Categories
Veterinary Medicine

Balanced vasodilators

Sodium nitroprusside

Sodium nitroprusside is a potent arteriolar and venodilator drug with a similar mechanism of action to the organic nitrates, h has a very short duration of action and is administered by continuous intravenous infusion starting at an initial infusion rate of 1-5 μg kg-1 min-1. It reduces pulmonary and systemic vascular resistance decreasing ventricular filling pressure and is most useful in the management of acute, life-threatening cardiogenic pulmonary oedema. The dose can be titrated upwards to effect whilst monitoring arterial blood pressure since excessive falls in arterial blood pressure are an indication of overdosage. The effects are reversed within 1-10 min of slowing the infusion rate allowing fine control of the drug’s effects. Since delivery of the drug requires accurate control at a low rate of fluid administration, an infusion pump should be used. In dogs with severe cardiac failure resulting from poor systolic function (dilated cardiomyopathy), a drug providing positive inotropic support (for example dobutamine) is required in addition to sodium nitroprusside, otherwise the reduction in preload caused by venodilation may result in a precipitous fall in cardiac output. Intravenous infusion of sodium nitroprusside should not exceed 48 h since toxic metabolites (thiocyanate) build up in the circulation. Infusions should be stopped gradually rather than abruptly to prevent rebound increases in vascular resistance and cardiac filling pressures.

Prazosin

Prazosin is a balanced vasodilator drug which can be given orally to dogs. It is an alpha1-selective adrenoceptor antagonist which blocks excessive sympathetic stimulation of vascular alpha1-adrenoceptors without affecting the autoinhibition of noradrenaline release by presynaptic alpha2-adrenoceptors. The recommended dosage is 1 mg tid for dogs weighing less than 15 kg and 2 mg tid for dogs weighing more than 15 kg. In humans and experimental animals, although prazosin is very effective initially, with repeated dosing its effects become attenuated, possibly as the renin-angiotensin system assumes greater importance in regulating vascular tone.

Angiotensin converting enzyme inhibitors

Given the effects of angiotensin II which are central to the pathophvsiology of chronic heart failure, the effects of drugs which inhibit the formation of angiotensin II by inhibition of anglotensin converting enzyme (ACE) are predictable. They are balanced vasodilators and will enhance the excretion of sodium and water by reducing circulating levels of aldosterone and ADH; thus they have a potassium-sparing diuretic effect. Angiotensin converting enzyme is also responsible for the breakdown of the natural vasodilator, bradykinin and some of the effects of ACE inhibitors can be attributed to potentiating bradykinin. Their effects on the vasculature are less profound and slower to take effect when compared to hydralazine and nitroprusside, hence these drugs are preferred to the ACE inhibitors when dealing with cases of life-threatening pulmonary oedema due to left-sided heart failure. Indeed, clinical signs may continue to improve for several weeks in human heart failure patients on ACE inhibitors and multicentre controlled clinical trials in veterinary medicine suggest that the same is true in veterinary medicine. Small but significant effects have been demonstrated on survival time of dogs with dilated cardiomyopathy and mitral valvular heart disease treated with enalapril.

Captopril was the first ACE inhibitor to be produced. It contains a sulphydryl group which causes certain side effects which are common to sulphydryl compounds, namely alterations in taste perception, proteinuria and drug-induced blood dyscrasias. The recommended dosage is 0.5-2.0 mg kgr-1 three times daily. Oral absorption is reduced by food. Exceeding the upper limit of this dose gives no further beneficial therapeutic effect but increases the drug’s toxiciry. Angiotensin II may maintain glomerular filtration pressures in the face of poor renal perfusion by constricting the efferent arteriole more than the afferent arteriole. Removal of this protective mechanism may precipitate acute renal failure in some patients with subclinical, pre-existing renal dysfunction. Hence blood plasma urea and creatinine should be determined in animals before and after they are put on ACE inhibitors. As with other vasodilator drugs, hypotension is a possible side effect, particularly if used in combination with high doses of diuretics. In humans. ACE inhibition has been associated with a drug-induced cough.

Enalapril is an ACE inhibitor with significant advantages over captopril. It does not possess a sulphydryl group and so lacks the associated side effects mentioned above. It is a pro-drug, the active form being a metabolite, enalaprilat, formed by the liver. The onset of action is slower than captopril and its duration of effect is longer (12-14 h). Recommended dosing in dogs is 0,5-1.0 mg kg-1 every 12-24 h and in cats is 0,25 mg kg-1 every 12 h. Side effects are those associated with ACE inhibition described above for captopril.

Benazepril is an ACE inhibitor recently licensed for veterinary use. It shares many properties with enalapril, lacking a sulphydryl group and being a pro-drug. In addition, the excretion of the active metabolite from the body occurs both in the bile and the urine. This contrasts with enalapril, which is eliminated in the urine only where dose adjustment may be necessary in animals with significant impairment of renal function. The recommended dose rate of benazepril for the dog is 0.25 to 0.5 mg kg-1 orally every 24 hours. Currently, there is no authorized dose rate for cats.

Categories
Drugs

Amlodipine Besylate (Norvasc)

Calcium Channel Blocker

Highlights Of Prescribing Information

Calcium channel blocker used most often for treating hypertension, especially in cats

Slight negative inotrope; use with caution in patients with heart disease, hepatic dysfunction

Potentially may cause anorexia & hypotension in cats early in therapy

Hypertension may rapidly reoccur if dosages are missed

What Is Amlodipine Besylate Used For?

Oral amlodipine appears to be a useful agent in the treatment of hypertension in cats and many consider it the drug of choice for this indication. In pharmacokinetic studies, amlodipine has decreased blood pressure in dogs with chronic renal disease, but its efficacy in treating hypertensive dogs has been disappointing.

Hypertension in cats is usually secondary to other diseases (often renal failure or cardiac causes such as thyrotoxic cardiomyopathy or primary hypertrophic cardiomyopathy, etc.) and is most often seen in middle-aged or geriatric cats. These animals often present with acute clinical signs such as blindness, seizures, collapse or paresis. A cat is generally considered hypertensive if systolic blood pressure is > 160 mmHg. Early reports indicate that if antihypertensive therapy is begun acutely, some vision maybe restored in about 50% of cases of blindness secondary to hypertension.

Pharmacology / Actions

Amlodipine inhibits calcium influx across cell membranes in both cardiac and vascular smooth muscle. It has a greater effect on vascular smooth muscle, thereby acting as a peripheral arteriolar vasodilator and reducing afterload. Amlodipine also depresses impulse formation (automaticity) and conduction velocity in cardiac muscle.

