Pharmacology Lecture 1

Pharmacology can be defined as the study of substances that interact with living
systems through chemical processes, especially by binding to regulatory molecules
and activating or inhibiting normal body processes.

The interactions between a drug and the body are conveniently divided into two
classes. The actions of the drug on the body are termed pharmacodynamic processes.
These properties determine the group in which the drug is classified, and they play the
major role in deciding whether that group is appropriate therapy for a particular
symptom or disease.

The actions of the body on the drug are called pharmacokinetic processes.
Pharmacokinetic processes govern the absorption, distribution, and elimination of
drugs and are of great practical importance in the choice and administration of a
particular drug for a particular patient, eg, a patient with impaired renal function.

Pharmacokinetics
• Absorption: First, absorption from the site of administration permits entry of the
drug (either directly or indirectly) into plasma.

• Distribution: Second, the drug may then reversibly leave the bloodstream and
distribute into the interstitial and intracellular fluids.

• Metabolism: Third, the drug may be biotransformed by metabolism by the liver or

other tissues.

• Elimination: Finally, the drug and its metabolites are eliminated from the body in
urine, bile, or feces.
Using knowledge of pharmacokinetic parameters, clinicians can design
optimal drug regimens, including the route of administration, the dose, the frequency,
and the duration of treatment.

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 Routes of drugs administration:
A. Enteral:
Enteral administration (administering a
drug by mouth) is the safest and most
common, convenient, and economical method
of drug administration. The drug may be
swallowed, allowing oral delivery, or it may
be placed under the tongue (sublingual), or
between the gums and cheek (buccal),
facilitating direct absorption into the
bloodstream.
Oral administration provides many
advantages. Oral drugs are easily self-
administered, and toxicities and/or overdose
of oral drugs may be overcome with antidotes,
such as activated charcoal.
However, the pathways involved in oral
drug absorption are the most complicated, and
the low gastric pH inactivates some drugs. A
wide range of oral preparations is available
including enteric-coated and extended-release
preparations.
Placement under the tongue allows a drug to
diffuse into the capillary network and enter
the systemic circulation directly.

Sublingual administration has several advantages, including ease of

administration, rapid absorption, bypass of the harsh gastrointestinal (GI)
environment, and avoidance of first pass metabolism.
The buccal route (between the cheek and gum) is similar to the sublingual route.

B. Parenteral:
The parenteral route introduces drugs directly into the body by the injection.
Parenteral administration is used for drugs that are poorly absorbed from the GI tract
(for example, heparin) or unstable in the GI tract (for example, insulin). Parenteral
administration is also used if a patient is unable to take oral medications (unconscious
patients) and in circumstances that require a rapid onset of action.

In addition, parenteral routes have the highest bioavailability and are not
subject to first-pass metabolism or the harsh GI environment. Parenteral
administration provides the most control over the actual dose of drug delivered to the
body. However, these routes of administration are irreversible and may cause pain,
fear, local tissue damage, and infections. The three major parenteral routes are
intravascular (intravenous or intra-arterial), intramuscular, and subcutaneous.

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1. Intravenous (IV): IV injection is the most
common parenteral route. It is useful for
drugs that are not absorbed orally.
IV delivery permits a rapid effect and a
maximum degree of control over the amount
of drug delivered. When injected as a bolus,
the full amount of drug is delivered to the
systemic circulation almost immediately. If
administered as an IV infusion, the drug is
infused over a longer period of time, resulting
in lower peak plasma concentrations and an
increased duration of circulating drug levels.
IV administration is advantageous for drugs
that cause irritation when administered via
other routes, because the substance is rapidly
diluted by the blood. IV injection may
inadvertently introduce infections through
contamination at the site of injection. It may
also precipitate blood constituents, induce
hemolysis, or cause other adverse reactions if
the medication is delivered too rapidly and
high concentrations are reached too quickly.
Therefore, patients must be carefully
monitored for drug reactions, and the rate of
infusion must be carefully controlled.

2. Intramuscular (IM): Drugs administered IM can be in aqueous solutions, which

are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly.
Depot preparations often consist of a suspension of the drug in a nonaqueous vehicle
such as polyethylene glycol.

3. Subcutaneous (SC): Like IM injection, SC injection provides absorption via

simple diffusion and is slower than the IV route. SC injection minimizes the risks of
hemolysis or thrombosis associated with IV injection and may provide constant, slow,
and sustained effects. This route should not be used with drugs that cause tissue
irritation, because severe pain and necrosis may occur.
Drugs commonly administered via the subcutaneous route include insulin and
heparin.

