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Home , Calcium channel blocker, Dantrolene, Diltiazem, Drug interaction, Lidocaine, Muscle relaxant

436

Anaesthetic implications of 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 block- Physiology - calcium/calcium channel blockers Uses of calcium channel blockers ers for the practising anaesthetist. These have Traditional played an expanding role in therapeutics since their pectoris introduction and thus anaesthetists can expect to see increasing numbers of patients presenting for anaes- thesia who are being treated with calcium channel Newer and investigational Cardiac blockers. Other reviews have emphasized the basic - Hypertrophic of calcium channel blockers. 1-7 - Cold cardioplegia - Physiology - calcium/calcium channel blockers Actions on Calcium plays an important role in many physio- Asthma Obstetrics logical processes, such as , en- - Premature labor zyme systems, , metabo- - Pre-eclampsia lism, synaptic transmission, and Achalasia and oesophageal excitability. Especially important is the role of Increased intraocular pressure therapy calcium in and conduction Protective effect on after radiocontrast Cerebral as well as in vascular reactivity. 7 Induced hypotensive anaesthesia Thus, it can be anticipated that any interfering Drag 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 -induced arrhythmias marily phospholipids arranged in a bilayer. Inter- With other drugs spersed throughout are macromolecular proteins and glycoproteins traversing the membrane, form- Beta adrenergic blockers ing channels. These channels are relatively specific to certain ions. Recently, channels which regulate 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, Inhibition of 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 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 , the resulting action potential has a slowly 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 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 , calcium is the important ion responsible for phase 0 depolarization, not sodium. Under abnormal condi- about contraction. In smooth muscle, , tions such as and ischaemia, ventricular rather than troponin acts as the 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 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. 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 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 , 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 . 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 trivalentcations 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. , Calcium channel blockers function by altering calcium uptake across the cellular membrane and , nitroprusside, nitroglycerine also by affecting intracellular uptake and release Inhalational anaesthetics: , 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 cardiovascularsystem (in viva)

Vasodilation 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. and is almost devoid of slow It is interesting that both nifedipine and 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 . 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 , 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 seem to be at Initially, calcium channel blockers were introduced ends of the spectrum of clinical activity, with for the treatment of angina, arrhythmias and hyper- diltiazem in the middle. All calcium channel block- tension. ers have a negative inotropic and The benefits for the patient with angina are effect in vitro with nifedipine having the greatest twofold. First, the calcium channel blockers act as effect. 6 Alternately, in the intact organism, there coronary vasodilators and increase blood supply to are reflex responses that offset these negative the myocardium. This is especially relevant in the effects. The potent vasodilating effect of nifedipine treatment of patients with Prinzmetal's angina. causes a decrease in which results in a Secondly, peripheral tends to decrease sympathetic stimulation of the heart via the barore- afterload and therefore reduce the work of the heart ceptors. Thus, in vivo, nifedipine has negligible and reduce myocardial oxygen consumption. De- effect on myocardial depression, sinus node activity creased myocardial contractility also reduces the and AV conduction. Alternatively, verapamil has oxygen consumption. 2'~ its greatest effect on the sinus node activity, thus In the treatment of arrhythmias, verapamil and to Jenkins and Scoates: CALCIUM CHANNEL BLOCKERS 439

