How Drugs Act Flashcards
what are the protein targets for drug binding
- receptors
- enzymes
- specific circulating plasma proteins
- carrier molecules
- ion channels
what are the 4 superfamilies of receptos
- ligand gated ion channels
- g protein coupled receptors
- kinase linked and related receptors
- nuclear receptors
describe ligand gated ion channels
- ionotropic
- composed of 4-5 subunits
describe g protein coupled receptors
- metabotropic receptors
- 7 trans membrane spanning domains
- heptahelical receptors
- serpentine receptors
describe kinase linked and related receptors
- large and heterogenous group
- single trans membrane spanning domain
describe nuclear receptors
steroid superfamily
nicotinic acetylcholine receptor subtypes occur in different ______ regions and these differ from subtype in _______
brain; muscle
what are the receptor subtypes
-different genes, different phenotypes
- same gene, different phenotypes
how can there be different genes and different phenotypes
different genes encode for different subtypes
how can there be same gene different phenotypes
- alternative mRNA splicing
- single nucleotide polymorphisms
what does alternative mRNA splicing do
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
splicing has a big role in:
G-protein coupled receptors
what do single nucleotide polymorphisms often result in
different drug receptor efficacy
ligand gated ion channels share structural features with:
voltage gated ion channels
what are examples of ligand gated ion channels
- nicotinic acetylcholine receptor
- gamma- aminobutyric acid type A receptor (GABAa)
- glutamate receptors
what do GABAa receptors do
inhibitory NT
what do glutamate receptors do
excitatory NT
what is the nicotinic acetylcholine receptor made of
pentamer
- 4 different polypeptide subunits
- each subunit crosses plasma membrane 4 times
- 2 alpha, 2 beta, 1 delta, and 1 gamma
what is the mechanism of nicotinic acetylcholine receptors
- acetylcholine binds
- conformational change occurs
- transient opening of central aqueous channel
- Na+ flows from outside to inside cell down electrochemical gradient
- cell depolarizes
what are examples of GPCRs
- muscarinic acetylcholine receptor
- opioid receptors
- GABAb)
- serotonergic receptors
- adrenergic receptors
- angiotensin II receptors
- endothelin receptors
- histamine receptors
- photon receptors
what is the mechanism of GPCRs
- 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
is GTP or GDP higher intracellularly normally
GTP
what are the important things to know about GPCRs
- there is significant signal amplification from one ligand-receptor interaction
- heterogeneity of G proteins allow for substantial diversity in GPCR signaling in various tissues
why is there significant signal amplification from one ligand receptor interaction
activated GTP bound G proteins remain active much longer
what are the agonists of opioid receptors
- heroin
- morphine
- oxycodone
- hydrocodone
what are the competitive antagonists of opioid receptors
- naloxone
- naltrexone
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
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
what does increased dosage of morphine do to respiratory rate
decreases it
what type of receptors are protease activated receptors
GPCRs
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
what are examples of protease activated receptors
- thrombin
- mast cells following degranulation
what receptors are susceptible to desensitization
GPCRs
what are the 2 mechanisms which desensitization occurs
- receptor phosphorylation
- receptor internalization
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
what do single nucleotide polymorphisms do
one amino acid change can result in different phenotypes of receptor
what does cross talk and collaboration between GPCRs occur with?
