Calcium channel blockers bind to receptors on voltage-gated Ca2+ channels
* L, N, T subtypes
--> Keeps these channels in an inactive (closed) state
--> Decreased intracellular [Ca2+]
All clinically useful calcium channel blockers
--> Binds to alpha1 subunit of L-type Ca2+ channel
--> Decreased Ca2+ influx into cells
--> Shorter phase 2 of the cardiac action potential
Verapamil and diltiazem acts
* Mainly on the SA and AV node
* Also some effects on the arteries
Nifedipine and nicardipine
* Greater effects on peripheral and coronary arterdies
* No effects on the SA and AV nodes (and thus HR, except for (???) reflex tachycardia)
Safety may be in question
Possible increased risk of cardiovascular risk and cancer
Synthetic derivative of papaverine (an opium extracted smooth muscle relaxant, unrelated to morphine)
Used as racemic mixture
Dextroisomer
* No effect on slow calcium channels
* Acts on fast sodium channels
--> Responsible for the local anaesthetic effect
Levoisomer
* Acts on slow calcium channels
* Effect dominates the effect of dextroisomer
Overall,
NB:
Protein binding = 83-93%
* Low protein binding in comparison with nifedipine, nicardipine, and diltiazem
IV
* Dose = 75-150microgram/kg
* Onset = 1-3min
PO
* Dose = 80-160mg/kg Q8H
* Onset < 30 minutes
* High absorption (>90%)
* High first-pass hepatic extraction (75-90%)
* Low bioavailibility (10-20%)
Elimination half-time = 3-7 hours
* May last 6 hours
Renal clearance = 70%
Hepatic clearance = 15%
Metabolite = norverapamil
* Active
* Contributes to the antiarrhythmic property
Primary affinity for peripheral arterioles
Minimal dilation effects on venous capacitance vessels
Nifedipine has:
Overall, due to decreased BP
--> Increased peripheral sympathetic nervous system activity
--> Reflex tachycardia
Protein binding = 92-98%
PO
* Dose = 10-30mg Q8H
* Onset <20min
* High absorption (>90%)
* Moderate first-pass hepatic extraction (40-60%)
* Bioavailability = 65-70%
S/L
* Onset = 3min
IV
* Dose = 5-15microgram/kg
* Onset < 1-3min
Elimination half-time = 3-7 hours
Renal clearance = 80%
Hepatic clearance < 15%
Metabolite is inactive
Greatest vasodilating effect of all calcium channel blockers
* Especially in coronary artery
Highly lipid-soluble
--> Greater entry into CNS
Used in patients with subarachnoid haemorrhage
* Stops cerebral vasospasm
May also have a role in cerebral protection after global ischaemia (in cardiac arrest)
Only oral formulation available
Minimal effect on myocardial contractility
Anti-ischaemic effect in acute coronary syndrome
* Comparable to beta-blockers
Similar to verapamil