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The calcium channel blockers: PHARMACOLOGY AND CLINICAL APPLICATIONS No group of drugs has progressed so quickly from the phase of basic and clinical investigation to the stage of general clinical use in cardiovascular disorders as the calcium channel blockers, Since the introduction of perhexiline maleate as an effective agent in vasospastic angina in 1975, we have witnessed the investigation, approval and competitive release of nifedipine, verapamil and diltiazem. All are available for the treatment of patients with obstructive and vasospasfic forms of angina and in various other cardiovascular disturbances. Several congeners of these drugs are also under various stages of investigation. The concept of slow-channel inhibition has provided a new approach to the therapy of several cardiovascular disorders and has clarified possible new pathogenic mechanisms of myocardial isehaemia. Indications and directives for the use of these agents in clinical practice have been based on relatively small numbers of studies, as well as on extrapolation to the clinical situation of observations gathered from bench experiments in intact and isolated tissuc preparations. As clinical use of these drugs continues to expand in the reality of clinical practice, some of the early concepts relating to the pharmacology of these drugs may change. Unexpected side-effects may also become apparent, modifying our initial enthusiasm as well as clarifying the indications for their use. Basic considerations The calcium ion plays a key role in the contraction of both types of muscle and in the regulation of electrical activity of cardiac muscle and specialized conducting tissue. In the resting stage, the regulatory protein tropomyosin prevents the interaction of the contractile proteins acdll and myosin. Calcium plays an essential role in the steps linking electrical depolarization of the cell to its subsequent contraeCANANAESTHSOC J 1983 / 30:3/ppS5-Sl0

Henry F. Mizgala MD

tion. When a muscle cell is stimulated, an action potential results which is the result of multiple ionic fluxes across the cell membrane. Phase O, or the upstroke of the action potential, is caused by the rapid depolarization of the cell, generated by sodium ion influx through the fast channels. During phases 1 and 2, representing the beginning of repolarization, calcium and to a very small extent sodium ions flow through the slow channels. Phase 3 is repolarization and this results from potassium ions moving out of the cell, by virtue of the concentration gradient. Phase 4 represents the resting membrane potential and is generated by the active pumping of sodium out of the cell, in exchange for potassium. During phases 1 and 2 of the action potential the transmembrane calcium current triggers the release of further quantities of calcium stored in the sareoplasmic reticulum. As the concentration of calcium ion in the cytoplasm reaches a critical concentra~ion of 10-r M, calcium binds to the regulatory protein troponin, neutralizing the inhibitory action of tropomyosin. The subsequent interaction of actin and myosin causes contraction. Free calcium is then pumped back into the sarcoplasmic reticulum and when its concentration in the cytoplasm is reduced to below 10-7 M the muscle relaxes. Calcium may originate from extracellular sources or from intra-cellular calcium stores. The former is bound to the cell surface, while intraeellular calcium is stored in the sarcoplasmie reticulum. In skeletal muscle, the calcium involved in contraction originates mainly from the internal

Dr. H.F. Mizgala, Facultyof Medicinc,the University of British Columbia,2775 Heather Street, Vancouver, B.C., V5Z 3J5.

$6 stores of the sarcoplasmic reticulum. In cardiac muscle, sarcoplasmic reticulum is less plentiful and the extracellular calcium which flows from the cell surface to the interior during the action potential plays a more important role. Membrane calcium may play an even more important role in the contraction and maintenance of tone in vascular smooth muscle. In the sinus and A-V nodes, events are different. The sodium channel is absent and :hese cells are depolarized by the inward calcium current. Thus, because of the dependence of calcium, sinus and A-V nodal cells are very sensitive to calcium blocking drttgs.

