Calcium Channel Blockers Flashcards by Brooke Thornburg

ion channels

-proteins that form pores in plasma membrane
-gating, ion selectivity, pharamacology categorization
-passive - allows ions to flow down gradient

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ion channel flow

-determined by concentration gradient or electrical gradient

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Membrane potential

-excitable cells have neg inward potential across membrane bc selective permeability of resting membrane to K+
-K+ high inside
-Na+ low inside

-free Ca2+ very low inside and very high outside (15,000 fold difference)

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membrane potential gradient maintained by

-active transport of Na+ out and K+ in
-channels that seletively let K+ out of cell at voltages near resting membrane potential

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Nerst equation

-membrane potential (Emem)
- -98mV at 37degreesC

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Membrane potential at rest

-set by K+ permeability
-neg ions do NOT cross membrane
-K+ going in and out in equilibrium, only K channels open
-resting negative potential

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Effect of ions on membrane potential

-Increases as sodium moves in
-Ca channels maintain membrane potential more positive while Na closes (=plateau = contraction)
-K+ decreases it back to -93mV

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structure of voltage gated channels (Kcsa)

-selectivity filter outside
-gate inside
-Kcsa is H+ gated K+ channel from bacteria
-closed when helices at gate are crossed

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structure of voltage gated channels (MthK)

-ca2+ gated K channel
-similar to Kcsa
-selectivity filter and gate
-crystalized in presence of Ca2+
-hinge point

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structure of voltage gated channels (KvAP)

-4 subunits
-positively charged residues
-senses membrane potential
-if inside neg = inward pull = closed
-if inside less negative = move upward and outward = open

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Voltage gated Ca2+ channel family

Cav 1.1-1.3
-Cav2.1-2.3

-1.3, 2.1-1.3 neurons
-1.1 skeltal muscle
-1.2 cardiac

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Cav1.2

-L-type voltage-gated ion channel
-cardiac, smooth muscle
-Ca2+ entry triggers contraction

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Block of channels in smooth muscle

-vasodilation
-dec blood rpessure
-relieve angina

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Block of channels in cardiac muscle and SA/AV node

-antiarryhmic

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Vasc and smooth muscle contraction

-Ca induced Ca release (CICR)
-Ca influx via 1.2 induces Ca release from intracellular stores via RYR2 in the SR (release to cytoplasm, doesnt leave cell)
-extracellular Ca required for contraction

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Vasc smooth muscle contraction mech

-Ca2+ channels (L-type)
-inc Ca concentration from intracellular stores
-Ca calmodulin inc
-myosin LC kinase
-myosin LC-PO4 + actin
=contraction

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Cardiac muscle contraction

-Ca ions from SR bindtroponin C
=displacement of tropomyosin
=allows myosin to bind actin
=contraction

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Skeletal muscle contraction

-mechanical coupling btween Cav1.1 and RYR1
-extracellular Ca not required
-CCBs dont interfere here
-triad in t-tubule physically linked

CCB chemical classes

-dihydropyridines
-phenylalkylalmines
-benzothiazepines

Dihydropine CCBs structure

-dihydopyridine ring (2 double bonds and nitrogen and aryl group)

Dihydropyridine members CCBs

-nifedipine (Procardia) (no chiral center)
-Isradipine (DynaCirc)
-Felodipine (plendil)
-Amlodipine (Norvasc)
-nisoldipine (sular)
-Nimodipine (nimotop) (prevent neuropathies good brain penetration)
-Nicardipine (Cardene)

-Clevidipine (Cleviprex)

Amlodipine structure

-primary amine off of ether
=longer action

Nifedipine structure

-no chiral center
-shorter duration
-bind and unbind quickly
-watch reflex tachycardia

Clevidipine (Cleviprex

-designed to fall apart
-short duration
-1-15min t1/2
-IV infusion to tx HTN when PO admin not favored
-formulated w soy and egg lipids

Clevidipine metabolism

-esterases -first cleavage product still blocks channels -second cleavage product inactive

Dihydropyridine mech

-guessing from enatiomers -interference w gating -(+) blocks current, interferes opening -(-) potentiates current, interferes closing

Tissue selectivity of dihydropyridines

-more potent in relaxing smooth muscle (esp coronary artery) -do not compromise cardiac function -not antiarrhytmic -vascular over cardiac

vascular tissue selectivity of CCBs is result of

-amino acid differences in channel splice variants -differences in membrane potential properties

characteristics of dihydropyridine block

-voltage-dependence -affinity of drug for channel is different at different voltages -allosteric binding site -bind closed channels to prevent opening = tonic block -no frequency dependence -MARKED tonic block

Clinical considerations for DHPs (vascular selectivity)

-dec in peripheral resistance -dilation of artioles -dec afterload -little effect of HR or CO -nisol-, felo-, nicar-, isra-, amlo-, nifedipine all vasoselective -nimodipine selective in cerebral arteries - use in hemorrhage to prevent neuropathy -reflex tachycardia secondary to vasodilation except amlodipine

DHP considerations

-vascular selectivity -reduce oxygen demand in heart (efficacy in angina) -nifedipine only one that depresses cardiac function -may inhibit artherosclerosis

DHP PK factors

-all DHPs bound to serum proteins -undergo first pass metbolism in liver -amlodipine has slow onset and long duration

Nifedipine

-inc risk of subsequent MI? -prompt release may inc risk of heart attack -rapid decrease in BP can lead to reflex tachycardia

Phenylalkylamine class drug

-Verapamil (Calan, Isoptin)

Verapamil

-vasodilation but less potent than DHPs -slows conduction through SA and AV nodes (reduce HR and force of contraction) -reflex tachycardia is blunted -works via frequency dependent block

Verapamil mech

-freq dependent block =channel has to open for drug to enter pore -binds IN pore -very little tonic block

Benzothiazepine class drug

-Ciltiazen (Cardizem)

Diltiazem clinical considerations

-causes vasodilation less potent than DHPs -slows conduction through SA and AV nodes -initial reflex tachycardia -directly inhibits heart less than verapamil but more than DHPs -some freq dependent block of Ca and some tonic block

Diltiazem mech

-some tonic block -some frequency block -bind in pore kind of

summary of DHP effects

-inc HR -most vasodilation

summary of verapamil effects

-DEC HR -DEC AV and myocard contraction -inc vasodilation

Diltiazem summary

-dec HR -dec AV cond, myocard contract -inc vasodilation but just a lil

CCB side effects

-ankle edema -constipation (verapamil) -facial flushing (DHPs) -tachycardia (DHPs)