to albumin are pharmacologically inactive, only the
free fraction is active, thus albumin serves as reservoir of the drug and
slows its elimination from the vascular bed and the body.
Volume of Distribution, (Vd): is the amount of drug in the body tissues to

its plasma concentration, the volume of distribution is given by the
following equation:
Body Water Compartments: the water represents approximately about 50

to 70 % of body weight, being rather less in women than men, body water
is distributed into 2 major compartments:
1. The Extracellular Fluid (ECF): comprises 1/3, and consists of the blood
plasma, interstitial fluid, and transcellular fluid, including (CSF,
intraocular, peritoneal, pleural, pericardial, synovial fluids, lymph, gastric and
pancreatic secretions).
2. The Intracellular Fluid (ECF): represents 2/3 present in the cells as

cytosol.
Once a drug enters the body its molecules exist in bound or free forms in
each compartment, only the free form is able to move from one compartment to
another, the drug can distribute to any one of the following
compartments:
a) The plasma compartment: if the drug binds extensively to albumin or
has a large MW, it is too large to move out from the blood into the ESF,
thus drug will retains in the blood, therefore this drug has a low Vd..
b) The ECF: if the drug has a low MW, or not bound to plasma protein, it
readily leaves the plasma toward the ECF, hydrophilic molecules cannot
pass the plasma membrane, thus the drug has a median Vd , (distributes
as 50% in plasma+ 50% in interstitial fluid).

c) The ICF: if the drug with a low MW and it is hydrophobic, it can move
from the plasma to both interstitial and intracellular compartments,
therefore the drug has a large Vd.
Drug Elimination: this term includes metabolism and excretion.
Elimination: in elimination the drug is inactivated and may remain in the

body, the amount of active drug is reduced after absorption.
Excretion: is the removal of drugs (unchanged) or metabolic wastes that

have been produced by chemical reactions of the body, in excretion the
drug no longer remains in the body.
Renal Elimination:
a. Glomerular filtration: only the free fraction of a drug is eliminated by
glomerular filtration, the higher the glomerular filtration rate (GFR), the
higher the elimination of a drug.
b. Tubular secretion: some drugs are impermeable (large MW,) to the

glomerulus so they leave it via the efferent arterioles, which form a
capillary plexus surrounding the proximal tubule and eliminated by
active transport, e.g. peniciilin and diuretics.
c. Distal tubular reabsorpion: as drug moves toward the distal

convoluted tubule, its concentration is increased and exceeds the
perivascular space, if it is uncharged it will be reabsorbed back into the
systemic circulation, so the pH of the urine can determine the degree of
drug reabsorption, (making the molecules of a drug charged (not
absorbed) or uncharged or the pH either too acidic or basic depending on
a given drug.
Clearance of The Drug: defined as the rate of elimination to the drug

plasma concentration at a given time, clearance is the most important
factor determining drug concentration and it depends on 3 main factors:
a. Binding to albumin: drugs that bind to proteins (albumin and α1-acid

glycoprotein) are not eliminated rapidly and conversely drugs that can't
bind to proteins are rapidly eliminated because of their free fraction.

b. Renal function: the ability of the diseased kidney to eliminate a drug is
decreased thus leading to its accumulation and toxicity.
c. Hepatic function: the ability of the diseased liver to metabolize and to

eliminate a drug is diminished leading to drug's toxicity.
The Half-Life of the drug (t ½): is the time required for drug’s plasma
concentration to be reduced by one-half, e.g. the required time for a drug
A of 100 mg to be reduced to 50 mg is 2 hours.
- The t ½ is a very important pharmacokinetic parameter which is determined by

the Vd and clearance, it is useful in designing the frequency of drug use.
-The longer the t ½ of a drug, the less its frequent use, and conversely the shorter
the ½, the more its frequent use.
Types of Elimination:
1. First order elimination: the rate of elimination depends on

concentration of drug in the plasma, the higher concentration, the greater
the amount of drug eliminated per unit time, the half-life and clearance are
constant, the concentration in the blood will be decreased by 50% for
every half-life, most drugs in clinical use demonstrate first order kinetics.
2. Zero-order elimination: the rate of elimination is constant regardless its

concentration in the plasma, e.g. aspirin (at high doses), ethanol and
phenytoin.
Clinical Situations Resulting In Increased Drug t ½:

a. Decreased renal blood flow: e.g. in cardiogenic shock, heart failure
and bleeding.
b. Interaction between drugs: the addition of a second drug that

displaces the first drug from albumin binding increases the Vd.
c. Renal disease: due decreased extraction ratio of the kidney which is

defined as drug concentration in the plasma from the arterial to the
venous side of the kidney.

d. Hepatic disease: may be as a result from hepatitis or interaction
between 2 drugs, e.g. drug A decreases the metabolism of drug B, leading
to accumulation and toxicity of drug B.
Drug Accumulation: when a drug is given repeatedly at regular intervals,

which are shorter than 4 or 5 half-lives, the drug will accumulate, and
thus the steady state will be achieved, it depends mainly on ½, binding,
and functions of the liver and the kidney.
Steady State of The Drug, or Maintenance Does: is defined as the state at

which absorbed fraction is equal to eliminated fraction, (the plasma
concentration is constant) and achieved by the frequent use of the drug,
e.g. 50% of the steady state is achieved by the first t½, 75% by the second
t½ and 90% at the third t½, therefore usually the steady state is achieved
in about 4-5 t½.
Loading Dose of Drug: is defined as the use of a large single dose to

achieve desired plasma level rapidly, followed by a slow infusion to
reach the steady state, and could be calculated as:
Loading dose= Vd.TC (target concentration).
Drug Biotransformation, Metabolism, (First-Pass Effect):
Definition: defined as a process which is characterized by inactivation of

a drug followed by its elimination by the bile, but some agents enter the
body as inactive substances, (prodrugs) and must be converted to become
active drugs, the liver is the major site for drug metabolism, but it can
occur in other tissues, (intestine, skin, brain, lungs, kidneys and plasma).
Microsomal mixed function: Many drug-metabolizing enzymes are

located in the rough and smooth EPR of the liver and intestine, the
activity of these enzymes requires the reducing agent NADPH
(nicotinamide adenine dinucleotide phosphate) and molecular O2.
There are 2 main enzymes:

a. Flavoprotein NADPH- cytochrome P450 reductase.
b. Hemoprotein cytochrome P450: CYP or P450: is so called because in its
reduced form, (ferrous) it binds to carbon monoxide to form a complex
that absorbs light at 450.

Structure: The CYP system is composed of microsomal izozymes within
the EPR, family name: is indicated by a number followed by a capital
letter for the subfamily, e.g. CYP3A, another number indicates the
specificity of izozyme, e.g. CYP3A4.
Function: it is very important for the metabolism of many endogenous

compounds (steroids, lipids, proteins, pigments) and exogenous
substances, (drugs and xenobiotics) for detoxification, toxins formation,
activation, and inactivation of substances and conversion of lipophilic
molecules to polar molecules.
First-Pass Metabolism: is a process in which a drug administered by

mouth is absorbed from the gastrointestinal tract and transported via the
portal vein to the liver, where it is metabolized. As a result, in some cases
only a small proportion of the active drug reaches the systemic
circulation and its intended target tissue. First-pass metabolism can be
bypassed by giving the drug by parenteral, sublingual or buccal routes.
Phases of Drug Metabolism;

The kidneys cannot eliminate lipophilic agents, that readily cross plasma
membrane and are reabsorbed in the distal tubules ,therefore lipophilic
agents must first metabolized in the liver using 2 general reactions called
phase І and phase ІІ.
Phase І: is responsible for conversion of lipophilic molecules of a drug to

a more polar metabolites, (water-soluble) by introduction or unmasking a
functional polar groups such as –OH–NH2 –SH or – COOH, it includes
the following processes:
1) Oxidation: e.g. catecholamines or histamine.
2) Reduction: e.g. chloral hydrate into active trichloroethanol.
3) Hydrolysis: e.g. acetylcholine into choline and acetic acid.
Results of phase І: the drug may be activated, inactivated or unchanged,

and if metabolites are too polar, they are readily eliminated, if they are
not too polar they undergo phase ІІ.
Phase ІІ: this phase consists of conjugation reactions; many metabolites

from phase І are too lipophilic and must be conjugated with endogenous
substrates such as: glucuoronic acid, sulfuric acid, acetic acid, water or amino
acids. Glucuronidation is the most common and the most important
reaction, neonates are deficient in this system making them too sensitive
to drugs e.g. chloramphenicol and aspirin.
Gray Baby Syndrome: or Grey Syndrome is a rare but serious side

condition that occurs in newborn infants (especially premature babies)
following the intravenous administration of the antimicrobial
chloramphenicol, due to a lack of glucuronidation reactions occurring in
the baby, thus leading to an accumulation of toxic chloramphenicol
metabolites as well as insufficient renal excretion of the unconjugated
drug.
Clinical features: toxic levels of chloramphenicol after 2–9 days result in:
vomiting, hypotension , cyanosis (gray) blue discolouration of lips and
skin, hypothermia and cardiovascular collapse, hepatoencephalopathy
and death.
Reye’s Syndrome: is a potentially fatal condition which develops in

children that have been treated with aspirin, causing damage to many
organs especially the liver and brain as well as hypoglycemia, fever,
hyperventilation, headaches, nightmares, seizures, fatty liver is detected
by biopsy with minimal inflammation and severe encephalopathy (with
swelling of the brain). The liver may become slightly enlarged and firm,
and there is a change in the appearance of the kidneys. Jaundice is not
usually present. In children it is better to replace aspirin by acetaminophen
(paracetamol).
Results of phase ІІ: more polar compounds that are therapeutically

inactive, and are easily excreted in the urine.
Orders of Phases:
a. Drugs that have an –OH, NH2, –SH or–COOH directly enter phase ІІ,
and become conjugated, without phase І metabolism, and therefore
excreted in the urine.
b. It is not necessary for some drugs to enter hepatic metabolism in order,

e.g. isoniazid is first acetylated and then hydrolyzed.
Enzyme Induction: some drugs can increase the activity of these izozymes
by accelerating their synthesis or by inhibiting their degradation, and
thereby resulting in rapid drug metabolism, hence decreasing their
pharmacologic action, e.g. the long–term use of phenobarbital leads to

decreased its hypnotic effect, due to increased activity of izozymes that
rapidly inactivate the drug, the CYP inducers include carbamazepine,
phenobarbital, phenytoin and rifampin.
Enzyme Inhibition: on the other hand, other drugs can inhibit the activity
of izozymes of P-450 system, leading to decreased drug metabolism,
which results in accumulation of the drug and therefore its toxicity, e.g.
the free concentration of digoxin (inotropic drug used in CHF) will be
increased in the presence of qiunidine (antiarrhythmic drug), because it
inhibits metabolism of digoxin, leading to its accumulation and therefore
its toxicity, (severe arrhythmias), CYP inhibitors are digoxine, cimetidine
and cyclosporine.
Clinical Importance: it should be kept in mind that giving a patient

several drugs at the same time, can lead to drug-drug interactions, e.g.
drug A inhibits the metabolism of drug B, resulting in drug B toxicity, or
drug B increases metabolism of drug A, thus drug A does not exert its
sufficient pharmacologic effect.
Metabolism of Drugs Into Toxic Products: it is important to note that the

P-450 system not only has ability to detoxify drugs, but also to metabolize
them into toxic metabolites, which are very toxic to internal organs, e.g.
the antitumor drug cyclophosphamide is an inactive prodrug, that is
converted into 2 pharmacologic active substances, phosphoramide
(anticancer effect) and acrolein that shows a very toxic effect on the
urinary bladder, it can cause hemorrhagic cystitis, this process is reversed
by prescribing Mensa, that inactivates the toxic compound (acrolein).
Factors Affecting Metabolism:

a. Genetic factors: genetic polymorphisms depends individually on the
activity of enzymes, e.g. some people rapidly acetylate isoniazid (drug
against tuberculosis), its t ½ is about 1 hour, whereas other persons
slowly acetylate it, its t ½ is about 3 hours, this may be due to defect in
this enzyme rather than in its synthesis.
b. Physiologic factors: the metabolism of drugs is altered in infants, very

young and old patients, resulting from absorption, distribution and
elimination of drugs, male metabolizes drugs much faster than female
does.

c. Drug-drug interactions: is associated with the co-administration of 2
drugs that interfere with metabolism of each other, may be appear in
induction or inhibition of the P-450 system.
Interactions Between Endogenous Compounds and Drugs: some drugs

compete each other in conjugation with the same endogenous compound
(glutathione, glucronic acid and sulfate), e.g. drug A and B are conjugated
by the substance C, if a drug B is conjugated by the substance C, the drug
A will not be metabolized completely, because of depletion of the
substance C, and consequently the toxicity of drug A develops.
d. Diseases:
1. Hepatic diseases: affect hepatic metabolism of some drugs, such
diseases are alcoholic hepatitis, cirrhosis (altered architecture of the liver),
hemochromatosis (excessive accumulation of iron), viral and drug-
induced hepatitis (toxic).
2. Cardiac diseases: develops due to reducing hepatic blood flow to the

liver, resulting in reduction of drugs, reaching hepatocytes, consequently
decreased drug metabolism, because hepatic clearance is equal to hepatic
blood flow.
3. Lung disease: in patients with chronic pulmonary insufficiency and in

cancer state.
d. Endocrine diseases: hypothyroidism and hyperthyroidism may alter

the metabolism of several drugs.
Capsules, Tablets and Prescription Writing:

1. Capsules: are solid dosage form in which the medication (powder,
liquid or semisolid) contained within hard or soft gelatin shells, they are
neat and elegant in appearance, providing a tasteless and odorless means
of administrating medicine, ready solubility of gelatin at the gastric pH
ensure rapid release of medication in the stomach.
Types of Capsules:
1. Sustained release capsules: are indicated for maintenance of persistent
effective concentration of a drug in the blood, consisting of 2 parts:
immediate and sustained release portion.

2. Enteric coated capsules: capsules that have been coated or treated to
resist dissolution in gastric juice, they release their contents in the
intestine, they are indicated if the drug is ulcerogenic or if a high local
concentration of a drug is required in the intestine.
Tablets: are solid dosage forms, containing medical substances with or

without suitable diluents that may be prepared by compression or
molding.
Forms:
1. Chewable tablets: used in situations in which the effect of the
medicament is needed immediately e.g. gastric distress.
2. Soluble or dispersible tablets and Effervescent tablets: used in patients

with facial bone fractures, or with irritable stomach.
3. Buccal and sublingual tablets: the buccal route (between gums and
cheek) permits direct absorption into the venous systemic circulation,
bypassing the hepatic portal system and first-pass metabolism, this
process may be fast or slow depending on the physical formulation of the
product, the sublingual route offers the same as the buccal route, e.g.
nitroglycerine is absorbed in 2 minutes under the tongue providing fast
relive from acute angina pectoris.
4. Implantation tablets: these tablets are inserted surgically, slowly

absorbed into the body and their duration of action is long, e.g. the use of
hormones (contraceptives, corticosterone and testosterone).
5. Tablets Coating:
a. Sugar coating: used to mask unpleasant taste, odor and to protect the
ingredient from decompression as a result of exposure to air.
b. Compression Coating: makes it possible for 2 incompatible drugs to be
incorporated together in one tablet, by placing one drug in the core and the
other in the coating.
Prescription Writing: is a physician's written order to a pharmacist for a

specific medication for a specific patient.
Parts:
1. Physician's name professional degree, address and telephone number.
2. Name, address and age of the patient.

3. Date.
4. Diagnosis.
5. Subprescription: the symbol R is an abbreviation for recipe.
6. Inscription or the body of the prescription: contains the names and
quantities of drugs ordered:
a. Drugs can be prescribed by their generic names or their proprietary

(brand) names.
b. The weights and volumes of drugs should be written in the metric

system, (g, mg, ug) for weights and (ml) for volumes.
c. If a prescription contains several ingredients in a mixture, they are

written in the following order: Bases (principle ingredient), Adjuvant
which enhances the action of the basis, Corrective which corrects
undesirable effects of the basis and adjuvant and Vehicle which is the
agent used as the solvent in the solution to increase the bulk or dilute the
mixture.
7. Directions to the Pharmacist: directions are usually written in English

but occasionally a few Latin abbreviations are used:
a: before, aa: of each. ad lib: as much as wanted
ac: before meals, bid: twice a day. c: meal.
c: with cap: capsule d: day
disp: dispense gtt: drop no: number
non rep: do not repeat. p : after
- pc: after meals
po: by mouth prn: if needed qd: every day
qh: every hour qid: 4 times a day. q4h: every 4 hours
s~ : without SS: one half. sig: write.
Stat: immediately (now). tab: tablets tid: 3 times a day.
In case for a single drug, this consists of writing the total quantity to be
dispensed, e.g. Send 20 tablets, in case of many ingredients, it is usually
written by either a short sentence such as make a solution or a word such
as Mix.
8. Directions to Patient: the directions to the patient should be written in

Arabic language including instruction to the drug amount, frequency of
the dose, route of administration and duration of therapy.

9. Physician's signature at the bottom of the prescription.
Classes of Prescription:
A. Precompounded: a drug or mixture of drugs supplied by a
pharmaceutical company.
R. Digoxin Tablets 0, 25 mg
Send 100 tables.
B. Compounded: the type in which the physician selects the drugs, doses
and pharmaceutical forms desired and the pharmacist prepares the
medication.
Aspirin 6g
Acetaminophen 6g
Amobarbital 1 g.
Mix and divide into 20 capsules, 1 cap/d.
Narcotic Prescription: narcotic drugs (morphine) require a special form

obtained from the ministry of health, it includes the name of the
prescribing physician, his address, the patient's name, age, address,
diagnosis, date and signature of physician, the quantity should be written
in numbers and in letters, written in ink, and is not returned to the
patient, kept by the pharmacist.
Policy in Prescription Writing:

a. Never give a ready-written prescription.
b. Write deliberately and without hesitation.
c. Avoid re-writing a prescription.
d. Do not converse with the patient while writing.
e. Write in clear handwriting.
f. Avoid erasing, crossing out and tearing up a prescription in the
presence of the patient.

Receptor Interactions
Competitive
Inhibition
Antagonist Receptor
Antagonist-Receptor
DENIED!
Complex

Receptor Interactions
Non-competitive Antagonist
Inhibition
Agonist Receptor
DENIED!
‘Inhibited’-Receptor

A day in the life WOW - distribution
• distribution to liver,
kidney, brain,
etc. first
• muscle, viscera,
skin later
• later phase
accounts for
most of the
extravascular
drug
Redistribution
• highly lipid soluble drugs
• redistribute from highly
perfused organs to other areas
• e.g., thiopental

Elimination
of drugs from the body
M KIDNEY LIVER
A
J filtration metabolism
O secretion secretion
R (reabsorption)
M LUNGS OTHERS
I
N exhalation mother's milk
O sweat, saliva etc.
R

Agonist Dose Response Curves
Full agonist
Partial agonist
Response
Dose

Drug Elimination
Drug molecule
More hydrophilic Conjugate

metabolite II
De-conjugation
and reuptake
(entero-hepatic
Bile cycling)
Kidney Intestines
Urine Feces

`

Drug Liver
Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder
Portal circulation
Gut
CYP Substrate  Substrate

concentration  Toxicity
CYP Inhibitor
CYP Substrate  Substrate

 Efficacy
CYP Inducer concentration

UNIT 2
CHEMOTHERAPEUTIC DRUGS
Definition of Antibiotics: substances which are effective in the treatment of

infectious diseases, they have an ability either to kill (bactericidal) or to inhibit
the growth of an invading microorganisms (bacteriostatic).
Classification of Antimicrobial Agents:
a. Chemical Structure: e.g. penicillins, cephalosporines, tetracyclines,

macrolides and others….
b. Activity Against Particular Types: antifungals, antivirals, antimycobacterial,

antibacterial agents and antineoplastics (tumor).
c. By Their Mechanism of Action (Site of Action):
1. Inhibitors of cell wall synthesis: penicillines, cephalosporines, vancomycin

and cycloserine.
2. Inhibitors of plasma membrane: amphotericine, nystatine and polymyxine.
3. Protein synthesis inhibitors: tetracyclines, aminogylycosides, macrolides,

chloramphenicol and clindamycin.
d. Antibiotics Affecting DNA/RNA:
1. Direct actions: on DNA replication (quinolones), direct action on RNA

synthesis (rifampine).
2. Indirect actions: sulfonamides (interfere with the formation of folic acid by

inhibition of dihydropteroate synthetase), and trimethoprim (inhibition of
dihydrofolate reductase).
Selection of Antimicrobial Agents: requires the knowledge of the following:

1) Identification and sensitivity of the organism: it is central to identify the
microorganism, whether it is gram-negative or gram-positive on the basis of
Gram's stain, about 50% of peptidoglycan compose the cell wall of gram-

positive, organisms about 40 to 45% acidic polymer and about 5 to 10% proteins
and polysaccharides.
The cell wall of negative gram organisms is more complex, from the plasma
membrane outward it consists of the following: a periplasmic space containing
enzymes, peptidoglycan layer comprises only 5% of the cell wall mass, linked to
lipoprotein and an outer membrane consisting of a lipid bilayer, in addition
proteins in the outer membrane which from channels (porins).
2) The site of action: adequate levels of antibiotic should reach the site of
infection to be eradicated; natural barriers may prevent penetration of
antibiotics:
a) Blood-brain-barrier (BBB): the penetration and concentration of an antibiotic

in the CSF is particularly influenced by the following:
1. Lipid solubility: the lipid solubility of a drug plays a central role in determining
the penetration of a drug into the CSF, metronidazole has significant penetration
into the CNS, whereas β-lactam antibiotics (penicillin) are ionized and have low
solubility in lipids, and therefore have limited penetration through the intact
BBB, but in the case of inflammation, the barrier doesn’t function effectively and
permeability to penicillins is increased.
2. Molecular weight: a compound with a low MW has an enhanced ability

to cross the BBB, drugs with high MW, e.g. vancomycin penetrates
poorly, even in the presence of meningitis.
3. Protein binding of the drug: a high degree of protein binding restricts the
entry of a drug into the CSF; the amount of free portion plays a major role
to penetrate the CNS.
b. Placenta: all antibiotics cross the placenta, adverse effects to the fetus
are rare; except for tetracyclines which chelate Ca causing inhibition of
bone growth, so they are contraindicated in pregnancy, children and
nursing mothers, aminoglycosides also are not indicated in pregnancy
because of their ototoxicity.
3) Status of the patient:

a. Immune system: antibiotics do not eliminate bacteria, they either kill or
inhibit their growth, eradication of microorganisms depends on the
activity of the immune system, HIV, advanced age, diabetes and chronic

use of immunosuppressants require higher doses than usual to overcome
infecting organisms.
b. Renal function: a diseased kidney causes accumulation of antibiotics that

are eliminated by this route; therefore serious adverse effects can
develop.
c. Hepatic function: antibiotics that are eliminated by the liver should be

avoided in hepatic disorders, whereas antibiotics excreted renally are
preferred.
d. Chemotherapeutic spectra: refers to the species of microorganisms

affected by the drug, spectra could be classified into the following types:
Chemotherapeutic Spectra: refers to the species of microorganisms

affected by the drug, spectra could be classified into the following types:
1) Narrow spectrum: antibiotic acts only on a single or limited group of
microorganism, e.g. antimycobacterial agents.
2) Extended spectrum: these antibiotics are effective on gram-positive

organisms and also on a significant number of gram- negative bacteria,
e.g. ampicilin.
3) Broad spectrum: antibiotics that widely affect microorganisms

(tetracyclines and chloramphenicol), they can affect the normal flora of
the body and precipitate a superinfection of an organism, such as
Candida albicans the growth of which normally is checked by the normal
microflora.
Combinations of Antimicrobial Agents: it is therapeutically to treat

patients with the single agent that is most specific for the infecting
organism, this strategy:
a. Reduces the possibility of superinfection.
b. Decreases the emergence of resistant organisms.
c. Minimizes toxicity.
However, situations in which combinations of drugs are employed do
exist, e.g. treatment of TBs.
Antibiotic Resistance: can be described as the ability of a microorganism

to survive and to resist the effects of an anti-bacterial medication. In other
words, it is the lost of effectiveness of an antimicrobial drug over bacteria
and other microorganisms, resistance may be caused by the following
mechanisms:
1) Genetic Alterations:
a. Spontaneous mutations of DNA: chromosomal alterations may occur
by insertion, deletion or substitution of one or more nucleotides with the
genome, the resulting mutation may persist, be corrected by the organism
or be lethal to the cell. Bacteria with a mutation that allows them to
survive, live to reproduce, e.g. the incidence of rifampine resistance when
approved as a monotherapy against tuberculosis.
b. DNA transfer of drug resistance: resistance is acquired due to DNA

transfer from one bacterium to another, resistance properties are encoded
in extrachromosomal R factors (plasmids which are part of DNA).
2) Altered expression of proteins in drug-resistant organisms: drug

resistance may be mediated by several mechanisms that are:
a. Modification of target sites: alteration of an antibiotic's target site can
confer resistance to one or more related antibiotics e.g. decreased binding
of penicillin to its target site because of alterations in proteins.
b. Decreased accumulation: decreased uptake or increased efflux of an

antibiotic, because the antibiotic is unable to attain access to the site of
infection in sufficient levels to kill or to inhibit its growth, occurs either
due to alterations in channels of microorganisms or increased activity of
pump efflux, gram-negative organisms can limit the penetration of certain
agents such as β-lactam antibiotics, tetracyclines and chloromphenicol.
3) Enzymic activity: the ability of the microorganism to inactivate or to

destroy the antibiotic, examples include:
a. β-lactamases (penicillinases): can destroy the β-lactam ring of penicillins
and cephalosporines.
b. Acetyltransferases: transfer an acetyl group to the antibiotic (inactivation
of chloramphenicol and aminoglycosides).
c. Esterases: hydrolyze the lactone ring of macrolides.
Complications of Antibiotic Therapy:

1) Hypersensitivity: frequently occurs, e.g. penicillins, despite their
absolute selective microbial toxicity, can cause severe hypersensitive
reactions from urticaria to anaphylactic shock.
2) Direct toxicity: aminoglycosides can cause ototoxicity by direct action

on the organ of Corti, chloramphenicol is less specific to microorganism,
produces severe side effects (aplastic anemia, gray baby syndrome) so it
is reserved for life-threatening conditions.
3) Superinfection: particularly with the use of broad spectrum antibiotics

or combinations of agents can lead to alterations of the normal microbial
flora of respiratory, digestive and genitourinary systems, permitting the
overgrowth of microorganisms especially fungi which are difficult to
cure.
BACTERICIDAL ANTIBIOTICS
I. Inhibitors of Cell Wall Synthesis:
I. 1. Beta-Lactam Antibiotics: they are so-called due to their β-lactam

ring; the members of this group are penicillins, cephalosporins,
monobactams, carbapenems and β-lactamases inhibitors.
1.1. A. Pharmacology of Penicillins:
Penicillins: are the most widely effective and the least toxic antibiotics,
compared to other antibiotics, they share features of chemistry,
mechanism of action, pharmacologic and clinical effects of beta-lactam
antibiotics.
Classification of Penicillins:
1. Nature Penicillins: (narrow spectrum): are obtained from

fermentations of the mold penicillium chrysogenum, members are:
a. Penicillin G or benzylpenicillin. b. Procaine penicillin.
c. Benzathine penicillin. d. Phenoxymethylpenicillin.
They are susceptible to inactivation by β-lactamases (penicillinases) and
unstable in the gastric acid.
e. Penicillin V: it is more stable in gastric acid than penicillin G, penicillin
V is not utilized for the treatment of bacteremia because of its higher

minimum bactericidal concentration which is defined as the minimum
amount of a drug needed to eliminate the infection.
2. Anti-Staphylococcal Penicillins: methicillin, nafcillin, oxacillin,

cloxacillin and dicloxacillin: all are penicillinase resistant penicillins.
3. Extended Spectrum Penicillins: ampicillin and amoxicillin
4. Antipseudomonal Penicillins: carbenicillin, ticarcillin and

piperacillin (most active): they are so called because of their activity
against pseudomons aeruginosa.
Mechanism of Action: all beta-lactam antibiotics are bactericidal, generally

the bacterial cell wall consists of peptidoglycan, containing
polysaccharides, N-acetylglucosamine and N-acetylmuramic acid attached to
5 amino acids, the peptide terminates in 2 D-alanine amino acids,
penicillins bind to penicillin binding proteins (PBPs), then they catalyze
transpeptidation that removes the terminal alanine to form a crosslink
with a nearby peptide, thus penicillins interfere with the last step of cross
linking peptide formation, which maintains integrity to the bacterial cell
wall, in addition disinhibtion or activation of autolysins takes place
which maintain lysis of the cell wall.
Pharmacokinetics:
a. Administration: the route of administration depends mainly on the
stability of the drug to gastric acid and severity of infection, ticarcillin,
piperacillin, ampicillin are combined with beta-lactamase inhibitors
(have no antibacterial activity) that inhibit lactamase enzymes produced by
organisms and therefore allowing beta-lactam antibiotics to exert their
effects, combinations of penicillins for oral and parenteral uses with beta-
lactamase inhibitors include:
1. Amoxicillin or ticarcillin are combined to calvulanic acid.
2. Ampicillin is combined with sulbactam.
3. Piperacillin is combined with tazobactam.
b. Absorption: methicillin and nafacillin are ineffective orally, whereas

dicloxacillin, ampicillin and amoxicillin are acid-stable agents, food
delays their absorption except for amoxicillin (well absorbed than
ampicillin), so they should be given at least 1-2 h. before or after meals.

c. Distribution: all beta-lactam antibiotics are widely distributed
throughout body fluids and tissues, they cross the placental barrier, but
with no teratogenic effects, they do cross the BBB only in the state of
inflammation.
d. Metabolism and excretion: metabolism is usually insignificant,

excretion mainly occurs through secretory tubules of the kidney as well
as glomerular filtration, the t ½ of pencillin G is about 30 minutes to 1
hour, prolonged to 10 hours in patients with renal failure, the uricosuric
probenecid inhibits the secretion of penicillins, thus increasing its
duration of action, nafcillin is primarily cleared by the biliary route.
Resistance: to penicillins occurs due to one of the following mechanisms:

a. Inactivation of penicillin: is the most common cause because of
penicillinases production that destroys penicillins.
b. Modification of target PBPs: when PBPS have low affinity for binding to
beta-lactam antibiotics.
c. Imparied penetration of a drug to target PBPs: especially in gram (-)

because of their impermeable outer cell wall membrane which is absent
in gram (+) organisms, as well as down regulation of porins or absence of
the proper channel.
d. The presence of pump efflux: garm (-) organisms can produce cytoplasmic
and periplasmic protein components which pump the antibiotic outside
the cell.
Clinical Uses:
1. Penicillin G: is the drug of choice for infections caused by gram (+)
organisms (staphylococcus, streptococcus, enterococci) gram (-) cocci
(gonorrhoeae, meningiococcus), spirochetes and non-β-lactamase-producing
staphylococci.
A single I.M injection of benzathine penicillin, 1.2 million units is satisfactory
for treatment of β-hemolytic streptococcal pharyngitis.
Giving IM injection of Pencillin G once every 3-4 weeks provides satisfactory
prophylaxis against reinfection with beta-hemolytic streptococci.

2. Penicillin V: its spectrum is similar to penicillin G, but rarely used
because of its poor bioavailability, employed primarily for minor oral
infections.
3. Antistaphylococcal penicillins: used mainly for infections caused by

penicillinase-producing staphylococci, ineffective against enterococci, gram
(-) and anaerobic bacteria, they are given orally every 6 hours for
staphylococcal infection.
4. Extended penicillins: they are similar to penicillin G, more effective

against gram (+) bacilli (diphtheria), ampicillin is the drug of choice for
treatment of listeria moncytogenes; amoxicillin and ampicillin are widely
used in the treatment of respiratory infections, amoxicillin is employed
prophylactically by dentists for patients with abnormal heart valves who are to
undergo extensive oral surgery, however resistance can develop to these
antibiotics.
5. Antipseudomonal penicillins: in addition to their activity against

Pseudomonas aeruginosa, they are also effective against many gram-
negative bacilli (rods), but not against klebsiella which produce
penicillinase.
Adverse Effects: penicillins are the safest drugs among all antibiotics,
although side effects can occur, they include:
1. Hypersensitivity: is the most important side effect due to its metabolite

(penicillonic acid) ranging from maculopapular rash, fever, swelling,
dyspnea, angioedema to anaphylaxis, cross allergic reactions do occur
among the beta-lactam antibiotics.
2. Diarrhea: is common due to disruption of the normal balance of

intestinal flora, commonly occurs with agents that are incompletely
absorbed or with an extended antibacterial activity.
3. Nephritis: all penicillins can cause interstitial nephritis, especially

methicillin which is no longer used.
4. Neurotoxicity: particularly if pencillins are injected intrathecally, or

after excessive IV infusion, this can cause seizures, especially in epileptic
patients.

5. Hematologic toxicities: decreased agglutination of thrombocytes,
predispose to hemorrhage, especially with carbencillin and ticarcillin use.
6. Caution toxicity: because penicillins are prescribed as Na or K salts,

toxicities may be caused by the large quantities of Na or K, excess Na can lead
to hypokalemia.
I.1.B. Pharmacology of Cephalosporins
Definition: the cephalosporins are β-lactam antibiotics, that are similar to

penicillins chemically, in M.O and in toxicity, but they are more stable
than penicillins to bacterial β-lactamases, most cephalosporins are
produced semisynthetically, they are destroyed by a metallo-β lactamase.
Antibacterial spectrum: cephalosporins classified as first, second, third

and forth generations on the basis of bacterial susceptibility and
resistance to β-lactamases, and therefore have a broader spectrum of
activity; generally they are ineffective against staphylococcus aureus and
enterococci.
1. Pharmacology of The First Generation:
Oral Drugs: cephalexin (the prototype), cephradine, cephaparin and

cefadroxil: absorbed from the gut to a variable extent, their tissue
concentrations are lower than the serum, eliminated by glomerular
filtration and tubular secretion, probenecid blocks secretion and thus
increasing their levels, prescribed mainly for minor infections, (UTI and
cellulitis), never for serious infections in despite of their broad spectrum.
Parenteral Drugs: cefazolin is the only parenteral cephalosporin among

drugs of first-generation, given either IM or I.V, cefazolin penetrates into
the bone, eliminated by the kidney, clinically is the drug of choice for
surgical prophylaxis and for patients who are allergic to penicillin (mild
reactions) but not anaphylaxis, cephazoiln is not used for the treatment of
meningitis, because it can't penetrate the CSF.
2. Pharmacology of The Second Generation:
Agents: cefuroxime, cefaclor, cefamandole, and related cephamycins

(cefoxitin and cefmetazole): available as oral and parenteral forms, the
prototype is cefuroxime which has the longest half-life, although crosses
CNS, cefuroxime is not used in meningitis, employed for the treatment of
gram negative bacteria causing bronchitis, pneumonia, sinusitis and
otitis, cefoxitin is useful in patients with intraabdominal sepsis and pelvic
inflammatory disease (PID).
3. Pharmacology of The Third Generation:

Agents: Cefixime, cefotaxime, cefoperazone and ceftriaxone.
Compared to the first and second generations, they are active in lower
doses; produce more resistance against β-lactamase, as well as a good
penetration into the CSF, the half-life of ceftriaxone is 6 to 8 hours,
whereas for cefoperazone of 2 hours, excretion primarily occurs by the
kidneys, except for ceftriaxone and cefoperazone which are eliminated by the
liver.
Clinically ceftriaxone and cefixime are the first line therapy for the
management of gonorrhea which is resistant to penicillins therapy,
meningitis caused by pneumococci and meningiococci, recommended for
empirical therapy of severe infections e.g. unknown cause of sepsis and
UTI.
4. Pharmacology of The Fourth Generation:

Cefepime is the only drug of fourth generation it is more resistant to
hydrolysis by beta-lactamases, its clinical indications are similar to that of the
third generation, has a wide antibacterial spectrum against-strepto-
staphylococci, enterobacter, escherichia coli, klebsiella pneumonia and
pseudomonas aeruginosa, administered only parenterally, very effective
against most penicillin-resistant strains of streptococci.
Adverse Effects:
1. Allergy: represented by fever, skin rashes, granulocytopenia, hemolytic
anemia and anaphylaxis, they should be avoided or used with caution in
patients, who have had mild allergic reactions to penicillins.
2. Local side effects: irritation with pain after I.M and thrombophlibitis after
I.V. injections.
3. Nephrotoxicity: which includes interstitial nephritis and tubular
necrosis, it is better to use cephalosporins that are eliminated by the bile.
4. Bleeding: especially with the use of cefamandole, cefoperazone and
cefometazole because of their hypoprothrombinemia (anti-vitamin K
effects), administration of vitamin K1 corrects the problem.

5) Superinfection: many second and particularly third-generation are
ineffective against gram-positive organisms, especially methicillin-
resistant staphylococci and enterococci, during treatment with such
drugs, these resistant organisms as well as fungi, proliferate and may
induce superinfection.
I-2. Pharmacology of Vancomycin.
Mechanism of action: vancomycin is an antibiotic that acts by inhibiting

synthesis of bacterial wall, it binds to D-alanine and inhibits the
transglycosylase, so preventing further elongation of peptidoglycan, that
becomes weakened and the cell tends to lysis, the cell membrane is also
damaged.
Antibacterial spectrum: is a bactericidal antibiotic that produces activity

only against gram-positive bacteria, most staphylococci including those
producing β-lactamase and those resistant to nafcillin and methicillin, it
kills staphylococci slowly and only if cells are actively dividing.
Pharmacokinetics:
Vancomycin is poorly absorbed from the gut, it is used orally ONLY in
the treatment of antibiotic-induced enterocolitis caused by clostridium
difficile, mainly prescribed I.V, the drug is widely distributed in the body,
poorly penetrates throughout inflamed meanings, eliminated by
glomerular filtration.
Clinical Indications:
a. Sepsis or endocarditis: caused by methicillin-resistant staphylococci

aureus (MRSA), however it is not as effective as monotherapy;
vancomycin is combined with gentamicin as alternative therapy for the
treatment of enterococcal endocarditis in patients with serious penicillin
allergy.
b. Meningitis: vancomycin is utilized in combination with cefotaxime or

ceftriaxone for meningitis caused by a highly penicillin-resistant of
pneumococcus.

c. Prophylaxis: in dental patients and in patients with prosthetic heart
valves.
Resistance: occurs rarely, develops due to DNA mutations represented

mainly by replacement of D-alanine binding site of peptidoglycan by D-
lactate, as well as impermeability of vancomycin or decreased its binding
to receptors.
Adverse Reactions:
a. Local: vancomycin is a tissue irritant; it can cause phlebitis at the site of
injection.
b. Organic: actually ototoxicity and nephrotoxicity are rare, but
administration of another oto-nephrotoxic (aminoglycosides) increases
the risk of these toxicities.
d. Red man or red neck syndrome: is characterized by flushing due to
histamine release caused by rapid infusion, could be avoided by
prolonging the infusion period to 1-2 hours, or pretreatment with an
antihistamine such as diphenhydramine.
II. Pharmacology of Aminoglycosides:
Definition: are group of bactericidal antibiotics, obtained from

streptomyces, aminoglycosides that are derived from it have mycin
suffixes, whereas those derived from Micromonospora end in micin,
Agents: streptomycin, neomycin, kanamycin, amikacin, gentamicin,

tobramycin and sisomicin.
Mechanism of action: initially they cross porins by passive diffusion,

then the drugs are transported actively into the cytoplasm by an oxygen-
dependent process, transport is enhanced by penicillin and vancomycin,
irreversibly inhibit bacterial protein synthesis by binding to the 30S subunit
of bacterial ribosome, inducing misreading of mRNA, which causes a
nonfunctional or toxic protein, as well as interference with the initiation
complex of peptide formation.
Antibacterial spectrum: all aminoglycosides are bactericidal, (the

mechanism is not clear) in despite of protein synthesis inhibition,
effective against aerobic organisms, since anaerobes lack the O2 requiring
transport system.

Pharmacokinetics: because they are highly polar drugs, aminoglycosides
are not given orally, except for neomycin (its clinical use is restricted for
skin infections), they should be given parenetarally, (IM or IV),
aminoglycosides have a significant post-antibiotic effect, which can reach
several hours, usually prescribed once daily (large dose) instead of
multiple smaller doses, cleared mainly by the kidney via glomerular
filtration, aminoglycosides do not penetrate into the CNS, even with
inflamed CSF, to achieve a high concentrations in the CNS they are
administered intrathecally or intraventricularly, high accumulation in the
renal cortex and in the endo-perilymph of the inner ear occurs, they have
an ability to penetrate the placental barrier, (in despite of their polar
molecules) the normal t ½ is about 2-3 hours, increasing to 24-48 hours in
patients with renal disorders.
Clinical Uses:
1. Streptomycin: is used as a first line therapy for TBs in combination
with other anti TBs agents, never used alone.
2. Gentamicin: is used for:

a. Endocarditis and Pneumonia caused by E. coli, frequently used in
combination with penicillin.
b. Meningitis: caused by gram negative bacteria has been treated by
intrathecal injection of gentamicin, however neither intrathecal nor
intraventricular was beneficial in neonates with meningitis, (treated
successfully by cephalosporins III generation such as ceftriaxone).
c. Treatment of infected burns, wounds, or skin lesions and in attempts to
prevent intravenous catheter infections.
3. Aminoglycosides are effective against plague and tularemia.
Resistance: it occurs due to the following mechanisms:

a) Decreased uptake of drug when the O2–dependent transport system is
absent for them or the absence of channels.
b) Low affinity of 30 subunit for aminoglycosides.
c) Inactivation of aminoglycosides by acetyltransferases and
phosphotransferases.

Adverse Effects: it is important to monitor plasma levels of
aminoglycosides to avoid concentrations that can cause toxicities, the
most common side effects are
1. Ototoxicity: vestibular and cochlear, deafness may be irreversible,
appears seriously in patients taking another ototoxic e.g. lasix, vertigo
and loss of balance also can occur.
2. Nephrotoxicity: ranging from mild renal impairment to severe

irreversible renal failure.
3. Neuromascular paralysis: often results after direct intraperitoneal or

intrapleural application due to either a decrease of acetylcholine release
from pooling vesicles or decreased sensitivity of postsynaptic site, treated
by calcium gluconate or neostigmine.
4. Allergic dermatitis: especially with the use of neomycin.
III. Pharmacology of Fluoroquinolones: they are classified into:
a. First Generation: the prototype of quinolones is nalidixic acid which is

effective in the treatment of uncomplicated lower UTIs; its use is limited,
because it is rapidly excreted.
b. Second Generation: ciprofloxacin, norfloxacin, lomefloxacin and

ofloxacin.
c. Third Generation: gatifloxacin, levofloxacin and moxifloxacin.
d. Fourth Generation: Trovafloxacin.
Mechanism of action: the drugs enter the bacterium by passive diffusion,

exerting their antimicrobial effect by inhibition of DNA gyrase or
(topoisomerases II) and topoisomerases IV during bacterial growth, these
enzymes are responsible for replication and transcription, thus cleavage of
DNA and the death of the cell is followed (bactericidal effect), in gram (-)
organisms e.g. E. coli the inhibition of DNA gyrase is more significant
than that of topoisomerase IV, whereas in gram (+) such as
staphylococci, the opposite is true.

