Generic Name: Lisinopril
Common Brand Names: Zestril (AstraZeneca — U.S.), Prinivil (Merck — U.S.)
Popularity: Fourth most commonly prescribed drug between 2002-2007 (U.S.)
Class: Ace inhibitor
Treatment Uses — For treatment of hypertension, usually in patients not responsive to thiazide diuretics alone. To improve survival following acute myocardial infarction (AMI) or patients with heart failure. For protection of kidney function in patients with diabetes as well as a variety of other diseases causing progressive decline in kidney function. Treatment and prevention of progressive retinal degeneration in patients with diabetes. Has been shown effective for prevention of migraines in some patients. Useful for treating post renal transplant erythrocytosis (PTE), a progressive increase in hematocrit occurring in 6.5 percent to 35.8 percent of kidney transplant recipients that can result in thromboembolic events such as stroke or blood clots in extremities. Helpful for treating cyclosporine induced hypertension in solid organ transplant patients. Cyclosporine, used to prevent transplant rejection, causes both hypertension (27 percent of liver, 50 percent of kidney, and 90 percent of heart transplant patients) and progressive deterioration of kidney function. Studies on the effectiveness of ace inhibitors for preventing restenosis (repeat blockages) following percutaneous coronary angioplasty (PTCA or roto rooter procedures on the coronary arteries) have been largely inconclusive, meaning that lisinopril probably has no positive influence on the rate of repeat blockage following PTCA.
Lisinopril belongs to a family of drugs called ace inhibitors or angiotensin converting enzyme inhibitors (ACEI). The drug names often end in “-pril” (captopril, enalapril etc.) and work by inhibiting the production of angiotensin converting enzymes, which are responsible for elevating blood pressure by constriction of blood vessels.
Dosing and Administration — For treatment of hypertension in adults, the initial oral dose is 10 milligrams once daily, adjusted by blood pressure response at two to four week intervals. Existing diuretic therapy should be discontinued at least two days before starting lisinopril. If this is not possible, initial dosing should be lowered to 5 milligrams once daily. To assure 24-hour control, blood pressure should be assessed just prior to taking lisinopril. Usual adult dosing ranges from 20 to 40 milligrams once daily and should not exceed 80 milligrams per day. When starting diuretic agents in patients already taking lisinopril, initial dosing should be lowered and consideration given to lowering the lisinopril dose. For treatment of heart failure in adults, initial oral dosing is 2.5 to 5 milligrams once daily adjusted at two to four week intervals by blood pressure response and functional status. Typical heart failure dosing ranges from 5 to 20 milligrams once daily and should not exceed 40 milligrams per day. High (35 milligrams daily) and low (2.5 milligrams daily) have similar outcomes improving functional status, so there appears no good reason to aggressively reach beyond doses of 10 milligrams daily. Following MI in adults (as an adjunct to aspirin and beta-blocker therapy), lisinopril is dosed orally at 5 milligrams once daily for two days, then 10 milligrams once daily for six weeks. For post MI patients with resting systolic blood pressures (SBP) below 120 mmHg, initial dosing of lisinopril should begin at 2.5 milligrams once daily and escalate to 5 milligrams once daily (maintenance dose) with close attention to SBP. Maintenance dosing of 2.5 milligrams should be considered if hypotension (SBP less than 100 mmHg) develops in the first three days of therapy. Drug discontinuation is recommended if SBP remains less than 90 mmHg for more than one hour while on lower dose lisinopril. For renal protection and prevention of retinal degeneration, target dosing in adults is 10 to 20 milligrams once daily. Maximum dosing for any indication in adult patients should not exceed 80 milligrams per day. Note that abrupt discontinuation of lisinopril has not been associated with rapid increases in blood pressure compared to pretreatment measurements.
Dosing recommendations for treatment of hypertension in children 6 years of age or older call for initial doses of 0.07 milligrams per kilogram of the child’s body weight up to a total of 5 milligrams once daily, titrated to blood pressure response. Doses exceeding 40 milligrams daily and/or above 0.61 milligrams per kilogram per day have not been studied in children. There are no recommendations for using lisinopril in patients under 6 years of age.
