Which of the following ace inhibitors used to treat heart failure has an iv dosage form?

Enalapril Maleate (Po), Enalaprilat (Iv)

Enalapril: Vasotec, Epaned, and generics

Enalaprilat: generics; previously available as Vasotec IV

Angiotensin converting enzyme inhibitor, antihypertensive

Enalapril:

Tabs (Vasotec and generics): 2.5, 5, 10, 20 mg (scored)

Oral solution (Epaned): 1 mg/mL (150 mL); contains sodium benzoate

Oral suspension: 0.1, 1 mg/mL

Enalaprilat:

Injection: 1.25 mg/mL (1, 2 mL); contains benzyl alcohol

Hypertension:

Infant and child:

PO: 0.08 mg/kg/24 hr up to 5 mg/24 hr once daily; increase PRN over 2 wk.

Max. dose (higher doses have not been evaluated): 0.58 mg/kg/24 hr up to 40 mg/24 hr

IV: 0.005–0.01 mg/kg/dose Q8–24 hr;max. dose: 1.25 mg/dose

Adolescent and adult:

PO: 2.5–5 mg/24 hr once daily initially tomax. dose of 40 mg/24 hr ÷ once daily–BID

IV: 0.625–1.25 mg/dose IV Q6 hr; doses as high as 5 mg Q6 hr is reported to be tolerated for up to 36 hr.

Enalaprilat

Enalaprilat is the only available angiotensin-converting enzyme (ACE) inhibitor that can be administered intravenously. Enalaprilat lowers BP within 15 to 30 minutes, but the BP response in hypertensive emergencies is unpredictable, in part because of variable degrees of plasma volume expansion. The initial recommended dose for enalaprilat is 0.625 to 1.25 mg administered over 5 minutes. The maximal single dose should not exceed 5 mg for patients receiving diuretics and 1.25 mg for patients with renal impairment.2 The initial dose can be repeated after 1 hour if clinical response is inadequate. The total daily dose should not exceed 20 mg. In patients with severe renal insufficiency, the dose should be decreased because the compound is excreted primarily by the kidney.

Enalaprilat is more effective in patients with high-renin forms of hypertension, and may induce a dramatic fall in BP in patients who are volume depleted by previous dietary sodium restriction or diuretic use.2 African Americans seem to respond poorly to enalaprilat, possibly because of their low renin levels. Because enalaprilat may induce severe hypotension in volume-depleted patients, it should be used with caution in patients who are at risk for cerebral hypotensive episode. In patients with hypertensive emergency, the response rate is about 65% and it is not dependent on the initial dose.2 Thus a low dose of 0.625 mg may be adequate for initial treatment of hypertensive crisis.28 In one study, enalaprilat was compared with intravenous urapidil and sublingual nifedipine in the management of hypertensive crisis. Only 70% of the patients in the enalaprilat group achieved goal BP (<180/95 mmHg within 45 minutes after start of treatment) versus 96% and 71% in the urapidil and nifedipine groups, respectively.29

The most common adverse effect is hypotension. The risk for hypotension increases in patients with evidence of renal hypertension, volume-depleted patients, and patients with prior use of diuretics. Enalaprilat is contraindicated in patients with evidence of bilateral renal artery stenosis or in patients with unilateral stenosis of a single kidney.30 Thus enalaprilat is particularly useful in hypertensive emergencies associated with congestive heart failure or high renin levels, and can be easily replaced by oral enalapril for long-term maintenance therapy.

General Principles for Managing Hypertensive Emergencies

Although therapy with parenteral antihypertensive agents may be initiated in the ED, patients with a hypertensive emergency should be admitted to an ICU for continuous BP monitoring, clinical surveillance, and continued parenteral administration of an appropriate agent (Tables 37.1 and37.2). Specific BP levels do not determine the severity and the emergency of the situation because the autoregulatory structural and functional changes may vary among individuals, such that some may develop target organ damage at lower BP.

Understanding of autoregulation as well as cardiovascular (CV) comorbidities such as age and extent of vascular disease are crucial for therapeutic decisions; sudden lowering of BP into a normal range could lead to inadequate tissue perfusion.12 Clinical data document that lowering BP in hypertensive emergencies is beneficial: papilledema and exudates regress, hypertensive encephalopathy vanishes, pulmonary edema resolves, and renal function improves. However, there is also evidence that abrupt lowering of BP can be harmful. For example, the use of sublingual nifedipine with potent but unpredictable BP lowering may shunt blood away from the penumbra of the brain (ischemic penumbra), resulting in a vascular infarct.22 Thus the goal of antihypertensive therapy is not to normalize BP rapidly, but rather to prevent target organ damage by gradually reducing BP while minimizing the risk for hypoperfusion.

