How Drugs Act Flashcards
(101 cards)
1
Q
what are the protein targets for drug binding
A
- receptors
- enzymes
- specific circulating plasma proteins
- carrier molecules
- ion channels
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
3
Q
describe ligand gated ion channels
A
- ionotropic
- composed of 4-5 subunits
4
Q
describe g protein coupled receptors
A
- metabotropic receptors
- 7 trans membrane spanning domains
- heptahelical receptors
- serpentine receptors
5
Q
describe kinase linked and related receptors
A
- large and heterogenous group
- single trans membrane spanning domain
6
Q
describe nuclear receptors
A
steroid superfamily
7
Q
nicotinic acetylcholine receptor subtypes occur in different ______ regions and these differ from subtype in _______
A
brain; muscle
8
Q
what are the receptor subtypes
A
-different genes, different phenotypes
- same gene, different phenotypes
9
Q
how can there be different genes and different phenotypes
A
different genes encode for different subtypes
10
Q
how can there be same gene different phenotypes
A
- alternative mRNA splicing
- single nucleotide polymorphisms
11
Q
what does alternative mRNA splicing do
A
single gene can give rise to more than one receptor isoform
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
13
Q
splicing has a big role in:
A
G-protein coupled receptors
14
Q
what do single nucleotide polymorphisms often result in
A
different drug receptor efficacy
15
Q
ligand gated ion channels share structural features with:
A
voltage gated ion channels
16
Q
what are examples of ligand gated ion channels
A
- nicotinic acetylcholine receptor
- gamma- aminobutyric acid type A receptor (GABAa)
- glutamate receptors
17
Q
what do GABAa receptors do
A
inhibitory NT
18
Q
what do glutamate receptors do
A
excitatory NT
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
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
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
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
23
Q
is GTP or GDP higher intracellularly normally
A
GTP
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
25
why is there significant signal amplification from one ligand receptor interaction
activated GTP bound G proteins remain active much longer
26
what are the agonists of opioid receptors
- heroin
- morphine
- oxycodone
- hydrocodone
27
what are the competitive antagonists of opioid receptors
- naloxone
- naltrexone
28
what is the effect of morphine binding to receptor
- decreased intracellular K+ hyperpolarizes the cell making it refractory
- decreased intracellular Ca2+ reduces NT release and depolarization
29
what would happen if you add naloxone to morphine and why
dose response curve would shift to the right because naloxone is a competitive antagonist of morphine
30
what does increased dosage of morphine do to respiratory rate
decreases it
31
what type of receptors are protease activated receptors
GPCRs
32
what is the mechanism of protease activated receptors
- protease cleaves off part of N-terminal domain of receptor
- "tethered agonist" remaining attached domain is free to interact with ligand binding domain
33
what are examples of protease activated receptors
- thrombin
- mast cells following degranulation
34
what receptors are susceptible to desensitization
GPCRs
35
what are the 2 mechanisms which desensitization occurs
- receptor phosphorylation
- receptor internalization
36
what is an example of desensitization in GPCRs
- 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
37
what do single nucleotide polymorphisms do
one amino acid change can result in different phenotypes of receptor
38
what does cross talk and collaboration between GPCRs occur with?
