| ACE INHIBITORS|
|General Monograph, |
|Angiotensin Converting Enzyme Inhibitor, |
|Action And Clinical Pharmacology: The renin-angiotensin system is a complex neuroendocrine system involved in the regulation of hemodynamics and water and electrolyte balance. When released from the kidney in response to a decrease in blood volume, renal perfusion pressure or plasma sodium concentration, renin acts on its substrate, angiotensinogen, to form angiotensin I. Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II. Inhibitors of ACE suppress the production of angiotensin II, which is the most vasoactive product of the renin-angiotensin system.
Patients with lower levels of renin, e.g., blacks, may experience a lesser antihypertensive response to monotherapy with ACE inhibitors.
Angiotensin II exerts many varied physiologic effects, including stimulation of aldosterone secretion, a direct systemic and coronary vasoconstrictive action as well as a positive inotropic effect, both directly and indirectly, through enhanced sympathetic outflow. Inhibition of ACE leads to decreased systemic arteriolar resistance and mean diastolic and systolic blood pressure. In patients with CHF, inhibition of ACE results in decreased afterload and heart rate as well as increased cardiac output, stroke volume and stroke work.
ACE inhibitors have many clinical applications, including the treatment of hypertension, CHF, left ventricular dysfunction and diabetic nephropathy. While large scale studies have not been conducted with every agent for every indication, evidence to date suggests that the clinical and adverse effects of ACE inhibitors tend to apply to these drugs as a class rather than to individual agents.
When ACE inhibitors are combined with thiazide diuretics, the antihypertensive effect is approximately additive.
ACE is known to be the same enzyme as kininase II, which catalyzes other physiologic reactions including the breakdown of the vasodilating autocoid, bradykinin. The extent to which potentiation of bradykinin is responsible for the beneficial or adverse clinical effects of ACE inhibitors is not clearly known.
The action of ACE inhibitors may not completely block the production of angiotensin II. Alternative pathways such as tissue-based chymases may facilitate the formation of angiotensin II from its precursors, independently of ACE.
Pharmacokinetics: With the exception of enalaprilat, which is given i.v., ACE inhibitors are absorbed to varying degrees from the gastrointestinal tract after oral administration. The rate and/or extent of absorption of certain agents may be decreased in the presence of food, although it is not clear whether this is clinically important in every case.
Some ACE inhibitors are converted in the liver and/or gastrointestinal mucosa to active metabolites; elimination of unchanged drug or metabolites may be renal or fecal. Table I contains various comparative pharmacokinetic parameters.
Indications And Clinical Uses: The pharmacologic effects of ACE inhibitors are thought to be of a class rather than individual nature (see Pharmacology). However, the labeled indications for specific agents may differ. At present, all of the ACE inhibitors available in Canada are marketed as antihypertensives for the treatment of mild to moderate essential hypertension, either alone or in combination with other drugs, particularly thiazide diuretics. Several agents (captopril, cilazapril, enalapril, fosinopril, lisinopril and quinapril) include an indication for the treatment of CHF, in combination with other agents such as thiazide diuretics or digoxin. Three agents, captopril, enalapril and ramipril, are indicated in the treatment of left ventricular dysfunction, to prevent symptomatic heart failure and reduce the frequency of hospitalization (see Table II). Captopril includes an indication for the treatment of diabetic nephropathy in patients with proteinuria.
The i.v. formulation of enalaprilat is indicated for the treatment of hypertension when the oral route is not practical.
Table II lists the labeled indications of the various ACE inhibitors.
Contra-Indications: In patients with known hypersensitivity to a particular ACE inhibitor, the specific agent in question is contraindicated. All ACE inhibitors are contraindicated in patients with a history of angioedema related to previous use of any member of this class. Products containing a fixed combination of an ACE inhibitor and a thiazide diuretic are also contraindicated in anuric patients and those with hypersensitivity to thiazides or other sulfonamide-derived drugs. tag_WarningWarnings
Manufacturers' Warnings In Clinical States: Pregnancy (see Precautions, Pregnancy): When used in pregnancy during the second and third trimesters, ACE inhibitors may cause significant fetal morbidity or mortality and should be discontinued as soon as possible if pregnancy is detected.
