Pharmacodynamics

Question 1

why is the “magic range” of drug MW value between 100 and 1,000

Answer 1

too large, drug has a hard time getting around in the body

too small, drug has too many off-target interactions and binding is too loose because it is tiny (trouble with specificity)

Question 2

what is the intrinsic response of antagonists

Answer 2

none - they only block action of agonists by binding to receptors, they do not produce any pharmacological response

Question 3

_____ determines the quantitative relationship between drug dose and pharmacological response

what 2 factors dictate this relationship

Answer 3

RECEPTORS determine quantitative relationship between drug dose and pharmacological response

dictated by:
1. number of drug-bound receptors (dependent on affinity)
2. total number of receptors (determines maximal effect)

Question 4

number of drug-bound receptors is determined by ______

Answer 4

equilibrium dissociation constant, Kd

measure of affinity of drug for receptor

[remember that LOW Kd = HIGH affinity]

Question 5

how do you describe the quantitative relationship between drug effect (E) and drug dose (D)

Answer 5

E = [D]xEmax
————-
[D] + EC50

EC50 = effective drug concentration that produces 50% of max effect

Question 6

when are semilog plots of E (effect) vs log[D] (drug concentration) useful?

Answer 6

allows for greater range of drug concentrations to be examined

shape of curve changes from hyperbolic to sigmoidal

EC50 is found at inflection point of curve (where slope stops increasing, starts decreasing)
Emax is found at plateau (just like in hyperbolic curve)

Question 7

drug potency is determined by ___ value

Answer 7

low EC50 = HIGHER potency

less drug required to produce desired effect

also minimizes potential for adverse effects to arise (because less drug is needed)

Question 8

drug efficacy is determined by ____ value

Answer 8

HIGH Emax = HIGH efficacy

drugs that elicit higher max effect are more efficacious

Question 9

potency vs efficacy

Answer 9

potency: how much drug do I need to elicit a response? (depends on EC50)

efficacy: what is the largest response this drug can elicit? (depends on Emax)

Question 10

by definition, a partial agonist has lower _____ than a full agonist

Answer 10

partial agonists are ALWAYS less EFFICACIOUS (Emax) than agonists

however, potency (EC50) may be the same or more

Question 11

because antagonists have no intrinsic activity, how do you measure their impact?

Answer 11

plot graded dose-response curve of an agonist in the presence of differing concentrations of antagonist

log[D] on x-axis of dose-response curve will ALWAYS ALWAYS be an agonist**

Question 12

2 types of antagonist and their definitive principle (in pharmacology)

Answer 12

competitive - reversible (and can be overcome by high concentrations of agonist)

non competitive - irreversible

Question 13

what is a characteristic limitation of competitive antagonists

Answer 13

effect is reversible, and with a high enough concentration of agonist present antagonist can be overcome

Question 14

in a graded dose-response curve of an agonist in the presence of a competitive antagonist, what parameter will NOT change

Answer 14

Emax will NOT change - inhibition can be overcome by increasing concentration of agonist (efficacy is unchanged)

EC50 will increase, making the agonist appear less potent

Question 15

match:
beta-blocker
proton pump inhibitor

competitive antagonist
non-competitive antagonist

Answer 15

beta-blocker: competitive antagonist of NE/E

proton pump inhibitors (Prilosec): non competitive/irreversible antagonist of proton pump in stomach lining, preventing acidification of gut

Question 16

what is the effect of noncompetitive antagonists on the graded dose-responses curve of an agonist

Answer 16

EC50 (potency) is unchanged (curve is NOT shifted right)

Emax (efficacy) is DECREASED (curve does not reach maximal plateau)

irreversible antagonists bind receptors permanently, effectively taking those out of the pool of available receptors (this is not overly toxic because cells can make more receptors)

Question 17

chemical antagonism

Answer 17

one drug may antagonize the actions of a second drug (by binding to it)

example: Protamine (positively charged) antagonizes anticoagulant actions of Heparin (negatively charged) by binding Heparin in electrostatic manner

Question 18

pharmacokinetic antagonism

Answer 18

referred to as drug-drug interaction

drugs induce metabolism of other drugs, thereby antagonizing actions of metabolized drugs

example: Phenobarbital induces metabolic clearance of anticoagulant Warfarin

Question 19

drug selectivity for a certain tissue can arise from over-expression of a given receptor, in which case the tissue has ______

what is the effect of this

Answer 19

spare receptors

basically means extra receptors, enhance tissue sensitivity to drug

expression of more receptor than is needed for max response —> agonist can induce maximal response without binding all available receptors

you can use a low dose and target this specific tissue without effecting anything else!

Question 20

how can you demonstrate (using dose-response curve) the presence of spare receptors?

Answer 20

create graded dose-response curve of agonist in presence of increasing irreversible antagonists

irreversible antagonist SHOULD decrease Emax

BUT, when there are spare receptors, Emax is unchanged until there are no more spare receptors (at high antagonist concentration)

ALSO, there will be a right shift (increasing EC50) as irreversible antagonist decreases number of spare receptors, until there are none left, and EC50 begins to stay the same

Question 21

how will EC50 and Emax appear on a graded-dose response curve of an agonist in the presence of an irreversible antagonist, when the agonist is acting in a tissue with spare receptors?

Answer 21

until irreversible antagonist blocks the rest of the spare receptors (at high concentrations)…

EC50 INCREASES (less potent) with increasing [antagonist]
and
Emax says the SAME

Question 22

2 key limitations of graded dose-response curves

Answer 22

1. difficult to construct when pharmacological response is “either-or” (aka, quantal event)
2. graded dose-response profile in an individual may have limited applicability to others (inter-individual variability)

Question 23

how can limitations of graded dose-response curves be overcome

Answer 23

quantal dose-response curve: determining dose of drug required to produce specific response in multiple individuals

plots cumulative % of individuals responding versus log(dose)

quantal dose response = done in a person, information comes from clinical trails

median effective dose (ED50): dose at which 50% of individuals exhibit response

%max: max percentage of individuals that ultimately exhibit the response

Question 24

what parameters are measured in quantal dose-response curves

Answer 24

quantal = done in people (clinical trials)

ED50: median effective dose, dose at which 50% of individuals exhibit response (measures potency)

%max: max % of individuals that ultimately exhibit response (measures efficacy)

Question 25

in quantal dose-response curves, what measures potency and what measures efficacy

Answer 25

ED50 = potency

%max = efficacy

Question 26

how do you measure how safe a drug is

Answer 26

therapeutic index = TD50/ED50

TD50: median toxic dose, dose at which 50% of individuals experience toxic response

TI is the margin of safety, should be HIGH

Question 27

Penicillin has a therapeutic index of 25-30… is this drug safe?

Answer 27

YES

TI = TD50/ED50

so safe drugs have high TI (wide margin of safety)

you want the toxin dose-response curve to be very far right of the effective dose-response curve

Question 28

what therapeutic index indicates a toxic drug?

Answer 28

less than 5

TI = TD50/ED50

*ideally, want a TI of at least 10

Question 29

drug prescriptions must have 3 pieces of information (regarding the drug):

Answer 29

1. identity of drug
2. dose of drug
3. frequency of administration

Question 30

in pharmacotherapeutic decision making, drug selection is based on ____ and ____ ,
dose of drug is determined by _____ ,
and frequency of drug is dictated by _____

Answer 30

drug selection: efficacy and toxicity
dose: potency
frequency: pharmacokinetic properties