RTKs
39
what are kinase linked and related receptors mainly involved with
events controlling cell growth and differentiation
40
how do kinase-linked and related receptors act
indirectly by regulating gene transcription
41
what does signal transduction of kinase linked and related receptors involve
dimerization of two receptor molecules followed by autophosphorylation of tyrosine residues
42
describe the structure of kinase linked and related receptors
all have large extracellular ligand binding domains connected via single membrane spanning domain to an intracellular domain which has enzymatic activity
43
what are the 3 major families of kinase linked and related receptors
- receptor tyrosine kinases
- serine/threonine kinases
- cytokine receptors
44
what domain of RTKs have tyrosine kinase activity
intracellular domain
45
what are examples of RTKs
- epidermal growth factor receptor
- nerve growth factor
- toll-like receptors
- insulin receptors
46
what does the insulin receptor do
- 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
describe serine/threonine kinases
-smaller group than RTKs
- structurally and functionally very similar to RTKs
- phosphorylate serine and threonine instead of tyrosine
48
what is an example of a serine/threonine kinase
transforming growth factor (TGF)
49
what are examples of cytokine receptors
- interleukins
-interferons
- chemokines
50
cytokine receptors lack:
intrinsic enzymatic activity in intracellular domains
51
what do cytokine receptors do
associate and activate other kinases
52
what is an example of a cytokine receptor
- JAK binds and activates the Jak-STAT pathway
- downstream turns on or off gene expression
53
what are ligand examples for nuclear receptots
- estrogens
- progestins
- androgens
- glucocorticoids
- mineralocorticoids
- vitamin D
- vitmain A
- fatty acids
54
what are the two locations in the cell that nuclear receptors are found
cytoplasmic and nuclear
55
what are the two types of domains on nuclear receptors
- ligand binding and DNA binding domains
56
what is the mechanism of action of cytoplasmic nuclear receptors
- 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
describe nuclear receptors in the nucleus
- constitutively present in nucleus
- form heterodimers with RXR
58
what do nuclear receptors do
interact with hormone response elements on genes to regulate gene expression
59
what is an example of nuclear receptor
androgen receptor
60
what is the effect of the androgen receptor activation in skeletal muscle
an increase in contractility because it causes an increase in the production of actin and myosin
61
what are the best enzyme drug targets
enzymes that are key rate-limiting steps in biochemical reactions
62
what is the strategy of enzymes as drug targets
to reduce enzyme activity through drug inhibition
63
describe non-competitive enzyme inhibitors and give example
drug may covalently modify the enzyme
- ex: aspirin acetylates cyclooxygenase
64
describe competitive enzyme inhibitors and give example
- drug is often a structural analog of the natrually occurring substrate
- ex: HMG-CoA reductase inhibitor
65
what is the classic HMG-CoA reductase inhibitor
Statins
66
what do statins do
competitively inhibit rate limiting step in cholesterol biosynthesis in liver
- liver upregulates LDL receptors thereby reducing plasma LDL concentrations
67
what is the statin we need to know
lovastatin
68
lovastatin acts on what rate limiting stp
mevalonate formation
69
what circulating plasma protein causes disease and/or symptoms
tumor necrosis factor alpha (TNF alpha)
70
TNF alpha is elevated in:
RA, crohn's disease, psoriasis, ankylosing spondylitis
- in severe cases of aphthous ulcers
71
lowering TNF alpha in RA and Crohns does what?
decreases symptoms and may delay progression
72
what are the monoclonal antibodies that recognize, bind and remove TNF alpha from circulaiton
infliximad and adalimumbad
73
what does etanercept do
soluble TNF alpha receptor that binds and decreases TNF alpha
74
what antibody binds IL2
daclizumab
75
what antibody binds IL5
mepolzumab
76
why are carrier molecules good drug targets
they regulate key cellular events
77
what are the small molecule transporters
- NT uptake
- organic ion transporters
- p-glycoprotein
78
what does p-glycoprotein do
protective role in moving potential toxicants out of GI epithelial cells back into lumen to prevent absorption
79
what drug blocks p-glycoprotein
verapamil
80
why do you want to block p-glycoprotein
- could increase absorption of some drugs
- could potentially increase activity of anti-cancer drugs
81
describe Na+/K+ ATPase
- 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
what drug inhibits Na+/K+ ATPase
digoxin
83
what are the types of voltage gated ion channels
- Na+ channels
- Ca2+ channels
- K+ channels
84
what are the types of Ca2+ channels
- Long
- Transient
- Neuronal
85
what are the types of Na+ channels
fast and slow types
86
what are the types of K+ channels
voltage and ligand gated types
87
what is the resting membrane potential in voltage gated ion channels
-90mV
88
what is the depolarized membrane potenital in voltage gated ion channels
0 mv
89
what type of drug is verapamil
Ca++ channel blocker
90
what does verapamil do
- 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
what is the mechanism of action of the contraction of cardiac muscle
- 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
what does ATP stand for
adenosine trophosphate
93
what does RyR stand for and what type of channel is this
- ryanodine receptor
- ligand activated calcium channel
94
what does CICR stand for
calcium induced calcium release
95
what does SERCA stand for
sarcoplasmic/endoplasmuc reticulum Ca2+ ATPase
96
what happens during the P wave
atrial depolarization
97
what happens during the T wave
ventricular repolarization
98
what happens during the QRS complex
ventricular depolarization
99
what do calcium channel blockers do
- reduce calcium influx into the cardiac muscle reducing intracellular calcium and force of contraction
- negative ionotropic effect
100
what is the negative chronotropic effect of calcium channel blockers
- 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
