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Pharmacology I > How Drugs Act > Flashcards

How Drugs Act Flashcards

1
Q

what are the protein targets for drug binding

A
  • receptors
  • enzymes
  • specific circulating plasma proteins
  • carrier molecules
  • ion channels
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2
Q

what are the 4 superfamilies of receptos

A
  • ligand gated ion channels
  • g protein coupled receptors
  • kinase linked and related receptors
  • nuclear receptors
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3
Q

describe ligand gated ion channels

A
  • ionotropic
  • composed of 4-5 subunits
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4
Q

describe g protein coupled receptors

A
  • metabotropic receptors
  • 7 trans membrane spanning domains
  • heptahelical receptors
  • serpentine receptors
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5
Q

describe kinase linked and related receptors

A
  • large and heterogenous group
  • single trans membrane spanning domain
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6
Q

describe nuclear receptors

A

steroid superfamily

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7
Q

nicotinic acetylcholine receptor subtypes occur in different ______ regions and these differ from subtype in _______

A

brain; muscle

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8
Q

what are the receptor subtypes

A

-different genes, different phenotypes
- same gene, different phenotypes

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9
Q

how can there be different genes and different phenotypes

A

different genes encode for different subtypes

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10
Q

how can there be same gene different phenotypes

A
  • alternative mRNA splicing
  • single nucleotide polymorphisms
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11
Q

what does alternative mRNA splicing do

A

single gene can give rise to more than one receptor isoform

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12
Q

splicing can result in:

A

inclusion or deletion of one or more mRNA coding regions giving rise to short or long forms of protein

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13
Q

splicing has a big role in:

A

G-protein coupled receptors

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14
Q

what do single nucleotide polymorphisms often result in

A

different drug receptor efficacy

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15
Q

ligand gated ion channels share structural features with:

A

voltage gated ion channels

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16
Q

what are examples of ligand gated ion channels

A
  • nicotinic acetylcholine receptor
  • gamma- aminobutyric acid type A receptor (GABAa)
  • glutamate receptors
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17
Q

what do GABAa receptors do

A

inhibitory NT

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18
Q

what do glutamate receptors do

A

excitatory NT

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19
Q

what is the nicotinic acetylcholine receptor made of

A

pentamer
- 4 different polypeptide subunits
- each subunit crosses plasma membrane 4 times
- 2 alpha, 2 beta, 1 delta, and 1 gamma

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20
Q

what is the mechanism of nicotinic acetylcholine receptors

A
  • acetylcholine binds
  • conformational change occurs
  • transient opening of central aqueous channel
  • Na+ flows from outside to inside cell down electrochemical gradient
  • cell depolarizes
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21
Q

what are examples of GPCRs

A
  • muscarinic acetylcholine receptor
  • opioid receptors
  • GABAb)
  • serotonergic receptors
  • adrenergic receptors
  • angiotensin II receptors
  • endothelin receptors
  • histamine receptors
  • photon receptors
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22
Q

what is the mechanism of GPCRs

A
  • agonist binds to region inside receptor
  • conformational change in cytoplasmic side
  • G protein affinity for nucleotide GDP is reduced and GDP dissociates
  • GTP binds
  • GTP bound G protein dissociates from the receptor
  • GTP bound g protein engages downstream mediators
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23
Q

is GTP or GDP higher intracellularly normally

A

GTP

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24
Q

what are the important things to know about GPCRs

A
  • there is significant signal amplification from one ligand-receptor interaction
  • heterogeneity of G proteins allow for substantial diversity in GPCR signaling in various tissues
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25
Q

why is there significant signal amplification from one ligand receptor interaction

A

activated GTP bound G proteins remain active much longer

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26
Q

what are the agonists of opioid receptors

A
  • heroin
  • morphine
  • oxycodone
  • hydrocodone
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27
Q

what are the competitive antagonists of opioid receptors

A
  • naloxone
  • naltrexone
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28
Q

what is the effect of morphine binding to receptor

A
  • decreased intracellular K+ hyperpolarizes the cell making it refractory
  • decreased intracellular Ca2+ reduces NT release and depolarization
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29
Q

what would happen if you add naloxone to morphine and why

A

dose response curve would shift to the right because naloxone is a competitive antagonist of morphine

