1. Pharmacology
        1.4. Cardiovascular drugs
1.4.4. Calcium channel blockers

Calcium channel blockers

[Ref: SH(H)2:p395]

Classification

Phenylalkylamines (selective for AV node)
Dihydropyrimidine (selective for arterial beds)
Benzothiazepines (selective for AV node)

Mechanism of actions

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

Actions

Comparative effects of calcium channel blockers

Summary

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)

Drug interactions

Chronic treatment

Safety may be in question

Possible increased risk of cardiovascular risk and cancer

Phenylalkyamine

Verapamil

Synthetic derivative of papaverine (an opium extracted smooth muscle relaxant, unrelated to morphine)

Used as racemic mixture

Actions

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,

Clinical uses

NB:

Pharmacokinetics

Protein binding = 83-93%
* Low protein binding in comparison with nifedipine, nicardipine, and diltiazem

Administration

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

Elimination half-time = 3-7 hours
* May last 6 hours

Renal clearance = 70%

Hepatic clearance = 15%

Metabolism

Metabolite = norverapamil
* Active
* Contributes to the antiarrhythmic property

Dihydropyrimidine

Primary affinity for peripheral arterioles

Minimal dilation effects on venous capacitance vessels

Nifedipine

Compared to verapamil

Nifedipine has:

Overall, due to decreased BP
--> Increased peripheral sympathetic nervous system activity
--> Reflex tachycardia

Clinical uses

Side effects

Pharmacokinetics

Protein binding = 92-98%

Administration

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

Elimination half-time = 3-7 hours

Renal clearance = 80%

Hepatic clearance < 15%

Metabolism

Metabolite is inactive

Nicardipine

Greatest vasodilating effect of all calcium channel blockers
* Especially in coronary artery

Nimodipine

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)

Amlodipine

Only oral formulation available

Minimal effect on myocardial contractility

Anti-ischaemic effect in acute coronary syndrome
* Comparable to beta-blockers

Benzothiazepines

Diltiazem

Similar to verapamil

 

 

 

 

 

 



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