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Veterinary Medicine

Hypertrophic cardiomyopathy in the cat

The incidence of hypertrophic cardiomyopathy (HCM) is higher in the cat than it is in the dog. hypertrophic cardiomyopathy can be classified as primary or secondary. The aetiology of the primary or idiopathic form is unknown. A recent survey of 74 cases of hypertrophic cardiomyopathy showed no apparent breed predilection ; others have suggested that the Persian breed may be predisposed. The disease rarely occurs in the Siamese. Burmese and Abyssinian breeds in which there is a much higher incidence of dilated cardiomyopathy. Secondary hypertrophic cardiomyopathy most commonly occurs in association with hyperthyroidism.

Idiopathic hypertrophic cardiomyopathy typically occurs in young to middle-aged cats (mean age 6,5 years) and males are more commonly affected.

Pathophysiology

Hypertrophic cardiomyopathy is characterized by symmetrical hypertrophy of the interventricular septum and left ventricular free wall. Occasionally there may be evidence of left ventricular outflow obstruction especially if there is disproportionate hypertrophy of the septum. Partial aortic outflow obstruction may also be caused by anterior motion of the mitral valve during early systole but this appears to be a rare occurrence in feline hypertrophic cardiomyopathy. Indeed, echocardiographic studies have shown that most cats with hypertrophic cardiomyopathy do not have left ventricular outflow gradients and it appears therefore that obstructive hypertrophic cardiomyopathy, as occurs in dogs, is rare in cats.

Left ventricular hypertrophy results in decreased myocardial compliance, interference with normal diastolic filling due to impaired myocardial relaxation, and an increase in left ventricular end-diastolic pressure (despite a normal or often reduced end-diastolic volume). Decreased myocardial compliance may be aggravated by focal or diffuse endocardial fibrous tissue deposition. Pressure overload within the left ventricle may also be associated with mitral valve dysfunction and regurgitation leading to left atrial enlargement.

The decrease in stroke volume ultimately leads to a reduction in cardiac output and decreased coronary perfusion resulting in myocardial ischaemia. Abnormal myocardial handling of calcium may be a factor in the pathogenesis of hypertrophic cardiomyopathy (an increase in intracellular calcium inhibits complete myocardial relaxation which may explain why calcium blocking drugs have been shown to improve diastolic function significantly in affected cats.

More recently, excessive circulating levels of growth hormone has been implicated in the pathogenesis of hypertrophic cardiomyopathy. Cats with acromegaly due to functional pituitary tumours have hypertrophic cardiomyopathy (Q). It has also been shown that non-acromegalic cats with hypertrophic cardiomyopathy have significantly increased levels of growth hormone compared to normal cats and cats with other forms of cardiac disease but whether this is cause or effect is not clear.

Hypertrophic cardiomyopathy: Clinical signs

Recent studies have demonstrated the heterogeneity of feline hypertrophic cardiomyopathy with regard to the wide spectrum of clinical, electrocardiographic, radiographic and echocardiographic features of the disease. Some cases of hypertrophic cardiomyopathy remain asymptomatic until the cat is stressed. The clinical signs of hypertrophic cardiomyopathy are typically those of left-sided congestive heart failure. Bright and others showed that 61 % of cats with hypertrophic cardiomyopathy had a history of respiratory distress characterized by the acute onset of dyspnoea progressing to mouth breathing. Affected cats become lethargic, anorexic and may cough. Occasionally heart sounds may be muffled due to the presence of pleural or pericardial fluid, Clinical examination may reveal diffuse pulmonary crackles and the presence of a gallop rhythm and / or systolic murmur. Other more variable signs include prolonged capillary refill time and pallor or cyanosis of the tongue and mucous membranes- Animals showing severe signs of cardiac failure are often hypothermic with weak femoral pulses. The increased tendency towards thrombus formation may result in acute onset of hindlimb (less frequently forelimb) paralysis or lameness with cold limb extremities (see section on arterial thromboembolism).

Electrocardiography

Almost 70% of cases may be expected to have an abnormal ECG. Abnormalities reported include increased amplitude and width of P and R waves (P waves >0.04 s and >0,2 mV; QRS complexes >0.04 s and R waves >0.9 mV in lead II), arrhythmias (atrial or ventricular premature contractions) and conduction disturbances. Left anterior fascicular bundle branch block, with deep S waves in leads 1, 11 and 111 and left axis deviation, is particularly common.

Radiographic findings

Radiographic abnormalities consisting of mild to moderate left atrial and left ventricular enlargement or biventricular enlargement with evidence of pulmonary venous congestion and / or oedema are present in more than 80% of cases. Biventricular enlargement may lead to elevation of the trachea and increased sternal contact and, on the dorsoventral view, the enlarged atria may result in a ‘valentine-shaped’ heart. Occasionally there may also be radiographic signs of right heart failure (right ventricular enlargement, hepatomegaly and ascites.

Echocardiography

Hypertrophic cardiomyopathy is characterized by symmetric or less frequently asymmetric hypertrophy of the inter-ventricular septum and left ventricular free wall, and enlarged hypertrophied papillary muscles which contribute to a marked reduction in left ventricular internal dimensions. Most cases show evidence of a moderate degree of left atrial dilation and fractional shortening is usually normal or increased. Occasionally there is systolic anterior motion of the septal mitral valve leaflet and Doppler studies may show mitral regurgitation. Mild pericardial effusion may be evident.

Angiocardiography

With the increased use of ultrasound angiocardiography is rarely required. In the absence of ultrasound facilities, non-selective angiocardiography (injection of the contrast agent via the jugular vein) can be used to demonstrate the hypertrophied left ventricle and papillary muscles and regurgitation of contrast into the dilated left atrium. Circulation time is usually normal.

Prognosis of Hypertrophic cardiomyopathy

The prognosis for hypertrophic cardiomyopathy is guarded and other causes of left ventricular hypertrophy such as systemic hypertension, hyperthyroidism, acromegaly, chronic anaemia and congenital subaortic stenosis (rare in the cat) should be excluded. Plasma T3 and T4 concentrations should always be determined even when no thyroid nodules can be palpated in the neck.

Hypertrophic cardiomyopathy: Treatment

Cats presented with severe respiratory distress should be given oxygen and confined to a cage in the first instance. Initially frusemide may be given intravenously or intramuscularly (1-2 mg kg-1 body weight); thereafter it may be given orally at a dose rate of 1 mg kg-1 body weight two or three times daily. One of the main aims of therapy should be to reduce the heart rare to less than ISO beats per minute in order to improve cardiac filling.

Diltiazem not only decreases the heart rate in cats with hypertrophic cardiomyopathy but increases myocardial relaxation, decreases myocardial oxygen demand and dilates the coronary vasculature. It has minimal negative inotropic and peripheral vasodilating properties compared to other calcium blocking agents such as verapamil. A dose of 1.75-2.4 mg kg-1 body weight per os three times daily (mean effective dose 1.78 mg kg-1) has been shown to effectively reduce pulmonary congestion and improve left ventricular filling with no apparent side effects.

Recent work has shown that the survival times of cats with hypertrophic cardiomyopathy may be prolonged with the use of calcium Mocking agents such as diltiazem. About 94% of cats in one study receiving diltiazem survived longer than 6 months. Cats which show no clinical signs on initial presentation and those with heart rates less than 200 beats per minute survive significantly longer than do cats with emboli or congestive heart failure, 60% of which fail to survive 6 months.

Beta-blocking drugs such as propranolol (2,5-5,0 mg per os twice or three limes daily) slow the heart rate and improve diastolic filling. Propranolol is the antidysrhythmic drug of choice for cats but its effects on myocardial compliance in cases of feline hypertrophic cardiomyopathy have not been documented.

Although vasodilators are generally contra-indicated in cats with hypertrophic cardiomyopathy, captopril (3.12-6.20 mg twice or three times daily) may be useful In cases with severe mitral regurgitate on and signs of refractory congestive heart failure.

The administration of digoxin is contraindicated in cats with hypertrophic cardiomyopathy since myocardial contractility is often normal or increased. Aspirin (25 mg kg-1 body weight every 72 h) should be given to minimize the risk of throntboembolic disease although there is no evidence to date to suggest that aspirin, if given prophylactically, decreases the incidence of arterial thrombosis in cats with hypertrophic cardiomyopathy.

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Veterinary Medicine

Hypertension

The methods for measuring blood pressure and reported normal blood pressure measurements in small animals are extremely variable. Blood pressure should be measured with the animal unsedated, relaxed and minimally restrained. Heart rate should be within normal resting limits (an increased heart rate tends to increase the diastolic blood pressure measurement). Direct measurements can be performed by percutaneous puncture of the femoral artery connected to pressure sensing and recording equipment. Non-invasive indirect measurements can be obtained using Doppler ultrasound or, in dogs, oscillometric techniques. Normal direct and indirect measurements for dogs and cats are given in site.

In dogs, hypertension should be suspected if systolic and diastolic measurements greater than 180 mm Hg and 100 mm Hg respectively, are obtained using an indirect Doppler ultrasound technique. In cats, hypertension is defined as sustained systolic and diastolic pressures greater than 170 mm Hg and 100 mm Hg, respectively, using a Doppler technique (Morgan, 1986); systolic / diastolic pressures greater than 200 / 145 should certainly be regarded as abnormal.

Hypertension can be classified as primary (essential) or secondary. Most cases of hypertension in small animals are secondary to other diseases. Regulation of arterial blood pressure depends on the interaction of a number of neural, cardiac, renal and humoral factors which affect cardiac output, plasma volume and vascular tone. Deregulation of these pressor and volume homeostatic mechanisms may initiate a hypertensive state. Activation of the renin-angiotensin-aldosterone system, altered adrenergic activity, and the release of vasopressor substances by the kidney and antidiuretic hormone from the neurohypophysis (the latter in response to increased angiotensin II levels) act together to increase peripheral vascular resistance and retain sodium and water. Increased vascular ‘stiffness’ associated with atherosclerosis and arteriosclerosis may also play a role in creating a hypertensive state.

Primary (essential) hypertension

Spontaneous hypertension has been reported in dogs, including a colony of primary hypertensive dogs bred from two naturally occurring cases. Diagnosis of primary hypertension essentially involves ruling out secondary causes. Since spontaneous hypertension can result in secondary renal changes (glomeruloscterosis) and renal insufficiency, identification of the primary disease process is often extremely difficult. High sodium diets have been implicated in the pathogenesis of primary hypertension. A high sodium diet may be expected to accelerate the disease process if fed to an animal with pre-existing hypertension; it is not clear, however, if a high sodium load alone can result in hypertension.

Secondary hypertension

In the cat, renal disease and hyperthyroidism are both common causes of hypertension. Primary renal disease is the most common cause of hypertension in dogs. Hypertension may also be associated with hypothyroidism, hyperadrenocorticism, diabetes mellitus, phaeochromocytoma, primary hyperaldosteronism, hyperparathyroidism (resulting in hypercaleaemia), acromegaly and hyperoestrogenism. Other potential, but less well documented, causes include polycythaemia, anaemia, renin-producing tumours, coarctation of the aorta, obesity and ageing).

Clinical signs

Hypertension leads to glomerulosclerosis and a loss of functional nephrons. If renal function is already compromised hypertension may accelerate progression towards end-stage renal failure. Hypertension also results in concentric hypertrophy of the left ventricle which predisposes the myocardium to ischaemia and the development of arrhythmias. Hypertensive retinopathy is characterized by choroidal haemorrhage and focal retinal detachments. Some animals present with sudden onset blindness due to complete retinal detachment, papilloedema, intraocular haemorrhage or glaucoma. Neurological signs are usually attributed to cerebral haemorrhage; cerebral infarction associated with atherosclerosis of the cerebral arteries is occasionally seen in dogs with hypothyroidism.

Hypertension: Treatment

The main objective is to identify and treat appropriately the underlying disease (for example renal failure). When a specific disease cannot be identified and primary hypertension is suspected, therapy should be directed against the mechanism responsible for the hypertension, that is an attempt should be made to reduce the circulating blood volume, decrease sympathetic tone and / or inhibit the renin-angiotensin-aldosterone pathway. Suitable therapeutic strategies are summarized below.

Reduce sodium intake to 0.1-0.3% of the diet (10-40 mg kg-1 dry matter). Sodium restriction potentiates the action of antihypertensive drug therapy. Prescription diets are available which fulfil these requirements.

Diuretics. Frusemide has a natriuretic action and can be used in the face of renal failure. Spironolactone is a more appropriate drug for treating hyperaldosteronism.

Beta-adrenergic blocking drugs decrease cardiac output and decrease renin release by blocking the beta receptors on the juxtaglomerular apparatus. Their use is indicated in feline hyperthyroidism where hypertension is due to excessive adrenergic stimulation.

Alpha-adrenergic blocking drugs such as prazosin can be used as balanced vasodilators and can be used safely in animals with renal dysfunction.

Hydralazine is an arterial vasodilator. It lowers blood pressure but does not protect the kidney against glomerulosclerosis. Hydralazine may result in reflex sympathetic stimulation and renin release and therefore may have to be given with beta blockers.

Calcium channel blockers such as verapamil and diltiazem cause vasodilation. Verapamil is a renal vasodilator and may transiently increase glomerular filtration rate.