Pharmacokinetics: the oral bioavailability is 80-95 %, their absorption is
delayed in the presence of cations such as Mg, Ca and antacids,
accumulation occurs in prostate, macrophages and kidneys, eliminated
primarily by the kidney, but trovafloxacin and moxifloxacin are excreted by
the liver.
Clinical Uses:
1. U.T.I: orally norfloxacin is commonly used in treating complicated and
uncomplicated forms.
2. Several infections: bacterial diarrhea caused by shigella, salmonella, E.

coli and infections of soft tissues, bone and joints.
3. Intra-abdominal and respiratory tract infection.
4. Genitourinary infections: gonococcal infection and chlamydial

urethritis, cervicitis, vaginitis and prostatitis.
Adverse Effects: generally they are well tolerated, the most common
unwanted effects are:
1. G.I.T effects: nausea, vomiting and diarrhea.
2. CNS effects: headache, dizziness, insomnia and phototoxicity
particularly with the use of lomefloxacin, (discontinued in the US).
3. Nephrotoxicity: crystalluria may develop.
4. Cardiac arrhythmias: especially with the use of levofloxacin, moxifloxicin
and gatifloxacin that is withdrawn from sales in the USA in 2006 because
of its serious side effects, (hyperglycemia in diabetics and hypoglycemia
in patients receiving oral hypoglycemics).
Contraindications: pregnancy, nursing mother, persons under 18 years,

since they cause reversible arthropathy, arrhythmia and hypokalemia.
V. Pharmacology of Mitronidazole (Flagyl):
M.O: is bactericidal antibiotic against anaerobic bacteria, its mechanism

of action is unclear but it is proposed that metronidazole inhibits nucleic
acid synthesis.
Pharmacokinetics: the drug is well absorbed following oral route,

available for IV use and as rectal suppository, distributed widely in

tissues, penetrates into CSF, vaginal, seminal fluids and saliva, the
metabolism occurs in the liver by glucoronidation, eliminated in the
urine.
Clinical Uses: mainly approved for the treatment of amebiasis, infections caused
by E. histolytica, vaginitis (trichomonas) and colitis caused by clostridia.
Adverse Effects:
a. GIT disturbances: nausea, vomiting, abdominal cramps and diarrhea are the
most common side effects.
b. Peripheral neuropathy: dizziness and vertigo.
Caution: use of this agent should be avoided in the first trimester of pregnancy.
BACTERIOSTATIC ANTIBIOTICS
I. Pharmacology of Chloramphenicol:
Mechanism of action: is a bacteriostatic antibiotic which inhibits

microbial protein synthesis (it blocks transpeptidation by reversible binding to
50S subunit of bacterial ribosome (bacterial ribosome consists of 50S and 30S
subunits, whereas mammalian consists of 60S and 40S subunits), but
because of its toxicity, its use is restricted to life-threatening infections in
patients who don't respond to other antibiotics.
Antimicrobial spectrum: Chloramphenicol is a broad-spectrum antibiotic

active not only against bacteria, (gram-positive and gram-negative
organisms) but also against Rickettsia, aerobic and anaerobes, it may be
bactericidal for hemophilus influenzae, nesseria meningitides, but
ineffective in chlamydiae.
Pharmacokinetics: administered orally or I.V, completely and rapidly

absorbed because of its lipophilic nature, chloramphenicol is widely
distributed throughout the body, readily enters the CNS, inactivated by
conjugation with glucoronic acid, it inhibits the CYP hepatic system,
excreted mainly by tubular secretion.
Clinical Uses:

1. Rickettsial infections: in children for whom tetracyclines are
contraindicated.
2. Meningitis: caused by meningococcus, it is alternative to β-lactam

antibiotics if patients are allergic to one of them.
3. Topical use: Chloramphenicol is used topically in the treatment of eye

infections, because of its wide antibacterial spectrum and its penetration
into ocular tissues and aqueous humor.
Adverse Effects:
a. G.I.T disturbances: nausea, vomiting and diarrhea, oral or vaginal
candidiasis may occur as a result of alteration of normal microbial flora
(superinfection).
b. Bone marrow toxicity: commonly causes a dose-related reversible

suppression of RBCs production, aplastic anemia is rare but unrelated to
dose and could be fetal.
c. Gray babe syndrome: neonates lack an effective glucuronic acid

conjugation mechanism and underdeveloped hepatic function, so
detoxification of drug does not occur and therefore it accumulates, the
syndrome is characterized by vomiting, flaccidity, hypothermia, gray
(cyanosis) color, depressed breathing, cardiovascular collapse and death.
Resistance: the antibiotic is inhibited by the enzyme acetyl-coenzyme A

transferase.
Drug Interactions: Chloramphenicol is a potent of inhibitor of hepatic

microsomal enzymes responsible for the metabolism of many drugs such
as warfarin and phenytion.
II. Pharmacology of Tetracyclines
Agents: tetracycline, oxytetracycline, chlortetracycline, doxycycline

minocycline and demeclocycline.
Mechanism of action: tetracyclines inhibit protein synthesis

(bacteriostatic effect) by binding reversibly to the 30S subunit of bacterial

ribosome, thereby inhibiting access of the amino tRNA to mRNa
ribosome complex (A site).
Antibacterial Activity: Tetracyclines are broad-spectrum antibiotics,

active against gram-positive-negative bacteria (anaerbos, rickettsiae,
chlamydia, mycoplasma pneumonia and cholera).
Pharmacokinetics:
Absorption and distribution: all tetracyclines are adequately but
incompletely absorbed following oral administration, absorption
decreases in the presence of food, except for doxycycline and minocycline,
tetracyclines form non-absorbable complexes with Mg, Ca, Fe and Al,
widely distributed to tissues and body fluids. Although all tetracyclines
enter the CSF, (their levels are insufficient to produce therapeutic effects),
except minocycline that penetrates the BBB in the absence of inflammation
(ineffective for CNS infection), all tetracyclines cross the placenta and
reach the fetus, causing chelation with Ca, which leads to damage-
growing bones and teeth.
Metabolism and excretion: metabolized in the liver to form soluble

glucoronides, which secreted into the bile, most of them reabsorbed from
the intestine (enterohepatic circulation), obstruction of bile duct, hepatic
ducts and renal dysfunction can increase their half-lives, all tetracyclines
are eliminated in the urine, except for doxycycline that is cleared by the
bile, it could be used in infectious patients suffering from renal disorders.
Tetracyclines are also excreted in breast milk.
Resistance: it develops due to the following mechanisms:

a. Decreased accumulation of the antibiotic due to either impaired influx or
increased efflux by transport protein pump.
b. Ribosome protection due to production of proteins that interfere with
tetracycline binding to the ribosome.
c. Enzymatic inactivation of tetracyclines by acetyl-transferase.
Clinical Uses:
1. First line therapy: tetracyclines are the drugs of choice in infections
caused by rickettsiae, mycoplasma pneumoniae, some spirochetes,
chlamydial, brucellosis, cholera and plaque.

2. Peptic ulcer: tetracyclines are used if peptic patients are allergic to
penicillins, or metronidazole for the treatment of gastric and duodenal
ulcer caused by Helicobacter pylori.
3. Urinary tract infection (UTI): Tetracyclines are used in the

management of UTI, which is better treated by metronidazole,
cephalosporins (III generation) or ampicillin.
Side Effects:
a. Gastrointestinal effects: ranging from anorexia, nausea, vomiting,
diarrhea, to development of oral and vaginal candidiasis, pruritus and
enterocoloitis, because they modify the normal flora and overgrowth of
proteus, staphylococci, clostridia and candida (superinfection).
b. Bone and teeth: because tetracyclines bind Ca, discoloration and

hypoplasia of the teeth and deformity or bone growth inhibition.
c. Fatal hepatotoxicity: commonly occurs in pregnant women who received

high doses of tetracyclines, and those with preexisiting hepatic disease,
they may impair liver function, leading to hepatic necrosis.
d. Kidney toxicity: so doses of tetracyclines should be adjusted in renal

patients.
e. Local tissue reaction: I.V administration of tetracyclines can lead to

venous thrombosis, whereas IM injection is irritable and painful.
f. Phototoxicity: especially with the use of demeclocycline which causes

irritation to sunlight or ultraviolet light.
g. Vestibular reactions: dizziness, vertigo, nausea and vomiting due to

tetracycline accumulation in the endolymph, particularly occurs with
minocycline.
Contraindications:
1. Renal diseases: because all tetracyclines aggravate azotemia by
interfering with protein synthesis, except for doxycycline, which is cleared
in the feces.
2. Pregnant, nursing women and children under 8 years.

III. Pharmacology of Macroliodes
Agents: erythromycin, clarithromycin, azithromycin and roxithromycin.
Mode of action: macrolides bind irreversibly on the 50S subunit of the

bacterial ribosome, therefore inhibiting translocation step of protein
synthesis, generally considered to be bacteriostatic antibiotics, their
binding site is identical or in close to that for clindomycin and
chloramphenicol, (macrolides compete with them) at high doses they are
bactericidal.
Antibacterial Spectrum:
1. Erythromycin: is effective against the same organisms as penicillin G,
therefore widely used in patients allergic to penicillin.
2. Clarithromycin: similar to erythromycin, but also effective against

haemophilus influenza, its activity against Chlamydia and H. pylori is
higher than erythromycin.
3. Azithromycin: less active against streptococci and staphylococci than

erythromycin, but more active against respiratory infections caused by
haemophilus influenzae.
Pharmacokinetics:
Administration and absorption: erythromycin is destroyed by gastric acid
and must be administered as enteric-coated tablets, but azithromycin and
clarithromycin are stable to gastric acid, I.V administration of
erythromycin is associated with a high incidence of thrombophlebitis,
food decreases absorption of erythromycin and azithromycin, but can
increase that of clarithromycin.
Distribution: erythromycin is distributed to all body fluids except the CSF,

all macrolides concentrate in the liver.
Metabolism and excretion: erythromycin is extensively metabolized, it is a

potent CYP inhibitor, azithromycin has the longest t ½ and longest volume of
distribution, it does not undergo metabolism, erythromycin and
azithromycin primarily eliminated in the bile, partial reabsorption occurs
through the enterohepatic circulation in contrast to clarithromycin which

is eliminated by the kidney, and partially by the liver, so its doses should
be adjusted in patients with renal disorders, it inhibits metabolism of
some drugs such as theophyllin and carbamazepine.
Clinical Uses:
1. Corynebacterial infections: erythromycin is the drug of choice in
diphtheria and corynebacterial sepsis.
2. Respiratory, neonatal, ocular, genital and Chlamydial infections.
3. Alternative in patients who are allergic to penicillins.
4. Prophylaxis of endocarditis during dental procedures in individuals with
valvular heart disease.
Adverse Effects:
1. G.I.T effects: are very common including anorexia, nausea vomiting and
diarrhea.
2. Liver toxicity: particularly erythromycin can produce acute cholestatic
hepatitis (jaundice) due to its metabolite estolate, so erythromycin is
contraindicated in hepatic patients.
3. Ototoxicity: transient deafness has been associated with high doses of
erythromycin.
Resistance: resistance occurs due to 3 main mechanisms:

a. Reduced permeability of the cell membrane or active efflux.
b. Production of esterases that hydrolyze macrolides.
c. Modification of the ribosomal binding site (ribosomal protection) by
chromosomal mutation.
V. Pharmacology of Clindamycin:
Clindamycin is a derivative of lincomycin, although structurally distinct,

it resembles erythromycin in its activity but it is more toxic.
Antibacterial activity: active against strepto-staphylo and pneumococci,

inactive against enterococci, aerobic organisms and C. difficile.
Mechanism of action: interferes with protein synthesis by binding to 50S

subunit of the bacterial ribosome, it interferes with translocation reactions.

Pharmacokinetics: orally is well absorbed, widely distributed into all
tissues except the CSF, penetrates into the bone, even in the absence of
inflammation, metabolized in the liver and excreted by the bile.
Clinical Applications:
1. Severe infections: caused by anaerobes e.g. bacteroides fragilis, that
causes abdominal infection.
2. Pelvic abscesses.
3. Prophylaxis of endocarditis: with valvular heart disease during dental
procedures.
Adverse Effects: G.I.T disorders, liver dysfunction, skin rashes and
antibiotic-associated colitis caused by C. diffecile, which is treated
primarily by metronidazole or vancomycin, (should be reversed for a
condition that does not respond to flagyl) neutopenia may occur.
VI. Pharmacology of Sulfonamides or (Antifolates):
Agents: mafenide, sulfadiazine, sulfacetamide, sulfisoxazole,

sulfamethoxazole and sulfasalazine.
Role of folic acid: is essential cofactor required for synthesis of purines

and pyrimidines (precursors of RNA and DNA) and other compounds
required for cellular growth and replication, the sulfa drugs are inhibitors
of folic acid synthesis.
Mechanism of action
Synthesis of folic acid: p-aminobenzoic acid (PABA) is converted into
dihydrofolic acid under the influence of dihydropteroate synthase, then by
dihydrofolate reductase into tetrahydrofolic acid (active form of folic
acid), which is the precursor of purines and nucleic acids.
Sulfonamides are structural analogs of PABA that inhibit competitively
dihydropteroate synthase, thus preventing the synthesis of bacterial folic
acid from PABA, in contrast human can't synthesize folate and must
obtain it in his diet.
Antibacterial spectrum: sulfa drugs are bacteriostatric, effective against

both gram-positive and gram -negative bacteria, Chlamydia, E. coli,
Klebsiella, Salmonella, Shigella and Enterobacter.

Pharmacokinetics: Most sulfa drugs are well absorbed after oral
administration by the small intestine, an exception is sulfasalazine that is
not absorbed when administered orally or as suppository and therefore it
is used in the treatment of chronic inflammatory bowel disease (crohn's
disease, ulcerative colitis), local intestinal flora split sulfasalazine into
sulfapyridine (its absorption can lead to toxicity) and 5-aminosalicylate
that exerts anti-inflammatory effect.
IV sulfonamides are given for patients who are unable to tolerate oral
preparations, sulfa drugs well penetrate into the normal CSF and
placenta, metabolized in the liver to a product which devoid
antimicrobial activity, but toxic to the kidney, their accumulation can
cause crystalluria, (stone formation) elimination occurs mainly by
glomerular filtration.
Clinical Uses:
1. Absorbable agents: sulfa drugs are rarely used as monotherapy, they
combine with trimethoprim, sulfisoxazole and sulfamethaxazole, usually
are indicated for the treatment of UTI and nocardia.
2. Non-absorbable agents: sulfasalazine is widely used in the treatment

of chronic inflammatory bowel diseases.
3. Topical Agents:
a. Silver sulfadiazine and mafenide are used in burn units to reduce burn-
associated sepsis, because they prevent colonization of bacteria, silver
sulfadiazine is preferred to mafenide, because the latter can cause pain
and metabolic acidosis by blocking carbonic anhydrase.
b. Sulfadiazine in combination with pyrimethamine is the preferred form for
treatment of toxoplasmosis and chloroquine-resistant malaria.
c. Sodium sulfacetamide ophthalmic solution or ointment is effective in the
treatment of bacterial conjunctivitis.
Adverse Effects of Sulfonamides:
1. Hypersensitivity: allergic reactions (skin rashes, angioedema, fever,

photosensitivity and diarrhea) are the most common side effects of sulfa
drugs
2. Nephrotoxicity: represented by crystalluria, hemoturia or even

obstruction, sulfa precipitate in the urine, especially at neutral or acid pH,
except for sulfisoxazole and sulfamethoxazole which are more soluble at
urinary pH than other sulfa drugs, crystalluria is treated by
administration of Na bicarbonate to alkalinize the urine.
3. Hemopoeitic disturbances: hemolytic anemia, granulocytopenia and

thrombocytopenia.
4. Kernicterus: is a disorder occurring in newborns due to free levels of

billirubin, and its penetration into baby’s CNS because sulfa displace
billrubin from binding sites on serum albumin.
Contraindications: in newborns and pregnant women at term.
VII. Pharmacology of Trimethoprim
Mechanism of action: the active form of folate is tetrahydrofdic acid that is

formed by dihydrofolate reductase; this enzyme is inhibited by
trimethoprim, resulting in decreased tetrahydrolfolate coenzymes
required for purine, pyrimidine and amino acids.
Pharmacokinetics: because the drug is a weak acid, high concentrations

of trimethoprim are found in the prostatic and vaginal fluids, it also
penetrates the CSF, undergoes little hepatic metabolism and eliminated
unchanged in the urine.
Antibacterial spectrum: is similar to sulfamethoxazole, but trimethoprim

is more potent than sulfonamides, and could be used alone in acute U.T.I
and bacterial prostatitis.
Resistance: is due to altered dihydrofolate reductase that has a low

affinity for trimethoprim.
Pharmacology of CO-Trimoxazole:
CO-Trimoxazole is a combination of trimethoprim with sulfamethoxazole
because of the similarity of their pharmacokinetics.
Mechanism of action: it is a bactericidal compared to the bacteriostatic

activity of sulfonamide alone, Co-trimoxazol inhibits 2 sequential steps in
the synthesis of tetrahydrofolic acid, sulfamethoxazole inhibits the

incorporation of PABA into folic acid and trimethoprim renders
reduction of dihydrofolate to tetrahydrofolate.
Antibacterail spectrum: Co-trimoxazole has a broader spectrum of

antibacterial action than sulfa alone, effective against UTI, respiratory
ampicillin-chloramphenicol-resistant systemic salmonella infections and
chloroquine-resistant malaria.
Pharmacokinetics: administered orally or I.V, because trimethoprim is

more lipophilic than sulfamethoxazole, it is distributed widely through
the body fluids, penetrates to CSF, accumulates in prostatic and vaginal
fluids, which are more acidic than plasma, and then accounts for the
treatment of prostatitis and vaginitis, both drugs are eliminated renally.
Clinical Uses:
1. Oral Co-trimoxazole: is effective against pneumonia, shigellosis,
salmonella, U.T.I vaginitis and prostatitis.
2. I.V Co-trimoxazole: used against pneumocystis pneumonia, AIDS,
severe shigellosis, typhoid fever and severe U.T.I.
Adverse Effects:
1. Dermatologic reactions: skin rash is the most common side reaction.
2. G.I.T disturbances: nausea, vomiting, glossitis and stomatitis due to
folate deficiency.
3. Hematologic: megoblastic anemia, leukopenia and thrombocytopenia
may occur.
ANTIFUNGAL AGENTS
Definition of Mycoses: is a group of chronic infection diseases caused by fungi,

many of them are superficial, involving not only the skin, but fungi may
penetrate the skin causing subcutaneous infections or more deep resulting in
systemic mycosis.
Structure of Fungi: Fungi unlike bacteria are eukaryotic cells, they have
rigid cell walls composed largely of chitin (a polymer of N-
acetylglucosamine), rather than peptidoglycan, (characteristic component
of most bacterial cell walls) the fungal cell membrane contains ergosterol
rather than cholesterol, found in mammalian membranes, these chemical

characteristics are useful in targeting chemotherapeutic agents against
fungal infections.
Systemic mycoses are most difficult to treat, fungal infections are
resistant to antibiotics, and conversely bacteria are resistant to the
antifungal agents.
A. Antifungal Drugs For Systemic Infections

a. Amphotericin B: Amphotercin A and B are antifungal antibiotics
produced by Streptomyces nodosus, Amphotercin A is not in clinical use,
Amphotericin B is the most effective and widely used antifungal drug
against systemic mycosis.
M.O: it act by binding to ergosterol that present in cell membrane of

sensitive fungi, it forms amphotercin B- associated pores (channels)
allowing electrolytes (particularly K) and small molecules to move
outside the cell, resulting in cell death.
Pharmacokinetics: it is poorly absorbed from the gut, and used only when
fungi present in lumen of G.I.T, the IV infusion should be given very slowly
due to its nephrotoxicity, amphotercin B is extensively bound to plasma
protein, distributed throughout the body, it does cross the placenta, but
little is found in the CSF, intrathecal therapy approved for fungal
meningitis, this therapy is poorly tolerated and fraught with difficulties
related to maintaining CSF access, thus the intrathecal therapy with
amphotercin B is being increasingly supplanted by other therapies, but
remains an option in cases of fungal CNS infections that have not
responded to other agents.
Metabolism and elimination: amphotericin B mainly is metabolized in

the liver, excreted slowly in the urine and partially in the bile, adjustment
of dose is required in patients with extreme renal dysfunction, the t ½ is
approximately 15 days.
Clinical Use: amphotericin B remains the antifungal agent with the

broadest spectrum of action, it is either fungicidal or fungistatic, it is the
drug of choice for severe systemic mycotic infections including fungal
pneumonia, crypotococcal meningitis, sepsis syndrome caused by fungi,
widely used as empiric therapy in cancer patients with neutropenia who
remain febrile on broad spectrum antibiotics; in addition topic forms are
available for fungal arthritis.
Resistance: may occur if ergosterol binding is impaired, either by
decreasing content of ergosteral or by modifying the sterol target thus
decreasing its affinity for the drug.
Adverse Effects: amphotericin B has a low therapeutic index, so it is a

toxic drug; small tests are done usually before its administration, to assess
the degree of toxicity, such as anaphylaxis and convulsions, adverse
effects are divided into:
1. Immediate reactions: fever, chills, muscle spasm, vomiting,
hypotension following I.V administration, to prevent these symptoms,
premedication of antipyretics, antihistamines, meperidine or
corticosteroids can abort this process.
2. Late toxicity: represented by renal impairment, decreased renal

perfusion and secretion, due to loss of potassium and magnesium,
resulting in renal tubular acidosis (prerenal failure), prevented by
prehydration saline infusions.
3. Other Side Effects: thrombophebitis and anemia, due to decreased

production of erythropoietin by damaged renal tubular cells, seizures
develop when it is given intrathecally.
b. Flucytosine: is a synthetic pyrimidine antimetabolite related to the

anticancer fluorouracil (5-FU).
Pharmacokinetics: the drug is well absorbed orally, it is poorly bound to

proteins, distributed throughout the body water compartments and
penetrates into the CSF, excreted via the kidney by glomerular filtration,
and its dose must be adjusted in patients with compromised renal
function.
Mode of action: flucytocine enters the fungal cells via the enzyme cytosine
permease (an enzyme not found in mammalian cells), it is converted into
fluorouracil (5-FU) then to 5-fluorodeoxyuridine monophosphate (5-
dUMP) and finally to fluorouridine triphosphate (FUTP), which inhibit
DNA and RNA synthesis; human cells are unable to convert the parent
drug to its active forms, the combination of flucytosine and amphotericin
B is synergistic, because the latter allows more of flucytosine to penetrate
throughout pores which made up by amphotericin B.
Resistance: can develop due to decreased levels of enzyme involving in
the metabolism of flucytosine, and for this reason it is not used as a single
therapy.
Clinical Use: used in combination with amphotericin B in treating

cryptococcal meningitis and in combination with itraconazole against
chromoblastomycosis.
Adverse Effects: due to formation of antineoplastic substance, (5-FU) by

intestinal flora, it can cause the following effects:
1) Hematologic toxicity: anemia, neutropenia, leukopenia and

thrombocytopenia (most common).
2) Hepatic dysfunction: with elevation of serum transaminases and alkaline
phosphatase.
3) GIT disturbances: nausea, vomiting, diarrhea and severe enterocolitis.
c. Azoles: are synthetic compounds that can be classified according to the

number of nitrogen atoms in the five-membered azole ring into:
1. Imidazoles: ketoconazole, miconazole and clotrimazole, exhibit a lesser

degree of selectivity that triazoles, accounting for their higher incidence
of drug interactions and adverse effects.
2. Triazoles: itraconazole, fluconazole and voriconazole, produce a selective
CYP inhibition, due to their greater affinity for fungal than for human
cytochrome P450 enzymes.
Topical Azoles: the 2 azoles most commonly used topically are miconazole
and clotrimazole that are rarely used parenterally because of their severe
toxicity, sometimes allergic reactions can occur with the use of azoles
(dermatitis, vulvular irritation and edema); miconazole increases the t 1/2
of warfarin and can result in bleeding even when it is applied topically.
1. Ketoconazole:
Mechanism of action: is very useful in treating systemic mycosis, all
azoles act by reduction of ergosterol synthesis, via inhibition of α-
demythelase (the enzyme required for demethylation of lanosterol into
ergosterol) therefore causing fungistatic effect, ketoconazole acts
synergistically with flucytosine and antagonistically with amphotercine B, in
addition to its antifungal activity, it inhibits gonadal and adrenal steroid
synthesis to decreased concentrations of testosterone and cortisol.
Pharmacokinetics: ketoconazole is administered only orally, it is absorbed

from gastric mucosa (requires gastric acid for dissociation), so antacids,
H2 blockers and proton pump inhibitors interfere with its absorption, it is
highly bound to plasma proteins, in spite of its limited penetration into
tissues, the drug is concentrated into lungs, bone, skin and soft tissues, but
does not enter the CSF, the metabolism occurs in the liver, the excretion
of ketoconazole occurs primarily via the bile.
Antifungal spectrum: ketoconazole is effective against Histoplasma,

Blastomyces, Candida, Dermatophytic infections but not aspergillius species.
Resistance: may occur due to mutations in α-demythelase gene, to which

ketoconazole should be bound, in addition the ability of some fungi to
pump azoles out of the cell.
Adverse Effects:
a. Gastrointestinal disorders: are very common.
b. Endocrine effects: gynecomastia, decreased lipido, impotence and
menstrual abnormalities.
c. Hepatic dysfunction: is rare, but dosage of the drug should be adjusted in
patients with hepatic disorders.
2. Fluconazole:
Antifungal spectrum and clinical use: differs from ketoconazole in that it
lacks endocrine side effects and crosses into the normal and inflamed
meanings. It is the zole of choice for infections of Cryptococcus neoformans.
Fuconazole is also effective against Candidemia, Cocidioidomycosis,
Blastomycosis and Histoplasmosis, in addition fluconazole is approved
prophylactically for reducing fungal infections in recipients of bone
marrow transplants.
Pharmacokinetics: is administered either orally or IV, its absorption is

independent on gastric secretion, poorly bound to plasma proteins, its
metabolism is insignificant, excretion mainly occurs renally, so doses
should be adjusted in patients with renal failure.

Adverse Effects: the incidence of side effects are less than those occurring
with ketocanazole, some GIT disorders, allergic reactions and hepatitis
can appear, fluconazole is a teratogenic and should not be used in
pregnancy.
3. Itraconazole: is a synthetic triazole, which has no endocrine side effects

like ketoconazole, pharmacokinetically itraconazole is absorbed well after
oral administration requiring gastric acid, it could be given IV or orally,
extensively bound to plasma proteins, widely distributed throughout the
body fluid compartments, especially into bone, sputum and adipose tissue,
poorly penetrates into the CSF, metabolized hepatically and eliminated
by the liver and kidneys.
Clinical Use: is now the azole of choice for the treatment of blastomycosis,
sporotrichjosis and histoplasmosis.
Adverse Effects: nausea, vomiting, rash, hypokalemia, edema and

headache, contraindicated in pregnancy.
4. Voriconazole: is the newest triazole, available in oral and IV

formulations, the drug is well absorbed following oral administration, it
is bound to plasma proteins but less than itraconazole, enters the CSF,
metabolized hepatically, it less affects the CYP system.
Clinical Use: Voriconazole is the drug of choice for invasive aspergillosis, it

is more effective than amphotercin B and against candida species including
fluconazole-resistant species.
Side Effects: are less than amphotercin B, the most common side effects
are: skin rash, elevated hepatic enzymes and visual disturbances (color
vision and brightness) occur immediately and resolve within 30 minutes.
d. Echinocandins: are the newest classes of antifungal agents to be

developed, the prototype is caspofungin, others are micafungin and
anidulafungin.
M.O: they act by blocking the formation of beta-D-glucan, thus resulting

in lysis and cell death, caspofungin is not effective orally, is highly bound
to plasma protein, the half-life is 9-11 hours, metabolized in the liver and
eliminated in the urine and feces, clinically it is limited to aspergillosis

and candida species, but it is alternative to amphotericin B and
itraconazole resistant therapy, the most common side effects are GIT
upset, allergic reactions, phlebitis and flushing.
B. Drugs For Superficial Mycotic Infections:

Fungi that cause superficial infections are called dermatophytes.
1. Terbinafine:
Mechanism of action: it is a fungicidal agent that decreases ergosterol
synthesis by inhibiting the enzyme requiring for eregosterol synthetic
pathway (squalene epoxidase), fungicidal effect is also due to accumulation
of toxic amounts of squalene.
Pharmacokinetics: is active orally, in despite of its low bioavailability

(about 40 %) due to first-pass effect, it is bound to plasma proteins,
deposited in the skin, nails and fat, it has a long t ½ ranging from 200 to
400 hours, excretion of the drug mainly occurs in the urine.
Clinical Use: is the drug of choice for the treatment of dermatophytes

(onychomycoses) and Candida albicans, duration of therapy is about 3
months, it is more potent than griseofulvin and itraconazole.
Adverse Effects: the drug usually is well tolerated, but some GIT upset
(dyspepsia, nausea and diarrhea) taste and visual disturbances may
develop, these effects are reversible, in despite of its extensive
metabolism it doesn’t affect the CYP system, so no significant drug
interactions does not occur.
2. Griseofulvin: is a fungistatic drug derived from species of penicillium,

its mechanism of action is unknown, but it is believed that griseofluvin
inhibits fungal mitosis, by binding to keratin, (keratolytic) it protects
skin from new infections, it must be administered for 2-6 weeks for skin
and hair infections, to allow replacement of infected keratin by resistant
structures, but 6 to 12 months for onychomycoses, allowing regrowth of
the new protected nail. Allergic reactions and hepatitis are the most
common side effects, griseofulvin increases the metabolism of warfarin,
and today it is replaced by terbinafine and itraconazole.
3. Nystatin: its structure, chemistry, mechanism of action and resistance

resemble those for amphotercin B, it is too toxic for parenteral

administration, so it is used either orally or topically for the treatment of
vaginal candidiasis and candida infections. Adverse effects are rare, but
unpleasant taste, nausea and vomiting can occur.
ANTIVIRAL DRUGS
Viruses: are obligate intracellular parasites, they lack both a cell wall and
a cell membrane, their replication depends primarily on metabolic
processes of the host, viruses are classified as DNA or RNA, depending
on the presence of nucleic acid.
Viral Replication: consists of 7 steps:

a. Adsorption: characterized by penetration of virus into susceptible host
cells.
b. Uncoating of viral nucleic acid.
c. Synthesis of early regulatory proteins e.g. DNA or RNA polymerasese.
d. Synthesis of RNA or DNA.
e. Synthesis of late structural proteins.
f. Maturation of viral particles.
g. Release of active virus from the cell.
General mechanism of action of antiviral drugs: act by blocking viral

entry into the cell, exit from the cell and to prevent be active inside the
host cell.
A. Agents Against Herpes Simplex Virus (HSV), Varicella Zoster Virus

(VZV) Infections:
1. Acyclovir:
Antiviral activity: is the most widely used antiviral drug, it is a cyclic
guanosine derivative, exerts antiviral activity against HSV-1, HSV-2, VZV,
Epstein-Bar virus (EBV), cytomegalovirus (CMV) and human
herpesvirus-6, (but weaker).
Mechanism of action: acyclovir is a pro-drug which requires three

phosphorylations to be active, first it is converted into monophosphate by
viral thymidine kinase then to di and triphosphate by host’s enzymes,
acyclovir triphosphate inhibits viral DNA synthesis by 2 mechanisms:
a. Competitive inhibition of deoxy GTP: the drug should be incorporated to DNA
chain.

b. As acyclovit becomes incorporated into the viral DNA, it causes premature
DNA-chain termination.
Pharmacokinetics: administration of the drug is available for

intravenous, oral and topical uses, acyclovir is well distributed
throughout the body, including the CSF, eliminated by glomerular
filtration and tubular secretion, its t 1/2 is about 2-3 hours.
Clinical Uses:
The drug is effective against primary genital herpes infections, varicella
zoster virus (VZV) if taken within 24 hours after the onset of rash, for
cutaneous zoster within 72 hours, because acyclovir inhibits only actively
replicating viruses, and has no effect on latent viruses, generally the
clinical symptoms of viral infections appear late at a time when most of
the viral particles have replicated, in contrast to bacterial infections in
which symptoms appear with bacterial proliferation, so at symptomatic
stage administration of drugs that block replication is ineffective,
acyclovir is the front drug for the treatment of HSVencephalitis,
approved prophilactically in transplant patients, resistance occurs due to
deficiency of thymidine kinase, especially in CMV or modification of
DNA polymerase.
Adverse Effects:
Side effects depend on the route of drug administration, local irritation
may occur after topical use, headache, diarrhea, nausea and vomiting
may result after oral administration, transient renal dysfunction and CNS
toxicities (tremors, delirium, headache, dizziness and seizures) in patients
receiving IV acyclovir.
Acyclovir Congeners: their clinical indications and side effects are similar to
acyclovir
a. Valacyclovir: is rapidly converted to acyclovir.
b. Famciclovir: it doesn't cause DNA chain termination, it is rapidly
converted to penciclovir, which shares some features of acyclovir, the t ½
depends on the virus, 10 hours in HSV-1, 20 hours in HSV-2 and 7 hours in
VZV or chickenpox.
B. Agents Used In Cytomegalovirus Infections
1. Ganciclovir:

M.O: is a cyclic guanosine analog that requires triphosphorilation for
activation prior to inhibit the viral DNA polymerase, causing termination
of viral DNA elongation.
Pharmacokinetics: Ganciclovir is available in oral, IV and intraocular

formulations, it is widely distributed in the body reaching the CSF, the
elimination of the drug occurs by glomerular filtration and tubular
secretion; it accumulates in patients with renal failure, its half-life is about
4 hours and intracellular t 1/2 is prolonged to 16-24 hours.
Antiviral Activity: it is effective against CMV, (up to 100 times greater than
acyclovir) HSV and VZV, approved mainly for the treatment of CMV
infection especially retinitis, colitis, and in esophagitis in HIV infected
patients and for CMV prophylaxis.
Adverse Effects:
a. Myelosuppression: represented by anemia and neutropenia.
b. CNS toxicity: headache, seizures, and mental abnormalities.
c. Teratogenicity: ganciclovir is contraindicated in pregnancy.
2. Valganciclovir: is the valyl ester of ganciclovir, metabolized in the

intestine and liver into ganciclovir, eliminated by kidneys, clinical uses
and side effects are similar to those produced by ganciclovir.
Specific Antivirals:
1. Cidofovir: is a cytosine nucleotide analog, in which phosphorylation is

independent on viral enzymes, acts as a potent inhibitor of DNA
replication against CMV, HSV-1, HSV-2, VZV, EBV, adenovirus and
human papillomavirus.
Pharmacokinetics: although the half-life of the cidofovir is 2, 5 hours, its

active metabolite (cidofovir diphosphate) has a prolonged intracellular half-
life of 17-65 hours, in addition to a separate metabolite (phosphocholine)
with the t ½ of 87 hours, which serve as reservoir of active drug, direct
intravitreal administration of cidofovir is not recommended because of
ocular toxicity, penetrates poorly into the CSF, eliminated by the kidney.
Clinical Use: mainly employed for CMV retinitis in patients with AIDS,
and against many acyclovir-gancyclovir resistant strains.

Adverse Effects: the principle side effect of the drug is nephrotoxicity,
which could be decreased in the presence of probenecid which blocks
tubular secretion, amphotercin B, aminoglycosides, foscarnet and
NSAIDs should be avoided.
2. Foscarnet: is fosphonoformic acid that acts by inhibiting viral DNA or

RNA polymerases and HIV reverse transcriptase directly without
requiring phosphorylation for its antiviral activity.
Pharmacokinetics: is not given orally, prescribed intravenously, widely

distributed in the body, enters the CSF, the t ½ is about 3-7 hours, may be
deposited in bone with a half-life of several months, cleared by the
kidney.
Clinical Indications: foscarent is mainly used for CMV retinitis, colitis

and esophagitis in HIV patients, if infection is resistant to ganciclovir, as
well as viral infections (HSV, CMV, VZV) resisting acyclovir.
Adverse Effects: nephrotoxicity, anemia, nausea, hypo or hypercalcemia,

hypo or hyperphosphatemia, saline preloading helps to prevent
nephrotoxicity, penile ulcerations may be due to high levels of ionized
drug in the urine, CNS toxicities can occur.
C. Anti-Influenza Agents:
1. Amantadine and Rimantadine:

M.O: inhibit uncoating viral RNA of influenza A within infected host
cells, by blocking the viral protein M2, which functions as an ion channel
thereby preventing replication. Rimantadine is more active than
amantadine, they are limited to influenza A infections, used for both
prophylaxis and treatment.
Amantadine by chance was found to have antiparkisonism effect.
Pharmacokinetics: both drugs are well absorbed orally, amantadine is

not metabolized extensively, it penetrates into the CSF, whereas
rimantadine has a longer half life and can't cross the CSF, it undergoes
extensive hepatic metabolism, and both drugs are excreted by the kidney.

Resistance: 50 % of resistance is associated with mutations of viral
protein M2 of viral membrane to which drugs should be bound.
Adverse Effects:
a. CNS toxicity: including insomnia, dizziness, ataxia and seizures.
b. GIT disturbances: nausea, vomiting, abdominal pain, caution should be
taken during pregnancy and in nursing mothers.
2. Zanamivir and Oseltamivir:

M.O: Drugs act by inhibition of neuraminidase which is essential for release
of active virus from infected host cells, they are active against both
influenza A and B, used for treatment and prophylaxis.
Zanamivir is administered via oral inhaler, only 10-20% of active
compound reaches the lungs, and the remainder is deposited in the
oropharynx, it has limited plasma protein binding, rapid renal clearance
and absence of significant metabolism, nasal and throat discomfort, cough
and bronchospasm are the major side effects.
Oseltamvir: is an orally administered prodrug, which is activated in the
gut and liver; excreted mainly in the urine, nausea and vomiting are the
most side effects, in order to decrease these unwanted GIT effect, the
drug is taken with food. Resistance can develop due to mutations in viral
neuraminidase.
E. Agents Used For Hepatitis:
1. Lamivudine: is a cytosine analog that inhibits HBS and HCV
polymerase and human immunodeficiency virus (HIV) reverse
transcriptase, hence decreasing viral replication, it must be
phosphorylated by host enzymes to the triphosphate form, its plasma half-
life is 9 hours but the intracellular t ½ in HBV is about 17 to 19 hours,
which permits infrequent dosing in HBV, response to lamivudine is more
rapid than to interferon. The drug is very well tolerated, with rare
occurrence of headache and dizziness, dose restrictions are necessary
when there is moderate renal failure.
2. Interferons (IFNs): are an endogenous proteins, (cytokines) which
inhibit virus replication via degradation of viral mRNA and tRNA, in
addition they produce immunomodulatory and antiproleferative
activities through cellular metabolic processes, they are classified
according to cell type from which they were derived, alpha, beta and
gamma.

Pharmacokinetics: interferon is not active orally, administered
subcutaneously or intravenously, very little active compound is found in
the plasma due to its extensive metabolism by the liver and kidney,
eliminated via glomerular filtration and tubular secretion. Clinically
interferon (α-2b) is approved for the treatment of HBV, HCV infections,
leukemia and Kaposi sarcoma, whereas interferon- β has some
effectiveness in the treatment of multiple sclerosis.
Side Effects: include flu-like symptoms e.g. fever, chills, arthralgias,

myalgias, GIT disturbances, lethargy, bone depression, alopecia, CHF
and allergy, contraindicated in terminal cirrhosis.

Gram-Positive Bacteria
Gram-Negative Bacteria
Chromosomal Mutations of DNA
Impermeability
Inactivation
Efflux
R plasmid
R plasmid
A B
By-pass Altered
Chromosomal mutation target
Mechanism of Action Of Penicillin

NAM NAG NAM NAG S UGAR
BACKBONE
L-Ala L-Ala
D-Glu D-Glu
L-Lys Gly Gly Gly Gly Gly L-Lys Gly Gly Gly Gly Gly
D-Ala D-Ala
D-Ala D-Ala
PENICILLIN
TRANS PEPTIDAS E
D-Alanine
NAM NAG NAM NAG S UGAR

BACKBONE
L-Ala L-Ala
D-Glu D-Glu
L-Lys Gly Gly Gly Gly Gly L-Lys Gly Gly Gly Gly Gly
D-Ala D-Ala
Cross linking

Acquired
resistance
can occur by
alteration of
target by
chromosomal
mutation.
Or acquisition on
plasmid encoding
resistance genes.

