Nitrates, Digoxin and Calcium Channel Blockers

 

Dr. Paul Forrest

Royal Prince Alfred Hospital

 

 

 

 

Nitrates

 

In anaesthesia, our main therapeutic use of nitrates is in the perioperative management of myocardial ischaemia or congestive cardiac failure.  Hence most of this section will pertain to the use of intravenous nitrates- of which the only  example in clinical use is nitroglycerine.

 

Nitroglygerine was used in the management of angina as ealy as 1879.  Since then, it has become on of the most widely used anti-ischaemic agents,  but it has also found a role in the treatment of a variety of other conditions where smooth muscle relaxation is sought (Table 1).

 

                                          

                                           Table 1.  Indications for nitrate therapy                              

                                           ________________________________________________

                                           Ischaemic heart disease

                                           Stable angina pectoris

                                           Unstable angina pectoris

                                           Acute myocardial infarction

                                           Postmyocardial infarction

                                           Vasospastic angina

 

                                           Congestive heart failure

                                           Acute heart failure with pulmonary oedema

                                           Chronic heart failure

 

                                           Miscellaneous

                                           Percutaneous coronary angioplasty

                                           Perioperative blood pressure control

                                            Treatment of oesophageal spasm

                                           Treatment of retinal artery occlusion

                                           Treatment of uterine hypertonus

                                           Treatment of biliary spasm

                                           Treatment of pulmonary hypertensive syndromes

                                                                                                                                                               

 

 

MECHANISM OF ACTION

The nitrates are members of a group of drugs known as nitrovasodilators.  Their mechanism of action at the tissue level has only recently been elucidated.  The nitrates are prodrugs which penetrate the vascular endothelium and are reduced to nitric oxide (NO), nitrosothiols and s-nitrosocysteine.  NO is the most important of these compounds and it is formed from the amino acid L-arginine.  The mechanism by which nitroglycerine is denitrogenated to NO is unclear.  NO exerts its vascular effects by activating the enzyme guanylate cyclase,  which converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).  cGMP in turn produces phosphorylation of protein kinase, which decreases cytosolic calcium and produces smooth muscle relaxation.

 

CARDIOVASCULAR EFFECTS

Nitroglycerine has numerous vascular effects that decrease myocardial ischaemia (table 2), although it is thought that those mechanisms that alter the balance between myocardial oxygen demand and supply are the most important.  Nitroglcerine dilates veins more than arteries, in contrast to nitroprusside.  Venodilatation occurs mainly in the limbs, splanchnic and mesenteric circulations.  This results in a reduction in cardiac preload,  afterload,  venticular wall tension and myocardial oxygen demand.

 

                                         

 

                                          Table 2.  Anti-ischaemic actions of nitroglycerine.

                                          decreased preload, afterload, myocardial oxygen consumption

                                          increased ventricular fibrillation threshold

                                          decreased size, extension and complications of myocardial infarction

                                          decreased platelet aggregation

                                          enhancement of thrombolytic therapy

                                          dilation of stenotic coronary arteries

 

 

The nitrates can also improve myocardial oxygen supply.  Nitroglycerine can dilate stenotic, atherosclerotic coronary arteries.  Nitroglycerine acts on the coronary circulation primarily by dilating large conductive vessels,  with only weak and transient effects on the small resistance vessels.  Hence while nitroglycerine decreases coronary perfusion pressure,  it both augments myocarial blood flow and redistributes it more favourably to increase the endo-epicardial blood flow.  Nitroprusside by comparison may decrease the collateral flow to areas of ischaemia by causing a decrease in coronary perfusion pressure or by dilating coronary resistance vessels to produce Ôcoronary steal,Ő which may worsen myocardial ischaemia (Table 3).

 

              Table 3.  Comparison of nitroglycerine(GTN) and nitroprusside(SNP).                

                                                                                          SNP                                GTN                                                                               

                     Preload                                                           -                           - -

                     Afterload                                                   - -                           -

                     MVO2                                                                                                                          -                           -

                     Ischaemic ECG changes                          +                          -

                     Stenotic gradient                                         0                           +

                     Toxicity                                               Cyanide                Methaemoglobin

                     Internal mammary flow                           +                          +

                     Saphenous vein flow                                 +                          -

                     Respiratory effects                                     ++                       +

                                                                                                                                                                         

                    

ANTIPLATELET AND ANTITHROMBOTIC EFFECTS

Nitroglycerine will produce prolongation of the bleeding time in a dose-dependent manner.  Initially this was thought to occur only with supraclinical doses, although there is now evidence that that nitroglycerine may alter platelet function at clinically relevant doses. 

The mechanism of action and metabolism of nitrates in platelets is similar to that in vascular smooth muscle, it too is mediated by NO, which activates guanylate cycalse.  The resultant increase in intracellular cGMP produces a decrease in platelet function. 

Despite the experimental evidence, the clinical relevance of the antiplatelet and antithrombotic effects of nitroglycerine has not been determined.

 

 

Clinical Pharmacology

 

A major advantage of the organic nitrates is their pharmacologic versatility, enabling a wide variety of dosing systems and formulations.  The nitrates that are in clinical use today are nitroglycerine, isosorbide dinitrate and recently, 5-isosorbide mononitrate. 