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three sites, the myocardium, vascular smooth muscle and the specialized electrophysiologic tissue of the heart. Blockade of calcium dependent excitationcontraction coupling processes inhibits myocardial contractility and decreases myocardial work and oxygen consumption. By decreasing smooth muscle tone in the coronary arteries the calcium channel blockers reduce coronary vascular resistance and increase coronary blood flow. There is also some experimental evidence to suggest that calcium channel blockers increase flow through collateral channels to ischaemic areas of the myocardium. The vasodilating effect of the calcium channel blockers also influences other arterial beds including the femoral, renal, mesenlefic, hepatic and pulmonary arterial systems. This widespread Pharmacology Papaverine, a precursor of verapamil, prenylamine vasodilatation reduces systemic arterial resistance (Segontin), fendiline and perhexyline maleate have and afterload which further diminishes myocardial been used for many years, particularly in Europe, as work. The effect of calcium channel blockers on the non-specific vasodilators of variable potency in the venous side of the circulation remains a matter of treatment of angina, peripheral vascular disease and controversy. However, it is believed that these for other indications. It is only in retrospect that drugs have very little effect on capacitance vessels these drugs were found to be slow channel blocking and therefore on preload. Calcium channel blockers agents Of the above, perhexyline maleate was also influence the sinus and A-V nodes as well as the introduced for clinical investigation in North Amer- atria. They depress to variable and dose-dependent ica in the mid-1960's as a non-beta blocking degrees the rate of sinus node discharge and also antianginal agent. In 1975, it was found to be inhibit conduction velocity through the A-V node effective in the prophylactic treatment of vasospas- and prolong its refractory period. tic angina. The introduction of the newer calcium It must be understood that the effects of the blocking agents and the high incidence of disturbing calcium channel blockers are vastly different in adverse reactions encountered with this drug has areflexic in vitro isolated heart or tissue preparamade perhcxyline maleate obsolete as a clinically tions compared to their effects in the intact animal useful drug and it has been withdrawn from further with reflexes. A pure dose-related effect occurs in clinical investigation. Although many new corn- the former while in the latter the effects are the net pounds are under investigation as calcium blocking result of the drug's direct effects and the sometimes agents, we will limit our discussion to nifedipine potent positive inotropic reflexes which follow and verapamil, both of which have been released for pronounced vasodilatation. Thus in vitro and in general use in Canada and the United States, and to equimolar doses, nifedipine has the most potent diltiazem which is now available in the United negative inotropic, chronotropie, dromotropic and vasodilating effects. These effects are least with States and whose approval is pending in Canada. Calcium channel blockers have the following diltiazem while verapamil occupies an intermediate characteristics. Their chemical structures are position (Table I). In the intact animal, the net heterogeneous and variable. They all have different haemodynamic effect resulting from vasodilation and variable effects on the contractility of the and sympathetically induced positive inotropic remyocardium and smooth muscles as well as varia- flexes may be an enhanced myocardial performance ble effects on cardiac conducting tissues. In addi- which masks the intrinsic negative inotropie effect tion, it is not certain that their pharmacologic effects of the slow channel blockers. In addition, haemoare entirely due to inhibitionor blockade of the slow dynamic effects may be further modified by individ channels. The calcium channel blockers influence ual response (susceptibility), the underlying funccardiovascular function variably and primarily at tional status of the myocardium, concomitant drugs

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BLOCKERS

TABLE I Relativephannaco~osiceffects Nifedipine

Verapami~ Diltiazem

(no refle~s) NeB, inotrophy Neg. chronotrophy Neg. dromotrnphy Vasoditatation

++++ ++++ ++++ ++++

++ ++++ +++ ++

+ ++ +++ +

Intact animal: (reflexactivity) Neg. inotrophy Neg. chronotrophy Neg. dromotrophy Vasodilatatian

+§ ++

++ +++ +++ ++

+ ++ ++ +

Isolated tissue:

and perhaps by other undetermined factors. Thus, from limited human observations, as well as from animal experimentation, the in vivo effects of the three calcium antagonists under discussion have been summarized as follows (Table I). At doses used clinically, nifedipine has the most potent vasodilating effect, does not appear to depress the myocardium and has no appreciable effect on the sinus and A-V nodes. Verapamil has a significant effect on the sinus and A-V nodes, has significant vasodilating effects and has a negative inotropic effect. Diltiazem has a significant but lesser effect on the sinus and A-V nodes, has the least negative inotropie effect and is the least potent systemic vasodilator. However, considerable evidence suggests that diltiazem has a pronounced and more specific vasedilating effect on the coronary circulation. This classification based on animal experiments and sparse and sometimes contradictory data obtained in man remains our guide to therapy. It is therefore stated that nifedipine has the least effect on myocardial performance, is the least likely to cause congestive heart failure and is the best agent to use concomitantly with the beta adrenergic blocking drugs. However, it must be emphasized that clinical experience remains limited, there are few comparative studies to suport these views, and only more extensive clinical experience will testify to the accuracy of these predicted clinical effects. Indications The clinical investigation of calcium channel blockers began about five years ago. All potential uses have not been identified although many are

