Calcium channel blockers

[Ref: SH(H)2:p395]

Classification

Phenylalkylamines (selective for AV node)

• Verapamil

Dihydropyrimidine (selective for arterial beds)

• Nifedipine
• Nicardipine
• Nimodipine
• Isradipine
• Felodipine
• Amlodipine

Benzothiazepines (selective for AV node)

• Diltiazem

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

• Slowing of HR
• Reduced myocardial contractility
• Decreased conduction speed at AV node
• Vascular smooth muscle relaxation
  --> Decrease in BP
• May also provide protection against ischaemic reperfusion injury

Comparative effects of calcium channel blockers

• All decrease BP
• HR
  * Decreased HR with verapamil and diltiazem
  * No change or increased HR with nifedipine and nicardipine
• All cause myocardial depression
• SA node
  * SA node depression verapmil and diltiazem
  * No SA node depression with nifedipine and nicardipine
• AV node conduction
  * Markedly depressed with verapamil
  * Moderately depressed with diltiazem
  * No change with nifedipine and nicardipine
• Coronary artery dilation
  * Greatest with nicardipine
  * Marked in nifedipine
  * Moderate with diltiazem and verapamil
• Peripheral artery dilation
  * Marked with nifedipine and nicardipine
  * Moderate with verapamil and diltiazem

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

• Potentiates myocardial depressant effects of anaesthesia
• Potentiates neuromuscular blockade
• Increased risk of local anaesthetic toxicity
  * Verapamil and diltiazem both have LA properties
• Hyperkalaemia
  * Calcium channel blockers slow inward movement of K+
• Dantrolene
  --> Can cause hyperkalaeia
• Platelet function
  * (???)
• Digoxin
  * (???)
• H2 antagonists
  --> May increase plasma level of calcium channel blockers

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,

• Major depressant effects on AV node
• Negative chronotropic effect
• Negative inotropic effect
  * Especially in pre-existing LV dysfunction

Clinical uses

• SVT
• Vasospastic angina pectoris
• Essential HTN
• Hypertrophic cardiomyopathy

NB:

• Post MI mortality is not decreased

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:

• Greater coronary and peripheral arterial vasodilation
• Little to none direct depressant effect on SA or AV node

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

Clinical uses

• Angina pectoris
  * Especially ones associated with coronary artery spasm

Side effects

• Flushing
• Vertigo
• Headache
• Peripheral oedema (venodilation)
• Hypotension
• Paresthesia
• Skeletal muscle weakness
• Hepatic and renal dysfunction (rare)
• Coronary artery vasospasm on abrupt discontinuation

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

• Mainly acts on AV node
• Also a first-line treatment for SVT