β-3-glucan
Polyenes Imidazoles Triazole Allylamines synthase Others
inhibitors
nystatin miconazole fluconazole naftifine caspofungin griseofulvin
amphotericin
clotrimazole itraconazole terbinafine micafungin flucytosine
B
voriconazole butenafine tolnaftate

ketoconazole anidulafungin

Antifungal Agents- Sites of action
Echinocandins
Inhibit fungal cell wall
biosynthesis
Griseofulvin
Inhibits mitotic
spindle formation

Bactericidal Antibiotics Bacteriostatic Antibiotics
Vancomycin Tetracydines
Fluoroquinolones Sulfonamides
Metronidazole Macrolides
Gentamicin Trimethoprim
Co-trimoxazole Chloramphenicol
Carbapenems Clindamycin
Penicillins Lincosamides
Cephalosporins
Monobactams

UNIT 3
ANALGESICS
Definition: drugs that reduce pain centrally without affecting

consciousness or other sensations.
Classification:
A. Non Narcotic Analgesics: Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs) or analgesic antipyretics, i.e. slaicylates.
B. Narcotic Analgesics: drugs that cause dependence such as morphine.
C. Other Analgesic Drugs: relive special types of pain by different

mechanisms, they are not proper analgesics e.g. caffeine in headache and
obtundants that diminish sensation of dentine and so allowing for painless
evacuation, e.g. phenol, creosote, alcohol and others.
A. NON- NARCOTIC ANALGESICS (NSAIDs)
Three pharmacologic actions are produced by NSAIDs:
1. Analgesic effect: They relive or reduce pain. (Painkillers)
2. Antipyretic effect: they lower fever (pyrexia) to normal without affecting

its cause; they don’t affect normal body temperature.
3. Anti-inflammatory and anti- rheumatic effects: most of them except

paracetamol.
NSAIDs: are group of chemically dissimilar agents that differ in their

antipyretic, analgesic and anti-inflammatory activities, the prototype of
this group is aspirin, (acetylsalicylic acid).
Classification of NSAIDs: they are classified according to:

A. Selectivity: Non selective COX inhibitors and COX-2 Selective Inhibitors.
C. Receptor binding: reversible and irreversible NSAIDs.
B. Chemical Structure: they include

I. Salicylates Derivatives: are salicylic acid derivatives, they are classified
according to their route of administration into:
a. Locally acting: salicylic acid and methyl salicylates.
b. Systemically acting: acetyl salicylic acid (aspirin) and Na Salicylates.
Mechanism of Action: NSAIDs anti-inflammatory effect is mediated

through inhibition of cyclooxygenase (COX), which produces several
prostaglandins (PGs) from arachidonate, PGs have a variety of effects on
blood vessels, on nerve endings and cells involved in inflammation, there
are 2 types of COX enzymes- COX-1 (constitutive) and COX-2
(physiologic and pathologic). The 5- lipooxygenase pathway of
arachidonate metabolism yields leukotriens, which have a power
chemotactic effect on eosinophils, neutrophils and macrophages, they
promote bronchoconstriction and alteration in vascular permeability.
Various NSAIDs have additional possible mechanisms of action,
including inhibition of chemotaxis, depression of IL-1, decreased production of
free radicals and superoxide and interference with Ca mediated intracellular
events.
Aspirin is the prototype of NSAIDs, and most commonly used and is the
drug to which all other anti-inflammatory agents compared, about 50% of
patients show intolerance to aspirin that is the only agent which irreversibly
acetylates (inactivates) COX enzymes, thus inhibiting prostaglandin
synthesis at the thermoregulatory center in the hypothalamus antipyretic
effect), prevents sensitization of pain receptors to mediators (analgesic
effect) and at peripheral target sites (anti-inflammatory effect), other
NSAIDs are reversible inhibitors of COX.
Pharmacokinetics: Aspirin is rapidly absorbed form the stomach and the

upper intestine, rapidly hydrolyzed to acetic acid and salicylate, (active
form) by esterases in tissues and blood, salycylate is converted into polar
molecules which are readily eliminated in the urine, at low doses (650
mg/day) the t ½ of aspirin is 3.5 h, but at higher doses (4 g daily), it has a
t ½ of 15 hours, it crosses both the BBB and BPB, alkalinization of the
urine accelerates its excretion, at low doses the secretion of uric acid is
decreased, and conversely at high doses enhances the elimination of uric
acid.
Actions of NSAIDs:

1. Anti–inflammatory effects: has a weak anti-inflammatory effect,
aspirin only at high doses produce anti-inflammatory effect; is not useful
in the treatment of inflammation.
2. Analgesic actions: by decreasing PGE2 release, aspirin decreases the

sensitivity of receptors to bradykinin, histamine and other mediators
released locally by the inflammatory process, it is a potent analgesic, the
salicylates are used mainly for the management of pain of low or
moderate intensity arising from integumental structures rather than
arising from the viscera. NSAIDs are superior to narcotic analgesics to
reduce pain associated with inflammation. Combinations of opioids and
NSAIDs are effective in treating pain caused by malignancy.
3. Antipyretic effects: reduction of fever by decreasing PGE1 and PGE2 at

the thermoregulatory centre in the hypothalamus, via dilating peripheral
blood vessels (sweating), and peripheral inhibition of IL-І.
4. G.I.T inhibition of PGE2 and PGF2a : normally PGI2 inhibits gastric

secretion, whereas PGE2 and PGF2a protect the mucosa of the stomach
and intestine, aspirin causes an increased in gastric acid secretion and
reduces mucus protection, it may lead to arising of erosions, ulcers,
nausea, vomiting and hemorrhage.
5. Platelets: normally TXA2 enhances aggregation of thrombocytes,

promotes vasospasm and causes proliferation effect on endothelium
whereas PGI2 decreases their aggregation and maintains vasodilation,
Aspirin at low doses (60-80 mg daily ) inhibits thrombocytic TXA2 irreversibly
without affecting endothelial TXA2 of blood vessels, because platelets
have no nuclei they cannot synthesize new enzyme and this the anti-
aggregant effect lasts for the life span of platelets (8-10 days), leading to
prolongation of bleeding time, aspirin doses should be reduced but not
discontinued before any dental or surgical procedures.
6. Actions on the kidney: NSAIDs inhibit PGE2, PGI2 synthesis, thus

resulting in decreasing renal blood flow and therefore retention of Na
and water, edema and interstitial nephritis can occur with all NSAIDs
except aspirin.
Therapeutic Uses:

1. As Antipyretics, analgesics: (600 mg/day), widely used in the
management of gout (but not at low doses) rheumatic fever and
rheumatic arthritis, but it does not relief visceral pain as in pneumonia or
liver pain.
2. Cardiovascular indications: aspirin is employed for prophylaxis of MI

and unstable angina at the dose of 160 mg every other day, it facilitates
closure of patent ducts arteriosus (PDA) because PGE1 and PGE2 are
involved in opening of the DA.
3. Colon cancer: it is proposed that long term therapy of aspirin,

decreases the incidence of colon cancer.
Diflunisal: is a derivative of acetylsalicylic acid, it is not metabolized into

salicylate, consequently aspirin induced salicylism does not occur.
Mild salicylism is characterized by nausea, vomiting, hyperventilation,
headache, mental confusion, dizziness and tinnitus: ringing in the ears, whereas
severe form is manifested by restlessness, delirium, hallucinations, convulsions,
coma and death due to respiratory failure. Diflusinal is 3 to 4 times more
potent than aspirin, as an analgesic and an anti-inflammatory but has no
antipyretic affect, because it has no ability to enter the CNS.
Adverse Effects: the most common side effects of aspirin are:

1. GIT problems: epigastric distress, nausea, vomiting and microscopic GI
bleeding, aspirin should be taken with food and large volume of fluid to
diminish GI disturbances.
2. Prolonged bleeding time: due to irreversible inhibition of platelet

aggregation.
3. Hypersensitivity: represented by urticaria, angioneurotic edema and

bronchoconstriction.
4. Reye’s Syndrome: occurs in children, due to inadequate development

of the hepatic CYP system, clinically is characterized by fulminating
hepatits and cerebral edema termed as (hepatoencephalopathy), children
should be given acetaminophen rather than aspirin.
6. Respiratory depression: may induce asthma, throughout shifting

arachidonic acid metabolism toward lipooxygenase pathway, with the

formation of leukotrines, which play a central role in the genesis of
asthma.
II. Propionic Acid Derivatives: ibuprofen, (the prototype) fenprofen,

naproxen and ketoprofen.
In contrast to aspirin, they exert more anti-inflammatory actions than

aspirin; they are nonselective reversible blockers of prostaglandins.
In comparison to indomethacin: ibuprofen causes less fluid retention.
Clinical Uses: widely used in the treatment of chronic inflammatory

diseases (CID) such as rheumatoid arthritis and osteoarthritis, it is
effective in closing PDA in preterm infants with much the same efficacy
and safety as indomethacin.
Note: the concomitant administration of ibuprofen and aspirin

antagonizes the irreversible platelet inhibition induced by aspirin, thus
treatment with ibuprofen in patients with increased cardiovascular risk
may limit the cardioprotective effects of aspirin. On the other hand
aspirin may decrease the total antiinflammatory effect of ibuprofen
concomitantly.
Adverse Effects: the most common side effects are GIT distress, ranging
from dyspepsia to bleeding, which are less intense than that of aspirin,
headache, pruritus, fluid retention and tinnitus, fenprofen is individually
toxic to the renal system and may precipitate interstitial nephritis.
III. Indoleasetic Acids: indomethasin (the prototype), sulindac and

etodolac.
Indomethacin is a potent nonselective reversible COX blocker and may

also inhabit PLA and PLC as well as decreasing T- cell, B-cell
proliferation
In contrast to aspirin, indomethasin is more potent than aspirin as an

anti-inflammatory agent, but inferior to it as an antipyretic.
Clinical Uses: it has been used to accelerate closure of PDA, widely

approved for the treatment of rheumatic diseases: gout, ankylosing

spondylitis which affects the cartilaginous joints of the spine and
surrounding tissues, postepisotomy pain, diabetes insipidus, an
ophthalmic preparation is effective for conjunctivitis and gingivitis to
reduce gingival inflammation by oral rinse.
Side Effects: the most common side effects are GIT disturbances (nausea,
vomiting, bleeding especially with the use of indomethacin which is
usually prescribed rectally), frontal headache (frequent), pancreatitis,
hypersensitivity reactions such as asthma and urticaria may develop.
IV. Oxicam Derivatives: piroxicam and meloxicam.
Clinical Uses: autoimmune conditions such as rheumatic arthritis,

ankylosing spondylitis, octeoarthritis and acute gout, side effects are
similar to other NSAIDs, meloxicam at low doses is a selective COX-2
inhibitor, but it is not selective as celecoxib.
V. Phenylbutazone: has a powerful anti-inflammatory action, but weak

analgesic and antipyretic effects, prescribed if other NSAIDs have failed,
but it is inferior to aspirin and indomethasin, the drug is poorly tolerated;
the most common adverse effects are G.I.T upset, agranulocytosis and
aplastic anemia, it is no longer approved for human use.
VI. Other Analgesics:
1. Diclofenac: is the most widely used drug, utilized for long-term

therapy in treating of rheumatoid arthritis, osteoarthritis, it is more
potent than indomethacin or naproxen, available for oral, ophthalmic,
parenteral and rectal therapy, its side effects are similar to other NSAIDs
especially hepato-renal toxicity, a preparation combining diclofeac and
misoprostol (PGE1 analog) decrease upper GIT ulceration but may result
in diarrhea.
2. Acetaminophen or Paracetamol: in contrast with narcotic analgesics, it

doesn't cause dependence or tolerance, acting by inhibition of PGs
synthesis in the CNS, this explains it’s antipyretic and analgesic
properties, it less affects COX in peripheral tissues (gastric) has no effect on
platelets and a weak anti-inflammatory effects.

Pharmacokinetics: acetaminophen is rapidly absorbed form the GI tract,
metabolized in the intestine and liver into the active metabolite
acetaminophen sulfate and toxic N-acetyl-p-benzoquinone which reacts
with glutathione to form nontoxic compound, excreted with its
metabolites mainly in the urine.
1. As analgesic and antipyretic: is an alternative substitute of aspirin in
patients with gastric or bleeding disorders, its potency is equivalent to
aspirin.
2. In children: is the drug of choice as antipyretic, aspirin is

contraindicated because of inadequate development of CYP system.
3. Gout: unlike aspirin acetaminophen does not antagonize the uricosuric

agent probenecid, and therefore there is no retention of uric acid.
Side Effects: with normal therapeutic doses, does not cause any
significant side effects, but with large doses hepatic necrosis (due to
depletion of glutathione) and renal necrosis may occur.
Pharmacology of COX-2 Selective Inhibitors (Coxibs): celecoxib (the

prototype), valdecoxib, rofecoxib and etoricoxib.
Mechanism of action: coxibs were developed in attempt to inhibit PGs

synthesis by the COX-2 isozyme induced at sites of inflammation without
affecting the actions of the constitutively active housekeeping COX-1,
coxibs exert the same analgesic, antipyretic and anti-inflammatory
effects of non selective NSAIDs.
Advantages: reduce GIT adverse effects associated with non-selective

COX inhibitors, they do not inhibit platelet aggregation which is
mediated by TXA2 produced by COX-1, (prolongation in bleeding time
doesn’t occur, while aspirin prolongs it), they produce more safe effect on
gastric mucosa, decreasing the incidence of ulceration and GIT
hemorrhage.
Disadvantages: in therapeutic doses inhibit COX-2 enzyme which is

required for normal functioning of kidneys and brain, may increase the
incidence of hypertension and edema and therefore, they are

contraindicated in renal failure and inflammatory processes in the
brain, as well as they do inhibit COX-2-mediated prostacyclin synthesis
in the vascular endothelium; as a result they don’t offer the
cardioprotective effects, compared to aspirin.
Celecoxib: is a highly selective reversible COX-2 inhibitor, it is effective

in the management of chronic inflammation, e.g. rheumatoid arthritis and
osteoarthritis, useful in desmenorrhea and acute gouty arthritis especially
in patients suffering from peptic ulcer or bleeding disorders.
Side Effects:
a. GIT effects: in despite of their selectivity on COX-2, GIT symptoms
including nausea, vomiting, diarrhea and dyspepsia may appear.
b. Nephrotoxicity (hypertension and edema): but less than with the use of
non selective NSAIDs, it is contraindicated in patients with hepatic,
severe heart disease, renal failure and in sensitive patients to
sulfonamides.
Clinical Pharmacology of NSAIDs: all NSAIDs, including aspirin are

about equally efficacious with a few exceptions:
a. Effectiveness: aspirin (even at high doses) is less effective than

indomethacin in treating ankylosing spondylitis.
b. Toxicity: all NSAIDs exert GIT distress; especially meclofenamate,

tolmetin (not used clinically due to its too short t ½) and indomethasin
exert greatest toxicity, whereas aspirin and ibuprofen are less toxic.
c. Non-acetylated salicylates: they produce more anti-inflammatory

action than acetylated salicylates, but less analgesic effect (sodium
salicylate, choline salicylate), less blocking of COX-1 than does aspirin, and
therefore preferred in patients with renal dysfunction, asthma, and
bleeding tendencies.
d. Diclofenac and sulindac: are the most hepatotoxic agents among other
NSAIDs, so they are contraindicated in patients with hepatic dysfunction.

B. OPIOIDS (NARCOTIC ANALGESICS)
Opioids: are natural or synthetic substances that produce morphine like

effects, extracted from the opium poppy.
Classification of Opioid Substances:

I. Strong Agonists: morphine, fentanyl, alfentanil and sufentanil.
II. Moderate Agonists: codeine and propoxyphene.
III. Mixed Agonist-Antagonists and Partial Agonists: buprenorphine,

nalbuphine and pentazocine
IV. Antagonists: naloxone and naltrexone.
Classification of Opioid Receptors:
1. Mu opioid receptors: they are implicated in supraspinal, spinal

analgesia, euphoria, sedation, decreased GIT motility, inhibition of
respiration and a modulation of hormone and neurotransmitters release.
2. Kappa (K) opioid receptors: are associated with spinal analgesia,

sedation, disphoria and pupil constriction.
3. Delta (δ) opioid receptors: they are involved in dysphoria,

hallucinations and pupil dilation.
Distribution of Opioid Receptors:

Opioid alkaloids (morphine) produce analgesia through actions at
receptors in the CNS that respond to certain endogenous opioid peptides,
the families have been described in details are the endorphins, enkephalines
and leucine-enkephalin, these receptors are located in the:
1. Brainstem: opioid receptors mediate respiration, cough, nausea and

vomiting and maintenance of BP.
2. Medial thalamus: mediates deep pain.
3. Spinal cord: receptors are involved in the receipt and integration of
incoming sensory information.
4. Hypothalamus: receptors here affect neuroendocrine secretions.

5. Limbic system: the greatest concentration of opiate receptors in the
limbic system is located in the amygdalem they are not involved in
analgesia but influence emotional behavior.
6. Periphery: opioids also bind to peripheral sensory nerve fibers and their
terminals, as in the CNS they block Ca dependent release of excitatory,
proinflammatory processes (Substance P) from these nerve endings.
7. Immune cells: the role of these receptors in nociception (response to
painful stimuli) has not been determined.
I. Pharmacology of Strong Agonists:

1. Morphine: is the prototype drug of this group contained in crude
opium, exerts a strong analgesic effect, showing a high affinity for Mu
receptors and varying affinities for kappa and delta receptors.
Pharmacokinetics:
Absorption and distribution: absorption of morphine from the GIT is slow,
the drug is usually given parenterally, rectal suppositories of morphine have
been used when oral and parenteral routes are undesirable.
The transdermal patch provides stable blood levels of drug and better pain
control while avoiding the need for repeated parenteral injections,
(fentanyl rather than morphine is indicated for the management of persistent
unremitting pain), morphine rapidly enters all body tissues, including
PBB, so it should be avoided during pregnancy and labor to produce
analgesia, a small amounts of morphine can cross the BBB, its
lipophilicity is less than fentanyl and heroin that readily penetrate into the
brain, and rapidly induce euphoria.
Metabolism and elimination: morphine is metabolized to morphine-6-

glucoronide which is a very potent analgesic; the duration of action is
about 4 to 6 hours, eliminated mainly by the urine and partially in the
bile.
Pharmacodynamics: morphine and other agonists, produce their effects

by binding to opioid receptors, (found in the CNS and involved in
transmission and modulation of pain ) via G-proteins, especially show a high
affinity for Mu receptors, leading to hyperpolarization, (inactivation of
Ca channels and activation of K channels), presynaptic inhibition of
transmitters release, glutamic acid (the principle excitatory amino acid
released from nociceptive nerve terminals), as well as substance P, Ach,
NE and 5HT.

Pharmacologic Actions:
a. Analgesia: relief of pain without the loss of consciousness, by inhibiting
pain pathway in the brain and the spinal cord, opioid analgesics are
unique in that they can reduce both aspects of the pain experience,
especially the affective aspects, in contrast NSAIDs have no significant
effect on the emotional aspects of pain.
b. Euphoria: produces a powerful well-being sense, caused by stimulation

of ventral tegmentum.
c. Respiration: causes respiratory depression by reduction of the sensitivity

of respiratory central receptors to carbon dioxide, the respiratory
depression is the most common cause of death in acute opioid poisoning.
d. Antitussive properties: codeine but not morphine depresses cough reflex,

which does not correlate with analgesia and respiratory depression,
because the receptors involved in antitussive action appear to be different
from those involved in analgesia.
e. Miosis: morphine causes activation of the parasympathetic NS, due to

stimulation of mu and kappa receptors leading to pupil constriction (pin
point pupil "PPP"). Miosis is a pharmacologic action to which little or no
tolerance develops.
f. Emesis: morphine directly stimulates chemoreceptors of the brainstem,

resulting in nausea and vomiting.
g. Gastrointestinal tract: morphine relives diarrhea, and dysentery, by

decreasing motility of the GIT smooth muscle, and hence producing
constipation.
h. Cardiovascular system: morphine has no major effects on the heart or BP,

except at large doses, when hypotension (is believed due to decreased CO
and release of histamine) and bradycardia can occur, except for meperidine
that blocks muscarinic receptors, resulting in tachycardia.
i. Histamine release: morphine induces release of histamine from mast

cells, causing urticaria, pruritus, sweating, vasodilation and
bronchoconstriction, so asthmatics should not receive the drug.

j. Hormonal actions: morphine inhibits the release of gonadotropin-
releasing hormone (GnRH), corticotrophin-releasing hormone (CRH) ►↓
LH, FSH, testosterone and cortisol, whereas the concentration of PRL (by
inhibiting dopamine), GH and ADH (urinary retention) is increased.
Clinical Uses:
1. Analgesia: severe acute pain of M.I, cancer, renal and hepatic colics (with
atropine) is reduced by morphine which accelerates the sedative and
hypnotic actions of flurazepam that has no analgesic properties.
2. Acute pulmonary edema: is fluid accumulation in the alveoli and

parenchyma of the lungs, it leads to impaired gas exchange and may
cause respiratory failure, it is caused either by failure of the left cardiac
ventricle to adequately remove blood from the pulmonary circulation
("cardiogenic pulmonary edema"), or an injury to the lung parenchyma or
vasculature of the lung ("noncardiogenic pulmonary edema"), clinically it is
characterized by dyspnea, tachypnea, dizziness, weakness, pulmonary
hypertension, hypoxia and infiltration of interstitial tissue of the lungs,
morphine reduces anxiety and dyspnea probably by perception of
shortness of breath and by reducing preload and afterload.
Furosemide (lasix) is a loop diuretic that frequently indicated in the
management of pulmonary edema.
3. Relieve of cough: suppression of cough is achieved at lower doses than

those required for analgesia, morphine is not used for this purpose,
codeine, noscapine, levopropoxyphene and dextromethorphan are more
antitussives than morphine.
4. Diarrhea: by decreasing the motility of GIT, any kind of diarrhea could

be controlled, except infectious diarrhea which is treated by antibiotics,
loperamide is the most commonly used antidiarrheal opioid.
5. Anesthesia: the opioids are usually used for premedication, prescribed

before anesthesia and as anesthetics at large doses.
6. Neuroleptoanestheis: is a combination of the narcotic analgesic

(fentanyl) and a neuroleptic agent (droperidol), usually used in severe
ischemic or cancer pain.

7. Shivering: although all opioid agonists have some propensity to reduce
shivering, meperidine is reported to have the most pronounced anti-
shivering effect due to blocking of alpha-2 adrenoceptors.
Adverse Effects: include the following:
a. General symptoms: respiratory depression, nausea, vomiting,

dysphoria, increased intracranial pressure (ICP), urine retention and
constipation.
b. Tolerance: develops from repeated uses, resulting in decreased efficacy

of opioids (tolerance to RD, analgesic, euphoric, antidiuretic, emetic,
hypotensive and sedative effects, but not to meiotic, convulsant and constipating
effects), tolerance generally doesn't become clinically manifest until after
2-3 weeks of frequent exposure to ordinary therapeutic doses, tolerance
develops most easily when large doses are given at short intervals and is
minimized by giving small amounts of drug with longer intervals,
tolerance may be associated with decreased sensitivity of morphine
receptors to opioids.
c. Physical dependence: occurs readily and very rapidly with morphine

and opioids, because of discontinuation of morphine resulting in
abstinence syndrome that is characterized by excitation, lacrimation,
sweating, piloerection, rhinorrhea, hyperthermia, mydrasis, yawing,
hostility and muscular aches, patients take opioid agonists to relief or to
prevent these symptoms. The time of onset, intensity and duration of
abstinence syndrome depend on the drug previously used and may be
related to its biologic half-life, with morphine or heroin, withdrawal sings
usually start within 6-10 hours after the last dose, peak effects seen at 36-48
hours, after which most of the signs and symptoms gradually subside. By
5 day most of the effects have disappeared, but some may persist for
month, in the case of meperidine signs disappear within 24 hours, with
methadone may last as long as 2 weeks.
d. Psychologic dependence (addiction): euphoria, sedation, indifference to

stimuli and sedation caused by the opoiods especially when injected IV,
tend to promote their compulsive use, these factors constitute the
primary reasons for their abuse, frequently addicts die from respiratory
depression or AIDS infection.

Contraindications:
a. Head injury: due to retention of carbon dioxide (hypercapnia), that
causes cerebral vasodilatation, which elevates CSF pressure.
b. During pregnancy: the fetus may become physically dependent in

uterus and manifest symptoms of withdrawal syndrome in the early
postpartum period.
c. Bronchial asthma: because morphine enhances the release of

histamine.
d. Hepatic and renal dysfunctions: lead to longer half-life, their

accumulation and toxicity.
e. Endocrine diseases: patients with Addison’s disease (hypocortisolism)

and hypothyroidism may have prolonged and exaggerated responses to
opioids.
2. Fentanyl and its analogs: Sufentanil is an analog of fentanyl, 5 to 7

times more potent than fentanyl, Alfentanil is less potent than fentanyl,
but acts more rapidly and has a markedly shorter duration of action
Pharmacokinetics: fentanyl is injected IV, intrathecally, epidurally,

available as transdermal patchs. Remifentanil is metabolized rapidly by
blood and tissue esterases and therefore it has a short t 1/2, fentanyl is
metabolized in the liver into inactive metabolites and eliminated in the
urine.
Actions: chemically is related to meperidine, more effective than

morphine, has a rapid onset and short duration (15 to 30 minutes).
Clinical Use: commonly used for anesthesia in combination with the

typical neuroleptic droperidol for analgesia in postoperative patients and
during labor.
Side Effects: the most common side effects associated with fentanyl are
hypoventilation and pupil constriction. The fentanyl patches are
contraindicated in acute and postoperative pain or pain that can be
ameliorated with other analgesics.

II. Pharmacology of Moderate Agonists:
1. Propoxyphene: is a derivative of methadone, it is well absorbed

following oral administration, metabolized in the liver, has a weak
analgesic effect, usually combined with aspirin or acetaminophen, the
most common side effects are nausea, vomiting, abdominal pain, and
constipation; in large doses it causes cardio-pulmonary intoxication,
depression, convulsions, hallucinations, and confusions.
2. Codeine: is an oral effective agent, less potent than morphine in analgesia,

but a very strong antitussive effect, produces less euphoria than morphine,
often combined with aspirin and acetaminophen, codeine could be
replaced by dextromethorphan, levopropoxyphene and noscapine.
III. Pharmacology of Mixed Agonist- Antagonists and Partial Agonists:
Definition: drugs that stimulate one type of opioid receptors, but block
another, their effects depend on previous exposure to opioids:
a. In individuals who have not received opioids show agonist activity and are
used to relieve pain.
b. In patients with opioid withdrawal dependence, produce blocking effects.
1. Pentazocine:
M.O: promotes an analgesic effect, binds to all opioid receptors, it is a
weak competitive antagonist at mu and δ receptors, but partially activates k
receptors, administered either orally or parenterally, (but not I/M because of
its irritant properties) increases mean aortic pressure and pulmonary
arterial pressure, produces less euphoria than morphine, despite its
antagonistic effect, pentazocine doesn't oppose the respiratory depression
of morphine, but it can precipitate a withdrawal syndrome in a morphine
abuser, the drug decreases renal blood flow, it could be combined with
acetaminophen, clinically used to relive moderate pain.
2. Buprenorphine: is an antagonist at δ and k receptors, but as partial agonist

at mu receptors, slowly dissociates from them, so has a long duration of
action, administered either sublingually or parenterally, clinically used in
opiate detoxification and maintenance as well as dependence, because it
has a less severe and shorter duration of withdrawal symptoms
compared to methadone, causes little sedation, RD and hypotension even
at high doses.

Adverse Effects: respiratory depression (can be treated by naloxone),
hypo or hypertension, nausea, vomiting and dizziness.
3. Nalbuphine: is an antagonist at mu receptors and strong agonist at K

receptors, usually given parentrally, differs from pentozocine and
buprenorphine in that it has minimal psychomimetic actions plus a
ceiling effect for respiratory depression, antagonized by naloxone.
Tramadol: is a centrally acting analgesic whose M.O is predominantly

based on blockade of serotonin reuptake, inhibition of norepinephrine
transporter function, it is partially antagonized by naloxone, so it is
believed that tramadol is a weak agonist at Mu receptors, clinically used to
relive moderate to moderately severe pain, produces less RD than
morphine, the major side effects are association with seizures, so it is
contraindicated in epilepsy, another serious risk is the development of
serotonin syndrome if selective serotonin reuptake inhibitors, MAO
inhibitors or antidepressants are co-administered.
IV. Pharmacology of Opioid Antagonists:

1. Naloxone: is a competitive antagonist at mu, k and δ receptors but
more affinity exerts on mu, this explains its rapid reverse effect on
respiratory depression (within 30 seconds) , clinically is used to reverse the
coma and respiratory depression associated with opioid overdose, but it
has minimal reversal analgesic effect, naloxone has a half life of 60-100
min, because of its relatively short duration of action, a depressed patient
who has been treated and recovered may lapse back into RD, produces
no pharmacologic effects in normal individuals.
2. Naltraxone: has actions similar to naloxone, but it is proposed because

of its longer it ½ (10 hours) a single oral dose of naltrexone blocks the
effect of injected heroin for up to 48 hours approved in combination with
-2 adrenomimetic) or buprenorphine, for
rapid narcotic detoxification, naltrexone facilitates abstinence from
nicotine (cigarette smoking) with reduced weight gain, the most common
side effect is hepatotoxicity.

Synthesis of Inflammatory
Mediators
Plasma Membrane NSAIDs
Anti-inflammatory steroids
Benoxaprofen
Glucocorticoids
Zileuton
NSAIDs Arachidonic acid
aspirin
Prostaglandin H2 synthase Lipoxygenase
Prostaglandins (PG) Leukotrienes (LT)
Thromboxane A2 synthase
Thromboxanes (TXA)
NSAIDs
Dazoxiben
IL-1 (inflammation)
IL-1R
Membrane phospholipids
Anti-inflammatory steroids
Glucocorticoids
Phospholipase A2
Arachidonic acid LTA4

NSAIDS (aspirin) Glutathione S-
transferase
Cyclooxygenase
LTB4 LTC4
PGH2 PGG2
synthase
LTD4
PG hydroperoxidase
LTE4
PGD2 synthase TXA2 synthase
PGD2 PGH2 TXA2
PGI2 synthase PGE2 synthase
PGF2
PGI2 (PC) synthase PGE2
PGF2a

Housekeeping
Unwanted side- Endothelial integrity
effects PGI2 Vascular patency
Gastric mucosal integrity
Constitutive COX1
PGE2 Bronchodilation
Renal function
TXA2 Platelet function
NSAIDs
PGE2
Inducible COX2 PGF2a Inflammation
Inflammatory
Proteases
Therapeutic anti-
inflammatory effects
COX-2 also in • Endothelium, brain, spinal cord

• Kidney (Macula densa), ovaries, uterus
ARACHIDONIC ACID
COX -1 _ _ COX -2
Platelet
TXA2 Endothelial
ASPIRIN
PGI2
Vasoconstriction Vasodilation
Platelet Aggregation
Anti-Platelet Aggregation

Mechanism of Action of Opioids
Primary
afferent
, d, k receptors cause
Presynaptic
terminal {  gCa++
 Transmitter release
 receptors cause
Postsynaptic
neuron {  gK+, IPSP
Spinal pain-
transmission
neuron
Basic and Clinical Pharmacology. 8th ed. 2011.

UNIT 4
LOCALLY ACTING DRUGS
Definition: are oily or fatty substances, used to act on their site of

application, they soften and protect the skin and mucus membrane.
Classification:
1. Emollients:
1. Fixed oils (vegetable oils): they are esters of unsaturated fatty acids e.g.
olive oil, cotton seed oil and almond oil.
2. Fats: e.g. they are esters of saturated fatty acids e.g. wool fat.
3. Waxes: are esters of fatty acid with alcohol, e.g. bees wax.
2. Astringents: drugs when applied locally over skin or mucous

membrane they cause precipitation of surface proteins, but do not destroy
cells, they just cause contraction and wrinkling of tissues, so astringents
provide protection of the underlying tissues.
Examples:
a. Vegetable astringents: e.g. tannic acid.
b. Salts of heavy metals: silver nitrate, ferric chloride, zinc oxide and lead
acetate.
Actions & Clinical Uses:

1. Protect the skin & mucous membrane from irritation.
2. Local hemostatic by precipitation of blood proteins at site of bleeding.
3. Local analgesic by precipitation of nerve receptor protein.
4. Local antiseptic by precipitation of surface protein of bacteria.
5. Precipitation of alkaloids as tannic acid used in strychnine poisoning.
6. Hardening the skin and prevent bed sores.
3. Demulcents or Mucoprotective Agents: are colloidal substances with

high molecular weight, with water form a mucilaginous solution that
protects the underlying tissue, demulcents applied internally to the GIT
in the form of drinks, to the throat as lozenges pastilles or gargles and to
the eye as drops.
Examples:
1. Arabic gum: is used as suspending or emulsifying agent.

2. Glycyrrhiza: locally they are demulcents while internally they hide the
bad taste of drugs.
3. Glycerin: demulcent on mucous membrane and emollient on skin.
4. Demulcents at home e.g. milk, starch and eggs.
Clinical Uses:
a. Protect skin & mucous membrane
b. Provide stable emulsion and suspension.
c. Increase viscosity of drugs and therefore delaying their rate of
absorption and excretion.
d. Mask bad taste of drugs.
4. Counter- Irritants or Rubefacients:

Definition: substances when applied locally to the intact skin can relive
deep pain in viscera or muscles, e.g. treatment of myositis.
M.O:
1. Block the pain from viscera supplied by segmental spinal nerve.
2. They produce redness of the skin by causing dilation of the capillaries
and an increase in blood circulation, consequently washing the
accumulated metabolites & toxins
Examples of irritants used as counter -irritation:

1) Physical: heat (bath – fomentation – diathermy – short wave therapy).
2) Chemical: Methyl salicylate, menthol (are frequently used in joints and
muscles pains) and tincture iodine.
5. Obtundants: drugs which minimize or diminish sensation of dentin

and so allowing painless excavation, they act by:
a. Paralyzing nerve fiber, e.g. oil of clove, but it produces mild initial
stimulation.
b. Precipitation of cellular protein or nerve fibers e.g. astringents, alcohol
and silver nitrate.
An Ideal Obtundant Should:

a. Act without initial pain.
b. Not stain the teeth.
c. Penetrate quickly through the dentin but not too deep, to avoid pulp
inflammation.

Examples:
1. Phenol and cresote.
2. Oil of clove: causes initial stimulation followed by paralysis of nerve.
3. Alcohol 70-75%: is astringent and antiseptic, cavity should be dry if
moist it will dilute it.
4. Zinc chloride (astringent): neither penetrates deep nor stains the teeth as
well as is not toxic to the pulp.
5. Silver nitrate: is a very powerful astringent, only used on cavity not on
mucus membrane, it stains teeth in black.
6. Parafomaldehyde: it liberates formalin that is obtundant, it doesn’t stain
the teeth.
7. Solution of Na ethylate: decomposes in tissues into NaOH + alcohol, has
no initial stimulation, its onset of action is rapid and penetrates deep and
does not cause staining of teeth.
6. Mummifying Agents: substances that produce aseptic dryness and

hardness of pulp tissue and root canal, they are applied when pulp or
contents of root cannot be removed (act as astringents and antiseptics) and
to stop the bleeding and spread of infection to the root canals.
Examples: tannic acid, formaldehyde 10%, parafolmaldehyde, cresol,

cresote, idoform, phenol, and silver nitrate that stain teeth in black thus
not used in frontal teeth.
All mummifying agents: are obtundants but not all obtundants are
mummifying agents.
7. Bleaching Agents: agents that are used in smoking e.g. H2O2 and Na
peroxide they liberate nascent oxygen.
8. Keratolytic Agents:
Definition: drugs that dissolve the horny layer of the skin such as corns
and warts e.g. salicylic acid as Whitefield's ointment (6% benzonic acid
and 3% salicylic acid). Clinically used:
a. To Removal of warts and corns.
b. For treatment of some cases of seborrheic dermatitis.
c. For management of fungal infection of the skin.

9. Local Antiseptics and Disinfectants:
Disinfectant: is a substance used to kill microorganisms in an inanimate

environment.
Antiseptic: is an agent used to inhibit bacterial growth of
microorganisms.
Sterilization: procedures that kill microorganisms on instruments and
dressings including dry heat and exposure to ethylene oxide.
I. Protoplasmic Poisons:
A. Silver salts:
a. Silver nitrat:e as a local antiseptic and astringent for ulcers.
b. Silver proteinate: it produces its antiseptic action through liberation of
silver ion, it acts as demulcent used as eye drops 10%, it may cause scleral
black pigmentation if used for long time.
B. Halogens:
a. Iodine tincture iodine: applied on mucus membrane and for cleaning the
skin before surgery, the most common side effect is ulcer formation if it is
applied in larger doses or for long time.
b. Chlorine: chlorinated lime is used to disinfect water; it is also a
bleaching agent.
C. Phenolic Derivatives:
a. Phenol: it is a very irritant substance; ulcer formation is a frequent side
effect.
b. Cresol: used in 1% to disinfect hands and 5 % for instruments.
c. Alcohol 70%: as an astringent and antiseptic.
II. Oxidizing Agents:

a. Hydrogen peroxide (H2O2): liberates nascent oxygen which is an
oxidizing agent, used to clean wounds, NOT USED IN JAW FRACTURE
because it leads to infection dissemination.
b. K permanganate: as antiseptic and disinfectant, it liberates oxygen, used
as disinfectant in vegetables and for gastric lavage in alkaloid (morphine)
poisoning.
III. Antiseptic Dyes:

a. Gentian violet: 1% used in gingivitis.

b. Methelene blue: as urinary antiseptic and for detoxification of
methemoglobinemia.
c. Acrofluvin C: 1% for skin before operation.
IV. Cationic Detergents: They accumulate at bacterial cell membrane,

causing a decrease in surface tension and escape of enzymes & proteins,
leading to bactericidal action. Cetrimide is used in burns, wound,
preoperative cleaning of skin and for storage of sterile surgical
instruments.
V. A Mouthwash or Mouth rinse: is a chemotherapeutic agent used to

enhance oral hygiene, some manufacturers of mouthwash claim that
antiseptic and anti-plaque mouth rinse kill the bacterial plaque causing
cavities, gingivitis, and bad breath.
Ingredients: chlorohexidine gluconate, benzoic acid and hexidine.
Indications:
a. Reduce oral bacteria.
b. Remove food particles.
c. Reduce bad breath.
d. Provide a pleasant taste.

UNIT 5
BLOOD PHARMACOLOGY
Hemostasis: is regulated dynamic process of maintaining fluidity of

the blood, repairing vascular injury, and limiting blood loss while
avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital
organs.
Blood coagulation: is the conversion of fluid blood to a solid gel (clot),

namely the conversion of soluble fibrinogen into insoluble fibrin.
Clotting factors: present in the plasma as inactive precursors, they are
activated by proteolysis, the addition of the suffix (a) designs their
activation, activation of one factor catalyzes the activation of next factor
and so on, generally there are 13 clotting factors:
Factor I: Fibrinogen.
Factor II: Prothrombin.
Factor III: Tissue thromboplastin or tissue factor.
Factor IV: Calcium.
Factor V: Proaccelerin or labile factor.
Factor VI: Accelerin (non in use).
Factor VII: Stable factor.
Factor VIII: Antihemophilic factor with von-Willebrand factor.
Factor IX: Christmas factor.
Factor X: Stuart-Prower factor.
Factor XI: Plasma thromboplastin.
Factor XII: Hageman factor.
Factor XIII: Fibrin-Stabilizing factor.
The process consists of 2 interrelated pathways, exactly they are not

separated:
1. Extrinsic System (In Vivo): following tissue damage, the process is initiated by
the activation of tissue thromboplastin (III) which is a cofactor of VII factor that
undergoes proteolysis and becomes VIIa, the formed complex (IIIa+VIIa),
activates factors IX and X in the presence of Ca and phospholipid (PL) which is
released from activated platelets, coagulation is sustained by further generation
of factor X via the complex IXa, VIIIa, PL and IVa, because complex (IIIa+VIIa ) is

rapidly inactivated by tissue factor pathway inhibitor and antithrombin III, the
outcome is activated X (Xa).
2. Intrinsic System (In Vitro, contact with glass): it commences when the XIIa
adheres to a negatively charged surface, it catalyses the XI to become XIa that
converts IX into IXa which is in the presence of factors VIIIa, PL and IVa activates
the X (Xa), at this point the 2 pathways converge.
3. Formation of Thrombin and Fibrin: the Xa in the presence of Va, PL and Ca

catalyzes the conversion of prothrombin into IIa which cleaves fibrinogen into
insoluble fibrin (Ia), in the presence of Ca, XIII convents into XIIIa that stabilizes
fibrin, thrombin also promotes aggregation of thrombocytes, cell proliferation
and contraction of smooth muscle, on the other hand it exerts anticoagulant effect
by activating the protein C pathway.
Regulation of Coagulation and Fibrinolysis: There are 2 systems that antagonize

coagulation:
a. Fibrin Inhibition: represented by α1-antiprotease, α2-macroglobulin, α2-

antiplasmin and antithrombin in addition to proteins C and S that are activated via
thrombomoduline, these proteins inactivate factors II, IX, X, XI and XII.
b. Fibrinolysis: is accomplished by the conversion of plasminogen (inactive

protein) into plasmin (active enzyme) which lysis fibrin, and thus preventing
thrombosis.
Types of Thrombi:
a. White Thrombus: platelet rich thrombi forms in the arteries in which flow and
rate are high. Occlusive arterial thrombi cause serious disease by producing
ischemia of lower extremists or vital organs and can result in limb amputation or
organ failure.
b. Red Thrombus: tends to be more fibrin rich, contains large numbers of RBCs,
forms in veins, can cause severe swelling and pain of the affected extremity, but
the most feared consequence is PE this occurs when part or all of the clot breaks
off from its location in the deep venous system and travels as an embolus through
the right side of the heart into the pulmonary circulation. Sudden occlusion of a
large pulmonary artery can cause right cardiac failure and sudden death.

Note: If coagulation and fibrinolytic systems are pathologically activated, the
hemostatic system may careen out of control leading to generalized
intravascular clotting and bleeding, this process is called Disseminated
Intravascular Coagulation Syndrome (DICS).
Drugs Used In Coagulation Disorders: are divided into 2 groups:

I. Drugs Used In Thrombosis: thrombus is the formation of unwanted clot
within the blood vessels, e.g. acute myocardial infarction (AMI), deep
vein thrombosis (DVT), pulmonary embolism (PE) and acute ischemic
stroke.
II. Drugs Used In Bleeding Disorders: such as hemopillia and vitamin k

deficiency.
ANTICOAGULANTS
Definition: substances that prevent clotting, according to their actions on

thrombosis they could be divided into 2 categories:
I. Indirect Thrombin Inhibitors.

II. Direct Thrombin Inhibitors.
I. Pharmacology of Indirect Thrombin Inhibitors: they are so called

because their anticoagulant effect is exerted by interaction with
antithrombin III, the prototype drug of this group is heparin it is so called
because it was firstly extracted from the liver.
Chemistry of Heparin: heparin is stored in mast cells, in addition to

histamine; it is not a single substance but a mixture of sulfated
mucopolysaccharids, obtained from porcine intestine or bovine lung.
Mechanism of action: heparin acts indirectly by binding to antithrombin

III, causing a rapid anticoagulant effect, in vivo and vitro, effect occurs
within minutes after I.V injection, in the absence of heparin, antithrombin
III interacts very slowly with thrombin and factor Xa. Heparin molecules
bind antithrombin III inducing a conformational change that accelerates
its rate of action about 1000-fold. Heparin also serves as a catalytic
template for the interaction of antithrombin III and the activated
coagulation factors. Heparin serves as a true catalyst, allowing
antithrombin III to rapidly combine with and inhibit circulating

thrombin and factor Xa, antithrombin III inhibits ІІ, XII, XI, IX and X
clotting factors.
Forms of Heparin: there are 2 forms of heparin: high molecular weight

(HMW) and low molecular weight (LMW).
a. HMWHs: (5000-30 000 Daltons) by binding to antithrombin III forms a

complex which inhibits especially thrombin and Xa, its t ½ is short (1
hour) active in both vivo and vitro.
b. LMWHs: (less than 5000) by binding to antithrombin III forms a

complex that inhibits only Xa and has less effect on II, its t ½ is about 5 to
6 hours, its activity in vitro is less than HMW, due to its weak action on ІІ.
Agents of LMWHs Hs: enoxaprin, dalteparin and tinzaparin, in contrast

with HMWHs have equal efficacy, increased bioavailability (90% in
contrast to 20%) from the SC injection, its half life is longer and hence less
frequent dosing requirements, usually once or twice daily is sufficient,
the antcoagulant is predicable but for HMWHs is variable and finally less
frequent bleeding.
Pharmacokinetics of Heparin:
Absorption: heparin is poorly absorbed from the gut, because of its
charged and large molecules, so it must be given parenterally, either by
deep S/C (effects appear in 1-2 hours after injection) or I.V. I.M injection
is contraindicated, because of the formation of hematoma.
Distribution and metabolism: heparin rapidly binds to plasma proteins

inactivated in the liver and excreted in the urine; diseases of liver and
kidney prolong its t ½.
Placental barrier: heparin doesn’t cross placental barrier, so it could be

given safely in pregnancy.
Therapeutic Uses:
a. Deep vein thrombosis and pulmonary embolism: decreases the
incidence of recurrent thromboembolism.
b. Prophylaxis of postoperative venous thrombosis in patients
undergoing elective surgery (hip replacement) and those in the acute
phase of MI.

c. Pregnant women with thromboembolism or with prosthetic heart
valves.
d. The drug is also used in extracorporeal devices (dialysis machines) to
prevent thrombosis.
Heparin Toxicity:
1. Bleeding: is the major side effect of heparin, its dosage is monitored by
activated partial thromboblastin time (aPTT): defined as the time required
for plasma to clot in the presence of kaolin (activator of XII), cephalin (substitute
PL) and Ca, normally PTT is 25 to 35 seconds, heparin therapy should
range the 1.5-2.5, times the normal control of PTT, heparin is also
monitored by anti-Xa units (0.2-0.7 units).
2. Thrombocytopenia: occurs in 1-4% of individuals treated with UFH

early, 2 types of this abnormality have been identified:
a. Type I is common: involves a mild decrease in platelet number due to
nonimmunologic mechanisms, occurs within the first 5 days of treatment
and is not serious.
b. Type II, platelets are activated by an immunoglobulin G-mediated

reaction with a heparin-platelet factor 4 complex, causing platelet
aggregation and release of platelet contents, this can result in
thrombocytopenia and thrombosis-dangerous complications of heparin
therapy occurring between the fifth and fourteenth days of treatment- that
range from mild to life-threatening. Platelet counts can drop 50 percent or
more, and thromboembolic complications can develop.
Contraindications:
a. Bleeding disorders (hemophilia, thrombocytopenia).
b. Sever hypertensive patients.
c. Patients who have had surgery of the brain, spinal cord, and eye.
d. Endocarditis, tuberculosis and peptic ulcer.
Treatment of Heparin Toxicity:

Protamine Sulfate: (antidote of heparin) is a highly basic positively peptide
that combines with negatively charged heparin, forming a complex
devoid of anticoagulant activity.
For every 100 units of heparin remaining in the patient, administer 1mg;
The infusion should not exceed 50 mg in 10-minute period, because
protamin can exert anticoagulant effect.

