Pharmacodynamics

Question 1

bioavailability

Answer 1

the concentration of bioactive drug in the systemic circulation

Question 1

pharmacokinetics (ADME-T)

Answer 1

what the body does to the drug

Question 2

pharmacodynamics

Answer 2

‘what the drug does to the body’

the relationship between drug concentration at the site of action and the intensity/duration of the effects

Question 3

main drug targets

Answer 3

• voltage/ligand ion channels
• enzymes
• transporters
• receptors

Question 4

drug targets at the synapse

Answer 4

• voltage gated calcium channels
• precursor transport channels
• synthesis enzymes
• vesicular transporters
• postsynaptic receptors (metabotropic/ionotropic)
• presynaptic regulatory receptors
• degradation enzymes
• reuptake channels

Question 5

GPCRs

Answer 5

proteins composed of 7 transmembrane domains, with an extracellular N terminus and intracellular C terminus

Question 6

G proteins

Answer 6

heterotrimeric proteins (aby) that change conformation upon receptor activation to dissociate into an alpha subunit and a beta-gamma dimer which can both exert effects

Question 7

Affinity

Answer 7

the ability of a drug to bind to a receptor

defined by Kd: the concentration of a drug required to occupy 50% of receptors

Question 8

potency

Answer 8

a measure of the concentration of a drug required to produce an effect

defined by EC50: the concentration of a drug required to produce 50% of the maximal response

Question 9

Efficacy

Answer 9

the ability of a drug to produce a response

defined by Emax on a concentration-response curve

Question 10

Define agonist & partial agonist, in terms of drug efficacy

Answer 10

agonists have 100% efficacy at full receptor occupancy, whereas partial agonists will never reach Emax

Question 11

fractional occupancy

Answer 11

Fo = [A]/(Kd+[A])

describes the percentage of receptors occupied at a given time

Question 12

Kd equation

Answer 12

Kd = (k-1)/(k+1)

a function of the dissociation constant (k-1) and the binding constant (k+1)

Question 13

concentration response curve

Answer 13

defines efficacy and potency

Effect = Emax.[A] / (EC50+[A])

Question 14

desensitisation of ion channels

Answer 14

phosphorylation by GRK facilitates recruitment of beta-arrestin

Question 15

downregulation of ion channels

Answer 15

clathrin-mediated internalisation and subsequent sorting of vesicles for recycling or degradation

Question 16

tolerance

Answer 16

the development of a diminishing response to the same dose of drug

Question 17

mechanisms of tolerance

Answer 17

pharmacological down regulation of agonist receptors or up-regulation of antagonising receptors

pharmacokinetic altering of metabolism

Question 18

competitive reversible antagonists

Answer 18

bind reversibly to orthosteric site, but do not activate the receptor
= affinity but no efficacy

shift the dose-response curve to the left

surmountable, as can be overcome with increasing concentration of agonist

Question 19

examples of competitive reversible antagonists

Answer 19

naloxone (opioid antagonist)
haloperidol (dopamine receptor antagonist and antipsychotic)
clozapine (serotonin/dopamine antagonist and an atypical antipsychotic)

Question 20

partial agonists as antagonists

Answer 20

partial agonists can prevent the full action of an agonist by occupying receptors to produce decreased efficacy

Question 21

buprenorphine

Answer 21

a partial agonist that is used as an antagonist for opioid dependence, as it helps manage withdrawal and prevents effectiveness of full opioid agonists such as heroin

Question 22

irreversible competitive antagonism

Answer 22

drug binds covalently to orthosteric site of receptor

flattens dose-response curve

not surmountable, and will reduce the number of receptors available to agonist

Question 23

receptor reserve

Answer 23

the idea that some regions have excess receptors, such that the maximum response can be achieved without complete receptor occupancy

eg: the neuromuscular junction has a large amount of receptors, so high concentration of antagonists are needed to diminish response

Question 24

why can irreversible antagonists resemble reversible antagonists

Answer 24

due to receptor reserve

Question 25

inverse agonists

Answer 25

bind to the orthosteric of the site and decrease the constitutive activity of a receptor
= affinity and negative efficacy

Question 26

allosteric modulators

Answer 26

drugs that bind to a site other than the orthosteric site that can modulate affinity or efficacy of endogenous ligands or indirectly (in)activate the receptor

Question 27

advantages of allosteric modulators

Answer 27

• ceiling effect: a progressive inability to shift dose-response curve with increasing concentrations
• greater selectivity
• maintain the spatial and temporal nature of endogenous signalling
• probe dependence: have different responses depending on the agonist

Question 28

ortho-allosteric ligands

Answer 28

linking of an allosteric modulator to an orthosteric ligand via an appropriate spacer moiety

allows subtype specificity with orthosteric action