436 Anaesthetic implications of calcium channel Leonard C. Jenkins aA MD CM FRCPC blockers Peter J. Scoates a sc MD FRCPC CONTENTS The object of this review is to emphasize the anaesthetic implications of calcium channel block- Physiology - calcium/calcium channel blockers Uses of calcium channel blockers ers for the practising anaesthetist. These drugs have Traditional played an expanding role in therapeutics since their Angina pectoris introduction and thus anaesthetists can expect to see Arrhythmias increasing numbers of patients presenting for anaes- Hypertension thesia who are being treated with calcium channel Newer and investigational Cardiac blockers. Other reviews have emphasized the basic - Hypertrophic cardiomyopathy pharmacology of calcium channel blockers. 1-7 - Cold cardioplegia - Pulmonary hypertension Physiology - calcium/calcium channel blockers Actions on platelets Calcium plays an important role in many physio- Asthma Obstetrics logical processes, such as blood coagulation, en- - Premature labor zyme systems, muscle contraction, bone metabo- - Pre-eclampsia lism, synaptic transmission, and cell membrane Achalasia and oesophageal spasm excitability. Especially important is the role of Increased intraocular pressure therapy calcium in myocardial contractility and conduction Protective effect on kidney after radiocontrast Cerebral vasospasm as well as in vascular smooth muscle reactivity. 7 Induced hypotensive anaesthesia Thus, it can be anticipated that any drug interfering Drag interactions with calcium channel blockers with the action of calcium could have widespread With anaesthetic agents effects. Inhalation agents In order to understand the importance of calcium - Effect on haemodynamics - Effect on MAC in cellular excitation, it is necessary to review some Neuromuscular blockers membrane physiology. Cell membranes are pri- Effects on epinephrine-induced arrhythmias marily phospholipids arranged in a bilayer. Inter- With other drugs spersed throughout are macromolecular proteins Digoxin and glycoproteins traversing the membrane, form- Beta adrenergic blockers Quinidine ing channels. These channels are relatively specific Theophylline to certain ions. Recently, channels which regulate Dantrolene Pathophysiological alterations (other than cardio- vascular) with anaesthetic implications Decrease in lower oesophageal sphincter tone From the Department of Anaesthesia, Faculty of Effects on intracranial hypertension Medicine, University of British Columbia, Asthma Vancouver General Hospital and Royal Columbian Muscular dystrophy Hospital, Vancouver, British Columbia. Hypoxic pulmonary vasoconstriction Address correspondence to: Dr. Leonard C. Jenkins, Malignant hyperthermia Inhibition of platelet aggregation Department of Anaesthesia, University of Hyperkalemia British Columbia, Room 3200, 910 West 10th Avenue, Summary Vancouver, British Columbia V5Z 4E3. CAN ANAESTH SOC J 1985 / 32:4 / pp436-47 Jenkins and Scoates: CALCIUM CHANNEL BLOCKERS 437 flOW of sodium and calcium have been identified. 7 The sodium channels are also known as fast channels because influx of sodium via these chan- ~L_NO ~ ~ OCH nels is responsible for the rapid (phase 0) upstroke of the action potential seen in the myocardial cell. H)COOC COOCH) OCOCH 1 N The calcium channels are known as slow channels H~C CH I I O /CH 1 CH;.CH~N\ CH ~ because when fast channels are blocked, as with H " i lidocaine, the resulting action potential has a slowly Nifedipine niltiazem rising and falling pattern as seen in the normal SA node or AV node action potential. Calcium fluxes play an important role in altering CH30--~ C--I CH~-- CH,--C;H,--N--CH~ CH,~-- OCH ~ the membrane potential during cellular excitation in CH,O ~--4~ C~-N E~'-- OCH j most myocardial cells. Sodium influx produces the Verapamil phase 0 of the action potential and calcium influx (After I) during phase 1 and 2 of the action potential contributes to the formation of the plateau. 2'~ FIGURE However, in the SA node and AV node of the heart, calcium is the important ion responsible for phase 0 depolarization, not sodium. Under abnormal condi- about contraction. In smooth muscle, calmodulin, tions such as hypoxia and ischaemia, ventricular rather than troponin acts as the receptor protein. cells may also become dependent on calcium for Rapid reduction of calcium ion concentration in the production of phase 0 of the action potential. 2 sarcoplasma must occur for relaxation to take place. The flow of ions through the membrane channels In skeletal muscle the calcium needed for excita- have been shown to be regulated by a number of tion-contraction is stored in the sarcoplasmic reti- gates. This is most clearly demonstrated for the culum and energy dependent processes bring about sodium channels but is felt to be similar for calcium its re-uptake after release. Cardiac muscle contains channels. 