 

NITROGLYCERINE

Nitroglycerine is highly extracted from blood by the liver.  It has a very short half-life of 2.8minutes and it is widely distributed, with a volume of distribution of aboul 3L/kg.  Nitroglycerine is volatile and relatively unstable,  tablets lose their effectiveness oner 4-6 months.  The usual routes of administration are sublingual, intravenous or topical.  Intravenous infusion solution should be made up immediately prior to use in a glass bottle as it readily migrates into plastic.  The usual infusion concentration is 100µg/ml,  the infusion rate is titrated to effect but is usually in the range of 0.5-1.5µg/kg/min.

Topical nitroglycerine is prepared as an ointment or as a patch.  Nitroglycerine patches produce sustained plasma concentrations although this may encourage the development of tolerance.

 

ISOSORBIDE DINITRATE

Isosorbide dinitrate differs from nitroglycerine by its longer terminal elimation half-life (20 minutes iv., 64 minutes sublingually).  It also has a high first-pass metabolism, it is broken down to 5-isosorbide- mononitrate and 2-isosorbide -mononitrate which are both more active than their parent compound.  The longer half-life of isosorbide dinitrate and its metabolites may increase the likelihood of tolerance developing.

 

 

Side Effects

 

Side effects from the nitrates are few, regardless of the route of administration.  The most common adverse effects are hypotension (especially orthostatic) and headache.  Nausea and occasionally bradycardia have been reported with nitroglycerine. Nitroglycerine may also aggravate hypoxia by inhibiting hypoxic pulmonary vasoconstriction and worsening V/Q mismatch.  High doses of nitroglycerine may produce methaemoglobinaemia.  Topical nitrates may produce skin reactions.

 

 

Clinical Uses of Nitrates

 

1.     Acute myocardial infarction  Early nitroglycerine therapy following acute myocardial infarction has been shown to decrease infarct size,  improve ventricular function and reduce the incidence of complications,  including both early and late mortality.  Intravenous therapy is recommended for 48 hours if possible.

 

2.        Chronic therapy after myocardial infarction.  Healing of myocardial infarction takes 3-6 months.  During this time, the infarct area undergoes expansion, with stretching, thinning and dilatation.  Nitrate therapy during this period produces improved left ventricular function, less ventricular dilatation and a reduced frequency of aneurysm formation.

 

3.        Unstable angine.  Nitroglycerine is a clinically effective therapy for unstable angina.  Nitroglycerine has not been shown to be more effective than isosorbide dinitrate paste in the treatment of unstable angina,  although it is the preferred agent because of its rapid onset and titratability.

 

4.        Stable angina pectoris.  Nitrates are effective in the management of stable angina, however, there remains uncertainty as to their ideal utilisation.  Nitrates are as effective as §-blockers or calcium channel blockers as monotherapy for chronic angina. 

            Oral nitrates may be more effective than transdermal, furthermore continuous use should be avoided to prevent the development of tolerance-hence a Ônitrate-freeŐ interval of at least 8 hours/day may be necessary.

            The use of a nitrate-free interval has been associated with rebound ischaemia and a decrease in exercise tolerance, these are inconsistent findings however and their clinical relevance is unclear.

 

5.        Perioperative use of nitroglycerine.  There is little evidence to support the use of prophylactic nitroglycerine to reduce ischaemia in patients with coronary artery disease undergoing cardiac or non cardiac surgery.  During cardiac surgery, nitroglycerine has been shown to be ineffective as prophylaxis but effective as therapy for internal mammary artery spasm.

 

6.        Congestive heart failure.  With its multiple beneficial haemodynamic effects, there is little doubt about the efficacy of nitroglycerine in acute CHF.  It is assumed to be of value in chronic CHF but this has not been unequivocably proven. 

            Some recent work suggests that the concomitant use of oral hydrallazine will prevent the early development of nitrate tolerance in patients with CHF.

 

7.        Miscellaneous uses.  Nitroglycerine is an effective agent in the treatment of uterine hypertonus.  It has also been used to manage perioperative hypertension and to induce hypotension.  Nitroglycerine is also a first-line drug in the treatment of pulmonary hypertension associated with ischaemia and ventricular dysfunction.

 

 


Digoxin

 

 

Pharmacology

 

Digoxin is the most widely used member of the digitalis glycosides.  The digitalis glycosides have been used for over two centuries, the principal clinical uses currently are in the treatment of congestive heart failure and in the treatment of atrial arrhythmias.  Digoxin is a positive inotrope and enhances automaticity while slowing impulse propagation in conductive tissue. 

 

MECHANISM OF ACTION

Digoxin exerts its positive inotropic effect independently of the sympathetic nervous system although in common with it,  both ultimately act to raise the level of intracellular calcium.  Digoxin brings this about by first binding to the a-subunit of sodium-potassium ATPase (which is increased in CHF).  ATPase generates the energy for the extrusion of sodium fron the cell during phase 4 of the membrane potential..  Therefore inhibition of ATPase results in an influx of sodium and an efflux of potassium from the cell.  This increases phase 4 depolarisation and causes the resting membrane potential to become less negative.  The rise in intracellular sodium also produces an increase in intracellular calcium through Na+-Ca++exchange, which results in increased contractility.  Increased intracellular calcium is associated with decreased intracellular pH, which increases inward sodium movement and outward H+ movement, further increasing intracellular sodium and inotropy. 

