al committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. quinapril tablets may be used alone or in combination with thiazide diuretics. heart failure quinapril tablets are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. in using quinapril tablets, consideration should be given to the fact that another ace inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. available data are insufficient to show that quinapril tablets do not have a similar risk (see warnings ). angioedema in black patients : black patients receiving ace inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. it should also be noted that in controlled clinical trials ace inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

ccepted medical care, and carefully observed until the swelling disappears. in instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, emergency therapy including, but not limited to, subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 ml) should be promptly administered (see adverse reactions ). patients taking concomitant mammalian target of rapamycin (mtor) inhibitor (e.g., temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. intestinal angioedema : intestinal angioedema has been reported in patients treated with ace inhibitors. these patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and c-1 esterase levels were normal. the angioedema was diagnosed by procedures including abdominal ct scan or ultrasound, or at surgery, and symptoms resolved after stopping the ace inhibitor. intestinal angioedema should be included in the differential diagnosis of patients on ace inhibitors presenting with abdominal pain. patients with a history of angioedema : patients with a history of angioedema unrelated to ace inhibitor therapy may be at increased risk of angioedema while receiving an ace inhibitor (see also contraindications ). anaphylactoid reactions during desensitization : two patients undergoing desensitizing treatment with hymenoptera venom while receiving ace inhibitors sustained life-threatening anaphylactoid reactions. in the same patients, these reactions were avoided when ace inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. anaphylactoid reactions during membrane exposure : anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ace inhibitor. anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. hepatic failure : rarely, ace inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. the mechanism of this syndrome is not understood. patients receiving ace inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ace inhibitor and receive appropriate medical follow-up. hypotension : excessive hypotension is rare in patients with uncomplicated hypertension treated with quinapril alone. patients with heart failure given quinapril commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. caution should be observed when initiating therapy in patients with heart failure (see dosage and administration ). in controlled studies, syncope was observed in 0.4% of patients (n=3203); this incidence was similar to that observed for captopril (1%) and enalapril (0.8%). patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include patients with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. it may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or cautiously increase salt intake (except in patients with heart failure) before initiating therapy with quinapril in patients at risk for excessive hypotension who are able to tolerate such adjustments. in patients at risk of excessive hypotension, therapy with quinapril should be started under close medical supervision. such patients should be followed closely for the first two weeks of treatment and whenever the dose of quinapril and/or diuretic is increased. similar considerations may apply to patients with ischemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident. if excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. a transient hypotensive response is not a contraindication to further doses of quinapril, which usually can be given without difficulty once the blood pressure has stabilized. if symptomatic hypotension develops, a dose reduction or discontinuation of quinapril or concomitant diuretic may be necessary. neutropenia/agranulocytosis: another ace inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen vascular disease, such as systemic lupus erythematosus or scleroderma. agranulocytosis did occur during quinapril treatment in one patient with a history of neutropenia during previous captopril therapy. available data from clinical trials of quinapril are insufficient to show that, in patients without prior reactions to other ace inhibitors, quinapril does not cause agranulocytosis at similar rates. as with other ace inhibitors, periodic monitoring of white blood cell counts in patients with collagen vascular disease and/or renal disease should be considered. fetal toxicity pregnancy category d use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. when pregnancy is detected, discontinue quinapril as soon as possible. these adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. if oligohydramnios is observed, discontinue quinapril, unless it is considered life-saving for the mother. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to quinapril for hypotension, oliguria, and hyperkalemia (see precautions, pediatric use ). no teratogenic effects of quinapril were seen in studies of pregnant rats and rabbits. on a mg/kg basis, the doses used were up to 180 times (in rats) and one time (in rabbits) the maximum recommended human dose.