For most patients with hypertensive emergency, the mean BP should be reduced by no more than 20% to 25% within the first hour.6,8 A DBP target between 100 and 110 mm Hg or a reduction of 25% compared with the initial baseline, whichever is higher, is an appropriate goal within the next 2 to 6 hours. Reduction of DBP to less than 90 mm Hg or by 35% of the initial mean BP has been associated with major organ dysfunction, coma, and death. Similarly SBP should be reduced to levels around 160 mm Hg within the first hour and slowly over the next 24 hours reduced to levels around 140 mm Hg. If the degree of BP reduction is well tolerated and the patient is clinically stable, further gradual reductions toward levels below 140/90 mm Hg should be implemented within the next 24 to 48 hours.

An important consideration before initiation of intravenous therapy is assessment of the patient's volume status. With the exception of patients presenting with volume overload and pulmonary edema, some patients with a hypertensive emergency may be volume depleted because of pressure natriuresis, and diuretics should not be used; rather, fluid administration may help restore organ perfusion and prevent a precipitous fall in BP.9 Diuretics especially should be avoided in hypertensive emergencies because of catecholamine excess states (pheochromocytoma, monoamine oxidase inhibitor crisis, cocaine intoxication), because these patients are usually volume depleted.

Enalaprilat

Enalaprilat is an IV form of an ACE inhibitor that blocks the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor.135 Thus ACE inhibition leads to vasodilation because of decreased levels of angiotensin II.135 Enalaprilat is also the active form of enalapril that is given by mouth and immediately hydrolyzed by hepatic esterases to the active dicarboxylic acid, enalaprilat.135 Interestingly, ACE also metabolizes bradykinin; hence bradykinins increase during ACE inhibition, and this effect may contribute to vasodilation as well.136 In any event, ACE inhibitors decrease systemic vascular resistance and thus afterload and systolic wall stress. Consequently, CO and stroke volume improve.135 The rationale behind the use of an ACE inhibitor is to attenuate renal damage caused by hyperfiltration and subsequent proteinuria from activation of the renin-angiotensin system.77

ACE inhibitors are cleared predominantly by the kidneys. Therefore doses of these agents need to be reduced in patients with renal insufficiency.135 ACE inhibitors are most potent in patients with high renin levels; significant decreases in BP can occur in this population. Thus patients with elevated renin levels need to be monitored closely after receiving IV enalaprilat. Enalaprilat should not be used in patients with myocardial infarction, bilateral renal artery stenosis, pregnancy, or preeclampsia/eclampsia.137 Use in preterm infants before glomerular development is complete is also controversial.

The pediatric dose for enalaprilat is 5 to 10 μg/kg/dose IV every 8 to 24 hours as determined by BP response.138 The adult dose for enalaprilat is 0.625 mg to 1.25 mg IV every 6 hours.139

Malignant HTN, Hypertensive Emergencies, and Hypertensive Urgencies

Definitions:

Malignant HTN occurs with HTN when there are grades III and IV retinopathy (exudates, hemorrhages, and papilledema).

The rate of BP rise is a critical factor in the development of malignant HTN.

Complications and mortality rates are much higher in malignant HTN compared with essential HTN.

Requires immediate BP reduction (not necessarily into normal ranges) to prevent or limit target organ disease.

Hypertensive emergencies occur when the BP elevation is >180 mm Hg systolic and/or >120 mm Hg diastolic without evidence of new or progressive organ dysfunction. It requires rapid lowering of BP to prevent end-organ damage.

Hypertensive urgencies are BP elevations >180 mm Hg systolic and/or >120 mm Hg diastolic with end-organ damage that should be corrected within 24 hr of presentation.

Most clinicians suggest lowering the BP to <160 mm Hg/<100 mm Hg or to a level no more than 30% lower than the patient’s baseline BP.

Therapy: The choice of therapeutic agents varies with the cause. IV medications are preferred in hypertensive emergencies.

Nitroprusside is the drug of choice in hypertensive encephalopathy, HTN and intracranial bleeding, malignant HTN, HTN and heart failure, dissecting aortic aneurysm (used in combination with propranolol); its onset of action is immediate. Because it is metabolized to cyanide, patients should be carefully monitored for toxicity (mental status changes, acidemia).

Fenoldopam is a vasodilator agent useful for the short-term (up to 48 hr) management of severe HTN when rapid but quickly reversible reduction of BP is required. It should be avoided in patients with glaucoma.

Other commonly used agents are the IV CCBs nicardipine and clevidipine (useful for urgent treatment of HTN in the ICU or operating room), the beta-blocker esmolol (useful in aortic dissection or postoperative HTN), labetalol (combined β-adrenergic and α-blocker useful in patients with coronary disease), phentolamine (useful for catecholamine-related emergencies), IV nitroglycerin (used in patients with cardiac ischemia and hypertensive crisis), and hydralazine (used for hypertensive emergencies in pregnancy.

Table 7 summarizes IV medications useful in hypertensive crisis.