II. Pharmacology of Direct Thrombin Inhibitors: hirudin and lepirudin
Mechanism of action: exert their anticoagulant effect by directly binding

to the active site of thrombin (inhibition) in contrast to indirect thrombin
inhibitors as LMWHs which act through binding (activation) to
antithrombin.
Clinical Use: hirudin is a specific irreversible thrombin inhibitor

administered parenterally for patients with heparin-induced
thrombocytopenia and monitored by a PTT, it has a short t ½ (1 hour),
contraindicated in patients with renal disease.
Pharmacology of Oral Anticoagulants: Warfarin (the prototype drug)

and dicumarol.
Pharmacokinetics: warfarin is well absorbed, following oral

administration has a high bioavailability, warfarin is 99 % bound to
plasma albumin, which prevents its diffusion into the CSF, urine and
breast milk, drugs that have a greater affinity for albumin binding site,
such as sulfonamides, can displace the anticoagulant and lead to a
transient elevated activity. It has a low volume of distribution, but a long
t ½ 36 hours, metabolized in the liver into inactive metabolites that are
excreted in the urine and stool. Warfarin does cross the PBB.
Mechanism of action: Normally vitamin K is involved in the synthesis of

active prothrombin and other clotting factors (VII, IX and X), this appears
in conversion of glutamic acid to γ-carboxyglutamic acid in the presence
of O2, CO2 and active form of vitamin K (KH2) (hydroquinone) which
requires reactivation, that occurs by oxidation of vitamin K epoxide (KO)
into its active form via vitamin K reductase enzyme which is inhibited by
warfarin, the result is inactive biologically (non-coagulatory) proteins, in
addition to this action warfarin activates physiologic anticoagulants
especially C and S proteins.
Sources of Vitamin K: vitmain K is derived from vitamin K1

(phytonadione, found in plants) and K2 (menaquinone which is
synthesized by bacteria in the GIT).
Properties of Warfarin:

1. It is active only in Vivo.
2. Onset of anticoagulant effect is only after 8 to 12 hours; maintenance
dose is achieved in 24 hours, even if it is given I.V.
3. The anticoagulant effect persists for a few days, after the drug has been
stopped.
Clinical Indications: oral anticoagulants are used for the treatment of

chronic forms of thrombosis rather than acute which is treated by
heparin, it is also utilized for the prophylaxis of thrombosis.
Monitoring of Warfarin therapy: International Normalized Ratio (INR)

is used, which is the ratio of patient's PT to PT of plasma obtained from
healthy subject on no medication, INR should be at the average 2,5-3,5
on warfarin therapy and for normal range for a healthy person is 0.9–1.3.
Patients with some types of artificial heart valves or other medical
conditions increasing thrombotic risk have a recommended range of 2,5-
3,5.
Note: Prothrombin time (PT): is the time required for plasma to clot in
the presence of exogenous thromboplastin, the normal PT is 11-15
seconds.
Note: A high INR level such as INR=5 indicates that there is a high chance of
bleeding, whereas if the INR=0.5 then there is a high chance of having a clot.
Adverse Effects:
a. Bleeding disorder: is the most common side effect, especially
hemorrhage, of the bowel or the brain, which is reversed by
administration of vitamin K1 and fresh plasma. However, reversal
following administration of vitamin K takes approximately 24 hours.
b. Fetus toxicity: in addition to bleeding there is a high risk of abnormal
bone formation, because warfarin prevents the formation of γ-
carboxyglutamic acid, which found in the bone, so it should be avoided
in pregnancy.
c. Hepatitis and necrosis of soft tissues are rare symptoms.
Clinical Pharmacology of Anticoagulants: heparin (usually LMWHs) is

used acutely, for short-term therapy, (5 to 7 days) whereas warfarin is
employed for prolonged therapy, (3 to 6 months).

Platelet AGGREGATION INHIBITORS
Platelet aggregation inhibitors decrease the formation or the action of

chemical signals that promote platelet aggregation. The last step in this
response to vascular trauma depends on a family of membrane GP
receptors that-after activation-can bind adhesive proteins, such as
fibrinogen, von Willebrand factor, and fibronectin. The most important of
these is the GP IIb/IIIa receptor that ultimately regulates platelet
interaction and thrombus formation. Thus, platelet activation agents,
such as TXA2, ADP, thrombin, serotonin, and collagen, all promote the
conformational change necessary for the GP IIb/IIIa receptor to bind
ligands, particularly fibrinogen. Fibrinogen simultaneously binds to GP
IIb/IIIa receptors on two separate platelets, resulting in platelet cross-
linking and aggregation.
The platelet aggregation inhibitors inhibit COX-1 or block GP IIb/IIIa or
ADP receptors, thereby interfering in the signals that promote platelet
aggregation. Since these agents have different mechanisms of actions,
synergistic or additive effects may be achieved when agents from
different classes are combined.
Clinical Uses: These agents are beneficial in the prevention and treatment
of occlusive cerebrovascular, PVD and cardiovascular diseases, in the
maintenance of vascular grafts and arterial patency, and as adjuncts to
thrombin inhibitors or thrombolytic therapy in myocardial infarction.
Mechanism of action:
A. Aspirin: is the only irreversible COX inhibitor that prevents TXA2
synthesis, the inhibitory effect is rapid, apparently occurring in the portal
circulation. Aspirin is frequently used in combination with other drugs
having anticlotting properties for example, heparin or clopidogrel. NSAIDs,
such as ibuprofen, inhibit COX-1 by transiently competing at the catalytic
site. Ibuprofen, if taken concomitantly with, or 2 hours prior to aspirin, can
antagonize the platelet inhibition by aspirin. Therefore, aspirin should be
taken at least 30 minutes before ibuprofen or at least 8 hours after
ibuprofen.
B. Ticlopidine and clopidogrel: these drugs irreversibly inhibit the binding of

ADP to its receptors on platelets and, thus, inhibit the activation of the GP
IIb/IIIa receptors required for platelets to bind to fibrinogen and to each
other.
C. Abciximab: is a monoclonal antibody, that binds to GP IIb/IIIa
receptors, the antibody blocks the binding of fibrinogen and von
Willebrand factor; consequently, aggregation does not occur, another
member of this group is eptifibatide.
E. Dipyridamole: a coronary vasodilator is employed prophylactically for

angina pectoris. It is usually given in combination with aspirin or warfarin;
it is ineffective when used alone. Dipyridamole increases intracellular
levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase,
resulting in decreased thromboxane A2 synthesis. It may potentiate the
effect of prostacyclin to antagonize platelet stickiness and, therefore,
decrease platelet adhesion to thrombogenic surfaces; dipyridamole is
effective for inhibiting embolization from prosthetic heart valves.
HEMOSTATIC DRUGS
1. Vitamin K: is a fat-soluble vitamin, which requires bile salts for

absorption form the gut, there are 2 natural forms of vitamin K: K1
(phytonadione), found in plants (leafy green vegetables) and K2
(menaquinone) found in human tissues that is synthesized by microflora
of the intestine.
Pharmacokinetics: available in tablets (5mg) and ampules (50 mg); the

onset of action is delayed for 6 hrs and accomplished by 24 hrs.
1. Warfarin toxicity: infusion should be done slowly, because it can cause
dyspnea, chest and back pain leading even to death.
2. Vitamin K deficiency: as supplemental therapy either due to disorders of

liver-intestine diseases, or in hospitalized patients in ICU because of poor
diet, parenteral nutrition, recent surgery, multiple antibiotic therapy and
uremia.
3. Vitamin K is currently administered to all newborns to prevent hemorrhage

disease of vitamin K deficiency, which is especially common in
premature infants
Note: K3 (Menadione) is a water–soluble salt, and should never used

clinically, because it lacks coagulatory property.

2. Plasma Fractions:
a. Plasma factors: freeze concentrates of plasma containing prothrombin,
factors IX and X and VII are commonly available for treating deficiencies
of these factors e.g. hemophilia B is treated by IX factor.
b. Desmopressin Acetate: increases activity of VIII factor and used to

treat hemophilia A (deficiency of VIII factor or von-Willebrand disease.
Generally the VIII factor is linked to a von-Willebrand factor (vWF)
which represents 99% of a complex, when endothelial cells are stripped
away by trauma, subendothelial vWF becomes exposed and binds to
platelets through the receptors GP IIb/IIIa, facilitating adhesion of
platelets to damaged area, it serves as a carrier for VIII factor, thus vWF is
crucial to the normal process of platelet adhesion.
von-Willebrand disease is a disorder characterized by spontaneous
bleeding from mucous membrane, excessive bleeding from wounds,
menorrhagia and a prolonged bleeding time (normally 2-7 minutes) in
the presence of normal count of thrombocytes, (140,000-450, 000) because
vWF stabilizes factor VIII by binding to it, deficiency of vWF is associated
with a secondary decrease in VIII. Desmopressin acetate can be used in
preparation for minor surgery such as tooth extraction without any requirement
for infusion of clotting factors if the patient has a documented adequate response.
c. Cryoprecipitate: plasma protein fraction obtained by whole blood;

used to treat deficiencies of fibrinogen such as that occurs in DICS and
liver disease, VIII deficiency and von-Willbrand disease if desmoprosin is
not indicated.
3. Pharmacology of Fibrinolytic Inhibitors: Aminocaproic acid and its

analog tranexamic acid.
Mechanism of action: inhibit competitively fibrinolysis (conversion of

plasminogen into plasmin or fibrinolysin) thus preventing lysis of fibrin.
Pharmacokinetics: the drugs are rapidly absorbed orally, and cleared

from the body via the kidneys, administered IV as loading dose of 5 g,
over 30 minutes to avoid hypotension.
Clinical Uses: they are used as adjunctive therapy in hempophilia,

bleeding form fibrinolytics, (streptokinase, urokinase and alteplase),
prophylaxis for rebleeding from intracranial aneurysms, post GIT
bleeding, hemorrhage of the urinary bladder, secondary to radiation- and
drug-induced cystitis and postprostatoectomy.
Adverse Effects: intravascular thrombosis, hypotension, diarrhea,

myopathy nasal stuffiness and abdominal discomfort.
Contraindications: DICS and genitourinary bleeding from the upper tract

because of high incidence of excessive clotting.

Vitamin K
VII
Vitamin K Utilization Synthesis of
Reduced IX Dysfunctional
Coagulation
X Factors
II
Warfarin

DICS
SYSTEMIC
ACTIVATION OF
 An acquired COAGULATION
syndrome
characterized by
systemic Intravascul Depletion of
ar platelets and
intravascular deposition coagulation
coagulation of fibrin factors
 Coagulation is
always the initial Thrombosis
of small and Bleeding
event midsize
vessels
Organ failure
DEATH

UNIT 6
AUTONOMIC PHARMACOLOGY
Introduction To The Nervous System: The autonomic nervous system

(ANS) beside the endocrine system, maintains coordination, control, and
communication of several body functions, endocrine system acts by
sending signals to target organs via chemical substances that interact in
low concentrations with their receptors, they are called hormones,
whereas the N.C acts by sending signals with the help of electrical
impulses of neurotransmitters.
Anatomical Division of The Nervous System (NS):

1) The Central Nervous System: (CNS) includes the brain and the spinal
cord.
2. The Peripheral Nervous System: (PNS) which includes all nerves that
are located outside the CNS, it means, any nerve that enters or leaves the
CNS.
The Neurons of The ANS:
1. Afferent Neurons (fibers): whose neurons carry information to the CNS,

they are important in reflex regulation, e.g. decreased blood pressure is
detected by carotid sinus and aortic arch that act in attempt to stimulate
efferent neurons.
2. Efferent Neurons: whose neurons carry signals from the CNS,

consisting of preganglionic neuron (bodies of I neuron are located within
the CNS), which arise either from the brain or the spinal cord and
postganglionic neuron, whose cell bodies are located in the ganglia,
(situated outside the CNS) that are an aggregation of cell bodies of
neurons, these ganglia function as relay stations between a preganglionic
neuron and a second nerve cell. The postganglionic neuron terminates on
the effector organs, viscera, cardiac muscle and exocrine glands.
Functional Classification of The PNS:
1. Somatic N.S: is responsible for regulation of voluntary functions e.g.

skeletal muscle contraction, respiration and posture.

2. Autonomic N.S: this portion regulates involuntary functions, without
the conscious participation of the mind; it is composed of efferent
neurons that innervate smooth muscle of the viscera, cardiac muscle,
vasculature, and the exocrine glands, thereby controlling digestion,
cardiac output, blood flow, and glandular secretions.
Divisions of The ANS :

1.The sympathetic (thoracolumbar) division: The sympathetic division
consists of short pregangloinic fibers originating from thoracic and lumbar
regions of the spinal cord and synapse (most of them) in 2 paravertebral
chains, that lie in either side of the spinal cord, the remaining
sympathetic preganglionic fibers terminate in prevertebral ganglia which
lie in front of the vertebrae, (abdominal cavity, usually on the ventral
surface of the aorta) axons of postganglionic fibers are long and run from
these ganglia to visceral organs.
NOTE: The adrenal fibers from medulla serve as postganglionic

sympathetic ganglia and receive preganglionc fibers from the
sympathetic NS, lacking axons, the adrenals respond by releasing
hormones (mainly adrenaline and less amount of noradrenaline).
2. The parasympathetic (craniosacral) division: its preganglionic fibers

(first neuron) are long arising from the:
- IIICN that carries impulses to the eye.
- VII-IXCNs are involved in innervations of salivary glands and
nasopharynx.
- XCN that carries impulses to thoracic and abdominal viscera.
- SIII-SIV of the spinal cord.
All above mentioned preganglionic fibers synapse in ganglia, from which
postganglionic fibers (short) arise (second neuron), and terminate either
near the effectors or within them.
3. The Enteric Nervous system (ENC): is a specialized collection of the NS

that is located within the wall of the G.I.T (from the esophagus to the
distal colon) consisting of myenteric plexus (located between the circular
and longitudinal muscular layers) and submucosal plexus, receiving
preganglionic fibers from parasympathetic division as well as postganglionic
sympathetic axons, so here the fibers of both sympathetic and
parasympathetic of NS, are interconnected and also sensory input from
the wall of the gut.
Functions of The ENS: it is responsible for controlling the secretion and
motility (peristalsis) of the GIT, by releasing several mediators, including:
1. Excitatory: stimulate peristalsis, e.g. calcitonin gene related peptide
(CGRP) enhances release of mediators e.g. acetylcholine, serotonin, and
substance P.
2. Inhibitory: inhibit peristalsis, e.g. noradrenaline, vasoactive intestinal

peptide, nitric oxide (NO), motilin, ATP and dopamine.
Neurotransmission In The ANS:

There are over 50 chemical substances that act as neurotransmitters, but
only 6 compounds are most commonly involved in the therapeutic
actions of drugs, (norepinephrine, acetylcholine, dopamine, serotonin,
histamine, and GABA)
a. Cholinergic Fibers: they are so called because transmission is mediated

by acetylcholine; drugs affecting these fibers are called Cholinergic
Drugs.They act by releasing acetylcholine, which acts via nitric oxide
(NO) these include:
a. All preganglionic fibers of both autonomic (sympathetic and
parasympathetic N.S, and adrenal medulla) and somatic nervous system,
(neuromuscular junction) which has no ganglia, so all fibers leaving the
CNS are cholinergic.
b. Most parasympathetic fibers release acetylcholine.
c. Sympathetic fibers of sweat gland.
2. Adrenergic Fibers: in which transmission is mediated by

norepinephrine, except for renal vasculature, which is mediated by
dopaminergic transmission, agents that affect adrenergic fibers are
termed Adrenergic (Noradrenergic) Drugs.
Other Neurotransmitters are CGRP, cholecystokinin, enkephalin,

galanin, neuropeptide Y, ATP, GABA, NO, serotonin (5-HT), histamine,
substance P, VIP and others.
Note: All neurotransmitters and hormones are too hydrophilic to

penetrate the lipid bilayer of plasma membrane, so they should bind to
their specific receptors on the cell membrane to bring about their actions.

Functions of The ANS:
1. Most organs are innervated by both divisions of the ANS, which
antagonizes each other.
2. Organs receiving only sympathetic innervations are:

The adrenal medulla, kidney, blood vessels (skin, skeletal muscles and
abdominal) BP mainly via alpha (vasoconstriction) beta receptors
(vasodilation), pilomotor muscles, sweat glands and liver.
3. Organs receiving only parasympathetic innervations are:

Lacrimal glands, smooth muscles of the GIT and bronchioles.
Functions of The Sympathetic NS:

The effects are to increase heart rate, BP, metabolic processes, dilation of
pupils and bronchioles, fight or flight response in addition to stimulation of
adrenal glands (more release of adrenaline), it is not essential for life,
stimulation occurs during exercise and stress, it is called ergortropic
system that leads to energy expenditure.
Functions of The Parasympathetic NS:

It is responsible for essential body functions e.g. digestive processes and
elimination of wastes, it acts to antagonize or balance the sympathetic
actions and dominant in rest and digest situations, it is so called
trophotropic system, because its activation leads to growth.
Classification of Autonomic Receptors:-

1. Colinoceptors include the following: (M1, M2, M3, NM, NN), M means
muscarinic, while N refers to nicotinic receptors.
2. Adrenoreceptors: (α, 1, 2 β1, 2, 3) and dopamine receptors, including (D1, 2,

3, 4).
CHOLINERGIC DRUGS
I. Cholinergic Transmission: involves 6 steps:

1. Synthesis of acetylcholine: choline (derived from glycine) is
transported from the ECF compartment into cholinergic neurons by a
carrier that cotransports Na, this is inhibited by the drug hemicholinum,
choline acetyltransferase (CAT) catalyzes choline with acetyl Co A to
form acetylcholine.

2. Storage of acetylcholine: acetylcholine is transported actively from the
cytoplasm into pooling vesicles to protect it from degradation; this process
is blocked by the drug vesamicol.
3. Release of acetylcholine: occurs via exocytosis resulting from the

activation of Na channels, which is followed by increased the cytoplasmic
concentration of Ca, that evokes rupture of vesicles, and therefore
acetylcholine is released, this step is blocked by the drug botulinum toxin.
4. Binding to receptors: acetylcholine diffuses across the synaptic cleft

and binds to cholinoceptors, which are located on the postsynaptic
membrane; this step is blocked by the drug atropine.
5. Degradation or inactivation: acetylcholine is rapidly hydrolyzed by

acetylcholinesterases (in both pre-postsynaptic membranes) this step could
be blocked by physostigmine or organophosphate compounds and
butyrycholinesterases (found mainly in the heart and plasma) in the
synaptic cleft into choline and acetic acid or acetate.
6. Recycling of choline: choline is recaptured by a sodium co-transport

carrier back into the neuron, where it is acetylated and stored for next
depolarization.
Cholinoceptors: on the basis by which, the alkaloid acetylcholine (Ach)

acts there are 2 families:
1) Muscarinic Receptors (M): these receptors bind to acetylcholine and

muscarine, show a low affinity for nicotine, there are 3 main classes:
M1: (Neuronal): found in ganglia and gastric partial cells.
M2: (Cardiac): found in cardiac cells, smooth muscles and autonomic

inhibitory neurons, (decrease acetylcholine secretion).
M3: (Glandular): mainly present in exocrine glands, endothelium and

smooth muscles.
M4 and M5: are less prominent receptors and appear to play a greater role
in the CNS than in the PNS.

2) Nicotinic Receptors: (N) these receptors bind to both acetylcholine and
nicotine, but show a low affinity for muscarine, there are 2 types:
1. Muscle type: (NM): found in neuromuscular junction.
2. Neuronal type: (NN): found in neuronal ganglia.
II. Basic Pharmacology of Cholinimemetics Drugs:
Definition: substances that stimulate actions of the PSNS, they are classified
pharmadynimacally into 2 groups:
II-1. Direct Cholinimemetics: agents that bind directly to choliniceptors,

thus, activate and increase cholinoceptor's affinity for binding to
acetylcholine, chemically classified into:
a. Choline Esters: Acetylcholine, Methacholine, Bethanechol, Carbachol.

b. Cholinomimetic Alkaloids: Pylocarpine, Nicotine, Muscarine and
Lobeline.
II- 2. Indirect Cholinimemetics: agents that produce their actions

indirectly by inhibition of acetylcholinosterase, which is responsible for
inactivation of acetylcholine, and therefore increasing the concentration
of the endogenous Ach.
Pharmacokinetics: Choline esters are poorly absorbed and poorly

distributed into the CNS because they are hydrophilic, although all are
hydrolyzed in the GIT (less active by this route), they differ markedly,
Ach is very rapidly hydrolyzed typically 5-20 seconds, methacholine,
carbachol and bethanichol are more resistant to hydrolysis and have longer
duration of action. Cholinomemtic alkaloids are well absorbed from most
sites of administration, nicotine a liquid is sufficiently lipid soluble to be
absorbed across the skin, muscarine is less completely absorbed from the
GIT compared to alkaloids but is nerveless toxic when ingested,
acidification of urine accelerates clearance of cholinomimetics alkaloids.
II-1 Pharmacodynemics of Direct Cholinomimetics:
1. Activation of M1 and M3 occurs with the help of Gs-protein which in

turn activates PLC that results in hydrolysis of phosphatidylinositol-

biphosphate (PIP2) to yield DAG and IP3, leading to increased
intracellular concentration of Ca, which results in contraction or
secretion.
2. Activation of M2 stimulates Gi-protein that inhibits adenylyl cyclase

which results in decreased intracellular concentration of cAMP and
activation of K channels, leading to bradycardia and vasodilation.
3. Activation of nicotinic receptors occurs by binding of acetylcholine to

nicotinic receptors (NM or NN ), with subsequent activation of Na channels
and inactivation of K channels, that results in depolarization, (contraction
of skeletal muscles or neurotransmission respectively )
II- 2. Indirect Cholinimemetics or Anticholinosterases: drugs that

increase concentration of endogenous acetylcholine (Ach) within the
synaptic cleft, by inhibiting acetylcholine-metabolizing enzyme,
(acetylcolinosterase, which located in both pre-and postsynaptic
membranes) rather than by binding (stimulation) to receptors, classified
into:
II-2-1. Reversible: Physostigmine, Neostigmine, Pyridostigmine and
Edrophonium.
II-2-1. Irreversible (covalently bind to acetylcholinesterase,) including:

organophosphate compounds, (Isoflurophate and Echothiophate), Parathion,
Malathion, Malaoxon and Paraxon.
Note: all cholinomemtics stimulate both receptors except bethanichol and

pilocarpine that activate only muscarinic.
Clinical Pharmacology of Cholinomemetics:
Drugs with no clinical use: because Ach is metabolized rapidly, it has a

very short t half life; Carbachol has a high potency and long t ½, only
used as miotic agent.
1) The eye: for the treatment of glaucoma which is characterized by

increased intraocular pressure (IOP). Without treatment, increased IOP
results in damage to the retina and optic nerve and blindness, there are
two types of glaucoma:

a. The open-angle from: is a chronic condition and treatment is largely
pharmacologic.
b. The closed –angle form: is associated with a shallow anterior chamber, in
which a dilated iris can occlude the outflow drainage pathway at the
angle between the cornea and ciliary body, must be controlled on an
emergency basis with drugs or prevented by surgical removal part of iris
(iridectomy).
Five General Groups of Drugs Are Used:
1. Cholinomemetics (both) reduce IOP by contraction of ciliary body and

hence facilitating the outflow of aqueous humor and by decreasing its
secretion, Pilocarpine is the most widely used drug, other utilized
medicines are physostigmine, echothiophate and isoflurophate. For
chronic glaucoma these drugs have been largely replaced by topical beta blockers
and prostaglandin derivatives.
2. Beta blockers: Timolol, betaxolol and carteolol.
3. Prostaglandin F2a: Latanoprost and travoprost.
4. Diuretics: Acetozolamide, dorzolamide and brinzolamide.
5. Alpha agonists: Adrenaline.
Acute glaucoma: is treated by a combination of pilocarpine and

physostigmine.
2. Gastrointestinal diseases: in situations with depression of smooth

muscles without obstruction e.g. atony of the stomach and bowel and
congenital megacolon, and sometimes in patients with reflex esophagitis,
bethanicol is the most widely used drug among direct and indirect
cholinomimetics. Pilocarbine has long been used to increase salivary
secretion, but today Cevimeline is a new direct –acting muscarinc agonist
used for treatment of dry mouth associated with radiation damage of the
salivary glands.
3. Urinary tract: bethanichol (has little or no effect on nicotinic receptors)

and neostigmine, are the drugs of choice in patients with urinary
retention, and atony of the bladder, without obstruction, because
perforation may occur due to increased pressure.
4. Neuromuscular junction: for myasthenia gravis is an autoimmune

disease, characterized by destruction and atrophy of cholinergic nicotinic

receptors and therefore decreasing their number especially on the
neuromuscular junction, clinically manifested by the following symptoms:
ptosis, diplopia, difficulty in speaking and swallowing and in severe form
paralysis of respiration, only anticholinosterases could be used but not
direct cholinomemetics, indirect cholinomemtics are used for both, as
diagnostic tool (edrophonium) and as treatment (neostigmine and
pyridostigmine).
5. Recovery after operation: to reverse neuromuscular blockade used for

surgical anesthesia, (neostigmine and edrophonium).
6. Antimuscarinic drug intoxication: neostigmine usually is used to

reverse the actions produced by atropine which blocks the muscarinic
cholinergic receptors.
Toxicity of Choinomimetics:
SLUDGEM: useful to remember some of the symptoms of increased
cholinergic stimulation through the mnemonic SLUDGEM:
Salivation, Lacrimation, Urination, Defecation, GIT upset Emesis and
Miosis or Muscle spasm.
Treatment of Toxicity: atropine is usually used in large doses to reverse

toxic effects produced by this group, and the use of pralidoxime
(cholinesterase regenerator) which has an ability to reactivate inhibited
acetylcholinesterase.
III. Basic Pharmacology of Cholinoceptor-Blocking Drugs,

Cholinoblockers or Cholinolytics
Definition: drugs that block effects produced by the parasympathetic NS;

by binding to cholinergic receptors.
Classification: - cholinolytics like agonists on the basis of their specific

affinities are divided into:
III-A. Antimuscarinic Cholinolytics: antagonize actions associated with

muscarinic cholinergic fibers.
III- B. Antinicotinic Cholinolytics: interfere with the actions exerted by

nicotinic cholinergic fibers, in their turn they are subdivided into:

B-1. Ganglion- Blocking Agents: substances that block all ganglia of the
ANS.
B-2. Neuromuscular Blockers: responsible for blocking effects of the

somatic NS (nicotinic neuromuscular junction) causing paralysis of
skeletal muscles.
III- A. Antimuscarinic Cholinoblockers: agents that selectively block

muscarinic receptors, and have no effect on nicotinic receptors.
Classification: chemically categorized into 2 groups:
A-1. Tertiary Alkaloids: the prototype is Atropine (hyoscyamine),

Scopolamine (hyoscine), Pirenzipine, Tropicamide and Benzotopine.
A-2. Quaternary Amines: Propantheline, Ipratropium, Oxytropium and

Glycopyrrolate.
Pharmacokinetics: atropine is found in the plant belladonna alkaloid;

tertiary alkaloids are well absorbed from the gut and conjunctival
membranes, rapidly distributed and because of their lipophilicity enter
the CNS. Scoplamine has greater CNS effects that most other
antimuscarincs. Elimination of atropine from the blood occurs in 2
phases, the t ½ of the rapid phase is 2 hours and that of the slow phase is
13 hours, but in the eye atropine has a longer duration of action which is over
72 hours.
Quaternary Compounds are poorly absorbed in contrast to tertiary,
because of their lipophobic and charged molecules, poorly enter the CNS,
so they have prominent peripheral effects.
Pharmacodynemics: atropine is a non-selective competitive reversible

antagonist of muscarnic receptors, by binding to cholinoceptors, it
prevents (reduces) interaction between Ach and cholinoceptors, acting by
decreasing concentration of IP3 and adenylyl cyclase.
Clinical Pharmacology (Clinical Applications) of Cholinolytics:

1. CNS Uses:
A. Parkinson disease: is neurologic disorder characterized by excessive
cholinergic transmission, and decreased dopaminergic transmission,

clinically is manifested by tremor, bradykinesia and paralysis, among
antichoinergics benzotropine is the drug of choice, but the combination
of an antimuscarinic agent with a dopamine precursor drug (Levodopa)
can sometimes provide more effective therapy than with a drug alone.
B. Motion sickness: scopolamine is the drug of choice for preventing

nausea and vomiting, resulting from vestibular dysfunction, it could be
given orally, parentrally and as transdermal patches that last for 48 to 72
hours.
2. Ophthalmologic uses:
Tropicamide usually is employed rather than atropine topically as eye
drops or ointments (to prevent the loss of atropine via nasolacrimal duct
into the nasopharynx) to produce mydriasis, and hence facilitating
ophthalmic examinations. The other important ocular effect of
antimuscarinics is to weaken contraction of ciliary muscle or cycloplegia
that results in loss of the ability to accommodate, the fully atropinized eye
cannot focus for near vision.
The second ophthalmologic use (Homatropine) is to prevent synechia
(adhesion) formation in uveitis and iritis.
3. Surgical producers: atropine and scopolamine, (amnesia is unwanted

effect here is desirable) are used for preoperative conditions and for
reducing laryngospasm during anesthesia, because halogenated
anesthetics cause excessive airways secretions.
4. Respiratory system: Ipratropium, Titotropium and Oxytropium are

synthetic analogs of atropine that are effective in asthmatic patients and
chronic obstructive pulmonary disease (COPD), used by inhalation to
reduce their systemic effects and to achieve a rapid and effective
therapeutic effect. Titotropium has a longer bronchodilator action than
ipratropium and can be given once daily because it slowly dissociates
from M3 receptors.
5. Cardiovascular disorders: moderate to high doses of atropine cause

tachycardia, however lower doses often result in initial bradycardia before
the effects of peripheral vagal block become manifest. Arterial blood
pressure is not affected, but at toxic doses atropine will dilate the
cutaneous vasculatures. Atropine may be used to block vagal discharge
(cardiac pain) in patients with myocardial infarction (MI).
6. G.I.T: antimuscarinic agents now are rarely used for peptic ulcer
treatment, except for Pirenzepine (selective M1 blocker) because Atropine
does not affect gastric secretion, but may be used as antidiarrheal agent,
Atropine is considered to be an antispasmodic agent used to relax smooth
muscles of the G.I.T and gallbladder (hepatic colic in addition to use of
narcotic analgesics).
7. Urinary disorders: Oxybutynin (selective M3 blocker) reduces

hypermotility of the urinary bladder and its spasm after urologic surgery,
involuntary urination and enuresis and renal colic without obstruction.
Darifenacin and Solifenacin are recently approved antagonists that have
greater selectivity for M3 than Oxybutonin. Antimuscarinic agents have been
used in urolithiasis to relive the painful ureteral muscle spasm caused by
passage of the stone; however their usefulness in this condition is
debatable.
8. Cholinergic (Organophosphate) Poisoning:
A. Atropine Sulfate: is used to reverse excessive effects produced by

cholinomimetics in large doses of 1-2 mg, I.V every 5-15 min until signs of
effects appear (mydraisis, dry mouth and tachycardia).
B. Pralidoxime: is a cholinesterase regenerator, it does not enter the CNS,

given IV 1-2 g over 15-30 minutes, in excessive doses, Pralidoxime can
induce neuromuscular weakness. Diacetylmonoxime on the other hand
crosses the BBB and in experimental animals can regenerate some of the
CNS cholinoserase effects.
Side Effects: Dry mouth, blurred vision (cycloplegia), tachycardia,

agitation, hot and flashed skin, body temperature, constipation, and
urinary retention. These effects are memorized in the adage dry as bone, blind
as a bat, red as beet, mad as a hatter.
Contraindications:
1. Glaucoma: IOP is more elevated because of mydriatic effect.
2. Prostatic hyperplasia: due to urine retention.
3. Peptic ulcer: it exacerbates symptoms of peptic ulcer.

III-B. Basic and Clinical Pharmacology of Antinicotinic Drugs:
Here we will discuss only ganglion-blockers, the other group of
antinicotinics will be covered in section of anesthesia.
Definition: agents that competitively block the actions of acetylcholine

and similar agonists at nicotinic receptors of both parasympathetic and
sympathetic ganglia, and adrenal glands, these agents are important and
used in pharmacologic and physiologic researches, because they block all
autonomic outflow.
Agents: Hexamethonium and Trimethaphan are used in the management

of hypertensive emergencies and dissecting aortic aneurysm in producing
hypotension, which can be of value in neurosurgery to reduce bleeding in
the operative filed and in the treatment of patients undergoing
electroconvulsive therapy.
Mecamylamine blocks central nicotinic receptors and has been used as
adjunctive therapy with the transdermal nicotine patch to reduce nicotine
craving in patients attempting to quit smoking.
Toxicity: Clinically they are limited because of their non-selective actions,

so they can cause severe systemic side effects such as orthostatic
hypotension (due to decreased both PVR and venous return, especially marked in
upright position), reflex moderate tachycardia, constipation, sedation, tremor
and mental abnormalities, especially with the use of Mecamylamine,
cycloplegia, urinary retention and impairment of erection and ejaculation.
ADRENERGIC DRUGS
I. Adrenergic Transmission: it is so called because their actions are

mediated by the neurotransmitters norepinephrine NE or (epinephrine
E), which are released from the terminal endings of nor-adrenergic
adrenoceptors; the process is composed of 5 steps:
1. Synthesis of norepinephrine: Phenylalanine is the starting substance,

which is converted into tyrosine under the influence of phenylalanine
hydroxylase, tyrosine is transported by a Na carrier into the adrenergic
neuron and hydroxylated into dihydroxyphenilalanine (DOPA), by
tyrosine hydroxlase, (this step is inhibited by metyrosine which inhibits
tyrosine hydroxylase) then DOPA is decarboxylated to form dopamine.

2. Storage of norepinephrine: dopamine is transported into pooling
vesicles, by an amine transport system, this step is inhibited by reserpine,
then dopamine may be remain as neurotransmitter or may be
hydroxylated into norepinephrine by dopamine β-hydroxylase.
3. Release of norepinephrine: when an action potential reaches nerve, an

increased intracellular concentration of free Ca evokes vesicles to rupture
releasing norepinephrine; this process is prevented by guanethidine and
bretylium, but activated by tyramine, ephedrine and amphetamine.
4. Binding to receptors: norepinephrine diffuses into the synaptic cleft,

and binds to adrenceptors, which are located on postsynaptic membrane,
using both cAMP and phosphatidylinositol 3, 5-bisphosphate (PIP2)
pathways, this step is inhibited by using adrenoblockers such as propranolol.
5. Removal of norepinephrine:
5-1: Catecholamines may be methylated by an enzyme catechol O-
methyltransferase (COMT) which is located on postsynaptic membrane,
with the formation of metanephrine, normetanephrine, vanillmandelic
acid (VMA) and homovanilic acid (HVA) that are excreted in the urine.
Selective COMT inhibitors such as Tolcapone and Entacapone prolong the
action of levodopa by diminishing its peripheral metabolism.
5-2: Catecholamines are removed by monoamine oxidase enzymes, MAO

found in mitochondria and plasma, there are 2 types of MAO enzymes:
MAO A metabolizes NE, 5HT and dopamine and MAO B that
metabolizes only dopamine. Selegiline is a selective irreversible inhibitor
of MAO B at normal doses, but at higher doses it blokes MAO A, used as
adjunctive therapy in Parkinsonism, Rasagiline is more potent than
Selegiline.
5-3: First reuptake: Catecholamines may be recaptured back into neuron;

this step could be inhibited by the antidepressants such as imipramine, cocaine
and lithium.
5-4: Second reuptake: Catecholamines may be transported into

postjunctional cell and smooth muscle via tissues that are located outside
neurons.

Adrenoceptor Classification: on the basis of their responses to adrenergic
agonists, (epinephrine, norepinephrine and the synthetic adrenomimitec
isoproterenol) there are 2 types of adrenoceptors:
1. α Receptors:: show a strong response to E and NE but a weak response

to isoproterenol. On the basis of their affinity for binding to adrenergic
agonists and antagonists they are subdivided into 2 types: α1 and α2.
2. β Receptors: show a strong response to isoproterenol, with less

sensitivity to E and NE. On the basis of their affinity for binding to
adrenergic agonists and antagonists they are subdivided into 3 types: β1
β2 and β3
1. Types of α Receptors:
1-A. α1 Receptors (Excitatory): have a high affinity to phenylephrine than

α2, located primarily on the postsynaptic membrane, act by stimulation
G- protein, which in turn causes hydrolysis of PIP2 with the formation of
(IP3 activates PKA) and (DAG activates PKC) that leads to increased
cytoplasmic concentration of Ca. Activation of these receptors results in
vasoconstriction, bronchospasm, contraction of uterus, decreases motility of GIT,
aggregation of thrombocytes and mydrasis.
1-B. α2 Receptors: (Inhibitory): have a high affinity to clonidine than α1

located primarily on the presynaptic membrane, act by inhibition of
adenylyl cyclase activity and then decreasing I/C concentration of
cAMP, the result is to decrease the sympathetic outflow or briefly
decreasing the release of NE, and therefore the hypotensive effect, as well
as a decrease in insulin secretion.
2. β Receptors: activation of these receptors occurs with the help of Gs

protein, which activates adenylyl cyclase, that causes increased I/C
concentration of cAMP, leading to increased contraction of the heart and
vasodilatation, on the basis of their affinity for binding to adrenergic
agonists or antagonists there are 3 subtypes: all act by increased
intracellular concentration of cAMP.
2-1. β1: are found mainly in the heart, activation causes positive ino-
dromo and chronotropic effects, enhances lipolysis and release of renin.

2-2. β2: stimulation of these receptors causes bronchodilation,
vasodilation, relaxation of uterus and tachycardia, but less than activation
of β1 (approximately 80% of cardiac adrenergic receptors are β1, the
reminder are dopamine and β2 receptors, the result is to increase release
of glucagon and activation of glycogenolysis, leading to hyperglycemia.
2-3. β3: activation of presynaptic receptors leads to release of

catecholamines, whereas stimulation of postsynaptic receptors results in
lipolysis.
II. Sympathomimetics or Adrenomimetics: agents that mimic or

stimulate the effects of the sympathetic N.S directly or indirectly,
chemically they could be divided into:
II-A. Catecholamines: chemically characterized by the presence of the

catechol group, with the short t ½.
Agents: Epinephrine, Norepinephrine, Isoproterenol and Dopamine: they

are characterized by the following properties:
a. High potency: show the highest potency in activating α and β

receptors.
b. Pharmacokinetics: they are ineffective orally; because they are rapidly

inactivated by COMT and MAO (located in neurons, GIT and in the
liver), they are polar and therefore poorly penetrate into the CNS.
Nevertheless most of these drugs have some clinical CNS effects such as tremor,
anxiety and headache
II-B. Non– Catecholamines: chemically they have no catechol group, so

they are not inactivated by COMT; consequently their half-lives are
longer than catecholamines, increased lipid solubility of many of them
permits greater access to the CNS.
Agents: Phenylephrine, Ephedrine, Tyramine Amphetamine and others.
Pharmacodynamics: Adrenomimetics have several actions in stimulating

sympathetic effects:

1. Direct action: drugs that bind and activate α and β receptors,
(epinephrine, isoproterenol, phenylephrine and norepinephrine), effects
are similar to those that produced by stimulated sympathetic NS and the
release of adrenaline from the suprarenal glands.
2. Indirect action: (amphetamine and tyramine) their actions are

dependent on their ability to enhance the actions of endogenous
catecholamines, indirect agents may have either of 2 different
mechanisms:
2-1: They may displace stored catecholamines from adrenergic nerve
endings, e.g. tyramine.
2-2: May decrease the clearance of released NE either by:
First: Inhibiting reuptake of catecholamines already released, e.g. the M.O
of cocaine and antidepressants.
Second: Preventing the enzymatic metabolism of NE, e.g. MAO and
COMT inhibitors.
3. Mixed-action agonists: ephedrine has not only the ability to stimulate

adrenoceptors, but and to release norepinephrine.
1. Direct Specific Sympathmimetics:
A. Epinephrine (E): is an agonist at both α and β adrenoceptors.
Actions:
Cardiovascular system: under physiologic conditions E functions largely
as hormone acting at distant cells after its release from the adrenals
E affects mainly the heart, causes positive inotropic, dromotropic and
chronotropic effects via activation of β1 and β2 adrenoceptors, thus
increasing CO, E constricts arterioles in the skin, mucus membrane and
viscera but dilates blood vessels of skeletal muscles (β2).
BP: systolic blood pressures (SBP) is increased, but diastolic blood
pressure (DBP) is decreased and hence the PVR is diminished.
Renal blood flow is decreased.
Respiratory system: is a powerful bronchodilator via activation of β2

receptors, physiologically antagonizing action of histamine that causes
bronchospasm.

Metabolism: E increases glycogenolysis in the liver via β2 and β3 effects,
accelerates catabolism of lipids into free fatty acids and glycerol and causes a
decrease in insulin release via α2 effect leading to hyperglycemia.
Pharmacokinetics: it has a rapid onset of action, but a brief duration of

action used IV, SC, by inhalation, and topically, it is never used orally or
IM, has a short t ½.
Therapeutic Applications:
1. Asthma: is very effective for acute asthma, and other conditions with
bronchospasm, but the use of selective β2 agonists is preferred, e.g.
terbutaline, salbutamol and pirbuterol.
2. Glaucoma: it reduces IOP (mydriasis) via α1 receptors

(vasoconstriction) of cilliary blood vessels, and then reducing the
production of aqueous humor.
3. Anaphylactic shock: is the drug of choice for the treatment of

anaphylactic shock, because it antagonizes histamine.
4. Anesthesia: it is usually used to increase the duration of action of local

anesthesia by producing vasoconstriction at the site of injection, delaying
absorption and metabolism of local anesthetic.
Adverse effects: anxiety, fear, tension, headache, severe hypertension,

(ischemic or hemorrhagic insult) arrhythmia, and pulmonary edema.
B. Norepinephrine (NE) or (levarterenol): since NE is a neurotransmitter,

it should stimulate all receptors but it has a potent effect on α1 and β1
(similar to E) and a minimum effect on β2 receptors.
Actions:
Cardiovascular system: BP: increases both SBP and DBP and therefore
increases PVR affecting both arteries and veins including kidneys via α1
effect. Compensatory baroreflex activation tends to overcome the direct
positive inotropic effect; (NE induces reflex bradycardia via activation of
baroreceptors, due to increased PVR, if atropine is given before NE
tachycardia is evident. NE elevates oxygen requirement of the myocardium.