a lesser extent diltiazem have been found to be Achalasia and oesophageal spasm 16-18 effective in terminating supraventricular arrhyth- Studies in which patients received infusions of mias. Verapamil is now considered the agent of verapami116 and nifedipine~7' 18 resulted in a statisti- choice in terminating acute episodes of paroxysmal cally significant decrease in resting lower oesopha- supraventricular in adults and chil- geal pressure in both normal subjects and patients dren. The effect is produced as a result of slowing of with achalasia. The studies suggested that vera- conduction through the AV node and/or prolonging pamil may have a potential use as a drug therapy in refractoriness. 2 Nifedipine, because it has negligi- treating the clinical symptoms of achalasia and ble effects on the SA node or AV node is not useful diffuse . for treatment of supraventricular arrhythmias. Ven- Increased intraocular pressure therapyl 9 tricular arrhythmias are not particularly responsive It has been shown clinically that calcium channel to calcium channel blockers. 2 blockers are capable of significantly decreasing Hypertension has been successfully treated with the raised intraocular pressure. calcium channel blockers. Decrease in systemic Protective.effect on kidney after radiocontrast vascular resistance produced by nifedipine can be Studies have shown a lack of rise of plasma used to manage hypertension.2 creatinine in patients treated before coronary anglo- grams with nifedipine compared to those without Newer and investigational uses pretreatment, 2~ thus indicating a possible future role in renal protection. Cardiac Recent studies have successfully demonstrated the Cerebral vasospasm 2 use of nifedipine in hypertrophic cardiomyopathy 9 Calcium channel blockers are potent cerebral and as an adjunct to cold cardioplegia. 1o Nifedipine arterial dilators." Cerebral arterial spasm induced has been reported as a beneficial inhibitor of by a variety of techniques in laboratory animals is hypoxie pulmonary vasoconstrictionI~ in pulmo- blocked by nifedipine and verapamil. However, nary hypertension and in patients with chronic there are no large, well-designed investigations in obstructive pulmonary disease. ~~ humans showing the efficacy of calcium channel blockers in intracerebrai arterial spasm. Actions on platelets Both nifedipine and verapamil have been shown Induced hypotensive anaesthesia Verapamil has been given as single 0.07 mg'kg -l to inhibit aggregation of platelets caused in vitro by collagen, the second phase of ADP induced boluses to electively induce in pa- aggregation and aggregation caused by ionophore tients undergoing neuroleptanaesthesia. Mean A2318713 (see also discussion on inhibition of blood pressure decreased from 108 to 84 (p< platelet aggegation). 0.001) without significant change in heart rate or pulmonary pressure. These effects were Asthma reversed by 15mg-kg -t of . Verapamil and nifedipine have been studied for For a prolonged effect, an infusion of verapamil potential benefits in the treatment of both intrinsic would be necessary. 2 asthma and exercise induced asthma.14'~5 Verapa- mil has been shown to inhibit post-exercise in- Drug interactions with calcium channel blockers duced bronchospasm in susceptible persons, i5 It is apparent that calcium channel blockers may interact with anaesthetic agents and also with other Obstetrics drugs which are commonly encountered in surgical Merin I has suggested that the smooth muscle patients. dilating effects may be therapeutic for premature labour in obstetrics and also therapeutic for pre- With anaesthetic agents eclamptic toxemia of , by virtue of the vasodilating effects. Investigational clinical trials INHALATION AGENTS are being contemplated, Haemodynamic effects. Only one human study has 440 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

been reported demonstrating the of verapamil alters MAC for halothane in dogs. MAC halothane anaesthesia and intravenous verapamil was reduced from 0.97 to 0.72 per cent. Knowledge 0.15 mg'kg-t given over ten minutes. 21 This study that verapamil treatment increased the depth of investigated eight patients scheduled for coronary anaesthesia, possibly on the basis of fast channel artery bypass . All patients had normal left blockade, may require adjustment of the dose of ventricular function at rest and were being treated anaesthetic agent. However, no human data are with long-term beta-adrenergic blockers. Halo- available to date. thane produced a marked reduction in mean arterial pressure, cardiac index, and left ventricular con- Neuromuscular blockers tractility as documented by a decrease in left Currently there are no published controlled studies ventricular peak positive dP/dT. Addition of vera- in man evaluating the interactions of neuromuscular pamil caused further depression (16 per cent) of left blocking agents and the calcium channel blockers. ventricular peak positive dP/dT accompanied by a Considerable animal data have been collected and, small increase (3 mmHg) in left ventricular end- although showing some species variation, they diastolic pressure. The combined negative inotropic strongly suggest an important effect at the neuro- properties of halothane and verapamil did not muscular junction. produce any overt untoward effects even in the Studies of the effects of calcium channel blockers presence of chronic low-dose beta-blocker therapy. alone on the have revealed The predominant haemodynamic effect of vera- that in most species there is a progressive dose- pamil was systemic vasodilation resulting in a related reduction in twitch height with the adminis- further reduction in MAP (12 per cent) while heart tration of verapamil or nifedipine. 