RTKs
what are kinase linked and related receptors mainly involved with
events controlling cell growth and differentiation
how do kinase-linked and related receptors act
indirectly by regulating gene transcription
what does signal transduction of kinase linked and related receptors involve
dimerization of two receptor molecules followed by autophosphorylation of tyrosine residues
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
what are the 3 major families of kinase linked and related receptors
- receptor tyrosine kinases
- serine/threonine kinases
- cytokine receptors
what domain of RTKs have tyrosine kinase activity
intracellular domain
what are examples of RTKs
- epidermal growth factor receptor
- nerve growth factor
- toll-like receptors
- insulin receptors
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
describe serine/threonine kinases
-smaller group than RTKs
- structurally and functionally very similar to RTKs
- phosphorylate serine and threonine instead of tyrosine
what is an example of a serine/threonine kinase
transforming growth factor (TGF)
what are examples of cytokine receptors
- interleukins
-interferons - chemokines
cytokine receptors lack:
intrinsic enzymatic activity in intracellular domains
what do cytokine receptors do
associate and activate other kinases
what is an example of a cytokine receptor
- JAK binds and activates the Jak-STAT pathway
- downstream turns on or off gene expression
what are ligand examples for nuclear receptots
- estrogens
- progestins
- androgens
- glucocorticoids
- mineralocorticoids
- vitamin D
- vitmain A
- fatty acids
what are the two locations in the cell that nuclear receptors are found
cytoplasmic and nuclear
what are the two types of domains on nuclear receptors
- ligand binding and DNA binding domains
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
describe nuclear receptors in the nucleus
- constitutively present in nucleus
- form heterodimers with RXR
what do nuclear receptors do
interact with hormone response elements on genes to regulate gene expression
what is an example of nuclear receptor
androgen receptor
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
what are the best enzyme drug targets
enzymes that are key rate-limiting steps in biochemical reactions
what is the strategy of enzymes as drug targets
to reduce enzyme activity through drug inhibition
describe non-competitive enzyme inhibitors and give example
drug may covalently modify the enzyme
- ex: aspirin acetylates cyclooxygenase
describe competitive enzyme inhibitors and give example
- drug is often a structural analog of the natrually occurring substrate
- ex: HMG-CoA reductase inhibitor
what is the classic HMG-CoA reductase inhibitor
Statins
what do statins do
competitively inhibit rate limiting step in cholesterol biosynthesis in liver
- liver upregulates LDL receptors thereby reducing plasma LDL concentrations
what is the statin we need to know
lovastatin
lovastatin acts on what rate limiting stp
mevalonate formation
what circulating plasma protein causes disease and/or symptoms
tumor necrosis factor alpha (TNF alpha)
TNF alpha is elevated in:
RA, crohn’s disease, psoriasis, ankylosing spondylitis
- in severe cases of aphthous ulcers
lowering TNF alpha in RA and Crohns does what?
decreases symptoms and may delay progression
what are the monoclonal antibodies that recognize, bind and remove TNF alpha from circulaiton
infliximad and adalimumbad
what does etanercept do
soluble TNF alpha receptor that binds and decreases TNF alpha
what antibody binds IL2
daclizumab
what antibody binds IL5
mepolzumab
why are carrier molecules good drug targets
they regulate key cellular events
what are the small molecule transporters
- NT uptake
- organic ion transporters
- p-glycoprotein
what does p-glycoprotein do
protective role in moving potential toxicants out of GI epithelial cells back into lumen to prevent absorption
what drug blocks p-glycoprotein
verapamil
why do you want to block p-glycoprotein
- could increase absorption of some drugs
- could potentially increase activity of anti-cancer drugs
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
what drug inhibits Na+/K+ ATPase
digoxin
what are the types of voltage gated ion channels
- Na+ channels
- Ca2+ channels
- K+ channels
what are the types of Ca2+ channels
- Long
- Transient
- Neuronal
what are the types of Na+ channels
fast and slow types
what are the types of K+ channels
voltage and ligand gated types
what is the resting membrane potential in voltage gated ion channels
-90mV
what is the depolarized membrane potenital in voltage gated ion channels
0 mv
what type of drug is verapamil
Ca++ channel blocker
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
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
what does ATP stand for
adenosine trophosphate
what does RyR stand for and what type of channel is this
- ryanodine receptor
- ligand activated calcium channel
what does CICR stand for
calcium induced calcium release
what does SERCA stand for
sarcoplasmic/endoplasmuc reticulum Ca2+ ATPase
what happens during the P wave
atrial depolarization
what happens during the T wave
ventricular repolarization
what happens during the QRS complex
ventricular depolarization
what do calcium channel blockers do
- reduce calcium influx into the cardiac muscle reducing intracellular calcium and force of contraction
- negative ionotropic effect
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
