CALCIUM CHANNEL BLOCKERS AND AEC INHIBIORS ANAESTHETIC IMPLICATIONS

CALCIUM CHANNEL BLOCKERS Are a diverse group of structurally unrelated compounds that selectively interferes with the inward calcium movement across the myocardial and vascular smooth muscles. Calcium plays a key role in the electrical excitation of the cardiac cell and vascular smooth muscle cells.

Introduction

Role of Ca⁺⁺ in Cardiac and Smooth Muscle

• Changes in intracellular Ca⁺⁺ regulate contraction through different mechanisms in cardiac and smooth muscle:
  • In cardiac muscle, Ca⁺⁺ binding to troponin C relieves troponin inhibition of actin-myosin interactions
• In smooth muscle, Ca⁺⁺ binding to calmodulin activates myosin light chain kinase which in turn phosphorylates the P-light chain of myosin. This triggers contraction (i.e.- actin-myosin interactions), but there appear to be additional Ca⁺⁺ regulatory mechanisms
• There are a variety of ion pumps, channels, and exchangers that are directly involved in controlling intracellular Ca⁺⁺, thus many possible sites for therapeutic agents to act

Regulation of Intracellular (Cytoplasmic) Ca⁺⁺ Concentration

• At rest, the cytoplasmic free Ca⁺⁺ concentrations are normally maintained at very low concentrations (<100 ca="" nm="" relative="" sup="" the="" to="">++

concentrations found extracellularly (> 1 mM)

Molecular Structures Involved in Ca⁺⁺ Regulation

• The cell membrane has a low natural permeability to divalent cations and Ca entry in to the cell can occur only through ion specific channels.
• Molecular structures in the plasmalemma/sarcolemma that regulate Ca⁺⁺ influx:
  • Plasmalemmal Ca⁺⁺-channels allow extra cellular Ca⁺⁺ to enter cells and fall into 3 major categories: voltage-dependent, receptor-operated, and stretch-operated

Voltage (potential)-dependent Ca⁺⁺-channels (homologous to Na⁺- and K⁺-channels, they consist of at least three types in the body: L, T, and N, and possibly a P-type)

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  • L-type channels: So named because they are long acting. Large sustained conductance, inactivate slowly, widespread in cardiovascular system, are responsible for plateau phase (slow inward current) of action potential, may trigger release of internal Ca⁺⁺, sensitive to Ca⁺⁺-channel blockers, cardiac L-channels are regulated by cAMP-dependent protein kinase (phosphorylation enhances probability of channel opening at a given membrane potential)
  • T-type channels: Structurally similar to L-type channels; inactivate rapidly; highest abundance in cardiac cells that lack a T-tubule system (SA nodal tissue); involved in cardaic pacemaker activity, growth regulation, and triggering contraction in vascular smooth muscle; low abundance in adult ventricular myocardium
  • T-type channels are not very sensitive to most of the L-type Ca⁺⁺-channel blockers (mibefradil being the exception)
  • N-type channels: Appear to be found only in neuronal cells, and are not very sensitive to the Ca⁺⁺-channel blockers used for treating cardiovascular disorders
  • P-type channels are seen in purkinje cells.
• Volatage gated Calcium Channels(VOCC)
  • They have five subunits, a1, a2, b,g,d – a1 forms the channel pore a2 and d are joined by a disulphide bridge. A1 and b subunits have sites for cAMP dependent protein kinase phosphorylation.

Receptor-operated Ca⁺⁺-channels (e.g. alpha₁-adrenergic receptors): Not very sensitive to Ca⁺⁺-channel blockers "Stretch"-operated or "leaky" Ca⁺⁺-channels – Otherwise called store operated channels.they are operated through a mechanism called as capacitative Ca entry. There is no Ca entry when the stores are filled but the Ca enters the cell when the stores are empty.(may be important in maintaining vascular smooth muscle tone): Do not appear to be sensitive to Ca⁺⁺-channel blockers Molecular structures in the plasmalemma responsible for Ca⁺⁺ efflux:

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  • Ca⁺⁺-pumps (ATPases): Operated through a mechanism known as capacitative Ca entry.there is no Ca entry when the stores are filled but Ca enters when the stores are empty.Actively extrude Ca⁺⁺ against a large gradient; some forms of this enzyme are calmodulin-regulated
  • Na⁺/Ca⁺⁺-exchanger (3Na⁺ / 1Ca⁺⁺): A major mechanism for removal of cytoplasmic calcium in myocardium; rate of Ca⁺⁺ efflux depends upon Na⁺ gradient across plasmalemma

