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 ‘coronary steal,’ 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 ß-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 ‘nitrate-free’ 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 “slow” 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 a_1c 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, platelets…)

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