Calcium-Channel Blockers and Anaesthesia

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Review Article Calcium-channel blockers and Pierre-Georges Durand MD,* Jean-Jacques Lehot MD,* Pierre Fo~x D I)l'h~" anaesthesia

Verapamil was the first calcium-channel blocker (CCB). It has Contents been used since 1962 in Europe then in Japan for its anti- Comparative pharmacology of calcium-channel blockers arrhythmic and coronary vasodilator effects/ The CCB have (CCB) become prominant cardiovascular drugs during the last 15 - Classification and chemical characteristics ),ears. Many experimental and clinical studies ha ve defined their - Mechanism of action mechanism of action, the effects of new drugs in this therapeutic - Pharmacokinetics class, and their indications and interactions with other drugs. - Interactions Due to the large number of patients treated with CCB it is - Pharmacodynamic effects important for the anaesthetist to know the general and specific Indications not related to anaesthesia problems involved during the perioperative period, the interac- - Confirmed indications tions with anaesthetics and the practical use of these drugs. - Possible indications Pharmacological interactions in anaesthesia Le verapamil a dtd initialement utilis6 comme un bloqueur des - Halogenated anaesthetics canaux calciques (CCB). 11 a ~t~ utilis6 depuis 1962 eta Europe - Other anaesthetics puis au Japon pour ses propri~tds anti-arythmiques et ses - Neuromuscular relaxants effets vaso-dilatateurs coronariens, i Les CCB sont devenus des Perioperative use drogues cardiovasculaires de choix depuis les 15 dernikres - Myocardial ischaemia ann~es. Plusieurs ~tudes cliniques et expErimentales ont dr - Hypertension leurs mdcanismes d'action, leurs effets et leurs indications ainsi - Arrhythmias que leurs interactions avec les autres mddicaments. Aussi, 6tant - Malignant hyperthermia donnd le grand nombre de patients traitEs avec les CCB, il est Conclusion d'une importance majeure que I'anesthEsiste sache les pro- bldmes g~ndraux et spEcifiques qu'emmt?ne ce groupe de m~dicaments durant la pdriode pr~-opr les interactions avec les anesthdsiques et I'utilisation pratique de ces mddica- Comparative pharmacology of CCB ments. Classification and chemical characteristics The classification proposed by the World Health Organ- ization 2 (Table 1) divides the CCB into two groups: Group A consists of CCB selective for slow calcium Ca + +

Key words channels (verapamil and derivatives; dihydropyridines PHARMACOLOGY:calcium channel blockers. (DHP): nifedipine, nicardipine, nimodipine, nitrendipine, diltiazem); Group B consists of CCB non-selective for From the Anaesthesia and Intensive Care Department, slow Ca ++ channels (diphenylpiperazines, prenylamine H6pital Cardio-vasculaire et Pneumologique. Lyon (France)* derivatives, bepridil, perhexiline). and the Nuffield Department of Anaesthetics, The Radcliffe Spedding's classification 3'7 divides CCB into three Infirmary, Oxford (U.K.).i" groups according to their mechanism of action: Group I is Address correspondence to: Dr. P-G. Durand, Department made up of DHP which act through a membrane site; of Anaesthesia and Intensive Care, H6pital Cardio-vasculaire Group 11 (verapamil, diltiazem) is an heterogenous group ct Pneumologique - 69394 Lyon Cedex 03 - France. made up of hydrophobic molecules acting through two Accepted for publication 16 July, 1990. different sites on the calcium channels; Group 111 (flunari-