Pharmacokinetics

No feline-specific data on the drug’s pharmacokinetics was located. In humans, amlodipine’s bioavailability does not appear to be altered by the presence of food in the gut. The drug is slowly but almost completely absorbed after oral administration. Peak plasma concentrations occur between 6-9 hours post-dose and effects on blood pressure are correspondingly delayed. The drug has very high plasma protein binding characteristics (approximately 93%). However, drug interactions associated with potential displacement from these sites have not been elucidated. Amlodipine is slowly, but extensively metabolized to inactive compounds in the liver. Terminal plasma half-life is approximately 35 hours in healthy humans, but is prolonged in the elderly and in those patients with hypertension or hepatic dysfunction.

Before you take Amlodipine Besylate

Contraindications / Precautions / Warnings

Because amlodipine may have slight negative inotropic effects, it should be used cautiously in patients with heart failure or cardiogenic shock. It should also be used cautiously in patients with hepatic disease or at risk for developing hypotension. A relative contraindication for amlodipine exists for humans with advanced aortic stenosis.

There is concern that using amlodipine alone for treating hypertension in cats with renal disease may expose glomeruli to higher pressures secondary to efferent arteriolar constriction. This is caused by localized increases in renin-angiotensin-aldosterone axis activity thereby allowing progressive damage to glomeruli. It is postulated that using an ACE inhibitor with amlodipine may help prevent this occurrence ().

Adverse Effects

Because of amlodipine’s relatively slow onset of action, hypotension and inappetence is usually absent in cats. Infrequently, cats may develop azotemia, lethargy, hypokalemia, reflex tachycardia and weight loss. In humans taking amlodipine, headache (7.3% incidence) is the most frequent problem reported.

Reproductive / Nursing Safety

While no evidence of impaired fertility was noted in rats given 8X overdoses, amlodipine has been shown to be fetotoxic (intrauterine death rates increased 5 fold) in laboratory animals (rats, rabbits) at very high dosages. No evidence of teratogenicity or mutagenicity was observed in lab animal studies. In rats, amlodipine prolonged labor. It is unknown whether amlodipine enters maternal milk. In humans, the FDA categorizes this drug as category C for use during pregnancy (Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.)

Overdosage / Acute Toxicity

There were 69 exposures to amlodipine reported to the ASPCA Animal Poison Control Center (APCC; www.apcc.aspca.org) during 2005-2006. In these cases 59 were dogs with 7 showing clinical signs; the remaining 10 cases were cats with 2 showing clinical signs. Common findings in dogs, recorded in decreasing frequency included anorexia, lethargy, tachycardia, acidosis and bradycardia. Common findings in cats, recorded in decreasing frequency included lethargy and polydipsia.

Limited experience with other calcium channel blockers in humans has shown that profound hypotension and bradycardia may result. When possible, massive overdoses should be managed with gut emptying and supportive treatment. Beta-agonists and intravenous calcium maybe beneficial.

How to use Amlodipine Besylate

Amlodipine Besylate dosage for cats:

For treatment of systemic hypertension:

a) 0.625 mg (1/4 of a 2.5 mg tablet) PO once daily; some larger cats (>4 kg) or those with severe hypertension may require doses as high as 1.25 mg PO twice daily. Titrate dosage carefully, based upon BP determinations. ()

b) 0.625-1.25 mg (total dose) PO once daily. Amlodipine Besylate of choice; often successful as a single agent. Can be combined with an ACEI, beta-blocker or diuretic if needed. Maximum effect seen within 7 days of therapy. ()

Amlodipine Besylate dosage for dogs:

For adjunctive therapy for refractory heart failure:

a) For treatment of advanced mitral valve degeneration as an afterload reducer after ACE inhibitor maintenance therapy has been established: 0.2-0.4 mg/kg PO twice daily. Initiate therapy at 0.1 mg/kg PO twice daily and uptitrate weekly while monitoring blood pressure. ()

b) As an arterial vasodilator particularly in dogs moderately refractory, or recurrent CHF secondary to mitral regurgitation and maintained blood pressures: 0.1 mg/kg ql2-24h initially; titrate up as needed to 0.25 mg/kg PO ql2-24h; monitor blood pressure. ()

For treatment of systemic hypertension in dogs with chronic renal disease:

a) 0.05-0.25 mg/kg PO once daily. In many dogs, amlodipine appears to be less effective, even at high doses (1 mg/kg/day). ()

b) 0.1-0.2 mg/kg PO ql2-24h ()

Client Information

■ May give with food

■ Missing dosages can cause rapid redevelopment of symptoms and damage secondary to hypertension

Chemistry / Synonyms

Amlodipine besylate, a dihydropyridine calcium channel-blocking agent, occurs as a white crystalline powder that is slightly soluble in water and sparingly soluble in alcohol.

Amlodipine Besylate may also as: amlodipini besilas, UK-48340-26, or UK-48340-11 (amlodipine maleate); many trade names are available.

Storage / Stability

Store amlodipine tablets at room temperature, in tight, light resistant containers.

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:

Amlodipine Tablets: 2.5 mg, 5 mg, 10 mg; Norvasc (Pfizer); Amvaz (Reddy); (Rx)

Fixed-dose combination products with benazepril (Lotrel) or atorvastatin (Caduet) are available.

Categories
Diseases

Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.

Glomerulonephritis

The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.

Categories
Diseases

Management of Chronic Mitral Valve Insufficiency

Ideally, therapy of chronic mitral valve insufficiency would halt the progression of the valvular degeneration. Improvement of valvular function by surgical repair or valve replacement would likewise stop further deterioration. However, no therapy is currently known to inhibit or prevent the valvular degeneration, and surgery is usually not technically, economically, or ethically possible in canine and feline patients. The management of chronic mitral valve insufficiency is therefore concerned with improving quality of life, by ameliorating the clinical signs and improving survival. This usually means that therapy is tailored for the individual patient, owner, and practitioner and often involves concurrent treatment with two or more drugs once signs of heart failure are evident. Management of chronic mitral valve insufficiency will be discussed in five groups of patients: those without overt signs of heart failure (asymptomatic), those with left mainstem bronchial compression, those with syncope, those with mild to moderate heart failure, those with recurrent heart failure, and those with severe and fulminant heart failure. Possible complications are discussed separately. It is unusual to treat cases of isolated chronic mitral valve insufficiency in cats and details of drug dosages for cats are therefore not included in this section.