Enalaprilat

Enalaprilat, an intravenous ACE inhibitor, is the active metabolite of orally administered enalapril.94 Enalaprilat inhibits ACE, suppressing formation of angiotensin II, thus reducing systemic vascular resistance and arterial BP. As with other ACE inhibitors, the degree of BP reduction is directly related to circulating renin levels, such that persons with low renin levels may develop only minimal decreases in BP during enalapril treatment, whereas persons with high levels of renin, as in volume depletion secondary to diuretic treatment or dialysis, may experience precipitous hypotensive effects.95 Intravenous enalaprilat is effective in conditions of severe hypertension complicated by high renin levels—in particular, scleroderma and other forms of renal vasculitis—but otherwise its efficacy is variable, precluding its general use in most hypertensive emergencies.

Enalaprilat

Enalaprilat is an intravenous angiotensin-converting enzyme inhibitor. The recommended dose is 5 to 10 mcg/kg to a maximum of 1.25 mg per dose, given as an intravenous bolus every 8 to 24 hours as needed. It has been used safely for blood pressure control in pediatric patients.47,48 However, the effects can be variable, and individuals most likely to respond are those with high renin levels, renal artery stenosis, or a mass lesion of the kidney. In addition, enalaprilat may cause significant hypotension in volume-contracted patients, or may cause acute renal failure in patients with bilateral renal artery stenosis. Due to these potential side effects, the inability to titrate, and the potential for a delayed onset of action (up to 60 minutes), other medications are preferable to enalaprilat in the setting of a hypertensive emergency.

Enalaprilat

Enalaprilat

Enalaprilat is an intravenous form of angiotensin-converting enzyme (ACE) inhibitor. ACE converts angiotensin I to angiotensin II, which is a potent systemic vasoconstrictor. Hence, administration of ACE inhibitor lowers SVR and increases venous capacitance. Blood pressure does not change significantly if cardiac output can increase to compensate for the fall in SVR.

In adults with congestive heart failure secondary to ischemic heart disease, enalaprilat administered either as a bolus or continuous infusion improves hemodynamics and oxygen delivery, although it had no impact on cardiac index.178

With the exception of treatment of acute hypertensive crisis, there are no data on the use of enalaprilat in children. Extrapolation of the indications for enalaprilat can be made from the oral ACE inhibitors. Captopril has been used successfully in three patient populations: congestive heart failure in dilated cardiomyopathy, congestive heart failure in large left-to-right shunts, and systemic hypertension. A hypereninemic state and, consequently, increased angiotensin levels characterize all of these conditions. Congestive heart failure symptoms and signs diminish in the majority of patients with dilated cardiomyopathy during the first month of therapy with captopril.17 These children experience a decrease in SVR that is balanced by an increase in cardiac index so that systemic blood pressure is usually unchanged.19

In contrast, patients with CHF due to restrictive cardiomyopathy usually do not respond favorably to captopril.19 Cardiac output does not increase to compensate for the fall in SVR, and these children experience systemic hypotension.

Infants with large left-to-right shunts (e.g., VSD) and CHF may have a favorable response to captopril.204,215,217 The hemodynamic response depends on the baseline SVR, so that infants with increased SVR (greater than 20 U/m2) as well as increased pulmonary-to-systemic flow ratio (Qp:Qs) and pulmonary artery pressure are most likely to achieve a reduction in Qp:Qs after captopril.217

Captopril has been used for children with renal hypertension. The antihypertensive effects are seen after repeated doses over the course of several days. In these patients, the mean initial dose was 1.3 mg/kg/day and the mean sustaining dose was 2.2 mg/kg/day.36

There are few significant complications from ACE inhibitors. Hypotension is the major hemodynamic complication. It is more common at high doses and in young infants. Blood pressure should be monitored closely at the start of captopril therapy, and dosages are increased gradually. Renal insufficiency occurs rarely.217 The mechanism is thought to be a reduction in efferent arteriolar tone, which is needed to maintain adequate glomerular filtration.86

Pharmacokinetics

Enalapril is the ethyl ester of enalaprilat. It has little pharmacological activity until it is hydrolyzed in the liver to enalaprilat. Enalapril is available commercially as the maleate salt. Enalapril maleate is absorbed better from the gastrointestinal tract in dogs than enalaprilat. The affinity for enalaprilat for the angiotensin I binding sites on ACE is approximately 200,000 times that of ACE.

In dogs, enalapril maleate achieves peak concentration within 2 h of administration. Bioavailability is approximately 60%. Enalapril is metabolized to enalaprilat. Peak serum concentration of this active form occurs 3–4 h after an oral dose. The half-life of accumulation is approximately 11 h and duration of effect is 12–14 h. Steady-state serum concentration is achieved by the fourth day of administration. Excretion of enalapril and enalaprilat is primarily renal (40%) although 36% is excreted in the feces. Approximately 85% of an oral dose is excreted as enalaprilat.

The pharmacodynamics of enalapril have been examined in experimental dogs. A dose of 0.3 mg/kg administered per os results in approximately 75% inhibition of the pressor response to angiotensin I. This effect lasts for at least 6 h and is completely dissipated by 24 h after administration. A dose of 1.0 mg/kg produces only slightly better inhibition (approximately 80%) for at least 7 h. About 15% inhibition is still present 24 h after oral administration.