under active investigation. The direct coronary vasodilating effect of calcium channel blockers has made them the treatment of choice for the "vasospastic" or "variant" forms of angina pectoris, whether or not occlusive atherosclerotic lesions are present. The slow channel blockers prevent vasospasm and provide effective prophylaxis to patients during the active phase of this disturbance. All three are equaUy effective but it must be emphasized that 15-20 per cent of patients with proven vasospastic angina may show little or no response to any one of these three agents but may respond to another. In such cases, all three agents may have to be given consecutively until a favourable response has been achieved. Nifedipine, verapamil and diltiazem have been used successfully in the prophylactic treatment of stable angina and in the acute and chronic management of unstable angina. They appear to be at least as effective as beta adrenergic blocking drugs in their ability to increase exercise tolerance and reduce the frequency and severity of anginal attacks. The relative efficacy of these three agents in stable and unstable angina remains uncertain. Few comparative trials have been reported. Whether the calcium channel blockers will replace beta adrenergic blocking drugs as first-line prophylactic treatment for chronic effort-related angina awaits the results of further experience. However, in many patients with direct contraindications to beta blockers, such as asthma or intolerable adverse effects, the slow channel blockers offer an effective alternative, Because nifedipine appears to have no negative inotropic effect it has been promoted as the drug of choice for the treatment of anginal syndromes. However, there have been anecdotal reports of patients treated with nifedipine who have developed cardiac deeompensation. There have also been reports of patients with known obstructive coronary artery disease who have developed a paradoxical increase in the severity and frequency of anginal attacks after beginning treatment with nifedipine. In the presence of high-grade and critical lesions this phenomenon is not totally unexpected. Indeed there are several potential mechanisms to explain this apparent paradox. Systemic hypotension may be sufficient to compromise coronary flow distal to the critical obstructive lesions. In addition, the potential positive inotropic reflexes resulting from vaso-

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dilation can increase myocardial contractility and heart rate thereby increasing myocardial oxygen consumption above a critical level, While this paradox has not been encountered in patients with purely vasospastic angina, its occurrence in the presence of occlusive coronary artery disease is disturbing and its use particularly in the more severe forms of angina should be carefully monitored. Verapamil is a very useful agent in the treatment of re-entrant supraventricular tachyarrhythmias. It is rapidly effective in acutely converting these dysrhythmias and its long-term oral administration provides effective prophylaxis against recurrences. Verapamil may convert 15-30 per cent of patients with atrial flutter or atrial fibrillation to normal sinus rhythm but its greatest use in fllese dysrhythmias is in regularizing and slowing the ventricular response. Nifedipine has no clinically significant anti-arrhythmic properties. The anti-arrhythmic potential of diltiazem is presently under investigation. Several studies indicate that verapamil is of benefit to patients with hypertrophic cardiomyopathy, It reduces left ventricular outflow obstruction, increases exercise capacity and offers symptomatic retief in patients who have failed to benefit from treatment with propanolol. Improvement has been observed in patients with both the obstructive and the non-obsmaetive forms of this disease. Although well tolerated, its use has been associated with complications in some patients including acute pulmonary oedema, sinus node inhibition and impairment of A-V node conduction. Its exact mechanism of action in this disorder remains unclear. Though clearly beneficial to such patients, it can only be recommended as treatment of first choice in patients who have specific contraindications to the use of beta adrenergic blocking agents. Both niledipine and verapamil have been shown to be of some value in the treatment of various forms of arterial hypertension. The exact and specific role of these agents in the long-term treatment of hypertensive disorders remains to be clarified. Experimental evidence indicates that all three calcium channel blockers under discussion have shown considerable promise when used as myocardial protective agents during open heart surgery. They are also under active investigation in the limitation of the size of experimentally induced myocardial infarction. Other potential indications for slow channel blockers under investigation include other vasospastic disorders such as Raynaud's

TABLEI/ Pharmacokiaeficproperties(oral)

Dose (rag) Onset Peak Half-life Elimination Renal G.L

Nifedipine

Verapamil Diltiazem

10-20 qid 15-20 rams. 1-2 hrs. 4 hrs.

80-160 rid 2 hrs. 5 hrs. 3-7 hrs.

60-120tid 15-20 rains. 30 mins. 4 hrs.

80% 20%

80% 20%

25% 75%

phenomenon and cerebrovascuIar spasm associated with subarachnoid haemorrhage. Non-cardiovascular areas of investigation include anaphylactic shock, acute tubular necrosis and anoxic brain syndromes following cardiac arrest.