Intracellular molecular structures involved in regulating cytoplasmic Ca⁺⁺:

• Molecular structures in the sarcoplasmic/endoplasmic reticulum (SR), an important intracellular site for sequestration and rapid release of Ca⁺⁺
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    • Ca⁺⁺ release channels: IP₃-sensitive, Ca⁺⁺-sensitive, ryanodine-sensitive
    • Ca⁺⁺-ATPases (pumps): Responsible for resequestration of Ca⁺⁺
• Molecular structures in the mitochondria, a slowly exchanging Ca⁺⁺ reservoir
  • Ca⁺⁺ uniporter: Ca⁺⁺ uptake is driven by proton extrusion
  • Electroneutral Na⁺/Ca⁺⁺ exchanger

Sites of Ca⁺⁺-Channel Blocker Action

• The conventional channel blockers bind to L-type channels ("slow channels") which are abundant in cardiac and smooth muscle (which may partially explain rather selective effects on the cardiovascular system)
  • Different classes of L-type Ca⁺⁺ channel blockers bind to different sites on the alpha₁-subunit
  • Different sub-classes of L-type channel exist which may contribute to tissue selectivity
• Newer calcium channel blockers with different specificities have also been developed:
  • Bepridil, a drug with Na⁺ and K⁺ channel blocking activites in addition to L-type channel blocking activities
  • Mibefradil, a drug with T-type calcium channel blocking activity as well as L-type calcium channel blocking activity

Chemistry of Ca⁺⁺ Channel Blockers

• Five major classes of Ca⁺⁺ channel blockers are known with diverse chemical structures:

1. Benzothiazepines: Diltiazem
2. Dihydropyridines: Nicardipine, nifedipine, nimodipine and many others
   • There are also dihydropyridine Ca⁺⁺-channel activators (Bay K 8644, S 202 791)
3. Phenylalkylamines: Verapamil
4. Diarylaminopropylamine ethers: Bepridil
5. Benzimidazole-substituted tetralines: Mibefradil

Mechanism of Action Phenylalkylamines bind to the intracellular portion of the alpha1 subunit of the L type channel and physically occlude the channel. Dihydropyridines – prevent Ca entry in to the vascular smooth muscle by an allosteric modulation of the L type voltage gated calcium channels. Benzothiazepines – act at the L type alpha1 subunit. Mechanism of action is less well understood. It has two additional actions

1. May act on the Na/K pump decreasing the amount of intracellular sodium available for exchange with extra cellular calcium.
2. Inhibit the Ca calmodulin binding.

Pharmacology of Ca⁺⁺ Channel Blockers

Effects on Vascular Smooth Muscle

• L-type Ca⁺⁺ channel blockers inhibit L-type voltage-dependent Ca⁺⁺ channels
• T-type Ca⁺⁺ channel blockers inhibit T-type voltage-dependent Ca⁺⁺ channels
• Little or no effect of Ca⁺⁺ channel blockers on receptor-operated channels or on release of Ca⁺⁺ from SR
• "Vascular selectivity" is seen with the Ca⁺⁺ channel blockers
  • Decreased intracellular Ca⁺⁺ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure)
  • Little or no effect of Ca⁺⁺-channel blockers on venous beds -> no effect on cardiac preload (ventricular filling pressure)
  • Specific dihydropyridines may exhibit greater potencies in some vascular beds (e.g.- nimodipine more selective for cerebral blood vessels, nicardipine for coronary vessels)
  • Little or no effect on nonvascular smooth muscle (e.g. -tracheal smooth muscle)

Effects on Cardiac Cells

Magnitude and pattern of cardiac effects depend on the class of Ca⁺⁺ channel blocker