Angiotensin converting enzyme inhibitors are balanced vasodilators. The decreased production of aldosterone results in increased salt and water excretion. These drugs are nephrotoxic so care should be taken if there is evidence of renal dysfunction.

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Veterinary Medicine

Positive inotropic agents

An ideal positive inotropic agent should increase the force of contraction of cardiac muscle at a given degree of end-diastolic stretch without reducing efficiency of energy use, increasing the heart rate or predisposing to cardiac arrhythmias. The drug should also lack vasoconstrictor action on peripheral blood vessels.

Drugs which enhance myocardial intracellular cyclic AMP concentration

Beta-adrenergic agonists and phosphodiesterase type III / IV inhibitors will both raise intracellular cyclic AMP and increase myocardial contractility. The synthetic catecholamine, dobutamine is the beta-adrenoceptor agonist of choice since it has selective action on beta-adrenoceptors and at dose rates which increase the force of contraction (3-7 μg kg-1 min-1), it has minimal effects on heart rate and no vasoconstrictor effects. It is used in the intensive care of severe myocardial systolic failure. It is rapidly taken up and metabolized by the tissues and has to be given by continuous intravenous infusion, the rate of which should be accurately controlled by an infusion pump. Continuous ECG monitoring is required to detect increases in heart rate and the onset of arrhythmias which are indicative of toxicity. Some studies in human medicine have suggested long-term beneficial effects even following brief dobutamine infusions. Similar studies have not been reported in veterinary medicine and the cost of the drug may be prohibitive for many patients.

The bypyridine compounds amrinone and milrinone (phosphodiesterase type III / IV inhibitors) were heralded as having great promise on their introduction, being potent positive inotropes with little effect on heart rate and possessing mild arteriolar vasodilator activity. Indeed, initial studies of the use of milrinone in dogs with systolic failure (which is orally active) proved promising. Unfortunately, no placebo-controlled trials have been performed in veterinary medicine and human studies have shown a detrimental effect of milrinone on long-term survival in patients with chronic congestive heart failure. Such findings cast serious doubt on the future of such drugs. Indeed, it has been suggested that any drug which produces its positive inotropic effects by raising cyclic AMP in the myocardium will have long-term detrimental effects in the same way as chronic exposure of the myocardium to high concentrations of catecholamines is thought to be toxic.

Cardiac glycosides

Controversy over the use of this group of drugs in the management of heart failure has been present in the literature of both human and veterinary medicine for many years, yet their popularity among clinicians survives. Most would agree that the primary indication for cardiac glycosides is in the management of supraventricular tachycardia, particularly where this co-exists with systolic myocardial dysfunction, as is often the case in dilated cardiomyopathy in dogs. The controversy surrounds their use in heart failure patients which are in normal sinus rhythm and results of large-scale controlled trials in human medicine are only beginning to be reported.

The classical actions of cardiac glycosides on the failing heart are to increase the force of contraction of the heart muscle and decrease the heart rate via a number of both central and peripheral effects which result in increased vagal tone to the heart. In addition, other reflex effects occur which inhibit both sympathetic nerve and renin-angiotensin system activity. The ability of the drugs to increase the sensitivity of cardiac and arterial baroreceptors so that they respond to lower pressures leading to a reduction in sympathetic tone may underlie these beneficial circulatory effects which are now thought to occur independently of any positive inotropic action. These effects give sound reasons for employing cardiac glycosides in heart failure patients where systolic muscle function is not affected (such as valvular heart disease) although alternative means of achieving these effects now exist (for example ACE inhibitors).

Digoxin is the only cardiac glycoside which currently is readily available for use by the veterinary practitioner. The narrow therapeutic index of glycosides means that the digoxin dosage should be accurately calculated for each animal. In dogs, less than 20 kg a dose of 0.005-0.01 mg kg-1 bid is recommended whereas dogs greater than 20 kg in weight should receive 0.22 mg m-2 bid (a total dose of 0,25 mg bid should not be exceeded). The dosages should theoretically be based on lean body weight. Dosing on a twice daily basis prevents large peaks and troughs in plasma concentration. The half-life of digoxin in the dog is reported to be 23-39 h. In the cat, a dose of 0.01 mg kg-1 every other day is recommended and a 30% reduction should be made if aspirin and frusemide are administered concurrently. Renal excretion of digoxin is an important route of elimination and reduced renal function will lead to toxicity occurring at these dose rates. Food will reduce the rate of absorption of digoxin from the gastrointestinal tract and the absorption characteristics will vary from one formulation to another. Use of digoxin can be facilitated by monitoring scrum levels of the drug which should fall between 1.0 and 2.5 ng ml-1. This therapeutic range should be achieved within three to five half-lives of starting therapy (that is within 3-5 days). Rapid digitalization by giving loading doses is rarely necessary and is associated with a higher incidence of toxicity.

Signs of digoxin toxicity (anorexia and vorniring) are due to the effects of the drug on the chemoreceptor trigger zone in the medulla. In addition, myocardial toxicity will result in cardiac arrhythmias, particularly of ventricular origin. Unfortunately, myocardial toxicity can occur without gastrointestinal signs, particularly in dogs with myocardial systolic failure. Hypokalaemia and hypomagnesaemia caused by diuretic therapy will enhance the toxicity of digoxin so blood plasma electrolyte concentrations should be monitored. Concurrent use of other drugs such as quinidine and verapamil will also increase the risk of toxicity, therefore a reduction in digoxin dosage should be made if these drugs are given in combination. In managing digoxin toxicity, electrolyte abnormalities should be corrected and ventricular arrhythmias treated with lignocaine.

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Veterinary Medicine

Supraventricutar tachydysrhythmias

Sinus tachycardia (heart rates greater than 160-180 bpm in the dog and 240 bpm in the cat respectively) can occur in response to pain> fright, fever, anaemia, circulatory shock and hyperthyroidism, all states where sympathetic tone to the heart increases and as a result, the rate of impulse generation and conduction is enhanced. Drugs such as levothyroxine and bronchodilators such as terbutaline, if given in excess, may produce sinus tachycardia as a side effect. Treatment of the underlying condition (or cessation of the offending drug) will be sufficient, in most cases, to reduce the heart rate and drug therapy is not usually necessary.

Supraventricular tachydysrhythmias develop, most commonly, in animals where there is stretch of the atria (particularly the left atrium), for example, in dogs with dilated cardiomyopathy or mitral valvular insufficiency, and in cats with hypertrophic cardiomyopathy. Some congenital defects such as mitral and tricuspid dysplasia, patent ductus arteriosus and ventricular septal defect, which lead to atrial stretch, are also associated with supraveniricular tachydysrhythmias. The larger the normal heart size of the animal, the more readily supraventricular arrhythmias (particularly atrial fibrillation) will be supported. Indeed, a recent survey has shown that in Irish wolfhounds the incidence of atrial fibrillation is about 10% in apparently healthy animals. Size, however, does not appear to be the only factor involved as the same survey found no cases of atrial fibrillation in normal Old English mastiffs.

Management of supraventricular tachydysrhythmias

Most commonly, paroxysmal or sustained atrial tachydysrhythmias (usually atrial fibrillation) are associated with animals showing signs of congestive heart failure. Management of these arrhythmias should be part of the treatment of the heart failure since an uncontrolled heart rate will lead to severe compromise of cardiac function. Digoxin is the drug of choice in the management of these cases (with the exception of re-entrant supraventricular tachycardia occurring in animals with ventricular pre-excuation syndrome, where it is contraindicated) since it is the only drug currently available which slows conduction through the AV node without reducing myocardial contractility. This is particularly important in animals with poor systolic function as is the case in dilated cardiomyopathy. In severe cases of congestive heart failure due to dilated cardiomyopathy, it may be desirable to give a more effective positive inotrope, such as dobutamine. Dobutamine, however, will tend to increase conduction through the atrioventricular node, thus accelerating the ventricular response rate in atrial fibrillation. Concurrent treatment with digoxin will tend to reduce the ventricular response rate. If possiblel slow digitalization is recommended (see earlier for dose rates). High loading doses are dangerous, particularly in dogs which are hypoxic and have poor myocardial contractility.

Digoxin will not convert atrial arrhythmias into sinus rhythm but reduces the significance of the arrhythmia by slowing the ventricular response. The ideal ventricular rate which should be aimed for in the management of atrial arrhythmias has not been determined for the dog or cat. Most cardiologists would suggest that rates in excess of 160 bpm in the dog under examination conditions are too high. Some suggest training the owners to record the heart rate at home using a stethoscope and suggest a target: rate of between 70 and 110 bpm in the dog and 80-140 bpm in the cat. Such heart rates can rarely be achieved by the use of digoxin alone. Measurement of serum digoxin levels should be made after 5 days on maintenance therapy to ensure that the therapeutic serum concentration of digoxin has been achieved but not exceeded. Additional drug therapy may then be instituted in an attempt to reduce the heart rate further

The second drug recommended for use in atrial arrhythmias is diltiazem (0.5 mg kg-1 three times daily for dogs, twice daily for cats). Diltiazem is a calcium channel blocker which has effects on both cardiac and vascular smooth muscle. Conduction of electrical impulses through the atrioventricular node relies on slow calcium channels and diltiazem slows conduction through the atrioventricular node. It has the potential to reduce cardiac muscle contractility, which partly depends on calcium entry during the cardiac action potential. Diltiazem is thought to have less of a negative inotropic effect when compared with verapamil, possibly because it also reduces afterload whereas verapamil is less effective in this respect. Both verapamil and diltiazem reduce the excretion of digoxin which may necessitate a reduction in the dose of digoxin if combined with a calcium channel blocker. Calcium channel blockers are the drugs of choice in the management of re-entrant supraventricular tachycardia in animals with ventricular pre-excitation syndrome. Conversion of atrial arrhythmias into a normal sinus rhythm has been reported following the use of calcium channel blockers (Johnson, 1984)+ The conversion is short-lived in animals with underlying cardiac disease unless therapy is maintained. The arterial vasodilator properties of diltiazem will also reduce afterload and enhance coronary blood flow during diastole.

Beta-adrenoceptor antagonists can also be used to reduce the ventricular response rate in cases of supraventricular tachydysrhythmia. Propranolol is a non-selective beta-adrenoceptor antagonist which can be used for this purpose at an oral dose rate of 0.5-1 mg kg-1 twice or three times daily. The negative inotropic effect of propranolol will be particularly marked in animals relying on sympathetic drive to compensate for poor myocardial contractility. Beta-blockers, therefore, should be used with caution in any animal with signs of congestive heart failure, particularly when poor systolic function is likely to be the underlying cause. Cardioselective beta-blockers have been produced, with the main advantage that they show less tendency, compared with propranolol, to precipitate asthmatic attacks by blocking the protective bronchodilator effect of circulating adrenaline. Dose rates are available for drugs such as atenolol and metoprolol but we currently lack experience with the use of such drugs in veterinary medicine.

It should be remembered that digoxin, calcium channel blockers and beta-blockers all decrease conduction through the atrioventricular node via different mechanisms and so will have a synergistic effect when administered together. When introducing a second drug, close monitoring of the patient is necessary to ensure that excessive reduction in the heart rate does not occur Recently, adenosine has been used in human medicine to convert unstable supraventricular tachycardia into sinus rhythm and the development of drugs with favourable pharmacokinctics which are selective for cardiac adenosine receptors may, in the future, add to the therapeutic alternatives available for the management of supraventricular tachydysrhythmias.

With atrial tachydvsrhythmias of sudden onset following surgery or trauma, where there is no sign of cardiomegaly or congestive heart failure, it may be reasonable to attempt to convert the rhythm into normal sinus rhythm. This can be attempted by the use of quinidine or diltiazem. Quinidine has antimuscarinic properties and so may increase the ventricular rate initially before converting the rhythm back into sinus rhythm. For this reason, it is recommended to digitalize the animal before attempting conversion with quinidine. When administering quinidine with digoxin, it should be remembered that quinidine displaces digoxin from skeletal muscle binding sites so raising the serum concentration of digoxin. A 50% reduction in the digoxin dose is recommended under these circumstances.

Animals (usually large breed dogs) with atrial fibrillation where the ventricular response rate is relatively slow (<150 bpm) and where there is no evidence of heart failure are likely to develop problems eventually. When they are not showing clinical signs it is reasonable to follow them and give no therapy, particularly as the optimum heart rate for a dog with atrial fibrillation has not been established.

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Drugs

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based (Abelcet, Fungizone)

Antifungal

Highlights Of Prescribing Information

Systemic antifungal used for serious mycotic infections

Must be administered IV

Nephrotoxicity is biggest concern, particularly with the deoxycholate form; newer lipid based products are less nephrotoxic & penetrate into tissues better, but are more expensive

Renal function monitoring essential

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based interactions

What Is Amphotericin B Desoxycholate, Amphotericin B Lipid-Based Used For?

Because the potential exists for severe toxicity associated with this drug, it should only be used for progressive, potentially fatal fungal infections. Veterinary use of amphotericin has been primarily in dogs, but other species have been treated successfully. For further information on fungal diseases treated, see the Pharmacology and Dosage sections.

The liposomal form of amphotericin B can be used to treat Leishmaniasis.

