Pharmacology Basics

PHARMACOLOGY
(Greek “Pharmakon” – drug, “logos” - teaching)

The science that studies the interaction of the chemical

substances with live organisms, drugs administration for
treatment and prophylaxis of various diseases and
pathological processes
• Brand – original drug which is defended by patent
and may be produced during patent term only by this
pharmaceutical firm

• Generic – when term of patent is discontinued the

drug may be produced by different pharmaceutical
companies under new product (trade) names but at
the basis of original active substance (similar
quantity, route of administration etc.)

• All generics are much more cheaper compared to

brands, that is the main reason – why they are so
popular among the patients
Nadolol
( β1, β 2 - adrenoblocker )
Becotide = Beclometh
(beclomethasone dipropionate)
Biopharmaceutics

Introduction to Pharmacology 1
• Bio – life
• Pharmaceutics
– general area of study
concerned with the formulation,
manufacture, stability and
effectiveness of pharmaceutical
dosage forms.
Biopharmaceutics
• study of the factors
influencing the
bioavailability of a drug
in man and animals and
the use of this
information to optimize
pharmacological or
therapeutic activity of
drug products in clinical
application.
Biopharmaceutics

• study of the influence of formulation on therapeutic

activity of a drug product.
• What the “Drug do to the Body”
Biopharmaceutics

• study embracing this relationship between the

physical, chemical and biological sciences as
they apply to drugs, dosage forms, and to
drug action.
Biopharmaceutics

• Modern biopharmaceutics is the study of the

relationship of the physico-chemical properties
and in vitro behavior of the drug and drug
product on the delivery of the drug to the
body under normal or pathologic conditions.
Drug
• agent intended for use in the diagnosis,
mitigation, treatment, cure or prevention of
disease in man or in other animals.
• It may be:
1. synthetic 4. biological
2. semi-synthetic 5. natural
3. chemical
Drug
• Modern drugs are potent chemical substances
that must be fabricated into a drug product
before use.
• Generally, the drug is combined with other
ingredients into a drug formulation, which may
be a solution, tablet, capsule or suppository.
Rationale
• The development of biopharmaceutic principles
allowed for the rational design of drug products,
which would enhance the delivery of active drug,
and optimize the therapeutic efficacy of the drug
in the patient.
Drug Product
• a finished dosage form that contains an active
drug ingredient generally, but not necessarily, in
association with inactive ingredient.
• formulation or matrix in which the drug is
contained
• The term may also include a dosage form that
does not contain an active ingredient intended
to be used as placebo.
Drug Action
• result of an interaction between the drug
substance and functionally important cell
receptors or enzyme systems.
• This response is due to the alteration in the
biologic processes that were present prior to the
drug administration.
• In vitro – glass
referring to a process or reaction carried out
in a culture dish or test tube
• In vivo – in the living organism
Effects of Biopharmaceutics
• Generic equivalency
• Drug availability
• Therapeutic efficacy
• Drug substitution
Pharmacokinetics

Introduction to Pharmacology 1
Definitions

• Pharmacokinetics
• The process by which a drug is absorbed,
distributed, metabolized and eliminated by the
body

• Pharmacodynamics
• The interactions of a drug and the receptors
responsible for its action in the body
Pharmacokinetics
THE PART OF PHARMACOLOGY THAT CONCERNED
WITH THE
A BSORBTION,
D ISTRIBUTION,
M ETABOLISM (BIOTRANSFORMATION)
AND
E XCRETION
OF DRUGS

WHAT THE ORGANISM DOES TO THE DRUGS

Pharmacokinetics: Life Cycle of a
Drug

• Absorption
• Distribution
• Degradation
• Excretion
 Slow Absorption

• Orally (swallowed)

• through Mucus Membranes

– Oral Mucosa (e.g. sublingual)
– Nasal Mucosa (e.g. insufflated)

• Topical/Transdermal
(through skin)
• Rectally (suppository)
Faster Absorption

• Parenterally (injection)
• Intravenous (IV)
• Intramuscular (IM)
• Subcutaneous (SC)
• Intraperitoneal (IP)

• Inhaled (through lungs)

 Fastest Absorption

• Directly into brain

– Intracerebral (into brain tissue)
– Intracerebroventricular (into brain
ventricles)