Angioedema: Angioedema has been reported with the use of ACE inhibitors. Involvement of the larynx may be fatal. If swelling is limited to the face and lips, discontinuation of the ACE inhibitor is usually the only corrective measure required. However, if there is involvement of the tongue, glottis or larynx, appropriate therapy (e.g., epinephrine) should be instituted as life-threatening airway obstruction may occur. Patients should be advised that swelling in the mouth or facial area or difficulty breathing or swallowing may be signs of angioedema and that they should discontinue the ACE inhibitor and contact their physician immediately if any of these symptoms occur.
Hypotension: Severe hypotension may occur with the use of ACE inhibitors, particularly in patients who are volume depleted, hyponatremic, receiving concomitant diuretics or on dialysis. ACE inhibitors should be used with caution in patients with cerebrovascular disease or ischemic heart disease, as severe hypotension could have serious consequences in these patients. In patients with severe heart failure with or without pre-existing renal insufficiency, ACE inhibitors may cause excessive hypotension with oliguria, azotemia and potentially fatal renal failure. In these patient groups, ACE inhibitors should be initiated under close medical supervision and monitored closely for the first few weeks of therapy and whenever the dose is increased.
Patients taking ACE inhibitors should be advised that vomiting, diarrhea, excessive perspiration or dehydration due to low fluid intake may cause an exaggerated decrease in blood pressure and that they should inform their physician if any of these conditions occur.
Neutropenia/Agranulocytosis: Neutropenia and bone marrow depression have occurred during therapy with ACE inhibitors. Periodic monitoring of white blood cell count is suggested, especially in patients with risk factors such as collagen vascular disease, renal failure or drug therapy that may cause immunosuppression. ACE inhibitors should be used with caution in these patients.
Patients should be advised to report any symptoms of infection, such as sore throat or fever, to their physician.
Precautions: Impaired Renal Function: Renal function should be evaluated prior to the initiation of ACE inhibitor therapy. Patients with impaired renal function, particularly those with bilateral or unilateral renal artery stenosis, may experience further deterioration of renal function, including acute renal failure, while taking ACE inhibitors. Patients with CHF or those receiving concomitant diuretic therapy may also be at increased risk. Reduction of ACE inhibitor dosage or discontinuation of diuretic therapy may be sufficient to restore adequate renal perfusion.
Although ACE inhibitors have been found to slow the progression of diabetic nephropathy in type I diabetic patients with documented proteinuria, some patients with pre-existing renal disease may be at increased risk of developing proteinuria while on ACE inhibitor therapy.
Hypersensitivity: Sudden, life-threatening anaphylactoid reactions have occurred during therapy with ACE inhibitors in patients undergoing hemodialysis with polyacrylonitrile (PAN) high-flux membranes and in patients being desensitized to hymenoptera venom (e.g., bees, wasps). Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema or shortness of breath occur, and appropriate treatment initiated. Antihistamines do not appear to provide symptomatic relief in these situations.
Hyperkalemia: Increases in serum potassium can occur during therapy with ACE inhibitors. Significant hyperkalemia usually occurs only in patients who are not on a concomitant thiazide diuretic, patients with impaired renal function, CHF or diabetes, or those who are taking other drugs which may raise serum potassium such as potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes.
Impaired Liver Function: Increases in liver enzymes and/or bilirubin, cholestatic jaundice and cases of hepatocellular injury with or without cholestasis have occurred during ACE inhibitor therapy, even in patients with no pre-existing liver disease. In most cases, these changes were reversible upon discontinuation of the drug. Patients reporting symptoms such as abdominal pain, muscle aches, vomiting, loss of appetite, etc., should be investigated for possible hepatic adverse effects. Patients with pre-existing liver disease should have baseline liver function tests prior to initiation of treatment. ACE inhibitors should be used with caution in these patients.
Cough: A persistent, dry cough has been reported with the use of ACE inhibitors, and a possible association must be considered in the differential diagnosis of patients presenting with cough. Accumulation of kinins in the respiratory tract, secondary to inhibition of kininase II, is thought to be a possible cause for the cough. A decrease in the ACE inhibitor dose may alleviate the cough and obviate the need for discontinuation. Cough has been associated with all ACE inhibitors; therefore, switching to a different agent may not result in improvement.