Pharmacology / Actions

Amphotericin B is usually fungistatic, but can be fungicidal against some organisms depending on drug concentration. It acts by binding to sterols (primarily ergosterol) in the cell membrane and alters the permeability of the membrane allowing intracellular potassium and other cellular constituents to “leak out.” Because bacteria and rickettsia do not contain sterols, amphotericin B has no activity against those organisms. Mammalian cell membranes do contain sterols (primarily cholesterol) and the drug’s toxicity may be a result of a similar mechanism of action, although amphotericin binds less strongly to cholesterol than ergosterol.

Amphotericin B has in vitro activity against a variety of fungal organisms, including Blastomyces, Aspergillus, Paracoccidioides, Coccidioides, Histoplasma, Cryptococcus, Mucor, and Sporothrix. Zygomycetes is reportedly variable in its response to amphotericin. Aspergillosis in dogs and cats does not tend to respond satisfactorily to amphotericin therapy. Additionally, amphotericin B has in vivo activity against some protozoa species, including Leishmania spp. and Naegleria spp.

It has been reported that amphotericin B has immunoadjuvant properties but further work is necessary to confirm the clinical significance of this effect.

Pharmacokinetics

Pharmacokinetic data on veterinary species is apparently unavailable. In humans (and presumably animals), amphotericin B is poorly absorbed from the GI tract and must be given parenterally to achieve sufficient concentrations to treat systemic fungal infections. After intravenous injection, the drug reportedly penetrates well into most tissues but does not penetrate well into the pancreas, muscle, bone, aqueous humor, or pleural, pericardial, synovial, and peritoneal fluids. The drug does enter the pleural cavity and joints when inflamed. CSF levels are approximately 3% of those found in the serum. Approximately 90-95% of amphotericin in the vascular compartment is bound to serum proteins. The newer “lipid” forms of amphotericin B have higher penetration into the lungs, liver and spleen than the conventional form.

The metabolic pathways of amphotericin are not known, but it exhibits biphasic elimination. An initial serum half-life of 24-48 hours, and a longer terminal half-life of about 15 days have been described. Seven weeks after therapy has stopped, amphotericin can still be detected in the urine. Approximately 2-5% of the drug is recovered in the urine in unchanged (biologically active) form.

Before you take Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

Contraindications / Precautions / Warnings

Amphotericin is contraindicated in patients who are hypersensitive to it, unless the infection is life-threatening and no other alternative therapies are available.

Because of the serious nature of the diseases treated with systemic amphotericin, it is not contraindicated in patients with renal disease, but it should be used cautiously with adequate monitoring.

Adverse Effects

Amphotericin B is notorious for its nephrotoxic effects; most canine patients will show some degree of renal toxicity after receiving the drug. The proposed mechanism of nephrotoxicity is via renal vasoconstriction with a subsequent reduction in glomerular filtration rate. The drug may directly act as a toxin to renal epithelial cells. Renal damage may be more common, irreversible and severe in patients who receive higher individual doses or have preexisting renal disease. Usually, renal function will return to normal after treatment is halted, but may require several months to do so.

Newer forms of lipid-complexed and liposome-encapsulated amphotericin B significantly reduce the nephrotoxic qualities of the drug. Because higher dosages may be used, these forms may also have enhanced effectiveness. A study in dogs showed that amphotericin B lipid complex was 8-10 times less nephrotoxic than the conventional form.

The patient’s renal function should be aggressively monitored during therapy. A pre-treatment serum creatinine, BUN (serum urea nitrogen/SUN), serum electrolytes (including magnesium if possible), total plasma protein (TPP), packed cell volume (PCV), body weight, and urinalysis should be done prior to starting therapy. BUN, creatinine, PCV, TPP, and body weight are rechecked before each dose is administered. Electrolytes and urinalysis should be monitored at least weekly during the course of treatment. Several different recommendations regarding the stoppage of therapy when a certain BUN is reached have been made. Most clinicians recommend stopping, at least temporarily, amphotericin treatment if the BUN reaches 30-40 mg/dL, serum creatinine >3 mg/dL or if other clinical signs of systemic toxicity develop such as serious depression or vomiting.

At least two regimens have been used in the attempt to reduce nephrotoxicity in dogs treated with amphotericin desoxycholate. Mannitol (12.5 grams or 0.5-1 g/kg) given concurrently with amphotericin B (slow IV infusion) to dogs may reduce nephrotoxicity, but may also reduce the efficacy of the therapy, particularly in blasto-mycosis. Mannitol treatment also increases the total cost of therapy. Sodium loading prior to treating has garnered considerable support in recent years. A tubuloglomerular feedback mechanism that induces vasoconstriction and decreased GFR has been postulated for amphotericin B toxicity; increased sodium load at the glomerulus may help prevent that feedback. One clinician (Foil 1986), uses 5 mL/kg of normal saline given in two portions, before and after amphotericin B dosing and states that is has been “… helpful in averting renal insufficiency….”

Cats are apparently more sensitive to the nephrotoxic aspects of amphotericin B, and many clinicians recommend using reduced dosages in this species (see Dosage section).

Adverse effects reported in horses include: tachycardia, tachyp-nea, lethargy, fever, restlessness, anorexia, anemia, phlebitis, polyuria and collapse.

Other adverse effects that have been reported with amphotericin B include: anorexia, vomiting, hypokalemia, distal renal tubular aci-dosis, hypomagnesemia, phlebitis, cardiac arrhythmias, non-regenerative anemia and fever (may be reduced with pretreatment with NSAIDs or a low dosage of steroids). Calcinosis cutis has been reported in dogs treated with amphotericin B. Amphotericin B can increase creatine kinase levels.

Reproductive / Nursing Safety

The safety of amphotericin B during pregnancy has not been established, but there are apparently no reports of teratogenicity associated with the drug. The risks of therapy should be weighed against the potential benefits. In humans, the FDA categorizes this drug as category B for use during pregnancy (Animal studies have not yet demonstrated risk to the fetus, hut there are no adequate studies in pregnant women; or animal studies have shown an adverse effect, hut adequate studies in pregnant women have not demonstrated a risk to the fetus in the first trimester of pregnancy, and there is no evidence of risk in later trimesters.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (Papich 1989), this drug is categorized as in class: A (Prohahly safe. Although specific studies may not have proved the safety of all drugs in dogs and cats, there are no reports of adverse effects in laboratory animals or women.)

Overdosage / Acute Toxicity

No case reports were located regarding acute intravenous overdose of amphotericin B. Because of the toxicity of the drug, dosage calculations and solution preparation procedures should be double-checked. If an accidental overdose is administered, renal toxicity maybe minimized by administering fluids and mannitol as outlined above in the Adverse Effects section.

How to use Amphotericin B Desoxycholate, Amphotericin B Lipid-Based

All dosages are for amphotericin B desoxycholate (regular amphotericin B) unless specifically noted for the lipid-based products.

Note: Some clinicians have recommended administering a 1 mg test dose (less in small dogs or cats) IV over anywhere from 20 minutes to 4 hours and monitoring pulse, respiration rates, temperature, and if possible, blood pressure. If a febrile reaction occurs some clinicians recommend adding a glucocorticoid to the IV infusion solution or using an antipyretic prior to treating, but these practices are controversial.

A published study () demonstrated less renal impairment and systemic adverse effects in dogs who received amphotericin BIV slowly over 5 hours in 1 L of D5W than in dogs who received the drug IV in 25 mL of D5W over 3 minutes.

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for dogs:

For treatment of susceptible systemic fungal infections:

a) Two regimens can be used; after diluting vial (as outlined below in preparation of solution section), either:

1) Rapid-Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W. Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given.

2) Slow IV Infusion Technique: Dilute quantity of stock solution to equal 0.25 mg/kg in 250-500 mL of D5W. Place indwelling catheter in peripheral vein and give total volume over 4-6 hours. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.5 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

b) In dehydrated, sodium-depleted animals, must rehydrate before administration. Dosage is 0.5 mg/kg diluted in D5W. In dogs with normal renal function, may dilute in 60-120 mL of D5W and give by slow IV over 15 minutes. In dogs with compromised renal function, dilute in 500 mL or 1 liter of D5W and give over slowly IV over 3-6 hours. Re-administer every other day if BUN remains below 50 mg/dl. If BUN exceeds 50 mg/dl, discontinue until BUN decreases to at least 35 mg/dl. Cumulative dose of 8 -10 mg/kg is required to cure blastomycosis or histoplasmosis. Coccidioidomycosis, aspergillosis and other fungal diseases require a greater cumulative dosage. ()

c) For treating systemic mycoses using the lipid-based products: AmBisome, Amphocil or Abelcet Give test dose of 0.5 mg/ kg; then 1-2.5 mg/kg IV q48h (or Monday, Wednesday, Friday) for 4 weeks or until the total cumulative dose is reached. Use 1 mg/kg dose for susceptible yeast and dimorphic fungi until a cumulative dose of 12 mg/kg is reached; for more resistant filamentous fungal infections (e.g., pythiosis) use the higher dose 2-2.5 mg/kg until a cumulative dose of 24-30 mg/kg is reached. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 2-3 mg/kg IV three days per week for a total of 9-12 treatments (cumulative dose of 24-27 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

e) For systemic mycoses using amphotericin B lipid complex (Abelcet): Dilute in 5% dextrose to a final concentration of 1 mg/mL and administer at a dosage of 2-3 mg/kg three times per week for 9-12 treatments or a cumulative dosage of 24-27 mg/kg ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B 0.5 mg/kg 3 times weekly until a total dose of 6 mg/kg is given, with ketoconazole at 10-20 mg/kg (30 mg/kg for CNS, bone or eye involvement) divided for 3-6 months ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 20 mg/day PO once daily or divided twice daily; 40 mg/kg divided twice daily for ocular or CNS involvement (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5-5 mg/kg PO once daily. If CNS/ocular involvement use ketoconazole at 20-40 mg/kg PO divided twice daily ()

c) For severe cases, using amphotericin B lipid complex (Abelcet): 1-2 mg/kg IV three times a week (or every other day) to a cumulative dose of 12-24 mg/kg ()

For cryptococcosis (see general dosage guidelines above):

a) Amphotericin B 0.5 – 0.8 mg/kg SC 2 – 3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B 0.15 – 0.5 mg/kg IV 3 times a week with ketoconazole 10-20 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

b) As an alternative to ketoconazole treatment: 0.5 mg/kg IV given over 6-8 hours. If dose is tolerated, increase to 1 mg/ kg given on alternate days until total dose of 7.5-8.5 mg/kg cumulative dose is achieved ()

For Leishmaniasis:

a) Using the liposomal form of Amphotericin B: 3-3.3 mg/kg IV 3 times weekly for 3-5 treatments)

b) Using AmBisome (lipid-based product): Give initial test dose of 0.5 mg/kg, then 3-3.3 mg/kg IV every 72-96 hours until a cumulative dose of 15 mg/kg is reached. May be possible to give the same cumulative dose with a lower level every 48 hours. ()

For gastrointestinal pythiosis:

a) Resect lesions that are surgically removable to obtain 5 – 6 cm margins. Follow-up medical therapy using the amphotericin B lipid complex (ABLC; Abelcet) product: 1-2 mg/kg IV three times weekly for 4 weeks (cumulative dose 12-24 mg). May alternatively use itraconazole at 10 mg/kg PO once daily for 4-6 months. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for cats:

For treatment of susceptible systemic fungal infections: a) Rapid-Infusion Technique: After diluting vial (as outlined below in preparation of solution section), dilute quantity of stock solution to equal 0.25 mg/kg in 30 mL of 5% dextrose. Using butterfly catheter, flush with 10 mL of D5W Infuse amphotericin B solution IV over 5 minutes. Flush catheter with 10 mL of D5W and remove catheter. Repeat above steps using 0.25 mg/kg 3 times a week until 9-12 mg/kg accumulated dosage is given. ()

For cryptococcosis (see general dosage guidelines above):

a) As an alternative therapy to ketoconazole: Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with flucytosine at 200 mg/kg/day divided q6h PO. Continue therapy for 3-4 weeks after clinical signs have resolved or until BUN >50 mg/dl. (Legendre 1989)

b) Amphotericin B 0.15-0.4 mg/kg IV 3 times a week with flucytosine 125-250 mg/day PO divided two to four times a day. When a total dose of amphotericin B reaches 4-6 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month with flucytosine at dosage above or with ketoconazole at 10 mg/kg PO once daily or divided twice daily ()

c) Amphotericin B 0.5-0.8 mg/kg SC 2-3 times per week. Dose is diluted in 0.45% NaCl with 2.5% dextrose (400 mL for cats, 500 mL for dogs less than 20 kg and 1000 mL for dogs greater than 20 kg). Concentrations greater than 20 mg/L result in local irritation and sterile abscess formation. May combine with flucytosine or the azole antifungals. ()

d) For treating systemic mycoses using the amphotericin B lipid complex (ABLC; Abelcet) product: 1 mg/kg IV three days per week for a total of 12 treatments (cumulative dose of 12 mg). Dilute to a concentration of 1 mg/mL in dextrose 5% (D5W) and infuse over 1-2 hours ()

For histoplasmosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole at 10 mg/kg q12h PO. Continue therapy for 4-8 weeks or until BUN >50 mg/dl. If BUN increases greater than 50 mg/dl, continue ketoconazole alone. Ketoconazole is used long-term (at least 6 months of duration. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission, then start maintenance). When a total dose of amphotericin B reaches 2-4 mg/ kg, start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or at 2.5-5 mg/kg PO once daily ()