Clinical Uses: it was used to treat vascular shock, because it increases
PVR, but dopamine is preferred, norepinephrine is never used in asthma.
C. Isoproterenol: is a direct acting synthetic catecholamine that mainly

stimulates β receptors, its actions on α receptors is insignificant, its
actions on the heart and alveoli are similar to E Clinically used for
stimulation of the heart in A-V blockade and cardiac arrest (parentrally),
it is rarely used in acute asthma. Isoproterenol can reverse adrenergic
blocker toxicity.
D. Dopamine (D): is the metabolic precursor of norepinephrine, occurs

naturally in the CNS (basal ganglia) and acts as neurotransmitter, as well
as in the adrenal medulla. D acts on D1 to D5, α and β receptors, it causes
positive ino-chronotropic effects (increasing BP), at very high doses
increases PVR, it does not enter the CNS, Dopamine is the drug of choice
for the management of vascular shock and is given by continuous
infusion, it does not constrict renal vessels, but increases renal blood flow,
thereby increasing glomerular filtration rate (GFR) and sodium exertion.
Notes:
1. Dopamine opposes actions of prolactin.
2. Its deficiency leads to Parkinsonism.
3. Its excessive activity results in schizophrenia.
E. Dobutmaine: was initially considered a relatively β1 selective agonist,

adrenomimetic, but recent studies reveal that dobutamine consists of 2
isomers: the (+) isomer is a potent β1 agonist and an α1 antagonist, and the
(-) isomer is α1 agonist which is capable of causing significant
vasoconstriction when given alone. Therapeutically is used primarily in
congestive heart failure (CHF), increases CO with a little change in HR; it
is superior to other sympathmimetics because it does not elevate oxygen
requirement of the myocardium.
F. Phenylephrine: is more selective for α1, than α2, it does not affect the
heart directly except for causing reflex bradycardia due to increased arterial
pressure (PVR), it is often used as nasal decongestant topically for
rhinitis, and to produce mydriasis for facilitating ophthalmic procedures
as well as to raise BP.

G. Methoxamine: is a α1 adrenergic agonist, used mainly to relive
paroxysmal supraventricular tachycardia, because of its indirect effect on
the vagus nerve, and to overcome hypotension during anesthesia induced
by the anesthetic halothane, methoxamine does not cause arrhythmia in
contrast to other adrenomimetics.
H. Clonidine, Methyldopa and Quanfacine: are α2 adrenomimetics chiefly

used in the treatment of essential hypertension to lower BP, by activation
of α2 adrenergic receptors, hence decreasing release of NE. Clonidine is
approved for the treatment of diarrhea in diabetics with autonomic
neuropathy, perhaps because of its activity to enhance salt and water
absorption from the intestine, in addition it reduces craving for narcotics
and alcohol withdrawal and may facilitate cessation of cigarette smoking.
Clonidine recently is recommended as a local anesthetic adjuvant for
spinal anesthesia.
I. Terbutaline, Albuterol and Metaproterenol:

They are selective β2 adrenomimetics that reduce uterine contractions in
premature labor, utilized in asthma therapy because they produce
bronchodilation.
2. Indirect Specific Sympathmimetics:

Amphetamine: it is a CNS stimulant (euphoriant), activates both α,
(hypertension) and β1 (tachycardia), its action is associated with the
release of catecholamines; used mainly as a stimulant in depression
syndrome, as well as appetite-suppressing agent and for narcolepsy.
A final application is in the attention deficit hyperactivity disorder
(ADHD) that is a behavior syndrome consisting of short attention span,
hyperkinetic physical behavior, and learning problems.
3. Mixed Sympathmimetics:
Ephedrine has an excellent oral absorption, penetrates into the CNS, acts
by enhancing the release of NE and by activating adrenergic receptors,
increases both SBP (cardiac stimulation) and DBP (vasoconstriction),
ephedrine dilates bronchioles but it is less potent than E or isoproterenol,
but duration of adrenaline is longer than ephedrine clinically used
prophylactically to prevent attacks rather than for management of acute
asthma. Ephedrine is approved in myasthenia gravis because it enhance
contractility and improves motor function, particularly when used in
conjunction with anticholineosterases

III. Basic Pharmacology of Adrenoceptor Antagonists:
Definition: are reversible competitive medications that block actions of

the SNS by binding to adrenergic receptors, so preventing interaction of
adrenoceptors with endogenous catecholamines, their efficacy is zero,
because they are antagonists.
Classification: antagonists like agonists are classified according to their

blocking effects on receptors into α, β and mixed antagonists.
III-1. Basic Pharmacology of α Adrenergic Blockers (Antagonists): on

the basis of covalent bonds formation, they are divided into 2 groups:
1. Reversible Adrenergic Antagonists: which rapidly dissociate from

adrenergic receptors, so their t ½ is short.
Agents: Phentolamine, Prazosin, Terazocin, Doxazocin and Labetolol.
2. Irreversible Adrenergic Antagonists: form covalent bonds slowly

dissociating from adrenoceptors and therefore they have a long t ½,
(Phenoxybenzamine).
Selectivity of α adrenergic blockers: on the basis of their responses to

adrenergic agonists and antagonists they are classified into:
A. α1 Antagonists: Prazocin, Terazocin, Alfuzocin, Tamsulosin,

Doxazocin and Phenoxybenzamine that shows selective blocking actions
on α1 than α2.
B. α2 Antagonists: Yohambine and Tolazoline.
C. Nonselective α Antagonists: phentalamine blocks both α1 and α2

equally.
Specific Agents of α Adrenergic Blockers:
1. Phentolamine: pharmacodynamically it is a potent competitive

reversible antagonist, blocks equally both α1 and α2 receptors, it causes a
reduction in PVR through blockade of α1, and blockade of α2
adrenoceptors, compensatory vasodilatation is sensed by baroreceptors

(located in the heart, aortic arch, V. cave and carotid sinus) are stimulated
and NE is released (due to blockade of α2) which results in activation of
unblocked β1-adrenoceptors leading to marked reflex tachycardia.
2. Phenoxybenzamine: binds covalently to both α1 postsynaptic (it blocks

α1 more than α2) and α2 presynaptic receptors, as well as histamine,
acetylcholine and serotonin receptors.
Pharmacologic actions: is a noncompetitive irreversible antagonist, with long

duration of action, prevents vasoconstriction of peripheral blood vessels
(via α1), resulting in reflex tachycardia and increased CO due to blocking
effect on presynaptic α2, so it is not useful in the management of
hypertension.
Epinephrine Reversal:
All α adrenergic blockers reverse the α agonist actions of epinephrine. For
example, the vasoconstrictive action of epinephrine is interrupted, but
vasodilation of other vascular beds caused by stimulation of β2 receptors
is not blocked. Therefore, the systemic blood pressure decreases in
response to epinephrine given in the presence of phenoxybenzamine .The
actions of norepinephrine are not reversed but are diminished, because
norepinephrine lacks significant α agonist action on the vasculature.
Clinical use of Phentalamine and Pheoxybensamine:
Pheochromocytoma: is a tumor of adrenal medulla or sympathetic

ganglion cells that releases a mixture of epinephrine and norepinephrine,
in response to chemical stimulation or spontaneously with excessive
sympathomimitic symptoms (sustained hypertension, severe headache,
palpitations, and increased sweating), they block receptors even in the
presence of excessive adrenergic agonists, phentolamine is used as a
diagnostic tool to differentiate hypertension which is associated with
pheochromocytoma from essential (idiopathic) hypertension, and during
operative procedures whereas phenoxybenzamine is usually used to control
hypertension in the preoperative period and for chronic treatment of
metastatic form of pheochromocytoma.
Adverse effects: postural hypotension, reflex tachycardia, (should be

blocked by β1 adrenoblocker) sedation, inhibition of ejaculation, nausea,
vomiting and possibility of tumor formation (mutagenesity).

3. Prazosin, doxazosin (longest half life) and terazocine: are selective
reversible competitive blockers on α1 than α2, this may explain the absence
of reflex tachycardia; (no release of norepinephrine because α2
adrenoceptors are unblocked), they decrease BP by relaxing of both
arterial and venous smooth muscle, causing peripheral vasodilation,
(decreased PVR).
Therapeutic Uses:
a. Chronic hypertension: due to their potent vasodilation and decreased
peripheral resistance, usually they are well tolerated, but the first dose
can produce exaggerated hypotensive response, resulting in syncope
(fainting) termed as first dose effect, this effect is prevented by giving the
drug at bedtime.
b. Benign prostatic hypertrophy (BPH): particularly Tamsulosin

improves urine flow (selective α1a blocker) due to its greater potency in
inhibiting contraction in prostate muscle.
Adverse Effects: dizziness, nasal congestion, drowsiness, orthostatic

hypotension, sexual dysfunction (impotency), Na retention, and GIT
disturbances.
III-2 Basic Pharmacology of β Adrenergic Blockers (Antagonists):
Definition and M.O: all clinical β blockers are reversible competitive

antagonists, acting by reducing bioavailability of receptors to endogenous
catecholamines, they lower BP, and unlike α-adrenoblockers they don’t
induce postural hypotension, because they have no effect on α receptors,
which remain functional, β blockers are categorized into:
A. Non-Selective β Adrenoblockers: they block both β1 and β2 receptors:

Propranolol, Carteolol, Carvedilol, Labetalol, Nadolol, Penbutalol, Pindolol,
Timolol, Sotalol and others….
B. Selective β1 antagonists: Nebivolol, Atenolol, Acebutolol, Betaxolol,

Pisoprolol, Esmolol and Metoprolol: drugs are selective for blocking of β1
adrenceptors than β2, so they could be used safely in pulmonary
obstructive patients, suffering from hypertension and IDDM, because
they don't block β2 adrenreceptos (decreased glycogenolysis and

glucagons secretion) and therefore hypoglycemia doesn't occur in
diabetic patients, in addition there is also no brochoconstriction in COPD
patients.
C. Antagonists With Partial Agonist Activity or Intrinsic

Sympathomimetic Activity (ISA): Acebutalol, Bopindolol, Carteolol,
Penbutolol, Oxyprenolol and Pindolol: they are not pure blockers, and can
produce a weak stimulant effect (partial agonist) on β1 and β2
adrenoreceptors, so they are called adrenoblockers with ISA, the result is
a much diminished effect on HR and CO, as well as they don’t affect
metabolism, so they could be used safely in HTN patients with
bradycardia and IDDM or NIDDM.
Pharmacokinetics: most of these drugs are well absorbed after oral

administration, rapidly distributed, and have a large volume of
distribution, propranalol and penbutolol readily cross the BBB because they
are quite lipophilic, most β- adrenergic antagonists have half-lives in the
range of 3-10 hours, except for esmolol with the shortest t ½ of 10 minutes,
whereas nadolol has the longest half-life among all most β- adrenergic
antagonists (24 hours), elimination occurs by both in the bile and urine,
the t ½ is prolonged in liver diseases, hepatic enzyme inhibition and renal
diseases.
Specific Agents:
Propranolol: is the prototype of β-adrenergic antagonist, it is a non-
selective adrenoblocker. The clinical Uses include:
1. The cardiovascular System:
a. Hypertension (HTN): it decreases BP by reducing CO, via inactivation of
β1 adrenoceptors, it causes negative chronotropic and inotropic effects,
and reflex vasoconstriction due to decreased CO and direct blocking
effect on β2 adrenoceptors as well as it blocks the renin -angiotensin-
aldosterone system, the drug usually used either with a diuretic or a
vasodilator.
b. Angina pectoris: is a syndrome of ischemic heart disease (IHD),

characterized by a severe chest pain, occurs due to imbalance between the
oxygen requirement of the myocardium and its delivery via coronary
arteries, that become spastic, it is a protective agent against the
development of new infarction, in past propranolol, timolol and metaprolol
are used only for prophylaxis, recent studies suggest that these blockers

are strongly indicated in acute phase of MI, in this setting, relative
contraindications include bradycardia, hypotension, moderate to severe LV
failure, shock, cardiac blockade and active airways disease.
c. Arrhythmia: especially sotalol for supraventricular tachycardia and for

ventricular tachycardia, but lidocaine is superior to propranolol.
d. Heart failure: at least three beta antagonists- metoprolol, bisoprolol and

carvedilol- are effective in reducing mortality in selected patients with
congestive heart failure (CHF).
2. Chronic glaucoma:
Because β- adrenoceptors facilitate the secretion of aqueous humor, they
could be used for lowering IOP by decreasing the secretion of aqueous
humor from the ciliary body, timolol and betaxolol are most commonly
used, but pilocarpine is still the front drug in acute attack of glaucoma.
3. Hyperthyroidism:
Is a pathologic condition, characterized by excessive secretion of thyroid
hormones, due to inflammation or tumor of the thyroid gland, in this
process there is an increase in the formation of newly β adrenoceptors,
the disease is manifested by tachycardia, arrhythmia, palpitations,
hypertension, sweating, tremor, nervousness and exophthalmus, propranalol
and others β blockers are effective in reducing hyperactivity of the
sympathetic N.S, especially tachycardia, palpitations, tremor and
sweating.
4. Migraine:
Is a severe unilateral headache, that involves the trigeminal nerve
distribution to intra and extracranial arteries, lasts of several hours to 1-2
days, propranolol is effective in reducing episodes of migraine due to its
vasoconstrictive effect on cerebral vasculature against CGRP and other
substances that cause vasodilatation, but samatriptan, eletriptan and
zolmitriptan (selective 5-HT agonists) are drugs of choice.
5. Portal hypertension:
Beta blockers have an ability to reduce portal vein pressure in patients
with cirrhosis.
Adverse Effects:

1. Bronchoconstriction: propranolol has a severe and serious side effect if
administered to asthmatic patients, due to its nonselective blocking action
on β2, so it is contraindicated in patients with COPD.
2. Arrhythmias: treatment with β antagonists should not be stopped

abruptly, because of the risk of precipitating cardiac arrhythmias; they
are gradually discontinued for 1 week.
3. Sexual impairment: since sexual function occurs through α-adrenergic

receptors, β blockers do not affect ejaculation, but some men can
complain of impaired sexual activity, (the mechanism is unknown).
4. Disturbances in metabolism: by inhibiting β2 adrenoceptors, beta

blockers decrease glycogenolysis and decreased glycogen release, and
therefore can lead to hypoglycemia, patients with IDDM are better
treated with β1 cardioselective blockers or adrenoblockers with ISA, chronic use
is associated with increased levels of VLDL and decreased concentration
of HDL.
Drugs Affecting NE Release Or Reuptake:
1. Resepine: is responsible for blocking of ATP protein that carries NE,

dopamine and 5 HT from the cytoplasm into vesicles in adrenergic
nerves, thus causing depletion of norepinephrine by its degradation via
cytoplasmic MAO, used mainly for hypertensive patients, it has a slow
onset of action and a long duration of action.
2. Guanthidine: acts centrally by blocking the release of NE from vesicles,

it displaces NE thus producing a transient increase in blood pressure,
rarely used for the management of hypertension, because it causes
orthostatic hypotension and sexual dysfunction in men.
3. Cocaine: is unique among local anesthetics in having the ability to

block ATPase of Na and K channels responsible for the reuptake (first) of
NE into the noradrenergic neurons, thus maintaining excessive
accumulation of NE within the synaptic cleft, resulting in a powerful
stimulant effect in the CNS.

Divisions of The ANS

Autonomic
Nervous
System
Sympathetic NS Parasympathetic NS
Adrenergic Cholinergic
neurotransmitters neurotransmitters
Alpha Beta
receptors receptors Muscarinic Nicotinic
β1
Catecholamines β2 Decreased
Tachycardia &
contractility and
HTN
HR
Contraction / Relaxation
Stimulation of VSM

Sites of Action

Classification of Cholinoceptors

Classification of Cholinoceptors
Muscarinic Cholinoceptors
Nicotinic Cholinoceptors

In Dual Innervated Organs, Muscarinic Receptor Blockade
Allows Sympathetic Dominance

Classes of Cholinergic Stimulants
Direct-acting Indirect-acting
Receptor agonists Cholinesterase inhibitors
Carbamates
PHYSOSTIGMINE Phosphates
Choline esters NEOSTIGMINE ISOFLUROPHATE
ACETYLCHOLINE Alkaloids PYRIDOSTIGMINE ECHOTHIPHATE
BETHANECOL PILOCARPINE Antidote
EDROPHONIUM
CARBACHOL PRALIDOXIMINE
METHACHOLINE

Adrenergic Receptors

Regulation of Blood Pressure

UNIT 7
CNS PHARMACOLOGY
Sedative (Anxiolytic) & Hypnotic Drugs
Anxiety: is an unpleasant state of tension apprehension or uneasiness

fear that seems to arise from an unknown cause.
Symptoms: involve the sympathetic system discharge, with tachycardia,

headache, dizziness, fear, palpitations, sweating, and trembling.
Types of Anxiety:
1. Primary anxiety: occurs due to pathologic dysfunction of the CNS

neurons, e.g. epilepsy and schizophrenia.
a. Mild anxiety: doesn’t require any treatment.
b. Chronic or severe anxiety: treated with sedative-anxiolytics or minor
tranquilizers, which also exert hypnotic effect (sleep-inducing) agents.
2. Secondary anxiety: occurs due the presence of organic diseases, e.g.

M.I, peptic ulcer or unpleasant situations.
Anxiolytics: are sedative substances that reduce anxiety causing a

calming effect, whereas hypnotics should produce drowsiness and
maintenance of sleep.
Classification of Anxiolytic– Hypnotic Agents:
I. Benzodiazepines (BZs).
II. Barbiturates.
III. Other anxiolytics- Buspirone, Hydroxyzine, Zolpidem, Chloral
hydrate and Zaleplon.
I. BENZODIAZEPINES
Description: are the most widely used anxiolytic drugs, because they are
safer and more effective compared to other minor tranquilizers.

A. Anxiolytic Agents: Diazepam, (the prototype) alprazolam,
chlordiazepoxide, clonozepam, clorazepate, lorazepam, and quazepam.
B. Hypnotics: Midazolam, triazolam, estazolam and flurazepam
Pharmacokinetics:
- Absorption and distribution: most agents are lipophilic so they are
rapidly and completely absorbed, but they differ depending on a number
of factors including lipophilicity, e.g. oral absorption of triazolam is more
than diazepam, while lorazepam is poorly absorbed from the gut,
clorazepate is converted into its active form (desmethydiazepam or
noridiazepam), the bioavailability of chrodiazepoxide and diazepam is
unreliable following I.M. injection, compared to other minor tranquilizes
most of barbiturates, zaleplon and zolpidem are well absorbed following oral
administration.
- Distribution: they bind to plasma proteins and widely distributed

throughout the body, the central actions of diazepam and triazolam
(more lipophilic agents) are faster than chlordazepoxide and lorazepam.
All sedative-hypnotics cross the PBB, so they should be avoided during
pregnancy.
Metabolism and excretion: most benzodiazepines are extensively

metabolized in the liver by oxidation and conjugation to active compounds,
the apparent half-life of the drug represents the combined actions of the
parent drug and its metabolites. Their effects are terminated not only by
excretion but also by redistribution. The benzodiazepines are excreted in
the urine as glucuronides or oxidized metabolites.
Types of GABA Receptors
a) GABAA: are responsible for opening of chloride channels (fast

component) of inhibitory postsynaptic action (IPSA), blocked by the drug
picrotixin, which can cause generalized convolutions.
b) GABAB: stimulation of these receptors results in either inactivation of

Ca channels or activation of K channels (slow component) of IPSA could be
activated by the antispasmodic drug Baclofen affecting GABAB receptors
at the level of the spinal cord.

Mechanism of Action: benzodiazepines bind to BZ1 receptors which are
located between α and γ subunits of GABAA receptors, (the
benzodiazepines receptors are found only in the CNS and parallel to those of the
GABA receptors), this binding enhances the affinity of GABA receptors to
this inhibitory neurotransmitter, resulting in activation of chloride
channels, and influx of chloride (Cl---) into the cell, leading to IPSP or
hyperpolarization, so they act indirectly to activate (Cl---) channels.
Duration of Actions: according to their half lives, they are divided into 3
groups:
a. Short acting drugs: the t ½ is about 3 to 8 hours, e.g. oxazepam and
triazolam.
b. Intermediate acting drugs: the t ½ is about 10 to 20 hours, e.g.
alprazolam, lorazepam and estazolam.
c. Long acting drugs: the t ½ is about 1 to 3 days, e.g. diazepam, clorazepate
and chlordiazepoxide.
Pharmacologic Actions: benzodiazepines produce:

a. Sedative (at low doses) and hypnotic actions (at high doses).
b. Anticonvulsant effect: Several of the benzodiazepines have

anticonvulsant activity and some are used to treat epilepsy (status
epilepticus) and other seizure disorders.
c. Muscle relaxation: At high doses, the benzodiazepines relax the

spasticity of skeletal muscle, probably by increasing presynaptic
inhibition in the spinal cord, where the GABAA receptors are largely
located.
d. Anesthesia and depression of cardiopulmonary system due to inhibition of

vasomotor centre in the medulla oblongata.
e. They do not affect the ANS; have neither antipsychotic (drugs that block
dopamine receptors, used in the management of schizophrenia, clinically is
manifested by agitation, hallucinations and delirium), nor analgesic activity.
f. Anterograde amnesia: The temporary impairment of memory with use of

the benzodiazepines is also mediated by GABAA receptors. This also
impairs a person's ability to learn and form new memories.

Clinical Applications:
1. Acute and chronic anxiety:

Diazepam is the most widely used drug for anxiety that accompanies
some forms of depression and schizophrenia; benzodiazepines (BZs)
should not be used for long time for the normal stress of life, because of
addiction potential. The choice of BZs is based on several pharmacologic
principles: a rapid onset of action, a relatively high TI bioavailability of BZs, a
low risk of drug interactions based on liver enzyme induction and finally
minimal effects on the cardiovascular system.
2. Muscular disorders from degenerative diseases:

Diazepam is effective in treating muscular spasm occurring in
degenerative diseases e.g. multiple sclerosis- is an inflammatory process
which is characterized by damage of myelin sheath around axons of the
CNS, most common in young women, leading to inability of the NS to
conduct impulses, clinically the neurological symptoms are hypoesthesia,
paraesthesia, muscle spasm, ataxia-difficulties with balance, dysarthria,
dysphagia, depression and visual problems.
3. Seizures: clonazepam is used in the management of chronic epilepsy,

whereas diazepam is the first line therapy for the management of
status epilepticus (is a life-threatening condition in which the brain is in a
state of persistent seizure, it is defined as one continuous, unremitting seizure
lasting longer than 30 minutes, or recurrent seizures without regaining
consciousness between seizures for greater than 30 minutes), finally
clonazepam, diazepam and chlordiazepoxide are used widely to treat
convulsions associated with alcohol withdrawal syndrome.
4. Sleep disorders: most commonly prescribed benzodiazepines are long

acting agents, e.g. flurazepam, triazolam and temazepam. Other hypnotics
are chloral hydrate, zolpidem and zaleplon.
Note: All hypnotics should be given usually less than 7-10 days, because of
dependence. The failure of insomnia to remit after 7-10 days of treatment may
indicate the presence of primary psychiatric or medical illness that should be
evaluated.

5. Anesthesia: diazepam, lorazepam and midazolam are used
intravenously usually in combination with other anesthetic agents;
benzodiazepines at high doses can induce the third stage of anesthesia.
6. Before uncomfortable procedures: e.g. endoscopy or before tooth

extraction, making the patient to cooperate in the procedure
Adverse Effects:
1. CNS disturbances: are the most common side effects of BZs, including
drowsiness, confusion, ataxia, amnesia, respiratory depression and cognitive
impairment (difficulty in receiving new knowledge).
2. Dependence: Psychological and physical dependence on

benzodiazepines can develop if high doses of the drugs are given over a
prolonged period.
- Psychologic Dependence or Addiction: is a dependency of the mind

that leads to psychological withdrawal symptoms such as cravings,
irritability, insomnia, depression, anorexia, etc. It is believed to be strongly
associated with the dopaminergic system of the brain.
- Physiologic Dependence or Withdrawal (Abstinence) Syndrome:

Abrupt discontinuation of anxiolytics results in mental withdrawal
symptoms: confusion, anxiety, tachycardia (palpitation), agitation, restlessness,
insomnia and tension. Patients take drugs in attempt to reduce withdrawal
symptoms.
Note: triazolam with short t ½ induces more sever withdrawal reactions

than flurazepam which has a long duration of action.
3. Allergic reactions: erythema and dermatitis.
4. Tolerance: is characterized by decreasing responsiveness to a drug

following repeated doses, arising from not fully understood mechanism,
but may be probably due to metabolism or changes in responses of the
CNS.
Precautions: Benzodiazepines are less dangerous than other anxiolytic

hypnotic agents; drug overdose is seldom lethal (TI is high), unless alcohol

or central depressants are taken concurrently and in patients with hepatic
dysfunction.
Benzodiazepine Antagonism: Flumazenil is the only antagonist having a

high a affinity for the BZs binding site on the GABAA receptors that can
rapidly reverse the effects of BZs, zaleplon and zolpidem but has no effect
on barbiturates, available only for IV administration, clinically used to
accelerate recovery from anesthesia induced by benzodiazepines or toxic
actions of BZs, used in several neurologic disorders, onset is rapid but
duration is short, with the half-life of one hour. Agitation, confusion,
dizziness, nausea and abstinence syndrome in patients who have
developed physiologic dependence are the most common adverse
effects.
II. BARBITURATES
The barbiturates at the past were used extensively, for sedation and
induction of sleep but today they have been replaced by benzodiazepines
because they:
a. Induce tolerance more than benzodiazepines.
b. Inhibit CYP system for many drugs, (especially warfarin,
phenobarbital enhances metabolism of wafarin, thus higher doses are
required to maintain a prolonged PT, and conversely abrupt of
phenobarbital reduces the metabolism of warfarin, causing bleeding).
c. They induce more severe physical dependence.
d. Barbitals produce very severe withdrawal syndrome: they can cause
severe seizures, coma and death.
Agents: phenobarbital, (the prototype) pentobarbital, secobarbital,

amobarbital and thiopental.
Pharmacokinetics: they are well absorbed orally and distributed widely

throughout the body, all barbiturates redistribute from the brain to
splanchnic areas, skeletal muscles and finally to adipose tissue, which
serves as reservoir of barbitals, from which the drugs are slowly leak out,
metabolized in the liver and excreted in the urine, this movement is
important in causing the short duration of anesthetic action, due to
decreased their concentration in the brain to a level below that necessary
to produce anesthesia, these drugs may remain in the body for long time,
after their administration, in despite of their redistribution in the body.

Mode of Action: like BZs, they neither bind to GABAA nor BZs receptors,
(the binding site is distinct from that of BZs), they stimulate GABAA action of
chloride entry, prolonging the duration of action of the chloride channel
opening, barbitals block glutamate receptors, as well as they interfere
with Na and K transport across the cell membrane.
Barbiturates Classification and Their Clinical Uses: is done on the basis

of their duration of action:
1. Long acting: phenobarbital (1-2 days) is very useful in the treatment of

tonic-colonic seizures of epilepsy- is the most common form of epilepsy,
tonic phase (less than 1 minute) involves abrupt loss of consciousness,
muscle rigidity and respiration arrest, followed by clonic phase (2-3
minutes) involves jerking of body muscles, lip or tongue biting and fecal
and urinary incontinence) and for acute state of epilepsy, (status
epilepticus).
2. Short acting: (3-8 hours) pentobarbital, secobarbital and amobarbital

effective as sedative and hypnotic agents.
3. Ultra–short acting: thiopental acts within seconds, duration of action

is about 30 minutes, used to induce IV anesthesia.
Actions of Barbiturates On The CNS: at low doses they depress CNS,

producing sedation but at high doses can cause hypnosis, anesthesia
(loss of sensation, amnesia, unconscious and skeletal muscle relaxation),
coma and death, they are not analgesics, conversely they may even
exacerbate pain, chronic use leads to tolerance.
Adverse Effects:
1. CNS effects: drowsiness, mental and physical sluggishness, (apathy).
2. Drug hangover: feeling of tiredness well after the patient awakes,

leading to impaired ability to function normally for many hours after
waking, nausea and dizziness may develop.
3. Physical dependence: abrupt withdrawal syndrome is similar to BZs,

(tremor, tachycardia, anxiety, nausea, vomiting and seizures) but more
severe than opiates or BZs and can result in death.

HISTAMINE PHARMACOLOGY
Location: is a chemical messenger and neurotransmitter, which is

secreted by mast cells or basophiles, brain, lungs and the stomach via
enterochromaffin like cells (ECL).
Synthesis: histamine is formed by decarboxylation of the amino acid L-

histidine under the influence of histidine decarboxylase, in basophiles
histamine is stored in granules which are biologically inactive, in addition
to heparin, once formed, histamine either stored or rapidly inactivated by
amine oxidase enzymes. The major metabolic pathways involve
conversion to N-methylhistamine, methylimidazoleacetic acid and
imidazoleacetic acid.
Release of histamine: histamine is released in the following conditions:
a. Immunologic: e.g. allergic reactions and anaphylaxis.

b. Chemical and mechanical release: due to injury of mast cells caused
by bacterial toxins, bee sting, and trauma.
Mechanism of Histamine Action: there are 4 types of histamine

receptors:-
1. H1: present in the brain, endothelium, and smooth muscle

(postsynaptic membrane), they are important in producing smooth
muscle contraction and increasing capillary permeability with the help of
PIP2, as a second messengers.
2. H2: found in gastric mucosa, cardiac muscle and immune cells

(postsynaptic membrane): activation of these receptors occurs through
increasing cAMP concentration by activation of adenylyl cyclase, leading
to gastric secretion.
3. H3: present in the brain and myenteric plexus (presynaptic membrane),

and stimulation of these receptors results in decreasing the mediator
release, mediated by decreasing Ca concentration through N-type Ca
channels.
4. H4: mainly are found on leukocytes in the bone marrow and circulating
blood, may have an important chemotactic effect on eosinophils and mast

cells (allergy and inflammation) their activation mediates the release of
cytokines.
Histamine Effects On Systems:
1) Nervous system: histamine is a powerful stimulant of sensory nerve

endings, especially those associated with the pain and itching, and plays a
major role as an endogenous neurotransmitter (mediator).
2) Cardiovascular system: decreases BP (by dilation of peripheral vessels

via (NO), the increase in heart rate is due to both mechanisms (reflex
tachycardia and direct effect of histamine on the heart), increased
contractility via H2 and finally increases pacemaker, cardiac edema results
from activation of H1 receptors leading to transduction of fluid into the
perivascular tissue.
3) Respiratory system: induces bronchoconstriction, mediated by H1

receptors, histamine considered to be one mediator among other
bronchoconstrictive substances in asthmatic patients.
4) Gastrointestinal tract: is a powerful stimulant of gastric acid secretion

mediated by H2 receptors in contrast, activation of H3 receptors inhibits
gastric secretion, histamine in large doses can cause diarrhea.
5) Skin: dilation and increased permeability of the capillaries results in

the triple responses: reddening color (due to dilation of small blood
vessels), edematous wheal formation, and flare (halo).
Clinical Use: histamine is not used therapeutically except as a diagnostic

test of bronchial hyperactivity and assessment of gastric secretion.
Histamine Antagonism: the actions of histamine could be opposed by

the following ways:
a) Physiologic antagonists: Epinephrine antagonizes actions of

histamine, this is very important in treating patients with allergic
reactions, e.g. anaphylaxis or bronchial asthma (BA).
b) Inhibitors of histamine release (Cromolyn and Nedocromil): drugs

that reduce degranulation of mast cells, (Mast Cells Stabilizers) thus

preventing its release; they are widely used for prophylaxis of BA. Beta 2
adrenoceptor agonists also appear capable of reducing histamine release.
These agents are also effective in reducing symptoms of allergic
rhinoconjunctivitis.
c) Pharmacologic antagonists, H Receptor Antagonists (Antihistamines): are

reversible competitive substances that block histamine receptors, hence
decreasing their bioavailability to endogenous histamine. Selective or
nonselective H1 and H2 are clinically available, but H3 antagonists are
available only for investigations.
Classes of H1 Receptor Antagonists are divided into 2 groups:
1) First Generation: they enter the CNS, causing strong sedative effect.
Agents: Carbinoxymine, Chlorpheniramine, Diphenhydramine,
Doxylamine, Hydroxyzine, Cyclizine, Meclizine
2) Second Generation: these substances are less lipophilic, they do not

penetrate the CNS, and so they lack the sedative and autonomic effects.
Agents: Fexofenadine, Loratadine and Cetirizine.
Pharmacokinetics: H1-receptar antagonists are rapidly absorbed

following oral administration, extensively metabolized in the liver and
widely distributed throughout the body, enter the CNS readily, the T 1/2
is about 4 to 6 hours, except for meclizine (12 to 24 h), metabolites are
eliminated mainly in the urine.
Clinical Use of H1-Antagonists:
1) Allergic reactions: they are the drugs of choice for the treatment of
rhinitis, urticaria and allergic dermatitis, because histamine is the
principle mediator in these reactions, but they are ineffective in patients
with BA because histamine is one of several boronchospastic mediators
and also in angioedema (due to kinins release).
2) Motion sickness: in addition to scopolamine, which exerts antiemetic

activity, H1-antagorists exert antimuscarinic effects, especially
diphenhydramine, dimenhydrinate, cyclizine and meclizine, which are the
most effective agents for prevention of nausea and vomiting induced by
motion sickness, they also have an ability to block actions produced by

serotonin and noradrenaline (alpha receptor blocking effects but not
Beta).
3) Insomnia: only diphenhydramine is used because of its strong sedative

properties, the use of second generation is ineffective.
4) Parkinsonism: is a pathologic neurologic condition, characterized by

imbalance between cholinergic and dopaminergic neurotransmissions,
causing rigidity of occipital muscles, dyskinesia, tremor (at rest) and even
paralysis, H1-antagorists are approved because they can inhibit
hyperactivity of acetylcholine.
5) Local anesthesia: due to their blocking effect on sodium channels as

does lidocaine, diphehydromine is more potent than procaine, it is used if
patients are allergic to conventional anesthetics, usually they are utilized
for premeducation.
Unwanted Effects:
1) Sedation: is the most frequent observed reaction, other CNS symptoms
are: tinnitus, fatigue, dizziness, lassitude, incordination and tremors.
2) Blocking of cholinoceptors: dry mouth, blurred vision, urinary

retention and constipation.
3) Antihistamines in high doses induce excitation and convulsions in

children.
4) Less common side effects are posture hypotension, allergic reactions

and arrhythmia.
GENERAL ANESTHETICS
General Anesthesia: is a surgical state maintaining analgesia, amnesia, loss

of consciousness, inhibition of autonomic reflexes and skeletal muscle relaxation.
Induction of Anesthesia: combination of several drugs is required,

because none of the currently available anesthetics can achieve all five of
these desired effects.

Goals of Premedication (Preanesthesia) To Anesthesia: are to calm the
patient, to relive pain and protect against undesirable effects of the
subsequently administered anesthetic or the surgical procedure. Skeletal
muscle relaxants (antinicotinic drugs) facilitate endotracheal intubation.
Commonly used preanesthetics include: anticholinergics, antiemetics,
antihistamines, BZs, barbitals and narcotic analgesics.
Anesthesia can be divided into Three Phases:

1. The induction phase is defined as the period of time from the onset of
administration of the anesthetic to the development of effective surgical
anesthesia in the patient, it depends on how fast effective concentrations
of the anesthetic drug reach the brain.
2. The maintenance phase: provides a sustained surgical anesthesia: the

anesthesiologist monitors the patient's vital signs and response to various
stimuli throughout the surgical procedure to carefully balance the
amount of drug inhaled and/or infused with the depth of anesthesia.
3. The recovery phase is the time from discontinuation of administration

of the anesthesia until consciousness and protective physiologic reflexes
are regained, it depends on how fast the anesthetic drug diffuses from the
brain.
Depth of Anesthesia:
The depth of anesthesia has been divided into four sequential stages.
These stages were discerned and defined with ether, with halothane and
other commonly used anesthetics, the stages are difficult to characterize
clearly because of the rapid onset of anesthesia.
Stage 1: Analgesia: loss of pain sensation, the patient experiences

analgesia without amnesia, later both analgesia and amnesia are
produced.
Stage 2: Excitement: the patient experiences delirium and excited,

respiration is irregular in depth and rate, HR and BP increase, to avoid
this excitation in patients, an ulta- short acting barbiturate, (thiopental) is
prescribed.

Stage 3: Surgical anesthesia: regular respiration and skeletal muscle
relaxation occur, eye movements cease and the pupils are fixed, surgery
may be started during this stage.
Stage 4: Medullary paralysis: represents severe depression of both

vasomotor and respiratory centers, without circulatory and respiratory
support, death would rapidly ensue.
Types of Anesthetics:-
A. Inhaled anesthetics.
B. Intravenous anesthetics.
C. Local anesthetics.
A. Inhaled (Halogenated) Anesthetics:

Agents: Methoxyflurane, Halothane, Enflurane, Isoflurane,
Sevoflurane, Desflurane and Nitrous oxide.
Pharmacokinetics: the rate of induction and depth of anesthesia depends

on factors that influence the uptake and distribution of anesthetic.
Uptake and Distribution:

The partial pressure (PP) of an anesthetic gas is the driving force that
moves the anesthetic into the alveolar space and then into the blood,
which transports it to the brain, and various other body compartments.
Because gases move from one compartment to another within the body
according to partial pressure gradients, a steady state is achieved when the
partial pressure in each of these compartments is equivalent to that in the
inspired mixture, for achieving the steady state the following factor are
important to know:
1. Solubility in the blood: determined by the blood gas partition

coefficient is an index of solubility in the blood, defines as the relative affinity
of an anesthetic for the blood compared with that of inspired gas, e.g.:
A. Nitrous Oxide (N2O): is an anesthetic gas with low blood solubility,
(blood gas-partition coefficient is low) a little of molecules dissolves in
the blood, thus balance between inhaled anesthetic and arterial blood
occurs rapidly and therefore the steady state is rapidly achieved.

B. Halothane: dissolves completely (blood gas-partition coefficient is high
(5 times more soluble than nitrous oxide) in the blood and greater
amounts of it and longer periods of time are required to achieve the steady state.
2. Anesthetic concentration in the inspired air: increasing concentration

of anesthetic in inspired air will increase its rate transfer into the blood.
3. Pulmonary ventilation: hyperventilation increases the speed of

induction of anesthesia, whereas hypoventilation decreases the onset of
anesthesia.
4. Pulmonary blood flow: an increase in pulmonary blood flow slows the

rate of induction of anesthesia (large volume of blood related to anesthetic)
and conversely a decrease in pulmonary blood flow increases the rate of
rise in arterial tension.
5. Alveolar-venous PP difference: depends mainly on uptake of the

anesthetic by tissues including nonneural tissues. Venous blood returning
to the lungs may contain significantly less anesthetic than arterial blood,
the greater this difference in anesthetic tensions, the more time it will take to
achieve equilibrium with brain tissue. During the induction phase of
anesthesia, the tissues that exert greatest influence on the arteriovenous
anesthetic concentration gradient are those that are highly perfused
(brain, heart, kidney, liver and splanchnic organs), combined together
these tissues receive over 75 of the resting CO, in the case of anesthetic
with relative high solubility in highly perfused tissues, venous blood
concentration initially is very low and equilibrium with the alveolar
space is achieved slowly. During maintenance of anesthesia the drug
continues to be transferred between various tissues depending on the
solubility of the agent, concentration gradient between the blood and tissue and
tissue blood flow, although muscle and skin constitute 50% of body mass
anesthetics accumulate more slowly than highly perfused tissues.
Although most anesthetics are highly lipophilic substances in adipose
tissues, the relatively low blood supply to these tissues delays
accumulation and equilibrium is unlikely to occur with most anesthetics
during a typical 1-3 hour operation.
6. Elimination: the time to recovery from anesthesia, depends on

elimination of anesthetic from the brain, determined by blood gas
partition coefficient therefore inhaled anesthetics that are insoluble in
blood and brain (blood gas-partition coefficient is low e.g. N2O) are
eliminated faster than more soluble anesthetics. 2 features differentiate
the recovery phase form the induction phase:
1. Transfer of an anesthetic from the lungs to blood can be enhanced by
increasing its concentration in inspired air, but the reverse transfer can't
be enhanced because the concentration in the lungs can’t be reduced
below zero.
2. At the beginning of the recovery phase the anesthetic gas tension in
different tissues may be quite variable, but at the start of induction of
anesthesia the initial anesthetic tension is zero in all tissues.
The Solubility of Anesthetics In The Blood: as well as in tissues could

be described in the following order: methoxyflurane> halothane >
enflurane> isoflurane > sevoflurane > desflurane> nitrous oxide.
Mechanism of action: all general anesthetics (halogenated and IV

anesthetics) exert their effects by stimulating GABAA receptors-chloride
channel transmission, they increase activity of the inhibitory glycine receptors,
as well as inhibition of cholinergic receptors resulting in hyprepolarization
except for ketamine, (IV anesthetic), which produces its action by
antagonizing the action of the excitatory neurotransmitter glutamic acid on
NMDA receptors.
Potency of Anesthetics: the potency of inhaled anesthetics is defined as

the Minimum Alveolar Concentration (MAC), which is the
concentration of anesthetic gas needed to eliminate movement among
50% of patients by skin incision, or as ED50, the percent of gas in a
mixture required to achieve the effect, therefore, MAC is small for potent
anesthetics such as halothane, and large for less potent agents such as
N2O, the more lipid-solubility of an anesthetic, the lower the concentration of
anesthetic needed to produce anesthesia.
Specific Agents:
1. Halothane: is the prototype of halogenated gases, a potent anesthetic,

but a weak analgesic, onset is slow but duration is long, usually co-
administered with nitrous oxide, halothane is oxidatively metabolized in
the liver into toxic substances (trifluroethanol and bromide ions), which are
responsible for hepatotoxicity, and therefore its doses should be adjusted
in hepatic patients.
Actions: all halogenated anesthetics cause bradycardia (due to
vagomimetic effect), hyperthermia, (because of increased concentration
of Ca in skeletal muscles) hypotension (due to decreased CO which could
be overcome by the α1 sympathomimitics - methoxamine or phenylephrine and
arrhythmias, (due to increased sensitivity of myocardium to
catecholamines) which can be serious if hypercapnia present.
Adverse Effects: fever, anorexia, nausea, vomiting and severe hepatitis in

adults, to avoid this condition a halothane anesthesia is not repeated at
intervals less than 2 to 3 weeks. Halothane is largely replaced in the US.
Note: Halothane is not hepatotoxic in pediatric patients and combined

with its pleasant odor, this makes it suitable in children for inhalation
induction.
Malignant Hyperthermia: In a very small percentage of patients,

halothane and the muscle relaxant succinylcholine have the potential to
induce malignant hyperthermia due to increased IC concentration of
calcium. Burn victims and individuals with Duchenne dystrophy,
myotonia and osteogenesis imperfecta, and central-core disease are
susceptible to malignant hyperthermia. Dantrolene is the antispasmodic
agent given because of its ability to block Ca channels of skeletal muscles.
2. Enflurane: in comparison to halothane is less potent, metabolized to

fluride which is excreted by the kidney, thereby it is contraindicated in
renal failure, it causes fewer arrhythmias, less sensitization of the heart to
catecholamines and greater effect on muscle relaxation, high
concentrations may cause muscle twitching.
3. Isoflurane and Desflurane: unlike other halogenated anesthetics that

decrease BP by ↓ CO (especially halothane and enflurane), they decrease
BP by causing peripheral vasodilation, significantly increase HR because
they cause less depression of the baroreceptor reflex, so desflurane is
useful in ischemic patients, because it increases coronary blood flow and O2
consumption, most halogenated anesthetics are bronchodilators except
desflurane and isoflurane.
4. Methoxyflurane: the most potent inhalation anesthetic because of its

high solubility in lipids, metabolized to flurane which is nephrotoxic, so it

is not recommended in patients with renal failure, mostly used in obstetric
practice, because it has no relaxation effect on the uterus.
5. Nitrous oxide (N2O): (Laughing gas) is a potent analgesic, but a week

general anesthetic induces rapid induction and rapid recovery from
anesthesia, thus it is combined with other potent agents (halothane).
Clinical Use: it is the safest of all anesthetics, administered in combination

with O2 for analgesia in dental surgery. N2O alone cannot produce
surgical stage of anesthesia, even at high doses, without adjunct agents.
Toxicity: at large doses it can cause pneumothorax, because it moves

very rapidly into and out of the body, hypoxia (it retards oxygen uptake
during recovery), it does not depress respiration, has the least effect on
the cardiovascular system and can cause megablastic anemia due to
dismeabolism of methionine.
Clinical Use of Inhaled Anesthetics: they are not used as monotherapy

for induction of anesthesia, used in combination with IV anesthetics.
B. Intravenous Anesthetics: Propofol, Etomidate, Ketamine, Barbitals,

BZs and Opioid analgesics are used as adjuncts to inhaled anesthetics
and as monotherapy without inhaled anesthetics, produce rapid
induction of anesthesia, intravenous anesthetics in action are faster than
inhaled anesthetics, and recovery is rapid, so they are extensively used
for short surgical procedures.
C. Local Anesthetics: drugs are applied locally to block nerve conduction

of sensory impulse from the periphery to the CNS, providing loss of
sensation in a limited region of the body, sometimes are used as analgesics.
Classification: chemically they are classified into:
1. Esters: Procaine (Novocaine) (short acting), Tetracaine (long acting),

Chloroprocaine, Cocaine and Benzocaine (surface action).
2. Amides: Lidocaine (medium), Mepivacaine, Ropivacaine, Bupivacaine

(long acting) Levobupivacaine and Prilocaine.

