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PT 1 > L9 Pharmacodynamics II > Flashcards

L9 Pharmacodynamics II Flashcards

1
Q

What are the two general potential responses to a drug binding to an intracellular receptor?

A
  1. Stimulate an intracellular enzyme

2. Regulate the cellular localization of the receptor and alter gene transcription (gene active receptor)

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2
Q

What are the two major therapeutic consequences of gene active receptors?

A
  1. Lag period (30 min to a few hours) before the effects may be observed due to the time it takes to synthesize new proteins
  2. Effects may persist for hours or days after the agonist is gone (slow turnover of enzymes or proteins synthesized)
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3
Q

What are the three general types of plasma membrane receptors?

A
  1. Ligand-regulated transmembrane enzymes (protein tyrosine kinase and cytokine receptors)
  2. Ligand-gated channel receptors
  3. G-protein family
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4
Q

Describe the structure of a ligand-regulated transmembrane enzyme receptor.

A

Receptor polypeptide crosses the membrane once and has an extracellular binding domain and an intracellular enzymatic domain (tyrosine/serine kinase or guanylyl cyclase)

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5
Q

Describe the series of events when a ligand binds to the extracellular domain of a ligand-regulated transmembrane enzyme receptor.

A
  1. Conformational change
  2. Dimerization
  3. Activation
  4. Downstream phosphorylation of proteins
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6
Q

___ of tyrosines on the receptor’s cytoplasmic side can intensify or prolong the duration of receptor activation.

A

Autophosphorylation

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7
Q

Ligand-regulated transmembrane enzyme receptors can be down-regulated via ___.

A

Endocytosis

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8
Q

What are three endogenous substances that utilize tyrosine kinase receptors?

A
  1. Insulin
  2. Epidermal growth factor (EDF)
  3. Atrial naturitic factor (ANF)
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9
Q

How is a cytokine receptor different from a tyrosine kinase receptor?

A

Utilize a separate tyrosine kinase that binds non-covalently and is not intrinsic to the receptor

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10
Q

What are the activation steps of a cytokine receptor?

A
  1. Ligand binding
  2. Conformational change
  3. Receptor dimerization
  4. JAKs are activated and phosphorylate tyrosine residues on the receptor
  5. Phosphorylation of tyrosine facilitates binding of STAT
  6. JAK phosphorylates STAT
  7. STATs dimerize, dissociate, and travel to the nucleus to regulate gene transcription
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11
Q

Describe the structure of ligand gated channel receptors.

A

Pentamer, 4 types of glycoprotein subunits (2 alpha, beta, gamma, delta) that form a cylindrical structure w/a channel

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12
Q

Describe binding to the nicotinic cholinergic receptor.

A

ACh binds to the alpha subunits, produces a conformational change, and opens the channel, allowing Na into the cell.

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13
Q

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

A

ACh, excitatory amino acids (gluamate and asparate), and GABA

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14
Q

Describe the structure of G-protein linked receptors.

A

Single polypeptide chain that traverses the plasma membrane 7 times; amino terminus is extracellular and carboxy terminus is intracellular

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15
Q

Which part of the G-protein linked receptor contains the pharmacophore?

A

Extracellular region

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16
Q

Which part of the G-protein linked receptor regulates the ability to interact with G-proteins?

A

Third intracellular loop

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17
Q

Which part of the G-protein linked receptor contains sites that are subject to phosphorylation and regulation?

A

Carboxy terminus

18
Q

What types of NT use G-protein linked receptors?

A

DA, NE, 5-HT, ACH

19
Q

Describe the activation of G-proteins.

A
  1. Ligand binds, conformational change
  2. Activated receptor binds G protein
  3. Conformational change leads to dissociation of GDP and binding of GTP
  4. GTP binding triggers dissociation of G-alpha from the receptor and the beta-gamma subunit
  5. Action
  6. GTP hydrolized to GTP, re-dimerization
20
Q

What is the primary mediator of activating second messengers?

