Pharmacodynamics

Question 1

What is the concept of “drug selectivity”? What is it dependent on?

Answer 1

The ability of a drug to “target” one receptor vs. another at any given clinical dose range. It is dependent on the relative affinities of a drug (KD) for various receptors.

Question 2

For ANY drug, how does selectivity change with drug dose?

Answer 2

selectivity DECREASES as drug dose INCREASES

Question 3

What is the dose-response relationship?

Answer 3

The correspondence between the amount of drug and the magnitude of the effect; increasing the dose increases the effect in a graded manner.

Question 4

What is drug potency?

Answer 4

The concentration or dose of drug needed to produce 50% of the drug’s maximal response (ED50).

Question 5

What does drug potency depend on? (2 things)

Answer 5

1) affinity of a drug for its receptor

2) efficiency with which receptor activation is coupled to response

Question 6

Maximal efficacy is used synonymously with the term _____________.

Answer 6

intrinsic activity

Question 7

Describe the intrinsic activity (max. efficacy) of full agonists vs. partial agonists vs. neutral antagonists vs. negative antagonists.

Answer 7

• Full agonists: activity=1
• Partial agonists: activity <1
• Neutral antagonists: activity=0
• Negative antagonists: activity <0

Question 8

A negative antagonists is also known as an ____________.

Answer 8

inverse agonist; can reduce the constitutive activity of receptors

Question 9

Does the clinical effectiveness of a drug depend on maximal efficacy (Emax) or potency (ED50)?

Answer 9

maximal efficacy!

easy way to remember: clinical effectiveness=efficacy

Question 10

Describe a system that would be considered to have “spare receptors,” or “receptor reserve.”

Answer 10

systems in which maximal response is achieved by doses of agonists that occupy only a small percentage (Fraction) of receptors

Question 11

In terms of receptors, what is required for a drug to achieve a maximal response?

Answer 11

• all receptors must be equally functional

- not all receptors must be occupied

Question 12

The magnitude of receptor reserve is most likely due to what?

Answer 12

the degree of response amplification following any given drug-receptor interaction

Question 13

What are the 3 effects of competitive antagonists on pharmacodynamics?

Answer 13

1) shift to right in dose response curve
2) increase in ED 50
3) no change in Emax
(inhibition is effectively overcome by

Question 14

What are the 2 main effects of non-competitive antagonists on pharmacodynamics?

Answer 14

1) decrease in Emax

2) NO change in ED50

Question 15

What are some non-pharmacological means to antagonizing drug effects?

Answer 15

• chemical inactivation
• physiologic use of opposing pathways
• biologic interactions (one drug may affect metabolism/pharmacokinetics of another)

Question 16

For ligand-regulated transmembrane enzyme receptors, what can intensify/prolong the duration of receptor activation?

Answer 16

autophosphorylation of tyrosines on the receptor’s cytoplasmic side (ex: autophosphorylation of insulin receptor persists long after insulin dissociates from receptor)

Question 17

How are transmembrane receptors subject to downregulation?

Answer 17

via endocytosis

Question 18

What are examples of endogenous substances that utilize tyrosine kinase receptors?

Answer 18

EGF, insulin, ANF

Question 19

What is the difference between tyrosine kinase receptors and cytokine receptors?

Answer 19

Cytokine receptors utilize a separate protein tyrosine kinase that binds non-covalently and is NOT intrinsic to the receptor.

Question 20

With cytokine receptor activation, what is the final product that dissociates, travels to the nucleus, and regulates gene transcription?

Answer 20

a dimer of STATs (phosphorylated by JAKs)

Question 21

Describe some signaling characteristics of the nicotinic cholinergic receptor (a ligand-gated receptor)

Answer 21

• pentamer consisting of 4 types of glycoprotein subunits that form a membrane channel
• ACh binding to alpha subunits produces a conformational change and transient opening of the channel
• open channel allows Na+ ions to pass from ECF into the cell
• time b/t binding and response is in milliseconds, allowing for very rapid transfer

Question 22

What are examples of neurotransmitters that signal via ligand-gated receptor mechanisms?

Answer 22

ACh, GABA, excitatory amino acids (glutamate and aspartate)

Question 23

In GPCRs, which side of the polypeptide chain is extracellular vs. intracellular?