Pregnancy (see Warnings): ACE inhibitors should not be taken during pregnancy. Hypotension, reversible or irreversible renal failure, anuria, skull hypoplasia and/or death have occurred in neonates exposed to ACE inhibitors during the second and third trimesters of pregnancy. Oligohydramnios, which may be associated with contractures of the limbs, craniofacial deformities, lung hypoplasia and intrauterine growth retardation, has also occurred. These effects do not appear to result from exposure during the first trimester; however, ACE inhibitor therapy should be discontinued as soon as possible if pregnancy is detected. In extremely rare cases where a therapeutic alternative is not found, the patient should be informed of the potential harm to the fetus and serial ultrasound examinations should be performed to monitor fetal development and intra-amniotic fluid status. If oligohydramnios occurs, the ACE inhibitor should be discontinued unless it is considered life-saving for the mother.
Lactation: Detectible levels of various ACE inhibitors have been found in breast milk. Although the respective manufacturers generally advise not to breast feed while taking ACE inhibitors, there is no evidence to date of harmful effects in infants.
Children: Although there is limited experience with the use of captopril in infants and children, safety and efficacy of ACE inhibitors in the pediatric population have not been established. There appear to be specific risks associated with their use in neonates and infants, such as oliguria and neurologic abnormalities, possibly caused by decreased renal and cerebral perfusion due to prolonged, excessive hypotension. Most manufacturers advise against the use of their product in children. The manufacturer of captopril recommends its use only when other measures for controlling blood pressure have not been successful.
Geriatrics: ACE inhibitors are presumed to be more effective in the treatment of hypertensive patients with high or normal plasma renin activity. Although renin activity may decrease with advancing age, an age-related decline in renal function may result in a higher area under the concentration-time curve for ACE inhibitors. The net effect is that no significant differences in blood pressure response or adverse effects have been reported in elderly patients taking ACE inhibitors, compared to the general population. However, the possibility of increased sensitivity to the hypotensive effects of these drugs in some elderly patients should be borne in mind.
Drug Interactions: Agents Causing Renin Release: The antihypertensive effect of ACE inhibitors is augmented by antihypertensive agents which cause renin release, such as thiazide diuretics.
Agents Increasing Serum Potassium: ACE inhibitors cause decreased aldosterone production which may lead to increased potassium retention by the kidney. When combined with agents such as potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, severe hyperkalemia may occur. Patients with diabetes, impaired renal function or CHF may be at increased risk. Frequent monitoring of serum potassium is recommended in patients when these agents are used concomitantly with an ACE inhibitor.
Allopurinol: Although a causal relationship has not been proven, it is possible that ACE inhibitor therapy has predisposed patients to hypersensitivity reactions to allopurinol including Stevens-Johnson syndrome and anaphylaxis. Due to the seriousness of the reaction, it is recommended that this combination be avoided until further study establishes the cause.
Alpha-blocking Agents: Patients taking ACE inhibitors may experience an exaggerated hypotensive response to the first dose of an alpha-blocker (e.g., doxazosin, prazosin, terazosin).
These drugs should be introduced at a lower initial dosage, with caution.
Diuretics: Patients on severe dietary salt restriction or those on diuretic therapy, especially if the diuretic was recently instituted, may experience excessive hypotension when ACE inhibitor therapy is initiated. This effect may be minimized by increasing salt intake or discontinuing the diuretic 2 to 7 days prior to introduction of the ACE inhibitor. If this is not feasible, the initial dose of the ACE inhibitor should be reduced and the patient's blood pressure carefully monitored following the dose. If hypotension occurs, the patient should be in a supine position, and i.v. normal saline may be given if necessary. Hypotension should subside once volume expansion occurs and is a not a contraindication to further ACE inhibitor therapy, once blood pressure has stabilized.
Iron: ACE inhibitor therapy may augment the systemic adverse effects of i.v. iron, such as fever, arthralgia and hypotension, possibly by decreasing the metabolism of kinins. This does not seem to be the case with oral iron salts. Concomitant ACE inhibitor and i.v. iron therapy should be avoided whenever possible.
Lithium: Lithium toxicity, including CNS symptoms, ECG changes and renal failure, has occurred in patients taking ACE inhibitors. Proposed mechanisms include decreased renal elimination of lithium due to decreased aldosterone secretion or decreased renal function. Frequent monitoring of lithium levels is recommended in patients taking these agents concurrently.