sed hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

hypotension occasionally can occur following the initial dose of quinapril. to reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with quinapril (see warnings ). then, if blood pressure is not controlled with quinapril alone, diuretic therapy should be resumed. if the diuretic cannot be discontinued, an initial dose of 5 mg quinapril should be used with careful medical supervision for several hours and until blood pressure has stabilized. the dosage should subsequently be titrated (as described above) to the optimal response (see warnings , precautions , and drug interactions ). renal impairment: kinetic data indicate that the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. recommended starting doses, based on clinical and pharmacokinetic data from patients with renal impairment, are as follows: creatinine clearance maximum recommended initial dose >60 ml/min 10 mg 30–60 ml/min 5 mg 10–30 ml/min 2.5 mg <10 ml/min insufficient data for dosage recommendation patients should subsequently have their dosage titrated (as described above) to the optimal response. elderly (≥65 years): the recommended initial dosage of quinapril in elderly patients is 10 mg given once daily followed by titration (as described above) to the optimal response. heart failure quinapril is indicated as adjunctive therapy when added to conventional therapy including diuretics and/or digitalis. the recommended starting dose is 5 mg twice daily. this dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. therefore, if the initial dosage of quinapril is well tolerated, patients should then be titrated at weekly intervals until an effective dose, usually 20 to 40 mg daily given in two equally divided doses, is reached or undesirable hypotension, orthostatis, or azotemia (see warnings ) prohibit reaching this dose. following the initial dose of quinapril, the patient should be observed under medical supervision for at least two hours for the presence of hypotension or orthostatis and, if present, until blood pressure stabilizes. the appearance of hypotension, orthostatis, or azotemia early in dose titration should not preclude further careful dose titration. consideration should be given to reducing the dose of concomitant diuretics. dose adjustments in patients with heart failure and renal impairment or hyponatremia pharmacokinetic data indicate that quinapril elimination is dependent on level of renal function. in patients with heart failure and renal impairment, the recommended initial dose of quinapril is 5 mg in patients with a creatinine clearance above 30 ml/min and 2.5 mg in patients with a creatinine clearance of 10 to 30 ml/min. there is insufficient data for dosage recommendation in patients with a creatinine clearance less than 10 ml/min (see dosage and administration , heart failure , warnings , and precautions , drug interactions ). if the initial dose is well tolerated, quinapril may be administered the following day as a twice daily regimen. in the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response.

(0.2) abdominal pain 1.0 (0.2) 0.7 heart failure quinapril has been evaluated for safety in 1222 quinapril treated patients. of these, 632 patients participated in controlled clinical trials. in placebo-controlled trials, discontinuation of therapy because of adverse events was required in 6.8% of patients with congestive heart failure. adverse experiences probably or possibly related or of unknown relationship to therapy occurring in 1% or more of the 585 patients in placebo-controlled congestive heart failure trials who were treated with quinapril are shown below. quinapril placebo (n=585) (n=295) incidence incidence (discontinuance) (discontinuance) dizziness 7.7 (0.7) 5.1 (1.0) coughing 4.3 (0.3) 1.4 fatigue 2.6 (0.2) 1.4 nausea and/or vomiting 2.4 (0.2) 0.7 chest pain 2.4 1.0 hypotension 2.9 (0.5) 1.0 dyspnea 1.9 (0.2) 2.0 diarrhea 1.7 1.0 headache 1.7 1.0 (0.3) myalgia 1.5 2.0 rash 1.4 (0.2) 1.0 back pain 1.2 0.3 see precautions, cough . hypertension and/or heart failure clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to 1.0% (except as noted) of the patients with chf or hypertension treated with quinapril (with or without concomitant diuretic) in controlled or uncontrolled trials (n=4847) and less frequent, clinically significant events seen in clinical trials or post-marketing experience (the rarer events are in italics) include (listed by body system): general : back pain, malaise, viral infections, anaphylactoid reaction cardiovascular : palpitation, vasodilation, tachycardia, heart failure, hyperkalemia, myocardial infarction, cerebrovascular accident, hypertensive crisis, angina pectoris, orthostatic hypotension, cardiac rhythm disturbances, cardiogenic shock hematology : hemolytic anemia gastrointestinal : flatulence, dry mouth or throat, constipation, gastrointestinal hemorrhage, pancreatitis, abnormal liver function tests, dyspepsia metabolism and nutrition disorders : hyponatremia nervous/psychiatric : somnolence, vertigo, syncope, nervousness, depression, insomnia, paresthesia integumentary : alopecia, increased sweating, pemphigus, pruritus, exfoliative dermatitis, photosensitivity reaction, dermatopolymyositis urogenital : urinary tract infection, impotence, acute renal failure, worsening renal failure respiratory : eosinophilic pneumonitis other : amblyopia, edema, arthralgia, pharyngitis, agranulocytosis, hepatitis, thrombocytopenia angioedema angioedema has been reported in patients receiving quinapril (0.1%). angioedema associated with laryngeal edema may be fatal. if angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with quinapril should be discontinued and appropriate therapy instituted immediately. (see warnings .) clinical laboratory test findings hematology : (see warnings ) hyperkalemia : (see precautions ) creatinine and blood urea nitrogen : increases (>1.25 times the upper limit of normal) in serum creatinine and blood urea nitrogen were observed in 2% and 2%, respectively, of all patients treated with quinapril alone. increases are more likely to occur in patients receiving concomitant diuretic therapy than in those on quinapril alone. these increases often remit on continued therapy. in controlled studies of heart failure, increases in blood urea nitrogen and serum creatinine were observed in 11% and 8%, respectively, of patients treated with quinapril; most often these patients were receiving diuretics with or without digitalis.