C. Other:

1. Oral inhalation: Inhalation routes, both oral and nasal, provide rapid delivery of a
drug across the large surface area of the mucous membranes of the respiratory tract
and pulmonary epithelium. Drug effects are almost as rapid as those with IV bolus.
Drugs that are gases (for example, some anesthetics) and those that can be dispersed

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in an aerosol are administered via inhalation. This route is effective and convenient
for patients with respiratory disorders (such as asthma or chronic obstructive
pulmonary disease), because the drug is delivered directly to the site of action,
thereby minimizing systemic side effects.

2. Nasal inhalation: This route involves administration of drugs directly into the
nose. Examples of agents include nasal decongestants.

3. Intrathecal/intraventricular: The blood–brain barrier typically delays or prevents

the absorption of drugs into the central nervous system (CNS). When local, rapid
effects are needed, it is necessary to introduce drugs directly into the cerebrospinal
fluid.

4. Topical: Topical application is used when a local effect of the drug is desired.

5. Transdermal: This route of administration achieves systemic effects by

application of drugs to the skin, usually via a transdermal patch. The rate of
absorption can vary markedly, depending on the physical characteristics of the skin at
the site of application, as well as the lipid solubility of the drug. This route is most
often used for the sustained delivery of drugs, such as the antianginal drug
nitroglycerin.

6. Rectal: Because 50% of the drainage of the rectal region bypasses the portal
circulation, the biotransformation of drugs by the liver is minimized with rectal
administration. The rectal route has the additional advantage of preventing destruction
of the drug in the GI environment. This route is also useful if the drug induces
vomiting when given orally, if the patient is already vomiting, or if the patient is
unconscious.

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 Schematic representation
of a transdermal patch.

Absorption of drugs:
Absorption is the transfer of a drug from the site of administration to the
bloodstream. The rate and extent of absorption depend on the environment where the
drug is absorbed, chemical characteristics of the drug, and the route of administration
(which influences bioavailability). Routes of administration other than intravenous
may result in partial absorption and lower bioavailability.

A. Mechanisms of absorption of drugs from the GI tract

Depending on their chemical properties, drugs may be absorbed from the GI
tract by passive diffusion, facilitated diffusion, active transport, or endocytosis.

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B. Factors influencing absorption

1. Effect of pH on drug absorption:

Acidic drugs (HA) release a proton (H+), causing a
charged anion (A−) to form:

Weak bases (BH+) can also release an H+. However, the

protonated form of basic drugs is usually charged, and
loss of a proton produces the uncharged base (B):

Most drugs are either weak acids or weak bases. A

drug passes through membranes more readily if it is
uncharged. Thus, for a weak acid, the uncharged,
protonated HA can permeate through membranes, and A−
cannot. For a weak base, the uncharged form B penetrates
through the cell membrane, but the protonated form BH+
does not. Therefore, the effective concentration of the
permeable form of each drug at its absorption site is
determined by the relative concentrations of the charged
and uncharged forms. The ratio between the two forms is,
in turn, determined by the pH at the site of absorption and
by the strength of the weak acid or base, which is
represented by the ionization constant, pKa .

2. Blood flow to the absorption site: The intestines

receive much more blood flow than the stomach, so
absorption from the intestine is favored over the stomach.

3. Total surface area available for absorption: With a

surface rich in brush borders containing microvilli, the
intestine has a surface area about 1000-fold that of the
stomach, making absorption of the drug across the
intestine more efficient.

4. Contact time at the absorption surface: If a drug

moves through the GI tract very quickly, as can happen
with severe diarrhea, it is not well absorbed. Conversely,
anything that delays the transport of the drug from the
stomach to the intestine delays the rate of absorption of
the drug.

Figure: A. Diffusion of the nonionized form of a weak acid through a lipid

membrane. B. Diffusion of the nonionized form of a weak base through a lipid
membrane

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5. Expression of P-glycoprotein:
P-glycoprotein is a trans-membrane transporter protein responsible for
transporting various molecules, including drugs, across cell membranes.
It is expressed in tissues throughout the body, including the liver, kidneys, placenta,
intestines, and brain capillaries, and is involved in transportation of drugs from tissues
to blood. That is, it “pumps” drugs out of the cells. Thus, in areas of high expression,
P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of
cells, it is also associated with multidrug resistance.

C. Bioavailability
Bioavailability is the rate and extent to which an administered drug reaches the
systemic circulation. For example, if 100 mg of a drug is administered orally and 70
mg is absorbed unchanged, the bioavailability is 0.7 or 70%. Determining
bioavailability is important for calculating drug dosages for non-intravenous routes of
administration.

