Pharmacodynamics

Question 1

What is pharmacodynamics?

Answer 1

Pharmacodynamics describes the relationship between drug level and effect.
OR ‘What a drug does to the body’

Question 2

What are dose-response curves?

Answer 2

Dose-response curves enable us to quantify biological effect of drugs on both molecular and physiological processes

Question 3

What is hysteresis?

Answer 3

The phenomenon in which the value of a physical property lags behind changes in the effect causing it.
– i.e. relationship between drug concentration and
effect is not direct

Question 4

What is counter-clockwise hysteresis?

Answer 4

the process in which effect can increase with time for a given drug concentration

Question 5

What is clockwise hysteresis?

Answer 5

the measured effect decreases with time for a given drug concentration

Question 6

How does counter-clockwise hysteresis work?

Answer 6

Sensitisation (up regulation of receptors)
Distribution delay to site of effect
Generation of agonist metabolite
Slow receptor kinetics
Time-dependent protein binding

Question 7

Give an clinical example of a drug that shows counter-clockwise hysteresis.

Answer 7

Isosorbide dinitrate

Question 8

How does clockwise hysteresis work?

Answer 8

Tolerance (down regulation of receptors)
Disequilibrium between arterial and venous conc.
Generation of antagonistic metabolite
Feedback regulation
Time-dependent protein binding

Question 9

Give an clinical example of a drug that shows clockwise hysteresis.

Answer 9

Temazepam

Question 10

Most drugs act by binding to a target. Name some exceptions. (4)

Answer 10

– osmotic diuretics
– antacids and chelating agents
– bile sequestrants
– certain anti-microbials and anti-tumour

Question 11

What are enzymes?

Answer 11

Globular proteins that catalyse reactions through binding of substrate in an active site. They speed up time to reach equilibrium and allow a lower activation energy for reaction.

Question 12

Enzymes may be extracellular or intracellular.

Give an example of the former, and two of the latter.

Answer 12

angiotensin converting enzyme

carbonic anhydrase, xanthine oxidase

Question 13

How does allopurinol work?

Answer 13

Inhibits the oxidation of xanthine to uric acid

Question 14

How does streptokinase work?

Answer 14

activates human plasminogen

Question 15

What are ion channels?

Answer 15

Ion channels allow ions to travel across an otherwise
impermeable membrane, passively down the
electrochemical gradient, at a high rate.

Question 16

What is the typical function of ion channels?

Answer 16

Typical function is to maintain resting membrane potential, to shape electrical signals including action potentials, and to regulate cell volume.

Question 17

Drugs may act to increase the probability of closed channels - give an example.

Answer 17

CCBs such as nifedipine

Question 18

Drugs may act to increase the probability of open channels - give an example.

Answer 18

Benzodiazepines

Question 19

Ion carriers/pump - what do these do?

Answer 19

Ion carriers / pump - actively moves ions across a plasma membrane against their concentration gradient. This requires energy from various sources, including ATP (e.g. Na+/K+ ATPase) and potential energy stored in an electrochemical gradient (e.g. Na+/Ca2+ exchanger).

Question 20

Ion carriers/pump - what are the three types?

Answer 20

uniporters (only one ion transported)
sympoters (ions going in same direction)
antiporters (in opposite directions)

Question 21

Receptors relay _____ _____ from ___________.

Answer 21

Relays chemical signals from outside to inside a cell.

Question 22

What are the main classifications of receptors? (3)

Answer 22

– G protein-coupled receptors
– Kinase linked
– Nuclear receptors

Question 23

Receptors may be membrane bound cell surface receptors, _________, or in the ______.

Answer 23

cytoplasmic, or in the nucleus.

Question 24

Which classification of receptors may have a longer-lasting effect?

Answer 24

Nuclear receptors

Question 25

Define affinity. What does this determine?

Answer 25

The strength of forces attracting ligand and receptor together. This determines the degree of association and dissociation of the drug and the receptor.

Question 26

The affinity of a drug for an individual receptor describes…?

Answer 26

how avidly the drug binds to the receptor (ie, the dissociation constant, Kd)

Question 27

Covalent binding of drug to receptor (e.g. fluoroquinolones acting on bacteria) leads to…?

Answer 27

formation of an irreversible link

Question 28

Aspirin irreversibly binds to its target enzyme. What is it called?

Answer 28

COX

Question 29

What is Kd?

Answer 29

Kd is the equilibrium dissociation constant and provides a mathematic measure of affinity (1/Kd).

Question 30

If the receptors have a high affinity for the ligand, the Kd will be…?
Why?