CAN J ANAESTH 1991 / 38:1 /pp75-89 76 CANADIAN JOURNAL OF ANAESTHESIA

TABLE I Classification of calcium-channel blockers ording to their vascular smooth muscle for T and L) and their CCB degree of specificity for calcium channels selectivity. The L channels are inhibited by DHP but DHP Specificity for slow seemed to have little effect on T and N channels, s CCB calcium-channel Voltage-operated channels are made up of sub-units. Some sub-units allow the CCB to link to the channels, 9 Group A Verapamil + + + others allow phosphorylation and activation of VOC Diltiazem Dihydropyridines through indirect stimulation by H2-agonists and beta- - nifedipine agonists I~ leading to Ca ++ entry into the cell. - nicardipine Calcium-channel blockers prevent activation of VOC, - nimodipine block Ca ++ entry into the cell and inhibit the excitation- - nitrendipine contraction coupling. Verapamil decreases allosterically Group B Diphcnyl piperazines + + + the fixation of DHP to the cell whereas diltiazem increases Prenylamine this fixation. ~1 Additionally, bepridil can attach to smooth Bepridil muscle calmodulin. ~2 The blockade of VOC takes place at Perhexiline rest with DHP but is frequency-dependent with verapamil and diltiazem. 13'14 In addition CCB may have a VOC zine, perhexiline, bepridil) possesses a structural homo- independent action through blockade of alpha2 post- geneity and is made up of lipophilic molecules which synaptic vascular receptors. ~s exhibit less selective mechanisms of action. Calcium-channel blockers are mixtures of isomers Pharmacokinetic variables (Table lI)16 possessing different levels of activity. For example, the Calcium-channel blockers exhibit relatively similar phar- nicardipine positive isomer is more powerful than its macokinetic properties. 17-19 The bioavailability of dil- negative isomer. The verapamil negative isomer is more tiazem shows important individual variations. 2~ Calcium- powerful than its positive isomer with regards to vascular channel blocker metabolism is essentially hepatic through and myocardial effects. 3 demethylation and dealkylation, leading to several possibly biologically active metabolites. Thus hepatic failure or decreased hepatic blood flow due to cardiac failure Mechanism of action slows the metabolism of CCB. 21 The elimination of the Calcium plays a fundamental role in the excitation- inactivated compounds takes place mainly in the kidneys. contraction coupling in myocardial cells and smooth However, chronic treatment prolongs the half-life be- muscle. Its penetration into the cell allows the Ca ++ cause of saturation of hepatic first-pass effect, i.e., release from the sarcoplasmic reticulum which is respon- verapamil elimination half-life is extended to 6-9 hr. 17 sible for muscle contraction. Contraction takes place in the myocardial cell because of the actin-myosin interac- Interactions tion facilitated by the troponin Ca ++ complex. In the Interactions with other drugs have been frequently re- vascular smooth muscle calmodulin plays the same role as ported. 22 Serum digoxin concentrations increase with troponin in the cardiac muscle and allows the actin- CCB treatment, probably through diminution of renal myosin interaction. 4'5 clearance. 23 Cimetidine increases bioavailability and Calcium enters into the cell through two types of serum levels of verapamil, dilitiazem and DHP. 24 Con- channels: receptor-operated channels (ROC) and voltage- versely verapamil increases serum theophyllin levels in operated channels (VOC). Calcium-channel blockers some patients. 25 decrease Ca ++ entry through the VOC during phase 2 of the action potential of the fast response cells (slow Pharmacodynamic effects (Figure) calcium channel) and during phase O of the action Cardiovascular effects differ according to the CCB potential of the slow response cells contained in the considered and result from direct effects and effects sino-atrial and atrio-ventricular nodes. elicited by stimulation of the baroreflex. 26 Calcium- Voltage-operated channels are a hundred-fold more channel blockers act on nodal tissue. In an in vitro study selective for Ca ++ than for Na § and have been divided with rat isolated atrial cells, Kawai et al. 27 found a similar into sub-types. 6"7 Hess s recognised three sub-types ("L" dose-dependent inhibitory effect of nifedipine, verapamil long-lasting inward calcium current; "T" transient inward and diltiazem characterized by increases in sinus recovery calcium current" "N" found in sensory neurones) accord- time, effective refractory period, and functional refrac- ing to their kinetics, size, conductance, voltage depen- tory period of the atrio-ventricular node. However, in dance, preferential localisation (i.e., myocardial cell and clinical studies, inhibitory effects were observed only Durand etal.: CALCIUM=CHANNEL BLOCKERS 77

TABLE Ii

Pharmacological properties of CCB Veraparnil Dihiazem Bepridil Nifedipine Nicardipi,e Nimodipine

Dose - Oral 80-160 rag.8 hr TM 30-120 rag.8 hr TM 200-300 rag- 24 hr TM 10-40 rag-8 hr TM 20mg.8 hr TM 240mg.24 hr -~ intranasa110 rag. 4 hr-

- IV 15-45 rag.24 hr -I 75-150 mg.24 hr -~ 4 mg.kg TM .24 hr TM 5-15 i.tg. kg TM 2-5 mg-hr -~ 2 mg-hr TM Oral absorption (%) >90 >90 90 >90 99 >90 Onset of action (min) <30 15 48-72 hr inlranasal 3, oral 20 20-60 30-90 First pass extraction by liver after oral administration (%) 75-90 70-80 30-40 40-60 20-40 90 Bioavailability (%) 20 25-50 60 50 30 5- I0 Protein binding (%) 90 80 99 90 98 99 Elimination half-time (hr) 4-10 2-6 33 3-5 3-5 2 Therapeutic plasma concentration (ng. ml-~) 50-250 I00- 250 300- 1100 10-100 5-100 10-30 Excretion (%) - Renal 85 40 1 80 55 20 - Hepatic 15 60 99 20 45 80