23'24'27-3~ Dil- rate remained unaffected. The PR interval remained tiazem has been shown to augment indirect twitch unchanged throughout the study. The authors tension when administered to dogs. 8 pointed out that, despite the reduced myocardial In animals, effects of both depolarizing muscle oxygen demand, caution must be exercised in dose relaxants 29,3~ and nondepolarizing muscle selection of each drug to avoid regional myo- relaxants are augmented by verapami]. 27'29-31 cardial ischaemia due to the combined hypotensive However, again, human evidence is lacking. The effects of halothane and verapamil. This study is reversal of the combined /calcium applicable only in patients with normal left ven- channel blocker did not seem to be any tricular function at rest. Studies in animals 22-24 also different to that without the calcium channel show similar changes to those reported in man. blocker. 27,31 In essence, when dealing with patients who are Although no human research has been done, two being treated with verapamil, one should be cau- case reports have recently appeared in the litera- tious in using this agent with halothane and/or ture that indicate problems when calcium channel further verapamil as significant myocardial depres- blockers have been used. 32'33 sion may result. This may be especially impotant in A patient with Duchenne's muscular dystrophy 32 patients with pre-existing myocardial impairment. presented with atrial futter. Following administra- No studies of interactions of nifedipine or diltia- tion of 6.0 mg verapamil, he became cyanotic and zem with inhalational agents have been reported lost consciousness. He was ventilated by mask and and only one study in animals zs demonstrated intubated. the effects of verapamil with other inhalational Subsequent reverted his rhythm to agents (enflurane and isoflurane). In this study, normal sinus rhythm. However, despite haemo- there was a lower blood pressure, more myo- dynamic stability and clear sensorium he was not cardial depression and more conduction abnor- able to be extubated because of respiratory insuffi- malities with enflurane and verapamil than with ciency. Verapamil appeared to have triggered the either halothane or isoflurane. precipitous apnoea. The authors suggest that the margin of safety of the neuromuscular junction Effects on MAC. Only one study has shown the must be impaired before the neuromuscular block- effects of calcium channel blockers in depth of ing effects of verapamil become clinically apparent. anaesthesia 26 as reflected by the manner in which Van Poorten 33 reported a case of prolonged Jenkins and Scoates: CALCIUM CHANNEL BLOCKERS 441

paralysis after vecuronium in a patient being treated to be 1.6 times as potent as procaine 2 in this regard. with verapamil. The patient was a 66 year old with Overall, the animal data and the human case renal failure controlled with regular dialysis. She reports strongly suggest that there is an augmenta- developed intra-abdominal sepsis and also episodes tion of both depolarizing and nondepolarizing of intermittent supraventricular tachycardia neces- neuromuscular blockade when calcium anatago- sitating treatment with 5 mg of verapamil 1V three nists are concurrently administered. The anaesthe- times daily. She was booked for exploratory laparo- tist should be aware of this potential problem and tomy, no were given three days prior to should carefully monitor the neuromuscular junc- surgery and she was dialyzed the day prior to tion, titrating drugs to the desired effect. surgery. Anaesthesia was induced with 200mg thiopentone and maintained with 66 per cent nitrous Effects on epinephrine induced arrhythmias z2 oxide in oxygen. was achieved The antiarrhythmic effects of verapamil were with 8 mg vecuronium and was adminis- studied during 1.1 MAC halothane anaesthesia in tered as required. Ten minutes after induction a dogs, in which the epinephrine arrhythmogenic further 2 mg of vecuronium was given based on a dose was determined with and without the addition single twitch response to two per cent of control of 0.2 mg'kg -~ of verapamil. Verapamil elevated value. No further vecuronium was needed for the dose of epinephrine required to produce ven- another 90 minutes when a further 1 mg was given. tricular . Verapamil was also shown to The operation ended 50 minutes after the last dose be effective in terminating episodes of ventricular of vecuronimn; single twich response was 20 per tachycardia induced by epinephrine infusion but not cent of control value and administration of 3 mg regular . The relevance of and 1 mg returned single these data to humans is yet to be determined. twitch response to only 60 per cent of control. A total of 3 mg more of neostigmine was given over INTERACTION WITH OTHER DRUGS the next 90 minutes before the patient was suffi- ciently recovered to permit extubation. Compared Digoxin 34 - Verapamil reduces the total body to their previous experience with renal failure of digoxin by 35 per cent due to impair- patients and veeuronium administration, the au- ment of its elimination. This results in an increase in thors suggest that this represented both a prolonged plasma concentrations by 60-80 per cent. Vera- dosing interval and prolonged recovery. The au- pamil does not alter the positive inotropic effect of thors stated that, in most renal failure patients, a digoxin on the heart as shown by measurements of comparable dose required top ups at 20-30-minute systolic time intervals. 