 

CARDIOVASCULAR EFFECTS

Digoxin will augment myocardial contractility in both the failing and the non-failing heart without raising cardiac output (as heart rate decreases).  Preload is reduced which in turn, decreases MVO2 and angina.  In normal patients, digoxin increases systolic BP, pulse pressure and SVR by a direct constrictor effect on arterial and venous smooth muscle.  However in patients with CHF, digoxin decreases SVR and venomotor tone. 

 

The major action of digoxin on the conducting system is to prolong AV nodal refractoriness and to thereby reduce the ventricular response to supraventricular tachyarrhythmias.  The effect of digoxin on the SA node and atria are unpredictable, while ventricular excitability is usually enhanced.  The net result is increased vagal activity, delayed AV conduction and bradycardia. 

 

Arrhythmic effects from digoxin arise from an extension of the same effects that increase contractility; an overload of intracellular calcium results in afterdepolarisation by activation of calcium-sensitive channels, these arrhythmic effects are exacerbated by the loss of myocardial potassium that occurs.

 

Digoxin also appears to normalise the baroreceptor and other neuroendocrine responses to CHF.  Plasma renin activity is reduced,  ANP is increased (which may account for the initial diuretic effect seen after digitalisation) and noradrenaline levels and sympathetic tone are reduced. 

 

Although digoxin is a weak inotrope, it remains an important drug in the management of chronic CHF, particularly in combination with ACE inhibitors and vasodilators and when atrial fibrillation coexists with CHF.

 

Pharmacokinetics

 

The onset of action of digoxin occurs 15-30 minutes after iv. administration and peaks in 1.5-5 hours.  The oral bioavailability of digoxin tablets is less than 85%, although the bioavailablity of the gelatin capsule preparation is 90-95%, which may necessitate a reduction in dose from the tablets.  Intramuscular use is unrelaible and painful.  The volume of distribution is large, at 5-8Lkg.  It is extensively bound to heart muscle.  Digoxin is eliminated primarily by glomerular filtration and tubular secretion, although some hepatic metabolism occurs.  The elimination half life is 36 hours.  About 30% is excreted unchanged in the urine. 

 

The therapeutic level of digoxin is 0.5-2.0ng/mL, with toxicity occurring at levels of 2.5ng/mL or greater.  Digoxin doses should be reduced in renal failure.

 

Indications

 

The indications for digoxin therapy are summarised in table 4.

 

i)       CHF.  Digoxin has been a mainstay in the treatment of CHF due to its inotropic effects and the reduction of MVO2 that occurs.  Digoxin is usually introduced after diuretics and ACE inhibitors. It has been shown to improve symptoms and morbidity,  although not survival in patients in sinus rhythm. Digoxin does appear to be of greatest benefit with more severe left ventricular dysfunction.  Withdrawing digoxin in patients who are clinically stable on diuretics and ACE inhibitors has been shown to produce clinical deterioration. 

         

ii)      ATRIAL ARRHYTHMIAS.  Digoxin may be used to slow the ventricular response to atrial fibrillation or flutter.  However, it is no more effective than placebo in converting atrial fibrillation to sinus rhythm.  In the emergency management of atrial fibrillation, diltiazem or esmolol are preferred to digoxin because of their much more rapid action.

 

          Table 4.  Guidelines for digoxin therapy                                                                                                                                              

 

          Digoxin Beneficial

 

          Patients with moderate or severe systolic left ventricular dysfunction alone or in combination with ACE inhibitors.               

          Patients with acute myocardial infarction and atrial fibrillation

          Patients with congestive heart failure associated with atrial fibrillation

         

          Digoxin Indication Unclear

         

          Patients with normal ventricular haemodynamics during diuretic, ACE inhibitor or vasodilator therapy

          Patients with primarily diastolic ventricular dysfunction

          Patients with decreased left ventricular ejection fractions after myocardial infarction

 

          Digoxin Probably Not Indicated

 

          Patients with acute myocardial infarction with sinus rhythm and mild heart failure

          Patients with isolated right ventricular failure

 

 

Dosage and Administration

 

Loading doses of digoxin are often used because its slow elimination, otherwise steady-state concentrations may take a week to achieve.  For rapid digitalisation of a patient with CHF, a total oral dose of 10-15µg/kg is given in three divided doses every 4 hours.  More frequent loading may produce toxicity.  Maintenance doses 0.125-0.5mg/day., depending on clinical response (heart rate reduction), plasma levels and the occurrence of side effects.  Alternatively, the patient can be more slowly digitalised with 0.125-0.5mg/day given over 7 days. 

 

Intravenous loading can be achieved by giving 0.5-0.75mg. followed in 1hour (but preferably 2-3 hours) by further 0.125-0.25mg increments up to 2mg total.  The effect is maximal within 1-3 hours and digitalisation is complete within 12 hours.  Maintenance doses are needed in 12-24 hours . 

