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Pharmacology > How drugs act? > Flashcards

How drugs act? Flashcards

1
Q

What are the 5 major protein targets for drug action?

A
  1. Receptors
  2. Enzymes
  3. Specific Circulating Plasma Proteins
  4. Carrier Molecules (Transporters)
  5. Ion Channels
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2
Q 
 Protein molecule which function 
to recognize and respond to 
endogenous chemical signals
• recognize/bind specific endogenous 
ligands
• may also recognize/bind xenobiotics
 Classified based on ligands
 Grouped into 4 major 
superfamilies
A

Receptors

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3
Q

What are the 4 superfamilies of receptors?

A
  • Ligand-Gated Ion Channels
  • G-Protein Coupled Receptors
  • Kinase-Linked & Related Receptors
  • Nuclear Receptors
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4
Q

How many subunits are found in ligand-gated ion channels?

A

4-5 subunits

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5
Q

Which subfamily of receptors form dimers?

A

Kinase-Linked

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6
Q

variation may arise from ______:

  • 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
A

alternative mRNA splicing

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7
Q

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

A

 Ligand-Gated Ion Channels

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8
Q

— 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

are examples of what subfamily of receptor?

A

Ligand-gated ion channels

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9
Q

— 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

A

• nAChR

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10
Q
  • largest superfamily of receptors
  • “metabotropic” receptors
  • 7 transmembrane spanning domains
A

 G-Protein Coupled Receptors

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11
Q

• The following are examples of _____ receptors:
— 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)

A

 G-Protein Coupled Receptors

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12
Q

______ of Opioid Receptors
— heroin, morphine, oxycodone,
hydrocodone

A

Agonists

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13
Q

______ of Opioid
Receptors
— naloxone, naltrexone

A

• Competitive Antagonists

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14
Q

— 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
* protease cleaves off part of N-terminal domain of receptor
* “tethered agonist”: remaining attached domain is free to interact with ligand-binding domain
— examples:
* thrombin: a protease involved in blood clotting activates PAR
* PAR-2 is activated by a protease released from mast cells following degranulation

A

• Protease Activated Receptors (PAR)

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15
Q 
— applicable to all GPCRs
— occurs via 2 main mechanisms
* receptor phosphorylation
* receptor internalization
— example:
* b-adrenergic receptors
* b-arrestin phosphorylates receptor 
reducing receptor affinity for G-proteins
* receptor can then be internalized
* all is rapidly reversible
A

• Desensitization

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16
Q

What are the 3 ways a GPCR can be desensitized?

A

Phosphorylation
Internalization in lysosome
Endocytosis

17
Q

— 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

A

Kinase-Linked & Related Receptors

18
Q

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

A

Kinase-Linked & Related Receptors

19
Q

What are the three major families of Kinase-Linked & Related Receptors?

A

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

20
Q 
— insulin receptor
* activates PI3 kinase 
pathway
» turns on or off gene 
expression
» activates glycogen 
synthesis
* activates Mitogen-
Activated Protein (MAP) 
Kinase pathway
» turns on or off gene 
expression
A

• Receptor Tyrosine

Kinases (RTKs)

21
Q 
— smaller group than RTKs
— structurally and functionally very similar 
to RTKs
— phosphorylate serine and threonine 
instead of tyrosine
— e.g. transforming growth factor (TGF)
A

• Serine/Threonine Kinases

22
Q

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

A

• Cytokine Receptors

23
Q 
— ligand-activated transcription factors
— ligand examples:
* estrogens, progestins, androgens, 
glucocorticoids, mineralocorticoids, vitamin D, 
vitamin A (retinoid receptors), fatty acids, etc.
— two main locations in the cell
* cytoplasmic
* nuclear
— ligand-binding and DNA-binding domains
A

Nuclear receptor

24
Q

Of all receptor superfamilies, which one must have ligand get into cell to activate receptor?

A

Nuclear receptor

25
Q

— cytoplasmic
* 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
— nuclear (e.g. fatty acid receptors)
* constitutively present in nucleus
* form heterodimers with Retinoid X Receptor (RXR)
— interact with hormone response elements on genes to regulate gene expression
• Example: Androgen Receptors

A

• Nuclear Receptors (“Steroid Superfamily”)

26
Q

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

A

enzymes

27
Q

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

A

• HMG-CoA Reductase Inhibitors

“Statins”

28
Q

— monoclonal antibodies that recognizes TNF-a

— bind TNF-a removing it from circulation

A

• Infliximab and adalimumab

29
Q
  • important in moving substances across lipid bilayer membranes
  • often good drug targets as they regulate key cellular events
A

Ion and Small Molecule Transporters

30
Q
  • neurotransmitter uptake (norepinephrine, 5-HT, glutamate, etc.)
  • organic ion transporters (organic acids and bases)
  • p-glycoprotein (Multi-Drug Resistance)
A

Small molecule transporters

31
Q

— 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
* could increase absorption of some drugs
* could potentially increase activity of anti-cancer drugs

A

• p-glycoprotein (Multi-Drug Resistance)

32
Q

________ important everywhere
— establishes electrochemical gradient by moving Na+ out and K+ in against concentration gradient
— requires energy (ATP) to function
— key in all muscle contraction, nervous conduction, ion gradient establishment, etc
— often provides the driving force for other ion transporters
— can be inhibited by drugs (e.g. digoxin, a cardiac glycoside used for heart failure)

A

• Na+/K+ ATPase

33
Q 
• structure
— very similar in structure and function 
to ligand-gated ion channel receptors
• Ca++ channels (L, T, N types)
• Na+ channels (fast and slow types)
• K+ channels (voltage- and ligand-
gated types)
— produce at least 9 different K+ currents 
in heart, vascular smooth muscle, and 
other tissues such as pancreas
A

Voltage-Gated Ion Channels

34
Q 
— channels open or close depending upon 
the electrical gradient (voltage) across the 
plasma membrane
* resting membrane potential ~ -90 mV
* depolarized membrane potential ~ 0 mV
— channels change opened/closed or 
activated/resting states as electrical 
potential changes from -90 mV to +10 mV 
(inside relative to outside)
— channels often susceptible to binding by 
various compounds, including xenobiotics
A

• voltage-dependent gated ion channels

35
Q

— Ca++ Channel Blocker
* 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

A

Verapamil

36
Q

______ inhibits
L type Ca channel
reduces heart rate and contractility

A

Verapamil

Pharmacology (12 decks)

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