Calcium Channel Blockers Flashcards
ion channels
-proteins that form pores in plasma membrane
-gating, ion selectivity, pharamacology categorization
-passive - allows ions to flow down gradient
ion channel flow
-determined by concentration gradient or electrical gradient
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)
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
Nerst equation
-membrane potential (Emem)
- -98mV at 37degreesC
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
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
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
structure of voltage gated channels (MthK)
-ca2+ gated K channel
-similar to Kcsa
-selectivity filter and gate
-crystalized in presence of Ca2+
-hinge point
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
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
Cav1.2
-L-type voltage-gated ion channel
-cardiac, smooth muscle
-Ca2+ entry triggers contraction
Block of channels in smooth muscle
-vasodilation
-dec blood rpessure
-relieve angina
Block of channels in cardiac muscle and SA/AV node
-antiarryhmic
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
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
Cardiac muscle contraction
-Ca ions from SR bindtroponin C
=displacement of tropomyosin
=allows myosin to bind actin
=contraction
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)