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30
Q

what does increased dosage of morphine do to respiratory rate

A

decreases it

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31
Q

what type of receptors are protease activated receptors

A

GPCRs

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32
Q

what is the mechanism of protease activated receptors

A
  • protease cleaves off part of N-terminal domain of receptor
  • “tethered agonist” remaining attached domain is free to interact with ligand binding domain
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33
Q

what are examples of protease activated receptors

A
  • thrombin
  • mast cells following degranulation
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34
Q

what receptors are susceptible to desensitization

A

GPCRs

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35
Q

what are the 2 mechanisms which desensitization occurs

A
  • receptor phosphorylation
  • receptor internalization
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36
Q

what is an example of desensitization in GPCRs

A
  • beta adrenergic receptors are desensitized by Beta- arrestin phosphorylating receptor which reduces affinity for G-proteins
  • receptor can then be internalized
  • all is rapidly reversible
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37
Q

what do single nucleotide polymorphisms do

A

one amino acid change can result in different phenotypes of receptor

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38
Q

what does cross talk and collaboration between GPCRs occur with?

A

RTKs

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39
Q

what are kinase linked and related receptors mainly involved with

A

events controlling cell growth and differentiation

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40
Q

how do kinase-linked and related receptors act

A

indirectly by regulating gene transcription

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41
Q

what does signal transduction of kinase linked and related receptors involve

A

dimerization of two receptor molecules followed by autophosphorylation of tyrosine residues

42
Q

describe the structure of kinase linked and related receptors

A

all have large extracellular ligand binding domains connected via single membrane spanning domain to an intracellular domain which has enzymatic activity

43
Q

what are the 3 major families of kinase linked and related receptors

A
  • receptor tyrosine kinases
  • serine/threonine kinases
  • cytokine receptors
44
Q

what domain of RTKs have tyrosine kinase activity

A

intracellular domain

45
Q

what are examples of RTKs

A
  • epidermal growth factor receptor
  • nerve growth factor
  • toll-like receptors
  • insulin receptors
46
Q

what does the insulin receptor do

A
  • activates PI3 kinase pathway
  • turns on or off gene expression
  • activates glycogen synthesis
  • activates MAP kinase pathway which turns on or off gene expression
47
Q

describe serine/threonine kinases

A

-smaller group than RTKs
- structurally and functionally very similar to RTKs
- phosphorylate serine and threonine instead of tyrosine

48
Q

what is an example of a serine/threonine kinase

A

transforming growth factor (TGF)

49
Q

what are examples of cytokine receptors

A
  • interleukins
    -interferons
  • chemokines
50
Q

cytokine receptors lack:

A

intrinsic enzymatic activity in intracellular domains

51
Q

what do cytokine receptors do

A

associate and activate other kinases

52
Q

what is an example of a cytokine receptor

A
  • JAK binds and activates the Jak-STAT pathway
  • downstream turns on or off gene expression
53
Q

what are ligand examples for nuclear receptots

A
  • estrogens
  • progestins
  • androgens
  • glucocorticoids
  • mineralocorticoids
  • vitamin D
  • vitmain A
  • fatty acids
54
Q

what are the two locations in the cell that nuclear receptors are found

A

cytoplasmic and nuclear

55
Q

what are the two types of domains on nuclear receptors

A
  • ligand binding and DNA binding domains
56
Q

what is the mechanism of action of cytoplasmic nuclear receptors

A
  • most are bound to heat shock proteins when no ligand is present
  • most form homodimers upon ligand binding
  • some form heterodimers with Retinoid X receptor
  • translocate to nucleus to regulate gene expression
57
Q

describe nuclear receptors in the nucleus

A
  • constitutively present in nucleus
  • form heterodimers with RXR
58
Q

what do nuclear receptors do

A

interact with hormone response elements on genes to regulate gene expression

59
Q

what is an example of nuclear receptor

A

androgen receptor

60
Q

what is the effect of the androgen receptor activation in skeletal muscle

A

an increase in contractility because it causes an increase in the production of actin and myosin

61
Q

what are the best enzyme drug targets

A

enzymes that are key rate-limiting steps in biochemical reactions

62
Q

what is the strategy of enzymes as drug targets

A

to reduce enzyme activity through drug inhibition

63
Q

describe non-competitive enzyme inhibitors and give example

A

drug may covalently modify the enzyme
- ex: aspirin acetylates cyclooxygenase

64
Q

describe competitive enzyme inhibitors and give example

A
  • drug is often a structural analog of the natrually occurring substrate
  • ex: HMG-CoA reductase inhibitor
65
Q

what is the classic HMG-CoA reductase inhibitor

A

Statins

66
Q

what do statins do

A

competitively inhibit rate limiting step in cholesterol biosynthesis in liver
- liver upregulates LDL receptors thereby reducing plasma LDL concentrations

