Pharmacodynamics II Flashcards
Define stereospecificity.
particular for asymmetric carbon bonds
Define saturability.
- only a finite number of receptors
- after all receptors are occupied, increasing dose will not increase response b/c saturated
List the types of drug receptors.
INTRACELLULAR
- stimulate an intracellular enzyme
- gene active receptors
MEMBRANE-BOUND
- ligand-regulated transmembrane enzymes
- ligand-gated channel
- GPCRs
Describe the activation of GPCRs.
- agonist binds to receptor => formation of ternary complex with G-protein
- GTP binds to G-protein
- alpha-GTP dissociates from beta, gamma, receptor, and agonist
- GTP-bound G-protein is active intermediate that changes activity of effector (ion channel, enzyme, etc.)
- GTPase converts GTP to GDP => inactivation of G-protein => GDP-G-protein has higher affinity for receptor => returns to plasma membrane
List the steps involved in adenylyl cyclase signaling pathways. What are the downstream effectors?
- activation of Gs protein
- activation of AC
- makes cAMP from ATP
- activates protein kinase A
- downstream phosphorylation => amplification
List the steps involved in phospholipase C signaling pathways. What are the downstream effectors?
- activation of Gq protein
- activation of PLC
- cleaves PIP2 (phosphoinositide) => DAG + IP3
DAG
4. activates PKC => phosphorylation => amplification
IP3
- increases intracellular calcium
- Ca binds to Calmodulin
- downstream phosphorylation => amplification
How can drugs produce beneficial vs toxic effects? What are the strategies used to maximize beneficial effects?
- action at the same receptor => extended therapeutic effect
===> monitor dose, alternative therapy - 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) - actions at different receptors
===> choose drugs with better receptor selectivity
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)
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
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
What is the purpose of G-protein separating from the receptor?
allows for amplification of signal because it can travel and activate multiple enzymes
What is the purpose of downstream reversible phosphorylation in signaling cascades?
- amplification: activates many substrates
- flexibility: many substrates, many kinases
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
- agonist induces phosphorylation of receptor => B-arrestin binds = reversible
- receptor down-regulation
- post-receptor adaptation - uncoupled from second messenger or GP domains
DOSE-RESPONSE CURVE
- ED50 increased
- Emax reduced if receptor reserve exceeded