Pharmacokinetics: classic pharmacokinetics plays a lesser role than with
systemic therapeutics which is critical to the potential development of
adverse effects specifically cardiac and CNS toxicity.
Absorption: systemic absorption of local anesthetic from the site of

administration is determined by several factors:
1. Dosage.
2. Site of injection: application of local anesthetic to a highly vascular area
results in more rapid absorption than if it is injected into a poorly
perfused area.
3. Drug tissue binding.
4. Local tissue blood flow.
5. Physicochemical properties of the drug itself: anesthetics that are more lipid
soluble are generally more potent, have a longer duration of action, and
take longer to achieve their clinical effects, extensive protein binding also
serves to increase the duration of action.
6. The presence of vasoconstrictor substances: e.g. epinephrine that reduces
absorption, by its vasoconstrictive effect (reducing blood flow), this
useful for short-acting drugs, e.g. procaine and mepivacaine
Distribution:
A. Localized: anesthetics delivered into the subarachnoid space will be
diluted with the CSF, the pattern of distribution will be dependent on
specific gravity relative to the CSF and the patient's position, solutions are
called hyperbaric, isobaric and hypobaric, and will be respectively descend,
remain relatively static or ascend within the subarachnoid space due to
gravity when the patient sits upright.
B. Systemic: the initial alpha phase reflects rapid distribution in highly

perfused organs, followed by a slower beta phase reflecting distribution
into less well perfused tissues (muscle and gut).
Metabolism and Excretion:

A. Ester local anesthetic: are hydrolyzed very rapidly in the plasma by
circulating butyrylcholinesterase (pseudocholinesterases), therefore
procaine and chloroprocaine have very short t ½ < 1 minute.
b. Amide local anesthetic: are hydrolyzed by hepatic cytochrome P-450

system into more water soluble molecules, that are excreted in the urine,
there is considerable variation in the rate of liver metabolism of

individual amides with prilocaine (fastest)> lidocaine> mepivacaine >
ropivacaine= bupivacaine and levobuipivacaine (slowest), as a result toxicity
from amides is more likely to occur in hepatic patients, e.g. the average
half life of lidocaine may be increased from1,6 hours in normal patients to
more than 6 hours in patients with severe liver disease. Decreased hepatic
elimination of local anesthetics would also be anticipated in patients with
reduced hepatic blood flow.
Pharmacodynamics:
1. The primary mechanism of local anesthetics is to block Na channels, so
reducing the influx of Na prevents depolarization, local anesthetics gain
access to their receptors from the cytoplasm or the membrane, the more
lipid–soluble (non-ionized, uncharged) form reaches effective intracellular
concentrations more rapidly than does the ionized form, once inside the axon,
the ionized form is more effective than non-ionized (the non-ionized is
important for reaching the receptor site and the ionized in causing the
effect).
Pharmacologic Effects: sensitivity of nerve fibers to local anesthetics

depends on:
1. Fiber diameter: smaller fibers are blocked more easily than larger
fibers.
2. Myelination: myelinated fibers are blocked more easily than

unmyelinated, because activated pain fibers fire rapidly.
3. Anatomic location: fibers located in the periphery of a thick nerve

bundle are blocked sooner than those in the core, because they are early
exposed to higher concentrations of local anesthetics, e.g. during spinal
anesthesia, motor paralysis may impair respiratory activity and
autonomic nerve blockade resulting in hypotension.
Effects on other excitable membranes: local anesthetics have weak

neuromuscular blocking effects, but their effects on cardiac cell
membrane are very important so some anesthetics are used as
antiarrhythmic agents in doses lower than required to produce nerve
block (lidocaine and bupivacaine).
Clinical Pharmacology: local anesthetics can provide a highly effective

analgesia in well defined regions of the body, the usual routes include:

a. Topical application (nasal mucosa, wound margins).
b. Injection of peripheral nerve ending and nerve trunks, (perineural
infiltration).
c. Injection into the epidural or subarachnoid space of the spinal cord.
d. Intravenous anesthesia of the arm or leg (brief block) for short surgical
procedures requiring time less than 45 min.
Choice of Local Anesthetics: the choice depends on the duration of

action and consequently local anesthetics are categorized into 3 groups:
a. Short acting drugs: Procaine and Chloroprocaine.
b. Intermediate acting drugs: Lidocaine, and Prilocaine.
c. Long acting drugs: Tetracaine and Bupivacaine.
Onset of Action:
1. Vasoconstriction: several benefits may be derived from addition of a
vasoconstrictor to a local anesthetic;
First, localized neural uptake is enhanced because of higher sustained
local tissue concentrations that can translate clinically into a longer
duration block.
Second, peak blood levels will be lowered as absorption is more closely
matched to metabolism and elimination and the risk of systemic toxic
effects is reduced.
Third, when epinephrine is incorporated into a spinal anesthetic, E may
not only contribute to prolongation of the local anesthetic effect via its
constrictive actions, but also exerts a direct analgesic effect mediated by
postsynaptic alpha-2- adrenoceptors, within the spinal cord, this
recognition has led to the clinical use of the alpha-2 agonist clonidine as
a local anesthetic adjuvant for spinal anesthesia.
2. Carbone dioxide: the onset of local anesthetic can be accelerated by

solution saturated with CO2, which crosses the plasma membrane
rapidly, resulting in intracellular acidosis, which in turn attracts the
cationic form of the local anesthetic.
3. Hyperkalemia enhances local anesthetic activity, while hypercalcemia

may antagonize it.
4. Tachyphylaxis: loss of effectiveness after repeated injection of local

anesthetic is most likely due to extracellular acidosis that attracts the
cationic form (effective form) of local anesthetic.

Pregnancy and Local Anesthesia: Pregnancy increases susceptibility to
local anesthetic toxicity, especially with Bupivacaine use, that can cause
cardiac arrest during labor anesthesia, (0, 75% is banned by the FDA but in
low concentrations as 0, 25 are frequently used to achieve prolonged peripheral
anesthesia and analgesia for postoperative pain control), the development of
local anesthetic toxicity in pregnancy may be associated with increased
concentrations of estrogen and progesterone.
Toxicity:
1. CNS: all local anesthetic at low doses produce sedation, sleepiness,
visual and auditory disturbances, restlessness, metallic taste and tongue
numbness. At higher doses, nystagmus and muscular twitching develop,
followed by tonic-clonic convulsions which are treated by thiopental,
propofolol or benzodiazepines (midazolam, diazepam) whereas muscular
excitation (tremor) could be reversed by the neuromuscular blocking agent
e.g. succinylcholine, which is ineffective in central convolutions, because it
acts at peripheral nicotinic receptors.
2. Neurotoxicity: all local anesthetics are toxic to nerve tissue especially

chloroprocaine and lidocaine, they produce transient radicular irritation,
when used for spinal anesthesia, resulting from pooling of high
concentrations of the local anesthetic in the cauda equina.
3. Cardiovascular system: local anesthetics block cardiac Na channels

and thus depress excitability and conduction, at high doses they block Ca
channels, reduce contraction of smooth muscle, therefore leading to
hypotension except for cocaine because it inhibits norepinephrine
reuptake, leading to vasoconstriction, hypertension and arrhythmias,
Bupivacaine is the most cardiotoxic local anesthetic. Reversal of
bupivacaine toxicity (experimentally) is done by IV infusion of lipid, the
mechanism is unknown, but it is strongly believed that is lipids have an ability
to extract a lipophilic drug from aqueous plasma and tissue targets,
a mechanism termed lipid sink. Plans to publicize this treatment more
widely have been published.
4. Hematologic effects: the administration of large doses of prilocaine can

lead to accumulation of the metabolite toluidine, which converts
hemoglobin into methemoglobin that causes cyanosis; cyanotic patients are

treated with ascorbic acid (vitamin C) or methylene blue that rapidly convert
methemoglobin to hemoglobin, so reversing action of toluidine.
5. Allergic reactions: especially develop in patients with ester local

anesthetics, due to their metabolism to p-aminobezonic acid derivatives,
but amides rarely cause allergic reactions.
SKELETAL MUSCLE RELAXANTS
General Description: Drugs that affect skeletal muscles include two

different therapeutic groups
1. Neuromuscular (NM) Blockers or Skeletal Muscle Relaxants: agents

that produce paralysis or relaxation of skeletal muscles, during surgical
procedures and in I.C.U. NM blockers interfere with transmission at the
NM end plate and lack CNS activity.
2. Spasmolytics: drugs that reduce spasticity in several neurologic

conditions such as multiple sclerosis and stroke, that are associated with
abnormally high reflex activity in the neuronal pathways which control
skeletal muscles, acting in the CNS or in the skeletal muscle cell rather than at
the neuromuscular junction
Agents: Diazepam, Baclofen (GABABR-agonist), Tinazidine (selective
alpha-2 agonist), Dantrolene, Botilinum toxin and Gabapentin (antiseizure
drug).
Normal Neuromuscular Transmission: the transmission at the motor end

plate is similar to pregaglionic cholinergic nerves, associated with
activation of Na and inactivation of K channels, increased IC
concentration of Na results in activation of Ca channels, as well as its
release from the endoplasmic reticulum, the result is increased
cytoplasmic concentration of Ca that evokes rupture of pooling vesicles
with the release of acetylcholine which diffuses toward the synaptic cleft
and binds to its nicotinic cholinergic receptors, the subsequent movement
of Na and K through the channel is associated with depolarization of the
end plate (this change in voltage is termed the motor end plate) leading to
skeletal muscle contraction.
Neuromuscular Blockade: Blockade of end plate function can be

accomplished by two different mechanisms:

a. Non-Depolarizing Type (Antagonists): are competitive reversible
substances that bind to nicotinic cholinergic receptors at the NM junction,
and hence reducing interaction between Ach and its receptors, they
prevent access of the neurotransmitter to its receptor and thereby preventing
depolarization, the prototype of this group is tubocurarine, others are
Metocurine ,Mivacurium, Doxacurim, Pancuronium, Rocuronium and
Vecuronium.
B. Depolarizing Type (Agonists): agents that block cholinergic

transmission by an excess of depolarizing agonist, Succinylcholine
is the prototype and the only clinically available depolarizing muscle
relaxant.
Pharmacokinetics:
a. Nondepolrizing agents: Generally because all of the neuromuscular

blocking (depolarizing and nondepolarizing) agents are polar they are
given either I.M or I.V, they don’t enter the CNS, because they are ionized
so they have a limited volume of distribution, drugs that are excreted by
the kidneys have the longer t ½, therefore longer duration of action,
(pancuronium, tubocurarine) than drugs that are excreted by the liver
have shorter t ½ , and therefore shorter duration of action,
(mivacurium,(metabolized by plasma cholinesterase) rocuronium and
(vecuronium which is the most clinically used drug.
b. Depolarizing Drugs: the brief duration of action of succinylcholine (5-

10 minutes) is due to rapid hydrolysis via butyrylchoilnesterase and
pseudocholinesterase in the liver and plasma respectively, so it is usually
given by continuous infusion, mivacurium and succinylcholine.
Blockade may be prolonged in patients with genetic variants of plasma
cholinesterase that is the predominant pathway for succinylcholine
elimination, so its metabolism occurs very slowly, succinylcholine is not
metabolized by acetylcholinesterase.
Mechanism of Action:
Nondepolarizing Drugs:
1) At low doses: nondepolarizing blocking agents are reversible
competitive blockers, their actions could be overcome by using

anticholinesterases such as neostigmine, edrophonium or pyridostigmine.
2) At high doses: block strongly the nicotinic cholinergic receptors leading

to further weakening of NM transmission, and reduce the ability of
acetylcholinesterase inhibitors to reverse the actions of nondepolarizing
muscle relaxants.
Actions: not all muscles are equally sensitive to blockade, muscles

paralysis occurs in the following sequence: first muscles that are
pralayzed are muscles of fingers, small muscles of orbit, then limb muscles,
trunk muscles, cervical muscles, intercostals muscles and lastly the diaphragm.
Therapeutic Uses: adjunctive drugs in anesthesia during surgery to relax

skeletal muscle.
Special Characteristics of Certain Muscle Relaxants:

A. Effect on autonomic ganglia: tubocuraraine blocks but succinycholine
stimulates.
B. Effects on cardiac receptors: pancuronium blocks moderately but

succinycholine stimulates.
c. Ability to release histamine: succinylcholine (slight), whereas

tubocuraraine and mivacurium (moderate).
Adverse Effects:
1. Respiratory paralysis.
2. Autonomic effects:
a. Hypotension: tubocuraraine and to a lesser extent metocurine and
mivacurium can produce hypotension as a result of histamine release,
premedication with an antihistamine attenuates this hypotension.
b.Vagolytic effect: pancuronium causes a moderate increase in HR and a

small increase in CO, by blocking muscarinic cholinergic receptors,
another mechanism of pancuronium-induced tachycardia is release of NE
and blockade of its uptake.

c. Bronchospasm: is produced by agents that release histamine such as
mivacurium, but insertion of endotracheal tube is the most common reason for
bronchospasm after induction of anesthesia.
Drugs Interactions:
a. Cholinesterase inhibitors: can overcome the action of nondepolarizing
agents, but with increasing dose, they can produce depolarizing block.
b. Halothane, calcium blockers and aminoglycosides: enhance NM blockade.
c. Local anesthetics: only in high doses local anesthetics can block NM
junction
Depolarizing Agents:
Mechanism of action: succinylcholine binds to the nicotinic receptors and
acts to depolarize junction, its NM effects are like those of Ach except that
succinylcholine produces a longer effect at the myoneuronal junction
The NM blocking effect of succinylcholine consists of two 2 phases:
Phase 1(Transient Fasciculations or Twitching): reacts with the nicotinic

receptor to open the channel and cause depolarization of the motor end
plate leading to skeletal muscle contraction (twitching), because
succinylcholine is not metabolized effectively at the synapse the
depolarized membranes remain depolarized and unresponsive to
subsequent impulses, in contrast to nondepolarizing blockers block is
augmented not reversed by cholinesterase inhibitors.
Phase 2 (Desensitizing): continuous depolarization causes resistance of

receptors to succinylcholine, and the membrane becomes repolarized as
Na channels are blocked, later in phase II the characteristics are nearly
identical to those of nondepolarizing agents with possible reversal by
cholinesterase inhibitors.
Therapeutic Uses:
1. Surgical relaxation: especially in intra-abdominal and intra-thoracic
surgery.
2. Endotracheal intubation: by relaxing the pharengeal and laryngeal

muscles, NM blocking agents facilitate laryngoscopy and placement of
endotracheal tube that minimizes the risk of pulmonary aspiration during
general anesthesia.

3. Control of ventilation: in patients with severe respiratory failure such
as bronchospasm and pneumonia.
4. Treatment of convulsions: succinylcholine is useful occasionally in the

management of seizures associated with epilepsy or local anesthetic
toxicity; the method is effective in despite of inability of NM blockers to cross the
BBB.
Adverse Effects:
a. Postoperative muscle pain and muscle dystrophy: Myalgia is the most
common side effect, occurs secondary to the unsynchronized contractions
of adjacent muscle fibers, just before the onset of paralysis.
b. Hyperthermia: especially when halothane is used as an anesthetic, plus

succinylcholine, malignant hyperthermia can develop due to excessive
release of Ca from the EPR of skeletal muscles, treated usually by the
spasmolytic drug dantrolene, which blocks excessive Ca release from the
EPR.
c. Apnea: may be due to genetic deficiency of plasma cholinesterase,

resulting in prolongation action of succinycholine, which can lead to
paralysis of the diaphragm.
d. Cardiac arrhythmias: especially when co administered with halothane,

because, it stimulates autonomic nicotinic receptors at both the
sympathetic and parasympathetic ganglia and muscarinic cardiac
receptors, the negative inotropic and chronotropic responses to
succinylcholine can be attenuated by administration of anticholinergic drug
such as glycopyrrolate or atropine.
e. Increased intraocular pressure: may be due to transient dilation of

choroidal blood vessels.
f. Increased intragastric pressure: may lead to emesis, more likely in

patients with delayed gastric emptying, such as DM, obesity and
esophageal dysfunction.
G. Hyperkalemia: patients with burns and neuromuscular diseases

respond to succinylcholine by excessive release of K, which can cause
cardiac arrest.

M.O of Action of Local Anesthetics

UNIT 8
CARDIOVASCULAR PHARMACOLOGY
Hypertension (HTN): is defined as persistent high levels of BP, in which

the systolic pressure is above 140 mm Hg and diastolic pressure is above 90 mm
Hg, but in elderly population hypertension is defined as systolic pressure
above 160 mm Hg and diastolic pressure above 90 mm Hg. Sustained
hypertension damages blood vessels in kidney, heart, and brain, it is the
major cause of heart failure, renal failure and dementia. Hypertension is
called the Silent Killer, because it occurs without symptoms (about one-
third of the people with hypertension do not know that they have it) until organ
damage has occurred.
Classification:
1. Primary or Essential Hypertension: represents about 90% of
hypertension, and has no medical cause, it is also called idiopathic.
2. Secondary Hypertension: occurs due to the presence of organic

diseases:
a. Renal disease: renal stenosis, glomerulonephritis, pyelonephritis, kidney
tuberculosis, glomerulosclerosis.
b. Endocrine disorders: Cushing’s disease (hypercortisism),
pheochromocytoma, primary aldosteronism, hyperthyroidism, obesity
and diabetes mellitus (DM).
c. Drugs: e.g. the long term use of oral contraceptives and steroids.
d. Vascular disorders; e.g. coaractaion of the aorta that is a congenital
condition whereby the aorta narrows in the area where the ductus
arteriosus (ligamentum arteriosum after regression) inserts. Arterial
hypertension in the arms with normal to low blood pressure in the lower
extremities is classic symptom of coaractation of the aorta.
Basic Physiology of Blood Pressure (BP):
BP is directly proportional to the product of cardiac output (CO) multiplied

by peripheral vascular resistance (PVR).
BP = CO X PVR.
These two factors are under the control of the following anatomic sites:
1. Heart: increased CO or tachycardia elevates BP.

2. Kidneys: regulate the volume of intravascular fluid, and release renin
(indirect vasoconstrictor) in addition, kidneys secrete vasodilators e.g.
prostaglandins and nitric oxide.
3. Arterioles: precapillary vessels represent afterload.
4. Venules: capacitance vessels represent preload.
Center of BP: Located in the vasomotor area of medulla, it consists of

pressor and depressor areas.
Pathogenesis of Essential Hypertension:

1. Stimulation of the vasomotor centre, (sympathetic division): with release
of NE that causes constriction of blood vessels (increased PVR), at the
same time, activation of S.N.S leads to release of epinephrine from the adrenal
medulla, causing additional vasoconstriction.
2. Vasoconstriction: leads to decreased renal perfusion, causing the release

of renin (an enzyme produced by juxtaglomerular cells in response to
vasoconstriction and decreased serum of sodium), it catabolizes plasma
angiotensinogen (a protein made by the liver), to angiotensin І which in turn is
converted into angiotensin ІІ by the angiotensin-converting enzyme (ACE)
in the periphery, angiotensin ІІ elevates BP by:
a. Vasoconstriction: it increases PVR by vascular SMCs contraction.
b. Aldosterone secretion: is secreted from the adrenal cortex; it enhances the
reabsorption of Na.
3. Decreased Na excretion leads to increased vascular volume and CO.
Clinical Stages of Hypertension:
First Stage: (170-100 mm Hg) is characterized by increased CO and normal

PVR or may be slightly increased, clinically no hypertrophy of LV, normal
optic nerve and analysis of the urine.
Second Stage: (180- 120 mm Hg), the CO is normal but PVR is increased, in this
stage hypertrophy of LV is present, it is manifested by edema of optic disc,
proteinuria, oliguria and hematuria.
Third Stage: (200-130 mm Hg), in this stage CO is decreased, whereas PVR is

markedly increased, clinically is characterized by CHF, thrombosis of cerebral
arteries, hemorrhage of optic disc, MI, nephrosclerosis, uremia, and anuria.

Diagnosis: requires three separate sphygmomanometer measurements at
one weekly interval. Initial assessment of the hypertensive people should
include a complete history and physical examination. It should be noted
that diagnosis depends on measurement of BP and not on symptoms
reported by the patient.
Approach to Antihypertensive Drugs:

All antihypertensives act on one or more of the four anatomic control sites
and produce their mechanisms by interfering with normal mechanisms of
BP regulation, and then antihypertensives are categorized into 4 categories:
I. Sympathoplegic Agents: classified according to the site at which they

impair the sympathetic reflex:
A. Central acting antihypertensives: agents that interfere with the
sympathetic reflex at the level of CNS, so generally they induce sedation,
mental depression, and disturbances of sleep, e.g. methyldopa (used
primarily for hypertension during pregnancy) and clonidine.
B. Ganglion- blocking agents: e.g. Hexamethonium and Trimethaphan are

used in the management of hypertensive emergencies.
C. Adrenergic neuron blocking agents: lower BP by preventing physiologic

release of Ne from postganglionic sympathetic neurons, e.g. Guanthedine
and Reserpine.
D. Adrenoceptor antagonists: are divided into:

D-1: Beta adrenoceptor blockers: in their turn subdivided into:
D-1-a: Non selective beta- adrenoblockers namely Propranolol: it is indicated
for I stage of hypertension and to prevent reflex tachycardia, associated
with vasodilators.
D-1-b: Selective β1-adrenoblockers e.g. atenolol preferred for hypertensive
patients with asthma.
D-1-c: β adrenoblockers with (ISA): e.g. pindalol, preferred for hypertensive
patients with bradycardia or peripheral vascular disease.
D-2: Alpha adrenoceptor blockers: are divided into:

D-2-a: Non selectivea adrenoblockers: e.g. phentolamine, they are not used in
hypertension management.
D-2-b: Selective a1 adrenoblockers: e.g. prazocin are effective mainly in the II
and III stages of hypertension, because they can cause retention of Na and
water diuretics are prescribed so they are used in combination with others
antihypertensive drugs.
II. Direct Vasodilators: Hydralazine, Minoxidil, Sodium Nitroprusside,

Diazoxide and Ca channel blockers- Verapmail, Nifedipine, Amlodipine and
Diltiazem: agents are responsible for relaxation of smooth muscles of either
arterioles, venules or both, (therefore reducing preload, and afterload) they
act by decreasing peripheral vascular resistance, work best when given in
combination with others antihypertensive drugs, tachyphylaxis may develop
rapidly.
III. Inhibitors of Angiotensin: include:

III-1: Angiotensin Converting Enzyme (peptidyl dipeptidase) Inhibitors, 'ACEIs'
Captopril, Enalopril, Ramipril and Lisinopril: are substances that block the
activity of the renin-angiotensin-aldosterone system. Lower BP principally by
decreasing PVR. HR and CO are not significantly changed unlike direct
vasodilators these agents don’t result in reflex tachycardia and can be used
safely in ischemic heart disease. Another mechanism of their hypotensive
action is that ACEIs inactivate metabolism of bradykinin-a potent vasodilator
which works by stimulating prostacycline and nitric oxide release. So due to
accumulation of bradykinin- dry cough and angioedema may develop.
Note: The concernment use of NSAIDs may impair the hypotensive effects of
ACEIs by blocking bradykinin mediated vasodilation.
III-2: Angiotensin-Receptor Antagonists: Losartan,Valsartan, Ibresartan and

Eprosartan: block angiotensin II receptors hence reducing activity of
angiotensin II: differ from ACEIs in that they have no action on bradykinin
metabolism and therefore they are more selective blockers of angiotensin,
cough and edema can occur but less than with ACEIs.
IV. Diuretics: agents that increase the excretion of water and Na, leading to
reduction of blood volume and consequently decreasing BP, they act at
different site of the Nephron- is the morphologic and physiologic unit of
the kidney, histologically has the following components:
A. The glomerulus: is represented by a tuft of capillaries with the formation

of Bowman’s capsule.
B. The proximal convoluted tubule (PCT): most of sodium biocarbonate

(under the influence of carbonic anhydrase enzyme), chloride, water, glucose

and amino acids are reabsorbed, in addition to this function, the proximal
convoluted tubule serves as a secretion system for organic acid and bases,
uric acid, some diuretics and antibiotics are secreted (cleared) from the blood
into the proximal tubule’s lumen. Drugs that affect this element of the
nephron are called Carbonic Anhydrase Inhibitors, e.g. Alcetazolamide.
C. The descending loop of Henle, (thin part): is permeable to water that

moves by osmosis, (but not to Na) agents that affect this element of the
nephron are called Osmotic Diuretics such as manitol and urea.
D. The ascending loop of Henle, (thick diluting part): reabsorbs sodium

chloride via NaCl ATPase system, impermeable to water, Medications
affecting this portion are termed Loop diuretics, such as Furasemide (lasix)
Etacrynic acid, Toresemide and Bumetanide.
E. The Distal convoluted tubule (DCT): about 10% of sodium chloride is

reabsorbed; impermeable to water, it is responsible for secretion of
ammonia, K and H ions, reabosrbtion of Na and Ca (via PTH). Agents
affecting this segment are called Thiazide Diuretics, e.g. chlorothiazide and
chlorthalidone.
F. The Collecting duct (CD): ADH acts here to reabsorb water and
aldosterone acts to reabsorb Na. Drugs that affect this part are called
Potassium-Sparing Diuretics e.g. spironalctone and eplerenone.
DRUGS USED IN ANGINA PECTORIS
Introduction: Ischemic heart disease (IHD): is one of the most common

cardiovascular disease in developed countries and angina pectoris is the
most common condition involving tissue ischemia in which vasodilators
are used. The most common cause of angina is atheromatous obstruction of the
large coronary vessels, inadequate blood flow in the presence of coronary
artery disease (CAD), results in effort (classic) angina.
Transient spasm of localized portions of these vessels, which is usually,

associated underlying atheromas results in vasospastic or variant which
is also called Prinzmetal angina.
The primary pathogenesis of angina is an imbalance between the oxygen

requirement of the heart and the oxygen supplied to it via the coronary arteries

that become spastic and due to endothelial dysfunction which is associated
with impaired vasodilation.
Unstable Angina (Acute coronary Syndrome): is said to present when

episodes of angina occur at rest and when there is an increase in the
severity, frequency, and duration of chest pain in patients with previously
stable angina.
Factors increasing myocardial oxygen requirement include: tachycardia,

hypertension, smoking, hypodynamia, physical exercise, DM, stress and
hyperlipidemia.
In Theory, the imbalance between oxygen delivery and myocardial

demand can be accelerated by decreasing oxygen demand (drugs reducing
cardiac size, HR, or force) or by increasing delivery (by using vasodilators).
Three Classes of Medications Are Used In Angina:

A. Organic Nitrates: Nitroglycerin, Isosoribid mononitrate, Isosoribid dinitrate
and Amyl nitrate.
Pharmacokinetics: Nitroglycerin and isosorpid dinitrate are ineffective

orally because they undergo extensive hepatic metabolism, so they are
given sublingually and reach therapeutic blood levels within a few
minutes. Amyl nitrate is available as an inhaler and isosoribid mononitrate is
a metabolite of isosoribid dinitrate and has an oral bioavailability of
100%.
M.O: Nitrates act by conversion to nitrite ions and then to nitric oxide
(NO) which increases I/C concentration of cGMP that inactivates myosin
light chain kinase (MLCK) and hence preventing the interaction between
actin and myosin, which leads to relaxation of smooth muscles, in
addition to this process, prostacyclin may be involved and exerts
vasodilatation. The primary direct result of an effective dose of nitroglycerin is
marked relaxation of veins with increased venous capacitance and decreased
ventricular preload.
B. Calcium Blockers: Nifedipine, Verapamil, Amlodipine and Diltiazem
M.O: Generally there are several recognized Ca channels, (L, (present

mainly in cardiac and smooth muscles as well as neurons) T, N, R and P/Q).

The blockers currently available for clinical use in cardiovascular
conditions are L-type channel blockers, Ca channel antagonists inhibit
the influx of Ca into the cardiomyocyte and smooth muscle cells of
coronary artery thereby; a decreased of IC concentration of Ca results in
decreased contractility, sinus node pacemaker rate, A-V node conduction
velocity and vasodilatation in smooth muscles.
Specific Agents:
1) Nifedipine: is an orally effective potent vasodilator that affects mainly

vessels rather than the heart, useful in the treatment of variant angina,
hypertension and Reynaud's syndrome, it can cause reflex tachycardia,
hypotension, flushing and headache.
2) Verapamil: slows cardiac conduction directly and thus decreasing HR

and O2 demand, it causes greater negative inotropic effect than does
nifedipine, but it is a weaker vasodilator, used mainly for angina,
arrhythmia, migraine and hypotension, contraindicated in patients with
A–V blockade and in combination with digitalis.
3) Diltiazem: is an intermediate in its actions: reduces heart rate lesser

than verapamil, decreases BP lesser than verapamil, its clinical uses are
similar to nifedipine, it can be used in spastic angina, but its effect is
lesser than nifidipine.
C. β- adrenoblockers: Although they are not vasodilators except carvedilol

and nebivolol, β- adrenoblockers are useful in the management of effort
angina. The beneficial effects are decreased HR, BP and contractility- which
decrease myocardial oxygen requirements at rest and during exercise. They
decrease mortality in patients with recent MI and improve survival and
prevent stroke in patients with hypertension
AGENTS USED IN CARDIAC ARRHYTHMIAS
Arrhythmias: dysfunctions, cause abnormalities in impulse formation

and conduction in the myocardium.
Electrophysiology of Cardiac Rhythm:

The impulse originates in the SA node, which is located at the opening of
the superior vena cave into the RA, frequency is about 60 –100 bpm, then

it spreads through the atria and enters the A-V node (conduction here is
slow), then it spreads over the His–Purkinje system and invades all parts
of ventricles.
Phases of Action Potential of The Heart:

. Phase 0: Rapid depolarization: is characterized by opening of fast (M)
Na+ channels, Na rushes in, leading to depolarization.
.Phase I: Partial repolarization: is represented by inactivation of h
gates Na channels, rapid activation and inactivation of K channels
causing efflux of K.
. Phase 2: Plateau: is associated with the opening of Ca channels and
consequently Ca influx, K begins to leave the cell.
. Phase 3: Repolarization: is represented by inactivation of Ca gates
and outflow of K leading to repolarization.
. Phase 4: Pacemaker potential: depolarization results from gradual
activation of sodium channels (activation of M gates) and outflux of K
Refractory Period: is the time between the phase 0 and the phase 3 in
which the cell will not respond to any stimulus, even if it is stronger than
that causes action potential, because the cell at this period is resting.
Clinical Classification of Cardiac Arrhythmias: classified on the basis of

anatomic site of abnormality:
I. Atrial Arrhythmias: atrial flutter and fibrillation.
II. A-V node Arrhythmias: supaventricular tachycardia (SVT) and (AV)
nodal reentry or circuit movement in which one impulse reenters and
excites areas of the heart more than once.
III. Ventricular Arrhythmia: ventricular tachycardia (VT) and ventricular
fibrillation.
Classification of Antiarrhythmic Agents: classified according to their

predominant effects on the action potential into 5 classes:
1. Class I: Sodium Channel Blockers.
2. ClassII: β- Adrenoblockers.
3. Class III: Agents Prolonging The Effective Refractory Period (ERP).
4. Class IV: Calcium Channel Blockers.

5. Class V: Other Antiarrhythmic Agents e.g.: adenosine, K and others.
1. Class I: Sodium Channel Blockers.
Definition: agents that inhibit the influx of sodium into the cell (slows
phase 0), according to their effects on the action potential duration and
kinetics of Na channels they could be subdivided into the following
subclasses:
Class IA: Quinidine, Procainamide and Disopyramide.

Prolong the action potential duration and refractory period and dissociate from
the channels with intermediate kinetics.
Quinidine: is the prototype drug of this group, it is rapidly and completely

absorbed after oral administration, binds to albumin and α1-acid glycoprotein,
extensively metabolized in the liver to 3-hydroxy quinidine, which exerts the half
biologic activity of the parent drug, eliminated by hepatic way in the bile and
unchanged in the urine.
Therapeutic Uses: it is used to maintain sinus rhythm in the atrial flutter or

fibrillation (acute MI), A-V and ventricular tachycardia (VT). It prevents reentry
arrhythmia.
Side Effects:
a. Quinidine can cause SA, AV blockades, or asystole, so it is limited and
replaced by Ca antagonists.
b. At toxic doses it can cause by itself ventricular tachycardia, because it has an

atropine-like effect.
c. Quinidine increases the toxicity of digitalis: it accelerates digoxin’s steady

state by replacing its binding from plasma proteins.
d. GIT distress including nausea, vomiting and diarrhea.
e. Cinchonism Toxicity: is a syndrome including blurred vision, tinnitus,

headache, disorientation, and psychosis.
Class IB: Lidocaine and Mexiletine.

Shorten the action potential duration, and dissociate from Na
channels with rapid kinetics.
Lidocaine is the prototype of this class, given only parenterally (I.V),

because it undergoes extensive metabolism in the liver, so its
bioavailability is very low, distribution in patients with heart failure
is decreased, eliminated by the bile; consequently, its doses must be
adjusted in patients with hepatic dysfunction.
M.O: is a local anesthetic, blocks activated and inactivated Na channels,

with rapid recovery, (lidocaine is one of the least cardiotoxic of the
currently used Na channel blockers) and has no effect on conduction,
and therefore it doesn't produce any effect on atrial or A-V
arrhythmias.
Clinical Use: the drug of choice in treating ventricular tachycardia,

ventricular fibrillation, associated with MI and for digitalis toxicity.
Lodocaine should not be used for prophylaxis of arrhythmia, because of the
incidence of asystole.
Side Effects: it is a safe drug for the heart, but in excessive doses it
may cause hypotension (reduction of CO), neurologic paresthesia
tremor, central nausea, hearing disturbances and convulsions.
Class IC: Flecainide and Propfenone.

Have minimal effects on the action potential duration, and dissociate
from Na channels with slow kinetics.
Flecainide markedly slows phase 0 depolarization, it is well absorbed

and has a half life of 20 hours, currently used for SV tachycardia and
premature ventricular contraction (PVC).
Side Effects: dizziness, blurred vision, headache, all IC agents can

aggravate preexisting arrhythmias (persistent VT tachycardia), that is
resistant to treatment.
2. Class II: β- Adrenoblockers:

M.O: reduce phase 4 thus depressing automaticity, prolonging the A-V
conduction and decreasing HR used in all form of tachyarrhythmias, reduce
mortality rate in patients recovering from MI.

Toxicity:
a. CNS: sedation, sleep disturbances, depression, and psychosis.
b. Non-selective blockers: propranalol or sotalol can cause severe
bronchoconstriction in patients with asthma because of inactivation of
β2 adrenergic receptors.
c. Cardiac: bradycardia, heart failure, and arrhythmia.
d. Hypoglycemia in diabetic patients, due to blocking of β2

adrenoreceptors.
3. Class III: Agents Prolonging The ERP:

Amiodarone, Satolol and Bretylium
Agents that prolong phase 3 repolarization, as well as they block K

channels.
A. Amiodarone: the drug is incompletely absorbed following oral

route, metabolized extensively in the liver by the cytochrome P-450
system with the prolonged T ½ (several months), it inhibits hepatic
metabolizing enzymes especially those that metabolize digoxin and
warfarin, thus, allowing for their accumulation and toxicity.
M.O: it has complex effects showing class I, II, III actions and
prolong the duration of the ERP.
Clinical Uses: is very effective in severe refractory SV and ventricular

tachycardia and atrial fibrillation, it is limited to treat serious
ventricular arrhythmias, accumulates in many tissues causing
pulmonary fibrosis, gastrointestinal tract intolerance, tremor, ataxia,
hypo or hyperthyroidism and hepatotoxicity.
B. Satolol has both β adrenergic receptor-blocking (class 2) and

prolongs the ERP (class 3). Pharmacokinetically it is well absorbed with
high bioavailability, it is not metabolized and not bound to plasma
proteins, excretion mainly occurs via the urinary system, used
primarily for the management of severe VT( following M.I), to maintain
sinus rhythm in patients with atrial fibrillation, and for the treatment of
SVT and VT in children.

Side Effects: hypotension, bronchospasm, bradycardia and A-V
blockade.
C. Bretylium: it interferes with catecholamine release and prolongs
ventricular (not atrial) repolaraization usually administered
parenterally, and used for severe VT; postural hypotension is the most
common side effect.
4. Class IV: Calcium Channel Blockers: Verapamil and Diltiazem.
Mechanism of Action: agents decrease Ca influx, slow A-V conduction

and HR. Verapami and diltiazem have antiarrhythmic effect, but nifedipine
does not share antiarrhythmic efficacy and may precipitate arrhythmia.
Pharmacokinetically Verapami and diltiazem are well absorbed after oral

administration, verapamil is extensively metabolized in the liver, and
therefore its doses should be adjusted in hepatic patients.
Clinically are used to treat atrial arrhythmias, verapamil is the drug of

choice for the treatment of SVT; they are also indicated in hypertension.
The use of verapamil in sustained ventricular tachycardia can result in severe
hemodynamic collapse.
Adverse Effects: A-V blockade and hypotension.
5. Class V: Other Antiarrhythmic Agents: Adenosine, K and Magnesium.
A. Adenosine: is a nucleoside that occurs naturally throughout the body,

blocks Ca channels and activates the influx of potassium, therefore
maintaining hyperpolarization, the drug is rapidly cleared from the body
has a short t ½ (less than 10 seconds), so it is given in a continuous
infusion (I.V). Adenosine is the drug of choice for conversion of paroxismal
SVT to sinus rhythm. It has low toxicity, however it can cause flushing,
chest pain, hypotension, and atrial fibrillation.
B. Potassium: it stabilizes resting membrane leading to polarization.
C. Magnesium: influence Na, K and Ca channels.

Clinical Use: Both potassium and magnesium are indicated in patients
with digoxin arrhythmia.
DRUGS USED IN ACUTE HEART FAILURE (CHF)
Definition of CHF: is a syndrome, in which the heart is unable to pump

sufficient blood (decreased CO) to meet the metabolic needs of the body,
characterized by dilation of LV, RV or both, the most common cause is MI,
which leads to a rapid failure of the left heart. Etiologically the CHF may
be caused by atherosclerosis, hypertension, DM, valvular heart disease
and cardiomyopathy.
Types of CHF: two major types of CHF can be distinguished:

approximately 50% of younger patients have systolic failure (resulting
from MI) with reduced mechanical pumping action (contractility). The
remaining group has diastolic failure (as a result of hypertrophy) with loss
of adequate relaxation playing a major role in reducing filling and CO.
Pathophysiology of CHF:
A. Activation of the Sympathetic NS: causes activation of baroreceptores

that trigger β1- adrenoreceptors (tachycardia) and α1 adrenoreceptors
(vasoconstriction-increased afterload) leading to increased central venous
pressure, consequently preload develops.
b) Fluid retention: Reduced CO decreases renal blood flow, which is

compensated by activation of renin-angiotensin-aldosterone-ADH system
that causes edema, and hence enhancing preload.
c) Hypertrophy of the heart: LV or RV or both: the heart increases in size

and the chambers dilate, initially stretching of cardiac cells leads to rapid
contraction (compensated status), if these mechanisms fail to maintain
normal CO, the heart becomes decompensated.
Primary Signs of CHF: tachycardia, decreased exercise tolerance,

shortness of breath, cardiomegaly, peripheral or systemic edema due to RV
hypertrophy and pulmonary edema due to LV failure.

Three Pharmacologic Groups Are Used In CHF: the pharmacologic
approach is dependent on pathophysiologic aspects of the CHF:
I. Drugs Increasing Contractility:
I-1. Digitalis (Cardiac Glycosides): drugs that enhance cardiac muscle

contractility and thereby increasing CO. Digoxin and Digitoxin.
Mode of action: Cardiac glycosides act by inhibiting pump activity of

Na/K-ATPase, this results in increased IC concentration of sodium and
reduction of Ca expulsion from the cell by the Na/Ca exchange as well as
sequestration of Ca by the SER, with subsequent increased cytosolic
concentration of Ca.
Actions of digitalis on the cardiac muscle: cardiac glycosides at

therapeutic doses produce positive inotropic and tontropic effects, but
negative chronotropic (XCN) and dromotropic effects and finally they
decrease the ERP.
Notes:
1. Cardiac glycosides are effective in the treatment of atrial arrhythmias
such as atrial fibrillation and flutter because of their selective
parasympathetic action by reducing the conduction velocity.
2. Digoxin is not indicated in patients with diastolic failure.
Adverse Effects:
1. Gastrointestinal effects: anorexia, nausea and vomiting and diarrhea,
due to inhibition of Na/K ATPase in these tissues.
2. CNS effects: headache, fatigue, confusion, and blurred vision.
4. Renal damage: their doses should be adjusted in patients with renal

failure.
5. Drug interactions: Quinidine, amiodarone and verapamil cause a

reduction in digoxin's clearance and therefore accumulation leading to
their toxicity.
6. Severe arrhythmias: moving from SV tachycardia to complete heart

block, may result from hypercalcemia, hypomagnesemia and hypokalemia

which is most frequently observed in patients receiving thiazide or loop
diuretics and usually can be prevented by use of K-sparing agents.
Treatment of Digoxin Toxicity: the antidote is Digibind (Fab fragments,

Digoxin antibodies), which bind and inactivates the drug.
I-2: Bipyridines: Milrinone and Amrinone: mainly act by inhibition of

phosphodiesterase and thus increasing IC concentration of cAMP, which
results in increased contractility and vasodilation.
I-3: Beta Adrenomimetics: selective beta-1 agonist dobutamine has been

most widely used in patients with CHF.
II. Diuretics: especially furasemide (lasix) increases the excretion of water

and Na, resulting in decreased blood volume, hence reducing venous
pressure and ventricular preload, the result is reduction of salt and water
retention and edema and its symptoms, as well as reduction of cardiac size
leads to increased CO which is a major importance in systolic failure.
III. Vasodilators: are effective in acute HF because they reduce afterload,

preload or both, such as hydralzine and isosorbid dinitrate
ACEIs (captopril) and angiotensin antagonists (losartan) in addition to
mentioned above effects, ACEIs reduce salt and water retention by
decreasing aldosterone secretion.
Nesiritide: is a synthetic form of the endogenous peptide brain natriuretic

peptide (BNP) is used in acute HF but not in chronic, reduces venous and
arteriolar tone and causes diuresis.