34 This is clinically impor- intervals and could always be reversed with neo- tant, as addition of verapamil to steady-state di- stigmine. goxin therapy could precipitate . They concluded that the verapamil caused the prolongation of the block. They did not consider Beta-adrenergic blockers () 2t'35-39 - other causative possibilities such as myasthenie Considerable attention has been placed on the syndrome. possible interactions of calcium channel blockers Much speculation has been generated to explain and beta-adrenergic blockers for several reasons. the causes of the prolongation of neuromuscular Calcium channel blockers, and especially nifedi- block effects. Presynaptic alterations could be pine, depend on reflex sympathetic stimulation to responsible by reducing calcium conduction, alter- ameliorate the direct effects that they ing intracellular presynaptic calcium pools, cyclic have on the myocardium. Thus, when a beta- AMP levels, or inhibiting membrane calcium pump adrenergic blocker is added, it will unmask the mechanisms. All of these effects could lead to an direct effects of the . 37 interference of mobilization or re- Both beta-adrenergic blockers and verapamil and lease. It has also been postulated that these effects diltiazem slow conduction through the AV node and could be due to a local anaesthetic action of have direct myocardial depressant effects. verapamil on nerve conduction as a result of There are numerous case reports that show blockade of sodium channels. Verapamil has shown significant problems when verapamil and beta- 442 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL adrenergic blockers are used together. 3s In most lar ectopy. After achieving control of his arrhyth- instances, verapamil was used to treat paroxysmal mias, and with steady quinidine blood levels, he supraventricular tachycardia, or developed angina and, therefore, nifedipine 10 mg flutter. Adverse reactions varied from hypotension, three times a day was added. The ventricular ectopy AV block and to asystole and cardio- recurred and quinidine levels showed a significant genic shock. Most, but not all patients, had underly- decline. The dose of quinidine was increased to ing cardiac disease. 36-39 Thus, current guidelines35 control the ectopy. When nifedipine was subse- for use of intravenous verapamil in the presence of, quently discontinued, quinidine levels rose into the or coincidentally with, beta-blockers are: (a) the toxic range. patient should have ECG monitoring; (b) the The authors speculate that it was most likely administration of calcium channel blockers should nifedipine, through dilatation of the peripheral be separated by six hours from prior beta-adrenergic vasculature and possible augmentation of cardiac administration in patients with underlying heart output (by decreasing afterload), that has increased disease; (c) the combination of calcium channel the of quinidine. In treating blockers and beta-adrenergic blockers should not be patients who are receiving quinidine, it would administered to patients with AV node disease, appear possible that introduction of nifedipine may congestive or cardiomyopathy. lower quinidine levels and decrease effectiveness of One study does report negligible36 myocardial the drug. depressant effects and no change in heart rate when patients receiving chronic propranolol therapy were Theophylline 41"42 - A case history41 was reported treated with up to 0.1 mg'kg- ' of verapamil intrave- of a 76-year-old patient with chronic obstructive nously during heart catheterization. All patients pulmonary disease who was treated with sustained studied had normal left ventricular function. release theophylline and who developed paroxys- Other studies 35'39 have demonstrated the safety mal supraventricular tachycardia. She was treated of oral verapamil concomitantly used with beta- with verapamil 80 mg qSh. There was an initial adrenergic blockers in the treatment of angina good response and then a gradually increasing heart pectoris. Once again, all these patients had normal rate and increasing . The theophylline level left ventricular function. was 27.91.tg.ml-~, up from 14.5~g.ml -~ at the Finally, if an adverse interaction does occur after time of administration, prior to verapamil. administration of concomitant IV verapamil and The authors felt that the most likely cause of the oral or IV beta-adrenergic blockers, treatment problem was competitive hepatic . should consist of atropine, isoproterenol, calcium Verapamil and theophylline both undergo extensive and/or temporary pacing when necessary. 