• Negative inotropic effects are seen with some of the L-type channel blockers (a direct effect on myocardial L-type channels):
  • The negative inotropic effect is due to reduced inward movement of Ca⁺⁺ during the action potential plateau phase (due to inhibition of slow (L-type) channel)
  • Dihydropyridines have very modest negative inotropic effects
  • Mibefradil (a T-type channel blocker) has no negative inotropic effects because there are only a few T-type channels in adult ventricular muscle
• Negative chronotropic/dromotropic effects (pacemaker activity/conduction velocity leading to bradycardia) are also seen with some of the Ca⁺⁺ channel blockers
  • Verapamil (and to a lesser extent diltiazem) decrease the rate of recovery of the slow channel in AV conduction system and SA node, and therefore act directly to depress SA node pacemaker activity and slow conduction
    • Ca⁺⁺-channel block by verapamil and diltiazem is frequency- and voltage-dependent, making them more effective in cells that are rapidly depolarizing
  • Mibefradil has negative chronotropic and dromotropic effects
  • Nifedipine and related dihydropyridines do not have significant direct effects on the atrioventricular conduction system or sinoatrial node at normal doses, and therefore do not have direct effects on conduction or automaticity
    • The dihydropyridines can cause reflex increases in heart rate because of their potent vasodilating effects

Hemodynamic Effects

• All of the clinically-approved Ca⁺⁺-channel blockers:
  • Decrease coronary vascular resistance and increase coronary blood flow
  • Decrease peripheral resistance via vasodilatation of arterioles
  • Are without significant effect on venous tone at normal doses

Drug-Specific Effects

• Verapamil  - is the synthetic derivative of papaverine
• Supplied as recemic mixture.
• D- isomer – no activity on slow channels. Acts on fast sodium channels leading to local anaesthetic effect.
• L-isomer – slow channel blockers.
  • At doses that cause peripheral vasodilatation, verapamil has greater direct negative chronotropic, dromotropic (conduction), and inotropic effects than the dihydropyridines
  • The drug's direct negative chronotropic and dromotropic effects are able to overcome any reflex sympathetic response to the lowering of blood pressure, resulting in a drop in heart rate
  • The drug's direct negative inotropic effects can also overcome the reflex sympathetic response, resulting in a lowering of myocardial contractility
  • In patients with left ventricular dysfunction where sympathetic tone may already be high, the drug can can cause a dangerous decrease in contractility
• Dihydropyridines (e.g. nifedipine, nicardipine, and nimodipine)
  • Vasodilatation of arterial resistance vessels causes a reflex increase in sympathetic response
    • Because the dihydropyridines have very weak effects on the SA node and AV junction, there is an increase in heart rate due to the increase in sympathetic tone
    • Any weak direct negative inotropic effect of the drug is overwhelmed by the strong reflex sympathetic response
  • The overall hemodynamic effect is a drop in blood pressure, an increase in heart rate and contractility, and an increase in cardiac output
• Diltiazem
  • The hemodynamic effects of diltiazem are intermediate between the dihydropyridines and verapamil
  • The drug causes a modest lowering of heart rate and modest decrease in myocardial contractility, both of which are less than verapamil for a given drop in blood pressure
• Mibrefradil
  • This agent is a potent peripheral and coronary vasodilator. Its chronic effects on blood pressure, heart rate, and cardiac conduction velocity (PQ interval) are comparable to those of verapamil and diltiazem
  • In contrast to verapamil and diltiazem, this agent appears to have negligible negative inotropic effects
  • In contrast to the dihydropyridines, reflex tachycardia does not occur with mibefradil
  • This drug was voluntarily withdrawn from the market by Roche on June 8, 1998 less than one year after its introduction due to interactions with a variety of commonly used drugs

Table 1. Relative Cardiovascular Effects of Prototypical Calcium Channel Blockers (adapted from Goodman and Gilman (9th ed.) and Massie, Am. J. Cardiol. 80(9A)23I-32I(1997)).

The relative effects are ranked from no effect (0) to most prominent (+++++). Effects indicated in parentheses are estimated effects.

Pharmacokinetics

• All clinically-approved compounds are available for oral administration
  • Verapamil is also available for i.v. administration for interrupting supraventricular arrhythmias
• Absorption is nearly complete after oral administration
• Bioavailability is reduced because of first-pass hepatic metabolism
• There is significant binding of all channel blockers to plasma proteins (70-99%)
• Therapeutic effects are evident within 30-60 min after oral dose; peak effects within 15 min i.v.
• Typical plasma half-life is 1.5 to 6 hours (24-40 hours for bepridil, some of the newer dihydropyridines, and mibefradil)
  • Half-lifes may increase with repeated oral dose due to hepatic saturation
  • Longer half-lifes for elderly patients and patients with hepatic cirrhosis or renal insufficiency
• Verapamil, diltiazem, and possibly nicardipine inhibit hepatic enzymes
• Metabolism of verapamil, diltiazem, and nifedipine is inducible
• Diltiazem and verapamil have vasodilatory metabolites; dihydropyridines do not