Asymptomatic Disease

The stage when a patient starts to show clinical signs of chronic mitral valve insufficiency (CMVI), that is, have developed decompensated heart failure, is the end of a process started much earlier with the onset of valve leakage. The valvular leakage was compensated through a variety of mechanisms but as the leakage increases the valves eventually became incapable of preventing pulmonary capillary pressures from exceeding the threshold for pulmonary edema, and of maintaining forward cardiac output. It is likely that minor signs of reduced activity and mobility are present even before overt signs of heart failure develop. However, it is very difficult to objectively evaluate the presence of slight to moderately reduced exercise capacity in most dogs with chronic mitral valve insufficiency (CMVI), as they are often old small companion dogs, which if obese, have little, if any, demand on their exercise capacity. Furthermore, other concurrent diseases in the locomotor system or elsewhere are common and restrict exercise. Thus vague clinical signs such as slightly reduced exercise capacity in a typical dog with progressed chronic mitral valve insufficiency may or may not be attributable to chronic mitral valve insufficiency (CMVI).

This dilemma leads to the questions of when to start therapy, and if therapy before the onset of decompensated heart failure is beneficial, ineffective, or harmful. ACE-inhibitors are frequently prescribed to dogs with chronic mitral valve insufficiency before the onset on heart failure. At present, however, there is no evidence that administration of any medication to a patient with asymptomatic chronic mitral valve insufficiency has a preventive effect on development and progression of clinical signs of heart failure or improves survival. Two large placebo-controlled multicenter trials, the SVEP and the VetProof trials, have been conducted to study the effect of monotherapy of the ACE-inhibitor enalapril on the progression of clinical signs in asymptomatic chronic mitral valve insufficiency in dogs. Both failed to show a significant difference between the placebo and the treatment groups in time from onset of therapy to confirmed congestive heart failure.H’ The two trials differ in the following features: the SVEP trial included

only dogs of one breed (Cavalier King Charles spaniels) whereas the VetProof trial included a variety of breeds. The dogs in the VetProof trial were more frequently progressed cases of chronic mitral valve insufficiency than the dogs in the SVEP trial, and the SVEP trial comprised more dogs than the VetProof trial (229 versus 139 dogs). Suggested reasons for the non-significant findings in these trials include lack of activation of circulating RAAS activity in asymptomatic animals, low concentration of angiotensin II receptors in the canine mitral valve, or lack of effect of ACE-inhibitors on myocardial remodeling and progressive ventricular dilatation in mitral regurgitation (MR).

Owners of dogs with progressed asymptomatic chronic mitral valve insufficiency should be instructed about signs of developing heart failure and, in case of breeding, about the fact that the disease is significantly influenced by genetic factors. The disease may be monitored at regular intervals of 3 to 12 months if significant cardiomegaly is present. Milder cases do not warrant frequent monitoring (see Significance and Progression). Frequently asked questions from owners of dogs with asymptomatic chronic mitral valve insufficiency are if exercise should be restricted and if dietary measures should be instituted. At present there is little evidence-based information concerning the effects of exercise or diet on the progression of chronic mitral valve insufficiency in dogs. Dogs with mild chronic mitral valve insufficiency do not need any dietary or exercise restriction. However, from the pathophysiologic standpoint, strenuous exercise or diets with high sodium content should be avoided in progressed chronic mitral valve insufficiency as this may promote pulmonary edema. Furthermore, it is the authors’ experience that dogs with advanced asymptomatic chronic mitral valve insufficiency usually tolerate comparably long walks at their own pace and do better if obesity is avoided.

Patients with Left Mainstem Bronchial Compression Without Pulmonary Congestion and Edema

Severe left artial enlargement may produce coughing even in the absence of pulmonary congestion and edema by compression of the left mainstem bronchi, which may be identified on the lateral radiograph. With significant coughing, therapy is aimed at suppression of the cough reflex or reduction of the influence of the underlying cause for the compression, the left atrial enlargement. Cough suppressants such as butorphanol (0.55 to 1.1 mg/kg q6-12h PO), hydrocodone bitartrate (0.22 mg/kg q4-8h PO), or dextromethorphan (0.5 to 2 mg/kg q6-8h PO) may alleviate the coughing in some cases. Dogs with evidence of concurrent tracheal instability or chronic small airway disease may improve with a bronchodilator, or a brief course of glucocorticoids. Different xanthine derivatives, such as aminophylline (8 to 11 mg/kg q6-8h) and theophylline (Theo-Dur (sustained duration) 20 mg/kg q12h PO, Detriphylline (Choledyl) (sustained action) 25 to 30 mg/kg q12h PO), are commonly used bronchodilators, although the efficacy of these drugs varies considerably between individuals. Beta 2-receptor agonists such as terbutaline and albuterol should be used with caution in chronic mitral valve insufficiency dogs, as these drugs may produce unwanted elevation in heart rate and contractility as a consequence of myocardial beta 2-receptor stimulation. A reduction of left atrial size may be obtained either by reduction of the regurgitation or by reduction of pulmonary venous pressure. Regurgitation can be decreased by reducing aortic impedance with an arterial dilator or by contracting blood volume with a diuretic.

ACE-inhibitors or a directly acting arterial vasodilator, such as hydralazine, may reduce systemic arterial resistance. The ACE-inhibitors are substantially weaker arterial vasodilators than hydralazine. Side effects of ACE-inhibitors are infrequent, but monitoring of renal function and serum electrolytes, particularly potassium, may be indicated.

Hydralazine has been widely used in patients with chronic mitral valve insufficiency at an initial dosage of 0.5 mg/kg every 12 hours PO. The dosage is increased at daily to weekly intervals to an appropriate maintenance dose of 1 to 2 mg/kg every 12 hours PO, or until hypotension develops, detected either by blood pressure measurements or by clinical signs. Clinical hypotension is defined as a mean arterial blood pressure of less than 50 to 60 mm Hg or a systolic blood pressure below 90 mm Hg. Reflex tachycardia may develop in response to hypotension, and gastrointestinal problems are sometimes observed. In tachycardia, digoxin may be considered in order to limit the resting heart rate. As a consequence of hypotension, hydralazine may induce fluid retention and thereby is needed in the form of a diuretic. Patients that receive hydralazine should routinely be monitored, including having the owner check the heart rate at home and having renal function assessed periodically. Diuretic mono-therapy may be considered to decrease the mitral regurgitation by contracting the blood volume and thereby the left ventricular size. However, diuretics activate the renin-angiotensin-aldosterone system (RAAS), and in the long term may cause electrolyte disturbances. Accordingly, these drugs are often reserved for patients with signs of pulmonary congestion and edema or patients in which cough suppressants, glucocortocoids, and vasodilators have failed to alleviate clinical signs.

