Pharmacodynamics II Flashcards Preview

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Flashcards in Pharmacodynamics II Deck (13):
1

Define stereospecificity.

particular for asymmetric carbon bonds

2

Define saturability.

- only a finite number of receptors
- after all receptors are occupied, increasing dose will not increase response b/c saturated

3

List the types of drug receptors.

INTRACELLULAR
- stimulate an intracellular enzyme
- gene active receptors

MEMBRANE-BOUND
- ligand-regulated transmembrane enzymes
- ligand-gated channel
- GPCRs

4

Describe the activation of GPCRs.

1. agonist binds to receptor => formation of ternary complex with G-protein
2. GTP binds to G-protein
3. alpha-GTP dissociates from beta, gamma, receptor, and agonist
4. GTP-bound G-protein is active intermediate that changes activity of effector (ion channel, enzyme, etc.)
5. GTPase converts GTP to GDP => inactivation of G-protein => GDP-G-protein has higher affinity for receptor => returns to plasma membrane

5

List the steps involved in adenylyl cyclase signaling pathways. What are the downstream effectors?

1. activation of Gs protein
2. activation of AC
3. makes cAMP from ATP
4. activates protein kinase A
5. downstream phosphorylation => amplification

6

List the steps involved in phospholipase C signaling pathways. What are the downstream effectors?

1. activation of Gq protein
2. activation of PLC
3. cleaves PIP2 (phosphoinositide) => DAG + IP3

DAG
4. activates PKC => phosphorylation => amplification

IP3
4. increases intracellular calcium
5. Ca binds to Calmodulin
6. downstream phosphorylation => amplification

7

How can drugs produce beneficial vs toxic effects? What are the strategies used to maximize beneficial effects?

1. action at the same receptor => extended therapeutic effect
===> monitor dose, alternative therapy
2. actions at identical receptors in different tissues or via different pathways
===> administer lowest dose possible
===> administer adjunctive drug that lowers action of first drug
===> limit drug's effects on other parts of the body by changing administration route (ex: inhalant vs oral)
3. actions at different receptors
===> choose drugs with better receptor selectivity

8

List the types of drug response variations.

IDIOSYNCRATIC DRUG RESPONSE
- unusual response not seen in most of the population

QUANTITATIVE VARIATIONS IN DRUG RESPONSE
- more common; clinically relevant
- intensity of drug effect can be increased (pt is hyperreactive) or decreased (pt is hyporeactive) compared to most of the population
- intensity of drug effect changes throughout course of drug administration
==> decreased response (desensitization)
==> increased response (supersensitivity)

9

Compare homologous and heterologous desensitization in terms of:
- respective mechanisms
- effect on agonist dose response curves
- therapeutic consequences of the altered responsiveness to drugs

HOMOLOGOUS DESENSITIZATION
- mechanism: autophosphorylation of the B-adrenergic receptor via B-adrenergic receptor kinases

HETEROLOGOUS DESENSITIZATION
- mechanism: modification of receptors other than the specific type activated by the agonist; widespread effects
==> phosphorylation of the receptor itself, other receptors, uncoupling of GPs (post-receptor effect)

- effect on dose-response curves: shift to the right (increased ED50); Emax may decrease if receptor reserve exceeded or post-receptor adaptations have occurred
- therapeutic consequences: loss of activity for agonists interacting with those receptors

10

Define receptor supersensitivity. Describe the following:
- factors that can produce it
- effect on dose response curve
- therapeutic consequences

- loss of hormonal activity on the receptor => upregulation of receptors => increased coupling
- decreased ED50
- therapeutics: lower dose needed

11

What is the purpose of G-protein separating from the receptor?

allows for amplification of signal because it can travel and activate multiple enzymes

12

What is the purpose of downstream reversible phosphorylation in signaling cascades?

- amplification: activates many substrates
- flexibility: many substrates, many kinases

13

Describe the mechanism by which reduced responsiveness may occur. What is the effect on the dose-response curve?

REDUCED RESPONSIVENESS UPON DRUG EXPOSURE
- tachyphylaxis - rapid development of diminished response/desensitization
- pharmacological tolerance - gradual/slow development of diminished response (desensitization phenomenon)

MECHANISMS
1. agonist induces phosphorylation of receptor => B-arrestin binds = reversible
2. receptor down-regulation
3. post-receptor adaptation - uncoupled from second messenger or GP domains

DOSE-RESPONSE CURVE
- ED50 increased
- Emax reduced if receptor reserve exceeded