4 The external surface of the membrane relatively small amounts of stored calcium and has gates which open and close in response to vascular smooth muscle even less. These latter voltage changes in the membrane (voltage depen- tissues depend to a greater extent on transmembrane dent gates). The intemal surface has gates which influx of calcium for contraction to occur. It appears depend on phosphorylation of ATP to control ion that the calcium entering the cell during the plateau flows (phosphorylation dependent gate). For exam- phase plays an important role in inducing calcium ple, histamine or beta-adrenergic drugs may induce release from the sarcoplasmic reticulum, thus the formation of cyclic AMP thus modifying chan- bringing about contraction. L2,4.7,s nel proteins and altering calcium influx 7 The drugs currently used as specific calcium Calcium also plays a major role in bringing about channel blockers are verapamil, nifedipine and excitation-contraction coupling. In striated and diltiazem. These drugs are but a few of the myriad cardiac muscle, calcium ions in the cell inhibit the drugs that possess calcium blocking activity (Table binding of troponin and tropomyosin and thus bring I). A review of the structure of these drugs shows that they vary greatly. The figure depicts the TABLE 1 Drugsthat interfere with calcium actions structures of verapamil, nifedipine and diltiazem, t Ions: Various di- and trivalent cations This variability implies that there is no one receptor Calcium entry blockers: verapamil, nifedipine, that mediates the effects of the calcium channel diltiazem, lidoflazinetiapamil and others Papavarine blockers. Procaine, procainamide Calcium channel blockers function by altering Phenytoin calcium uptake across the cellular membrane and Diazoxide, nitroprusside, nitroglycerine also by affecting intracellular uptake and release Inhalational anaesthetics: halothane, enflurane mechanism. 2'8 Verapamil, which exists in a D & L and isoflurune isomer form in commercial preparations, acts pri- 438 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE II Summaryof clinical effects of calcium channel blockers on the cardiovascular system (in viva) Vasodilation Heart rate and A V Cardiac conduction depression systemic coronary Verpamil + + + + + + + + + Nifedipine 0 0 + + + + + + Diltiazem + + + + + + + AV- atrioventrlcular marily at the inner phosphorylation dependent gate making it very useful for terminating supraventricu- of the membrane. It has also been shown that the D lar arrhythmias, whereas nifedipine has no activity isomer of verapamil acts almost exclusively as a fast in this regard. channel blocker and is almost devoid of slow It is interesting that both nifedipine and isoflurane channel inhibition. Diltiazem also has some fast have little (but are not devoid of) influence on channel inhibition. Nifedipine is believed to act contractility and conduction, but markedly reduce primarily at the voltage dependent (outer) gate of systemic vascular resistance. Patients exposed to the calcium channel. 2.3.7 Diltiazem appears to act at both drugs may be expected to exhibit additive the inner phosphorylation dependent gate, like effects, which may be significant, on systemic verapamil.S vascular resistance and blood pressure, but little Most cardiovascular effects of calcium channel disturbance of myocardial contractility or conduc- blockers can be explained on the basis of selective tion. However, verapamil, in a dose which causes inhibition of transmembrane influx of Ca + § Inhibi- the same reduction in arterial pressure as nifedipine, tion of Ca ++ dependent membrane excitation ac- significantly impairs cardiac conduction and con- counts for the depressive effect of calcium channel tractility. 2 Similarly, the blood pressure decrease blockers on sinus automaticity and atrioventricular which accompanies halothane anaesthesia is princi- conductivity. Interference with the excitation-con- pally due to reduced myocardial contractility - and traction coupling process is the reason for their halothane appears to depress conduction more than negative inotropic effect. The effects of calcium isoflurane. 2 Thus, a patient exposed to verapamil channel blockers on the vascular smooth muscle and halothane may be expected to exhibit additive may result from either inhibition of excitation effects on contractitlity and AV nodal conduction. contraction coupling or from suppression of Ca ++ dependent smooth muscle spike activity. Uses of calcium channel blockers Table II is a summary of the clinical effects of calcium channel blockers on the cardiovascular Traditional system. Verapamil and nifedipine