one resulted in mean increases in potassium of 0.07 mmol/l (see precautions ). removal of angiotensin ii negative feedback on renin secretion leads to increased plasma renin activity (pra). while the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ace is identical to kininase ii, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated. pharmacokinetics and metabolism: following oral administration, peak plasma quinapril concentrations are observed within one hour. based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. the rate and extent of quinapril absorption are diminished moderately (approximately 25–30%) when quinapril tablets are administered during a high-fat meal. following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. quinaprilat is eliminated primarily by renal excretion, up to 96% of an iv dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. the pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5–80 mg doses and 40–160 mg in multiple daily doses. approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. in patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. there is a linear correlation between plasma quinaprilat clearance and creatinine clearance. in patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. elimination of quinaprilat may be reduced in elderly patients (≥65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see dosage and administration ). quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier. pharmacodynamics and clinical effects hypertension: single doses of 20 mg of quinapril provide over 80% inhibition of plasma ace for 24 hours. inhibition of the pressor response to angiotensin i is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. with chronic dosing, however, there is substantial inhibition of angiotensin ii levels at 24 hours by doses of 20–80 mg. administration of 10 to 80 mg of quinapril to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and/or volume-depleted (see warnings ). antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. during chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1–2 weeks. in multiple-dose studies, 10–80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5–11/3–7 mm hg. the trough effect represents about 50% of the peak effect. while the dose-response relationship is relatively flat, doses of 40–80 mg were somewhat more effective at trough than 10–20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. the antihypertensive effect of quinapril tablets continues during long-term therapy, with no evidence of loss of effectiveness. hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. use of quinapril with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. in patients with hypertension, quinapril 10–40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. heart failure: in a placebo-controlled trial involving patients with congestive heart failure treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril, reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac output/index. similar favorable hemodynamic effects were seen with oral quinapril in baseline-controlled trials, and such effects appeared to be maintained during chronic oral quinapril therapy. quinapril reduced renal hepatic vascular resistance and increased renal and hepatic blood flow with glomerular filtration rate remaining unchanged. a significant dose response relationship for improvement in maximal exercise tolerance has been observed with quinapril therapy. beneficial effects on the severity of heart failure as measured by new york heart association (nyha) classification and quality of life and on symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind, placebo-controlled study. favorable effects were maintained for up to two years of open label therapy. the effects of quinapril on long-term mortality in heart failure have not been evaluated.