Toxicities and Side Effects

• The calcium channel blockers are generally well-tolerated
• The most common side effects, particularly with dihydropyridines, are due to excessive vasodilatation (i.e.- dizziness, hypotension, headache, flushing, edema, etc.)
• Aggravation of myocardial ischemia has been reported, perhaps due to excessive hypotension resulting in decreased coronary perfusion, selective vasodilation in non-ischemic regions ("coronary steal"), and increased oxygen demand due to reflex tachycardia
  • Because of lower capacity to induce excessive peripheral arterial dilation and reflex tachycardia, verapamil and diltiazem are less likely to aggravate myocardial ischemia
• Serious toxic effects (bradycardia, transient asystole, exacerbation of heart failure) are rare and usually occur under specific conditions:
  • After i.v. administration of verapamil
  • During concurrent channel blocker/beta-adrenergic blocker administration
  • i.v. verapamil is specifically contraindicated in combination with beta-blockers due to the possibility of AV block or severe depression of ventricular function
  • Patients with moderate to severe ventricular dysfunction, SA node or AV conduction disturbances, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem
• Some channel blockers (e.g. - verapamil) can cause an increase in plasma digoxin levels and are therefore contraindicated for use in treating digitalis toxicity; AV block can also occur with concurrent treatment with channel blockers and digitalis
• Though mibefradil was found to be safe and well-tolerated when used alone, it inhibits the P-450 enzyme CYP 3A4 and thus can interfer with the metabolism of at least 26 other drugs, including certain HMG-CoA reductase inhibitors and other calcium channel blockers. When used in combination with other heart-rate lowering drugs such as beta-blockers, severe bradycardia could occur. Due to the difficulties in avoid these serious drug interactions, mibefradil was thus withdrawn from the market .

Therapeutic Uses of Ca⁺⁺-Channel blockers

The primary indications for the Ca⁺⁺-channel blockers are angina, arrhythmias, and hypertension:

Angina

Variant (vasospastic, Prinzmetal's) angina: This syndrome is a direct result of reduction in coronary flow, not an increase in myocardial oxygen demand

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  • Channel blockers are effective in treating variant angina due to their effects on coronary dilatation rather than alterations in peripheral hemodynamics
  • Verapamil, nifedipine, nicardipine, bepridil, and diltiazem are all effective
• Exertional (exercise-induced) angina, angina of efffort: Usually due to fixed coronary vascular obstruction (surgical revascularization or angioplasty may be beneficial)
  • Therapeutic effect is due to increased coronary blood flow, and/or decreased myocardial oxygen consumption (secondary to decreased peripheral resistance, heart rate and contractility); the latter effect is thought to be more important
  • In some patients, channel blockers, particularly dihydropyridines, may aggravate anginal symptoms due to reflex increase in sympathetic tone, decreased coronary perfusion pressure, or coronary steal; not usually seen with verapamil or diltiazem
  • Concurrent therapy with beta-adrenergic blockers and/or nitrates can be more effective than individual agents alone:
    • Beta-adrenergic blockers suppress reflex tachycardia (and have negative dromotropic, chronotropic, and inotropic effects which reduce oxygen consumption)
    • Dihydropyridines will not enhance dromotropic effects of beta-blockers; concurrent treatment with verapamil or diltiazem is effective, but can lead to AV block, severe bradycardia, and decreased ventricular function
  • Nitrates cause venous dilation and reduce cardiac preload (channel blockers have no effect on venous return at normal doses)
• Unstable (preinfarction, crescendo) angina: Recurrent angina associated with minimal exertion; prolonged and frequent pain; ECG patterns indicate myocardial damage; coronary flow is severely restricted and vasospasm occurs in some patients; thought to be due to fissuring of atheroscelortic plaques and subsequent platelet aggregation
  • Usual therapy includes nitrates and beta-blockers which primarily act to reduce oxygen consumption and thereby control pain, and long-term use of aspirin to reduce possibility of thrombosis (inhibition of platelet aggregation)
  • Ca⁺⁺ channel blockers (especially verapamil) may be particularly effective if underlying mechanism involves vasospasm