seems to be the most, 3~ and nicardipine the least cardiac I Reduced J Contractilib,I depressant after intracoronary injection. 32 V>N>DI These decreases in contractility, heart rate and afterload reduce myocardial oxygen consumption (M~,'O2). Unchanged I I Reduced I Preload - Alterload I In the normal and in the ischaemic myocardium N>D=VI intracoronary administration of CCB impaired left ven- N=D=V I tricular relaxation but conversely, because of decreased \ / afterload and sympathetic response, intravenous adminis- c s tration enhanced ventricular relaxation. 3~ Calcium- channel blockers have spasmolytic and vasodilator properties on the coronary circulation. Spasmolytic effects have been demonstrated in pharmacologically induced § § spasm 33 and clinical studies have confirmed functional / \ improvement. 34 A dose-dependent increase in coronary Reflex Sympathetic blood flow (CBF) has been demonstrated with all CCB I Variable Heart Rate I Stimulation both in normal and constricted coronary arteries. 35,36 N't D,,V, N>D=V Dihydropyridines have spasmolytic effects on the cerebral circulation and increase carotid blood flOW. 37'38 FIGURE Differential effects of the available calcium-entry Calcium-channel blockers reverse the decrease in renal blockers on the major determinants of left ventricular function. blood flow caused by angiotensin 1139 and diltiazem and D = diltiazem: N = nifedipine, V = verapamil; NC = no change. (Reproduced, with permission, from McCall et al.) nicardipine may increase glomerular blood flow in human nephropathies. 39'4~ Calcium-channel blockers may also protect kidneys against ischaemia. In sheep, verapamil 50 with verapamil and diltiazem but opposite effects were i.tg.kg -I was injected into the renal artery prior to one observed with nifedipine 27 and nicardipine. 2s hour ischaemia and this improved postischaemic creati- All CCB cause a dose-dependent decrease in mean nine excretion, at Conversely, nifedipine may induce arterial pressure and systemic vascular resistance (SVR). 29 acute renal failure in a few situations. 42 Thus further data The baroreflex-induced increase in heart rate is greater are needed to define the renal effects of CCB. with nifedipine than with verapamil or diltiazem 26 due to Calcium-channel blockers may also dilate pulmonary a more potent vasodilator effect of DHP. 3~ arteries, especially in the presence of hypoxaemic vaso- The effects of CCB on cardiac performance are constriction a3 or at an early stage of primary pulmonary complex. In vitro, all CCB demonstrate potent negative hypertension, aa'a5 A subsequent increase in venous ad- inotropic effects 31 but clinical studies have shown varia- mixture has been found by some authors 46 but not by tions of heart rate and afterload. 29 However, verapamil all. 47 Anti-atherogenic properties of CCB such as isradip- 78 CANADIAN JOURNAL OF ANAI:STHESIA