General Principle: The faster the absorption, the quicker the

onset, the higher the addictiveness, but the shorter the duration
 Absorption: Solubility
• Water-soluble
• Ionized (have electrical charge)
• Crosses through pores in capillaries, but not cell membranes

• Lipid(fat)-soluble
• Non-ionized (no electrical charge)
• Crosses pores, cell membranes, blood-brain-barrier

Dissociation constant or pKa  indicates the pH where 50% of

the drug is ionized (water soluble) and 50% non-ionized (lipid
soluble);
pKeq = pH + log [X]ionized/[X]non-ionized

This affects a drug's solubility, permeability, binding, and other

characteristics.
(hydroxyl group)

(amine group)
Distribution: Depends on Blood Flow and
Blood Brain Barrier
• Excludes ionized
substances;
• Active transport
mechanisms;
• Not uniform – leaky
(circumventricular areas)
 Bioavailability
• The fraction of an administered dose of drug that reaches the blood
stream.
• What determines bioavailability?
• Physical properties of the drug (hydrophobicity, pKa, solubility)
• The drug formulation (immediate release, delayed release, etc.)
• If the drug is administered in a fed or fasted state
• Gastric emptying rate
• Circadian differences
• Interactions with other drugs
• Age
• Diet
• Gender
• Disease state
Depot Binding
(accumulation in fatty tissue)
• Drugs bind to “depot sites” or “silent receptors” (fat,
muscle, organs, bones, etc)

• Depot binding reduces bioavailability, slows elimination,

can increase drug detection window

• Depot-bound drugs can be released during sudden

weight loss – may account for flashback experiences?
 Degradation & Excretion
• Liver
– Enzymes(cytochrome P-450)
transform drugs into more water-
soluble metabolites
– Repeated drug exposure increases
efficiency  tolerance

• Kidneys
– Traps water-soluble (ionized)
compounds for elimination via urine
(primarily), feces, air, sweat
Excretion: Other routes
• Lungs
alcohol breath
• Breast milk
acidic ---> ion traps alkaloids
alcohol: same concentration as blood
antibiotics
• Also bile, skin, saliva ~~
Metabolism and Elimination (cont.)
• Half-lives and Kinetics
• Half-life:
• Plasma half-life: Time it takes for plasma concentration of a
drug to drop to 50% of initial level.
• Whole body half-life: Time it takes to eliminate half of the
body content of a drug.
• Factors affecting half-life
• age
• renal excretion
• liver metabolism
• protein binding
First order kinetics
A constant fraction of drug is eliminated per unit of time.

When drug concentration is high, rate of disappearance

is high.
Zero order kinetics

Rate of elimination is constant.

Rate of elimination is independent of drug concentration.

Constant amount eliminated per unit of time.

Example: Alcohol
Comparison

• First Order Elimination • Zero Order Elimination

• [drug] decreases • [drug] decreases linearly
exponentially w/ time with time
• Rate of elimination is • Rate of elimination is
proportional to [drug] constant
• Plot of log [drug] or • Rate of elimination is
ln[drug] vs. time are linear independent of [drug]
• t 1/2 is constant regardless • No true t 1/2
of [drug]
 Drug Effectiveness
• Dose-response (DR) curve
• Depicts the relation between drug
dose and magnitude of drug effect
• Drugs can have more than one
effect
• Drugs vary in effectiveness
• Different sites of action
• Different affinities for
receptors
• The effectiveness of a drug is
considered relative to its safety
(therapeutic index)
ED50 = effective dose in 50% of population

100

% subjects 50
ED50

0
0 X
DRUG DOSE
 Therapeutic Index
• Effective dose (ED50)
= dose at which
50% population
shows response
• Lethal dose (LD50)
=dose at which 50%
population dies ED 50 LD50

• TI = LD50/ED50, an
indication of safety
of a drug (higher is
better)
 Potency
• Relative strength of response for
a given dose
– Effective concentration (EC50)
is the concentration of an
agonist needed to elicit half of
the maximum biological
response of the agonist
– The potency of an agonist is
inversely related to its EC50
value
• D-R curve shifts left with greater
potency
Efficacy
• Maximum possible effect relative
to other agents
• Indicated by peak of D-R curve
• Full agonist = 100% efficacy
• Partial agonist = 50% efficacy
• Antagonist = 0% efficacy
• Inverse agonist = -100% efficacy
Comparisons

C
HI
B

Average
Response
Magnitude

LO
0 X
DRUG DOSE
 Tolerance
(desensitization)

