Pharmacodynamic Principles (Guillespie)

Question 1

processes of clinical reasoning

Answer 1

1. data acquisition
2. problem representation
3. hypothesis generation (Ddx)
4. hypothesis testing (selecting, comparing, contrasting illness scripts)
5. diagnosis
6. treatment

Question 2

agonists

Answer 2

stimulatory

Question 3

antagonists

Answer 3

inhibitory

Question 4

chemical antagonists

Answer 4

drugs interact directly with other drugs to inhibit activity

Question 5

receptors

Answer 5

interact with drug to initiate observed effect

Question 6

acceptors

Answer 6

interact with drug but DO NOT directly change biochemical or physiological processes

Question 7

mechanisms of action

Answer 7

specific DNA sequences can function as receptors

most drug receptors are PROTEINS

most drugs act on receptors that ALTER CELLULAR SIGNALING PATHWAYS

Question 8

increase in concentration of drug

Answer 8

DOES NOT EQUAL and increase in effect/response

• [drug] will reach an inflection point and the effects will decrease → may become toxic
  
  • hormetic drug curve

Question 9

Achetylcholinesterase Inhibition

Answer 9

drug-receptor interaction affecting endogenous ligand concentration

• achetylcholinesterase terminates the effects of acetylcholine at synaptic cleft
  
  • inhibition = persistence of cholinergic effect

Question 10

Kx

Answer 10

intrinsic activity

binding DOES NOT equal activity

Question 11

termination

Answer 11

metabolize drug to drive equation to the left

diffuse away/uptake into another cell

Question 12

Kd

Answer 12

a measure of binding affinity (constant)

NO INFO on whether ligand is agonist/antagonist

Concentration of ligand required to occupy 50% of binding sites

lower Kd = higher affinity

Question 13

ideal plot

Answer 13

hyperbolic curve

Question 14

real plot

Answer 14

some drug may bind to nonspecific binding sites, meaning it is not easily saturable

total binding - non-specific binding = specific binding

specific binding is used to calculate Kd

Question 15

The “Log-Dose Response Curve”

Answer 15

percent of maximum is plotted as a function of dose of drug

Question 16

ED50

Answer 16

dose required for 50% of the population to obtain therapeutic effect

how potent a drug is

potency can only be used when drugs act on the SAME RECEPTOR

Question 17

EC50

Answer 17

dose required for an INDIVIDUAL to experience 50% of the maximum effect

Question 18

primary agonist

Answer 18

binds to same site as endogenous ligand to activate receptor

Question 19

allosteric agonist

Answer 19

binds to a distinct site and potentiates the activity of primary agonist (increases power of)

Question 20

inverse agonist

Answer 20

binds to same site as primary agonist, but paradoxically decreases baseline activity of receptor

Question 21

primary agonists using same mechanism of action

Answer 21

log-dose response curves will be parallel/have same slope

Question 22

full agonist

Answer 22

intrinsic activity of 1

Question 23

partial agonist

Answer 23

intrinsic activity <1

Question 24

intrinsic activity

Answer 24

reflects ability to initiate maximum response attainable by that receptor

Question 25

maximum effect of drug is determined by:

Answer 25

number of drug receptor complexes formed (Kd)

intrinsic ability of drug to initate response (Kx) → same proportion of receptors can be occupied with different responses

Question 26

Partial agonist with full agonist

Answer 26

as the concentration of the partial agonist increases, the response of the full agonist decreases (partial agonist competes and binds to receptors)

the portion of the response caused by the partial agonist increases, but the total response decreases until it reaches the value produced by the partial agonist alone

Question 27

allosteric agonist effects

Answer 27

increases effect of primary agonist (increases potency but not intrinsic activity)

does NOTHING alone

Question 28

inverse agonists effect

Answer 28

interacts with excitatory receptors but decrease response of tissue

Question 29

simple occupancy model

Answer 29

direct, linear relationship between percent of receptors occupied and maximum response

for a full response, all receptors must be activated

Question 30

spare receptor model

Answer 30

receptors exist in excess of number required to produce a full effect

increases sensitivity to agonists and decreases sensitivity to antagonists (more receptors must be taken out to reduce response)

Question 31

antagonists activity

Answer 31

lack intrinsic activity- must have agonist or NO EFFECT

Question 32

competitive antagonist

Answer 32

binds to same site as primary agonist

COMPETES with ligand for receptor occupancy

normal response but must add more agonist → curve shifts right

Rightward, parallel shift in log dose-response curve for agonist without diminishing its maximum response; ED50 is shifted right

Question 33

pseudo-irreversible agonist

Answer 33

binds with HIGH AFFINITY to the same site as the primary agonist

every receptor not inactivated is NORMAL

ED50 won’t change but effect drops (decrease in maximum response to agonist)

Question 34

Allosteric antagonist

Answer 34

binds to DISTINCT site from the primary agonist to DECREASE response to the agonist receptor

ED50 is shifted right (increased)

Question 35

IC50

Answer 35

response to antagonist is calculated as a percentage of the initial contraction of the tissue and plotted as a function of the antagonist dose

half maximum inhibitory concentration

RISES with increasing ligand concentration

Question 36

Ki

Answer 36

equivalence of Kd for an agonist

measures binding affinity of agonist

Question 37

Cheng Prusoff equation

Answer 37

determines Ki from the IC50 value

Question 38

graded dose-response curve

Answer 38

measures magnitude of response in an individual

Question 39

quantal dose-response curve

Answer 39

based on the frequency of a response in a POPULATION

Response of predetermined magnitude is defined

→ subjects falling below threshold: non-responders

→ subjects exceeding threshold: responders

Question 40

LD50

Answer 40

lethal dose for 50% of a group

Question 41

certain safety factor

Answer 41

TD1/ED99

TD1 is the dose producing toxicity in 1%

ED99 is the dose that produced a therapeutic effect in 99% of the population