For blastomycosis (see general dosage guidelines above):

a) Amphotericin B: 0.25 mg/kg in 30 mL D5WIV over 15 minutes q48h with ketoconazole: 10 mg/kg q12h PO (for at least 60 days). Continue amphotericin B therapy until a cumulative dose of 4 mg/kg is given or until BUN >50 mg/dl. If renal toxicity does not develop, may increase dose to 0.5 mg/ kg of amphotericin B. ()

b) Amphotericin B 0.15-0.5 mg/kg IV 3 times a week with ketoconazole 10 mg/day PO once daily or divided twice daily (for at least 2-3 months or until remission then start maintenance). When a total dose of amphotericin B reaches 4-6 mg/ kg start maintenance dosage of amphotericin B at 0.15-0.25 mg/kg IV once a month or use ketoconazole at 10 mg/kg PO either once daily, divided twice daily or ketoconazole at 2.5 – 5 mg/kg PO once daily. If CNS/ocular involvement, use ketoconazole at 20-40 mg/kg PO divided twice daily. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for rabbits, rodents, and small mammals:

a) Rabbits: 1 mg/kg/day IV ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for horses:

For treatment of susceptible systemic fungal infections:

a) For fungal pneumonia: Day 1: 0.3 mg/kg IV; Day 2: 0.4 mg/kg IV; Day 3: 0.6 mg/kg IV; days 4-7: no treatment; then every other day until a total cumulative dose of 6.75 mg/kg has been administered ()

b) For phycomycoses and pulmonary mycoses: After reconstitution (see below) transfer appropriate amount of drug to 1L of D5W and administer using a 16 g needle IV at a rate of 1 L/ hr. Dosage schedule follows: Day 1: 0.3 mg/kg IV; Day 2: 0.45 mg/kg IV; Day 3: 0.6 mg/kg IV; then every other day for 3 days per week (MWF or TTHSa) until clinical signs of either improvement or toxicity occur. If toxicity occurs, a dose may be skipped, dosage reduced or dosage interval lengthened. Administration may extend from 10-80 days. ()

For intrauterine infusion: 200-250 mg. Little science is available for recommending doses, volume infused, frequency, diluents, etc. Most intrauterine treatments are commonly performed every day or every other day for 3-7 days. ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for Llamas:

For treatment of susceptible systemic fungal infections: a) A single case report. Llama received 1 mg test dose, then initially at 0.3 mg/kg IV over 4 hours, followed by 3 L of LRS with 1.5 mL of B-Complex and 20 mEq of KC1 added. Subsequent doses were increased by 10 mg and given every 48 hours until reaching 1 mg/kg q48h IV for 6 weeks. Animal tolerated therapy well, but treatment was ultimately unsuccessful (Coccidioidomycosis). ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for birds:

For treatment of susceptible systemic fungal infections:

a) For raptors and psittacines with aspergillosis: 1.5 mg/kg IV three times daily for 3 days with flucytosine or follow with flucytosine. May also use intratracheally at 1 mg/kg diluted in sterile water once to 3 times daily for 3 days in conjunction with flucytosine or nebulized (1 mg/mL of saline) for 15 minutes twice daily. Potentially nephrotoxic and may cause bone marrow suppression. ()

b) 1.5 mg/kg IV q12h for 3-5 days; topically in the trachea at 1 mg/kg q12h; 0.3-1 mg/mL nebulized for 15 minutes 2-4 times daily ()

Amphotericin B Desoxycholate, Amphotericin B Lipid-Based dosage for reptiles:

For susceptible fungal respiratory infections: a) For most species: 1 mg/kg diluted in saline and given intratracheally once daily for 14-28 treatments ()

Client Information

■ Clients should be informed of the potential seriousness of toxic effects that can occur with amphotericin B therapy

■ The costs associated with therapy

Chemistry / Synonyms

A polyene macrolide antifungal agent produced by Streptomyces nodosus, amphotericin B occurs as a yellow to orange, odorless or practically odorless powder. It is insoluble in water and anhydrous alcohol. Amphotericin B is amphoteric and can form salts in acidic or basic media. These salts are more water soluble but possess less antifungal activity than the parent compound. Each mg of amphotericin B must contain not less than 750 micrograms of anhydrous drug. Amphotericin A may be found as a contaminant in concentrations not exceeding 5%. The commercially available powder for injection contains sodium desoxycholate as a solubilizing agent.

Newer lipid-based amphotericin B products are available that have less toxicity than the conventional desoxycholate form. These include amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec), amphotericin B lipid complex (ABLC, Abelcet), and amphotericin B liposomal (ABL, L-AMB, Ambisome).

Amphotericin B may also be known as: amphotericin; amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposome, amphotericin B phospholipid complex, amphotericin B-Sodium cholesteryl sulfate complex, anfotericina B, or liposomal amphotericin B; many trade names are available.

Storage / Stability / Compatibility

Vials of amphotericin B powder for injection should be stored in the refrigerator (2-8°C), protected from light and moisture. Reconstitution of the powder must be done with sterile water for injection (no preservatives — see directions for preparation in the Dosage Form section below).

After reconstitution, if protected from light, the solution is stable for 24 hours at room temperature and for 1 week if kept refrigerated. After diluting with D5W (must have pH >4.3) for IV use, the manufacturer recommends continuing to protect the solution from light during administration. Additional studies however, have shown that potency remains largely unaffected if the solution is exposed to light for 8-24 hours.

Amphotericin B deoxycholate is reportedly compatible with the following solutions and drugs: D5W, D5W in sodium chloride 0.2%, heparin sodium, heparin sodium with hydrocortisone sodium phosphate, hydrocortisone sodium phosphate/succinate and sodium bicarbonate.

Amphotericin B deoxycholate is reportedly incompatible with the following solutions and drugs: normal saline, lactated Ringer’s, D5-normal saline, Ds-lactated Ringer’s, amino acids 4.25%-dextrose 25%, amikacin, calcium chloride/gluconate, carbenicillin disodium, chlorpromazine HCL, cimetidine HCL, diphenhydramine HCL, dopamine HCL, edetate calcium disodium (Ca EDTA), gentamicin sulfate, kanamycin sulfate, lidocaine HCL, metaraminol bitartrate, methyldopate HCL, nitrofurantoin sodium, oxytetracycline HCL, penicillin G potassium/sodium, polymyxin B sulfate, potassium chloride, prochlorperazine mesylate, streptomycin sulfate, tetracycline HCL, and verapamil HCL. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

Human-Labeled Products:

Amphotericin B Desoxycholate Powder for Injection: 50 mg in vials; Amphocin (Gensia Sicor); Fungizone Intravenous (Apothecon); generic (Pharma-Tek); (Rx)

Directions for reconstitution/administration: Using strict aseptic technique and a 20 gauge or larger needle, rapidly inject 10 mL of sterile water for injection (without a bacteriostatic agent) directly into the lyophilized cake; immediately shake well until solution is clear. A 5 mg/mL colloidal solution results. Further dilute (1:50) for administration to a concentration of 0.1 mg/mL with 5% dextrose in water (pH >4.2). An in-line filter may be used during administration, but must have a pore diameter >1 micron.

Amphotericin B Lipid-Based Suspension for Injection: 100 mg/20 mL (as lipid complex) in 10 mL & 20 mL vials with 5 micron filter needles: Abelcet (Enzon); (Rx)

Amphotericin B Lipid-Based Powder for Injection: 50 mg/vial (as cholesteryl) in 20 mL vials; 100 mg (as cholesteryl) in 50 mL vials; Amphotec (Sequus Pharmaceuticals); 50 mg (as liposomal) in single-dose vials with 5-micron filter; AmBisome (Fujisawa; (Rx)

Amphotericin B is also available in topical formulations: Fungizone (Apothecon); (Rx)

Categories
Drugs

Amiodarone HCL (Cordarone, Pacerone)

Class III Antiarrhythmic

Highlights Of Prescribing Information

Antidysrhythmic agent that can be used in dogs for arrhythmias associated with left ventricular dysfunction or to convert atrial fib into sinus rhythm; very limited experience warrants cautious use

May be useful in horses to convert atrial fib or V tach into sinus rhythm

Contraindicated in 2nd, 3rd degree heart block, bradyarrhythmias

In DOGS: GI disturbances (vomiting, anorexia) most likely adverse effect, but neutropenia, thrombocytopenia, bradycardia, hepatotoxicity, positive Coombs’ test reported

In HORSES: Limited use, accurate adverse effect profile to be determined; Hind limb weakness, increased bilirubin reported when used IV to convert atrial fib

Many drug interactions

What Is Amiodarone HCL Used For?

Because of its potential toxicity and lack of experience with use in canine and equine patients, amiodarone is usually used when other less toxic or commonly used drugs are ineffective. It may be useful in dogs and horses to convert atrial fib into sinus rhythm and in dogs for arrhythmias associated with left ventricular dysfunction. In horses, one horse with Ventricular tachycardia was converted into sinus rhythm using amiodarone.

As the risk of sudden death is high in Doberman pinschers exhibiting rapid, wide-complex ventricular tachycardia or syncope with recurrent VPC’s, amiodarone maybe useful when other drug therapies are ineffective.

Pharmacology/Actions

Amiodarone’s mechanism of action is not fully understood; it apparently is a potassium channel blocker that possesses unique pharmacology from other antiarrhythmic agents. It can be best classified a Class III antiarrhythmic agent that also blocks sodium and calcium channels, and beta-adrenergic receptors. Major properties include prolongation of myocardial cell action-potential duration and refractory period.

Pharmacokinetics

Amiodarone may be administered parenterally or orally. Amiodarone is widely distributed throughout the body and can accumulate in adipose tissue. Amiodarone is metabolized by the liver into the active metabolite desethylamiodarone. After oral administration of a single dose in normal dogs, amiodarone’s plasma half-life averaged 7.5 hours, but repeated dosing increased its half-life from 11 hours to 3.2 days.

In horses, amiodarone has a low oral bioavailability (range from 6-34%) and peak levels of amiodarone and desethylamiodarone occur about 7-8 hours after an oral dose. After IV administration amiodarone is rapidly distributed with a high apparent volume of distribution of 31 L/kg. In horses, amiodarone is relatively highly bound to plasma proteins (96%). Clearance was 0.35 L/kg/hr and median elimination half-lives for amiodarone and desethylamiodarone were approximately 51 and 75 hours, respectively ().

In humans, oral absorption is slow and variable, with bioavailabilities ranging from 22-86%. Elimination half-lives for amiodarone and desethylamiodarone range from 2.5-10 days after a single dose, but with chronic dosing, average 53 days and 60 days, respectively.

Before you take Amiodarone HCL

Contraindications / Precautions / Warnings

Amiodarone is considered contraindicated in patients (humans) hypersensitive to it, having severe sinus-node dysfunction with severe sinus bradycardia, 2nd or 3rd degree heart block, or bradycardial syncope.

Clinical experience in veterinary patients is limited. Consider use only when other less toxic and more commonly used drugs are ineffective.

Adverse Effects

Gastrointestinal effects (e.g., anorexia, vomiting) are apparently the most likely adverse effects seen in the limited number of canine patients treated. Hepatopathy (bilirubinemia, increased hepatic enzymes) has been reported in dogs on amiodarone. Because hepatic effects can occur before clinical signs are noted, routine serial evaluation of liver enzymes and bilirubin is recommended. Other adverse effects reported in dogs include bradycardia, neutropenia, thrombocytopenia, or positive Coombs’ test. During IV infusion, pain at injection site, and facial pruritus and hyperemia have been noted. Corneal deposits may be seen in dogs treated with amiodarone, but this affect apparently occurs less frequently in dogs than in humans.

In human patients, adverse effects are very common while on amiodarone therapy. Those that most commonly cause discontinuation of the drug include: pulmonary infiltrates or pulmonary fi-brosis (sometimes fatal), liver enzyme elevations, congestive heart failure, paroxysmal ventricular tachycardia, and thyroid dysfunction (hypo- or hyperthyroidism). An odd effect seen in some individuals is a bluish cast to their skin. Reversible corneal deposits are seen in a majority of humans treated with amiodarone.

Clinical experience in dogs is limited; the adverse effect profile of this drug in people warrants its use in veterinary patients only when other less toxic agents are ineffective and treatment is deemed necessary.

Reproductive / Nursing Safety

In laboratory animals, amiodarone has been embryotoxic at high doses and congenital thyroid abnormalities have been detected in offspring. Use during pregnancy only when the potential benefits outweigh the risks of the drug. In humans, the FDA categorizes this drug as category D for use during pregnancy (There is evidence of human fetal risk, hut the potential benefits from the use of the drug in pregnant women may he acceptable despite its potential risks.)

Overdosage / Acute Toxicity

Clinical overdosage experience is limited; most likely adverse effects seen are hypotension, bradycardia, cardiogenic shock, AV block, and hepatotoxicity. Treatment is supportive. Bradycardia may be managed with a pacemaker or beta-1 agonists (e.g., isoproterenol); hypotension managed with positive inotropic agents or vasopressors. Neither amiodarone nor its active metabolite are dialyzable.

