75 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 possi- bly 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 after- load 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