35 Further first pass metabolism and have the N-demethylation studies are needed to understand the exact mecha- process in common. nism of this . The possibility of elevated concentrations of Thus, it would seem prudent to avoid the combi- theophylline must be considered when verapamil or nations of verapamil or diltiazem with beta- nifedipine42 therapy is used in a patient being blockers if at all possible, especially in patients with treated with theophylline. underlying cardiac disease. Although verapamil has been given safely to patients receiving beta block- Dantrolene - A recent report concerns swine (non- ers, 21'37'3s'39 all these studies have been done on MH susceptibles)43 anaesthetized with patients with normal left ventricular function, so and then started on verapamil 0.1 mg.kg -t this must be borne in mind if one considers using the followed by an infusion of 0.005mg'kg-I'hr-~. combination. After one hour, dantrolene was given in boluses of 1.0, 3.3 and 5.6mg.kg -~. All animals showed a Quinidine 4~ - A nifedipine-quinidine interaction profound decrease in cardiac output, and mean was reported in a 51-year-old male. He had an acute arterial pressure, and increase in central venous anteroseptal myocardial , developed con- pressure, pulmonary artery pressure and pulmonary gestive heart failure, with an ejection fraction of 20 capillary wedge pressures. All animals died with per cent and was treated with quinidine for ventricu- complete AV block followed by . The Jenkins and Scoates: CALCIUM CHANNEL BLOCKERS 443 authors suggest that the was implications in that the risk of regurgitation occur- due to the additive effects of verapamil blocking the ring during induction of anaesthesia and during calcium influx across slow channels in cardiac and mask ventilation techniques is increased in pa- vascular smooth muscle cells and the dantrolene tients on these drugs, due to the drugs' ability to blocking the calcium release from the sarcoplasmic lower the amount of pressure necessary to open the reticulum that were responsible for the deaths. The lower oesophageal sphincter. Fortunately, there authors admit that, although data from a porcine appears to be no effect on gastric emptying time. model cannot be extrapolated to humans, they felt that further studies were indicated to help evaluate a Effects on intracranial hypertension 45 possible fatal drug interaction before verapamil and Calcium channel blockers 45'a6 are believed to be dantrolene are used concomitantly in a clinical potent cerebral vasodilators, as well as antihyper- setting, a3 tensives. There is thus the potential of contributing Another study 44 investigated cardiovascular to an increase in similar to that changes in dogs anaesthetized with chloralose- which is known to occur with nitroglycerine47 and urethane when varying doses of dantrolene and nitroprusside. 4s verapamil were used. Although dantrolene was felt Studies of the effects of nifedipine on intracranial to augment the myocardial depression seen with pressure (ICP) in cats 46 both with normal and verapamil and also prolong the PR and AV inter- increased ICP, demonstrated a significant increase vals, it was not to the same dramatic extent seen in in ICP in both groups, but it was consistently larger the previous case reported. However, the authors in the group of cats already compromised. There felt that the combination of the drugs offered no was an associated critical reduction in cerebral advantage that justified their concomitant use. perfusion pressure. Verapamil has been studied in ten hypertensive Pathophysiologicai alterations (other than patients 45 with supratentorial mass lesions, under cardiovascular) with anaesthetic implications . Significant increases in ICP were seen (18 to 27 mmHg versus a reduction from Decrease in lower oesophageal sphincter tone 16- i s 18 to llmmHg in control patients), following Several studies have demonstrated that calcium 5.0 mg of verapamil intravenously. Cerebral perfu- channel blockers can reduce tower oesophageal sion pressure was also significantly reduced in the sphincter tone, in both normal subjects and in verapamil versus the control group despite similar patients with achalasia or oesophageal spasm. reductions in mean arterial pressure (MAP). The Verapamil m6 given in a dose of 0.15mg.kg -~ increases in ICP were readily reversed with hyper- intravenously over a two-minute period can de- ventilation and intravenous lidocaine (1.5 mg'kg-t). crease lower oesophageal sphincter tone by 30 per The authors concluded that calcium channel cent, in both normal and symptomatic patients. The blockers should be avoided in patients with com- duration of their effect was 25 minutes. The authors promised intracranial compliance unless ICP is did