Patients with Syncopes but Without Pulmonary Congestion and Edema

With advancing chronic mitral valve insufficiency it is not uncommon that episodes of syncope develop in otherwise asymptomatic dogs (see Clinical Signs). These episodes vary in frequency from isolated to multiple events every day. In dogs with chronic mitral valve insufficiency with syncope, it is important to ascertain that the patient is actually fainting and not suffering from neurologic or metabolic disease. Furthermore, it is important to rule out the presence of congestive heart failure or a bradyarrhythmia such as third degree AV-block or a tachyarrhythmia such as atrial fibrillation. Although ventricular tachyarrhythmias do occur in dogs with advanced chronic mitral valve insufficiency (CMVI), supraventricular tachyarrhythmia is far more common. Typically, the 24-hour (Holter) ECG shows episodes of a rapid supraventricular rhythm immediately followed by a bradycardia during which the dog faints. Management of these dogs often includes digoxin to control the supraventricular tachyarrhythmia. In fact, the frequency of syncopes may often be controlled at lower doses, such as 50%, of digoxin than the recommended dose (which is 0.22 mg/m2 q12h PO).The place for beta-blockers in controlling episodes of fainting in chronic mitral valve insufficiency dogs is not clear. Reports indicate positive results of carvedilol in some dogs. However, beta-blockers may reduce myocardial performance and some chronic mitral valve insufficiency dogs do not tolerate this type of therapy.

Patients Unth Pulmonary Edema Secondary To Chronic Mitral Valve Insufficiency

Considering the pathophysiology of chronic mitral valve insufficiency (CMVI), therapy should be directed toward (1) reduction of the venous pressures to alleviate edema and effusions, (2) maintainance of adequate cardiac output to prevent signs of weakness, lethargy and prerenal azotemia, (3) reduction of the cardiac workload and regurgitation, and (4) protection of the heart from negative long-term effects of neurohormones. Cases with mild pulmonary edema may be managed on an outpatient basis with regular re-examinations. Cases with moderate to severe pulmonary edema may need intensive care, including cage-rest and sometimes oxygen supplementation.

Mild to Moderate Heart Failure

Patients with mild to moderate heart failure usually present with cough, tachypnea, and dyspnea. It is not common for an untreated dog in congestive heart failure to present initially with isolated significant ascites. Signs of congestive heart failure are usually present on thoracic radiographs as pulmonary venous congestion and increased pulmonary opacity. In some cases, it may be difficult to appreciate mild edema owing to obesity, chest conformation, underinflated lungs, or presence of age-related changes. Radiographs from the patient obtained before the onset of clinical signs may be helpful for comparison. Dogs with mild to moderate heart failure should be treated. Treatment can often be managed on an outpatient basis and should include a diuretic, such as furosemide, and an ACE-inhibitor. The place of digoxin and other positive inotropes are more controversial for treating dogs with mild to moderate heart failure (see below). The dosage of furosemide should preferably be based on clinical signs rather than radiographic findings. A patient may breathe with ease even in the presence of radiologic signs of interstitial edema, or vice versa. The usual course of treatment of a case with mild to moderate heart failure is an initial intensive treatment with furosemide (2 to 4 mg/kg q8-12h) for 2 to 3 days, after which the dosage of the diuretic is decreased to a maintenance level, such as 1 to 2 mg/kg every 12 to 48 hours or lower. More severe cases of heart failure may require higher dosages. It is important to use an appropriate dosage of diuretic to relieve clinical signs but to avoid an unnecessarily high maintenance dosage. Overzealous use of diuretics may lead to weakness, hypotension, syncope, aggravation of prerenal azotemia, and acid-base and electrolyte imbalances. Often the owner can be instructed to vary the dosage, within a fixed dose range, according to the need of the dog.

The dosage of ACE-inhibitor (e.g., enalapril, benazepril, lisinopril, ramipril, and imidapril) is usually fixed and depends on the specific ACE-inhibitor used. ACE-inhibitors are indicated in advanced chronic mitral valve insufficiency with heart failure in combination with diuretics, because dogs in large placebo-controlled clinical trials receiving an ACE-inhibitor have been shown to have less severe clinical signs of disease, better exercise tolerance, and live longer than those not receiving an ACE-inhibitor. In the dose range that is recommended for use in dogs and cats, the vasodilating actions of the drugs are not prominent and side effects associated with hypotension, such as fainting and syncope, are rare. A reason for this may be that the short-term effects of ACE-inhibitors on the circulation are dependent on the activity of the RAAS prior to administration of the drug, the higher activity the more pronounced effect of the drug. In combination with diuretics, such as furosemide, the ACE-inhibitors have synergistic effect with the diuretic by counteracting the reflectory stimulation of RAAS that occurs in diuretic therapy. Thus they decrease the tendency for fluid retention and counteract a peripheral vaso-constriction and other negative effects on the heart.

Digoxin is controversial in treating dogs with chronic mitral valve insufficiency (CMVI). There is generally a lack of scientific evidence supporting the use of digoxin. Many cardiologists, however, initiate digoxin therapy when signs of heart failure first appear. Although digoxin is a comparably weak positive inotrope and myocardial failure may not be a prominent feature of chronic mitral valve insufficiency until progressed stages, digoxin has a place in heart failure therapy by reducing reflex tachycardia, by normalizing baroreceptor activity and by reducing central sympathetic activity. Thus digoxin may be useful to reduce the heart rate, such as when hydralazine is administered, or in supraventricular tachycardia such as atrial fibrillation, and to abolish or limit the frequency of syncope (see above).

The place for a positive inotrope in the management of chronic mitral valve insufficiency is controversial, since in small dogs signs of left-side heart failure usually precede overt myocardial failure. Nevertheless, the combined calcium sensitizer/PDE III inhibitor pimobendan is now approved for veterinary use in dogs with dilated cardiomyopathy and chronic mitral valve insufficiency in many European countries, Canada, and Australia at a dose of 0.25 mg/kg every 12 hours PO. Data from controlled clinical trials of pimobendan in veterinary patients is available, although its efficacy is less documented in chronic mitral valve insufficiency than in DCM. Recendy, two controlled clinical trials (the PITCH trial and a recendy completed study from UK) were presented (unpublished), The results indicate that dogs with chronic mitral valve insufficiency receiving pimobendan as adjunct therapy to diuretics show less severe signs of heart failure and are less likely to die or reach the treatment failure end-point than those receiving an ACE-inhibitor and diuretics. Many practitioners using pimobendan have experienced a dramatic improvement in overall clinical status in some CVMI dogs, even in dogs without overt myocardial failure. The reason for this may be that pimobendan, in addition to being a positive inotrope, has arterial vasodilating properties and differs from the pure phosphodiesterase III antagonists (such as milrinone) in that it increases myocardial contractility with minimal increase in myocardial energy consumption. Furthermore, positive inotropes may theoretically reduce the mitral regurgitation by decreasing the size of the left ventricle and the mitral valve annulus through a more complete emptying of the left ventricle. However, the increased contractility may also theoretically lead to an increased systolic pressure gradient across the mitral valve and thereby generate increased regur-gitation in some cases with high peripheral vascular resistance and increase the risk for chordal rupture in affected dogs. Therefore some cardiologists initiate pimobendan as adjunct therapy to other heart failure treatment in chronic mitral valve insufficiency dogs only when echocardiographic evidence of reduced myocardial performance (increased left ventricular end-systolic dimension) is evident. Whether or not this treatment strategy is the optimal use of calcium sensitizers has not been evaluated. Some cases of chronic mitral valve insufficiency with evidence of myocardial failure have evidence of disseminated myocardial micro-infarctions, most commonly as a consequence of widespread arteriosclerosis. Some of these patients might benefit from prophylactic antithrombotic and antiplatelelet therapy, although this has not been evaluated in veterinary medicine.