How to use Amiodarone HCL

Note: Some human references state that because of the potential for drug interactions with previous drug therapies, the life-threatening nature of the arrhythmias being treated, and the unpredictability of response from amiodarone, the drug should be initially given (loaded) over several days in an inpatient setting where adequate monitoring can occur.

Amiodarone HCL dosage for dogs:

For conversion of atrial fibrillation:

a) At the time of writing (2007) one case report () and one retrospective evaluation () have been published using amiodarone to convert atrial fibrillation in dogs. Dosage recommendations are yet to be fully defined; monitor the current literature for further recommendations.

For recurrent ventricular tachycardia not controlled with other less toxic drugs:

a) 10-25 mg/kg PO twice daily for 7 days, followed by 5-7.5 mg/kg PO twice daily for 14 days, followed by 7.5 mg/kg PO once daily ()

b) For ventricular arrhythmias secondary to occult cardiomyopathy in Doberman pinschers: 10 mg/kg PO twice daily for one week and then 8 mg/kg PO once daily. For severe V-Tach, mexiletine is added at 5-8 mg/kg three times daily for one week. Once efficacy confirmed, patient weaned off mexiletine. ()

c) Amiodarone as above in “b”, but after 6 months may be reduced to 5 mg/kg once daily. ()

d) 10-20 mg/kg PO q12h ()

Amiodarone HCL dosage for horses:

For conversion of atrial fibrillation or ventricular tachycardia: a) 5 mg/kg/hr for one hour, followed by 0.83 mg/kg/hr for 23 hours and then 1.9 mg/kg/hour for the following 30 hours. In the study (A fib), infusion was discontinued when conversion occurred or when any side effects were noted. 4 of 6 horses converted from A fib; one horse from V tach. In order to increase success rate and decrease adverse effects, regimen should be further adapted based upon PK/PD studies in horses. ()

Monitoring

■ Efficacy (ECG)

■ Toxicity (GI effects; CBC, serial liver enzymes; thyroid function tests; blood pressure; pulmonary radiographs if clinical signs such as dyspnea/cough occur)

Client Information

■ Because of the “experimental” nature (relatively few canine/equine patients have received this agent) and the toxicity dangers associated with its use, clients should give informed consent before the drug is prescribed.

Chemistry / Synonyms

An iodinated benzofuran, amiodarone is unique structurally and pharmacologically from other antiarrhythmic agents. It occurs as a white to cream colored lipophilic powder having a pKa of approximately 6.6. Amiodarone 200 mg tablets each contain approximately 75 mg of iodine.

Amiodarone HCL may also be known as: amiodaroni hydrochloridum, L-3428, 51087N, or SKF-33134-A; many trade names are available.

Storage / Stability/Compatibility

Tablets should be stored in tight containers, at room temperature and protected from light. A 3-year expiration date is assigned from the date of manufacture.

Injection should be stored at room temperature and protected from light or excessive heat. While administering, light protection is not necessary. Use D5W as the IV diluent. Amiodarone is reportedly compatible with dobutamine, lidocaine, potassium chloride, procainamide, propafenone, and verapamil. Variable compatibility is reported with furosemide and quinidine gluconate.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 4 substance. See the appendix for more information.

Human-Labeled Products:

Amiodarone Oral Tablets: 100 mg, 200 mg & 400 mg; Cordarone (Wyeth-Ayerst); Pacerone (Upsher Smith); generic; (Rx)

Amiodarone Concentrate for Injection (for IV Infusion): 50 mg/mL in 3 mL amps & vials; Cordarone (Wyeth-Ayerst); generic; (Rx)

Categories
Drugs

Aminophylline Theophylline

Phosphodiesterase Inhibitor Bronchodilator

Highlights Of Prescribing Information

Bronchodilator drug with diuretic activity; used for bronchospasm & cardiogenic pulmonary edema

Narrow therapeutic index in humans, but dogs appear to be less susceptible to toxic effects at higher plasma levels

Therapeutic drug monitoring recommended

Many drug interactions

What Is Aminophylline Theophylline Used For?

The theophyllines are used primarily for their broncho dilatory effects, often in patients with myocardial failure and/or pulmonary edema. While they are still routinely used, the methylxanthines must be used cautiously due to their adverse effects and toxicity.

Pharmacology/Actions

The theophyllines competitively inhibit phosphodiesterase thereby increasing amounts of cyclic AMP which then increase the release of endogenous epinephrine. The elevated levels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllines possess maybe a result of translocating intracellular ionized calcium.

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They have weak chronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation (centrally-mediated).

Pharmacokinetics

The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavail-abilities after oral administration are nearly 100% when non-sustained release products are used. One study in dogs that compared various sustained-release products (), found bioavailabilities ranging from approximately 30-76% depending on the product used.

Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses the placenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogs has been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85-1.02 L/kg. Because of the low volumes of distribution and theophylline’s low lipid solubility, obese patients should be dosed on a lean body weight basis.

Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine which has weakbronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance of theophylline. The reported elimination half-lives (mean values) in various species are: dogs = 5.7 hours; cats = 7.8 hours, pigs = 11 hours; and horses = 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half-lives and resultant serum levels. It could be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

Before you take Aminophylline Theophylline

Contraindications / Precautions / Warnings

The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.

The theophyllines should be administered with caution in patients with severe cardiac disease, seizure disorders, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lives of theophylline.

Adverse Effects

The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels; dogs appear to tolerate levels that may be very toxic to humans. Some mild CNS excitement and GI disturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.

Dogs and cats can exhibit clinical signs of nausea and vomiting, insomnia, increased gastric acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.

Reproductive / Nursing Safety

In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

Clinical signs of toxicity (see above) are usually associated with levels greater than 20 mcg/mL in humans and become more severe as the serum level exceeds that value. Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered the most life-threatening aspects of toxicity. Dogs appear to tolerate serum levels higher than 20 mcg/mL.

Treatment of theophylline toxicity is supportive. After an oral ingestion, the gut should be emptied, charcoal and a cathartic administered using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life threatening.

How to use Aminophylline Theophylline

Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinet-ic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed using the information found in the Chemistry section below. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Aminophylline Theophylline dosage for dogs:

a) Using Theochron Extended-Release Tablets or Theo-Cap Extended-Release Capsules: Give 10 mg/kg PO every 12 hours initially, if no adverse effects are observed and the desired clinical effect is not achieved, give 15 mg/kg PO q12h while monitoring for adverse effects. ()

b) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 11 mg/kg PO, IM or IV three times daily. ()

c) For adjunctive therapy of severe, acute pulmonary edema and bronchoconstriction: Aminophylline 4-8 mg/kg IV or IM, or 6-10 mg/kg PO every 8 hours. Long-term use is not recommended. ()

d) For cough: Aminophylline: 10 mg/kg PO, IV three times daily ()

e) As a broncho dilator tor collapsing trachea: 11 mg/kg PO or IV q6- 12h ()

Aminophylline Theophylline dosage for cats:

a) Using Theo-Dur 20 mg/kg PO once daily in the PM; using Slo-Bid 25 mg/kg PO once daily in the PM (Johnson 2000) [Note: The products Theo-Dur and Slo-Bid mentioned in this reference are no longer available in the USA. Although hard data is not presently available to support their use in cats, a reasonable alternative would be to cautiously use the dog dose and products mentioned above in the reference by Bach et al — Plumb]

b) Using aminophylline tablets: 6.6. mg/kg PO twice daily; using sustained release tablets (Theo-Dur): 25-50 mg (total dose) per cat PO in the evening ()

c) For adjunctive medical therapy for mild clinical signs associated with tracheal collapse (<50% collapse): aminophylline: 5 mg/kg PO, two times daily. ()

d) For adjunctive therapy for bronchoconstriction associated with fulminant CHF: Aminophylline 4-8 mg/kg SC, IM, IV q8-12h. ()

e) For cough: Aminophylline: 5 mg/kg PO twice daily ()

Aminophylline Theophylline dosage for ferrets:

a) 4.25 mg/kg PO 2-3 times a day ()

Aminophylline Theophylline dosage for horses:

(Note: ARCI UCGFS Class 3 Aminophylline Theophylline)

NOTE: Intravenous aminophylline should be diluted in at least 100 mL of D5W or normal saline and administered slowly (not >25 mg/min). For adjunctive treatment of pulmonary edema:

a) Aminophylline 2-7 mg/kg IV q6- 12h; Theophylline 5-15 mg/kg PO q12h ()

b) 11 mg/kg PO or IV q8-12h. To “load” may either double the initial dose or give both the oral and IV dose at the same time. IV infusion should be in approximately 1 liter of IV fluids and given over 20-60 minutes. Recommend monitoring serum levels. ()

For adjunctive treatment for heaves (RAO):

a) Aminophylline: 5-10 mg/kg PO or IV twice daily. ()

b) Aminophylline: 4-6 mg/kg PO three times a day. ()

Monitoring

■ Therapeutic efficacy and clinical signs of toxicity

■ Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10-20 micrograms/mL. In small animals, one recommendation for monitoring serum levels is to measure trough concentration; level should be at least above 8-10 mcg/mL (Note: Some recommend not exceeding 15 micrograms/mL in horses).

Client Information

■ Give dosage as prescribed by veterinarian to maximize the drug’s benefit

Chemistry / Synonyms

Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants but, they also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous); 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline (anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline (hydrous).

Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slight ammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.

Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

Aminophylline may also be known as: aminofilina, aminophyllinum, euphyllinum, metaphyllin, theophyllaminum, theophylline and ethylenediamine, theophylline ethylenediamine compound, or theophyllinum ethylenediaminum; many trade names are available.

Theophylline may also be known as: anhydrous theophylline, teofillina, or theophyllinum; many trade names are available.

Storage / Stability/Compatibility

Unless otherwise specified by the manufacturer, store aminophylline and theophylline oral products in tight, light-resistant containers at room temperature. Do not crush or split sustained-release oral products unless label states it is permissible.

Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline that can precipitate out of solution. Do not inject aminophylline solutions that contain either a precipitate or visible crystals.

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCL, erythromycin lactobionate, heparin sodium, hydro cortisone sodium succinate, lidocaine HCL, mephentermine sulfate, methicillin sodium, methyldopate HCL, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCL

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCL, doxorubicin HCL, epinephrine HCL, erythromycin gluceptate, hydralazine HCL, hydroxyzine HCL, insulin (regular), isoproterenol HCL, levorphanol bitartrate, meperidine HCL, methadone HCL, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCL, prochlorperazine edisylate or mesylate, promazine HCL, promethazine HCL, sulfisoxazole diolamine, tetracycline HCL, vancomycin HCL, and vitamin B complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluent used and it is suggested to consult specialized references for more specific information.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products: None

The ARCI (Racing Commissioners International) has designated this drug as a class 3 substance. See the appendix for more information.

Human-Labeled Products:

The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

Aminophylline Tablets: 100 mg (79 mg theophylline) & 200 mg (158 mg theophylline); generic; (Rx)

Aminophylline Injection: 250 mg (equiv. to 197 mg theophylline) mL in 10 mL & 20 mL vials, amps and syringes; generic; (Rx)

Theophylline Time Released Capsules and Tablets: 100 mg, 125 mg 200 mg, 300 mg, 400 mg, 450 mg, & 600 mg. (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; Theophylline Extended-Release (Dey); Theo-24 (UCB Pharma); Theophylline SR (various); Theochron (Forest, various); Theophylline (Able); Theocron (Inwood); Uniphyl (Purdue Frederick); generic; (Rx)

Theophylline Tablets and Capsules: 100 mg, 200 mg, & 300 mg; Bronkodyl (Winthrop); Elixophyllin (Forest); generic; (Rx)

Theophylline Elixir: 80 mg/15 mL (26.7 mg/5 mL) in pt, gal, UD 15 and 30 mL, Asmalix (Century); Elixophyllin (Forest); Lanophyllin (Lannett); generic; (Rx)

Theophylline & Dextrose Injection: 200 mg/container in 50 mL (4 mg/mL) & 100 mL (2 mg/mL); 400 mg/container in 100 mL (4 mg/ mL), 250 mL (1.6 mg/mL), 500 mL (0.8 mg/mL) & 1000 mL (0.4 mg/mL); 800 mg/container in 250 mL (3.2 mg/mL), 500 mL (1.6 mg/mL) & 1000 mL (0.8 mg/mL); Theophylline & 5% Dextrose (Abbott & Baxter); (Rx)

Categories
Drugs

Amikacin Sulfate (Amikin, Amiglyde-V)

Aminoglycoside Antibiotic

Highlights Of Prescribing Information

Parenteral aminoglycoside antibiotic that has good activity against a variety of bacteria, predominantly gram-negative aerobic bacilli

Adverse Effects: Nephrotoxicity, ototoxicity, neuromuscu-lar blockade

Cats may be more sensitive to toxic effects

Risk factors for toxicity: Preexisting renal disease, age (both neonatal & geriatric), fever, sepsis & dehydration

Now usually dosed once daily when used systemically

What Is Amikacin Sulfate Used For?

While parenteral use is only approved in dogs, amikacin is used clinically to treat serious gram-negative infections in most species. It is often used in settings where gentamicin-resistant bacteria are a clinical problem. The inherent toxicity of the aminoglycosides limit their systemic use to serious infections when there is either a documented lack of susceptibility to other, less toxic antibiotics or when the clinical situation dictates immediate treatment of a presumed gram-negative infection before culture and susceptibility results are reported.