ine have been demonstrated experimentally 48 but not ment of paroxysmal supraventricular tachycardias. 64 The confirmed in man. Endocrine effects have been shown; success rate of conversion to sinus rhythm was more than calcium-channel blockers increased plasma angiotensin !I 80 per cent after 10 mg IV in adults, and approached 100 concentrations without changes in plasma aldosterone and when combined with carotid sinus massage. 65 Diltiazem renin activity. 39 Verapamil has been shown to inhibit 0.15 mg" kg -~ IV or bepridil 2-4 mg.kg-i IV produced atrial natriuretic factor secretion induced by rapid ventri- similar results. 65"66 Calcium-channel blockers adminis- cular pacing. 49 tered orally preventively have been less successful. 67 Verapamil slowed the ventricular response during atrial Indications not related to anaesthesia fibrillation. 68 Verapamil, diltiazem or bepridil have been successful in treating ventricular arrhythmias during acute Confirmed indications myocardial infarction (AMI) and idiopathic ventricular The efficacy of CCB has been confirmed in coronary tachycardias with right bundle branch block and left axis artery disease (CAD), 5~ especially coronary spasm 34 in deviation. 69.7~ which most CCB have demonstrated similar effects: CCB reduced the number of episodes by 50 per cent in more Possible indications than 60 per cent of patients. Diltiazem and nifedipinc had Due to the role of Ca +4 in ischaemic myocardial cell additive effects but induced more untoward effects. 5t injury 71 CCB have been proposed for use in AMI. Several The action of CCB in angina pectoris results from an multicentre studies have shown no effect on mortality 72"73 increase in CBF in the ischaemic area 52 and from a but diltiazem decreased the incidence of cardiac events in reduction of MVO2. The M~/O2 decreases due to a AMI without Q wave 74 and AMI without LV failure. 75 reduction of afterload which is more pronunced with The role of CCB in the treatment of cardiac failure DHP, and to negative chronotropic and inotropic effects remains to be defined. 76 The reduction of SVR induced by induced by verapamil and diltiazem. A dose-dependent DHP might increase cardiac output in acute or chronic improvement of performance during exercise and a cardiac failure in the short term. However, this effect decrease in the number of angina pectoris crises has been seems to disappear in the longer term 77 and the negative demonstrated. 53"54 The combination of diltiazem and inotropic effect of DHP might have occurred, as reflex nifedipine was more effective in stable angina pectoris sympathetic compensation was less effective in these than diltiazem or nifedipine alone. 55 In patients with patients. 78 Therefore, CCB seem to be less effective than moderately depressed left ventricular (LV) function, the converting enzyme inhibitors or nitrates in the treatment combination of diltiazem with propranolol increased LV of cardiac fai]ure. 77'79 ejection fraction during exercise compared with pro- Verapamil improved function in 50 per cent of patients pranolol alone; 5~ this could have been due to the afterload who presented with obstructive cardiomyopathy. 8~ This reduction caused by diltiazem. Dihydropyridines seem improvement occurred at rest and during exercise, was better tolerated than diltiazem or verapamil when LV greater with verapamil than with nifedipine 81 and co- failure was present. 56 incided with an improvement of LV diastolic function. Calcium-channel blockers have been used in acute The LV intraventricular outflow pressure gradient de- hypertension. Bauer et al. 57 observed a ten per cent creased when the verapamil-induced cardiac depression decrease in systolic blood pressure in five patients given was more pronounced than the fall of SVR. diltiazem 0.3 mg .kg-I administered over three minutes. Calcium-channel blockers have been included in cold Nifedipine 5-30 mg PO or verapamil 5-10 mg IV also cristalloid cardioplegic solutions during cardiac surgery. have been used in acute hypertension. 57 Nifedipine 200 I-t,g"L-~ decreased the effects of myo- Calcium-channel blockers are also utilized in mild to cardial ischaemia but led to difficulties in weaning from moderate hypertension 58 though most studies involved a cardiopulmonary bypass. 8z'83 Diltiazem 150 Ixg.kg -~ relatively small number of patients observed for less than improved myocardial protection but elicited myocardial three months, sa Oral verapamil 240 mg daily in adults depression and conduction disturbances. 84 Verapamil 50 was as efficient as atenolol or propranolol. 59 Dihydro- mg added to the priming of cardiopulmonary bypass pyridines such as nicardipine or nitrendipine have also during coronary artery bypass graft (CABG) surgery been utilized. 6~ However, hypotension may occur, lead- prevented coronary vasospasm. 85 More studies are needed ing to myocardial ischaemia, especially with DHP such as to define the place of CCB in cardioplegia. 83"84 nifedipine at usual dosages. 61-63 Cerebral artery spasms are usually associated with Whilst DHP do not possess antiarrhythmic properties, sub-arachnoidal haemorrhage due to rupture of cerebral verapamil has been used for many years in the manage- aneurysm. Nimodipine administered through a nasogas- Durand eta[.: CALCIUM-CHANNELBLOCKERS 79 tric tube every four hours for three weeks decreased the thane for a similar decrease in arterial pressure, SVR was incidence of severe neurological deficits due to spasm in reduced only by nifedipine. 