 

 

Precautions and Contraindications

 

The eldely are more sensitive to digoxin and may require lower doses.  Dosing is on the basis of lean body mass.  Digoxin is relatively contraindicated in the presence of hypoxia, sinus node dysfunction, hypokalaemia, hypercalcaemia and hypertrophic cardiomyopathy. 

 

Digoxin should be avoided in patients with Wolff-Parkinson -White syndrome and wide-complex supraventricular arrhythmias (particularly atrial fibrillation) as acceleration of the ventricular response can occur due to shortening of the refractory period of the accesory pathway.  Ventricular fibrillation has been reported.

 

Digoxin should be used with caution in the presence of renal dysfunction.  An anephric patient should receive standard doses of digoxin, but less frequently (eg. 0.25mg every 3-4 days).  This also applies to patients on dialysis as digoxin is not appreciably dialysed.

 

Digoxin has been independently associated with an increased mortality rate in the first year after acute myocardial infarction and it probably should not be used in these patients.

 

In an experimental animal model,  digoxin use has been shown to worsen myocardial injury resulting from ischaemia induced from cardiopulmonary bypass and aortic cross-clamping.  This was hypothesised to be due to digoxin producing higher levels of intracellular calcium,  which aggravates ischaemic injury.  The clinical relevance of this finding is unknown.

 

In a small pilot study of asthmatic patients,  digoxin was shown to reduce FEV1 and increase bronchial hyperresponsiveness.  This is consistent with the observation that an increased salt intake is associated with worsening asthma.  Further studies are needed.

 

 

DRUG INTERACTIONS

Quinidine, amiodorone and verapamil will all increase serum digoxin concentrations.  Arrhythmias have been reported in digitalised patients receiving suxamethonium, possibly due to a direct effect or due to hyperkalaemia.  Digoxin toxicity may be exacerbated by thyroid hormone, calcium or catecholamines, reserpine, propanolol and diuretics..

 

 

 

 

Toxicity

 

Digoxin toxicity can occur in any patient although the elderly and those with hypothyroidism are particularly prone, along with abnormalites such as hypoxia, hypomagnesaemia, hypercalcaemia, hypokalaemia and in conjunction with the drugs previously listed.

 

The cardiac symptoms arise from enhanced automaticity and AV block.  This results in arrhythmias such as nonparoxysmal junctional tachycardia, ventricular bigeminy and trigeminy and PVCs, either alone or with VT.  Digoxin toxicity very rarely results in atrial fibrillation, atrial flutter or wide-complex VT.

 

Extracardiac symptoms include anorexia, nausea, vomiting, diarrhoea, abdominal pain, confusion, paraesthesias and convulsions. Visual changes occur less commonly.

 

MANAGEMENT

Potassium should be given if the level is low,  it decreases the binding of digoxin to the heart and it directlty antagonises some of the cardiotoxic effects of digoxin.  However, if the potassium level is already high,  further potassium administration may produce complete AV block or cardiac arrest.  For the same reasons,  potassium is also contraindicated if high degrees of A-V block are already present.

 

Serious clinical manifestations may be treated with digoxin-immune Fab fragments which will reverse the toxicity by binding digoxin.

 

For serious arrhythmias, lignocaine, procainamide, phenytoin, propanolol or DC cardioversion may be necessary.  Cardioversion may be necessary for drug-resistant VT; if used for atrial arrhythmias low energy levels should be used along with lignocaine to suppress PVCs.  DC countershock may precipitate ventricular arrhythmias which may be fatal.

 

 


 

Calcium Channel Blockers

 

 

Calcium channel blockers have become established agents in the treatment of hypertension, coronary artery disease and cardiac arrhythmias.  They exhibit varying pharmacologic profiles which depend largely on their differing

specificities for intinsic vascular or myocardial effects.

 

 

Pharmacology

Nine calcium channel blockers are marketed in the US for the treatment of hypertension, angina, supraventricular arrhythmias and one (nimodipine) for the short-term management of subarachnoid haemorrhage. Only diltiazem, verapamil, nicardipine and verapamil are available iv.

 

MECHANISM OF ACTION

Calcium antagonists block calcium entry into smooth muscle cells and myocardial cells.  Calcium entry into the cell induces liberation of calcium from the sarcoplasmic reticulum, which produces muscle contraction.  Entry of calcium into the cell is possible by either voltage-operated or by receptor-operated channels.  There are several types of voltage-dependent channels, including T (transient), L (long-lasting), N (neuronal) and P (purkinje) channels.  The T channel is activated at low voltages (-50mV) in cardiac tissue, plays a major role in cardiac depolarisation (phase 0) and is not blocked by calcium antagonists.  The L-channels are the classic ŇslowÓ channels, are activated at higher voltages (-30mV) and are responsible for phase 2 of the action potential.  The calcium antagonists inhibit activation of voltage-operated channels by binding stereoscopically to the a1c subunit of the L channel. Different classes of calcium-channel blockers act at different parts of this subunit. Blockade results in inhibition of calcium entry into the cell and inhibition of the excitation-contraction coupling.  N- channels are also resistant to blockade by calcium antagonists.

