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Pharmacology > How Drugs Act > Flashcards

How Drugs Act Flashcards

1
Q

Protein Targets for Drug Binding
(5)

A
  1. Receptors
  2. Enzymes
  3. Specific Circulating Plasma Proteins
  4. Carrier Molecules (Transporters)
  5. Ion Channels
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2
Q

. Receptors

A

 Protein molecule which function
to recognize and respond to
endogenous chemical signals
* recognize/bind specific endogenous
ligands
* may also recognize/bind xenobiotics

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3
Q

receptors
 Classified based on —
 Grouped into — major
superfamilies

A

ligands
4

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4
Q

Ligand-Gated Ion Channels

A

— “ionotropic” receptors

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5
Q

G-Protein Coupled Receptors
(4)

A

— “metabotropic” receptors
— “7 trans-membrane spanning domain” receptors
— “heptahelical” receptors
— “serpentine” receptors

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6
Q

Kinase-Linked & Related Receptors
(2)

A

— large and heterogeneous group
— single trans-membrane spanning domain

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7
Q

Nuclear Receptors

A

— “steroid superfamily”

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8
Q

*Ligand-Gated Ion
Channels Composed of
— of these subunits

A

4-5

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9
Q

Receptor Subtypes
* receptors in given family generally
occur in several molecular varieties or
“subtypes”
(4)

A

— similar architecture
— significant differences in amino acid
sequence
— often different pharmacologic properties
— nicotinic acetylcholine receptor subtypes
occur in different brain regions and these
differ from subtype in muscle

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10
Q

different genes, different phenotypes

A

— different genes may encode for different subtypes

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11
Q

same gene, different phenotypes
(2)

A

— variation may arise from alternative mRNA splicing
— single nucleotide polymorphisms

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12
Q

SKIPPED
— variation may arise from alternative mRNA splicing
(3)

A
  • single gene can give rise to more than one receptor isoform
  • splicing can result in inclusion or deletion of one or more mRNA coding regions giving rise to short or long forms of protein
  • big role in G-protein coupled receptors
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13
Q

— single nucleotide polymorphisms

A
  • often results in different drug-receptor efficacy
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14
Q

Ligand-Gated Ion Channels
(2)

A
  • share structural features with voltage-
    gated ion channels
  • “ionotropic” receptors
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15
Q

Ligand-Gated Ion Channels
examples
(3)

A

— nicotinic acetylcholine receptor (nAChR)
— gamma-aminobutyric acid type A receptor
(GABAA)
* inhibitory neurotransmitter
— glutamate receptors [N-methyl-D-aspartate
(NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid (AMPA), and kainate types]
* excitatory neurotransmitter

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16
Q

Ligand-Gated Ion Channels
* nAChR
(8)

A

— best characterized of all cell-surface receptors
— pentamer: four different polypeptide
subunits
* 2 a, 1 b, 1 g, and 1 d, MW from 43K-50K each
* each subunit crosses plasma membrane 4 times
— acetylcholine binds sites on a subunits
— conformational change occurs
— transient opening of central aqueous channel
— Na+ flow from outside to inside cell
* down electro-chemical gradient
— cell depolarizes
— all occurs in milliseconds

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17
Q

G-Protein Coupled Receptors
(3)

A
  • largest superfamily of receptors
  • “metabotropic” receptors
  • 7 transmembrane spanning domains
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18
Q

SKIPPED
G-Protein Coupled Receptors
examples
(10)

A

— muscarinic acetylcholine receptor (mAChR)
— opioid receptors (m, k, d)
— gamma-aminobutyric acid type B receptor (GABAB)
— serotonergic receptors (5-hydroxytryptamine or 5-HT, 1-7 types)
— adrenergic receptors (a and b types)
— angiotensin II receptors (1, 2, 3, 4 types)
— endothelin receptors (A, B, C types)
— histamine receptors (1, 2, 3 types)
— photon receptors (retinal rod and cone)

