Basic Pharmacology Course

Omer Elzain Elhado

~MBBS (OIU) , MSc. in Clinical pharmacology. 2017~

-3rd July 2017-

The Pharmacology “two arms”
o Pharmacodynamics
• “what the drug does to the body”
• The study of the effect(s) of drugs on body
processes
oPharmacokinetics
• “what the body does to the drug”
• The study of the movement of drugs in the
body (how it reaches and leaves its site of
action and at what concentration)
Pk-PD relationship
Pharmacodynamics: Overview
• Pharmacodynamics describes the actions of a
drug on the body and the influence of drug
concentrations on the magnitude of the
response.
• Most drugs exert their effects, both beneficial
and harmful, by interacting with receptors (that
is, specialized target macromolecules) present
on the cell surface or within the cell.
• The drug–receptor complex initiates alterations
in biochemical and/or molecular activity of a cell
by a process called signal transduction
The recognition of a drug by a receptor triggers
a biologic response
Simplification of drug action
What are receptors?
• Receptors are macromolecules that mediate a
biological change following ligand (drug)
binding.
• Receptors are located on the surface of or
within cells.
The drug-receptor complex
• Van der Waals forces, hydrogen and ionic bonds in the
active (binding) site typically mediate formation of the
drug-receptor complex → receptor affinity
An exception to the rule
A few drugs work via non-receptor mechanisms, for
example:
• Antacids - purely chemical basis via acid
neutralization in the stomach
• Osmotic diuretics - promote urine excretion by
altering water flow in the kidney independent of
receptors
There are four main classes of
receptors
 RECEPTOR FAMILIES

1. Ligand-gated ion channels.

2. G protein-coupled receptors.
3. Enzyme-linked receptors.
4. Intracellular receptors.
1. LIGAND-GATED ION CHANNELS
• Ionotropic receptors, regulate the flow of ion
across the cell-membrane.
• The response is very rapid (milliseconds).
• The neurotransmitter acts on the postsynaptic
membrane of a nerve or muscle increasing the
permeability to an ion.
• E.g fast neurotransmitters ,nicotinic
receptors, glutamate receptors & GABAA
receptors.
 2. G PROTEIN-COUPLED
RECEPTORS
• The receptor is a peptide with 7 membrane spanning
regions.
• It’s attached to a G protein which has 3 subunits α
binds GDP, β and Υ.
• Ligand binding, activates G protein, the GTP replaces
the GDP, the α-GTP dissociates.
• The dissociated subunits are called second
messengers.
• The response lasts seconds to minutes.

13
• The α-GTP subunit is responsible for the
1. production of cAMP a second messenger regulates
protein phosphorylation.
2. Activation of phospholipase C which generates IP3
& diacylgycerol which regulates Ca.
3. Ion channels especially Ca & K.
• E.g. muscarinic receptors, adrenoceptors, dopamine,
opiate receptors.
3.ENZYME-LINKED RCEPTORS
• Have a cytosolic enzyme activity as part of their
structure.
• Binding of a ligand to the extracellular domain
activates or inhibits the cytosolic enzyme activity.
• The response duration is minutes to hours.
• E.g. those having tyrosine kinase activity which
phosphorylates a protein leading to it’s modification
(insulin,growth factors, cytokines).
 4. INTRACELLULAR
RECEPTORS
• The ligand diffuses to the intracellular receptor.
• The complex migrates to the nucleus, binds to specific
DNA sequences leading to gene expression & protein
synthesis.
• The duration of response is hours to days.
Agonism and Antagonism

Agonists facilitate receptor

response

Antagonists inhibit receptor

response

(direct ant/agonists)
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
• Inverse receptor
 Important implications of
drug-receptor interaction

o drugs can potentially alter rate of any bodily/brain

function

o drugs cannot impart entirely new functions to cells

o drugs do not create effects, only modify ongoing ones

o drugs can allow for effects outside of normal

physiological range
 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
• TI = LD50/ED50, an indication of safety of a drug (higher
is better)
ED50 LD50
 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
 Dose response relationship
• The magnitude of the drug effect depends on
the drug concentration at the receptor site.
• The response is a graded effect, meaning that
the response is continuous and gradual.
• graph of this relationship is known as a
graded dose response curve.
Two important properties of drugs can be
determined by graded dose response curves.
1. Potency: a measure of the amount of drug
necessary to produce an effect of a given
magnitude.
EC50: concentration producing an effect that is
fifty percent of the maximum
2- Efficacy [intrinsic activity]: ability of a drug
to illicit a physiologic response when it interacts
with a receptor.
• It depends on the number of drug receptor
complexes formed and the efficiency of the
• coupling of receptor activation to cellular
responses.
• the maximal response (Emax) or efficacy is
more important than drug potency.
• Maximum effect Emax: is the point after
which no further increase in response even if
concentration is increased.
• Recognetion of Emax helps to avoid ineffectual
increases of dose with possible risk of toxicity.
• Sensitivity of a target organ to a drug conc. Is
reflected by the conc. Required to produce
50% of the maximum effect Emax.
• Decrease sensitivity leads to decrease
response and this is detected by a pt not
getting better despite the therapeutic conc.
was given.
• Decreased sensitivity may be due to abnormal
physiology (hyperkalemia & digoxin) or an
antagonist effect (Ca channel-blockers impair
the inotropic response to digoxin.
• Increase sensitivity is detected by exaggerated
response to a small or moderate doses. This is
detected by measuring the drug concentration.
• Quantal dose response: the influence of the
magnitude of the dose on the proportion of a
population that responds.
• It’s useful in determining doses to which most of the
population responds.
• Therapeutic index: is the ratio of the dose that
produces toxicity to the dose that produces a clinical
desired effect in a population.
• Therapeutic index= TD50/ED50
• TD50: the dose that produces toxic effect in ½ of the
population.
• ED50: the dose that produces therapeutic response in
½ of the population.
• It measures the drug safety.
• E.g Warfarin the critically bioavailability alters the
therapeutic effect.
Pharmacologic effects – side effects
• “A drug without side effects isn’t really a drug”

Side Effects / Adverse Effects

Mild, tolerable, Potentially life-

subside on their threatening &
own(e.g GI sustained
disturbances) (e.g seizures)

• Risks vs Benefits must be carefully weighed →

Therapeutic Index