Exam 1 - Lecture 1 & 2, Drug Action

Question 1

How to study receptors

Answer 1

1. Isolate and purify macromolecular component and study drug “structure-activity” relationships

info inferred from kinetics of drug-receptor interaction = binding sites

2. Determine amino acid sequence; clone and express receptor in cultured cells

enables study of receptor function in living cells, but isolated from components of native cells in intact tissue

Question 2

Types of binding of drugs to receptors

Answer 2

1. van der Waals attraction (weakest)
2. Hydrogen bond
3. Hydrophobic interaction
4. Ionic bond
5. Covalent bond (strongest)

Question 3

Receptor locations

Answer 3

typically cell surface, embedded in cell membrane

Question 4

Drugs that don’t act through receptors

Answer 4

Antacids
Osmotic diuretics and cathartics
Chelating agents which bind heavy metals

Question 5

Nature of drugs

Answer 5

Physical nature (solid, liquid, pH [affect absorption], hydrophilicity and hydrophobicity [changes receptor interaction])

Drug size ( small, large, typically MW 100-1000…as size increases absorption isn’t as effective)

Drug shape (stereoisomerism, ie carvedilol…R+ binds to Beta receptors much worse than S- (Kd = 54 vs 0.5)

Question 6

Agonist

Answer 6

Drug that causes specific physiological effect due to direct interaction with a receptor

Question 7

Antagonist

Answer 7

Compound that is devoid of intrinsic pharmacological activity but blocks the action of a specific agonist or an endogenous substance which produces the effect

Question 8

Allosteric modulator

Answer 8

A drug which binds to a different site on the receptor than that bound by endogenous ligands; can modulate positively or negatively

Question 9

Addition

Answer 9

When two agonist which produce the same effect are administered together, they produce an effect equal in magnitude to the sum of the effects of the individual drugs
A + B = A (solo) + B (solo)

Question 10

Synergism

Answer 10

When two agonist which produce the same effects are administered together, they produce an effect greater in magnitude than the sum of effects of the individual

A + B > A (solo) + B (solo)

Question 11

Potentiation

Answer 11

When drug is itself without effect, but if administered with a second drug, increases the effect of the second drug

Question 12

Drugs A and B can target….

Answer 12

One receptor or two separate receptors producing interacting effects

Question 13

Quantal ( all or none) dose response curves

Answer 13

Relates drug dose to frequency of drug-induced “all-or-none” pharmacological effect

Plot of response frequency vs dose yields normal distribution

Replotting curve in terms of percentage of subjects responding vs log of dose yields a sigmoid (S-shaped) curve

Examples include (dose of barbiturate to induce sleep)

Wide distribution yields shallow cumulative curve (S-shaped)

Question 14

Graded (quantitative) dose response curves

Answer 14

relates dose of drug to size of response of a single biological unit

Plot of magnitude of response vs log doe yields sigmoid curve

Examples include drug induced, graded changes in HR

Question 15

ED50

Answer 15

smallest dose of drug which is effective in 50% of individuals receiving the drug

Question 16

Linear vs Log plot

Answer 16

Linear - intuitive scaling

Semi-log plot - compact scaling

Question 17

Tolerance

Answer 17

When repeated admin of given dose of drug produces a decreased effect, or conversely larger doses must be administered to obtain the same effect observed with the original dose.

Time scale: days to months

Question 18

Tachyphylaxis

Answer 18

Very rapidly developing tolerance; decreasing effect of a drug following consecutive doses given at short intervals

Time scale: minutes to hours

Question 19

Supersensitivity

Answer 19

A heightened state of pharmacological responsiveness of a tissue or organ, leading to an exaggerated effect of an agonist

may be due to a compensatory increase in number of receptors, “up regulation”

Changes can be drug induced (prolonged exposure to antagonist) or due to denervation (destruction of neuronal input to the tissue)

Question 20

Desensitization

Answer 20

A reduced state of a pharmacological responsiveness of a receptor due to continuous presence of the agonist at that receptor

Maybe due to decrease in receptor number ie. down regulation or to a change in receptors conformational state to an inactive “desensitized” state

Question 21

LD50

Answer 21

smallest dose of a drug which is lethal in 50% of individuals receiving the drug

Question 22

Therapeutic index (TI)

Answer 22

LD50 / ED50

Question 23

Margin of safety

Answer 23

LD0.1 /ED99.9

More useful expression of drug safety

Question 24

Small Kd

Answer 24

its affinity for receptor is high

Question 25

Large Kd

Answer 25

its affinity for the receptor is low

Question 26

Kd = [D] when…

Answer 26

50% of receptors occupied

Question 27

Kd

Answer 27

K2/K1

equilibrium dissociation constant and is related to the affinity of the receptor for the drug

K2 = {D][R]
K1 = [DR]

Question 28

PAM effect on log chart

Answer 28

Can be left-ward shift, typically accompanied by an upward shift

Question 29

Agonist + Competitive Antagonist on Semi-log plot

Answer 29

Moves to right

Question 30

Agonist + Irreversible or Non-competitive antagonist on semi-log plot

Answer 30

lowers efficacy from agonist alone

Question 31

Intrinsic activity or efficacy

Answer 31

independent of the slope or position of dose-response curve

degree of effect obtainable for a given level of receptor occupancy, drugs with same efficacy elicit same maximal response

Question 32

Potency

Answer 32

used in comparing 2 or more drugs when specifically referring to the doses of each required to produce same effect

Location on access, slope show potency

Efficacy is more important than potency in selecting drugs for use in clinical situation

Question 33

Coupling

Answer 33

overall transduction process that links drug occupancy of receptors and pharmacologic response

Question 34

Spare receptors

Answer 34

Example:

If 4 coupling events yield max effect and only 4 G proteins are present to transduce signaling, having more receptors does not cause more effect….extra receptors are “spare”

Question 35

Pharmacological antagonism

Answer 35

Antagonist prevents an agonist from acting upon it receptor to produce a response

Question 36

Physiological antagonism

Answer 36

Occurs when 2 agonist act upon a tissue to produce opposing response, each agonist interacts independently with specific but different receptors

ex. Epinephrine and histamine

Question 37

Antagonism by neutralization

Answer 37

2 drugs combine with one another to form an inactive compound

ex. Heparin (-) and Protamine (+) form inactive ionic complex