Dosage and pharmacokineticconsiderations The dosage, administration, half-life and other pharrnacokinctic properties of nifedipine, verapami[ and diltiazem are outlined in Table II. Absorption from the gut is in excess of 90 per cent for all three compounds and all are almost completely protein bound. Onset of action is rapid for all three agents but the significant first pass hepatic extrac tion of verapamil limits its immediate bioavailability and slows its onset of action and peak effect, All three drugs are metabolized in the liver and final elimination is primarily renal for verapamil, and nifedipine. Nifedipine has been used in doses exceeding 20 mg four times a day but adverse effects tend to nullify the questionable benefit of these higher doses. Each drug should be started at the lower dose with gradual increase to fall doses within the next few days. Depression of sinus node automaticity may occur transiently at higher doses of verapamil and diltiazem and some caution is advised when using higher than the recommended doses. Particular care, and in some instances electrocardiographic monitoring, is advised when verapamil or diltiazem are administered to patients with slow resting heart rates. In the older age group, these two agents may unmask unexpected sick sinus syndrome. In the acute treatment of re-entrant supraventricular arrhythmias verapamil is used in a total dose of 0.15 mg,kg-', given slowly intravenously in two or three divided doses, The usual total adult dose is 10-15 rag. We recommend that verapamil always be administered under electrocardiographic monitoring. The negative ehronotropic effect of beta

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adrenergic blocking agents may be additive and may indeed be potentiated by intravenous verapami]. Since many patients with recurrent supraventricular tachyarrhythmias may be taking beta adrenergic blocking agents or other antiarrhythmic drugs it is absolutely essential to ensure that no beta adrenergic blocking drugs have been taken by the patient prior to the administration of intravenous verapamil. The additive negative chronotropic effect is markedly enhanced when verapamil is administered intravenously and cases of severe inhibition of impulse generation, including cardiac standstill, have been reported.

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mild congestive cardiac failure must therefore be monitored carefully. The onset of mild cardiac decompensation under such circumstances usually responds well to digitalis and diuretics without necessitating discontinuation of the calcium channel blocker. When given to patients receiving maintenance digoxin therapy nifedipine and verapamil can significantly increase serum levels of digoxin. Several studies have documented this phenomenon and there is evidence that the increased serum digoxin levels may be associated with clinical evidence of digitalis toxicity. When used concurrently with calcium blocking drugs, the dose of digoxin should Adverse effects and drug interactions be halved. Clinical experience with the calcium channel blockThe antianginal action of calcium channel blockers remains limited and all potential adverse effects ers differs from that of beta adrenergic blocking and drug interactions have not been identified. drugs and it was reasonable to predict that a Calcium channel blockers when used alone and in combination of both agents would exert an additive their proper doses are usually well-tolerated and effect. In fact, a number of reports have appeared free of serious adverse effects. Patient compliance indicating that a combination of nifedipine, veraphas been excellent. As with most vasodilators, all amil, or diltiazem with a beta adrenergic blocker three may produce the expected symptoms of provides an anti-anginal effect superior to either flushing, headaches, palpitation, dizziness and agent used alone. Because of nifedipine's apparent postural hypotension. These are most frequent and lack of negative inotropic effect, its potent aftedoad pronounced with nifedipine which is the most reducing action and lack of negative chronotropic potent vasodilator and infrequent with diltiazem. and dromotropic effects, it has been suggested as Disturbances of sinus node automaticity and A-V the drug of choice for combined treatment. Other conduction disturbances may occur with verapamil reports also suggest that verapamil or diltiazem can or diltiazem particularly in patients with occult be combined with beta blockers, provided precaudisturbauces of sinus or A-V node function. The tions are taken. Whichever combination is used we most frequent side-effect encountered with verap- advise caution in the clinical use of these combinaamil is mild constipation which can usually be tions. In patients with inadequate beta adrenergic easily managed. A disturbing adverse effect en- blockade the addition of nifedipine has been countered solely with nifedipine is leg oedema. observed to produce undue tachycardia and recurThis is most frequently seen in women, can be quite rent rest angina. When combining a beta adrenergic severe, does not respond to diuretics but disappears blocker with verapamil or diltiazem, the additive following discontinuation of the drug. Its mecha- negative chronotropic, dromotropic and inotropic nism remains unclear but is probably related to its effects may lead to excessive bradycardia, A-V potent vasodilating properties potentiated by hydro- nodal conduction disturbances or cardiac decomstatic factors relating to the upright position. On pensation. Such combinations are effective but in theoretical grounds diltiazem has been said to be the our opinion should not be initiated without careful agent with the least side-effects. In part this has in-hospital observation and close follow-up. With been confirmed by clinical studies but since it has respect to drug combinations in angina pectoris, we been available for general use only recently in the would particularly discourage the recently observed United States and still awaits approval in Canada, trend of combined therapy with subtherapeutic extensive clinical experience is lacking. We have doses of a calcium channel blocker, a beta adrenerfound verapamil to be well-tolerated and generally gic blocker and small doses of oral nitrates. It free of significant adverse effects. appears more logical to use these drugs individually All calcium channel blockers are intrinsically to full therapeutic doses before adding other drugs. myocardial depressants, Their use in patients with The negative inotropic effect of disopyrarnide