The way dogs with mild to moderate heart failure are managed after initiation of therapy varies. Typically, the dog is re-examined after 1 to 2 weeks of therapy, if the dog is managed on an outpatient basis, to monitor therapeutic outcome and to establish a suitable maintenance dosage of diuretic. Should the treatment response be satisfactory after this visit, dogs may often be managed by phone contacts and re-examinations every 3 to 6 months. More severe cases may require more frequent monitoring of the disease. In areas with a seasonal climate it may be valuable to re-examine the dog before the temperature increases and instruct the owner to avoid high ambient temperatures. The use of low-sodium diets as complementary therapy in heart failure is controversial. Currently, there are no clinical studies to support that they are beneficial in managing heart failure in dogs and cats. However, dogs with symptomatic chronic mitral valve insufficiency should avoid excessive intake of sodium. Dogs that are stable on their heart failure therapy usually tolerate walks at their own pace, but strenuous exercise should be avoided.

Recurrent Heart Failure

Once an appropriate maintenance dosage of furosemide has been set in a chronic mitral valve insufficiency patient with decompensated heart failure, the dosage has to be gradually increased, often over weeks or years. Reasons for increasing the dosage often include recurrent dyspnea caused by pulmonary edema or the development of ascites. Severe ascites, which compromises respiration, may require abdominocentesis. Many chronic mitral valve insufficiency cases with less severe ascites respond to an increased dose of diuretics. Even in case of abdominocentesis, the diuretic dosage should be increased as the ascites will re-occur without changed medication after evacuation. When the dosage of furosemide has reached a level of approximately 4 to 5 mg/kg every 8 to 12 hours, sequential blocking of the nephron should be considered by adding another diuretic. The drug of choice is spironolactone (1 to 3 mg q12-24h PO) which is an aldosterone antagonist and a potassium-sparing diuretic. A thiazide, such as hydrochlorothiazide (2 to 4 mg/kg q12h PO), or triamterene (1 to 2 mg/kg q12h PO) or amiloride (0.1 to 0.3 mg/kg q24h PO), may also be considered. The documentation of triamterene and amiloride in veterinary medicine is limited.

Because the furosemide treatment precedes and is used concomitantly with these drugs, the risk of hyperkalemia is low, even when they are added to a patient that is currently treated with an ACE-inhibitor. The risk of inducing prerenal azotemia, hypotension, and acid-base and electrolyte imbalances increases with the intensity of the diuretic treatment. However, the practitioner usually has to accept some degree of these disturbances when treating a patient with heart failure and, although common, they seldom result in clinical problems. A calcium senzitizer (pimobendan) is often introduced in cases with recurrent heart failure, as echocardiographic evidence of systolic dysfunction often has developed (see above).

Severe and Life-Threatening (Fulminant) Heart Failure

The causes of acute severe heart failure are often a ruptured major tendinous chord, development of atrial fibrillation, undertreatment of existing heart failure, or intense physical activity, such as chasing birds or cats, in the presence of significant chronic mitral valve insufficiency (CMVI). Patients with severe heart failure have radio-graphic evidence of severe interstitial or alveolar edema and have significant clinical signs of heart failure at rest. They are often severely dyspneic and tachypneic and have respiratory rates in the range of 40 to 90. They may cough white or pink froth, which is edema fluid. These dogs require immediate hospitalization and aggressive treatment. However, euthanasia should also be considered, if the dog is already on high doses of diuretics and other heart failure therapy, owing to the poor long-term prognosis. It is important not to stress dogs with severe or fulminant heart failure as stress may lead to death. Therefore thoracic radiographs and other diagnostic procedures may have to wait until the dog has been stabilized.

Dogs with significant dyspnea benefit from intravenous injections of furosemide at a relatively high dose (4 to 6 mg/kg q2-6h IV). The furosemide may be administered intramuscularly should placement of an intravenous catheter not be possible. Dogs with fulminant pulmonary edema may require Herculean furosemide doses at 6 to 8 mg/kg every 2 to 8 hours IV over the first 24 hours. The exact dosage of furosemide depends not only on severity of clinical signs but also on whether or not the dog is already on oral furosemide treatment. Oxygen therapy is always beneficial in hypoxemic patients and it can preferably be administered using an oxygen cage provided that the temperature can be controlled inside the cage. Nasal inflation or a facial mask may also be used provided that the animal accepts them without struggle. Once the dog has received furosemide and oxygen treatment, an arterial vasodilator and a positive inotrope may be considered to stabilize the patient.

Commonly used vasodilating agents are hydralazine per os or intravenous nitroprusside (2.0-10 mg/kg/min). Of these two vasodilators, hydralazine is most commonly used. Owing to the severity of heart failure, dogs without previous vasodilating therapy may receive an initial dose of hydralazine of 1 to 2 mg/kg PO. Titration of the hydralazine dosage as described above is indicated in dogs already on an ACE-inhibitor and blood pressure should be monitored to detect hypotension. Nitroprusside can only be administered as an intravenous infusion, which requires an intravenous catheter. This potent vasodilator has actions on both the venous and arterial circulation. However, it is not easy to control the effects of nitroprusside and the dosage has to be titrated under careful blood-pressure monitoring to avoid serious hypotension and to ensure efficacy. These disadvantages have prevented nitroprusside from being a commonly used arterial vasodilator.

A positive inotrope such as dobutamine, or more commonly the calcium-sensitizer pimobendan (0.25 mg/kg q12h PO), may be considered to stabilize the patient with fulminant heart failure. Pimobendan may be administered together with furosemide without any arterial vasodilator as the drug has vasodilating properties itself The dose of any concurrently administered arterial vasodilator has to be adjusted. Dobutamine is administered as a constant infusion usually in combination with nitroprusside. One problem with dobutamine that limits its use is that the patient needs to be weaned from IV to oral therapy within 1 to 2 days.