Amikacin is also approved for intrauterine infusion in mares. It is used with intra-articular injection in foals to treat gram-negative septic arthritis.

Pharmacology/Actions

Amikacin, like the other aminoglycoside antibiotics, act on susceptible bacteria presumably by irreversibly binding to the 30S ribosomal subunit thereby inhibiting protein synthesis. It is considered a bactericidal concentration-dependent antibiotic.

Amikacin’s spectrum of activity includes: coverage against many aerobic gram-negative and some aerobic gram-positive bacteria, including most species of E. coli, Klebsiella, Proteus, Pseudomonas, Salmonella, Enterobacter, Serratia, and Shigella, Mycoplasma, and Staphylococcus. Several strains of Pseudomonas aeruginosa, Proteus, and Serratia that are resistant to gentamicin will still be killed by amikacin.

Antimicrobial activity of the aminoglycosides is enhanced in an alkaline environment.

The aminoglycoside antibiotics are inactive against fungi, viruses and most anaerobic bacteria.

Pharmacokinetics

Amikacin, like the other aminoglycosides is not appreciably absorbed after oral or intrauterine administration, but is absorbed from topical administration (not from skin or the urinary bladder) when used in irrigations during surgical procedures. Patients receiving oral aminoglycosides with hemorrhagic or necrotic enteritises may absorb appreciable quantities of the drug. After IM administration to dogs and cats, peak levels occur from ½1 hour later. Subcutaneous injection results in slightly delayed peak levels and with more variability than after IM injection. Bio availability from extravascular injection (IM or SC) is greater than 90%.

After absorption, aminoglycosides are distributed primarily in the extracellular fluid. They are found in ascitic, pleural, pericardial, peritoneal, synovial and abscess fluids; high levels are found in sputum, bronchial secretions and bile. Aminoglycosides are minimally protein bound (<20%, streptomycin 35%) to plasma proteins. Aminoglycosides do not readily cross the blood-brain barrier nor penetrate ocular tissue. CSF levels are unpredictable and range from 0-50% of those found in the serum. Therapeutic levels are found in bone, heart, gallbladder and lung tissues after parenteral dosing. Aminoglycosides tend to accumulate in certain tissues such as the inner ear and kidneys, which may help explain their toxicity. Volumes of distribution have been reported to be 0.15-0.3 L/kg in adult cats and dogs, and 0.26-0.58 L/kg in horses. Volumes of distribution may be significantly larger in neonates and juvenile animals due to their higher extracellular fluid fractions. Aminoglycosides cross the placenta; fetal concentrations range from 15-50% of those found in maternal serum.

Elimination of aminoglycosides after parenteral administration occurs almost entirely by glomerular filtration. The approximate elimination half-lives for amikacin have been reported to be 5 hours in foals, 1.14-2.3 hours in adult horses, 2.2-2.7 hours in calves, 1-3 hours in cows, 1.5 hours in sheep, and 0.5-2 hours in dogs and cats. Patients with decreased renal function can have significantly prolonged half-lives. In humans with normal renal function, elimination rates can be highly variable with the aminoglycoside antibiotics.

Before you take Amikacin Sulfate

Contraindications / Precautions / Warnings

Aminoglycosides are contraindicated in patients who are hypersensitive to them. Because these drugs are often the only effective agents in severe gram-negative infections, there are no other absolute contraindications to their use. However, they should be used with extreme caution in patients with preexisting renal disease with concomitant monitoring and dosage interval adjustments made. Other risk factors for the development of toxicity include age (both neonatal and geriatric patients), fever, sepsis and dehydration.

Because aminoglycosides can cause irreversible ototoxicity, they should be used with caution in “working” dogs (e.g., “seeing-eye,” herding, dogs for the hearing impaired, etc.).

Aminoglycosides should be used with caution in patients with neuromuscular disorders (e.g., myasthenia gravis) due to their neuromuscular blocking activity.

Because aminoglycosides are eliminated primarily through renal mechanisms, they should be used cautiously, preferably with serum monitoring and dosage adjustment in neonatal or geriatric animals.

Aminoglycosides are generally considered contraindicated in rabbits/hares as they adversely affect the GI flora balance in these animals.

Adverse Effects

The aminoglycosides are infamous for their nephrotoxic and ototox-ic effects. The nephrotoxic (tubular necrosis) mechanisms of these drugs are not completely understood, but are probably related to interference with phospholipid metabolism in the lysosomes of proximal renal tubular cells, resulting in leakage of proteolytic enzymes into the cytoplasm. Nephrotoxicity is usually manifested by: increases in BUN, creatinine, nonprotein nitrogen in the serum, and decreases in urine specific gravity and creatinine clearance. Proteinuria and cells or casts may be seen in the urine. Nephrotoxicity is usually reversible once the drug is discontinued. While gentamicin may be more nephrotoxic than the other aminoglycosides, the incidences of nephrotoxicity with all of these agents require equal caution and monitoring.

Ototoxicity (8th cranial nerve toxicity) of the aminoglycosides can manifest by either auditory and/or vestibular clinical signs and may be irreversible. Vestibular clinical signs are more frequent with streptomycin, gentamicin, or tobramycin. Auditory clinical signs are more frequent with amikacin, neomycin, or kanamycin, but either form can occur with any of these drugs. Cats are apparently very sensitive to the vestibular effects of the aminoglycosides.

The aminoglycosides can also cause neuromuscular blockade, facial edema, pain/inflammation at injection site, peripheral neuropathy and hypersensitivity reactions. Rarely, GI clinical signs, hematologic and hepatic effects have been reported.

Reproductive / Nursing Safety

Aminoglycosides can cross the placenta and while rare, may cause 8th cranial nerve toxicity or nephrotoxicity in fetuses. Because the drug should only be used in serious infections, the benefits of therapy may exceed the potential risks. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, hut there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.) In a separate system evaluating the safety of drugs in canine and feline pregnancy (), this drug is categorized as in class: C (These drugs may have potential risks. Studies in people or laboratory animals have uncovered risks, and these drugs should he used cautiously as a last resort when the benefit of therapy clearly outweighs the risks.)

Aminoglycosides are excreted in milk. While potentially, amikacin ingested with milk could alter GI flora and cause diarrhea, amikacin in milk is unlikely to be of significant concern after the first few days of life (colostrum period).

Overdosage / Acute Toxicity

Should an inadvertent overdosage be administered, three treatments have been recommended. Hemodialysis is very effective in reducing serum levels of the drug but is not a viable option for most veterinary patients. Peritoneal dialysis also will reduce serum levels but is much less efficacious. Complexation of drug with either carbenicillin or ticarcillin (12-20 g/day in humans) is reportedly nearly as effective as hemodialysis. Since amikacin is less affected by this effect than either tobramycin or gentamicin, it is assumed that reduction in serum levels will also be minimized using this procedure.

How to use Amikacin Sulfate

Note: Most infectious disease clinicians now agree that aminoglycosides should be dosed once a day in most patients (mammals). This dosing regimen yields higher peak levels with resultant greater bacterial kill, and as aminoglycosides exhibit a “post-antibiotic effect”, surviving susceptible bacteria generally do not replicate as rapidly even when antibiotic concentrations are below MIC. Periods where levels are low may also decrease the “adaptive resistance” (bacteria take up less drug in the presence of continuous exposure) that can occur. Once daily dosing may decrease the toxicity of aminoglycosides as lower urinary concentrations may mean less uptake into renal tubular cells. However, patients who are neutropenic (or otherwise immunosuppressed) may benefit from more frequent dosing (q8h). Patients with significantly diminished renal function who must receive aminoglycosides may need to be dosed at longer intervals than once daily. Clinical drug monitoring is strongly suggested for these patients.

Amikacin Sulfate dosage for dogs:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 15-30 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for cats:

For susceptible infections:

a) Sepsis: 20 mg/kg once daily IV ()

b) 15 mg/kg (route not specified) once daily (q24h). Neutropenic or immunocompromised patients may still need to be dosed q8h (dose divided). ()

c) 10-15 mg/kg IV, IM or SC once daily (q24h) ()

Amikacin Sulfate dosage for ferrets:

For susceptible infections:

a) 8-16 mg/kg IM or IV once daily ()

b) 8-16 mg/kg/day SC, IM, IV divided q8-24h ()

Amikacin Sulfate dosage for rabbits, rodents, and small mammals:

a) Rabbits: 8-16 mg/kg daily dose (may divide into q8h-q24h) SC, IM or IV Increased efficacy and decreased toxicity if given once daily. If given IV, dilute into 4 mL/kg of saline and give over 20 minutes. ()

b) Rabbits: 5-10 mg/kg SC, IM, IV divided q8-24h Guinea pigs: 10-15 mg/kg SC, IM, IV divided q8-24h Chinchillas: 10-15 mg/kg SC, IM, IV divided q8-24h Hamster, rats, mice: 10 mg/kg SC, IM q12h Prairie Dogs: 5 mg/kg SC, IM q12h ()

c) Chinchillas: 2-5 mg/kg SC, IM q8- 12h ()

Amikacin Sulfate dosage for cattle:

For susceptible infections:

a) 10 mg/kg IM q8h or 25 mg/kg q12h ()

b) 22 mg/kg/day IM divided three times daily ()

Amikacin Sulfate dosage for horses:

For susceptible infections:

a) 21 mg/kg IV or IM once daily (q24h) ()

b) In neonatal foals: 21 mg/kg IV once daily ()

c) In neonatal foals: Initial dose of 25 mg/kg IV once daily; strongly recommend to individualize dosage based upon therapeutic drug monitoring. ()

d) Adults: 10 mg/kg IM or IV once daily (q24h)

Foals (<30 days old): 20-25 mg/kg IV or IM once daily (q24h).

For uterine infusion:

a) 2 grams mixed with 200 mL sterile normal saline (0.9% sodium chloride for injection) and aseptically infused into uterus daily for 3 consecutive days (Package insert; Amiglyde-V — Fort Dodge)

b) 1-2 grams IU ()

For intra-articular injection as adjunctive treatment of septic arthritis in foals:

a) If a single joint is involved, inject 250 mg daily or 500 mg every other day; frequency is dependent upon how often joint lavage is performed. Use cautiously in multiple joints as toxicity may result (particularly if systemic therapy is also given). ()

For regional intravenous limb perfusion (RILP) administration in standing horses:

a) Usual dosages range from 500 mg-2 grams; dosage must be greater than 250 mg when a cephalic vein is used for perfusion and careful placement of tourniquets must be performed. ()

Amikacin Sulfate dosage for birds:

For susceptible infections:

a) For sunken eyes/sinusitis in macaws caused by susceptible bacteria: 40 mg/kg IM once or twice daily. Must also flush sinuses with saline mixed with appropriate antibiotic (10-30 mL per nostril). May require 2 weeks of treatment. ()

b) 15 mg/kg IM or SC q12h ()

c) For gram-negative infections resistant to gentamicin: Dilute commercial solution and administer 15-20 mg/kg (0.015 mg/g) IM once a day or twice a day ()

d) Ratites: 7.6-11 mg/kg IM twice daily; air cell: 10-25 mg/egg; egg dip: 2000 mg/gallon of distilled water pH of 6 ()

Amikacin Sulfate dosage for reptiles:

For susceptible infections:

a) For snakes: 5 mg/kg IM (forebody) loading dose, then 2.5 mg/kg q72h for 7-9 treatments. Commonly used in respiratory infections. Use a lower dose for Python curtus. ()

b) Study done in gopher snakes: 5 mg/kg IM loading dose, then 2.5 mg/kg q72h. House snakes at high end of their preferred optimum ambient temperature. ()

c) For bacterial shell diseases in turtles: 10 mg/kg daily in water turtles, every other day in land turtles and tortoises for 7-10 days. Used commonly with a beta-lactam antibiotic. Recommended to begin therapy with 20 mL/kg fluid injection. Maintain hydration and monitor uric acid levels when possible. ()

d) For Crocodilians: 2.25 mg/kg IM q 72-96h ()

e) For gram-negative respiratory disease: 3.5 mg/kg IM, SC or via lung catheter every 3-10 days for 30 days. ()

Amikacin Sulfate dosage for fish:

For susceptible infections:

a) 5 mg/kg IM loading dose, then 2.5 mg/kg every 72 hours for 5 treatments. ()

Monitoring

■ Efficacy (cultures, clinical signs, WBC’s and clinical signs associated with infection). Therapeutic drug monitoring is highly recommended when using this drug systemically. Attempt to draw samples at 1,2, and 4 hours post dose. Peak level should be at least 40 mcg/mL and the 4-hour sample less than 10 mcg/mL.

■ Adverse effect monitoring is essential. Pre-therapy renal function tests and urinalysis (repeated during therapy) are recommended. Casts in the urine are often the initial sign of impending nephrotoxicity.

■ Gross monitoring of vestibular or auditory toxicity is recommended.