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19
Q

G-Protein Coupled Receptors
* agonist binds to region inside receptor surrounded by — domains

A

7 TM

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20
Q
  • conformational change in cytoplasmic side
    (3)
A

— spreads cytoplasmic side of 7 TM domains by ~1 nm compared to inactive conformation
— opens cavity in receptors cytoplasmic side
— cavity binds critical regulator surface of the G-Protein

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21
Q

G-Protein receptors sequence

A
  • G-Protein affinity for nucleotide GDP is reduced
    — GDP dissociates
  • GTP binds
    — GTP normally higher in concentration than GDP intracellularly
  • GTP-bound G-Protein dissociates from the receptor
  • GTP-bound G-Protein engages downstream mediators (a.k.a. “effectors”)
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22
Q

G-Protein Coupled Receptors
* agonist binds and dissociates …

A

rapidly
— a few milliseconds

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23
Q

G-Protein Coupled Receptors
activated GTP-bound G-proteins
remain

A

active much longer
— up to tens of seconds
— this produces significant signal
amplification from one ligand-receptor
interaction

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24
Q

heterogeneity of G-proteins allow for

A

substantial diversity in GPCR signaling
in various tissues

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25
Q

SKIPPED
G Protein: Gs
Receptor Ligands
Effector/Signaling Pathway

A

β-Adrenergic amines, histamine, serotonin,
glucagon, and many other hormones

↑ Adenylyl cyclase →↑ cAMP

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26
Q

SKIPPED
G Protein: Gi1, Gi2, Gi3
Receptor Ligands
Effector/Signaling Pathway

A

α2-Adrenergic amines, acetylcholine
(muscarinic), opioids, serotonin, and many
others

Several, including:
↓ Adenylyl cyclase →↓
cAMP
Open cardiac K+ channels
→↓ heart rate

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27
Q

SKIPPED
G Protein: Golf
Receptor Ligands
Effector/Signaling Pathway

A

Odorants (olfactory epithelium)

↑ Adenylyl cyclase →↑
cAMP

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28
Q

SKIPPED
G Protein: Go
Receptor Ligands
Effector/Signaling Pathway

A

Neurotransmitters in brain (not yet
specifically identified)

Not yet clear

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29
Q

SKIPPED
G Protein: Gq
Receptor Ligands
Effector/Signaling Pathway

A

Acetylcholine (muscarinic), bombesin,
serotonin (5-HT2), and many others

↑ Phospholipase C →↑
IP3, diacylglycerol,
cytoplasmic Ca2+

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30
Q

SKIPPED
G Protein: Gt1, Gt2
Receptor Ligands
Effector/Signaling Pathway

A

Photons (rhodopsin and color opsins in
retinal rod and cone cells)

↑ cGMP
phosphodiesterase →↓
cGMP (phototransduction)

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31
Q

G-Protein Coupled Receptor
Example
 Opioid Pharmacology
* Agonists of Opioid Receptors
— (4)
* Competitive Antagonists of Opioid
Receptors
— (2)

A

heroin, morphine, oxycodone,
hydrocodone

naloxone, naltrexone

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32
Q

G-Protein Coupled Receptors
* Protease Activated Receptors (PAR)
(2)

A

— activation of GPCR is normally a result of diffusible ligand in solution acting on a receptor
— but GPCR receptor activation can occur as a result of protease activation

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33
Q

— but GPCR receptor activation can occur as a result of protease activation
(2)

A
  • protease cleaves off part of N-terminal domain of receptor
  • “tethered agonist”: remaining attached domain is free to interact with ligand-binding domain
34
Q

Protease Activated Receptors (PAR)
examples:
(2)

A
  • thrombin: a protease involved in blood clotting activates PAR
  • PAR-2 is activated by a protease released from mast cells following degranulation
35
Q

G-Protein Coupled Receptors
* Desensitization
(2)