L-channels are found in vascular smooth muscle (arteriolar and venous), nonvascular smooth muscle (bronchial, GIT) and noncontractile tissues (pancreas, pituitary, white cells, plateletsÉ)

 

                                Table 5  Specificity of calcium antagonists for L-channels

                                High specificity

                                Verapamil

                                Diltiazem

                                Dihydropyridines       Nifedipine

                                                                          Nicardipine

                                                                          Nimodipine

                                                                          Nitrendipine

                                                                          Isradipine

                                Low specificity

                                Bepridil

                                Perhexilene

                                Flunarizine                                                             

 

The calcium antagonists in clinical use are comprised of drugs from three different classes:  Class I are the dihydropyridine derivates (Table5), Class II are the phenylalkylamines (verapamil) and Class III the benzothiazepines (diltiazem).

 

Different calcium antagonists have differing selectivities for calcium channels (Table 5).  High specificity means than the drug selectively blocks calcium channels,  low specificity means that the drug will also block fast sodium channels.  In turn,  there are differences between the drugs in their specificities for vascular or myocardial calcium channels.  The dihydropyridines are more specific than diltiazem or verapamil as calcium channel blockers in vascular smooth muscle,  by contrast the latter two produce more marked depression of calcium entry into myocardial cells.  There are also small differences in the mechanisms of action between verapamil, diltiazem and the dihydropyridines.

 

 

Pharmacokinetics

 

The pharmacokinetic properties of all of the calcium antagonists are similar (Table 6).  Their elimination half-lives range from 1.5-6.0 hours.  Protein binding is usually greater than 80% (albumen and a1-acid glycoprotein), their metabolism is mainly hepatic (cytochrome P-450) with a large first-pass effect.  Major metabolites are eliminated by the kidneys.

 

         

 

 

 

 

 

Table 6     Pharmacokinetics of Three Calcium Antagonists                                                                                                                  

                                                                          Verapamil                              Nifedipine                                          Diltiazem                     

Absorption                                         >79%                                                    >90%                                                    >90%

          Biavailability                           10-20%                                                45-62%                                                24-90%

          Onset of action (oral)           1-2h                                            15min                                                   15min

                                                     1/2-1min (iv)                                     2-3min (sl)                                         2-3min (iv)

          Peak action (oral)                  3-4h                                            1-2h                                            30min

                                                     2-5min (iv)                                         20min (sl)                                

Elimination half-life            3-7h                                             4h                                                           4h

Protein binding                      90%                                             90%                                            80%

Metabolism                                        liver                                            liver                                            liver

          first pass                                    85%                                            20-30%                                                50%

Metabolites activity             20-25% (norverapamil)                 none                                            50%(deacetyldiltiazem)    

Excretion (%)

          gastrointestinal            25                                                           15                                                           60

          renal                                 75                                                           85                                                           40

Dose                                                     iv: 0.075-0.15mg/kg            sl: 10-40mg tid                       iv: 0.15-0.25mg/kg

                                                                oral: 80-120mg tid or qid oral: 10-40mg tid or qid                oral: 30-90mg tid or qid

Therapeutic plasma conc.  80-100ng/l                                          25-100ng/l                                          40-200ng/l

Interaction with digoxin               Yes                                                        No                                                          No                                   

 

 

Pharmacodynamic effects.

 

The calcium antagonists are all arteriodilators to varying degrees with no effect on capacitance vessels.  Hence they will all produce a dose-dependent reduction in afterload, SVR and arterial blood pressure.  However, there are marked differences between the agents in their effects on myocardial function (Table 7).

 

 

 

                                                                Table 7.  Organ selectivity of calcium antagonists.                                                                   

                                                     Verapamil           Diltiazem           Nifedipine       Nicardipine       Nimodipine      Isradipine

          vasodilation                        ++                              +                       +++                         +++                     ++++                  ++++

          inotropy                                - -                               -                          0-                             0-                          0-                        0-

          heart rate                             - - -                         - - -                        +                              +                          ++                       ++

          A-V conduction               - - -                         - - -                        0                               0                          0                         0

 

 

Nifedipine is a potent arteriodilator with minimal venodilating effects.  Verapamil is less potent as an arteriodilator than the dihydropyridines more potent as a negative inotrope.  The actions of diltiazem lie between those of verapamil and nifedipine, it produces less vasodialation and negative inotropy than verapamil.

 

All of the calcium antagonists produce inhibition of atrial cells, depressing sinus activity and A-V conduction and increasing the effective and functional refractory period of A-V nodal tissue.  However, only verapamil and diltiazem produce a decrease in heart rate, this is because the pronounced vasodilation produced by the dihydropyridines results in reflex stimulation of adrenergic activity.  Similarly, all of the calcium antagonists are negative inotropes in vivo,  however, this effect is masked in the dihydropyridines due to their more pronounced effects on afterload and reflex sympathetic stimulation.

 

The calcium channel blockers produce coronary artery dilation and increase coronary blood flow.  Nimodipine, nifedipine and nicardipine are the most potent coronary vasodilators, especially of the epicardial vessels which are prone to vasospasm.  Diltiazam has been shown to be effective in blocking coronary vasospasm and in animals, all of the calcium blockers have been shown to dilate coronary arterial stenoses and improve collateral blood flow. 