106 man 86 and reduced the subsequent morbidity and mortal- Calcium-channel blockers and halogenated anaesthe- ity. 87 After clipping of intracranial aneurysm, IV nicar- tics may modify CBF through two possible mechanisms: dipine induced an increase in cerebral blood flow in the (1) decrease in coronary perfusion pressure, and (2) hypoperfused areas and a decrease in the hyperperfused coronary artery vasodilatation. Most studies found no areas. 88 However, this was accompanied by worsening of change in CBF in spite of a decrease in coronary perfusion the neurological status in patients with cerebral oedema. 88 pressure; i07'109'113"114 one study in open-chest sheep Nimodipine seems to present vasoregulator properties 89 found a 66 per cent decrease in CBF with halothane but further studies of cerebral blood flow and outcome are (inspired concentration = 1.2 per cent and after a needed. verapamil cumulative dose of 0.16 mg" kg-I. t~2 The In monkeys nimodipine 10 i,zg. kg-i administered five combination of nicardipine and isoflurane (at 1 MAC and minutes after cerebral ischaemia improved the outcome 2 MAC) caused a substantial decrease in arterial pressure and the histological score. 9~ In man, after cardiac arrest and an increase in CBF.I~I In open-chest animals asyn- IV nimodipine decreased the coma duration but did not chronism of LV wall motion was observed with 116 or change the final outcome. 9a Gelmers et al. 92 found a without ~12.1 ~3. i 15 critical coronary constriction. decrease in mortality when nimodipine was started orally Verapamil and diltiazem slow AH conduction; 27 as within 24 hr of acute ischaemic stroke, possibly because halothane and enflurane similarly slow AH conduction this treatment decreased the incidence of cardiovascular and the three halogenated anaesthetics slow HV conduc- complications. The beneficial effects of nimodipine could tion and intra-ventricular conduction,liT CCB and halo- be attributed to increased cerebral blood now 93.94 without genated anaesthetics may exert additive effects on the significant change in post-ischaemic cerebral metabol- conduction system. In dogs, enflurane (I.2 MAC with ism 95 but these effects are disputed. 96"97 diltiazem 40 mg.kg -1 rain -I 1V administered over a Dihydropyridines may be beneficial in Raynaud's syn- 40-min period t 18 led to a sinus arrest. Hantler et al. 119 drome, 9s'99 and nifedipine or verapamil in oesophageal reported two cases of sinus bradyeardia in patients treated spasm. IOO preoperatively with diltiazem and anaesthetized with enflurane and fentanyl. Pharmacological interactions during anaesthesia In dogs anaesthetized with halothane, enflurane or isoflurane (1.2 and 1.5 MAC), verapamil increased the Halogenated anaesthetics AH interval more than did diltiazem. ~17 Atlee et al. 1~7 in Experimental studies have determined the interactions their experimental study with verapamil or diltiazem between CCB and halogenated anaesthetics on the cardio- reported three cases of auriculo-ventricular block with vascular system. The negative inotropic effect of these enflurane and one complete heart block with halothane or combinations has been shown on isolated myocardial isoflurane. Bepridil 5 mg.kg -~ IV increased the AH cells ~~176 and in experimental studies with open 1~176 interval in dogs anaesthetized with enflurane but not with or closed ~~176 chests. Enflurane combined with CCB halothane or isoflurane. 120 However, nifedipine, in com- caused more myocardial depression than halothane or bination with halogenated anaesthetics, did not modify isoflurane. This has been demonstrated with verapamil in auriculo-ventricular conduction, tt7 One of the patients closed-chest animals during acute ~~176 and chronic 11~ described by Hantler et al. it9 presented with a Mobitz I experiments, with diltiazem on isolated myocardial cells 1~ auriculo-ventricular block associated with sinus brady- and with bepridil in open-chest dogs. ~05 Diltiazem or vera- cardia. pamil in combination with halothane decreased cardiac Calcium-channel blockers did not increase the depres- performance more than nifedipine ~~ or nicardipine. 1ii sant effects of halogenated anaesthetics on His-Purkinje The combination of CCB with halogenated anaesthe- and intraventricular conduction.117 On the other hand, tics also decreased mean arterial pressure. 1~176 At verapamil and diltiazem exhibited protective effects equianaesthetic potency, enflurane combined with vera- against epinephrine induced arrhythmias in dogs anaes- pamil 1~ or bepridil 1~ decreased arterial pressure more thetized with halothane. 121.12z than halothane or isoflurane. This was accompanied by Experimentally CCB enhanced the reduction of renal increased SVR and decreased cardiac output with both and carotid blood flows induced by halogenated anaes- enflurane~~176 and haiothane. 112 lsoflurane in combina- thetics. This has been shown with several combinations: tion with CCB either increased, 113 did not change 114 or nicardipine and isoflurane; I~1 verapamil and either halo- decreased 1~ SVR. In swine, anaesthetized with halothane, enflurane or isoflurane, io7.109 In rats, verapamil 80 CANADIAN JOURNAL OF ANAESTHESIA