Answer 23

amino terminus is extracellular; carboxy terminus is intracellular

Question 24

GPCRs are used by which neurotransmitters?

Answer 24

A variety, including dopamine, NE, serotonin, ACh.

Question 25

Activation of adenylyl cyclase produces ______.

Answer 25

cAMP, a second messenger that goes on to affect other cellular processes

Question 26

Describe the activation of the phosphoinositide hydrolysis pathway.

Answer 26

Agonist binding results in the G prot. subunit activating phospholipase C (PLC), which cleaves PIP2 into IP3 and DAG. IP3 increases intracellular Ca2+, while DAG activates protein kinase C (PKC).

Question 27

What is the quantal dose response curve?

Answer 27

it describes the relationship b/t drug dose and a specified effect in a population of individuals; it is obtained from the cumulative frequency distribution of drug doses that produce a specified (quantal) effect in a patient population

Question 28

What does the ED50 on a quantal dose-response curve represent?

Answer 28

It represents the dose of drug producing a specified endpoint (ex: therapeutic effect vs. lethal effect) in 50% of the population

Question 29

Can drug safety be better assessed from the therapeutic window or therapeutic index?

Answer 29

Therapeutic window; ideal is for the window to be broad and not narrow

Question 30

What can be determined from quantal dose-response curves?

Answer 30

1) Median effective dose (ED50) 2) Index of selectivity of drug actions (by comparing ED50 for different specified effects, like decongestion vs. sedation) 3) Estimate of the degree of safety of a drug for a therapeutic effect

Question 31

What is the therapeutic index?

Answer 31

It is a ratio used to describe the relative safety of a drug. Thus, it is the ratio of the dose of drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50).

Question 32

What is the therapeutic window?

Answer 32

A clinically relevant index of drug safety that represents the dosage range b/t the minimum effective therapeutic dose and the minimum toxic dose.

Question 33

List some variations in drug responsiveness.

Answer 33

- Idiosyncratic drug response (unusual response not normally observed in the majority of patients) - Quantitative variations (intensity of effect for a given dose may be greater/less in comparison to most patients; intensity of response may vary during the course of therapy)

Question 34

List the two main variations in receptor responsiveness to drugs (compensatory responses).

Answer 34

- receptor desensitization (in response to over-stim.) | - receptor supersensitivity (in response to under-stim.)

Question 35

What are the 2 types of desensitization?

Answer 35

- homologous | - heterologous

Question 36

What is tachyphalaxis?

Answer 36

the rapid development of diminished responsiveness to a drug

Question 37

What are the 3 main mechanisms that account for reduced responsiveness to a drug?

Answer 37

1) Agonist-induced phosphorylation (activated receptor is phosphorylated and β-arrestin binds) 2) Receptor down-regulation (loss of membrane-bound receptors) 3) Post-receptor adaptations (receptors "functionally uncoupled" from post receptor components due to modification of G-proteins or 2nd messenger enzymes)

Question 38

For mechanisms that cause reduced responsiveness to a drug, how is the dose-response curve affected?

Answer 38

These mechanisms will cause a right shift in the agonist dose-response curves (increased ED50) but no change in Emax, unless the receptor reserve is exceeded.

Question 39

What are 2 things that might explain desensitization-induced reduction in Emax?

Answer 39

1) Receptor reduction exceeding receptor reserve | 2) Post-receptor defects (changes in reserve of G proteins, enzymes, etc. required to maintain original Emax)

Question 40

Describe the difference between homologous and heterologous desensitization.

Answer 40

With homologous desensitization, kinases will only recognize and phosphorylate sites on the agonist-occupied receptor. Thus, there is loss of activity ONLY to agonists interacting with this modified receptor. With heterologous desensitization, agonist activation of one receptor subtype results in a decreased responsiveness of other receptor subtypes (specifically, receptors that were not directly activated by the agonist).

Question 41

Why does receptor supersensitivity occur?

Answer 41

A loss of activity on receptors, which leads to increased receptor density and/or enhanced receptor-effector coupling. (left shift)

Question 42

What are the protein kinases capable of promoting heterologous desensitization?

Answer 42

PKA and PKC