Patients with severe or fulminant heart failure need frequent initial monitoring of the respiratory rate because it reflects the clinical response to the furosemide treatment. Significandy decreased respiratory rate within the first hours indicates successful therapy, whereas absence of change indicate that furosemide is required at a higher dose or more frequently. Once the respiratory rate has decreased, the dose of furosemide may be reduced according to the status of the animal and clinical judgment. Abnormal laboratory findings such as pre-renal azotemia, electrolyte imbalances and dehydration are common after high doses of furosemide. Again, these abnormalities are seldom a clinical problem and the laboratory values often tend to shift towards normal with clinical improvement and as the dog starts to eat and drink. Dehydration is usually not severe even after intensive furosemide treatment and intravenous rehydration should be performed slowly and with caution in cases where it is needed, as the volume challenge may produce pulmonary edema.

 

Categories
Diseases

Angiotensin-Converting Enzyme Inhibitors

ACE Inhibitors

Despite their symptomatic benefits, diuretics should not be used as monotherapy in the management of congestive heart failure because they further activate the renin-angiotensin system. Drugs designed to inhibit angiotensin-converting enzyme block the formation of AT II, promote an increase in the circulating levels of bradykinin, and may temporarily reduce circulating aldosterone levels. Although angiotensin-converting enzyme inhibitors are frequendy categorized as balanced vasodilators, it appears likely that their beneficial effect on mortality is not mediated purely by hemodynamic alterations. They are relatively weak vasodilators compared with direct-acting arterial vasodilators such as hydralazine, and their ability to promote diuresis is much overshadowed by the less expensive loop diuretics. Rather, it is believed that angiotensin-converting enzyme inhibitors reduce mortality through their ability to blunt the detrimental consequences associated with long-standing activation of the RAS. Their early success has helped spearhead the current pharmacologic trend toward neurohormonal antagonism.

Activation of the neurohormonal cascade often begins with detection of arterial underfilling by mechanoreceptors in the carotid sinus and kidney. Regardless of whether this relative “hypotension” occurs secondary to low-output heart failure, severe mitral insufficiency, or profound hypovolemia, the common end-point is activation of the sympathetic nervous system and RAS. Additional activators of the renin-angiotensin-aldosterone system are reduced sodium delivery to the macula densa and sympathetic stimulation. Release of the protease renin from the juxtaglomerular apparatus promotes conversion of angiotensinogen to angiotensin I. Angiotensin-converting enzyme cleaves the C-terminal dipeptide from angiotensin I, thereby forming the octapeptide angiotensin II. In addition to being a potent vasoconstrictor, AT II has several other properties: (1) it is a primary secretagogue for aldosterone; (2) it potentiates presynaptic norepinephrine release; (3) it stimulates the release of antidiuretic hormone (vasopressin); (4) it promotes renal tubular sodium resorption; and (5) it has been linked to cardiomyocyte necrosis, apoptosis, and progression of ventricular fibrosis. Angiotensin-converting enzyme is also capable of cleaving the C-terminal dipeptide from bradykinin, therefore it appears to be a regulator of vasoconstrictive/ sodium retentive and vasodilative/natriuretic mechanisms. Although tissue angiotensin-converting enzyme and additional enzymatic pathways (e.g., chymase, cathepsin G, tonin, and tissue plasminogen activator) capable of producing AT II have been identified, their significance is unknown at this time.

ACE-inhibiting compounds are numerous and vary in their chemical structure, potency, bioavailability, and route of elimination. Most angiotensin-converting enzyme inhibitors, excluding captopril and lisinopril, are administered in the form of prodrugs that require conversion to their active form by hepatic metabolism. Enalapril requires conversion to enalaprilat, and benazepril is metabolized to benazeprilat. Although claims have been made that some formulations produce more profound angiotensin-converting enzyme inhibition, prolonged periods of efficacy, or superior tissue angiotensin-converting enzyme inhibition, the importance of these characteristics is unclear in naturally occurring heart failure.

The degree of angiotensin-converting enzyme inhibition and the duration of action of several agents, including benazepril, captopril, enalapril, lisinopril, and ramipril, have been evaluated in normal dogs. Hamlin and Nakayama documented that benazepril, enalapril, lisinopril, and ramipril were able to achieve similar degrees of angiotensin-converting enzyme inhibition after drug administration (about 75% inhibition at 1.5 hours and about 50% inhibition through 12 hours). Enalapril, lisinopril, and ramipril continued to display significant activity (about 25% inhibition) beyond 24 hours. These researchers also found that captopril was unable to reduce angiotensin-converting enzyme activity substantially, compared with control, beyond the 1 -5-hour sample. Whether captopril’s inability to suppress angiotensin-converting enzyme activity was a consequence of sample handling or merely an inability to suppress circulating versus tissue angiotensin-converting enzyme is uncertain. Evaluations of enalapril and benazepril in normal cats have identified maxima] angiotensin-converting enzyme inhibition of 48% and 98%, respectively, after single-dose administration. Benazepril was reported to show greater than 90% angiotensin-converting enzyme inhibition beyond 24 hours.

Excretion of the angiotensin-converting enzyme inhibitors is primarily via the kidneys, although benazepril appears to undergo significant biliary excretion in companion animals (about 50% in dogs and about 85% in cats). When angiotensin-converting enzyme inhibitors have been prescribed for patients with mild renal insufficiency, the recommendation historically has been to reduce both the dosage and frequency interval by approximately 50%. Administration of enalapril to dogs with experimental mild renal insufficiency is associated with a significant increase in the area under the curve (AUC) for the active metabolite enalaprilat. After benazepril was administered to the same dogs, no significant increase was seen in the AUC for benazeprilat. Whether concurrent cardiac disease, with its relatively depressed cardiac output, would be associated with impaired benazeprilat excretion is unclear. Current trends using “standard” doses of enalapril to treat glomerulonephritis and renal insufficiency are difficult to extrapolate to patients with heart failure and renal insufficiency because of their limited ability to increase cardiac output in the face of a reduced rate of glomerular filtration. In summary, the merits and limitations of the different formulations are unknown, and only the angiotensin-converting enzyme inhibitor enalapril has been specifically approved in the United States for the treatment of heart failure in dogs. The hypothesized improved safety of using benazepril rather than enalapril in patients with renal insufficiency has not been clinically evaluated in companion animals with cardiac disease.