and halothane or isoflurane inhibited hypoxaemic pulmo- nicardipine and halothane seemed to be safe. ~38 For nary vasoconstriction. 123 Merin, 139 and in our experience, preoperative CCB Pharmacodynamic and pharmacokinetic reasons ex- treatment allows the use of halogenated anaesthetics. plain these interactions. Pharmacodynamic interactions However, IV verapamil or diltiazem is not recommended can occur at the cellular level and in the autonomic in halothane or enflurane anaesthetized patients, espe- nervous system. Lynch et al.~2~'t25 showed that halo- cially when these patients present with cardiac failure or thane and enflurane had similar effects on the slow conduction disturbances. calcium channels in myocardial cells but the effects of isoflurane were different. 126 Durrett et al. 127 found that Other anaesthetics the negative inotropic effects of halothane depended upon During high-dose narcotic anaesthesia IV, CCB are intracellular mechanisms. Wheeler et al. ~28 showed that usually well tolerated. In dogs given fentanyl 150 halothane decreased Ca + + release from the sarcoplasmic i.Lg.kg-i 140 or 500 i.tg.kg-~, 14~ or alfentanil 160 reticulum. Terrar and Victory =29 showed that isoflurane p.g.kg-t, 142 injection of CCB caused no deleterious depressed the inward calcium current and the amplitude of effects but serum diltiazem levels greater than 1000 contraction in myocytes isolated from guinea-pig ventri- ng.ml -I induced auriculo-ventricular blocks. In dogs cle. Thus halogenates and CCB have additive effects on receiving fentanyl 150 ~g.kg -I , IV nifedipine 20 Isg'kg-1 myocytes. Recently, Nakao et al. 130 and Blanck et al. ~31 caused a decrease in arterial pressure and a tachycardia observed that nitrendipine could be displaced from its which led to myocardial ischaemia. 143 In dogs with membrane sites by halogenated anaesthetics in proportion critical coronary constriction, receiving similar fentanyl of their anaesthetic potency. Maze et al. 132 showed that anaesthesia, verapamil decreased coronary perfusion verapamil decreased the MAC of halothane. Halogenated pressure and increased heart rate leading to a reduction in anaesthetics impair the baroreflex responses 133 and hence systolic function and to early diastolic dysfunction. 144 In decrease the sympathetic response to CCB. In dogs anaes- CAD patients with good LV function during high-dose thetized with halothane one per cent (inspired concentra- fentanyl anaesthesia, verapamil 75-150 I~g' kg-1 IV was tion), the administration of nifedipine 10 Ixg" kg- ~ IV was well tolerated. 145 No pharmacokinetic interaction has accompanied by a reduction of arterial pressure and SVR been reported with narcotics. 141 together with a rise in heart rate and cardiac output; with Barbiturates decreased the calcium uptake from sarco- halothane two per cent nifedipine decreased arterial plasmic reticulum, ~46 and most general anaesthetics pressure to a greater extent but did not increase heart rate inhibited Na-Ca exchange at the sarcolemma. 147 How- and cardiac output. 133 ever, Pierrot et al. t48 injected diltiazem O. 15 mg.kg -I Pharmacokinetic interactions have also been demon- IV in swine anaesthetized with thiopentone 100 mg-kg-1 strated. Serum verapamil levels were increased by halo- and observed only a transient decrease in arterial pressure thane, enflurane or isoflurane, t3'* This increase was without any change in cardiac output. explained by either a reduction of hepatic blood flow 13s or The combination of CCB and local anaesthetics can a dysfunction of the autonomic nervous system. 134 enhance their cardiac toxicity. This was demonstrated in The negative inotropic effects induced by the combina- dogs with diltiazem or verapamil associated with lido- tion of CCB and halogenated anaesthetics may be caine, ~49 and with nifedipine associated with bupiva- reversed by calcium chloride ~~ t2 but is potentiated by caine, la~ Though verapamil did not modify lidocaine magnesium. Io3 However, calcium is ineffective in con- kinetics, =51 lidocaine decreased serum verapamil levels duction disturbances which may respond to isoprenaline, by increasing the initial volume of distribution and glucagon and electrostimulation. 1~8 verapamil total clearance. ~52 Few clinical studies have assessed the effects of the combination of CCB and halogenated anaesthetics. Schulte- Neuromuscular relaxants Sasse et al. 136 showed that verapamil 0.15 mg. kg -t IV Potentiation of succinylcholine or pancuronium muscle was well tolerated during anaesthesia with low inspired relaxation by CCB has been observed in cats 153 and concentrations of halothane (0.35 per cent) in CAD rats. 154 Calcium-channel blockers decreased the magni- patients. The IV administration of verapamil may be tude of the twitch or the vecuronium dosage necessary to hazardous in some circumstances. For example, Moiler et obtain a 50 per cent reduction of twitch. 155 In a rat a1.137 reported cardiac arrest when verapamil 5 mg was phrenic-hemidiaphragm preparation, Salvador et a1.=56 injected IV to reduce tachycardia in a 56-yr-old patient showed substantial potentiation of succinylcholine by during halothane anaesthesia who had presented with diltiazem or verapamil, and a potentiation of pancuron- haemorrhagic shock. However, the combination of IV ium by nicardipine. The interaction site may be the Durand etal.: CALCIUM-CHANNEL BLOCKERS 81 cholinergic post synaptic membrane. 154 These interac- few cardiovascular side-effects. Intravenous bepridil or tions were not found in man ~57'~58 possibly because sublingual nifedipine resolved coronary artery spasm, smaller concentrations were used. especially during CABG surgery, 170'171 and sublingual nifedipine 10 mg reduced the vascular resistance of Perioperative use venous coronary graft. 172