67
Q

what is the statin we need to know

A

lovastatin

68
Q

lovastatin acts on what rate limiting stp

A

mevalonate formation

69
Q

what circulating plasma protein causes disease and/or symptoms

A

tumor necrosis factor alpha (TNF alpha)

70
Q

TNF alpha is elevated in:

A

RA, crohn’s disease, psoriasis, ankylosing spondylitis
- in severe cases of aphthous ulcers

71
Q

lowering TNF alpha in RA and Crohns does what?

A

decreases symptoms and may delay progression

72
Q

what are the monoclonal antibodies that recognize, bind and remove TNF alpha from circulaiton

A

infliximad and adalimumbad

73
Q

what does etanercept do

A

soluble TNF alpha receptor that binds and decreases TNF alpha

74
Q

what antibody binds IL2

A

daclizumab

75
Q

what antibody binds IL5

A

mepolzumab

76
Q

why are carrier molecules good drug targets

A

they regulate key cellular events

77
Q

what are the small molecule transporters

A
  • NT uptake
  • organic ion transporters
  • p-glycoprotein
78
Q

what does p-glycoprotein do

A

protective role in moving potential toxicants out of GI epithelial cells back into lumen to prevent absorption

79
Q

what drug blocks p-glycoprotein

A

verapamil

80
Q

why do you want to block p-glycoprotein

A
  • could increase absorption of some drugs
  • could potentially increase activity of anti-cancer drugs
81
Q

describe Na+/K+ ATPase

A
  • moves Na+ out and K+ in against concentration gradient
  • requires energy
  • key in all muscle contraction, nervous conduction, ion gradient establishment
  • provides the driving force for other ion transporters
  • can be inhibited by drugs
82
Q

what drug inhibits Na+/K+ ATPase

A

digoxin

83
Q

what are the types of voltage gated ion channels

A
  • Na+ channels
  • Ca2+ channels
  • K+ channels
84
Q

what are the types of Ca2+ channels

A
  • Long
  • Transient
  • Neuronal
85
Q

what are the types of Na+ channels

A

fast and slow types

86
Q

what are the types of K+ channels

A

voltage and ligand gated types

87
Q

what is the resting membrane potential in voltage gated ion channels

A

-90mV

88
Q

what is the depolarized membrane potenital in voltage gated ion channels

A

0 mv

89
Q

what type of drug is verapamil

A

Ca++ channel blocker

90
Q

what does verapamil do

A
  • bind to L-type Ca2+ channels in heart and vascular smooth muscle
  • blocks movement of calcium from outside to inside
  • reduced cardiac contraction
  • slows cardiac conduction
  • reduces vascular smooth muscle contraction
  • reduces BP
91
Q

what is the mechanism of action of the contraction of cardiac muscle

A
  • depolarization of the membrane leads to calcium influx through L-type calcium channels
  • results in an increase in intracellular calcium
  • calcium stimulates further calcium release from the sarcoplasmic reticulum to further increase intracellular calcium
  • contractility increases with the increased availability of calcium for contraction
92
Q

what does ATP stand for

A

adenosine trophosphate

93
Q

what does RyR stand for and what type of channel is this

A
  • ryanodine receptor
  • ligand activated calcium channel
94
Q

what does CICR stand for

A

calcium induced calcium release

95
Q

what does SERCA stand for

A

sarcoplasmic/endoplasmuc reticulum Ca2+ ATPase

96
Q

what happens during the P wave

A

atrial depolarization

97
Q

what happens during the T wave

A

ventricular repolarization

98
Q

what happens during the QRS complex

A

ventricular depolarization

99
Q

what do calcium channel blockers do

A
  • reduce calcium influx into the cardiac muscle reducing intracellular calcium and force of contraction
  • negative ionotropic effect
100
Q

what is the negative chronotropic effect of calcium channel blockers

A
  • blockage of calcium channels in pacemaker (SA node), AV node, and Purkinje fibers in the heart, calcium channel blockers reduce depolarization and slow conduction of depolarizing waves through the heart
101
Q
A

Pharmacology I (12 decks)

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