A

— applicable to all GPCRs
— occurs via 2 main mechanisms
* receptor phosphorylation
* receptor internalization

36
Q

G-Protein Coupled Receptors
* Desensitization
example:
(4)

A
  • b-adrenergic receptors
  • b-arrestin phosphorylates receptor
    reducing receptor affinity for G-proteins
  • receptor can then be internalized
  • all is rapidly reversible
37
Q

SKIPPED
G-Protein Coupled Receptors
* Further Intricacies
(5)

A
  • receptor subtypes
    » one gene can give rise to multiple
    subtypes of receptors through
    alternative mRNA splicing
  • single nucleotide polymorphisms
    » one amino acid change can result in
    different phenotypes of receptor
  • cross-talk and collaboration between two
    different GPCRs or GPCR with receptor
    tyrosine kinase (RTK)
  • much, much more to be learned
  • many new drug targets
38
Q

Superfamilies of Receptors
* Kinase-Linked & Related Receptors
(4)

A

— involved mainly in events controlling cell growth and differentiation
— act indirectly by regulating gene transcription
— signal transduction generally involves dimerization of two receptor molecules followed by autophosphorylation of tyrosine residues
— all have large extracellular ligand-binding domain connected via single membrane spanning domain to an intracellular domain which has enzymatic activity

39
Q

Kinase-Linked & Related Receptors
— all have large extracellular ligand-binding domain connected via

A

single membrane spanning domain to an intracellular domain which has enzymatic activity

40
Q

Kinase-Linked & Related Receptors
* three major families
(3)

A

— Receptor Tyrosine Kinases (RTKs)
— Serine/Threonine Kinases
— Cytokine Receptors

41
Q

Receptor Tyrosine Kinases (RTKs)
(2)

A

— intracellular domain has tyrosine kinase
activity
— e.g. epidermal growth factor receptor,
nerve growth factor, Toll-like receptors,
insulin receptors

42
Q

Receptor Tyrosine
Kinases (RTKs)
— insulin receptor
(2)

A
  • activates PI3 kinase
    pathway
  • activates Mitogen-
    Activated Protein (MAP)
    Kinase pathway
43
Q

Insulin
* activates PI3 kinase
pathway
(2)
* activates Mitogen-Activated Protein (MAP)
Kinase pathway
(1)

A

» turns on or off gene
expression
» activates glycogen
synthesis

» turns on or off gene
expression

44
Q

SKIPPED
Activated Protein (MAP)
Kinase pathway

A

» turns on or off gene
expression

45
Q

Kinase-Linked & Related Receptors
* Serine/Threonine Kinases
(4)

A

— smaller group than RTKs
— structurally and functionally very similar
to RTKs
— phosphorylate serine and threonine
instead of tyrosine
— e.g. transforming growth factor (TGF)

46
Q

Kinase-Linked & Related Receptors
* Cytokine Receptors
(3)

A

— interleukins, interferons, chemokines,
etc
— lack intrinsic enzymatic activity in
intracellular domains!!
— associate and activate other kinases

47
Q

cytokines
associate and activate other kinases
(3)

A
  • binds and activates Janus Kinase (Jak)
  • Jak binds and activates Signal Transducers
    and Activators of Transcription
    » a.k.a. the “Jak-STAT” pathway
  • downstream turns on or off gene expression
48
Q

Superfamilies of Receptors
* Nuclear Receptors (“Steroid
Superfamily”)
(2)

A

— ligand-activated transcription factors
— ligand-binding and DNA-binding domains

49
Q

Nuclear Receptors (“Steroid
Superfamily”)
ligand examples:

A
  • estrogens, progestins, androgens,
    glucocorticoids, mineralocorticoids, vitamin D,
    vitamin A (retinoid receptors), fatty acids, etc.
50
Q

Nuclear Receptors (“Steroid
Superfamily”)
— two main locations in the cell
(2)