Myocardial ischaemia Hypertension While a large number of studies reported the value of The efficacy of CCB to prevent or to treat perioperative prescribing beta-blockers before anaesthesia to prevent hypertensive episodes has been widely reported. Vera- myocardial ischaemia 159 the answer is still unclear for pamil 0.1 mg'kg -I IV 173 or sublingual nifedipine 10 CCB. The recurrence of angina pectoris 24 hr after mg 174'175 prevented the laryngoscopy pressor response discontinuing CCB has been reported. ~6o The administra- without effect on heart rate. Calcium-channel blockers tion of nifedipine until the day of CABG surgery was have been used to induce controlled hypotension during accompanied by the need tbr more inotropic support but surgery. Zimpfer et al. 176 administered verapamil 0.07 less vasodilatation therapy after cardiopulmonary bypass mg-kg-I IV during neuroleptanalgesia; arterial pressure compared with patients who had received their last dose of decreased by 10-20 per cent during the first ten minutes nifedipine the day before surgery. 16~ Conversely, the due mainly to a decrease in SVR. Nicardipine IV continuation of diltiazem until anaesthesia did not intro- decreased arterial pressure to 50-60 mmHg in hip duce haemodynamic differences compared with a control surgery. This was accompanied by a decrease in SVR and group. 162 In spite of continuing verapamil and nifedipine an increase in cardiac output. 177 Kishi et al. ~78 adminis- until surgery, tachycardia occurred during laryngoscopy tered nicardipine (1-2 mg IV) to control hypertensive in CAD patients. 163 Three prospective studies attempted episodes in vascular surgery and observed no change in to define the role of CCB administered until surgery to right and left filling pressures and in heart rate. Nifedipine prevent myocardial ischaemia during CABG surgery. 164-166 seemed effective but its light sensitivity complicates its Slogoff and Keats I~ in 444 patients observed signifi- use. 179 Van Wezel et al. is0 compared veraparnil, nifedip- cantly more ischaemic episodes in patients administered ine and nitroglycerine IV to maintain arterial pressure less no treatment or only CCB prior to surgery than in patients than 120 per cent of control in CABG surgery. Nifedipine administered beta-blockers associated or not with CCB. and nitroglycerine were well tolerated but verapamil Chung et al. 165 confirmed these findings in 92 patients. increased the PQ interval, pulmonary artery, and pulmo- Tuman et al. 166 studied 803 patients given either beta- nary capillary wedge pressures. Intravenous nicardipine blocker, CCB or no treatment prior to surgery. Although was used in the management of phaeochromocytoma, is1 the CCB patients presented with greater LV dysfunction Its effects seemed due to otz post synaptic blockade and before surgery, the incidence of perioperative myocardial inhibition of catecholamine release from the tumour.t82 infarction and ischaemia was significantly greater in the Also, CCB have been used to control postoperative control group than in the CCB group, and in the CCB hypertension, lntranasal nifedipine 10 mg controlled group than in the beta-blocker group. The mortality rate, hypertension after carotid endarterectomy in 13 of 14 however, was similar between the groups. In these three patients, a second administration being effective in the studies, CCB seemed to prevent ischaemia less than last patient. This was accompanied by an increase in beta-blockers. However, these studies were not random- cardiac index andmixed venous oygen saturation and a ized and the groups' sizes were unequal. As tachycardia decrease in pulmonary capillary wedge pressure. 183 was correlated with ischaemic episodes 164 the inclusion Mullen et al. 184 compared IV diltiazem, intranasal of patients administered different CCB in the CCB groups nifedipine and IV sodium nitroprusside to treat hyperten- could have led to methodological bias. Henling et al. 167 sion after CABG surgery. The dosages necessary to showed that the preoperative administration of beta- obtain equivalent effects on arterial pressure were respec- blocker with CCB was not accompanied by a greater tively 150-300 ixg.kg -I, 20-50 mg and I j.tg. kg -I .min -I. incidence of conduction disturbances. Heart rate and MVO2 decreased only with diltiazem. In two randomized studies, ~68.169diltiazem 0" 15 mg- kg- i Indices of LV systolic function were reduced by diltiazem IV followed by a continuous infusion of 3-5 p.g. kg -I. or nifedipine but not by sodium nitroprusside. Only min -~ started before induction of anaesthesia and sodium nitroprusside decreased myocardial lactate up- continued till 3-12 hr after tracheal extubation in CAD take. Intravenous nicardipine 12.5 mg-hr-i was efficient patients undergoing non-cardiac surgery decreased the in 44 out of 47 patients in less than 15 min followed by a 3 incidence of ischaemic episodes and was accompanied by mg.hr -I infusion. Is5 In our experience, nicardipine 82 CANADIAN JOURNAl. OF ANAESTHESIA