Client Information

■ With appropriate training, owners may give subcutaneous injections at home, but routine monitoring of therapy for efficacy and toxicity must still be done

■ Clients should also understand that the potential exists for severe toxicity (nephrotoxicity, ototoxicity) developing from this medication

■ Use in food producing animals is controversial as drug residues may persist for long periods

Chemistry / Synonyms

A semi-synthetic aminoglycoside derived from kanamycin, amikacin occurs as a white, crystalline powder that is sparingly soluble in water. The sulfate salt is formed during the manufacturing process. 1.3 grams of amikacin sulfate is equivalent to 1 gram of amikacin. Amikacin may also be expressed in terms of units. 50,600 Units are equal to 50.9 mg of base. The commercial injection is a clear to straw-colored solution and the pH is adjusted to 3.5-5.5 with sulfuric acid.

Amikacin sulfate may also be known as: amikacin sulphate, amikacini sulfas, or BB-K8; many trade names are available.

Storage / Stability/Compatibility

Amikacin sulfate for injection should be stored at room temperature (15 – 30°C); freezing or temperatures above 40°C should be avoided. Solutions may become very pale yellow with time but this does not indicate a loss of potency.

Amikacin is stable for at least 2 years at room temperature. Autoclaving commercially available solutions at 15 pounds of pressure at 120°C for 60 minutes did not result in any loss of potency.

Note: When given intravenously, amikacin should be diluted into suitable IV diluent etc. normal saline, D5W or LRS) and administered over at least 30 minutes.

Amikacin sulfate is reportedly compatible and stable in all commonly used intravenous solutions and with the following drugs: amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cefoxitin sodium, chloramphenicol sodium succinate, chlorpheniramine maleate, cimetidine HCl, clindamycin phosphate, colistimethate sodium, dimenhydrinate, diphenhydramine HCl, epinephrine HCl, ergonovine maleate, hyaluronidase, hydrocortisone sodium phosphate/succinate, lincomycin HCl, metaraminol bitartrate, metronidazole (with or without sodium bicarbonate), norepinephrine bitartrate, pentobarbital sodium, phenobarbital sodium, phytonadione, polymyxin B sulfate, prochlorperazine edisylate, promethazine HCL, secobarbital sodium, sodium bicarbonate, succinylcholine chloride, vancomycin HCL and verapamil HCL.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with amikacin: aminophylline, amphotericin B, ampicillin sodium, carbenicillin disodium, cefazolin sodium, cephalothin sodium, cephapirin sodium, chlorothiazide sodium, dexamethasone sodium phosphate, erythromycin gluceptate, heparin sodium, methicillin sodium, nitrofurantoin sodium, oxacillin sodium, oxytetracycline HCL, penicillin G potassium, phenytoin sodium, potassium chloride (in dextran 6% in sodium chloride 0.9%; stable with potassium chloride in “standard” solutions), tetracycline HCL, thiopental sodium, vitamin B-complex with C and warfarin sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluent used; consult specialized references or a hospital pharmacist for more specific information.

In vitro inactivation of aminoglycoside antibiotics by beta-lac-tam antibiotics is well documented. While amikacin is less susceptible to this effect, it is usually recommended to avoid mixing these compounds together in the same syringe or IV bag unless administration occurs promptly. See also the information in the Amikacin Sulfate Interaction and Amikacin Sulfate/Lab Interaction sections.

Dosage Forms / Regulatory Status

Veterinary-Labeled Products:

Amikacin Sulfate Injection: 50 mg (of amikacin base) per mL in 50 mL vials; Amiglyde-V (Fort Dodge), AmijectD (Butler), Amikacin K-9 (RXV), Amikacin C (Phoenix), Amtech Amimax C (IVX), Caniglide (Vedco); generic (VetTek); (Rx); Approved for use in dogs.

Amikacin Sulfate Intrauterine Solution: 250 mg (of amikacin base) per mL in 48 mL vials; Amifuse E (Butler), Amiglyde-V (Fort Dodge), Amikacin E (Phoenix), Amikacin E (RXV), Amtech Amimax E (IVX), Equi-phar Equiglide (Vedco); (Rx); Approved for use in horses not intended for food.

WARNING: Amikacin is not approved for use in cattle or other food-producing animals in the USA. Amikacin Sulfate residues may persist for long periods, particularly in renal tissue. For guidance with determining use and withdrawal times, contact FARAD (see Phone Numbers & Websites in the appendix for contact information).

Human-Labeled Products:

Amikacin Injection: 50 mg/mL and 250 mg/mL in 2 mL and 4 mL vials and 2 mL syringes; Amikin (Apothecon); generic; (Rx)

Categories
Diseases

Progression Of Heart Failure

Traditionally heart failure has been perceived as a hemodynamic disorder that promotes weakness, the development of debilitating congestive signs, deterioration of cardiac function, and ultimately death. Although the initial cardiac insult varies, it was historically rationalized that ventricular remodeling and disease progression occur as consequences of the compensatory mechanisms that promote vasoconstriction and fluid retention. It was recognized that diseased hearts operate on a depressed and flattened Frank-Starling curve, such that volume retention and vasoconstriction, rather than promoting cardiac output, merely exacerbated congestive heart failure. The symptoms of heart failure developed as venous pressures breached the lymphatics’ ability to remove edema or as blood flow to exercising muscles was severely limited.

If disease progression were solely mediated by hemodynamic alterations, it was hypothesized, drugs capable of “unloading” the heart (e.g., vasodilators and positive inotropes) would retard this progression and improve survival. In the first Veterans Affairs Heart Failure Trial (V-HeFT) completed in 1985, prazosin or a combination of hydralazine and isosorbide dinitrate was used to decrease preload and afterload. Although prazosin was more effective at reducing blood pressure, only the hydralazine/isosorbide dinitrate combination reduced mortality compared with placebo. The discordance between the hemodynamic and prognostic findings could not be explained by the traditional perception of heart failure. Support for the hemodynamic hypothesis was further undermined by the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial completed in December of 1994, which found that administration of amlodipine to patients with severe chronic heart failure had no significant effect on mortality.

Similar to the use of vasodilators to decrease ventricular wall stress and increase cardiac output, potent inotropic drugs capable of increasing cyclic adenosine monophosphate levels were developed with the intent to improve survival. If poor pump performance were responsible for the progressive nature of heart failure, it was hypothesized, these positive inotropes should alter the natural course of cardiovascular disease. The phosphodiesterase inhibitor milrinone, which has potent inotropic and vasodilative properties, in fact was found to alter the course of heart failure but in a fashion opposite that expected. In October of 1990, the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial was stopped 5 months prior to its scheduled completion date because administration of oral milrinone was found to increase all-cause mortality by 28%. Patients with the severest symptoms (i.e., New York Heart Association (NYHA] class IV), who therefore would be the most likely to receive additional medical therapy, showed a 53% increase in mortality. Administration of the partial beta-agonist xamoterol also failed to improve survival in a study of 516 patients.

These drug trial failures were accompanied in the late 1980s and early 1990s by an evolution in the understanding of the traditional hemodynamic model of heart failure. It still was recognized that hemodynamic alterations accounted for the symptomatic manifestations of cardiac disease, but a new understanding of the condition resulted in the conclusion that the body’s compensatory neurohormonal mechanisms contributed to the dilemma of disease progression. Activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) was found to promote both adverse hemodynamic consequences and direct toxic effects on the myocardium. Cultured mammalian cardiomyocytes exposed to norepinephrine displayed a concentration-dependent decrease in viability that was attenuated significandy by beta-receptor blockade. In addition, norepinephrine was implicated in the provocation of ventricular arrhythmias and the impairment of sodium excretion by the kidneys. Pathophysiologic levels of angiotensin II were found to promote myocytolysis with subsequent fibroblast proliferation, and aldosterone was implicated in the process of myocardial extracellular matrix remodeling. These findings established a connection between hemodynamic mechanisms and neurohormonal consequences, which mutually promote a cycle of disease progression. The initial cardiac insult is followed by activation of neurohormonal compensatory mechanisms that produce further hemodynamic alterations and myocardial fibrosis. Cardiac output continues to decline, the compensatory mechanisms continue to be activated, and the disease process proceeds unabated.

This more complete understanding of the neurohormonal systems led to the development and use of drugs designed to antagonize the RAS. A breakthrough in the management of cardiovascular disease came with the utilization of angiotensin-converting enzyme (ACE) inhibitors in the mid to late 1980’s. Angiotensin-converting enzyme is capable of degrading vasodilative bradykinin and is responsible for cleaving relatively inactive angiotensin I to the potent vasoconstrictor angiotensin II (AT II). Indirectly angiotensin-converting enzyme is responsible for aldosterone production, because AT II is a primary stimulus for adrenal gland production of mineralocorticoids. Given angiotensin-converting enzyme’s critical position in the RAS, it was proposed that angiotensin-converting enzyme inhibition may promote beneficial hemodynamic and neurohormonal antagonistic and antifibrotic actions.

The angiotensin-converting enzyme inhibitor enalapril has been extensively studied in humans with varying stages of heart failure. In three studies, compared with placebo or the combination of hydralazine and isosorbide dinitrate, enalapril reduced all-cause mortality in humans with a reduced ejection fraction and heart failure.

In another study, compared with placebo, enalapril did not reduce the mortality rate in asymptomatic patients with reduced ejection fraction, although it delayed the onset of heart failure. Because angiotensin-converting enzyme inhibitors have been shown to alleviate symptoms, improve patients’ clinical status, and decrease mortality, the current recommendation is that all humans with heart failure due to left ventricular systolic dysfunction receive an angiotensin-converting enzyme inhibitor. The mortality reductions associated with administration of angiotensin-converting enzyme inhibitors lends support to the theory that disease progression is mediated by factors other than hemodynamics alone.

Management of Stable Compensated Congestive Heart Failure

Deficiencies of the Triple Drug Regimen

Potential therapeutic strategies

Management of Refractory Congestive Heart Failure

Management of Heart Failure Secondary to Diastolic Dysfunction

Maintenance Therapy

After stabilization, furosemide is switched to oral administration and the dose is decreased (6.25 mg given twice daily) to prevent excessive preload reduction, dehydration, and hypokalemia. In cases of hypertrophic cardiomyopathy, additional drugs may be instituted to reduce the heart rate and improve diastolic filling. Drugs frequently used in the management of HCM include the beta blocker atenolol and the calcium channel blocker diltiazem. Calcium channel Mockers theoretically can exert a beneficial effect in the management of HCM by modestly reducing the heart rate and contractility, thereby diminishing myocardial oxygen demand. Diltiazem may promote a direct positive lusitropic effect, and verapamil may partially reduce coronary endothelial dysfunction compared with propranolol. Atenolol (6.25 to 12.5 mg given orally every 12 to 24 hours) appears to exert better rate control and more consistently alleviates left ventricular outflow tract obstruction compared with diltiazem. Beta-adrenergic blockade may also prevent myocardial fibrosis by inhibiting catecholamine-induced cardiotoxicity and » may combat ventricular arrhythmias by decreasing myocardial oxygen consumption. One theoretical disadvantage of the use of beta blockers in the management of diastolic dysfunction is that phospholamban is an inhibitory protein that controls the rate of diastolic calcium uptake into the sarcoplasmic reticulum. Beta-adrenergic stimulation phosphorylates phospholamban and removes this inhibitory effect. Beta blockade may prevent this phosphorylation (and therefore decrease diastolic calcium uptake) and further impair the active process of ventricular relaxation.

Similar to beta blockers, with their proposed neurohormonal benefits, angiotensin-converting enzyme inhibitors likely are beneficial in the management of feline HCM. The authors have seen cats with symptomatic cardiomyopathy show marked neurohormonal activation. With this finding, and with the frequent requirement for furosemide to control pulmonary edema, it appears prudent to use enalapril (1.25 to 2.5 mg given orally every 12 to 24 hours) in the management of diastolic dysfunction. Although there is concern that afterload reduction may precipitate dynamic left ventricular outflow tract obstruction, recent data suggest that angiotensin-converting enzyme inhibitors can be used safely in cats with systolic anterior motion of the mitral valve.

Categories
Diseases

Management of Refractory Congestive Heart Failure

Over rime, many patients become refractory to standard medical therapy as disease progression continues or if a concurrent systemic disease process develops that exerts detrimental effects on the cardiovascular system (e.g., hyperadrenocorticism, hypothyroidism, renal failure, systemic Hypertension, neoplasia, anemia, pneumonia, or pulmonary thromboembolism). Infrequent causes of an acute bout of decompensation include the development of hemodynamically important arrhythmias, sudden rupture of chordae tendineae, or splitting of the left atrial wall subsequent to severe mitral insufficiency and elevated left atrial pressure. For these reasons, any patient that continues to show clinical signs of congestion or low cardiac output despite appropriate medical therapy should be closely re-evaluated. After determining whether the owner is administering the prescribed drugs at the appropriate intervals, the practitioner should obtain an ECG, thoracic radiographs, complete blood count, biochemical profile, and blood pressure measurement. Echocardiography often is warranted to characterize the severity of valvular insufficiency, the extent of chamber enlargement, and the degree of systolic dysfunction.

If an underlying disease process is identified, it should be managed appropriately before institution of therapy with new cardiac drugs. Attempts should be made to suppress significant ventricular arrhythmias; agents capable of slowing conduction through the atrioventricular node (e.g., calcium channel Mockers or beta blockers) may be required to help control the ventricular response rate in the face of atrial fibrillation. Potent afterload reduction with nitroprusside or hydralazine often is required to combat the effects of ruptured chordae tendineae. Left atrial tears are difficult to manage.