• Decreased response to same

dose with repeated (constant)
exposure
• or more drug needed to achieve
same effect
• Right-ward shift of D-R curve
• Sometimes occurs in an acute
dose (e.g. alcohol)
• Can develop across drugs (cross-
tolerance)
• Caused by compensatory
mechanisms that oppose the
effects of the drug
 Sensitization

• Increased response to same dose

with repeated (binge-like)
exposure
• or less drug needed to achieve
same effect
• Left-ward shift in D-R curve
• Sometimes occurs in an acute
dose (e.g. amphetamine)
• Can develop across drugs (cross-
sensitization)

It is possible to develop tolerance to some side effects AND sensitization

to other side effects of the same drug
 Mechanisms of Tolerance and Sensitization

• Pharmacokinetic
– changes in drug availability at site of action
(decreased bioavailability)
– Decreased absorption
– Increased binding to depot sites
• Pharmacodynamic
– changes in drug-receptor interaction
– G-protein uncoupling
– Down regulation of receptors
 Other Mechanisms of
Tolerance and Sensitization

• Psychological
As the user becomes familiar with the drug’s effects,
s/he learns tricks to hide or counteract the effects.
Set (expectations) and setting (environment)
Motivational
Habituation
Classical and instrumental conditioning (automatic
physiological change in response to cues)
• Metabolic
The user is able to break down and/or excrete the drug
more quickly due to repeated exposure.
Increased excretion
Drug-drug Interactions

• Pharmacokinetic and pharmacodynamic

• With pharmacokinetic drug interactions, one drug affects the
absorption, distribution, metabolism, or excretion of another.
• With pharmacodynamic drug interactions, two drugs have
interactive effects in the brain.
• Either type of drug interaction can result in adverse effects in
some individuals.
• In terms of efficacy, there can be several types of interactions
between medications: cumulative, additive, synergistic, and
antagonistic.
Cumulative Effects

Hi

Drug B
Response

Drug A
Lo
Time
The condition in which repeated administration of a drug may produce effects
that are more pronounced than those produced by the first dose.
Additive Effects

Hi

A+B
Response
A B

Lo
Time
The effect of two chemicals is equal to the sum of the effect of the two
chemicals taken separately, eg., aspirin and motrin.
Synergistic Effects

A+B
Hi

Response
A B

Lo
Time

The effect of two chemicals taken together is greater than the sum of their
separate effect at the same doses, e.g., alcohol and other drugs
Antagonistic Effects

Hi

A+B

Response
A B

Lo
Time

The effect of two chemicals taken together is less than the sum of their
separate effect at the same doses
Pharmacodynamics

Introduction to Pharmacology 1
Definitions

• Pharmacokinetics
• The process by which a drug is absorbed, distributed, metabolized
and eliminated by the body

• Pharmacodynamics
• The interactions of a drug and the receptors responsible for its
action in the body
 Pharmacodynamics

THE PART OF PHARMACOLOGY THAT CONCERNED WITH THE

BIOCHEMICAL AND PHYSIOLOGICAL EFFECTS OF DRUGS AND
THEIR MODE OF ACTION

IT INCLUDES THE DOSE-EFFECT RELATIONSHIP, FACTORS

MODIFYING DRUG EFFECTS, DOSAGE, DRUG TOXICITY

WHAT DRUGS DO TO THE ORGANISM

Pharmacodynamics

Pharmacological effect – clinical manifestation of drug

influence on the organism

Its basis is primary pharmacological reaction – the result

of drug influence on special structures of the organism
• Pharmacological effects may be identical but caused by
different pharmacological reactions:
Atropin and Adrenalin dilates the pupils, 1st inhibits M-
cholinoreceptos, 2nd – activates adrenoreceptors
• In contrary, different pharmacological effects may appear due
to the same pharmacological reaction:
Anaprilinum causes β-adrenoreceptors blockade that resulted
in hypotension, antiarrhythmic action and antianginal effect
Pharmacological Effects
• Local action: local anesthesia, astringent, covering,
irritating, necrotizing, adsorbing
• Reflex action: as a result of local irritation (Sol. Ammonii
caustici, Validolum, Charta Sinapis, expectorants of plant origin)
• Resorbtive (systemic) action – after drug absorption
or its introduction to blood stream):
1)Direct (primary) and
2)Indirect (secondary): cardiac glycosides: 1 – on heart, 2 –
diuretic effect
• Selective action (salbutamol, celecoxyb, doxazosin)
• Nonspecific action – on all cells of the organism: drugs
for general anesthesia, salts of heavy metals
• Basic (beneficial) action and adverse reaction
• Reversible and irreversible
Receptor Theory of Drug Action