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can also be potentiated by intravenous verapamil. The intravenous administration of one of these agents to patients chronically receiving the other has been associated with the onset of severe cardiac decompensation and this combination must be avoided. Very little is known of the interactions between calcium channel blockers and general anaesthetics and this may prove to be a problem as more patients treated with these drugs are admitted for elective and emergent surgery. There is evidence to suggest that the haemodynamic effects of anaesthetics may be related to interference with intracellular calcium interactions or calcium entry into myocardial or smooth muscle cells. This could theoretically potentiate the pharmacologic actions of calcium entry blockers and great caution must be exercised when calcium channel blockers are given to anaesthetized patients or when patients receiving these drugs must undergo surgery. The increasing popularity of intravenous verapamil for the treatment of postoperative supraventricular tachyarrhythmias is justified by its efficacy. However, we must emphasize again the dangers of this form of treatment in patients receiving beta adrenergic blocking drugs. The in vitro inhibition of myocardial contractility can be reversed by increasing extracellular calcium concentration. There is some controversy, however, as to whether this is clinically effective. Nevertheless we have successfully reversed what appeared to be excessive myocardial and sinus node depression due to excessive doses of verapamil with the administration of intravenous calcium chloride.

long-term safety. Particular caution is advised when they are combined with certain antiarrhythmic agents, digitalis and particularly beta adrenergic blocking agents. Little is known about their interaction with various general anaesthetic agents and for this reason particular vigilance is required as more patients receiving these agents are admitted for surgical procedures.

Summary and conclusions The calcium channel blockers provide an exciting and effective new therapeutic tool in the management of ischaemie cardiac syndromes and may prove popular and effective in the treatment of a variety of other disorders. They have provided a new approach to treatment and have added new insights into the pathogenesis of ischaemic cardiac syndromes. Their introduction into clinical practice has been swift and many of our concepts regarding their pharmacologic activities in man remain based on theoretic considerations. Their expanding clinical use and further comparative studies will undoubtedly provide further information in regard to indications, adverse effects, drug interaction and

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Suggested Bibliography 1 Antman EM, Stone PH, MzdlerdE, BranwauldE.

Calcium channel blocking agents in the treatment of cardiovascular disorders. Part I: Basic and clinical electrophysiologic effects. Ann Intern Med 1980; 93'. 875-85. Part II: Hemodynamic effects and clinical applications. Ann Intern Med I980; 93: 886-904. 2 Bala Subramanian V, Bowles MJ, Khurmi NS et al. Rationale for the choice of calcium antagonists

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in chronic stable angina. An objective double blind placebo controlled comparison of nifedipine and verapamil. Am J Cardiol 1982; 50:1173-9. BraunwaldE. Mechanism of action of calcium channel blocking agents. N Engl J Med 1982; 26: 1618-27. Henry PD, Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. Am g Cardiol t980; 46:1047-57. Klein HO, Kaplinsky E. Verapamil and digoain: Their respective effects on atrial fibrillation and their interaction. Am J Cardiol 1982; 50: 894-902. Lynch CP, Vogel S, SperalakisN, Halothane Depression of myocardial slow action potentials. Anesthesiology 1981; 55: 360-8.

7 Packer M, Leon MB, Bonow RO, Kieval J er al. Hemodynanfic and clinical effects of cembined

verapamil and propanolol therapy in angina pectoris. AmJ Cardio11982; 50: 903-12. 8 RobsonRH, Vishwanath MC. Nifedipine and beta blockade as a cause of cardiac failure. BrMedJ 1982; 284: 104. 9 Rosing R, Epstein SE. Verapamil in the treatment of hypertrophic cardiomyopathy. Ann Intern &led 1982; 96: 670-2. 10 Waters DD, Theroux P, Szlaehcic J, Mizgata HF. A comparative study of calcium ion antagonists in patients with variant angina, Clinical andlnvestigative Medicine 1980; 3: 129-35.