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PHS 931 > Block 1 Lecture 4 -- Pharmacodynamics II > Flashcards

Block 1 Lecture 4 -- Pharmacodynamics II Flashcards

1
Q

Pharmacophore:

A

the structural features of a drug that define how it interacts with a particular receptor

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2
Q

Pharmacophore (IUPAC):

A

an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response

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3
Q

What are the types of chemical bonding that can occur during association with a receptor?

A

1) covalent
2) ionic
3) hydrogen
4) van der walls

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4
Q

Energy of covalent bond:

A

100 kcal/mol

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5
Q

Energy of ionic bond:

A

5 kcal/mol

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6
Q

Energy of hydrogen bond

A

2 kcal/mol

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7
Q

Energy of Van der Waals forces:

A

0.5 kcal/mol

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8
Q

When might Van der Waals forces apply during drug-receptor interactions?

A

tertiary drug-receptor interactions

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9
Q

What is the therapeutic index?

A

relationship between desired effects to adverse reactions caused by the drug

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10
Q

Equation for TI

A

TD50/ED50

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11
Q

Receptor desensitization:

A

the refractory period of the receptor. DR complexes are formed but signal transduction is not possible or is reduced as a result of binding

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12
Q

What is homologous receptor desensitization?

A

agonist binding leads pathway activation that intrinsically turns off the same pathway

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13
Q

What is heterologous receptor desensitization?

A

desensitization caused by
depletion of intracellular signaling mechanisms
ex) multiple receptors using common signaling pathways

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14
Q

Natural Drug Tolerance:

A

high end of normal frequency distribution (Quantal DRC)

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15
Q

Acquired Drug Tolerance:

A

reduced sensitivity to a drug following long-term administration

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16
Q

What are types of acquired drug tolerance?

A

PK

PD

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17
Q

Tachyphylaxis:

A

the rapid, progressive lessening of a response following acute administration of a drug

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18
Q

What are the 4 receptor families?

A

LGIC
GPCR
ligand-gated TM enzymes
intracellular receptors

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19
Q

What are the ionotrophic receptors?

A

LGICs

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20
Q

What are the metabotrophic receptors?

A

GPCRs
Ligand-gated TM enzymes
intracellular receptors

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21
Q

What are types of LGICs?

A

1) nAChR (a4, a7)
2) ionotrophic glutamate (NMDAr, AMPAr)
3) GABAa
4) Glycine
5) 5-HT3

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22
Q

How do the nAChR’s vary?

A

a4 likes Na more than Ca

a7 likes Ca more than Na

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23
Q

What are the ionotrophic glutamate receptors and how do they vary?

A

NMDAr likes Ca more than Na

AMPAr likes Na more than Ca

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24
Q

What is the ion for the glycine LGIC?

A

Cl

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25
Q

Describe the ion affinity for the 5HT3 receptor.

A

Na more than Ca

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26
Q

Describe the characteristics of LGICs

A

1) protein subunits form ion channel
2) ligand binds a subunit
3) many allosteric modulators
4) rapid on, rapid off

27
Q

What is the largest receptor superfamily?

A

GPCR

28
Q

How are GPCRs placed into classes?

A

sequence homology/functional similarity

29
Q

What are the general details about GPCR classes?

A

6 classes
Class A/1 (Rhodopsin-like) has many human drug targets
– adrenergic, muscarinic, histamine, dopamine
Class B-F are mostly orphans

30
Q

What are some GPCR receptors?

A

1) adrenergic
2) muscarinic
3) metabotrophic glutamate
4) serotonin (- 5-HT3)
6) GABAb, cannabinoid, neuropeptides

31
Q

Describe GPCR structure.

A

amino extracellular
carboxyl cytoplasmic
7 transmembrane-spanning regions

32
Q

Gi mechanism

A

1) decreases cAMP
2) increases K+ efflux
3) inactivates Ca++ channels

33
Q

Gs mechanism

A

1) increases cAMP

2) activates Ca++ channels

34
Q

Gq mechanism

A

1) increases PLC activity
2) increases DAG, IP3
3) increases protein-po4
4) increases cytoplasmic Ca++

35
Q

What are classes of ligand-regulated TM enzymes?

A

1) Receptor TK
2) Receptor associated TK
3) Guanylate Cyclase
4) Ser/Thr Kinases

36
Q

What are types of Receptor TKs?

A

1) insulin receptor

2) neurotrophic factor receptors – VEGF, NGF, FGF

37
Q

What are types of Receptor Associated TKs?

A

Cytokine receptors (IL-6, IL-10)

38
Q

NGF

A

nerve growth factor

39
Q

FGF

A

fibroblast growth factor

40
Q

VEGF

A

vascular endothelial growth factor

41
Q

What are ligands for intracellular receptors?

A

corticosteroids, mineralocorticoids, sex, thyroid hormone, vit d, PPAR

42
Q

How long is required for an alteration in protein synthesis (via intracellular receptors)

A

hours

43
Q

What factors govern drug properties?

A

1) physical nature of drug
2) size of drug
3) shape of drug/stereoisomerism
4) type of chemical bonding during DR formation

44
Q

What drug sizes are used clinically and most useful?

A

clinically: 7-60,000 mw
useful: 100-1000 mw

45
Q

In equilibrium k1 notates:

A

rate of association between drug and receptor

46
Q

In equilibrium k-1 notates:

A

rate of dissociation of DR

47
Q

What is measured in an equilibrium radioligand binding assay?

A

affinity and saturation

48
Q

How is affinity determined in an equilibrium radioligand binding assay?

A

Affinity = (k1/k-1)

= DR association rate

49
Q

What is the equilibrium dissocation constant?

A

Kd – the [radioligand] when 50% is bound as DR and 50% is free
= k1 / k-1

50
Q

How are affinity and Kd related?

A

inversely proportional

51
Q

What is Bmax?

A

maximal number of receptors in the tissue studied

52
Q

Why does the law of mass action not predict drug efficacy in all patients?

A

PK and PD variability

53
Q

What are sources of PK variability?

A

gender, race, weight
…
compliance

Anything that effects ADME

54
Q

What are sources of PD variability?

A 
gender, race
drug intx, environment, concomitant dz
*placebo effect
*polymorphisms
*tolerance, tachyphylaxis
55
Q

What is acute behavioral tolerance?

A

tachyphylaxis

56
Q

What is pharmacodynamic tolerance?

A

when repeated drug administration causes a homeostatic change in cellular responsiveness of a target tissue

57
Q

What changes to the DRC do you expect from PD tolerance?

A

right-shift

possible decrease in max efficacy

58
Q

What are mechanisms of receptor down-regulation?

A

increased internalization
increased catabolism
reduced synthesis

59
Q

What is PK tolerance?

A

aka metabolic or drug disposition tolerance

– when repeated drug administration causes induction of catabolic enzyme systems

60
Q

What changes to the DRC do you expect from PK tolerance?

A

right-shift

no change in max efficacy

61
Q

When might cross tolerance occur?

A

When 2 drugs share similar MoA or catabolic enzymes

62
Q

When does sensitization usually occur?

A

w/ stimulant drugs due to changes in DA neurons of brain

– amphetamine, cocaine

63
Q

What changes to the DRC do you expect from sensitization?

A

left-shift

PHS 931 (29 decks)

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