• Receptors – the places where drugs bind to

tissues: macromolecules, enzymes, channels,
transport systems, genes
• Agonists: adrenalin, isadrine, morphine etc.
• Antagonists: atropin, anaprilin, dimedrol etc.
• Agonist-antagonist:
labetolol (1, 1-adreno-blocker, but activates
2-adrenoreceptors),
pentazocin (agonist delta- and kappa-opiate
receptors and mu-receptors antagonist)
Agonism and Antagonism

Agonists facilitate receptor

response

Antagonists inhibit receptor

response

(direct ant/agonists)
 Pharmacodynamics
• Receptor
– target/site of drug action (e.g. genetically-coded proteins
embedded in neural membrane)

• Lock and key or induced-fit models

– drug acts as key, receptor as lock, combination yields response
– dynamic and flexible interaction
 Pharmacodynamics (cont.)

• Affinity
– propensity of a drug to bind with a receptor

• Selectivity
– specific affinity for certain receptors (vs. others)
Modes of Action
• Agonism • Antagonism
• A compound that does the • A compound inhibits an
job of a natural substance. enzyme from doing its job.
• Does not effect the rate of • Slows down an
an enzyme catalyzed enzymatically catalyzed
reaction. reaction.
• Up/down regulation
• Tolerance/sensitivity at the
cellular level may be due to
a change in # of receptors
(without the appropriate
subunit) due to changes in
stimulation
Agonists/Antagonists
• Full A single drug can bind to a single
receptor and cause a mix of effects
(agonist, partial agonist, inverse agonist,
• Partial antagonist)

Functional Selectivity Hypothesis:

• Direct/Competitive Conformational change induced by a
ligand-receptor interaction may cause
differential functional activation
• Indirect/Noncompetitive depending on the G-protein and other
proteins associated with the target
receptor
• Inverse
 Important implications of
drug-receptor interaction

• drugs can potentially alter rate of any

bodily/brain function
• drugs cannot impart entirely new functions to
cells
• drugs do not create effects, only modify ongoing
ones
• drugs can allow for effects outside of normal
physiological range
Law of Mass Action
(a model to explain ligand-receptor binding)
• When a drug combines with a receptor, it does so at a rate
which is dependent on the concentration of the drug and
of the receptor

• Assumes it’s a reversible reaction

• Equilibrium dissociation (Kd) and association/affinity (Ka)

constants
• Kd = Kon/Koff = [D][R]/[DR]
• Ka = 1/Kd = Koff/Kon = [DR]/[D][R]
 Nonspecific Action of Drugs
Due to their physical and chemical properties

• Mannit increases osmotic pressure in kidneys

canalicules and causes diuretic effect
• Direct chemical interaction: Antacids (MgO,
NaHCO3) neutralize HCl, Trilon B (EDTA) binds salts
of heavy metals, Na citrate binds Ca-ions
• Physical-chemical interaction: Protamine sulfate
binds Heparin
• Due to the same structure with metabolites of the
organism drugs interferences with corresponding
metabolic processes : Sulfonamides (have the same
structure to PABA), Mercaptopurin (to folic acid and
purin)
 Bioavailability
of drugs

complex of pharmacokinetic processes that

maintenance active concentration of drug in the area
of specific receptors (part of administered drug that
reaches the systemic circulation and effects specific
receptors)
Pre-systemic Elimination
(first pass metabolism)
pre-systemic elimination – extraction of the
drug form blood circulatory system during it’s
first passage through the liver– it leads to
decreasing of bioavailability (and therefore,
decreasing of biological activity) of drugs

propranolol (anapriline), labetolol, aminazine,

acetylsalicylic acid, labetolol, hydralazine,
izadrine, cortizone, lidocaine, morphine,
pentazocine, organic nitrates, reserpine
• ONSET – the period between the moment of
drug introduction to the organism and the
beginning of its action
• DURATION OF DRUG ACTION – the period
then specific effects of the drug are
maintained
• WIDENESS of therapeutic action (therapeutic
window) – the distance between minimum
therapeutic and minimum toxic doses of drug