Enalapril Enalapril is one of the few drugs that has been closely evaluated in dogs with naturally occurring congestive heart failure. The first reported placebo-controlled studies in dogs were short-term investigations, the Invasive Multicenter Prospective Veterinary Evaluation of Enalapril study (IMPROVE; 21 days) and the Cooperative Veterinary Enalapril study (COVE; 28 days), both published in 1995. These studies enrolled dogs with mitral valve insufficiency or dilated cardiomyopathy (DCM) to evaluate the hemodynamic (IMPROVE) and clinical (COVE) benefits of enalapril. The drug decreased pulmonary capillary wedge pressures in dogs with dilated cardiomyopathy and improved the heart failure class, pulmonary edema scores, and overall evaluation for both groups of dogs with heart failure. The benefits of these short-term studies were more pronounced for dogs with dilated cardiomyopathy than for those with mitral valve insufficiency. The COVE investigators found that twice daily oral administration of enalapril (0.5 mg/kg) appeared to promote more significant improvements than once daily therapy. The LIVE study group followed a subpopulation of dogs from the two short-term studies to evaluate the long-term effects of enalapril administration. These researchers found that dogs treated with enalapril were able to continue the study for longer than those receiving placebo (157.5 versus 77 days, P = 0.006). In contrast to the results of the short-term studies, the beneficial effect was more prominent in dogs with mitral valve insufficiency (P = 0.041) than in those with dilated cardiomyopathy (P = 0.06). An additional study supporting the benefits of angiotensin-converting enzyme inhibitor administration to dogs with heart failure found that enalapril significandy increased the exercise tolerance of dogs with experimentally created mitral insufficiency.

Despite these symptomatic benefits, the hope that early institution of angiotensin-converting enzyme inhibition will delay the onset of heart failure may go unfulfilled. To date, enalapril has been unable to delay the onset of heart failure in asymptomatic cases of mitral insufficiency. Whether angiotensin-converting enzyme inhibitors can reduce mortality in dogs or cats with heart failure has yet to be determined; even so, preliminary evidence reported in 2003 looks supportive, although not conclusive, for cats with diastolic dysfunction.

Benazepril Similar to enalapril, benazepril is a prodrug that must undergo hepatic metabolism to produce the active compound, benazeprilat. Oral administration of benazepril has produced variable and conflicting degrees of angiotensin-converting enzyme inhibition. An initial study reported that peak plasma benazeprilat concentrations were achieved 2 hours after oral administration. The percentage of angiotensin-converting enzyme inhibition after a single dose of 0.5 mg/kg of benazepril administered to normal dogs was 99.7% after 2 hours, 95.2% after 12 hours, and 87.3% after 24 hours. Similar results were found for the same intervals at doses of 0.25 mg/kg (97.8%, 89.2%, and 75.7%) and 1 mg/kg (99.1%, 94.0%, and 83.1%). Maximal angiotensin-converting enzyme inhibition after 15 doses was attained in dogs receiving 0.25 mg/kg of benazepril once daily (96.9% at 2 hours, 92.5% at 12 hours, and 83.6% at 24 hours). A second study, which also evaluated a single dose of 0.5 mg/kg of benazepril in normal dogs, showed angiotensin-converting enzyme inhibition of 81% at 1.5 hours, 37% at 12 hours, and 10.3% at 24 hours. Prolonged administration of benazepril was not evaluated. A final study, in which 0.5 mg/kg of benazepril was administered orally once daily to dogs with mitral insufficiency, showed angiotensin-converting enzyme inhibition to be 33.3% at 1 week, 28% at 2 weeks, and 42.7% at 4 weeks.

Based on these conflicting results, the current dosing recommendations are broad (0.25 to 0.5 mg/kg given orally once or twice daily). Whether benazepril is clinically more effective or safer than enalapril for dogs and cats with congestive heart failure remains unclear.

Adverse effects The mechanism by which angiotensin-converting enzyme inhibitors exert their beneficial properties (e.g., inhibition of angiotensin II production) also lends to the potential for adverse consequences. Although infrequendy encountered, complications may include systemic hypotension, azotemia, and hyperkalemia.

ACE inhibitors reduce systemic vascular resistance by decreasing circulating levels of angiotensin II and increasing circulating levels of bradykinin. In patients with severe heart failure in which an increase in cardiac output is unable to sustain systemic blood pressure, symptomatic hypotension may develop. Although this complication is infrequent, its likelihood increases with concomitant overzealous use of diuretics. Unfortunately, the clinical signs associated with severe low-output heart failure and systemic hypotension are very similar (e.g., weakness, exercise intolerance, and possibly stupor), a fact that lends emphasis to an important point: if a patient appears refractory to medical management, the blood pressure should be evaluated before more aggressive measures to combat heart failure are instituted.

A second adverse effect attributed to angiotensin-converting enzyme inhibitors’ unique ability to decrease angiotensin II production is a reduction in the glomerular filtration rate (GFR) and the development of azotemia. The glomerular filtration rate is determined by the glomerular capillary pressure (GCP). Based on the knowledge that pressure is equal to the product of flow and resistance (P = Q x R), it can be ascertained that the glomerular filtration rate ultimately is determined by renal plasma flow and the degree of efferent arteriolar vasoconstric-tion. In cases of heart failure in which renal plasma flow is diminished, the glomerular filtration rate is supported by the ability of ATII to constrict the efferent renal arte-riole. angiotensin-converting enzyme inhibitors’ ability to depress production of AT II promotes efferent renal arteriolar vasodilatation and hence a reduction in the GFR. The failing heart cannot further increase cardiac output, and an acute bout of azotemia may subsequendy develop. A recent study evaluating early institution of enalapril therapy in dogs with compensated mitral valve insufficiency found that dogs allocated to an angiotensin-converting enzyme inhibitor were not at a more significant risk of developing azotemia compared with dogs receiving placebo. In the authors’ experience, mild increases in blood urea nitrogen (BUN) and creatinine occur frequendy after institution of therapy with an angiotensin-converting enzyme inhibitor and furosemide. However, the development of severe azotemia, necessitating discontinuation of the angiotensin-converting enzyme inhibitor or a reduction in its dosage, occurs infrequently. This complication seems to occur most often in patients with severe heart failure that require aggressive diuretic administration to control congestive signs. Prior to institution of enalapril therapy, the authors evaluate the baseline biochemical parameters and perform a second measurement of the BUN, creatinine, and electrolytes 5 to 7 days after the start of treatment. If patients become anorectic or develop gastrointestinal signs during this time, we instruct the owners to discontinue all drugs and immediately present the animal for veterinary attention.

Hyperkalemia may be encountered during therapy with angiotensin-converting enzyme inhibitors as the result of a reduction in the glomerular filtration rate and a decline in circulating aldosterone levels. In the absence of aldosterone, sodium loss is favored and potassium levels rise. This complication appears to occur infrequently, presumably because most of the potent diuretics have potassium-wasting properties and tend to prevent the development of hyperkalemia. The authors have rarely encountered an increase in potassium that necessitated a dosage reduction for or discontinuation of an angiotensin-converting enzyme inhibitor. There is concern that the addition of spironolactone may potentiate hyperkalemia, therefore periodic electrolyte monitoring is prudent in patients receiving an angiotensin-converting enzyme inhibitor and a potassium-sparing diuretic.