not comment on the possible complications of being monitored and proper therapy for intracranial potential regurgitation predilection. hypertension can be readily instituted. In another study, ~7 nifedipine was given as a sublingual dose 10-20mg. Lower oesophageal Asthma sphincter tone was also reduced by 30 per cent with Because calcium channel blockers play a role in the effect returning to baseline by one hour, in relaxation of smooth muscle, they have been patients with achalasia. Nifedipine was also studied studied in relation to clinical use in asthma. Ni- as to the effects on gastric emptying time and lower fedipine, 20 mg orally 14 did not produce any effect oesophageal sphincter pressure (LESP) in normal on the FEV~ of patients with intrinsic asthma, humans. ~s The LESP fell from 17.6 to 7.7 mmHg in however, subsequent inhalation of pro- these normals. There was no significant influence duced a significantly greater bronchodilatory effect on the rate of gastric emptying. compared to a group that received instead This significant reduction in LESP by calcium of nifedipine. The study showed that nifedipine channel blockers may have important anaesthetic potentiated beta adrenoceptor mediated broncho- 444 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL dilatation. This is of importance when treating oxygen content despite the decrease in PaO2. patients with simultaneous asthma and hyperten- Nifedipine may be a useful adjuvant to supplement sion or angina pectoris. oxygen in the treatment of hypoxic pulmonary Other studies Ls'49 have shown the lack of effect hypertension. of nifedipine or verapamil on baseline airway With anaesthesia, two aspects should be con- resistance. Verapamil, however, has been shown to sidered. Firstly, certain circumstances exist when have a protective effect on exercise induced asthma HPV works to our advantage, namely with one lung equal to that of sodium cromoglycate. 15 This is anaesthesia. Secondly, the reduction in PaO2 noted postulated to be in part related to inhibition of above may become more important under anaesthe- mediator release (histamine, prostaglandins) from sia when the reflex increase in C.O. may not be mast cells. present in order to increase oxygen delivery to the From these studies, it is useful to know that periphery and thus compensate for the lower PO2. calcium channel blockers, unlike beta-adrenergic blockers, will not have a detrimental effect on Malignant hyperthermia 5~ bronchial smooth muscle in asthmatic patients Because abnormal calcium transport plays an im- requiring these agents for the treatment of hyperten- portant role in the genesis of malignant hyperther- sion, angina or dysrhythmias. It could be antici- mia, it has been postulated that calcium channel pated that there may, indeed, be some potentiation blockers could have a beneficial effect in its of the effects of beta2 in the presence of prevention or treatment. calcium channel blockers. Verapamil has been shown to prevent muscle contracture in vitro in human muscle susceptible to Muscular dystrophy malignant hyperthermia in one report (cited in re- The patient with Duchenne's muscular dystrophy 32 ference 50). referred to previously received verapamil and de- A study of eight China/Poland pigss~ was under- veloped . The current consensus is taken using a loading dose of 0.5mg.kg -~ of that calcium channel blockers do not produce any verapamil and a constant infusion of 0.035 rag" detrimental effect on the neuromuscular function of kg- l.min- 1 during halothane anaesthesia. The only humans, unless there is some pre-existing compro- effect that was seen in this study was that a delay in mise. The implication is, though, to titrate calcium onset of the malignant hyperthermia process from channel blockers very cautiously in patients with one to five minutes in untreated animals to 25-30 neuromuscular problems, or avoid altogether, by minutes in animals treated with calcium channel choosing alternate agents. blockers. All the animals in the study eventually died. However, no treatment of the malignant ttypoxic pulmonary vasoconstriction hyperthermia was undertaken. Reports are now appearing about the use of nifedi- It would appear that calcium channel blockers pine for the treatment of hypoxic pulmonary vaso- alone, are ineffective in the treatment of malignant constriction (HPV) in association with chronic hyperthermia. Further studies are required to deter- obstructive pulmonary disease (COPD)) 1'12 No mine whether or not these agents might be useful long-term trials have been published, but acute adjuncts in the treatment of the condition. How- treatment regimes with oral nifedipine seem to lead ever, as previously noted, untoward interactions to decreased pulmonary artery pressure, especially with dantrolene may also preclude their use. in association with exercise 12 leading to increased exercise ability. Kennedy et al. ~2 in their study Inhibition of platelet aggregation 13 showed that there was significant reduction in the Studies in vitro with human platelets have shown PaO2 associated with the decrease in pulmonary that both verapamil and nifedipine have effects on vascular resistance index, presumably due to in- inhibiting platelet aggregation induced by various creased shunting. However, they point out that in activators, such as epinephrine, collagen and most cases there was a significant increase in diphosphate. 