If no underlying disease process is identified, several strategies may be used to manage these refractory patients. Afterload reduction using arterial vasodilators, preload reduction using additional diuretics or venodilators, or additional neurohormonal blockade using beta blockers or spironolactone may be warranted. The route of diuretic administration may be modified, or positive inotropic agents periodically may be given intravenously. The inherent risks and complications of treatment are greatest in patients with refractory heart failure, and referral to a specialist is wiser than embarking on an unconventional treatment protocol.

Vasodilators

Vasodilators promote smooth muscle relaxation of the arterioles (arterial vasodilators), veins (venodilators), or arteries and veins (balanced vasodilators). Although these drug classes promote a similar therapeutic end-point, vasodilatation, a variety of mechanisms are involved in achieving their effect.

Heart failure is associated with activation of the sympathetic nervous system and renin-angiotensin system. In the face of decreased cardiac output, these systems promote arteriolar vasoconstriction to maintain adequate perfusion pressure and venoconstriction to enhance venous return to the heart. Unfortunately, the arteriolar vasoconstriction further increases the workload of the failing heart; more energy must be expended to overcome high systemic vascular resistance, and less energy is available to expel blood into the aorta. Stroke volume (and hence cardiac output (CO]) decreases, but systemic vascular resistance (SVR) continues to increase in an effort to maintain blood pressure (BP = CO x SVR). The increase in preload promoted by venoconstriction also proves detrimental because the diseased heart, operating on the plateau of the Frank-Starling curve, is unable to further hypertrophy or increase its contractility. Ventricular end-diastolic pressures begin to rise, leading to the eventual formation of edema.

Based on these hemodynamic sequelae, it seemed apparent that a reduction in afterload and/or preload ultimately would reduce mortality. Interestingly, the first V-HeFT study found that prazosin, the agent most capable of reducing blood pressure, was unable to reduce mortality compared with placebo. The combination of hydralazine and isosorbide dinitrate reduced mortality, but in the V-HeFT II trial, enalapril was more effective than the combined vasodilators at preventing death. This beneficial effect was seen despite the inability of the angiotensin-converting enzyme inhibitor to reduce blood pressure. Obviously blood pressure and systemic vascular resistance are not synonymous, but these findings have detracted from the use of potent after-load reducers in the routine management of heart failure. Venodilators may still be effective at reducing the development of edema, but the problem of drug tolerance has limited their use to animals with refractory heart failure.

Amlodipine Amlodipine is a second-generation, dihydropyridine (DHP) calcium channel blocker that primarily produces arteriolar vasodilatation and is used in the treatment of systemic hypertension. Unlike the non-DHPs diltiazem and verapamil, amlodipine has little effect on conduction through the atrioventricular node, and its negative inotropic properties appear to be offset by a reduction in afterload. Although amlodipine was unable to reduce mortality in an evaluation of 1153 patients with left ventricular dysfunction and severe heart failure (P = 0.07), it did reduce the mortality rate by 31 % (P = 0.04) in the subgroup of patients with nonischemic DCM. Despite this mortality benefit, 14 of the 209 patients with dilated cardiomyopathy assigned to amlodipine developed pulmonary edema (compared with 2 of 212 patients assigned to placebo). The mechanism involved in this development was uncertain. An interesting application of amlodipine therapy may be for severe mitral valve insufficiency. A reduction in systemic vascular resistance (and hence the systolic left ventricular to left atrial pressure gradient) may serve to decrease the volume of mitral valve insufficiency. Potential benefits of amlodipine are its 30-hour half-life and peak effect in 4 to 7 days after institution of therapy to dogs. This slow onset of action may give the baroreceptors time to reset, thereby avoiding sympathetic activation and reflex tachycardia. The effective dose of amlodipine seems to vary; a common strategy is to institute therapy at a low dose (0.05 mg/kg given orally once daily), followed by slow titration up to 0.2 mg/kg until a reduction in blood pressure is achieved. Because of the drug’s long half-life, the authors typically monitor blood pressure weekly, using uptitration until the target blood pressure is attained.

Hydralazine Hydralazine is a direct-acting arterial vasodilator that promotes vasodilatation through an unknown mechanism. It was studied in the 1980s for the management of CDVD in dogs and was found to produce substantial decreases in mean arterial blood pressure, total systemic resistance index, and pulmonary capillary wedge pressure. Since that time, hydralazine appears to have been pushed aside by the angiotensin-converting enzyme inhibitors in the management of uncomplicated heart failure. This trend likely resulted from the commonly encountered side effects of hydralazine (i.e, symptomatic hypotension, anorexia, vomiting, and diarrhea), the presence of elevated aldosterone levels seen after hydralazine therapy compared with captopril, and the significant results of the V-HeFT II trial.

Hydralazine is still used in the acute management of decompensated heart failure when nitroprusside is unavailable (or impractical to use) because of its rapid onset of action. Similar to amlodipine, the reduction in systemic vascular resistance may reduce the volume of mitral insufficiency and promote an increase in the forward stroke volume. In contrast to amlodipine, the peak vasodilative effect of hydralazine occurs within 3 hours and subsides within 12 hours. Unfortunately, this same characteristic may result in reflex tachycardia and further stimulation of the sympathetic nervous system and RAS. A study by Haggstrom et al. identified significant increases in heart rate and plasma aldosterone and angiotensin II concentrations, as well as evidence of fluid retention, in Cavalier King Charles spaniels with mitral insufficiency that were treated with hydralazine monotherapy for 3 weeks. These findings suggest that angiotensin-converting enzyme inhibitors should be used concurrently with hydralazine if chronic afterload reduction is warranted.

For the management of fulminant congestive heart failure, hydralazine may be administered at a dosage of 2 mg/kg given orally twice daily to dogs with a systolic blood pressure above 100 mm Hg. The authors recommend blood pressure monitoring, with the twin goals of avoiding hypotension and monitoring therapeutic efficacy. Ideally the increase in effective cardiac output will counterbalance the hydralazine-mediated reduction in systemic vascular resistance, preventing the development of symptomatic hypotension.

Nitrates The nitrates, which include nitroglycerin, isosorbide dinitrate and isosorbide mononitrate, and nitroprusside, are a class of vasodilators that promote the formation of nitric oxide. Although nitroprusside administered intravenously is a potent balanced vasodilator, topical and oral administration of nitroglycerin and oral administration of isosorbide dinitrate and isosorbide mononitrate appear to promote primarily venodilatation. The premise behind venodilatation is to promote redistribution of the circulating blood volume from the heart and pulmonary vasculature to the systemic venous circulation. This reduction in preload should decrease ventricular enddiastolic, atrial, and pulmonary capillary pressures, shifting the Frank-Starling curve to the left and alleviating pulmonary edema. Currendy the efficacy of nitrates in the management of chronic heart failure is uncertain and may be limited by nitrate tolerance, the phenomenon in which continued drug exposure reduces the agent’s effectiveness.

Nitrogfycerin A 2% topical formulation of nitroglycerin combined with furosemide and oxygen (with or without hydralazine) is frequendy used in the management of acute heart failure. Anecdotal recommendations have called for application of nitroglycerin cream to a clipped or hairless region (V2 to 2 inches every 6 to 8 hours for dogs; tA-inch every 6 to 8 hours for cats) to promote continuous transdermal absorption and venodilatation. Studies evaluating the absorption of cutaneously applied nitroglycerin, the optimal site for topical administration, and the efficacy of this therapy for dogs or cats with heart failure have not been reported. There is a report that nitroglycerin applied to the auricular pinna promotes splenic vasodilatation in normal anesthetized dogs, but by no means should nitroglycerin replace furosemide as the primary agent for reducing preload and alleviating pulmonary edema.

Isosorbide dinitrate and isosorbide mononitrate Isosorbide dinitrate and its major metabolite, mononitrate, are orally administered venodilators that may help reduce preload and hence pulmonary edema. Similar to nitroglycerin, the orally administered nitrates have not been extensively studied in naturally occurring heart failure. However, Adin et al. were unable to document circulatory redistribution after a single dose of isosorbide mononitrate in normal dogs or in those with heart failure. Whether nitrates can regress cardiac remodeling in naturally occurring heart failure remains to be investigated.

Although their efficacy is unknown, isosorbide dinitrate (0.5 to 2 mg/kg given orally twice daily) and isosorbide mononitrate (0.25 to 2 mg/kg given orally twice daily) occasionally are used in the management of refractory heart failure or in combination with hydralazine or amlodipine for patients unable to tolerate angiotensin-converting enzyme inhibitors. Whether dosing-free intervals are required to combat the development of nitrate tolerance for dogs and cats is unknown.

Triple Diuretic Therapy

Although twice-daily administration of a loop diuretic appears to be the regimen most frequently used to manage congestive heart failure, there are physiologic benefits to altering the dosing frequency or combining agents from different classes. Although not a true component of diuretic resistance, the activity of the nephron in the absence of therapeutic diuretic concentrations must be kept in mind. The loop diuretics currently available are not long-acting formulations. Therefore the original diuretic effects have dissipated well before the administration of a second daily dose. During this time, when it is not inhibited, the Na+/K+/2Cl- pump promotes avid sodium resorption, possibly to a degree that negates any previous natriuretic effect. This highlights the point that, in cases of worsening heart failure, three times daily dosing of furosemide may be more beneficial than merely increasing the twice daily dose. In cases of right-sided heart failure, in which oral drug absorption may be impaired, changing the type of administration to the subcutaneous or intramuscular route may prove beneficial. Administration of a diuretic by means of a constant-rate infusion may prove the most beneficial during emergency treatment of heart failure, although frequent, moderate doses likely achieve a similar end-point.

No matter the dosing interval or the route of administration, the segments of the nephron distal to the loop of Henle are capable of producing diuretic resistance. Increased solute exposure to the distal nephron promotes hypertrophy and increased resorptive capacity of the early distal tubule, the connecting tubule, and the cortical collecting duct. Although the exact mechanisms are unclear, aldosterone has been implicated as promoting this process. Strategies to combat diuretic resistance associated with long-standing administration of a loop diuretic include (1) addition of a thiazide diuretic to encourage diuresis in the hypertrophied region and/or (2) addition of an aldosterone antagonist to target the proposed hypertrophic mechanism. This synergistic nephron blockade, using multiple agents with activity in different regions of the nephron, may allow a reduction in the dose of furosemide required to control the patient’s congestive signs. In the authors’ experience, furosemide and spironolactone, combined with conservative doses of hydrochlorothiazide, have palliated the congestive signs of many heart failure patients. However, this more aggressive diuretic management predisposes the patient to the development of electrolyte abnormalities and a reduction in cardiac output and the glomerular filtration rate unless care is taken to avoid overzealous volume contraction. Outpatients should be carefully and periodically evaluated through biochemical profiles to make sure that adverse effects are avoided.

Additional factors that can contribute to diuretic resistance include (1) poor cardiac output, which impairs delivery of the diuretic to its site of action; (2) prominent activation of the renin-angiotensin system; and (3) hypokalemia, which may impair the efficacy of the diuretic. If concern exists about diuretic resistance, care should be taken to optimize the angiotensin-converting enzyme inhibitor dose, to correct electrolyte imbalances, and to combat low-output conditions.

Dietary Sodium Restriction

Historically, sodium restriction has been recommended for patients with cardiovascular disease to decrease the delivery of sodium to and its resorption in the distal tubule. This recommendation was in place well before any of the current understanding of the renin-angiotensin system developed, and it therefore may need to be reevaluated.

It currendy is recognized that reduced sodium concentrations at the macula densa serve as a stimulus for renin release and subsequent production of angiotensin. A study of Cavalier King Charles spaniels with mild asymptomatic mitral valve insufficiency showed that a low-sodium diet (17 mg/kg/day) was associated with higher plasma renin activity and aldosterone concentrations than a control diet (96 mg/kg/day). In light of the concern that activation of neurohormonal pathways promotes the progressive nature of cardiovascular disease, the authors currendy do not use sodium restriction in asymptomatic patients. Whether symptomatic patients receive clinical benefit from sodium restriction is uncertain, but one study found that dogs with mitral valve insufficiency that were fed a low-sodium diet (24 mg/kg/day) had significandy smaller left atrial and left ventricular dimensions than they did when fed a moderate-sodium diet (42 mg/kg/day). Only a small number of dogs with dilated cardiomyopathy were enrolled in the study, but no significant differences in their echocardiographic parameters were seen between the two diets. Despite angiotensin-converting enzyme inhibitor therapy, greater than 70% of the dogs enrolled in the study had increased baseline concentrations of atrial natriuretic peptide and increased plasma renin activity and aldosterone concentrations; however, the dietary modifications were not associated with significant alterations from baseline.

Whether exclusively feeding a low-sodium diet to patients with heart failure is feasible often hinges on the palatability of the diet and the willingness of the owner to abandon treats and table scraps. Although uncertain of its clinical benefit or potential detriment, the authors often recommend a low- to moderate-sodium diet for patients with refractory heart failure. As evidenced by the study by Mallery et al., anorexia is a large contributing factor (68%) in the decision for euthanasia; therefore caution, education, and a willingness to abandon the regimen must accompany the prescription of a potentially less palatable, sodium-restricted diet.