Answer 30

low, as it will take a low concentration of ligand to bind half the receptors

Question 31

The ‘Law of Mass Action’ is a simple model of receptor ligand interactions with a number of assumptions.
What are they? (5)

Answer 31

– All receptors are equally accessible to ligands
– Receptors exist in one of two states: free or bound to ligand
– Bindings does not alter ligand or receptor
– Binding is reversible
– Receptors numbers are fixed

Question 32

Ligand-receptor interaction requires spatial interaction i.e…?

Answer 32

‘lock and key’

Question 33

Certain drugs exhibit stereospecific interactions where
different stereoisomers bind to different targets.
Give an example.

Answer 33

S(-) carvedilol binds to alpha- and beta-adrenoceptors,
but R(+) cavedilol binds selectively to alpha adrenoceptors.

Question 34

Affinity is determined by the strength of receptor ligand
interaction.
What are the three types?

Answer 34

– Electrostatic interactions (most common)
– Hydrophilic interactions
– Covalent bonds (least common)

Question 35

Define selectivity.

Answer 35

a drug’s ability to preferentially bind to certain receptors.
E.g. COX-2 selective NSAIDs are without significant effect on COX-1

Question 36

Define specificity.

Answer 36

Specificity of drug action relates to the number of different mechanisms involved. Non-specific = several mechanisms.

Question 37

Give an example of two specific drugs.

Answer 37

atropine (muscarinic receptor antagonist)

salbutamol (β2-adrenoceptor agonist)

Question 38

Give an example of a non-specific drug.

Answer 38

chlorpromazine causes blockade of D2-dopamine,

α-adrenergic, and muscarinic receptors.

Question 39

Define potency.

Answer 39

the concentration (EC50) or dose (ED50) of a drug required to produce 50% of the drug’s maximal effect

Question 40

Define median inhibitory concentration (IC50).

Answer 40

the concentration of an antagonist that reduces a specified response to 50% of the maximal possible effect

Question 41

Define efficacy.

Answer 41

the maximum effect (Emax) of a drug

Question 42

What are agonists?

Answer 42

drugs that bind to receptors, converting it to the

active conformation, resulting in a biologic response

Question 43

Full agonists result in a _____ by occupying all or a fraction of receptors.
Partial agonists results in a …. even when the drug occupies all of the receptors.

Answer 43

maximal response

less than maximal response

Question 44

How can partial agonists act as competitive antagonists in the presence of a full agonist?

Answer 44

as it competes for receptor occupancy, thereby producing a net decrease in the receptor activation as compared to that observed with the full agonist alone

Question 45

Partial agonists - their usefulness is derived from…?

E.g.?

Answer 45

their ability to enhance deficient systems while simultaneously blocking excessive activity (e.g.
methadone).

Question 46

Describe antagonists in terms of affinity and efficacy.

Answer 46

Antagonists have affinity (i.e. they bind) but no efficacy (i.e. have no effect) for their receptors, therefore binding will disrupt the action of an agonist at the receptors.

Question 47

What is an inverse agonist?

E.G.?

Answer 47

an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist.
E.g. naloxone

Question 48

What are competitive antagonists?

Answer 48

reversibly bind to receptors as the agonist, but without

activating the receptor, therefore “competing” for the same binding site

Question 49

What are non-competitive antagonists?

Answer 49

reduce the magnitude of the maximum response

attained by any amount of agonist

Question 50

What are allosteric modulators?

Answer 50

they indirectly influence (modulate) the effects of an agonist by binding to a site distinct from the agonist
they usually induce conformational change within the target

Question 51

What are positive allosteric modulators?

E.g.?

Answer 51

induces an amplification of the agonist’s effect, either by enhancing the affinity or the functional efficacy.
Benzodiazepines

Question 52

What are negative allosteric modulators?

Answer 52

reduces the effects of the agonist, but is inactive in the absence of the orthosteric ligand.

Question 53

Define chemical antagonism.

Answer 53

involves chemical interaction between a drug and either a chemical or another drug leading to a reduced or nil response.

Question 54

Define physiologic antagonism.

Answer 54

occurs when two drugs acting on different receptors and pathways exert opposing actions on the same physiologic system.

Question 55

Define pharamcokinetic antagonism.

Answer 55

the result of one drug suppressing the effect of a second drug by reducing its absorption, altering its distribution, or increasing its rate of elimination

Question 56

What are biological therapies?

Answer 56

engineered macromolecule products like protein and
nucleic acid–based drugs.
Often highly targeted, especially in monoclonal
antibodies.
Typically more specific and high potency / efficacy.
Typically act as antagonists (e.g. anti-inflammatory)