Arrhythmias

• i.v. verapamil (followed by oral administration) is a drug of choice for interrupting and controlling paroxysysmal supraventricular tachycardias (i.e. -- originating from ectopic foci in atrial or junctional tissue)
  • Verapamil (i.v.) is useful in the immediate reduction of ventricular response in response to atrial fibrillation and flutter (except when associated with Wolff-Parkinson-White syndrome, a conduction abnormality)
    - Contraindicated for atrial tachycardia caused by digitalis toxicity because of pharmacokinetic interactions that might lead to increased digoxin blood levels
    - Can cause severe hypotension or ventricular fibrillation in patients with ventricular tachycardia (due to reflex increase in sympathetic tone); verapamil is rarely useful in treating ventricular arrhythmias
• Diltiazem and bepridil are currently being evaluated for use in treating arrhythmias and appear to be similar in efficacy to verapamil
• Bepridil may also be useful in treating ventricular arrhythmias because of its ability to also block Na⁺ and K⁺ channels (but can lead to the proarrhythmia, torsades de pointes)

Hypertension

• The calcium channel blockers are generally safe and are as effective as beta-adrenergic blockers or diuretics in the treatment of mild to moderate hypertension
• Calcium channel blockers are especially effective in treating low-renin hypertension (common in blacks and the elderly)
• Channel blockers are well-tolerated; minor side-effects include dizziness, headache, flushing, and edema and are most usually associated with the dihydropyridines
• The use of L-type channel blockers should be avoided in patients with SA or AV nodal abnormalities or in patients with overt congestive heart failure
• Efficacy can be enhanced by combination with other types of antihypertensives, but specific drug combinations should be avoided:
  • Diltiazem or verapamil with beta-adrenergic blockers (can lead to AV block, cardiac depression, bradycardia)
  • Ca⁺⁺ -channel blockers with quinidine (reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes)
  • Verapamil with digoxin (can increase levels of digoxin, possible AV block)

Less Common/Experimental Uses of Calcium Antagonists

• Subarachnoid hemorrhage (nimodipine)
• Treatment of migraine (nimodipine, nifedipine)
• Raynaud's phenomenon (nifedipine, diltiazem)
• Posthemorrhagic cerebral vasospasm (nimodipine)
• Inhibition of platelet aggregation (unknown mechanism)
• To slow development of atherosclerosis (mechanism unknown)
• Hypertrophic cardiomyopathy (nifedipine, verapamil)
• Postinfarct tissue preservation

Anaesthetic Implications Calcium channel blockers are important to the anaesthesiologist because of the various drug interaction it can cause with the anaesthetic drugs. Myocardial depression ad peripheral vasodilation produced by volatile anaesthetics could be exaggerated by similar action of calcium channels blockers. The adverse effects seem to be greater in patients with pre  existing AV block or LVdysfunciton. Calcium channel blockers may potentiate neuromuscular blocking drugs, nevertheless, treatment with CCBs can be continued until the time of surgery without risk of significant drug interactions. Volatile anaesthetics have blocking effects on calcium channel. Also the similar actions of CCBs and volatile anaesthetics in producing myocardial depression, negative inotropy, depression of SA and AV node and peripheral vasodilation make them use with caution in patients with LV dysfunction or hypovolemia. Because of the tendency to produce AV block, verapamil should be used cautiously in patients being treated with digitalis or beta blockers. Calcium Channel blockers do not produce skeletal muscle relaxant effects. But the drug potentiate the effect of both depolarizing and non depolarizing muscle relaxants. Antagonism of neuromuscular blockade may be impaired because of diminished presynaptic release of acetyl choline in the presence of CCB.

• Verapamil has local anaesthetic property, this may increase the risk of  local anaesthetic toxicity when segmental anaesthesia is administered to patient being treated in this way.
• CCB slow the inward K+ ion movement, so hyperkalemia may occur in these patients following infusion of K+ containing solutions or administration of stored blood.
• CCBs may interfere with Ca mediated platelet function.
• CCBs may increase the plasma concentration of digoxin by decreasing its plasma clearance.

Treatment of Ca channel blocker toxicity
When there is significant hypotension –------ vasopressors
Significant reduction in heart rate--------------Isoprenaline or dopamine
AV block ----------------------------------------Cardiac Pacing ..