Lisinopril oral doses can be taken without regard to meals, although there have been reports of symptomatic hypotension with concurrent ingestion of garlic oil capsules. A compounding pharmacy can prepare a lisinopril liquid suspension (for children) that will remain stable for up to four weeks with refrigeration.
Dose reductions based on calculated creatinine clearance are recommended for patients with kidney dysfunction. Usually measured in millimeters per minute, creatinine clearance compares the level of creatinine in urine to the level in blood plasma, providing a picture of kidney function efficiency. True measurement compares a 24-hour urine sample to a blood levels. Formula derived estimates based on sex, age, weight and blood creatinine level are typically used to dose drugs with significant renal elimination. Normal creatinine clearances average 120 millimeters per minute for men and 95 millimeters per minute for women. For adult patients with creatinine clearances between 10 and 30 millimeters/minute, initial oral dosing of lisinopril should be reduced to 5 milligrams once daily. In patients with creatinine clearances below 10 millimeters/minute (end stage renal disease), initial dosing is 1.25 to 2.5 milligrams daily. Because most end stage renal disease patients will be on dialysis, note that up to half the plasma concentration of lisinopril can be removed in a typical hemodialysis run, often necessitating post hemodialysis supplementation of lisinopril. Based on blood pressure, a supplemental dose of 20 percent the usual daily lisinopril dose is recommended post hemodialysis.
Older patients normally require the same lisinopril dosing as younger patients. Studies do show higher maximum blood levels and nearly double plasma concentration times in older (greater than 55 years) compared to younger patients. Less aggressive dosing adjustments are recommended in older patients and consideration given to the likelihood that reduced maintenance doses may be necessary with prolonged lisinopril treatment.
Overdoses of lisinopril have generally resulted only in mild hypotension and occasionally bradycardia. Symptomatic hypotension and tachycardia may be the earliest clinically evident signs of lisinopril toxicity. These tend to occur within one hour of a toxic dose and peak between four to six hours after the dose. Hypotension usually responds to intravenous fluids. Hyperkalemia (elevated serum potassium levels) occurs even with therapeutic doses of lisinopril, and can become life threatening with overdoses especially in patients with renal insufficiency or those taking NSAIDs. Hemodialysis is effective in removing lisinopril from the body. There is no specific antidote for lisinopril overdoses; treatment should be supportive.
Pharmacology/Pharmacokinetics/Stability — Initial response to oral lisinopril occurs within one hour with peak blood pressure reduction at 6 hours corresponding with peak serum drug concentrations that appear from six to eight hours after ingestion. Effects of lisinopril on blood pressure last for 24 hours; the full 24-hour effect appears more consistent at daily doses of 20 milligrams and higher. The average half-life (time needed for half the active drug to be eliminated from the body) of lisinopril is 12 hours. The complete blood pressure lowering effects of lisinopril may take two to four weeks to appear. Feces excrete the largest amount of lisinopril as unchanged drug (69 percent); the remainder eliminated by the kidneys (up to 29 percent) and liver (7 percent). Use of ACEI during the second and third trimesters of pregnancy can cause injury and even death to the developing fetus. Lisinopril should be discontinued as soon as pregnancy is detected. Methyldopa, atenolol and pindolol are reasonable alternative agents for treatment of hypertension during pregnancy. Studies to determine whether or not lisinopril is excreted in human breast milk have not been conducted, but it is excreted in the breast milk of lactating rats. A decision should be made to either discontinue lisinopril use or stop breastfeeding depending on the importance of the drug to the mother.
Lisinopril oral tablets typically come in 2.5, 5, 10, 20, 30, and 40 milligram strengths, depending on manufacturer. Tablet appearance also varies by manufacturer. Like most medications, lisinopril tablets should be stored at controlled room temperature between 68-77 F with occasional variations to 59-86 F permitted. They should be protected from moisture, freezing, and excessive heat.