Coronary obstruction/Cardiac
pain/Cardiac Ischemia lesion
Obstruction: Pain : Cardiac

Impediment. Angina lesions
Stenosis  Pectoris Ischemia fibrosis.
Narrowing of blood
vessle
I) Obstruction Narrow
lumen
II) Occlusion
Pain : Cardiac
Occlusion:
Closed vessel Infarct lesions Infarct
Pain (necrosis).
Closure
of the
lumen

Congestive Heart Failure
LV Dysfunction causes Decreased Blood Pressure and

Decreased cardiac output Decreased Renal perfusion
Stimulates the Release

of renin, Which allows
conversion of
Angiotensin
to Angiotensin II.
Angiotensin II stimulates
Aldosterone secretion which
causes retention of
Na+ and Water,
increasing filling pressure

Atrial Arrythmias
Atrial Flutter -300-400 bpm
Atrial Fibrillation 120-200 bpm
Ventricular Arrythmias
Ventricular Tachycardia
Ventricular Fibrillation

Drugs Used In CHF

UNIT 9
G.I.T PHARMACOLOGY
The Innervation and The Hormones of The GIT:

a. Neuronal Control: ENS is specialized system located mainly in the wall of
GIT, it receives preganglionic fibers from the parasympathetic system as well as
postganglionic sympathetic axons, consisting of submucosal plexus and myenteric
plexus, (between circular and longitudinal layers), myentric plexus contains
CGRP which regulates motility by releasing excitatory neurotransmitters
proximally such as acetylcholine, serotonin and substance P, and inhibitory
neurotransmitters distally including VIP, NO, ATP and dopamine.
b. Hormonal Control: gastric secretion is regulated by:

1. The endocrine hormone (gastrin from antral G-cells) secreted into the
blood.
2. The paracrine or local histamine (H2 receptors) from parietal cells.
3. The vagal postgaglionic nerves acetylcholine (M3) receptors.
Physiology of Gastric Secretion: The stomach secretes about 2,5 L of gastric

juice daily, the principle exocrine secretions are pepsinogens from the chief cells or
peptic cells, HCl and intrinsic factor are secreted from gastric parietal cells.
Other cells that are the major source for histamine release are
enterochromofin like (ECL) cells containing receptors for acetylcholine (M1) and
gastrin, binding of histamine to H2 receptors on the parietal cells results in
activation of adenylyl cyclase, which increases the IC of cAMP that stimulates
acid secretion by activation of the H/K ATPpase, to secrete H ions into the
lumen of the stomach in exchange for K, binding of acetylcholine to
cholinoceptor is mediated mainly by increased cytocylic concentration of Ca.
Inhibitors of Gastric Secretion are represented by PGE2, and somatostatin
(produced by antral D-cells).
Drugs USED IN HYPERACIDITY (GASTRITIS & PEPTIC ULCER)

I. Antacids: M.O: are weak bases which react with gastric acid to form a salt
and water, thereby diminishing intragastric acidity, (neutralization acidity) in
addition they stimulate PGE2 synthesis.
Agents: Sodium biocarbonate, Calcium carbonate, magnesium hydroxide,
and aluminum hydroxide.
A. Sodium Bicarbonate: reacts with hydrochloric acid to form carbon

dioxide and sodium chloride, formation of carbon dioxide results in distention
and belching. Unreacted alkali is readily absorbed causing metabolic alkalosis.
Sodium chloride absorption may exacerbate fluid retention in patients with
HF, hypotension and renal failure.
B. Calcium Carbonate: reacts more slowly than sodium bicarbonate, so it

can cause distention and belching, excessive doses can lead to hypercalcemia, renal
insufficiency and metabolic alkalosis.
C. Magnesium Hydroxide and Aluminum Hydroxide: react slowly with

HCl to form magnesium chloride or aluminum chloride, because no gas is
generated, belching does not occur, metabolic alkalosis is also uncommon because
of the efficiency of the neutralization reaction, because unabsorbed magnesium
salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these
agents are commonly combined together (Maalox and Mylanta).
II. H2- Receptor Antagonists or H2-Blockers: Cimetidine (the prototype),

Ranitidine, Famotidine and Nizatidine.
Pharmacodynamics: are selective H2 (affect neither H1 nor H3 receptors),

reversible competitive antagonists, acting by decreasing IC concentration of
cAMP which inhibits gastric acid secretion produced by histamine, they suppress
basal and meal-stimulated secretion, the volume of gastric secretion and the
concentration of pepsin are also reduced, they are especially effective at
inhibiting nocturnal acid secretion (which depends largely on histamine), but they
have a modest impact on meal-stimulated acid secretion (stimulated by 3 factors).

Clinical Uses: H2 -receptor antagonists continue to be prescribed but proton
pump inhibitors are replacing them for most clinical indications
a. Gastro-Esophageal Reflux Disease (GERD) heartburn or dyspepsia: H2

antagonists provide longer therapeutic effect (6-10 hours) than do antacids (1-2
hours), may be taken prophylactically before meals.
b. Peptic Ulcer: all agents provide healing of duodenal and gastric ulcers
administered once daily, usually they are used in combination with other drugs
(antimicrobials) to eradicate Helicobacter pylori (HP).
c. Zollinger-Elison Syndrome: is a complex condition in which one or more tumors

form in the pancreas or in the duodenum, tumors are called gastrinomas, secrete
large amounts of the hormone gastrin, which causes excessive production of acid.
d. Prevention of bleeding from stress-related gastritis: in addition to proton

pump inhibitors, they increase intragastric pH and hence reducing the incidence
of clinically significant bleeding.
d. Non-Ulcer Dyspepsia: is seen frequently in gastritis B.
Adverse effects: H2-blockers are extremely safe drugs, however side effects
may appear such as CNS toxicity including headache, dizziness, confusions and
hallucination, especially in elderly patients or patients with hepatic or renal
dysfunctions, Cimetidine causes endocrine effects such as gynecomastia,
impotence and galactorrhea.
III. Proton Pump (H /K ATPase) Inhibitors: the most widely used agents
among others:
Agents: Omeprazole (prototype drug), Lansoprazole, Pantoprazole, and
Esomeprazole.
Pharmacokinetics: they are administered as acid-resistant enteric coated

formulations (capsules), to protect them from acid destruction, their molecules are

lipophilic so readily absorbed from the intestine, then transported to the acid
partial cells canaliculus, (become protonated) where they are converted to active
drugs, they should be administered 1h before meal, because absorption is
decreased in the presence of food, they have a short half-life (2 hours), but the
duration of acid inhibition is up to 24 hours, due to their irreversible inactivation of
pump proton, they undergo rapid biotransformation and eliminated in the urine
and feces.
Phaomacodynamics: act by binding to H/K ATPase enzyme of the parietal

cells, they suppress gastric secretion (last step), inhibit both basal fasting and
meal-stimulated secretion, compared to selective H2 antagonists they are more
potent, maintain rapid relief and faster ulcer healing, more than 90% of duodenal
ulcers heal within 4 weeks and a similar percentage of gastric ulcers within 6-8
weeks.
Clinical Uses:
1. GERD: (first line therapy) the most effective agents for erosive and non-
erosive esophagitis and complications of reflux disease.
2. Peptic Ulcer: which is associated with H.P, they provide both healing and
eradication, by producing direct minor antimicrobial activity, increasing intragastric pH
and lowering the minimal inhibitory concentrations of antibiotics against H.P.
Triple Therapy: is the best treatment regimen against ulcer consists of 14-day
regimen and include: Omeprazole twice daily, clarithromycin (500 mg) twice
daily and amoxicillin (1g) twice daily, or metronidazole 500 mg twice daily (1-2
weeks or longer) after completion of triple therapy, the proton pump inhibitor
should be continued once daily for a total of 4-6 weeks to ensure complete ulcer
healing. They are also used to heal NSAIDs-associated ulcer to prevent re-
bleeding from peptic ulcers, and gastrinomas.
Adverse Effects: generally they are well tolerated but with long-term therapy
side effects may develop such as headache, abdominal pain, diarrhea, increased
infection (salmonella, shigella) because of hypochlorhydria and hence decreased

resistance to microorganisms , hypergastrinemia due to inhibited acid (feedback)
or atrophic gastritis due to decreased acid secretion.
Mucosal Protective Agents:

1. Sucralfate: is a salt of sucrose which is negatively charged binds to
positively charged proteins in the base of ulcers or erosions forming a physical
barrier that restricts further damage and stimulates mucosal PGs and bicarbonate
secretion.
2. Prostaglandin Analogs: The human GI mucosa synthesizes prostaglandins

namely E and F. Misoprostol inhibits acid secretion and protects mucosa by
stimulating production of bicarbonate, it reduces and prevents the incidence of
NSAIDs-induced ulcers.
ANTIDIARRHEALS
Causes: increased motility of the GIT and decreased absorption of fluid are
major factors in diarrhea
Classification:
A. Antimotility Agents: Diphenoxylate and Loperamide Both are analogs

of meperidine they activate presynaptic opioid receptors in the ENS to
inhibit acetylcholine release and decrease peristalsis. At the usual
doses, they lack analgesic effects. Side effects include drowsiness,
abdominal cramps, and dizziness. Because these drugs can contribute to
toxic megacolon, they should not be used in young children or in patients
with severe colitis.
B. Adsorbents: Bismuth subsalicylate, Methylcellulose and Aluminum

hydroxide are used to control diarrhea, act by adsorbing intestinal toxins
or microorganisms and/or by coating or protecting the intestinal mucosa.
LAXATIVES
Laxatives are commonly used to accelerate the movement of food

through the gastrointestinal tract. These drugs can be classified on the
basis of their mechanism of action as:
A. Irritants and Stimulants: Senna is taken orally; it causes evacuation of
the bowels within 8 to 10 hours. It also causes water and electrolyte
secretion into the bowel. In combination products with a docusate-
containing stool softener, it is useful in treating opioid-induced
constipation.
Bisacodyl: is available as suppositories and enteric-coated tablets, is a

potent stimulant of the colon. It acts directly on nerve fibers in the
mucosa of the colon.
B. Bulk Laxatives: Methylcellulose, Psyllium seeds, and Bran

They are indigestible that form gels in the large intestine, causing water
retention and intestinal distension, thereby increasing peristaltic activity.
C. Osmotic Laxatives: Magnesium citrate, Magnesium sulfate, Sodium

phosphate, and Magnesium hydroxide.
They are nonabsorbable salts that hold water in the intestine by osmosis
and distend the bowel, increasing intestinal activity and producing
defecation in a few hours. Lactulose is a semi synthetic
disaccharide sugar that also acts as an osmotic laxative.
D. Stool Softeners (emollient laxatives or surfactants): Docusate sodium,

Docusate calcium, and Docusate potassium: agents that become emulsified
with the stool and produce softer feces and ease passage. They should not
be taken together with mineral oil because of the potential for absorption of the
mineral oil.
E. Lubricant Laxatives: Mineral oil and glycerin suppositories are

considered to be lubricants. They facilitate the passage of hard stools.
Mineral oil should be taken orally in an upright position to avoid its
aspiration and potential for lipid or lipoid pneumonia.

HOW IT WORKS AT THE RECEPTOR LEVEL
Combined neurocrine, endocrine and paracrine
Acetylcholine
neural input
events in the activation of gastric HCl secretion
neurocrine
ACh
receptor
PARIETAL cell
histamine
receptor
H/K
ECL cell P
histamine- transduction- HCl
secreting cell activation events
secretion
H/K
P
gastrin
receptor
paracrine
release of
Gastrin histamine
hormonal input ECL cell =
endocrine enterochromaffin-like cell
G cell =
gastrin-secreting cell
G cell

Drugs Affecting Gastric Secretion

Action of Anti-Ulcer Drug Groups

UNIT 10
ENDOCRINE PHARMACOLOGY
ADRENOCORTICOSTEROIDS
Physiology of The Adrenal Gland: the adrenal gland consists of 2 layers:

The cortex which produces corticosteroids and medulla that releases
catecholamines, the cortex histologically is subdivided into 3 zones:
a. Zona Fasiculata that releases Glucocorticoids.

b. Zona Glomerulosa which releases Mineralocorticoids
c. Zona Reticularis releasing Gonadocoricoids.
Pharmacology of Glucocorticoids: Cortisone, Betamethasone,

Beclomethasone, Dexamethasone, Prednisalone, Prednisone, Paramethasone,
Methylprednisalone and Triamcinolone.
Synthesis and pharmacokinetics: the principle glucocorticoid is cortisol

(hydrocortisone or compound F), it is well absorbed following oral
administration, its synthesis and secretion is regulated by adreno
corticotricotropic hormone (ACTH), the t ½ is about 60 to 90 min, about 90%
binds to corticosteroid–binding globulin (CBG) and alpha 2 globulin,
about 20 % is converted into cortisone in the kidney, under the influence of 11-
hydroxysteroid dehydrogenease, inactivated in the liver to
teterahydrocortisone and tetrahydrocortisol, elimination occurs via the
urine. The starting substance of corticosteroids is cholesterol which is
converted into pregnenolone under the influence of ACTH and AT ΙΙ.
Pharmacodynamics: most effects of glucocorticoids exerted by binding to

cytoplasmic or nuclear receptors, the receptor-hormone complex then is
actively transported into the nucleus, where it binds to DNA, activated
genes create new mRNA that moves back to the cytoplasm, translation
produces new proteins for cell processes and formation of lipocortins-1
which inhibits probably phospholipase A2 and therefore inhibition of
prostaglandins and leukotreines formation).
Physiologic Effects:
A. Metabolic: Glucocorticoids are catabolic hormones, they stimulate
gluconeogenesis, glycogenolysis, lipolysis, and proteolysis in muscles, fat
and bone but not in the liver leading to hyperglycemia, in excessive
production they cause redistributrion of lipids (facial, visceral, nuchal
and supraclavicular areas).
B. Anti-inflammatory and Immunosuppressive effects: due to their

ability to block mediators, especially histamine, prostaglandins and
leukotrienes of inflammation plus depression of macrophages to produce
antibody as well as cytokines such as TNF, IL-I, IL-II and interferon
(immunosuppressant).
C. Effects on the CNS: insomnia and euphoria followed by depression, at

large doses can cause increased ICP.
D. Endocrine: glucocorticoids inhibit the release of ACTH, GH, TSH and

LH.
E. Lungs: maintain production of surfactant which prevents collapse of

alveoli.
F. Bone: glucocorticoids oppose vitamin D actions, so decreasing Ca

absorption, increase activity of osteoclasts and decrease activity of
osteoblasts.
G. GIT: chronic use of glucocorticoids can lead to decreased immune

response against HP and the incidence of peptic ulcer.
Clinical Indications of Corticosteroids:
1. Addison’s Disease (Hypocortisolism): is a chronic adrenocortical

insufficiency, resulting from autoimmune process and tumors of the
adrenal gland, leading to destruction of cortex and decreased production
of gluco-mineralocorticoids. Addison's disease should also be
distinguished from secondary and tertiary adrenal insufficiency, which are
caused by deficiency of ACTH and CRH (produced by the
hypothalamus), respectively.
Clinical Picture: is characterized by hyponatremia, hypotension,

hyperkalemia, weakness, hyperpigmentation, hypoglycemia, and weight loss.

2. Cushing’s Syndrome: is bilateral hyperplasia of acortex in response to
ACTH-secreting pituitary adenoma (Cushing’s disease), treated with
large doses of cortisone during operation and after adrenoectomy.
3. Respiratory application: cortisol normally is responsible for fetal lung

maturation, but cortisol is not used for this purpose, (when delivery is
anticipated before 34 weeks of gestation), cortisol is replaced by betamethasone,
because it less binds mother's plasma protein and less metabolized by the
placenta, finally cortisol reduces the incidence of respiratory distress
syndrome.
4. Anti-inflammatory and immunosuppressive therapy: glucocorticoids

are indicated in several inflammatory disorders including asthma, eye,
ears, nose, eczema, allergy, anaphylactic shock, autoimmune diseases,
organ transplantation and malignancies.
Toxicity of Glucocorticoids:
1. Infection: suppression response to infection.
2. Adrenal gland suppression: suppression of endogenous glucocorticoid

synthesis, for therapy more than 2 weeks, the use of ACTH is
contraindicated.
3. Others: hypertension, hyperglycemia, euphoria, cataracts (alteration in

lens from normally clear to opaque, can lead to vision loss, moon face
with red cheeks and thinning of skin of extremities, intracranial
hypertension and peptic ulcer.
Contraindications: DM, peptic ulcer, hypokalemia, hidden infection,

osteoporosis and glaucoma.
Pharmacology of Mineralcorticoids: Aldosterone, Fludrocortisone

(commonly used) and Deoxycorticosterone.
The most important mineralocorticoid is aldosterone, small amounts of

deoxycorticosterone are also formed, aldosterone is synthesized mainly
by the zona glomerulosa of the adrenal cortex, it is regulated partially by
ACTH secretion and mainly by renin-angiotensin II, its ACTH suppression
is weaker than cortisol, the secretion of deoxycorticosterone mainly is
regulated by ACTH.

Physiologic actions: mainly promote reabsorption of Na from the DCT
and CDs, absorption of Na from the gut also is increased in the presence
of aldosterone, excessive secretion leads to Conn’s Disease.
Fludrocortisone is a potent steroid with both gluco-mineralocorticoid
activities, used commonly in Addison’s disease in combination with
cortisol.
Mineralocorticoid Antagonists:
1. Spironalctone: is a potassium-sparing diuretic, binds to aldosterone

receptors, forming inactive complex that prevents receptor translocation
into the nucleus, the result is reducing synthesis of proteins required for
Na absorption and therefore H and K secretion is inhibited, it causes
hyponatremia, hyperkalemia and metabolic acidosis.
Pharmacokinetics: the drug is completely absorbed orally, binds highly

to plasma proteins, extensively metabolized into an active metabolite
canrenone, spironalctone induces the CYP system, and its onset of action is
slow and lasts for 2-3 days.
Clinical Indications: used primarily in the treatment of primary

aldosteronism (Conn’s Disease): is a pathologic condition characterized
by oversecretion of aldosterone by an adrenal adenoma, its clinical
manifestations are hypertension, hypernatremia, hypokalemia (tetany)
hypervolemia, metabolic alkalosis and general weakness. Spironalctone has an
ability to block androgen receptors, so it is useful in the management of
hirsutism in women; aldosterone is useful also in secondary
aldosteronism due to CHF, hepatic cirrhosis and nephritic syndrome, because
it enhances diuresis and therefore decreasing CVP (↓ preload) in
combination with loop or thiazide diuretics.
Side Effects:
a. Hyperkalemia: (severe arrhythmia) greatly increased in the presence of
renal disease or drugs that reduce renin (beta adrenoblockers and NSAIDs)
or angiotensin ΙΙ activity (ACEIs, AT II antagonists).
b. Metabolic acidosis: due to inhibition of H/Na/K exchange.

c. Endocrine: because its structure has some similarity with sex hormones,
gynecomastia, impotence, BPH and menstrual abnormalities may occur.
d. Others: GI disturbances, sedation, headache, skin rashes and kidney

stones.
PANCREATIC HORMONES, ANTIDIABETIC AGENTS:
Basic Physiology of The Pancreas: the endocrine pancreas produces the

following peptide hormones:
1. Insulin by beta cells: the only hormone that lowers blood glucose.
2. Glucagon by alpha cells acts to oppose actions of insulin.
3. Amylin or islet amyloid polypeptide by PP cells or gamma cells:
modulates appetite, gastric emptying and glucagon and insulin secretion.
4. Somatostatin by delta cells: regulates/stops α and β cells
The exocrine pancreas produces digestive enzymes - trypsin, amylase and

lipase.
Diabetes Mellitus (DM): is a metabolic disorder characterized by chronic

hyperglycemia due to absolute deficiency (type I) or relative (type II)
deficiency of insulin, leading to macro and microvascular complications.
Etiology, Incidence and Pathophysiologic Aspects of Insulin-

Dependent Diabetes Mellitus (IDDM), (Type I):
IDDM affects mainly children and persons under age 30, characterized by
autoimmune process, nearly 80% to 90% of beta cells are destroyed
(necrosis), and this destruction is caused by islet cell autoantibodies,
probably triggered by viral infection and chemical toxins, leading to
absolute deficiency of insulin. Two phases of insulin release in response
to increased glucose levels are missing. (Normally there is a steady basal
release of insulin occurring in pulses every 15 to 30 minutes; insulin is released
in response to hyperglycemia by 2 phases:
a. Rapid phase: reflects release of stored glucose.
b. Slow (delayed) phase: represented by both continued release of stored and
new synthesis of insulin). Due to insulin deficiency activation of
gluconeogenesis, glycogenolysis, reduction of glycogenesis and glycolsis
take place, the levels of glucagon are elevated, all of which lead to
hyperglycemia, osmotic diuresis, glucosuria, poluria, polydipsia, polyphagia and
weight loss resulting from breakdown of nutritional stores, patients with
type 1 require chronic use of exogenous insulin.
Fasting Glucose: the average is 60 to 110 mg/dI.

Postprandial Glucose (after 2 hours): ranges form 65-140 mg/dl.
Glycohemoglobin: HbA1c : is a blood test that reflects average blood
glucose levels over the period of 2 to 3 months, elevated blood glucose
results in attachment of glucose with Hb, this complex lasts for the life
span of RBCs (90-120 days), normally glucose is less than 6 % of total Hb.
Secretion of Insulin: insulin primarily is secreted in response to blood

glucose which is taken up by β-cells and undergoes phosphorylation by
glucokinase (sensor of hyperglycemia), this reaction raises ATP
concentrations that blocks K channels and activates Ca gates leading to
insulin release by exocytosis.
GI Hormones: (secretin, gastrin, cholecystokinin, fatty acids and glucagon like

peptide) also trigger the release of insulin, that’s why oral glucose
stimulates more insulin release than IV glucose, whereas somatostatin,
glucagon and activation of α2 adrenoceptoros inhibit its secretion.
Metabolism of Insulin: is not taken orally because it is inactivated

rapidly in the G.I.T, thus it should be administered parenterally (S/C and
I.V), metabolized by insulinas of the liver and kidney, the half life is very
short about 3-5 minutes.
The Insulin Receptors: distributed in most tissues, but mainly found in

the liver, fat and muscle cells, insulin stimulates glycolysis, glycogen
synthase (activator of glycogenesis), inhibits glycogen phosphorylase
(blocker of glycogenolysis), lipolysis, proteolysis and consequently
preventing gluconeogenesis.
Clinical Pharmacology of Insulin:

Insulin preparations are classified according to their onset and duration
of action:
1. Rapid-Acting Insulin: insulin lispro and insulin aspart are given S/C
15 minutes before the meal, the onset of action within 5-15 min, duration
of action is about 3-5 hrs and the peak effect within 1h.

2. Short Acting Insulin: regular insulin or (crystalline zinc insulin)
(CZI), marked R on the bottle, the onset of action appears within 30 min
to 1h and lasts for 5-8 hrs, the peak is achieved by 2-3 hrs, administered
20 to 30 min before the meal, the only type of insulin that administered
I.V in the management of diabetic ketoacidosis and in pregnancy.
3. Intermediate-Acting Insulin:
A. Lente insulin: is a amorphous precipitate of insulin with zinc ion,
(semilente 30%) combined with 70% of ultralente (prolonged insulin), this
combination provides a relatively rapid absorption with a sustained
action making it the most widely used, but it is not suitable for I.V use.
B. Neutral protamine hagedorn, isophane insulin, insulin-NPH or

isophane insulin: is a suspension of crystalline zinic insulin combined
with the positively charged protamine, after SC injection, (nerve IV)
proteolytic tissue enzymes degrade the protamin to permit absorption of
insulin, its onset of action within 2-5 hrs, duration of action of 4-12 hrs,
because of its conjugation with protamine, usually combined with
regular, lispro or aspart insulin and given 2 or four times daily for insulin
replacement, used for all forms of DM except for diabetic ketoacidosis
and emergency hyperglycemia.
4. Long Acting Insulin: sometimes referred to as (peakless insulin)

because it tends to have a long slow sustained action rather than sharp.
A. Ultralente insulin: is a long acting insulin that is discontinued in the

US in 2005. One of the reasons for discontinuation was declining use due
to physicians favoring NPH insulin.
B. Insulin glargine: has a slow onset of action (1-1, 5 h), and achieves
maximum effect after 4-5 hrs, maintains prolonged hypoglycemic action
(11-24 hrs or longer), given once daily and shouldn't be mixed with other
insulins
Combinations of Insulin: For convenience, insulin lispro, aspart can be

acutely mixed with NPH insulin without affecting rapid absorption.
Insulins composed of isophane complexes of protamine with insulin
lispro and insulin aspart have been developed such as NPL- Neutral
Protamine Lispro (50% /50%) and NPA- Neutral Protamine Asparat

(70%/30). Premixed formulations of 70%/30% NPH/regular continue to be
available.
Adverse Effects of Insulin Preparations:
1. Hypoglycemia: is the most common complication of insulin therapy

characterized by sweating, tremor, tachycardia, nervousness and
confusion, in severe hypoglycemia seizures and loss of consciousness,
treated initially by prepared glucose tablets or fruit juice, severe
hypoglycemia is reversed by I.V 20-50 ml of 50% glucose solution over a
period of 2-3 minutes, or by injection of 1 mg of glucagon S/C or I.M, if
IV therapy is not available, non-selective β- blockers are contraindicated
2. Insulin allergy: is an immediate type of hypersensitivity represented

by local reactions, redness, tenderness, swelling and urticaria, due to
release of histamine from mast cells sensitized by insulin antibodies,
these reactions usually disappear with continued use of insulin,
antihistamines could be used 1 hour before insulin injection, systemic
reactions are rare.
3. Insulin resistance: develops due to formation of antibody against

insulin (human and animal).The primary treatment for insulin resistance is
exercise and weight loss. Low-glycemic load diet has also been shown to help;
prednisone is indicated to block the production of antibodies.
4. Insulin lipodystrophy: lipodystrophy refers to a localized disturbance

of fat metabolism in the form either lipoatrophy (loss of S/C fatty tissue
at the site of injection) or lipohypertrophy (the development of fibrofatty
masses caused by repeated use of an injection site), could be corrected by
changing the site of injection or with liposuction.
5. Increased cancer risk: attributed to insulin resistance and

hyperinsulinemia has been reported in individuals with insulin
resistance, treatment with insulin and sufonylureas which increase
circulating insulin levels, but not metformin.
Etiology Incidence and Pathophysiologic Aspects of Non-Insulin-

Dependent Diabetes Mellitus (NIDDM), (Type II):

NIDDM affects mainly people over age 40 years, has a strong genetic
factor, characterized by insulin resistance due to decreased sensitivity of
tissues to insulin, which becomes less effective at stimulating glucose
uptake by tissues, compensatory to overcome insulin resistance and to
prevent hyperglycemia, the pancreas releases insulin, this impaired
secretion of insulin is characteristic for NIDDM. Only the first phase is
missing in NIDDM, whereas the 2 phases are missing in IDDM.
The metabolic alterations are milder than IDDM, there is enough insulin
to prevent the breakdown of fat into free fatty acids and glycerol and
therefore ketoacidosis does not develop, this type can lead to
hyperglycemic hyperosmolar nonketotic syndrome or coma, persistent
hyperglycemia causes osmotic diuresis, to maintain osmotic equilibrium,
water shifts from the ICF compartment into ECF one, resulting in losses
of water and electrolytes, glucosuria, dehydration and hypernatremia, the
triggering factors of hyperosmolar coma are pneumonia, MI, ingestion of
medications that provoke insulin insufficiency e.g. thiazides and propranolol, the
treatment of NIDDM is achieved initially by the diet and oral
hypoglycemic agents, 30% or more will benefit from insulin therapy to
control blood gluclose.
Type III DM: refers to multiple other specific causes of elevated blood
glucose: pancreatoectomy, pancreatitis, non-pancreatic disease, drug
therapy, etc.
Type IV DM (Gestational Diabetes): is defined as any abnormality in

glucose levels noted for the first time during pregnancy in which the
placenta and placental hormones create an insulin resistance that is most
pronounced in the last trimester.
Pharmacology of Oral Hypoglycemic Agents:
I. Sulfonylureas:
A. First Generation: Tolbutamide, Chlorpropamide and Tolazamide.
B. Second Generation: Glibenclamide, Gyburide, Glibizide, Gliclazide

and Glimepiride.
Pharmacokinetics: the agents following oral administration are highly
bound to plasma proteins, metabolized in the liver and excreted either
hepatically or renally, tolbutamide is the safest sulfonylurea for use in
elderly diabetics because of its short t ½ (4-5 hrs), chlorpropamide should
be avoided in elderly because of its long t ½ (32 hrs), which can cause
hyponatremia and hypoglycemia.
The second generation are more prescribed than the first because they have
fewer adverse effects and drug interactions, glipizide has the shortest t ½
(2-4 hrs) among second generation agents, it should be taken 30 minutes
before the breakfast, produces less serious hypoglycemia than glyburide.
Glibenclamide is oxidized in the liver with the formation of moderately
active products, which are excreted in the urine, 50% of glibenclamide is
eliminated unchanged in the feces, its half-life of 10 hrs, in renal patients
doses of glibenclamide should be reduced due to accumulation of its
active metabolites.
M.O: Sulfonylureas lower blood glucose level by:
A. Stimulation of insulin release: by blocking K and activating Ca

channels leading to depolarization, so they require the presence of
functioning β-cells.
B. Reduction of serum glucagon levels: may be due to stimulation of
somatostatin action.
C. Increased binding of insulin to target tissues.
Side effects, Drug Interactions and Contraindications:

The most common side effects are weight gain, hyperinsulinemia and
hypoglycemia (polyphagia), contraindicated in renal and hepatic
patients, pregnancy (they cross the placenta) so pregnant diabetics are
treated with insulin, allopurinol, probenecid, phenylbutazone and
salicylates decrease their metabolism and elimination (first generation)
thus increased their hypoglycemic action.
II. Biguanides:
Pharmacodynamics: Phenformin is the older biguanide that

discontinued because of its association with lactic acidosis.
The only available biguanide for clinical use is Metformin which does
not stimulate insulin release from β-cells; it exerts its hypoglycemic effect by:
stimulation of glycolysis, inhibition of gluconeogenesis in the liver and kidneys,
slowing glucose absorption form the gut and finally it decreases levels of
glucagon in the blood.

In comparison with sulfonylurea metformin doesn't induce
hyperinsulinemia and does not require functioning of β-cells
Pharmacokinetics: the t ½ is about 1.5-3 hrs, metformin is neither bound

to proteins nor metabolized, excreted by the kidneys, because it impairs
hepatic metabolism of lactic acid, metformin may develop lactic acidosis.
Clinical Use: metformin is the drug of choice to treat NIDDM patients

with obesity because it doesn't cause polyphagia such as sulfonylureas, used
alone or in combination with other antidiabetics, (the dose of insulin
should be reduced) it is important to note that metformin decreases the
incidence of diabetic macro-microvascular complications probably by
reducing the ratio LDL/VLDL and rising HDL, compared to other
therapies which only modified micro-vascular morbidity.
Adverse effects: GIT discomfort, reduced absorption of vitamin B12, lactic

acidosis, but less than Fenformin in the presence of renal or hepatic
insufficiency.
AGENTS AFFECTING BONE MINERALS HOMEOSTASIS
Basic Pharmacology of Calcium and Phosphate:

The human skeleton consists of 80% of cortical bone (dense, compact or
outer layer) and 20 % of trabecular bone (the inner layer), calcium and
phosphate, are the major minerals that perform remodeling of the bone,
they are regulated by the parathyroid hormone (PTH), fibroblast growth factor
23 (FGF23), the steroid vitamin D, and secondary by calcitonin, prolactin, GH,
insulin, T4, glucocorticoids and sex steroids.
I. Pharmacology of PTH: is produced by parathyroid glands that contain

a Ca-sensitive protease capable of cleaving the intact hormone into
fragments, thereby limiting PTH production. The parathyroid gland also
contains the vitamin D receptors and the enzyme CYP27B1 that produce the
active metabolite of vitamin D. The metabolic clearance of PTH is rapid,
probably by renal and hepatic metabolism; it is responsible for increasing
serum of Ca and decreasing serum of phosphate.
Regulation of Ca Levels: in bones PTH acts on osteoblasts to secrete

Receptor Activator of Nuclear Factor κ B (RANK) protein, which acts on
osteoclasts and osteoclasts precursors to increase their activity and

number, so PTH mobilizes Ca from bone (resorption of bone). An antibody
that inhibits actions of RANK has been developed (Denosumab) for the
treatment of excess bone resorption as in osteoporosis and certain cancers. PTH
in low and intermittent doses increases bone formation. Teriparatide is a
recombinant PTH form used for treatment of osteoporosis.
In intestine: increases Ca absorption by stimulation the synthesis of

calcitirol. Finally in kidneys PTH increases Ca and Mg reabsorption. PTH
increases absorption of phosphate from the gut, accelerates their outflow
from the bone and promotes phosphate excretion.
II. Pharmacology of Vitamin D: vitamin D a prohormone rather than a

true because it must be further metabolized to gain biologic activity, there
are 2 sources of vitamin D:
A. Natural Vitamin D3 Cholecalciferol is generated from the skin under the

influence of ultraviolet irradiation, from its precursor 7- dehydrocholesterol,
which has been formed from cholesterol in the intestinal wall.
B. Plant Vitamin D2: Ergocalciferol is derived from ergosterol in plants.
Metabolism of Vitamin D: vitamin D is hydroxylated in the liver under

the action of Vitamin D 25-hydroxylse to form 25-hydroxyvitamin D
(25[OH] D), or Calcifediol then converted in the kidney under the
influence of alpha-1 hydroxylase to 1,25-dihydroxyvitamin D (1.25 [OH]2 D)
(Calcitirol) and 24, 25 dihydroxyvitamin D, only calcifediol and
calcitirol are available for clinical use; the most important regulators are
PTH and decreased levels of phosphate, clacifediol is the main vitamin D
metabolite in the circulation, the vitamin D-binding protein α-globulin
binds calcifediol and 24, 25 dihydroxyvitamin D with comparable high
affinity and vitamin D and calcitriol with lower affinity. The half life is
about 23 days; it is cleared via the liver, excess vitamin D is stored in
adipose tissue.
Actions of Calcitirol: It stimulates absorption of Ca by induction of new

protein synthesis (Ca-binding protein) and PO4 in the intestine,
mobilization of Ca from the bone as well as increases re-absorption of
calcium from renal tubules.

Role of Vitamin D On Bone Mineralization: vitamin D favors the
formation of osteoblasts from their precursors (monocytes), by
production of RANK, in addition it promotes the synthesis of calcium
binding protein (osteocalcin) involved in deposition of Ca into osteoid
matrix.
Interaction of PTH and Vitamin D: the secretion of PTH depends

primarily on Ca levels, hypocalcemia causes hyperproduction of PTH, and
conversely, hypercalcemia suppresses PTH release, concerning phosphate
any increase in phosphate stimulates PTH release, both hypercalcemia
and hyperphasphatemia inhibit the release of 1.25 (OH)2 D and
conversely increased 1.25 (OH)2 D inhibits PTH levels.
Clinical Uses of Vitamin D:

1. Preventing and treating rickets, a disease that is caused by vitamin D
deficiency in children.
2. Osteogenesis Imperfecta: a group of hereditary disease caused by

defective synthesis of type I collagen (the major component of ECM), is
characterized by too little bone resulting in skeletal fragility, blue sclera
(decreased collagen content), hearing loss (conduction defects in the
middle and inner ear bones) and small misshapen teeth (dentin
deficiency).
3. Chronic renal failure (CRF): is the inability of kidney to maintain

metabolic, fluid and electrolyte balance, resulting in uremia (retention of
urea and creatinine), hypoclacemia (due to decreased production of
calcitriol in renal tissues from calcifediol), hyperphosphatemia,
hyponatremia, hyperkalemia and anemia.
4. Hypocalcemia: is most commonly caused by primary hypoparathyroidism

(idiopathic) and secondary (after thyroidoectomy), deficiency of vitamin D
and chronic renal failure, clinically is characterized by neuromuscular
tetany (due to discharge of sensory and motor fibers in peripheral nerves)
parasthesia, laryngospasm, muscle cramps and convulsions.
Treatment of Hypocalcemia: in addition to vitamin D which is usually

combined with Ca preparations that are clinically available in 2 forms:
1) IV Ca: Ca gluconate (it has less irritant effect to veins) Ca chloride and
Ca gluceptate.
2) Oral Ca: Calcium carbonate which is often the preparation of choice,
Ca lactate, Ca phosphotate and Ca citrate.
5. Intestinal osteodystrophy is characterized by both osteoporosis and

osteomalacia due to malabsorption of Ca, hypocalcemia which is
associated with intestine diseases may be due to decreased formation of
7-dehydrocholesterol.
6. Hepatic diseases: reduce production of calcifediol, and consequently

altering Ca metabolism.
III. FGF23: Mainly synthesized in bone, it inhibits calcitriol production

and phosphate reabsorption in the kidney leading to hypophosphatemia,
hypocalcemia and consequently bone demineralization.
Pharmacology of Calcitonin: is secreted by parafollicular cells of the

thyroid gland has a short ½ (10 minutes) with renal clearance, it lowers
serum Ca and phosphate by the following effects, in bones: inhibits
osteoclastic resorption, in kidneys, stimulates elimination of both Ca and
PO4.
Glueocorticoids: physiologic concentrations of glucocorticoids are

required for osteoblast differentiation, excessive concentrations inhibit bone
formation, by decreasing osteoblast activity, they antagonize vitamin D
by increasing elimination of Ca ions by kidneys and decreasing
absorption of Ca from the gut, prednisolone is the antidote in vitamin D
intoxication.
Estrogens antagonize PTH and therefore are used for the management of
menopausal osteoporosis by reducing resorption of bone.
NON-HORMONAL AGENTS AFFECTING MINERAL

HOMEOSTASIS
Bisphosphonates: Etidronate, Pamidronate, Alendronate and

Risedronate.
Definition: are substances that prevent the loss of bone mass; they reduce
the risk of osteoporotic fracture in those who have had previous fractures.
However, they do not reduce fracture risk (spine hip and other locations) in
those with osteoporosis who have not previously had a fracture.

Mechanism of action: they inhibit bone resorption by decreasing
osteoclasts activity (acceleration of osteoclasts apoptosis), inhibition of
calcitriol production and intestinal Ca transport.
Clinical Uses:
1. Osteoporosis: is an abnormal loss of bone, an increase bone fragility
and susceptibility to fractures, most commonly develops in
postmenopausal women, but can occur in men, normally there is a
dynamic equilibrium between bone formation by osteoblasts, maintenance
by osteocytes and resorption by osteoclasts,. Any process that disrupts this
balance by increasing bone resorption relative to bone formation results
in osteoporosis.
Pathogenesis: Osteocalsats are derived from macrophages; the

mechanism is initiated by binding of receptor activator of nuclear factor
kB ligand (RANKL) to RNAK receptor (NFkB), (also known as TRANCE
Receptor) found on surface of stromal cells and osteoblasts that produce
also macrophage-colony-stimulating factor (M-CSF), which attaches to
distinct receptor on macrophage cell surface. RANK is synthesized by
osteoblasts and stromal cells, derived from its ability to activate the NFkB
transcriptional pathways that bear RNAK receptors, especially macrophages and
thus osteoclasts), together M-CSF and RANK convert macrophages into
osteoclasts, the main regulator of RANK is osteoprotegerin (OPG) that can
bind to RANK receptors and therefore blocking interaction of RANK
with its receptors (NFkB), so osteoporosis occurs due to dysregulation of
RANK, RANK ligand and osteoprotegerin, such dysregulation occurs in
aging, estrogen deficiency which is associated with production of
cytokines (IL-I and TNF), genetic factors (vitamin D polymorphisms, PTH
synthesis and responses), Ca nutritional states and glucocorticoid
therapy.Other Drugs Used In Osteoporosis: in order to prevent the
increased risk of breast and uterine cancer associated with estrogen
therapy, Selective Estrogen Receptor Modulators (SERM) have been
developed. Rloxifene and tamoxifene protect against spine but not hip
fractures unlike bisphpsphonates, Denosumab and Teriparatide which protect
against both. Vitamin D supplementation with Ca is also indicated.
b. Paget's Disease: is characterized by repetitive episodes of resorption

activity (osteolytic stage), followed by bone formation (mixed osteoclastic-

osteoblastic stage) and finally sclerosis (osteosclerotic stage) resulting in bone
gain mass, caused by Paramyxovirus that can activate osteoclasts by
producing IL-I and M-CSF, most commonly affected bones are skull,
femur, tibia, pelvic bones and vertebrae, skeletal deformities such as bowing
of femur and tibia, enlargement of the cranial skull and cortical
thickening of the long bones are seen, but facial skull is normal, impaired
hearing due to cranial nerve compression and dysfunction, the thorax is
compressed and immobile on respiration, kyphosis and heart failure.
c. Other Indications: bone metastasis (with or without hypercalcaemia),

multiple myeloma, primary hyperparathyroidism and osteogenesis
imperfecta.
Pharmacokinetics: all bisophosphonates are effective orally, except

pamidronate (IV), food decreases their absorption, rapidly cleared from the
plasma, but once bound to bone, they are cleared over a period of months to
years, elimination occurs renally, so their doses should be adjusted in
renal patients.
Side Effects: the most common side effects are gastric irritation and
esophageal ulcers which could be minimized by taking full glass of
water, etidronate is the only among all bisphosphonates which associated
with the incidence of osteomalacia following long-term therapy.
Pharmacology of Fluoride: is effective for prophylaxis of dental caries,

but under investigation for the treatment of osteoporosis, it is
accumulated in bones and teeth, where it may stabilize the
hydroxyapatite crystal, therefore increasing resistance of teeth to dental
caries. Fluoride in drinking water appears to be most effective in
preventing dental caries if consumed before the eruption of permanent
teeth.
Adverse Effects: nausea, vomiting, gastrointestinal blood loss, arthralgia,

arthritis, these symptoms could be reduced by taking the drug with
meals, at present fluoride is not recommended for treatment of
osteoporosis.

Corticosteroids are Gene-Active

Synthesis
Stimuli Part Principal
product
Angiotensin II Zona
Aldosterone
glomerulosa
ACTH Zona fasiculata Cortisol
& reticularis Adrenal androgens
Sympathetic Adrenaline &
nervous Medulla Nor-adrenaline
system
Corticosteroids
Lipocortin
Phospholipids
Phospholipase A2
Arachidonic acids
lipoxygenase Cycylooxygenase
Prostaglandins,
Leukotriene Thromboxane
Prostacyclins

Insulin affects many organs:
amino acids protein
 It stimulates skeletal muscle uptake synthesis
fibers.
 It stimulates liver cells. glycogen

glucose
synthesis
uptake
 It acts on fat cells
fat
 It inhibits production of certain synthesis
enzyme.
In each case, insulin triggers enzyme glycogen

these effects by binding to the production breaking
insulin receptor.