In contrast to IV administration, which confers 100% bioavailability, orally

administered drugs often undergo first-pass metabolism. This biotransformation, in
addition to the chemical and physical characteristics of the drug, determines the rate
and extent to which the agent reaches the systemic circulation.
Drug distribution:
Drug distribution is the process by
which a drug reversibly leaves the
bloodstream and enters the interstitium
(extracellular fluid) and the tissues.
For drugs administered IV,
absorption is not a factor, and the initial
phase (from immediately after
administration through the rapid fall in
concentration) represents the distribution
phase, during which the drug rapidly leaves
the circulation and enters the tissues. The
distribution of a drug from the plasma to the
interstitium depends on cardiac output and
local blood flow, capillary permeability, the
tissue volume, the degree of binding of the
drug to plasma and tissue proteins, and the
relative lipophilicity of the drug.

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Volume of distribution:
The apparent volume of distribution, Vd, is defined as the fluid volume that is
required to contain the entire drug in the body at the same concentration measured in
the plasma. It is calculated by dividing the dose that ultimately gets into the systemic
circulation by the plasma concentration at time zero (C0).

Amount of drug in the body

Vd = ---------------------------------------
C0
Although Vd has no physiologic or physical basis, it can be useful to compare
the distribution of a drug with the volumes of the water compartments in the body.
The fact that drug clearance is usually a first-order process allows calculation
of Vd. First order means that a constant fraction of the drug is eliminated per unit of
time. This process can be most easily analyzed by plotting the log of the plasma drug
concentration (Cp) versus time. The concentration of drug in the plasma can be
extrapolated back to time zero (the time of IV bolus) on the Y axis to determine C 0,
which is the concentration of drug that would have been achieved if the distribution
phase had occurred instantly. This allows calculation of Vd as

Dose
Vd = ------------
C0
For example, if 10 mg of drug is injected into a patient and the plasma
concentration is extrapolated back to time zero, and C0 = 1 mg/L, then Vd = 10 mg/1
mg/L = 10 L.

Drug clearance through metabolism:

Once a drug enters the body, the process of elimination begins. The three
major routes of elimination are hepatic metabolism, biliary elimination, and urinary
elimination. Together, these elimination processes decrease the plasma concentration
exponentially. That is, a constant fraction of the drug present is eliminated in a given
unit of time.
Most drugs are eliminated according to first-order kinetics, although some,
such as aspirin in high doses, are eliminated according to zero-order or nonlinear
kinetics. Metabolism leads to production of products with increased polarity, which
allows the drug to be eliminated. Clearance (CL) estimates the amount of drug cleared
from the body per unit of time.
The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell
membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-
soluble agents are first metabolized into more polar (hydrophilic) substances in the
liver via two general sets of reactions, called phase I and phase II.

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 Drug clearance through kidney:
Drugs must be sufficiently polar to be eliminated from the body. Removal of
drugs from the body occurs via a number of routes, the most important being
elimination through the kidney into the urine. Patients with renal dysfunction may be
unable to excrete drugs and are at risk for drug accumulation and adverse effects.
Elimination of drugs via the kidneys into urine involves the processes of
glomerular filtration, active tubular secretion, and passive tubular reabsorption.

1. Glomerular filtration:
Drugs enter the kidney through renal arteries, which divide to form a
glomerular capillary plexus. Free drug (not bound to albumin) flows through the
capillary slits into the Bowman space as part of the glomerular filtrate. The
glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish
significantly in renal disease. Lipid solubility and pH do not influence the passage of
drugs into the glomerular filtrate.
However, variations in GFR and protein binding of drugs do affect this
process.
2. Proximal tubular secretion: Drugs that were
not transferred into the glomerular filtrate leave
the glomeruli through efferent arterioles, which
divide to form a capillary plexus surrounding the
nephric lumen in the proximal tubule. Secretion
primarily occurs in the proximal tubules by two
energy-requiring active transport systems: one
for
anions (for example, deprotonated forms of
weak acids) and one for cations (for example,
protonated forms of weak bases). Each of
thesetransport systems shows low specificity and
can transport many compounds. Thus,
competition between drugs for these carriers can
occur within each transport system.
3. Distal tubular reabsorption: As a drug
moves toward the distal convoluted tubule, its
concentration increases and exceeds that of the
perivascular space. The drug, if uncharged, may
diffuse out of the nephric lumen, back into the
systemic circulation.
Manipulating the urine pH to increase the
fraction of ionized drug in the lumen may be
done to minimize the amount of back diffusion
and increase the clearance of an undesirable
drug. As a general rule, weak acids can be
eliminated by alkalinization of the urine,
whereas elimination of weak bases may be
increased by acidification of the urine. This
process is called “ion trapping.” For example, a
patient presenting with phenobarbital (weak
acid) overdose can be given bicarbonate, which 9
alkalinizes the urine and keeps the drug ionized,
thereby decreasing its reabsorption.
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