Cautions and Warnings — Lisinopril should not be used in patients with history of angioedema, especially ace inhibitor induced angioedema. Angioedema is swelling similar to hives, but beneath the skin surface. It can be life threatening when it involves the face or airway. Black patients experience disproportionately more ace inhibitor induced angioedema than other racial groups. All ace inhibitors have potential to produce anaphylactoid reactions (including angioedema); patients with insect venom allergies may have significantly greater allergic responses. Life threatening allergic reactions have been reported in ace inhibitor treated patients dialyzed with high-flux membranes. Lisinopril is also contraindicated in the second and third trimesters of pregnancy. Inadequate fluid volume status is likely to produce clinically significant hypotension and can lead to kidney damage. Careful attention to fluid volume status by prescribers is warranted and patients should be counseled that excessive sweating or dehydration might lead to excessive lowering of blood pressure without fluid replacement. Lisinopril should be used cautiously or not at all in patients with renal artery stenosis (narrowing). It has long been known that black patients do not respond as briskly to ace inhibitors as non-blacks; treatment may require higher doses to achieve desired effects in black patients.
Important Side Effects and Interactions — Adverse reactions are from studies of patients treated with lisinopril (and other ace inhibitors) for hypertension and heart failure. It should be noted that the higher rates of adverse reactions are often seen in heart failure patients. The most frequently reported adverse reaction from lisinopril is dizziness, occurring in 5 to 12 percent of patients, followed by headache in 4.4 to 5.7 percent of patients. Cough is the third most common adverse reaction and the most frequent reason for ace inhibitor discontinuation. A persistent, dry, nonproductive, tickling cough that worsens at night is estimated to occur in 0.7 to 48 percent of patients treated with ace inhibitors. The incidence of cough with lisinopril is 3.5 percent. Ace inhibitor cough tends to occur just after initiation of therapy, but can be delayed for up to six to 10 months. It is two to three times more common in women than men. Chinese, Japanese, Indian and black patients appear more susceptible. Dose reductions, cough medicines, and switching to a different ace inhibitor are ineffective for eliminating cough. Following discontinuation of the ace inhibitor, cough usually resolves within a few days to as long as four weeks. Hyperkalemia (elevated serum potassium levels) occurs in 2.2 to 4.8 percent of patients and is more common in patients with renal insufficiency or diabetes and in patients taking potassium sparing diuretics or using potassium containing salt substitutes. Hyperkalemia occurs nearly twice as often in patients on high dose (35 milligrams daily) lisinopril compared to patients on lower doses (2.5 milligrams daily). Gastrointestinal side effects are also reported with lisinopril including diarrhea (2.7 to 3.7 percent), nausea or abdominal pain (2 percent), and vomiting (1.1 percent). Rash is reported in 1.3 to 1.7 percent of lisinopril patients. Rarely, serious adverse reactions have been reported. These include renal failure, anaphylaxis, angioedema, MI, pancreatitis, Stevens-Johnson syndrome, vasculitis, systemic lupus erythematosus, and intestinal angioedema.
Considerable research investigating suspected linkages between ace inhibitors and beta blockers used to treat hypertension to development of diabetes has demonstrated that diabetes is 2.5 times more likely to develop in hypertensive patients compared to normotensive patients whether or not they are receiving antihypertensive treatment.
There are 101 drugs specifically reported to interact with lisinopril. Those significant to EMS providers include aspirin, which decreases the antihypertensive effect in up to 50 percent of patients taking lisinopril. Epidural bupivacaine has been associated with profound hypotension in ace inhibitor treated patients. Patients on ace inhibitors may require higher doses of erythropoietin to maintain target hematocrits. Plasma lithium levels may increase substantially when an ace inhibitor is introduced. Diuretics may result in hypotension when given to a patient on ace inhibitors with low fluid volume status. Nonsteroidal anti-inflammatory agents (NSAIDs) may decrease the antihypertensive effects of ace inhibitors.
In addition to the garlic oil capsules previously mentioned, two foods deserve some discussion as potential problems for ace inhibitor treated patients: licorice and potassium containing edibles. Licorice consumption increases blood pressure in healthy, normotensive adults and is believed to elevate blood pressure and reduce ace inhibitors effectiveness. As ace inhibitors increase serum potassium levels, caution should be exercised with potassium supplements and foods high in potassium such as bananas, potassium containing salt substitutes, etc.
Average Costs — U.S.
10 mg, 20 mg, 30 mg and 40 mg tablet (generic)
Patient cost: $0.41, $0.28, $0.35, and $0.40 each*
Large Hospital cost: $0.09, $0.15, $0.20, $0.19 each
*($4.00 at Wal Mart® and Target for 1 month supply)
References:
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed February, 2008).
2. Albany Medical Center Pharmacy, Albany, New York.