A
  • cytoplasmic
  • nuclear
51
Q

Superfamilies of Receptors
* Nuclear Receptors (“Steroid Superfamily”)
(3)

A

— cytoplasmic
— nuclear (e.g. fatty acid receptors)
— interact with hormone response elements on genes to regulate gene expression

52
Q

Superfamilies of Receptors
* Nuclear Receptors (“Steroid Superfamily”)
— cytoplasmic
(4)

A
  • most are bound to Heat Shock Proteins when no ligand is present
  • most form homodimers upon ligand binding (e.g. steroid receptors)
  • some form heterodimers with Retinoid X Receptor (e.g. thyroid hormone)
  • translocate to nucleus to regulate gene expression
53
Q

Superfamilies of Receptors
* Nuclear Receptors (“Steroid Superfamily”)
— nuclear (e.g. fatty acid receptors)
(2)

A
  • constitutively present in nucleus
  • form heterodimers with Retinoid X Receptor (RXR)
54
Q

Superfamilies of Receptors
* Nuclear Receptors (“Steroid Superfamily”)
* Example:

A

Androgen Receptors

55
Q

Enzymes as Drug Targets
* many enzymes serve as drug targets
(2)

A

— enzymes that are key rate-limiting steps in biochemical reactions are the best drug targets
— strategy is most often to reduce enzyme activity through drug inhibition

56
Q

non-competitive enzyme inhibitors

A

— drug may covalently modify enzyme
* aspirin acetylates Cyclooxygenase 1 and 2 to non-competitively and irreversibly inhibits

57
Q

competitive enzyme inhibitors
(2)

A

— drug is often a structural analog of the naturally occurring substrate
— example: HMG-CoA Reductase Inhibitors

58
Q

Enzymes as Drug Targets
* HMG-CoA Reductase Inhibitors
(“Statins”)
(2)

A

— competitively inhibit rate-limiting step
in cholesterol biosynthesis in liver
— structurally similar to hydroxy-methy-
glutaryl-coenzyme A

59
Q

Enzymes as Drug Targets
* HMG-CoA Reductase Inhibitors
(“Statins”)
competitively inhibit rate-limiting step
in cholesterol biosynthesis in liver

A
  • liver upregulates LDL receptors thereby
    reducing plasma LDL concentrations
60
Q

Enzymes as Drug Targets
* HMG-CoA Reductase Inhibitors
(“Statins”)
Statins:

A
  • lovastatin, atorvastatin, fluvastatin,
    pitavastatin, pravastatin, rosuvastatin,
    simvastatin
61
Q

Disease and/or Symptoms Produced by Elevated Circulating Plasma Proteins
* Tumor Necrosis Factor-a
(2)

A

— elevated in rheumatoid arthritis, Crohn’s disease, psoriasis, ankylosing spondylitis
— elevated in severe cases of aphthous ulcers

62
Q

Lowering TNF-a in RA or Crohn’s patients

A

decreases symptoms and may delay progression

63
Q

Infliximab and adalimumab
(2)

A

— monoclonal antibodies that recognizes TNF-a
— bind TNF-a removing it from circulation

64
Q

Etanercept

A

— soluble TNF-a receptor that binds TNF-a

65
Q

Many other examples
— daclizumab –
— mepolizumab –

A

antibody that binds interleukin-2
antibody that binds interleukin-5

66
Q

Ion and Small Molecule Transporters
(2)

A
  • important in moving substances across lipid bilayer membranes
  • often good drug targets as they regulate key cellular events
67
Q

SKIPPED
Small Molecule Transporters
(3)

A
  • neurotransmitter uptake (norepinephrine, 5-HT, glutamate, etc.)
  • organic ion transporters (organic acids and bases)
  • p-glycoprotein (Multi-Drug Resistance)
68
Q

p-glycoprotein (Multi-Drug Resistance)
(3)

A

— protective role in moving potential toxicants out of gastrointestinal epithelial cells back into lumen to prevent absorption
— overexpressed in certain tumor cells leading to drug resistance
— can be blocked by drugs