 

Both nicardipine and nimodipine are lipid soluble and can cross the blood-brain barrier.  Hence they can produce cerebral vasodilation and will increase cerebral blood flow.

 

The calcium channel blockers are all  vasodilators of the pulmonary vascular bed.

 

In common with §-blockers and nitrates, calcium antagonists also inhibit platelet aggregation.  This is due to the fact that calcium is a mediator involved in the release of platelet aggregatory factors such as ADP.  Inhibition of platelet aggregation may be an important effect of the anti-ischaemic drugs, particularly in the treatment of chronic disease.

 

 

Calcium Antagonists and Anaesthesia

 

ANAESTHETIC AGENTS

As the calcium channel blockers produce similar cardiovascular effects to the halogenated anaesthetic agents, they can have both additive and potentiating effects.  Because of their greater negative inotropic effects,  verapamil and diltiazem most markedly potentiate the myocardial depression produced by enflurane, followed by halothane and then isoflurane.  They may also produce dramatic additive effects on the inhibition of A-V conduction.  By contrast,  the dihydropyridines have a mainly additive effect with the volatile agents in reducing SVR,  although above 1.5-2 MAC potentiation occurs because this level of MAC will produce attenuation of baroreflex responses.  In addition, the dihydropyridines produce no significant alteration of A-V or intraventricular conduction when administerd with volatile anaesthetics.

 

The interaction between the calcium antagonists and the volatile agents is not purely pharmacodynamic, the volatile agents have been shown to inhibit their metabolism and to decrease hepatic blood flow, this may result in higher plasma levels and increased pharmacologic effect.

 

Patients who are taking calcium anatagonists preoperatively and who have good ventricular function will tolerate clinical concentrations of volatile agents.  However, the volatile agents may be less well tolerated in the presence of poor ventricular function or hypovolaemia and they should be used with caution as hypotension, bradycardia or heart block may occur. 

 

Many patients take both calcium antagonists and §-blockers chronically, this combination does not adversely affect perioperative cardiac cardiac conduction although these patients have a decreased heart rate and an increased P-R interval.  Intravenous verapamil (150µg/kg over 10min.) used to treat intraoperative SVT or coronary artery spasm in patients on chronic §-blockers will produce only a small reduction in blood pressure in patients with normal ventricular function.  However, in patients with poor ventricular function this combination may produce a significant reduction in cardiac output.

 

During opioid anaesthesia, calcium blockers produce minor additive effects only, even in the presence of §-blockade.

 

OTHER EFFECTS

In dogs, verapamil has been shown to decrease the MAC of halothane.  There is also laboratory and limited clinical data that verapamil also potentiates the effects of both depolarising and nondepolarising muscle relaxants.  In addition, verapamil may interact with some local anaesthetics through its minor effects on fast sodium channels.  The clinical relevance of these interactions is unclear.

 

 

Clinical Indications for the Calcium Antagonists

 

HYPERTENSION

Hypertension occurring in surgical patients is related mainly to an increase in SVR, hence vasodilator therapy is the mainstay of its treatment.  Acute intraoperative hypertension  occurs most commonly in patients undergoing cardiac or vascular surgery, and it is defined as a MAP above 110mmHg.  The rapid control of intraoperative hypertension is essential to avoid the adverse sequelae of myocardial ischaemia, depressed LV function and increased surgical blood loss. 

 

Nitroprusside has been the trditional drug of choice in the management of acute intraoperative hypertension,  however the dihydropyridines are also very effective and safe agents in this setting.  Intravenous nifedipine, nicardipine and isradipine have been shown to be as effective as nitroprusside in the management of perioperative hypertension in a variety of clinical trials.  Their use may be associated with a slight increase in heart rate. 

 

The ideal dosing regimen remains controversial, although a slow bolus or short infusion would seem to be appropriate as most perioperative hypertensive episodes are transient.  Dosage regimens are summarised in Table 8, it is important to titrate from lower doses initially to prevent hypotension occurring.

 

 

                     Table 48   Intravenous dosage of dihydropyrines for the treatment of hypertension.               

                                                                Initial dose (1-5min)mg                          Continuous infusion (µg/kg/min)

                     Nicardipine                   0.5-2 (bolus 0.5-1.)                         0.25-1

                     Nifedipine                     0.2-1 (bolus 0.2-5)                          0.3-1

                     Israpidine            0.1-0.5 (bolus 0.1)                           0.07-0.3

 

Nifedipine can also be given orally in the awake patient or sublingually in an awake or anaesthetised patient to treat perioperative hypertension.  A dose of 10-20mg is usually effective within 15-30 minutes.

