1-35 Pharmacodynamics-Receptors

Question 1

Receptor (characteristics)

Answer 1

biological specificity
chemical specificity (stereospecificity)
selective antagonism
cloning
sequencing
expression of specific receptor subtypes

Question 2

rectangular hyperbola

Answer 2

MM equation: y=[A]/ (Kd + [A])

Kd=[A][R]/[AR]

y is response
x is concentration of drug (log scale shows sigmoidal)

Question 3

EC50

Kd

Answer 3

Drug concentration that produces 50% of maximal effect, = Kd FOR DRUG BINDING

relevant for graded dose-response curves

Question 4

Types of drug antagonists

Answer 4

1. Competitive antagonist: bind orthosteric sties, reversibly inhibit, can overcome inhibition by increase concentration of agonist, shift curve right
2. Non competitive antagonists: irreversibly bind orthosteric or bind allosterically, decrease Max response
3. Uncompetitive antagonists: reduce the effects of agonists ONLY AFTER THE AGONIST HAS ACTIVATED THE RECEPTORS, decrease EC50 and max response

Question 5

Types of drug agonists

Answer 5

1. Full agonist: often endogenous, orthosteric binding, elicit max response
2. Partial agonist: bind orthosteric but cannot elicit a max response, in higher concentrations can act as competitive inhibitors of full agonists
3. Inverse agonist: orthosteric, if there is constitutive receptor activity they convert active receptors into an inactive conformation

Question 6

Spare receptors

Answer 6

observed when full agonists produce responses- they produce a full response by only using a few of the available receptors so addition of an antagonist causes right shift and still achieve full response UNTIL total receptor population is occupied and then will decrease effect

EC50 does not equal Kd, biology is wild

Question 7

Hill equation

Answer 7

describes cooperativity of drug binding- raise everything to power of n (n=binding sites?)

Question 8

Mechanisms of Cooperativity

Answer 8

binding of one molecule influences binding of another

more than one molecule bound is needed to activate, but binding is independent

relationship between binding and response is cooperative

multiple receptors existing as subunits sequentially activated/conformations changed

**constrained model (MWC model): two-state, inactive->active

**sequential model (KNF model): many intermediate conformational states

Question 9

Quantal dose-response curves

Answer 9

describe discrete events (pregnancy, death, sleep) ED50 used to describe dose at which 50% of folks show the desired drug effect

cumulative s-shaped of y:individuals responding, x:drug dose

LD50: lethal dose for half of animals

Question 10

Therapeutic index

Answer 10

toxic ED50/ therapeutic ED50 =higher ratio better!