69
Q

SKIPPED
p-glycoprotein (Multi-Drug Resistance)
can be blocked by drugs
(2)

A
  • could increase absorption of some drugs
  • could potentially increase activity of anti-cancer drugs
70
Q

Ion Transporters
* many transporters important in renal tubules

A

— drives water reabsorption and concentration of urine

71
Q

Ion Transporters
Na+/K+ ATPase important everywhere
— establishes
— requires
— key in all
— often provides the — for other ion transporters
— can be inhibited by

A

electrochemical gradient by moving Na+ out and K+ in against concentration gradient
energy (ATP) to function
muscle contraction, nervous conduction, ion gradient establishment, etc
driving force
drugs (e.g. digoxin, a cardiac glycoside used for heart failure)

72
Q

Voltage-Gated Ion Channels
* structure

A

— very similar in structure and function
to ligand-gated ion channel receptors

73
Q

Voltage-Gated Ion Channels
(3)

A
  • Ca++ channels (L, T, N types)
  • Na+ channels (fast and slow types)
  • K+ channels (voltage- and ligand-
    gated types)
74
Q

Voltage-Gated Ion Channels
(3)

A
  • Ca++ channels (L, T, N types)
  • Na+ channels (fast and slow types)
  • K+ channels (voltage- and ligand-
    gated types)
75
Q
  • K+ channels (voltage- and ligand-
    gated types)
    — produce at least
A

9 different K+ currents
in heart, vascular smooth muscle, and
other tissues such as pancreas

76
Q

Voltage-Gated Ion Channels
* voltage-dependent
— channels open or close depending upon
the
— channels change opened/closed or
activated/resting states as electrical
potential changes from
— channels often susceptible to binding by
various compounds, including

A

electrical gradient (voltage) across the plasma membrane
-90 mV to +10 mV (inside relative to outside)
xenobiotics

77
Q

channels open or close depending upon
the electrical gradient (voltage) across the
plasma membrane
* resting membrane potential ~ mV
* depolarized membrane potential ~ mV

A

-90
0

78
Q

From Molecular Events to Cellular Actions &
Beyond
* Rang & Dale’s Pharmacology
— uses “—” and “—” to understand impact of drugs on
molecular level and cellular level

A

excitation-contraction coupling
cell secretion

79
Q

verapamil
— Ca++ Channel Blocker
(6)

A
  • binds to L-type Ca++ channels in heart and vascular smooth
    muscle
  • blocks movement of Ca++ from outside to inside
  • reduces cardiac contraction (negative inotropic effect)
  • slows cardiac conduction (negative chronotropic effect)
  • reduces vascular smooth muscle contraction
  • reduces blood pressure
80
Q

Cardiac Muscle
— contraction of cardiac muscle
(4)

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 (calcium-induced
    calcium release) to further increase intracellular
    calcium
  • contractility increases with the increased
    availability of calcium for contraction
81
Q

Cardiac Excitation Contraction & Ca++ Channel Blockers as an example
 abbreviations
* ATP =
* RyR =
— ligand-activated Ca++ channel
* CICR =
* SERCA =
cardiac electrical activity

A

adenosine triphosphate
ryanodine receptor
calcium-induced, calcium release
sarcoplasmic/endoplasmic reticulum Ca++ ATPase

82
Q

Mechanism of Action
* Cardiac Muscle
— calcium channel blockers
(3)

A
  • calcium channel blockers reduce calcium influx into
    the cardiac muscle
  • thereby reduce intracellular calcium and force of
    contraction
    » negative inotropic effect
  • through similar blockade of calcium channels in pace-
    maker (SA node), AV node, and Purkinje fibers in the
    heart, calcium channel blockers reduce depolarization
    and slow conduction of depolarizing waves through
    the heart
    » negative chronotropic effect

Pharmacology (13 decks)

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