appears easier to administer than sodium nitroprusside. 5 Mc Call D. Excitation-contraction coupling in cardiac Nicardipine did not change heart rate and did not elicit and vascular smooth muscle: modification by calcium entry rebound hypertension at discontinuation, presumably due blockade. Circulation 1987; 75 (suppl V): V3-VI4. to stable plasma norepinephrine levels and longer biologi- 6 Reuter H. Scholz H. A study of the ion selectivity and the cal half-life. 186.187 The efficacy of nicardipine in reduc- kinetic properties of the calcium dependent slow inward ing blood pressure was similar to that of nitroglycerine but current in mammalian cardiac muscle. J Physiol (London) unlike nitroglycerine, nicardipine did not reduce the 1977; 264: 17-47. preload, thus it increased cardiac index. ~s8 7 Spedding M. Activators and inactivators of Ca 2+ channel: new perspectives. J Phamlacol 1985; 16, 4: 319-43. Arrhythmias 8 Hess P, Lansman JB, Nilius B, Tsien RW. Calcium Intravenous verapamil or diltiazem has been used to treat channel types in cardiac myocytes: modulation by supraventricular tachyarrhythmias during 189 or after w~ dihydropyridines and beta adrcnergic stimulation. J surgery, with few cardiovascular untoward effects. How- Cardiovasc Pharmacol 1986; 8 (suppl 9): SII-$21. ever, cardiac depression or auriculo-ventricular conduc- 9 Borsotto M, Barhanin J, Norman RI, Ladzunski M. tion disturbances may occur when CCB are associated Purification of the dihydropyridine receptor of the voltage- with beta-blockers. ~gt, 192 dependent Ca 2' channel from skeletal muscle transverse tubules using (+) IaHI PN 200-110. Biochem Malignant hyperthermia Biophys Res Commun 1984; 122: 1357-66. Experimental data suggested that CCB could prevent 10 Bkaily G, Sperelakis N. Injection of protein kinase malignant hyperthermia. 193 Unfortunately, the combina- inhibitor into cultured heart cells blocks calcium slow tion of dantrolene with verapamil caused cardiovascular channels. Am J Physiol 1984; 246: 630-4. collapses in swine '94 and man. 195 11 Murphy KMM, Gould R J, Largent L, Snyder SH. A unitary mechanism of calcium antagonist drug action. Conclusion Proc Natl Acad Sci 1983; 12, 80: 860-4. Like beta-blockers, CCB were initially used exclusively 12 Itoh H, L~'hikawa T, Hidaka H. Effects on calmodulin of by cardiologists. They are now at the disposal of bepridil, an antianginal agent. J Pharmacol Exp Ther anaesthetists and intensive care physicians, especially 1984; 230: 737-41. since the development of IV preparations. As these drugs 13 Lee KS, Tsien RW. Mechanism of calcium channel have profound effects on the cardiovascular system, blockade by verapamil, D600, diltiazcm and nitrendipinc extensive knowledge and understanding of their effects, in single dialysed heart cells. Nature 1983; 302: 790-4. including their interactions with anaesthetic agents, must 14 Dupuis BA. Electropharmacologie des inhibiteurs du lead to a more efficient and safer use. canal calcique lent. Les inhibiteurs du canal calcique lent en th6rapeutiquc cardiovasculaire. Geneva: Exccrpta Acknowledgement Medica 1985; 69-84. We thank Ms. Val6rie Lepage for manuscript preparation. 15 Van Zwieten PA, Timmermans PB, Thoolen M J, Wilffert B, De Jonge A. Inhibitory effects of calcium antagonist References drugs on vasoconstriction induced by vascular alpha-2 I Haas H, Hartfelder G. AIpha-isopropyl-alpha adrenoceptor stimulation. Am J Cardiol 1986; 57: [(N-MethyI-N-homo-veratryl)-gamma-amino-propyl]-3-4 11D-15D. dimethoxyphenyl acctonitril, eine Substanz mit 16 Mc Call D, Walsh RA, Frohlich ED, O'Rourke RA. coronargefassenweinterden Eingenshaften. Arzneimittel- Calcium entry blocking drugs: mechanism of action, forschung 1962; 12: 549-58. experimental studies and clinical uses. Curr Probl 2 Vanhoutte PM. The expert committee of the world health Cardiol 1985; I0, 8: 1-80. organization on classification of calcium antagonists: the 17 Thuillez C, Giudicelli JF. Pharmacologic cliniquc cardio- viewpoint of the rapporteur. Am J Cardiol 1987; 59: vasculaire des inhibiteurs du canal calcique lent. Les 3A-8A. inhibiteurs du canal calciquc lent en th6rapcutique 3 Thuillez C, Giudicelli JF. Definition et classification des cardiovasculaire. Geneva: Excerpta Medica 1985; 85-108. inhibiteurs du canal calcique lent. Les inhibitcurs du canal 18 Heno, PD. Comparative pharmacology of calcium calcique lent en th6rapeutique cardiovasculaire. Geneva: antagonists: nifedipine, verapamil and diltiazem. Am J Excerpta Medica, 1985; 7-15. Cardiol 1980; 46: 1047-58. 4 Braunwald E. Mechanism of action of calcium channel 19 KatesRE. Calcium antagonists. Pharmacokinetics blocking agents. N Engl J Med 1982; 307: 1618-27. properties. Drugs 1983; 25: 113-24. Durand etal.: CALCIUM-CHANNEl. BLOCKERS 83

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