A

G-alpha-subunit

21
Q

Describe the activation of adenylyl cyclase.

A
  1. Ligand binding
  2. G-protein activation
  3. Adenylate cyclase activated
  4. Adenylate cyclase catalyzes formation of cAMP
  5. cAMP activates protein kinase
  6. Kinase activity –> response
22
Q

Describe the activation of the phophoinositide hydrolysis pathway.

A
  1. Ligand binding
  2. G-protein activation
  3. PLC activation
  4. PLC cleaves PIP2 into DAG and IP3
  5. IP3 opens calcium channel, allowing calcium to flow out of the ER
  6. Calcium binds calmodulin to form a kinase, which phosphorylates things
  7. DAG forms PKC, which also phosphorylates things
23
Q

Describe the possible effects of one drug at one receptor.

A
  1. Beneficial (anti-coagulant activity)
  2. Toxic (excessive bleeding)

Strategies: manage dose, monitor effect

24
Q

Describe the possible effects of one drug at the same receptor in different tissues.

A
  1. Beneficial at one tissue
  2. Toxic at another

Strategies: add another drug to lower dose of first drug, give lowest dose to achieve effect, limit effects via route of administration

25
Q

Describe the possible effects of one drug at different receptors.

A
  1. Beneficial at one receptor
  2. Toxic at another

Strategies: give drug with greater selectivity

26
Q

What describes the relationship between drug dose and a specified effect in a population of individuals?

A

Quantal dose response curve

27
Q

What is the ED50 in the quantal dose response curve?

A

Median effective dose; the dose of drug that produces the desired response in 50% of people.

28
Q

What is the therapeutic index?

A

An estimate of the degree of safety of a drug for a specified therapeutic effect

29
Q

What is the therapeutic window?

A

Dosage range between the minimal effective therapeutic dose and the minimum toxic dose

30
Q

Drug safety can be better assessed from the ___.

A

Therapeutic window (than the therapeutic index)

31
Q

What is an unusual response that is not frequently observed in the majority of patients?

A

Idiosyncratic drug response

32
Q

What are two quantitative variations in response to drugs?

A
  1. Intensity of effect for a given dose may be hyper/hyporeactive
  2. Intensity of a response may vary during the course of therapy
33
Q

Why does receptor desensitization/supersensitivity occur?

A

Compensatory response invoked to counter the effect of the drug on the system in order to re-establish homestasis

34
Q

What s tachyphalaxis?

A

The rapid development of diminished responsiveness to a drug

35
Q

What is pharmacodynamic tolerance?

A

Desensitization that occurs slowly over time

36
Q

What are the three general mechanism of downregulation?

A
  1. Agonist-induced phosphorylation (binding of beta-arrestin)
  2. Receptor down-regulation (loss of membrane-bound receptors)
  3. Post-receptor adaptations (receptors become uncoupled from post-receptor components)
37
Q

What are the effects of downregulation on ED50 and Emas?

A

Increase ED50 (shift dose-response curve to the right), no change in Emax

38
Q

What happens in homologous desensitization of the beta-adrenergic receptor.

A

The receptors are phosphorylated by specific kinases (GRK2/3). These kinases only recognize and phosphorylate sites on the agonist-occupied receptor. This is followed by the binding of beta arrestin to the phosphorylated receptor. Loss of activity only occurs at agonists interacting with the modified receptor

39
Q

In homologous desensitization, the process is restricted to which part of the receptor population?

A

Receptors that were activated by the drug.

40
Q

What happens in heterogenous desensitiziation?

A

Agonist activation of one receptor subtype results in a decreased responsiveness of the other receptor subtypes

41
Q

What is supersensitivity?

A

A compensatory receptor mechanism in which the loss of activity on receptors leads to an increase in receptor density and/or enhanced receptor-effector coupling

42
Q

What happens to Emax and ED50/EC50 in supersensitivity?

A

Emax does not change; shift to the left in dose response curve, decrease in ED/EC50

PT 1 (34 decks)

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