13 oxygen delivery because of decreased SVR and Although the potential implication that calcium increased C.O. and n o change in the mixed venous channel blockers could possibly interfere with Jenkins and Scoates: CALCIUM CHANNEL BLOCKERS 445 coagulation perioperatively exists, there are no with calcium channel blockers and who requires clinical reports to substantiate this possibility and it anaesthesia will become more common. would appear that this is not an important problem. Calcium channel blockers may, under certain cirumstances, potentiate haemodynamic and MAC Hyperkalemia depressive effects of inhalation agents. There is also Several studies in animals found unexpected hyper- evidence that the effects of neuromuscular blocking kalemia following verapamil therapy. The first such agents may be potentiated. The anaesthetist should study43 was in swine being studied for the interac- be aware that the potential for interactions exists tion of verapamil and dantrolene. An incidental with digoxin, propranolol, quinidine, theophylline finding was a significant increase in serum potas- or dantrolene. sium in animals receiving both drugs, in some Of interest and some significance are the instances up to two times the initial level of anaesthetic implications of pathophysiological . alterations that can be induced by calcium channel In another study51 with dogs, the authors were blockers, by affecting lower oesophageal tone, concerned about the combined AV nodal conduc- intracranial hypertension, bronchomotor tone tion and myocardial depression of verapamil, halo- (asthma), muscular dystrophy, neuromuscular thane and hyperkalemia. Their model produced this function, hypoxic pulmonary vasoconstriction, ma- combination and the effects were monitored. KCI lignant hyperthermia, inhibition of platelet aggre- was infused until the EKG showed signs of severe gation and hyperkalemia. hyperkalemia. Haemodynamic measurements were Despite these significant potential anaesthetic obtained and the differences noted. Verapamil implications and because, at this time, in some treated dogs required, on the average, one third the instances withdrawal has clearly demonstrated in- dose of KC1 required to produce EKG changes and crease in the signs of myocardial ischaemia, it serum levels comparable to the control group would not seem necessary to recommend preopera- (-9.0mEq/L). There was also an augmentation of tive discontinuation of calcium channel blocker the haemodynamic effects compared to those seen in patients presenting for anaesthesia. It with hyperkalemia alone. is, however, appropriate that there is a high index of Although these studies were conducted in ani- awareness of potential problems, unless there is mals, and further study should be undertaken in some modification in inhalation anaesthetic concen- man, the data suggest that verapamil-treated dogs trations and neuromuscular blocker dosage. Moni- require less potassium than nontreated animals to toring of cardiovascular and neuromuscular func- develop haemodynamic effects of acute hyper- tions is essential. kalemia. Use of verapamil in renal failure patients Calcium channel blockers would appear to be could lead to a significant rise in serum potassium; currently the drugs of choice for angina pectoris, however~ further study is needed. arrhythmias or hypertension in patients with associ- ated chronic obstructive pulmonary disease.

Summary Clinical uses of calcium channel blockers are References expanding. In addition to the established uses in 1 Merin RG. Pharmacologic therapy in cardiac patients with arrhythmias, angina pcctoris or hyper- patients: calcium channel and beta-adrenergie block- tension, newer and to some extent investigational ing drugs. American Society of Anesthesiologists uses indicate widespread application. For instance, Refresher Course Lectures. 1984; 212. their use has been reported in hypertrophic cardio- 2 Reaves JG, Kissin I, LeU WA, Tosone S. Calcium myopathy and cold cardioplegia, as well as in entry blockers: uses and implications for anesthe- pulmonary hypertension, antiplatelet therapy, asth- siologists. Anesthesiology 1983; 57: 504-18. ma, achalasia and oesophageal spasm, increased 3 Merin RG. Slow channel inhibitors, intraocular pressure and in cerebral vasospasm. and cardiovascular function (Editorial). Anesthe- Their use in obstetrical practice has been proposed. siology 1981; 55: 198-200. Thus, the presentation of a patient who is treated 40pie LH. Calcium antagonists. Mechanisms, thera- 446 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

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