 

Many patients presenting for surgery are on calcium antagonists for the control of essential hypertension.  Approved drugs for this indication include amlodipine, nicardipine, nifedipine, nisoldipine, diltiazem and verapamil. The use of calcium channel blockers as antihypertensives may be associated with regression of established left ventricular hypertrophy. However, as there is a lack of evidence that their use reduces hypertension-related morbidity and mortality they are not recommended as first-line agents unless there are reasons to avoid the use of thiazides or §-blockers.  Verapamil is the most widely used calcium antagonist for the chronic management of hypertension,  it reduces SVR while its effects on the sinoatrial node prevents a reflex increase in heart rate.  In addition, verapamil has a mild natiuretic effect so compensatory sodium retention does not occur, hence it may be used as monotherapy as a diuretic may not be required.  The usual dose is 160-480mg/day given as divided doses, however a sustained-release preparation may allow once-daily dosing. 

 

Diltiazem is also effective in the management of essential hypertension,  in moderate doses (up to 360mg/day) it is about as effective as a thiazide diuretic, in higher doses it is equivalent to verapamil and may produce less constipation. Nifedipine capsules are less useful as chronic therapy as they need to be given 8th hourly and §-blockers may be needed to block the reflex tachycardia that may occur.  However, tachycardia is not such a problem with sustained-release nifedipine and it permits bd. dosing.

 

 

ARRHYTHMIAS

Both verapamil and diltiazem produce slowing of the ventricular response to supraventricular tachyarrhythmias through their depressant effects on A-V node function.  In arrhythmias due to A-V nodal re-entry circuits (paroxysmal SVT), verapamil 75-150µg/kg iv. is 90% effective in producing sinus rhythm within 5 minutes. 

 

Verapamil will also slow the ventricular response to atrial flutter and fibrillation (AF) although conversion to sinus rhythm is uncommon.  Acute AF responds much more rapidly to verapamil or esmolol (2-5 minutes) than to digoxin (onset 20-30 minutes, peak effect in 90 minutes).

 

Verapamil and diltiazem are also useful in the chronic management of atrial fibrillation, there is a large individual variation in the dose-response and the dosage is titrated accordingly.  Verapamil is more effective than digoxin in maintaining ventricular rate control in chronic AF during stress.

 

Patients with accessory pathways (Wolff-Parkinson-White syndrome) may have tachycardias effectively treated with verapamil if anterograde conduction occurs through the AV node (narrow QRS complex).  When anterograde conduction is through the accessory pathway (wide QRS complex), verapamil, along with digoxin, may worsen the tachycardia.

 

Diltiazem has been shown to be an effective prophylactic agent in the prevention of supraventricular arrhythmias after pneumonectomy. Digoxin may be no better than placebo in this setting.

 

The calcium antagonists are not  effective in the management of ventricular arrhythmias.   Verapamil has precipitated cardiovascular collapse and VF when used in the management of VT and it is contraindicated.

 

MYOCARDIAL ISCHAEMIA

Most episodes of myocardial ischaemia are silent and of these, most are related not to an increase in myocardial oxygen demand, but rather to a decrease in myocardial oxygen supply due to intermittent coronary vasoconstriction or spasm.

Calcium blockers decrease myocardial oxygen demand by producing myocardial depression and aside from nimodipine, their effect on coronary blood flow is not pronounced.  The most important effect of the calcium blockers on myocardial ischaemia may be the prevention of sympathetically mediated coronary vasoconstriction and spasm, this is a significantly different mechanism of action from the §-blockers which decrease MVO2. 

 

Calciumchannel blockers are as effective as §-blochers as monotherapy in the management of stable angina as monotherapy although they are less well tolerated long term. However they are normally given in combination with a nitrate or §-blocker for additional effect. Particularly effective combinations include dihydropyridines and §-blockers or diltiazem / verapamil and a nitrate. 

 

All of the calcium blockers are effective at reversing coronary spasm, reducing ischaemic episodes and reducing GTN consumption in variant (Prinzmetal) angina.

 

Unstable angina may involve coronary vasospasm, accelerated atherosclerotic processes or enhanced platelet aggregation.  The calcium channel blockers are as effective as §-blockers in the relief of symptoms from unstable angina, but not as monotherapy.

 

MYOCARDIAL INFARCTION

Calcium channel blockers do not compare favourably with §-blockers in reducing infarct size or mortality in the acute or chronic stages after myocardial infarction.

 

MYOCARDIAL PROTECTION

Myocardial dysfunction occurs after ischaemic myocardium is reperfused and is called ÔŇstunned myocardium.Ó The mechanisms involved in generating stunned myocardium and reperfusion injury are various, but the common associated factor is intracellular calcium overload. 

There is much interest currently on the efficacy of calcium blockers as cardioplegic agents in reducing reperfusion ventricular dysfunction,  however to date the results from animal experiments are not encouraging.  Calcium blockers have been shown to be cardioprotective for normal hearts,  but of no benefit in failing hearts.

 

HYPERTROPHIC CARDIOMYOPATHY

Verapamil improves the exercise capacity and symptoms of patients with obstructive cardiomyopathies by reducing outflow tract obstruction.  This may be brought about by improving diastolic function rather than by reducing the hypercontractile state.  Verapamil produces improved diastolic relaxation and ventricular filling.  Verapamil will also produce a reduction in ventricular muscle mass over time.

 

CONGESTIVE HEART FAILURE

The afterload-reducing effects of all the dihydropyridines improve the symptoms of CHF, their vasodilator effects offset their negative inotropic effects to produce improved forward flow.