Drug interactions Because aspirin inhibits cyclooxygenase and decreases prostaglandin formation, some have questioned whether administration of aspirin may negate some of the beneficial vasodilative properties exerted by angiotensin-converting enzyme inhibitors. An additional concern is that aspirin’s ability to reduce renal prostaglandin formation may worsen the angiotensin-converting enzyme inhibitor-induced reduction in the GFR. A recent retrospective analysis of six long-term, randomized trials of angiotensin-converting enzyme inhibitors found that aspirin did not significantly alter the beneficial effects of angiotensin-converting enzyme inhibitors in CHE Whether other commonly prescribed, non-steroidal anti-inflammatory agents blunt the potentially beneficial vasodilative properties of angiotensin-converting enzyme inhibitors is uncertain.

Categories
Veterinary Drugs

BENAZEPRIL HCL

Chemistry

Benazepril HCl, an angiotensin converting enzyme inhibitor, occurs as white to off-white crystalline powder. It is soluble in water and ethanol. Benazepril does not contain a sulfhydryl group in its structure.

Storage – Stability – Compatibility

Benazepril (and combination products) tablets should be stored at temperatures less than 86°F (30°C) and protected from moisture. They should be dispensed in tight containers.

Pharmacology

Benazepril is a prodrug, and has little pharmacologic activity of its own. After being hydrolyzed in the liver to benazeprilat, the drug inhibits the conversion of angiotensin I to angiotensin II by inhibiting angiotensin-converting enzyme (ACE). Angiotensin II acts both as a vasoconstrictor and stimulates production of aldosterone in the adrenal cortex. By blocking angiotensin II formation, ACE inhibitors generally reduce blood pressure in hypertensive patients and vascular resistance in patients with congestive heart failure.

Like enalapril and lisinopril, but not captopril, benazepril does not contain a sulfhydryl group. ACE inhibitors containing sulfhydryl groups (e.g., captopril) may have a greater tendency towards causing immune-mediated reactions.

Uses – Indications

Benazepril may be useful as a vasodilator in the treatment of heart failure and as a an antihypertensive agent. It may also be of benefit in treating the effects associated with valvular heart disease and left to right shunts. ACE inhibitors may also be of benefit in the adjunctive treatment of chronic renal failure and for protein losing nephropathies.

Pharmacokinetics

In healthy dogs, benazepril after oral dosing is rapidly absorbed and converted into the active metabolite benazeprilat with peak levels of benazeprilat occurring approximately 75 minutes after dosing. The elimination half-life of benazeprilat is approximately 3.5 hours in healthy dogs.

In humans, approximately 37% of an oral dose is absorbed after oral dosing and food apparently does not affect the extent of absorption. About 95% of the parent drug and active metabolite are bound to serum proteins. Benazepril and benazeprilat are primarily eliminated via the kidneys and mild to moderate renal dysfunction apparently does not significantly alter elimination as biliary clearance may compensate somewhat for reductions in renal clearances. Hepatic dysfunction or age does not appreciably alter benazeprilat levels.

Contraindications / Precautions / Reproductive Safety

Benazepril is contraindicated in patients who have demonstrated hypersensitivity to the ACE inhibitors.

ACE inhibitors should be used with caution in patients with hyponatremia or sodium depletion, coronary or cerebrovascular insufficiency, preexisting hematologic abnormalities or a collagen vascular disease (e.g., SLE). Patients with severe CHF should be monitored very closely upon initiation of therapy.

Benazepril apparently crosses the placenta. High doses of ACE inhibitors in rodents have caused decreased fetal weights and increases in fetal and maternal death rates; no teratogenic effects have been reported to date, but use during pregnancy should occur only when the potential benefits of therapy outweigh the risks to the offspring.

Minimal amounts of benazepril and benazeprilat enter maternal milk and do not apparently convey much risk to nursing offspring.

Adverse Effects – Warnings

Benazepril’s adverse effect profile in dogs is not well described, but other ACE inhibitors effects in dogs usually center around GI distress (anorexia, vomiting, diarrhea). Potentially, hypotension, renal dysfunction and hyperkalemia could occur. Because it lacks a sulfhydryl group (unlike captopril), there is less likelihood that immune-mediated reactions will occur, but rashes, neutropenia and agranulocytosis have been reported in humans.

Overdosage

In overdose situations, the primary concern is hypotension; supportive treatment with volume expansion with normal saline is recommended to correct blood pressure. Because of the drug’s long duration of action, prolonged monitoring and treatment may be required. Recent massive overdoses should be managed using gut emptying protocols as appropriate.

Drug Interactions

Concomitant diuretics or other vasodilators may cause hypotension if used with benazepril; titrate dosages carefully. Some clinicians recommend reducing furosemide doses (by 25 – 50%) when adding enalapril to therapy in CHF.

Hyperkalemia may develop if given with potassium or potassium sparing diuretics (e.g., spironolactone).

Non-steroidal anti-inflammatory agents (NSAIDs) may reduce the clinical efficacy of ACE inhibitors when they are being used as an antihypertensive agent. Indomethacin appears to be most likely to evoke this problem.

Laboratory Considerations

When using iodohippurate sodium I123/I134 or Technetium Tc99 pententate renal imaging in patients with renal artery stenosis, ACE inhibitors may cause a reversible decrease in localization and excretion of these agents in the affected kidney which may lead to confusion in test interpretation.

Doses

Doses for dogs:

For adjunctive treatment of heart failure:

a) 0.25 – 0.5 mg/kg PO once daily

b) 0.25 – 0.5 mg/kg PO once to twice daily

For adjunctive treatment of renal failure (progressive renal disease) or hypertension: a) 0.25 mg/kg PO once to twice daily

Monitoring Parameters

1) Clinical symptoms of CHF;

2) Serum electrolytes, creatinine, BUN, urine protein;

3) Blood pressure (if treating hypertension or symptoms associated with hypotension arise)

Client Information

Do not abruptly stop or reduce therapy without veterinarian’s approval.

Contact veterinarian if vomiting or diarrhea persist or is severe or if animal’s condition deteriorates.

Dosage Forms/FDA Approval Status

Veterinary-Approved Products:

None Human-Approved Products:

Benazepril HCl Oral Film-coated Tablets 5 mg, 10 mg, 20 mg, & 40 mg; Lotensin®; (Novartis);

(Rx) Also available in fixed dose combination products containing amlodipine (Lotrel®) or hydrochlorothiazide (Lotensin HCT®)