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| __NOTOC__
| | #REDIRECT [[Lisinopril#Pharmacology]] |
| {{Lisinopril}}
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| {{CMG}}; {{AE}} {{AM}}
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| ==Clinical Pharmacology==
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| ====Mechanism of Action====
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| Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. [[ACE]] is a peptidyl dipeptidase that catalyzes the conversion of [[angiotensin I]] to the vasoconstrictor substance [[angiotensin II]]. Angiotensin II also stimulates [[aldosterone]] secretion by the [[adrenal cortex]]. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased [[aldosterone]] secretion. The latter decrease may result in a small increase of serum [[potassium]]. In hypertensive patients with normal renal function treated with lisinopril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with lisinopril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L. Removal of [[angiotensin II]] negative feedback on renin secretion leads to increased plasma [[renin]] activity. ACE is identical to kininase, an enzyme that degrades [[bradykinin]]. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of lisinopril remains to be elucidated. While the mechanism through which lisinopril lower blood pressure is believed to be primarily suppression of the [[renin-angiotensin-aldosterone system]], lisinopril are antihypertensive even in patients with low-renin hypertension. Although lisinopril were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than nonblack patients. Concomitant administration of lisinopril and [[hydrochlorothiazide]] further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response were no longer evident.
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| ====Pharmacokinetics and Metabolism====
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| Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in [[acute myocardial infarction]] patients. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large intersubject variability (6%-60%) at all doses tested (5-80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability of lisinopril is reduced to 16% in patients with stable [[NYHA]] Class II-IV [[congestive heart failure]], and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with [[acute myocardial infarction]] is similar to that in healthy volunteers. Upon multiple dosing, lisinopril exhibits an effective half-life of accumulation of 12 hours.
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| Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the [[glomerular filtration rate]] is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and the area under the plasma concentration time curve (AUC) than younger patients. Lisinopril can be removed by [[hemodialysis]].
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| Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
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| ====Pharmacodynamics and Clinical Effects Hypertension====
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| Administration of lisinopril to patients with hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory [[tachycardia]]. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients. When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive.
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| In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.
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| In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy. The antihypertensive effects of lisinopril are maintained during long term therapy. Abrupt withdrawal of lisinopril has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.
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| Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a [[diuretic]]. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of lisinopril was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of lisinopril. In controlled clinical studies, lisinopril 20-80 mg have been compared in patients with mild to moderate hypertension to [[hydrochlorothiazide]] 12.5-50 mg and with [[atenolo]]l 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to [[hydrochlorothiazide]] in effects on systolic and diastolic pressure in a population that was 3/4 caucasian. Lisinopril were approximately equivalent to [[atenolol]] and [[metoprolol]] in effects on [[diastolic blood pressure]], and had somewhat greater effects on systolic blood pressure.
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| Lisinopril had similar effectiveness and adverse effects in younger and older (>65 years) patients. They were less effective in blacks than in caucasians.
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| In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in [[peripheral arterial resistance]] with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of lisinopril, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on [[glomerular filtration rate]] in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
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| In patients with renovascular hypertension lisinopril have been shown to be well tolerated and effective in controlling blood pressure.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LISINOPRIL (LISINOPRIL) TABLET [LEK PHARMACEUTICALS] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=27ccb2f4-abf8-4825-9b05-0bb367b4ac07 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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