 

CEREBRAL VASOSPASM AND ISCHAEMIA

Nimodipine and nicardipine are the only calcium blockers in clinical use that are lipid soluble and capable of crossing the blood-brain barrier, where they preferentially dilate cerebral vessels.  Nimodipine has been shown to slightly reduce neurological deficits in patients with proven cerebral vasospasm occurring after subarachnoid haemorrhage compared with placebo.  None of the calcium channel blockers is useful for ischaemic stroke. 

Nimodipine is useful in the prophylaxis of migraine syndromes.

In common with all direct-acting cerebral vasodilators, calcium antagonists will produce an increase in intracranial pressure, which may limit their usefulness in patients with severe intracranial hypertension.

 

 

Significant Adverse Effects

 

Verapamil increases digoxin levels (by reducing clearance), whereas diltiazem has variable effects and nifedipine no effect on digoxin levels.  Cimetidine, ranitidine, ketaconozole and advanced age increase the serum levels of the calcium blockers, possibly by reducing hepatic blood flow.

 

Pharmacodynamic drug interactions may occur: intravenous (but not oral) use of verapamil and §-blockers may produce asystole, this oral combination should also be avoided in the presence impaired LV function.

As may be predicted from their actions, the calcium antagonists may produce hypotension, CHF, bradycardia, AV block and asystole.  These effects are more likely to occur when they are combined with §-blockers or digoxin, or in the presence of hypokalaemia.

 

In a recent study on the perioperative use of nimodipine in cardiac valve replacement, nimodipine was found to have no effect on neurological outcome and the study was terminated when nimodipine was found to be associated with an increase in death rate due to major bleeding. 

 

There have been case reports of myocardial ischaemia and infarction after acute withdrawal of verapamil or diltiazem similar to §-blocker withdrawal.

 

Overdose of calcium channel blockers commonly presents as hypotension  and varying degrees of heart block. Treatment is with gastric lavage with activated charcoal, fluids and iv. calcium administration. Inotropes such as noradrenaline or amrinine may be necessary.

 

 

 

 

 

 

 

 

 

 

References

 

1.        Vasoactive Drugs.  BailliereŐs Clinical Anesthesiology; Volume 8, Number 1, March 1994 pp87-108, 137-147

 

2.         Cardiac Anaesthesia  Third Edition. Ed. Joel Kaplan,  W.B. Saunders 1993

 

3.         Drugs and Anaesthesia.  Second Edition, Wood and Wood.  Williams and Wilkins 1990

 

4.          Therapy of angina pectoris with long acting nitrates:which agent and when?  Abrams J,  Can. J. Cardiol..  1996 May; 12 Suppl C: 9C-16C

 

5.          Potential problems with intermittent nitrate therapy.  Parker JD  Can. J. Cardiol. 1996 May: 12 suppl C: 22-24

 

6.          Prevention of tolerance to haemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure.  Gogia H et. al.  J. Am. Coll. Cardiol.  1995 Dec: 26(7) 1575-80

 

7.          Nimodipine neuroprotection in cardiac valve patients: report of an early terminated trial.  Legault C et al.  Stroke 1996 Apr; 27(4): 593-8

 

8.          Treatment modalities for hypertensive patients with intracranial pathology:  options and risks.  Tietjen C et al.  Crit. Care Med.  1996 Feb: 24 (2):  311-22

 

9.          Resistance of the failing dystrophic hamster heart to the cardioprotective effects of diltiazem and clentiazem:  evidence of coronary vascular dysfunctions.  Tanguay M et al. Can. J. Physiol. Pharmacol.  1995 Aug; 73(8):  1108-17

 

10.       Is there a role for digoxin in patients with systolic dysfunction?  Williamson K.  Pharmacotherapy.  1996 Mar-Apr;  16(2 Pt 2): 37S-42S

 

11.       A pilot study to investigate the pulmonary effects of digoxin in patients with asthma.  Ayson M et al.  NZ Med. J.  1996 Feb 9;  109(1015): 36-7

 

12.       Digoxin and mortality in survivors of acute myocardial infarction:  observations in patients at low and intermediate risk.  Leor J et al.  Cardovasc. Drug Ther.  1995 Aug;  9(4):  609-17

 

13.       Intravenous digoxin in acute atrial fibrillation. Results of a randomised, placebo controlled multiicentre trial in 239 patients.  The Digitalis in Acute Atrial Fibrillation Group.  Eur. Heart J.  1997 Apr; 18(4): 649-54

 

14.       Effects of diltiazem versus digoxin on dysrhythmias and cardiac function after pneumonectomy.  Amar et al.  Ann. Thorac. Surg.  1997 May; 63(5): 1374-81

 

15.               Dilemmas in the acute pharmacological treatment of uncontrolled atrial fibrillation.  Elam et al. Am. J. Emerg. Med.1997 Jul; 15(4): 418-9

 

16.               Calcium antagonist drugs. Abernethy D, Schwartz J. NEMJ. 1999 Nov. 341 (19) 1447-53

 

17.               Metanalysis of trials comparing §-blockers, calcium antagonists and nitrates for stable angina. Heidenreich P et al. JAMA, May 26, 1999, 281 (20) 1927