NSAIDs: There is some evidence that the antihypertensive effect of ACE inhibitors may be antagonized by NSAIDs. Patients taking these agents concurrently should be monitored for signs of worsening heart failure or renal function.
Tetracyclines: The absorption of tetracyclines may be reduced when taken concurrently with quinapril, due to the presence of magnesium carbonate as an excipient in its pharmaceutical formulation.
Vasodilators: Although data on the combined effect of ACE inhibitors and other vasodilating drugs are not yet available, some manufacturers recommend that when possible, drugs such as nitrates should be discontinued prior to initiation of ACE inhibitor therapy. They should be given with caution at a lower dosage if subsequently resumed during ACE inhibitor treatment.
Adverse Reactions: Cardiovascular: Hypotension may occur in patients taking ACE inhibitors, particularly during initial therapy and in patients with other risk factors (see Warnings). Rarely, other cardiovascular effects symptoms such as chest pain, tachycardia, palpitations, angina and MI have occurred.
Dermatologic: A maculopapular rash has occurred, more frequently in patients with renal impairment. It usually appears within the first month of therapy and may disappear on its own, with a dosage reduction or discontinuation of the ACE inhibitor, or with oral antihistamine therapy. It has been postulated that this rash is mediated by kinins.
Photosensitivity and pemphigoid lesions have also occurred in patients taking ACE inhibitors.
Hematologic: Neutropenia, agranulocytosis and other blood dyscrasias have occurred during therapy with ACE inhibitors, especially in patients with additional risk factors (see Warnings). Patients should be advised to report symptoms such as sore throat or fever to their physician.
Hypersensitivity: Angioedema (see Warnings), serum sickness and bronchospasm have been reported. Anaphylactoid reactions have occurred in patients undergoing hemodialysis with PAN membranes or desensitization to hymenoptera venom (see Precautions).
Renal: Deterioration of renal function has occurred during therapy with ACE inhibitors, particularly in patients with predisposing conditions (see Precautions). Proteinuria, potentially progressing to nephrotic syndrome, has also been reported.
Respiratory: A persistent dry cough has been associated with the use of ACE inhibitors (see Precautions).
Taste Disturbances: Although more commonly reported with the use of captopril, all ACE inhibitors may cause a decrease in taste acuity or altered taste perception (e.g., metallic or salty taste). Taste disturbance usually occurs during the first 3 months of therapy and is usually reversible over 2 to 3 months, even if the ACE inhibitor is continued. Weight loss may accompany loss of taste.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis. tag_DosageDosage
Dosage And Administration: Oral: The initial dosage of ACE inhibitor therapy must be individualized, mainly due to the risk of hypotension, taking into consideration factors such as renal and/or hepatic failure, CHF, diuretic therapy, volume depletion or hyponatremia. Patients at increased risk should receive lower initial doses, with the first dose given under close medical supervision. Observation of patient should continue for at least 2 hours following administration, or until blood pressure has been stable for 1 hour.
Ideally, diuretic therapy should be discontinued 2 to 7 days prior to the introduction of an ACE inhibitor, and if necessary, resumed with caution once ACE inhibitor therapy is established. When discontinuation of diuretic prior to initiation of ACE inhibitor therapy is not possible, a reduced diuretic dosage should be considered.
Once therapy has been initiated, ACE inhibitor dosage should be gradually titrated to achieve the desired effect, depending on the indication for use. Table III lists dosage recommendations for ACE inhibitors in the treatment of hypertension, including initial, maintenance and maximum dosages. More detailed information may be found within individual product monographs, including specific dosage recommendations for different indications, titration guidelines and dosage adjustment in renal or hepatic failure.
I.V.: When the oral route is not feasible, the usual initial dosage of enalaprilat in the treatment of hypertension is 1.25 mg every 6 hours, administered i.v., either undiluted or mixed with up to 50 mL compatible diluent, over a period of at least 5 minutes (see product monograph). When converting from i.v. enalaprilat to oral enalapril, the initial dose should be 5 mg once daily, with subsequent adjustments as necessary.
Patients on diuretic therapy should receive a lower initial i.v. enalaprilat dosage of 0.625 mg over 5 minutes, with a second dose after 1 hour if an inadequate response is seen. Additional doses may be repeated at 6-hour intervals.