Action of Insulin on the Cell
Metabolism
Type I Diabetes Cell
Type I Diabetes Cell

Review A&P

UNIT 11
CANCER CHEMOTHERAPY
Cancer or Neoplasm: is a pathologic condition characterized by a shift in

the control mechanisms that regulate cell profilaration and differentiation
leading to formation of neoplastic cells.
Causes of Cancer: the incidence of specific types of cancer is associated

with the following factors:
1. Genetic predisposition.
2. Sex, age and race.
3. Environmental Chemical Carcinogens: ionizing radiation and exposure to

chemical carcinogens particularly those in tobacco smoke, asbestos and
benzene.
4. Viral infections: it has been proved that HBV and HCV are associated with
the development of hepatocellular carcinoma; HIV is associated with
Hodgkin's lymphoma and non-Hodgkin's lymphoma and herpes papiloma
virus is associated with head and neck cancers.
Normal Cell Proliferation Cycle:
Cell Cycle: proliferating cells progress throughout a series of checkpoints

and defined phases.
The Normal Cell Cycle: consists of the following stages:

1. G1 phase: starts by synthesizing the components necessary for synthesis
of DNA.
2. S Phase: during which synthesis of DNA takes place.
3. G2 Phase: is characterized by synthesis of cellular components required

for mitosis.

4. M Phase: during which mitosis occurs, generally there are 2
checkpoints: one between G1 and S and the second between G2 and M
which are regulated by 2 forces:
A. Positive forces: involve growth factors cyclins and cyclins-dependent

kinases (cdks), which stimulate the cell to start on the cycle:
A-1: The D family of cyclins (D/cdks) stimulates the process that takes the cell
through G1.
A-2: The (D/cdks) plus (E/cdk) promotes progression through S phase.
A-3: The cyclin A/cdk promotes progression through S phase.
A-4: The cyclin B/cdk stimulates progression through G2 phase.
b. Negative forces: which inhibit the actions of cyclins by p53 gene and
retionoblastoma gene (Rb):
A. If there is DNA damage (mutation) these inhibitors normally halt (stop)
the cycle at checkpoint I, allowing for repair.
B. If repair fails apoptosis is initiated.
5. G0 Phase or resting state: represents a phase where the cells are not
dividing, but can re-enter the cycle.
In Cancer cells: - the cycle is disrupted by:
a. Abnormal growth factor function.
b. Abnormal cyclin/cdk function.
c. Abnormal DNA synthesis.
d. Abnormal decrease in negative forces, owing to mutation.
Classification of Anticancer Drugs: According to their actions on the cell

cycle, antitumor agents are divided into 2 groups:
1. Cell Cycle-Specific (CCS) Agents: drugs which exert their actions on
cells traversing the cell cycle, effective for high growth-fraction tumors,
(only against replicating cells), e.g. in hematologic malignancies, these
include the following groups: antimetablities, antitumor antibiotics
(bleomycin), vinca alkoloids, etoposide and taxanes.
2. Cell- Cycle Non-Specific (CCNS) Agents: drugs which can sterilize

tumor cells whether they are cycling or resting, or CCNS agents can kill

both G0 and cycling cells, effective for both low growth fraction tumor
(solid) as well as for high growth fraction, they include: alkylating agents,
antitumor antibiotics (dactinomycin and mitomycin) anthracyclines,
camptothecins and platinum analogs.
Principles of Cancer Chemotherapy:

1. Goal of treatment: the goal is curative which requires the eradication of
every neoplastic cell, if it is attainable; the goal becomes palliation which
is temporary improvement of symptoms, signs and reduction of life-
threatening toxicities (metastasis) of cancer.
2. Indications: chemotherapy is indicated when neoplasms are

disseminated and not amenable to surgery, it is also used as a
supplemental treatment to prevent metastasis following surgery and
radiation.
3. Tumor susceptibility and the growth cycle: rapidly dividing cells are
generally more sensitive to anticancer drugs where as non-proliferating cells
(those in phase G0) usually survive the toxic effects of these agents.
4. Tumor growth rate: the growth rate of tumor initially is rapid, but
decreases as the tumor size increases due to inadequate vascularization;
reducing the tumor burden through surgery or radiation, increases their
susceptibility to anticancer drugs.
5. Log Kill Phenomenon: defined as a given dose of drug destroys

constant fraction of cancer cells by cytological count, before and after drug
therapy.
6. Combinations of the drugs: combination therapy is more effective than

monotherapy in most cancers, the advantages include anticancer drugs
provide maximal cell kill and may slow or prevent subsequent
development of cellular drug resistance.

The following principles are important for selecting appropriate anti
tumor drugs to use in combination chemotherapy:
a. Each drug should be active when used alone against the particular cancer.
b. The drugs should have different mechanisms of action.
c. Cross-resistance between drugs should be minimal.
d. The drugs should have different toxic effects.
Types of Chemotherapy:
1. Primary induction chemotherapy: refers to chemotherapy administered

as the primary treatment in patients who present with advanced cancer for
which no alternative treatments exists.
2. Neoadjunctive chemotherapy: the administration of therapeutic agents

before a main treatment. Neoadjuvant therapy aims to reduce the size or
extent of the cancer before using radical treatment intervention, thus
making procedures easier and more likely to succeed, e.g. neoadjuvant
hormone therapy prior to radical radiotherapy for adenocarcinoma of the
prostate.
3. Adjuvant chemotherapy: refers to use of chemotherapy as adjuvant to

local treatment such as surgery or radiation therapy.
4. Pulse therapy: involves intermittent treatment with very high doses of

anticancer drug doses that are too toxic to be used continuously, this
method is used successfully in therapy of acute leukemias and testicular
carcinomas.
5. Recruitment therapy (Synchrony): involves initial use of a CCNS drug

to a significant log kill, which results in recruitment into cell division in the
G0 phase followed by administration of a CCS drug that is active against
dividing cells, e.g. the use of vinca alkoaloid acting on M phase and
cytarabine affecting S phase may result in a grater killing effect on
neoplastic cells.

6. Rescue therapy: toxic effects of antitumor drug can be alleviated by this
method, e.g. high doses of methotrexate may be given for 36-48 hrs and
terminated before severe toxicity occurs to cells of the GIT and bone
marrow, Leucovorin which is accumulated more readily by normal than
tumor cells, is then administered, this results in rescue of normal cells
because leucovorin bypasses the dihydropholate reductase step in folic
acid. Other examples include the use of Mensa that traps acrolin, released
from cyclophosphamide, hence reducing the incidence of hemorrhagic
cystitis. Dexrazoxane inhibits free radicals and affords protection of
cardiomyocytes against anthracyclines (Doxorubcin).
Problems Associated With Chemotherapy

1. Resistance: is a major problem in cancer chemotherapy, the resistance
mechanisms include:
a. Increased DNA repair: is particularly important in the case of most
alkylating agents and cisplatin.
b. Formation of trapping agents: some tumor cells increase their production

of thiol trapping agents e.g. glutathione which interacts with anticancer
drugs, namely alkylating agent bleomycin, cisplatin and anthracyclines.
c. Change in target enzyme: e.g. decreased affinity of dihydrofolate reductase

to methotrexate.
d. Decreased activation of prodrugs: resistance to antimetabolites can result

from a decrease in the activity of the tumor cell enzymes needed to convert
these to their cytotoxic metabolites.
e. Inactivation of anticancer drugs: e.g. increased activity of enzymes

responsible for inactivation of antimetabooites (mostly).

f. Decreased drug accumulation: increased expression of a normal gene
(MDRI gene) for a cell surface glycoprotein, this gene accelerates efflux of
anticancer drugs.
Inherited resistance: some neoplastic cells are inherently resistant to most

anticancer drugs, (e.g. malignant melanoma, renal and brain cancers- absence of
response on the first exposure), properly due to mutation of p 53 suppressor
(decreased its activity), gene resulting in resistance to radiation therapy
and to a wide range of anticancer drugs.
Acquired resistance: develops in response to exposure to a given

anticancer agent.
2. Toxicity: anticancer drugs have no ability to distinguish cancer cells

from healthy cells; they can affect cells with rapid proliferation, so
depression of bone marrow, G.I.T mucosa and hair cells, contributing the
toxic manifestations. Most therapeutic anticancer drugs have a narrow TI.
Severe vomiting, stomatitis and alopecia are frequent, myelosuppresion
predisposes to infection, other adverse effects are associated with specific
agents, for example doxorubicin produces cardiotoxicity, belomycin can
cause pulmonary fibrosis.
3. The duration of adverse effects: variable, for example alopecia is

transient, but cardiac, pulmonary and bladder toxicities are irreversible,
vomiting could be controlled by antiemetic drug, megoblastic anemia which
is associated with methotrexate is minimized by administration of folic
acid and neutropenia is reduced by using filgrastim that is a human
granulocyte colony-stimulating factor (G-CSF).
4. Treatment induced tumor: because most antineoplastic agents are

mutagens, neoplasm may arise 10 or more years after cured cancer.

I. ALKYLATING AGENTS
Mecholrethamine, Cyclophosphamide, Chlorambucil, Carmustine,

Lomustine and Busulfan.
M.O: these agents exert their cytotoxic effect by transfer of their alkyl
groups, to various cellular constituents especially DNA, (the N7 position of
guanine in DNA) leading to impaired replication and therefore cell death,
although alkylating agents are not CCS, cells are most susceptible to
alkylation in late G1 and S, they are mutagenic and secondary malignancy
can occur.
Resistance: the mechanism of acquired resistance may involve:

a. Increased capability to repair DNA lesions.
b. Decreased transport of the alkylating drug into the cell.
c. Increased expression of activity of glutathione and glutathione-
associated proteins (S-transferase) which are needed to conjugate the
akylating agent.
1. Mechlorethamine: is unstable and solutions must be made up just

before administration, it is administered only IV and SC, administration
can lead to incidence of necrosis.
Clinical Uses: primarily in the treatment of Hodgkin's disease (B cell

neoplasm lymphoma) because it causes lymphocytopenia, as part of the
MOPP Regimen (mechlorethamine, oncovin "trade name of vincristine",
prednisolone and procarbazine), it is useful in the treatment of some solid
tumors.
Adverse Effects:
a. Severe nausea and vomiting: occur centrally and could be reduced by
pretreatment with 5-HT3 antagonist e.g. ondansetron, dolasetron, and
granisetron.
b. Severe bone marrow depression and latent viral infection.

2. Cyclophosphamide and Ifosfamide: they can be taken orally,
Cyclophosphamide is the most commonly used alkylating agent, both are
metabolized by the cytochrome P-450 system to active compounds
phosphoramide mustard which exerts cytotoxic effect and acrolein that causes
urinary bladder damage (hemorrhagic cystitis). The antidote Mensa can
detoxify actions of acroelin.
Pharmacokinetics: unlike mechlorethamine, both administered orally,

they enter the CSF; minimal amounts of the parent drug are excreted into
the feces or into the urine.
Therapeutic Uses: have a broad clinical spectrum, being used either singly or
in combination with other antitumor drugs, Burkitt lymphoma, breast
cancer, and for non-neoplastic entities e.g. nephritic syndrome and
rheumatoid arthritis.
Adverse Effects: the most common side effects for both drugs are alopecia,
nausea, vomiting, diarrhea, bone marrow depression especially
leukocytosis, hemorrhagic cystitis, fibrosis of the bladder, amenorrhea,
testicular atrophy, neurotoxicity with high doses of iofosfamide treatment,
secondary malignancies can arise years after therapy.
3. Nitrosoureas: Carmustine, lomustine and streptozocin which is

specifically toxic to the B-cells of pancreas, so it is useful in insulinoma, all
require biotransformation to active metabolites, producing their cytotoxic
alkylating effect on DNA strands (6 position of guanine of DNA). Resistance
probably results from DNA repair and glutathione, pharmacokinetically in
spite of their similarities in their structure, carmustine is used I.V, lomustine
is administered orally, because of their lipophilicity, they are distributed to
many tissues including the CSF, extensively metabolized in the liver,
elimination of the drugs occurs in the urine.
Therapeutically are mainly utilized in the treatment of brain tumors.
Adverse effects: hematopoietic depressions including aplastic anemia, pancytopenia,
renal and pulmonary toxicity, streptozocin has minimal bone marrow toxicity.

4. Platinum Analogs: Cisplatin, Carboplatin and Oxaliplatin
They are administered IV with saline-manitol solution, (to reduce nephrotoxicity
produced by cisaplatin), cisplatin has a major antitumor activity in solid tumors
lung cancer, esophageal, gastric, head, neck, testicular, ovarian and bladder
cancers in combination with bleomycin and etoposide whereas carboplatin less
exhibits renal, oto-neural and GIT toxicities, it has replaced cisplatin in various
combinations regimens. Carboplatin has greater myelosuppressant action.
Oxaliplatin is the first line therapy for metastatic colorectal cancer in combination
with fluropyerimidine and 5-flurouracil (5-FU) and leucovorin termed the
FOLFOX. Neurotoxicity is the main dose-limiting toxicity and is manifested by a
peripheral sensory neuropathy.
II. ANTIMETABOLITES
General mechanism of action of antimetabolites: they are structurally

related to normal cellular components, which interfere with the
availability of normal purine or pyrimindine, either by inhibiting their
synthesis or by competing with them in DNA, RNA synthesis, their
cytotoxic effect appears in S phase, so they are CCS drugs. They are
classified into:
II-1. Folic Acid Antagonists: Methotrexate (MTX): inhibits dihydrofolate

reductase, the enzyme is responsible for conversion of folic acid to its
active form tetrahydrofolate (FH4) thus preventing the synthesis of
thymidine, guanine, purine, neucleotides, amino acids and methionine, the
essential products of DNA replication, consequently inhibition of DNA,
RNA and protein synthesis takes place, generally the vitamin folic acid is
essential for replication of the cell, it is obtained from dietary sources or
produced by intestinal flora (small amounts).
Pharmacokinetics: the drug is readily absorbed from the GIT; it is also

administered I.M, I.V and intrathecally for the treatment of brain tumors
because it does not enter the CSF, MTX is metabolized to active substance

polyglutamate derivatives like tetrahydrofolate exert an inhibition on
dihydrofolate reductase, hence prolonging the action of MTX, the parent
drug and its metabolites are excreted via the urine, but some of the drug
and its metabolites are eliminated in the feces.
Therapeutic Applications: at high doses in combination with other

anticancer drugs for acute lymphocytic leukemia (ALL), choriocarcinoma,
Burkitt lymphoma in children, breast, head and neck cancers, excessive
depression of DNA, RNA and protein synthesis is reversed by
administration of Leucovorin which is converted directly into FH4,
bypasses the blocked dihydrofolate reductase, at low doses as a single
agent against psoriasis and rheumatoid arthritis. MXT could be used with
misoprostol to induce abortion.
Adverse Effects: the most common side effects are: GIT disorders,
myelosuppression, erythema, rash and urticaria. Care must be taken when
MXT is used in the presence of NSAIDs, penicillins and cephalosporins,
because they inhibit its excretion. MXT should be avoided in pregnancy.
Resistance: may be due to relative lack of dihydrofolate reductase,

reduced influx of MTX because of an alteration in the carrier-mediated
transport responsible for pumping the drug into the cell.
II-2. Purine Antagonists: Mercaptopurine (6-MP) and 6-thioguanine (6-

TG):
M.O: 6-MP and 6-TG are activated by hypoxantheine-guanine
phosphororibosyltransferases (HGPRTases) to form 6- mercaptopurine-ribose-
phosphate (6-MPRP) and other toxic metabolites that inhibit several
enzymes of de novo purine nucleoside synthesis.
Pharmacokinetics: both drugs have low oral bioavailability, distributed

widely except for the CSF, 6-MP is metabolized in the liver to 6-
methylmercaptopurine derivative which is catalyzed by xanthine oxidase;
administration of the purine analog allopurinol (common used in cancer

patients to reduce hyperurecemia following tumor lysis) can lead to
accumulation of 6-MP, because allopurinol inhibits xanthine oxidase, so it is
important to reduce the dose of 6-MP in patients receiving allopurinol, in
contrast to 6-TG such interaction does not occur, which can be used in full
doses with allopurinol, excretion mainly occurs via the kidneys.
Therapeutic Uses: primarily in the treatment of acute lymphoblastic

leukemia, its analog is azathioprine which is used as immunosuppressant
in Crohn's disease.
Side Effects: myelodepression, GIT upset and hepatoxicity.
II-3. Pyrimidine Antagonists: Fluorouracil (5-FU): is a prodrug, which

must be converted to:
a. Flurodeoxyuridine monophosphate (FdUMP) which inhibits thymidylate
synthase, that is responsible for conversion of deoxyuridine
monophosphate (dUMP) into deoxythymidine Monophospate dTMP
which is essential product of DNA synthesis.
b. Flurorouridine triphosphate (FUTP): interferes with RNA processing and
mRNA translation.
c. Flurodeoxyuridine triphosphate (FdUTP): inhibits DNA synthesis.
Pharmacokinetics: 5-FU is given IV or topically but not orally due to its

severe toxicity to the GIT, distributed well in the body and enters the CSF,
extensively metabolized by the liver, kidneys, and lungs, its half-life is
short (10-15 min), excreted in the urine, clinically is employed in the
treatment of slowly growing solid tumors (colorectal, breast, ovarian,
liver, esophagus, pancreas, head and neck carcinomas).
Adverse Effects: in addition to nausea, vomiting, diarrhea, alopecia and

severe ulceration of the oral and G.I tract, bone morrow depression,
anorexia and Hand-Foot Syndrome (erythematous desquamation of the
palms and soles) are the most frequent side effects.

II-4. Deoxycytidine Analogs: Cytarapine and Gemcitabine, cytarapine of
all the antimetabolites is the most specific for the S phase of the tumor cell
cycle, it is activated by kinases to 5-mononucleotide that inhibits DNA
polymerases, it is given parenterally with slow IV infusion, enters the CSF
and eliminated hepatically, cytarapine is an important component in
regimens for the treatment of leukemias. Cytarapine resistance develops
either due to a decrease its accumulation or its conversion.
III. PLANT ALKALOIDS
III. 1. Vinca Alkaloids, (Microtubule Inhibitors), Vincristine (Oncovin)

and Vinblastin
M.O: They are derived from plant vinca rosea, both are CCS drugs that
block mitosis in metaphase by preventing polymerization of tubulin to
microtubules thus preventing the formation of the miotic spindle, which is
essential for equal partition of DNA into 2 daughter cells during mitosis.
Pharmacokinetics: They are given I.V, penetrate most tissues except the
CSF, their rapid cytotoxic destructive effect results in hyperuricemia that is
ameliorated by allopurinol, metabolized in the liver and eliminated in the
feces.
Clinical Uses: generally are combined with other drugs: vincristine is

used in ALL in children, Wilms tumor, Hodgkin's, non Hodgking's
lymphomas, rabdomyosarcoma and choriocarcinomas, whereas
vinblastine is used in breast, germ cell cancers, Hodgkin's, non Hodgkin's
lymphomas and Kaposi's carcinoma.
Adverse Effects:
A. Shared toxicities: phlebitis, cellulites, nausea, vomiting, diarrhea and
alopecia.

B. Unique: vinblastine is more potent myelosuppressant, whereas
vincristine frequently causes peripheral neuropathy (paresthesias and
ataxia) and constipation.
III.2. Epipodophyllotoxins : Etoposide and Teniposide
M.O: they are derived from podophyllotoxins, and block cell division in the
late S-G2 phases of the cell cycle by inhibition of topoisomerase II, which
leads to DNA degradation.
Pharmacokinetics: etoposide is administered either I.V or orally, whereas

teniposide is administered only IV, they are highly bound to proteins and
widely distributed throughout the body, but they don’t enter the CSF,
metabolized extensively in the liver and eliminated in the urine.
Clinical Uses: Etoposide is approved for the treatment of germ cell cancer,
small cell and non-small cell lung cancer, Hodgkin's, non-Hodgkin's
lymphomas and gastric cancers, whereas as Teniposid is restricted only
for ALL.
Adverse Effects: myelosuppression especially leukopenia, G.I.T. , alopecia

and renal toxicity.
III.3. Taxanes: Paclitaxel (taxol) and docetaxel:

M.O; both drugs are active in the G2/M phases of the cell cycle; they act by
enhancement of tubulin polymerization, with the formation of unfunctional
miotic spindle resulting in mitosis inhibition.
Pharmacokinetics: administered I.V, they have a large volume of

distribution, but can't cross the CNS, undergo extensive metabolism in the
liver and eliminated by the bile, so doses should be reduced in patients
with hepatic dysfunction.

Clinical Uses: ovarian cancer, metastatic breast cancer, head, neck,
prostate and esophageal cancers.
Adverse Effects: the most common effect is neutropenia (reversed by

filgrastim, G-CSF), peripheral neuropathy; hypersensitivity reactions
including dyspnea. Hypotension, alopecia, vomiting and diarrhea are
uncommon.
IV. CAMPTOTHECINS
Topotecan and Irinotecan
M.O: S-phase specific agents which, inhibit the activity of topoisomerase I

involving in DNA synthesis, topotecan is indicated in the treatment of
advanced ovarian cancer as a second-line therapy following initial
treatment with platinum-based chemotherapy, and approved as second-
line therapy for small cell lung cancer, the elimination of the drug is via
the urine, so doses should be adjusted in patients with renal dysfunction.
Irinotecan is a prodrug, which is converted in the liver by the
carboxyesterase enzyme to active inhibitor of topoisomerase I, in contrast to
topotecan it is eliminated in the feces clinically is used in the treatment of
colorectal cancer (if no response to fluorouracil). The major two toxicities
are myleosuppression and diarrhea, there are 2 forms of diarrhea, early that
occurs within 24 hours after administration, (reduced by atropine) and late
usually occurs 3-10 days after administration, and can lead to dehydration.
V. ANTITUMOR ANTIBIOTICS
V-1. Anthracyclin Antibiotics: Doxorubicin and Daunorubicin are the most

widely used drugs
M.O: they exert their cytotoxic effect in the S/G2 phases by inhibition of
topoisomeras II, intercalation of DNA leads to its inhibition, they bind to cell
membrane causing alteration in its fluidity and ion transport, and finally they
generate free radicals and oxygen responsible for cardiotoxicity.

Pharmacokinetics: both drugs are given only I.V, widely distributed
throughout the body with no penetration into the CNS, metabolized
extensively in the liver and eliminated in the feces.
Clinical Applications: doxorubicin is the most widely used antibiotic for

the treatment of sarcomas and carcinomas (breast, lung, ovary, testicle,
thyroid and stomach) hematologic cancers (ALL, Hodgkin’s and non-
Hodgkin’s lymphomas) and neuroblastoma. Usually is used in
combination with cyclophosphamide, cisplatin and 5-FU.
Adverse effects: cardiotoxicity, G.I.T disturbances, alopecia and
myelosuppression.
V-2. Dactinomycin: mainly is used in combination with vincristine to treat

pediatric Wilms tumor and rhabdomyosarcoma and in conjunction with
MTX in the treatment of choriocarcinoma.
V-3. Mitomycin: it is an alkylating agent which is activated via the CYP

system, clinically used in combination with fluorouracil and radiation
therapy for hypoxic tumor steam cells, that are more sensitive to its
cytotoxic effect than normal cells and oxygenated tumor cells, it is active in
all phases of the cell cycle, it is also indicated in the treatment of squamous cell
cancer of the anus in combination with 5-FU and radiation therapy. In addition
it is used in carcinoma of cervix, stomach, pancreas and lung cancers.
Adverse Effects: hemolytic-urermic syndrome, thrombocytopenia and
renal failure.
V-4. Bleomycin: is a CCS drug which forms a complex with iron, the
DNA-belomycin-Fe2 undergoes extensive oxidation to belomycin-Fe3+
resulting in strand breakage of DNA in G2 phase. It is administered SC,
I.M or I.V, eliminated unchanged in the urine by glomerular filtration,
requiring dose adjustment in patients with renal failure, clinically is
approved for hematologic malignancies (Hodgkin's and non-Hodgkin's
lymphomas), squamous cell cancer of the skin, cervix and vulva. The most

common adverse effects are pulmonary toxicity (progressing from cough
to fibrosis), hypertrophic skin changes, hyperpigmentation, alopecia
(commonly), fever and chills, it does not cause myelosuppression.
V-5. Plicamycin: exerts its cytotoxic effect through inhibition of DNA or

RNA synthesis, mainly used in the treatment of bone tumors, testicular
cancer. Toxicities include hemorrhage, bone marrow suppression, hepatic
and renal toxicities.
V-6. Mitoxantrone: is an anthracene compound that binds to DNA to

produce breakage and inhibits both DNA and RNA synthesis, currently
used in the treatment of prostate cancer, breast cancer, myeloid leukemias, it
has a long ½ (75 hrs), excreted primarily via the hepatobiliray system.
Adverse Effects: myelosuppression (leukopenia), mucositis, nausea,
vomiting and alopecia, cardiotoxic, but less than doxorubicin, discoloration of
nails, sclera and urine may occur.
OTHER ANTITUMOR AGENTS
1. Glucocorticoids: Prednisone is the most commonly used glucocorticoid

in cancer chemotherapy and is widely used in combination therapy for
leukemias and lymphomas.
2. Sex Hormone Antagonists:

a. Tamoxifen is a selective estrogen receptor modulator (SERM), blocks
estrogen-sensitive cancer cells in breast tissue; it is used in breast
carcinoma and may have a preventive effect in women at high risk for
breast cancer.
Toxicity includes nausea, vomiting, hot flushes, vaginal bleeding and
venous thrombosis.
b. Flutamide is an androgen receptor antagonist used in prostatic

carcinoma. Toxicity includes gynecomastia, hot flushes and hepatic
dysfunction.

3. Gonadotropin-Releasing Hormone Analogs: Leuprolide, Goserelin and
Nafarelin are GnRH agonists effective in prostatic carcinoma, they inhibit
the release of pituitary luteinizing hormone (LH) and follicle-stimulating
hormone (FSH). Leuprolide may cause bone pain, gynecomastia, hematuria,
impotence and testicular atrophy.
4. Aromatase Inhibitors: Anastrozole and Letrozole inhibit aromatase that

catalyzes the conversion of androstenedione (an androgenic precursor) to
estrone; both drugs are used in breast cancer. Toxicity includes GIT upset,
hot flushes, bone and back pain, dyspnea and peripheral edema.
5. Imatinib: is an inhibitor of tyrosine kinase activity of the protein

product of the Bcr-Abl oncogene and prevents phosphorylation of the kinase
substrate ATP, indicated for the treatment of chronic myelogenous or
myeloid leukemia (CML), and GI stromal tumors. Toxicity includes
nausea, vomiting, peripheral and ankle edema, myalgias and CHF.
6. Interferons: are endogenous glycoproteins with antineoplastic,

immunosuppressant and antiviral actions, alpha-interferons are effective
against a number of neoplasms, including hairy cell leukemia, the early
stage of CML and T-cell lymphomas.
Toxic effects include myelosuppression and neurologic dysfunctions.
7. Monoclonal Antibodies: Rituximab is a monoclonal antibody to a

surface protein in non-Hodgkin's lymphoma cell.
Trastuzumab is a monoclonal antibody to a surface protein in breast
cancers.
General Toxicity: both can cause nausea and vomiting, chills, fever and
headache.
Rituximab: is associated with the incidence of hypersensitivity reactions
and myelosuppression.
Trastuzumab: may cause cardiac dysfunction including CHF.

Biologic Basis of Chemotherapy
Cell-cycle specific, or phase-specific agents;

Cell-cycle nonspecific or phase-non-specific agents

Resistance to MXT
Biologic Basis of Chemotherapy
Cell-cycle specific, or phase-specific agents;

Cell-cycle nonspecific or phase-non-specific agents

Summary of the main sites of action of cytotoxic agents. For some groups of drugs, only
one or two examples are given.
425

Drug Interactions Important In Clinical Dentistry
The potential for interactions with current medications should

always be considered when administering or prescribing any
drug. Fortunately, drug classes employed in dental practice are
relatively few in number and therapy is generally brief in
duration.
When two or more drugs are taken concurrently, they may
influence one another in a manner that results in either an
enhanced or diminished intensity of effect produced by any of the
drugs taken alone.
When the intensity is reduced, the interaction is generally
described as antagonistic. If the intensity is increased, the
interaction is described variably as summation, potentiation, or
synergism.
Classification of Drug Interactions:
1. Pharmaceutical Drug Interactions:

Occur when one drug alters the delivery of another to its target.
Drugs may alter the absorption, distribution, or elimination of one
another, this interaction may result either in diminished effects or
drug potentiation.
In terms of absorption, the most familiar is the delayed absorption
of tetracycline antibiotics by divalent cations found in antacids and
dairy products.
The principal mechanism regarding distribution relates to protein-
binding of drugs while circulating in serum. While protein-bound,
a drug is not available to distribute into targeted tissues.A drug
that is capable of displacing a bound drug from protein increases
the amount available for distribution and may enhance its effect.
One example is the potential for furosemide (Lasix) to displace warfarin
(Coumadin) and increase the risk for bleeding.
By far the most frequent and significant pharmacokinetic drug
interactions relate to drug metabolism or biotransformation. These
interactions occur when one drug induces or inhibits the enzyme
responsible for activation or inactivation of another drug.
Biotransformation may be required to activate or inactivate a
parent drug. These reactions occur primarily in the liver and may
proceed in either or both of two phases.
Phase I reactions consist of oxidation, reduction, and hydrolysis,
while Phase II reactions involve conjugations that generally confer
water solubility to the metabolite to expedite renal excretion.
Enzymes associated with Phase I reactions are the target of most
drug interactions.
The cytochrome P450 system is derived from the color of liver cells
(dark red) attributed to the iron content of the enzymes, and P450
refers to ultraviolet light wave length absorbed by the enzymes.
CYP 2D6 and 3A4 carry the most relevance for interactions in
dental practice.
2. Pharmacodynamic Drug Interactions:

Interactions may occur at identical receptor sites or by diverse
mechanisms on identical or related organs. It should be
reemphasized that interactions may be desirable or undesirable. A
diuretic promotes sodium and water excretion by the kidney,
while a beta-blocker reduces cardiac output. Their interaction
provides a greater reduction in blood pressure than either can
impart alone.
In dental practice, drug interactions are not as voluminous as they
are in medical practice. This is based on the fact that most drug
therapy is short-term and the number of drug classes prescribed is
small in comparison.
I. Sedatives and Antiemetics:

Midazolam ,triazolam , alprazolam, zolpidem and zaleplon are
substrates for CYP3A4, which provide their elimination. Drugs
that inhibit these enzymes can elevate serum concentrations and
prolong the elimination of these benzodiazepines. The risk for this
potentiation is most significant with the HIV protease inhibitors
and azole antifungals.
Promethazine, prochlorperazine and droperidol are used as
antiemetics and as sedatives. A portion of their action is predicated
on blocking dopamine receptors within the central nervous
system. They should be avoided in all patients with Parkinson’s,
but especially those medicated with dopamine agonists such as
levodopa.

II. Local Anesthetics:
The systemic effects produced by combinations of local anesthetics
follow principles of summation.
1. It is essential that local anesthetics be respected as CNS
depressants, and they potentiate any respiratory depression
associated with sedatives and opioids (Alcohol, CNS depressants,
antidepressants, antipsychotics, opioids, centrally acting
hypertensives and antihistamines). Serum concentrations required
to produce anesthetic-induced seizures are lower if hypercapnia
(elevated carbon dioxide) is present. Keep in mind that both liver
and renal functions decline 50% by age 65. Beta blockers reduce
hepatic blood.
2. Antiarrhythmic drugs: Increased cardiac depression may occur.
3. Anticholinestarases: Local anesthetics may antagonize the effects
of anticholinesterases on muscle contractility.
4. Amides: Alcohol, CNS depressants, opioids, antidepressants,
antipsychotics and antihistamines interactions result in increased
CNS and resp. depression may occur. Use caution.
Amiodarone, beta blocker, cimetidine reduce metabolism of
amides.
Interaction of amides and antiarrhythmic drugs leads to increased
cardiac depression.
Metabolism of lidocaine is reduced when Beta blockers and
cimetidine are co-administered. Use caution.
5. Esters: Anticholinesterases, sulfonamides reduce metabolism of
esters. Inhibition of sulfonamide action may occur.
III. Interactions of Analgesic Drugs Commonly Used in Dental Practice
Prescribed
Drug Object of Interaction Explanation of Interaction
Effectiveness of most classes of

NSAIDs Antihypertensives antihypertensive drugs is
reduced following prolonged use of
most NSAIDs. If
NSAIDs are required for more than 5
days, the patient’s

blood pressure control should be
assessed. Notably,
Calcium blockers have not been
implicated, it would be wise to replace the
NSAID with acetaminophen.
Antiplatelet effects of NSAIDs may add to

Warfarin (Coumadin) the anticoagulant
effect of warfarin; however, the primary
concern is that
gastrointestinal (GI) erosive effects of
NSAIDs may be
more prone to hemorrhage. [AVOID]
Bisphosphonates (eg, NSAIDs enhance GI toxicity of these
alendronate agents used for
osteoporosis. No concern with short-term
use (5-7 days).
Increased serum levels of methotrexate
Methotrexate lead to systemic
toxicity and increased incidence of
stomatitis. [AVOID if
high-dose methotrexate]
Lithium excretion is reduced and toxic
Lithium blood levels may
develop over 5-10 days of NSAID
therapy. Limit NSAID
use to 3 or 4 days.
Enhanced risk for GI bleeding. SSRIs may
SSRIs deplete platelet
serotonin required for aggregation. No
evidence of
concern for short-term use (5-7 days).
Ibuprofen may block the antiplatelet
Ibuprofen Aspirin action of aspirin;
Significance is equivocal. Issue can be
avoided if AM
dosage of ibuprofen is delayed for1-2
hours following
aspirin intake.
Acetami Chronic use of alcohol increases
nophen, likelihood of
hepatotoxicity. Reduce daily dose limit
of
acetaminophen from 4 g to 2 g.
Increased metabolism of acetaminophen,
Carbamazepine decreasing its
analgesic effect, but increasing
Phenytoin accumulation of
metabolite that is hepatotoxic. Not
significant at normal
doses for 5-7 days.
Profound sedation and respiratory
Opioids Sedatives/anxiolytics depression may occur
with any drug class having a sedative
effect.
Increased serum levels of carbamazepine
Propoxyphene Carbamazepine leading to
toxicity. [AVOID]
Codeine and These antidepressants inhibit conversion
hydrocodone SSRI antidepressants of prodrug to
active morphine derivative; analgesic
effect reduced.
Mechanism of interaction is unclear, but
Meperidine MAO inhibitors hypertensive
crisis, seizures, and coma have been
Phenelzine (Nardil) reported with this
Selegiline (eg, Eldepryl) combination. [AVOID]
*NSAIDs indicates nonsteroidal anti-inflammatory drugs; SSRIs,
selective serotonin reuptake inhibitors; and MAO, monoamine
oxidase.
IV. Vasopressors:
Epinephrine, Levonordefrin also known as α-
methylnorepinephrine (α-Me-NE):
1. Inhalation anesthetics (halothane): Increased chance of
arrhythmia.
2. Tricyclic antidepressants-high dose (amitriptyline, imipramine,
nortriptyline, etc): Increased sympathomimetic effects possible.
Limit epi to 0.04mg with high dose TCA's.
3. Beta-blockers (nonselective) (e.g. propranolol, nadolol): A severe
and potentially life-threatening hypertensive reaction and/or
marked bradycardia can develop. Cardioselective beta blockers
such as atenolol and metoprolol interact minimally. Limit epi to
0.04mg/2hr.

4. Typical antipsychotics (e.g. chlorpromazine): Vasoconstrictor
action inhibited, leading to possible hypotensive responses. Use
Cautiously.
5. Monoamine Oxidase Inhibitors (MAOIs): Slight possibility of

hypertensive crisis.
6. Selegiline: Slight possibility of hypertensive crisis.
7. COMT Inhibitors: Slight possibility of hypertensive crisis.
V. Antimicrobials: Antimicrobial drugs have been implicated in

numerous drug interactions. Fortunately for the dentist, both
periodontal and odontogenic infections are managed using a fairly
limited number of antibiotic classes.
Interactions of Antibiotic Drugs Commonly Used in Dental

Practice
Prescribed
Drug Object of Interaction Explanation of Interaction
All Decreased effectiveness of oral contraceptives has

antibiotics Oral contraceptives been suggested for
several antibiotic classes. However, most well-
designed studies do
not show any reduction in serum estrogen levels
in patients taking
antibiotics. The issue is highly equivocal.The
mechanism for this interaction relates to the
ability of antibiotics to reduce normal intestinal
flora that enhance bioavailability. Estrogens
and progestins normally undergo enterohepatic
recirculation, whereby absorbed steroids are
conjugated in bile and excreted into the
duodenum. Intestinal flora hydrolyze these
conjugates allowing the steroids to be
reabsorbed.Again, it can be said that short-term
use of antibiotics is probably not a concern, but
it would be prudent to order international
normalized ratio (INR) monitoring weekly
during prolonged use. This is particularly true
for cephalosporins, macrolides, and

tetracycline. two antibiotics must be avoided
entirely in patients taking warfarin.
Alterations in gut flora may retard the

Digoxin metabolism of digoxin in
roughly10% of patients. This may result in
dangerously high serum
levels of digoxin that may persist for several
weeks following
discontinuation of the antibiotic. The strongest
documentation has
been for erythromycin and tetracycline.
Patients should be
cautioned to report any signs of digitalis
toxicity during antibiotic
therapy.
Anticoagulant effect of warfarin may be increased
Warfarin (Coumadin) by several antibiotic
classes. Reduced synthesis of vitamin K by gut
flora is a putative
mechanism, but several antibiotics have
antiplatelet and
anticoagulant activity. Cephalosporins,
macrolides, and
doxycycline have the most convincing
documentation. Penicillins
and clindamycin would be preferred choices,
but prolonged use
requires caution.
Macrolides elevate warfarin levels. Enhanced
Macrolids Warfarin anticoagulant effect is
well established. [AVOID]
Increased serum levels of carbamazepine and
Carbamazepine valproic acid leading to
severe toxicity. Hospitalization has been
Valproic acid required. [AVOID]
Ergotamine, DHE, Erythromycin inhibits hepatic metabolism
Migranal) leading to elevated
ergotamine levels. Risk for severe vasospasm
causing cerebral
ischemia and/or ischemia of extremities.
[AVOID]
Macrolides inhibit the metabolism of
Theophyllines theophylline leading to toxic
serum levels. Conversely, theophylline reduces
serum levels of
erythromycin. [AVOID prescribing
erythromycin, except for brief
use as prophylaxis for subacute bacterial
endocarditis]
Digoxin (Lanoxin) Macrolides elevate digoxin levels. [AVOID]
Metronida Severe disulfiram-like reactions are well
zole Ethanol documented. [AVOID]
Metronidazole elevates warfarin levels.
Warfarin (Coumadin) [AVOID]
Tetracyclin Antacids, dairy products, and other agents
es Antacids containing divalent and
trivalent cations will chelate tetracycline and
limit their oral
absorption. Doxycycline is least influenced by
this interaction.
Digoxin (Lanoxin) Tetracyclines elevate digoxin levels. [AVOID].

REFERENCES
1. Basic and Clinical Pharmacology, 12 th Edition,

Bertram G. Katzung , MD, Ph.D, Susan B. Masters, Ph.D
and Anthony J. Trevor, Ph.D- 2012.
2. Pharmacology (Lippincott's Illustrated Reviews

Series), 5 th Edition, Richard A. Harvey PhD, Michelle A
Clark PhD, Richard Finkel PharmD, Jose A. Rey
PharmD BCPP, Karen Whalen PharmD BCPS,- 2012.
3. Rang and Dale's Pharmacology, H P Rang; MB BS

MADPhil FRS, M Maureen Dale MB BCh Ph.D; 7th
Edition- 2012.
4. Drug Dictionary For Dentistry: John G. Meechan, BSc,

BDS, FDS, PhD, R.A Robin Seymour- Oxford University
Press- 2002.
5. Pharmacology For Dentistry: Singh, Surender Ass.

Prof., Department of Pharmacology, All India Institute
of Medical Sciences, New Delhi.First Edition. 2007.
6. http://pharmacologycorner.com/.
7.http://www.simplestepsdental.com/SS/ihtSS/r.==/st.32
228/t.32228/pr.3.html.
8.http://www.homesteadschools.com/dental/courses/Dru
gs%20Used%20In%20Dentistry/text.htm
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UNIT 1

Pharmacology: pharmacon (drug), logus (science) is the study of

1) Medical Pharmacology: is the branch of pharmacology associated with

2) Clinical Pharmacology: is a science that deals with drug

3) Toxicology: is defined as a science involved in studying the toxicologic

4) Pharmacokinetics: refers to the study of actions produced by the body

5) Pharmacodynamics: is the study of the mechanism of action (M.O) of

6) Pharmaceutical Pharmacology: is the branch of pharmacology, deals

7) Pharmacogenetics: is the study of the genetic variations that cause

1 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

The Nature of Drugs:

Identification of The Drugs: the drugs are named according to their:

a. Chemical structure: e.g. N-acetyl Para amino-phenol (paracetamol)

b. International (Generic) name: e.g. aspirin.

c. Trade name: is specific for individual pharmaceutical companies, the

a. Internal: drugs may be synthesized within the body e.g. hormones.

b. External: Xenobiotics or toxins are not synthesized by the body, but

Interaction of Drugs With The Living Organism:

a. The majority of drugs have MW between 100 and 1000 unites.

2 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

c. Drugs with large MW don't diffuse readily from one compartment to

Drug Receptor Bonds: drugs act by 3 main processes:

b. Electrostatic bonds: is much more common, but weaker than covalent,

c. Hydrophobic bonds: the lipid-soluble drugs (lipophilic) readily

Drug Shape: in order to bind to receptors a drug molecule must has a

Pharmacodynamic Principles: Drugs bind to their receptors to produce

b. Antagonists or Lytics (Blockers): drugs that inhibit the physiologic

Duration of Drug Action: termination of drug action differs from one to

Inert Binding Site: is defined as the binding of a drug to non regulatory

Pharmacokinetics Principles: It is important for the drug to reach its

Permeation: drugs diffuse across the plasma membrane by 4 primary

1) Aqueous diffusion (Passive diffusion): drugs may diffuse passively

2) Lipid diffusion: is the most important among others, many drugs

3) Active transport: some drugs are insoluble or with large MW requiring a

4 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

Ionization of Weak Acids and Weak Bases: it is important to note that

Handerson-Hasselbalch Equation: is the ratio of protonated to

Protonation: is the combination of a drug with proton (H2) ions.

b. For weak bases: combination of weak base with a proton, produces

Drug Receptors and Pharmacodynamics:

Receptor: is a specific cellular component (usually proteins) that interacts

5 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

1. Enzymes: the drug brings about its effect either by activation or

2. Ion channels: the drug acts either by activation or inactivation of a

3. Structural proteins: some drugs act by binding to structural protein e.g.

Relation Between Drug Concentration and Response: the relation

Spare Receptors: present when the maximal drug response is obtained at

Mechanisms of Spare Receptors;

Sensitivity of Receptors: the decreased concentration of a drug, the more

6 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

b. Partial agonists: drugs that exert agonist-antagonist property, as in

Types of Antagonists: on the basis of their pharmacologic effects they are

a. Competitive antagonists: drugs that compete for binding to their

b. Irreversible antagonists: they are not competitive, with agonists for

Others Mechanisms of Drug Antagonism:

a. Chemical antagonism: the ability of drug A to antagonize drug B,

b. Physiologic antagonism: 2 agents opposing physiological effects by

7 AAUJ. (2014) Dr. Omar R. Sadeq., MD., Ph.D

b. Extracellular receptors: the drug binds to extacellular domain of