Zestril

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Zestril on Prescriptsy

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Zestril is a brand of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor manufactured by AstraZeneca.

It is prescribed for the treatment of hypertension (high blood pressure), symptomatic heart failure, short-term treatment following acute myocardial infarction (heart attack) in haemodynamically stable patients, and renal complications of type 1 diabetes mellitus (diabetic nephropathy).

Lisinopril is a long-acting ACE inhibitor with a duration of action of 24 hours, taken once daily, and is one of the most widely prescribed antihypertensive medications in the UK.

Zestril is a prescription-only medicine (POM) in the United Kingdom.

Hypertension affects approximately 1 in 3 adults in England, with over 6 million adults receiving antihypertensive treatment through the NHS.

It is the single largest modifiable risk factor for cardiovascular disease (including ischaemic heart disease, stroke, heart failure, and chronic kidney disease), responsible for more disability-adjusted life years lost globally than any other risk factor.

Heart failure affects approximately 900,000 people in the UK and carries a significant morbidity and mortality burden.

ACE inhibitors are a cornerstone of treatment for both conditions, recommended as first-line therapy by NICE for specific patient populations.

This page provides a comprehensive clinical guide to Zestril, covering its mechanism of action, indications, dosage, side effects, safety warnings, and how to obtain it in the United Kingdom.

Important safety information about Zestril

Before reading further, note these essential safety points about Zestril.

• Zestril is absolutely contraindicated in the second and third trimesters of pregnancy. If you become pregnant, stop Zestril immediately and contact your GP.
• Angioedema (sudden swelling of the face, lips, tongue, or throat) is a rare but potentially life-threatening side effect. Call 999 immediately if this occurs.
• Blood tests (kidney function and potassium) must be monitored before starting, after dose changes, and periodically during treatment.
• A persistent dry cough affects 5 to 15% of patients and resolves on stopping the medication.
• Do not take Zestril with potassium supplements or potassium-sparing diuretics without medical supervision.

Understanding the renin-angiotensin-aldosterone system

The renin-angiotensin-aldosterone system (RAAS) is a critical hormonal cascade that regulates blood pressure, fluid balance, and electrolyte homeostasis.

Renin is released from the juxtaglomerular cells of the kidney in response to reduced renal perfusion pressure, reduced sodium delivery to the distal tubule (detected by the macula densa), and sympathetic nervous system activation.

Renin cleaves the liver-derived substrate angiotensinogen to produce angiotensin I, an inactive decapeptide.

Angiotensin-converting enzyme (ACE), a zinc metallopeptidase located predominantly on the surface of pulmonary vascular endothelial cells (but also present in other vascular beds, the kidney, and the heart), converts angiotensin I to angiotensin II, the primary effector peptide of the RAAS.

Angiotensin II has multiple cardiovascular effects: direct arterial vasoconstriction (increasing systemic vascular resistance and blood pressure), stimulation of aldosterone secretion from the adrenal cortex (increasing sodium and water reabsorption in the distal nephron, expanding plasma volume), stimulation of antidiuretic hormone (ADH) release, stimulation of the sympathetic nervous system, and direct effects on cardiac and vascular remodelling (promoting myocardial hypertrophy, fibrosis, and vascular smooth muscle proliferation).

In heart failure, chronic RAAS activation is maladaptive, contributing to progressive ventricular dysfunction, sodium retention, and neurohormonal activation.

ACE also degrades bradykinin, a vasodilatory and natriuretic peptide, so ACE inhibition increases bradykinin levels, contributing to the therapeutic effect (and the cough side effect).

How Zestril works

Lisinopril is a lysine analogue of enalaprilat (the active form of enalapril) that directly inhibits ACE without requiring hepatic activation.

It binds to the zinc ion at the active site of ACE, preventing the conversion of angiotensin I to angiotensin II.

This produces several beneficial effects: reduced angiotensin II levels cause arterial vasodilation (decreasing peripheral resistance and blood pressure), reduced aldosterone secretion (decreasing sodium and water retention), reduced cardiac preload and afterload (beneficial in heart failure), and inhibition of maladaptive cardiac and vascular remodelling.

The increase in bradykinin levels contributes to vasodilation, natriuresis, and cardioprotective effects, although it also causes the dry cough characteristic of the ACE inhibitor class.

Lisinopril is unique among commonly used ACE inhibitors in that it is hydrophilic, not protein-bound, and not hepatically metabolised.

It is absorbed from the gastrointestinal tract with approximately 25% bioavailability (not affected by food), reaches peak plasma concentration in 6 to 8 hours, and has a duration of action of 24 hours, allowing once-daily dosing.

It is excreted entirely unchanged by the kidneys, which means dose adjustment is required in renal impairment and accumulation occurs with declining renal function.

Clinical evidence for Zestril

Hypertension

NICE guideline NG136 on hypertension recommends ACE inhibitors as first-line antihypertensive therapy for patients under 55 years of age and for patients of any age with type 2 diabetes (unless of African or Caribbean family origin, in whom a calcium channel blocker or ARB is preferred).

Lisinopril effectively reduces both systolic and diastolic blood pressure, with typical reductions of 10 to 15 mmHg systolic and 6 to 10 mmHg diastolic at standard doses.

The ALLHAT trial (the largest antihypertensive outcomes trial, with over 33,000 participants) compared lisinopril with amlodipine and chlorthalidone and demonstrated equivalent long-term cardiovascular outcomes for all three agents, confirming the efficacy of lisinopril for preventing heart attack, stroke, and cardiovascular death.

Heart failure

The ATLAS (Assessment of Treatment with Lisinopril And Survival) trial demonstrated that high-dose lisinopril (32.5 to 35 mg daily) was associated with a 12% lower risk of death or hospitalisation for heart failure compared with low-dose lisinopril (2.5 to 5 mg daily), supporting the practice of titrating ACE inhibitors to the maximum tolerated dose in heart failure.

NICE guideline NG106 on chronic heart failure recommends ACE inhibitors as first-line neurohormonal therapy for all patients with heart failure with reduced ejection fraction (HFrEF).

Acute myocardial infarction

The GISSI-3 trial (over 19,000 patients) demonstrated that early initiation of lisinopril after acute myocardial infarction reduced 6-week mortality by 11% compared with control.

The benefit was particularly pronounced in patients with anterior myocardial infarction, diabetes, and left ventricular dysfunction.

Current guidelines recommend starting an ACE inhibitor within 24 hours of acute MI in haemodynamically stable patients.

Diabetic nephropathy

The EUCLID study demonstrated that lisinopril reduced urinary albumin excretion and the progression of retinopathy in normotensive patients with type 1 diabetes, supporting its use for renal protection in diabetic nephropathy independent of its blood pressure-lowering effect.

Dosage and administration

Take Zestril once daily at the same time each day, with or without food. Dosage varies by indication.

For hypertension: start at 10 mg daily (2.5 to 5 mg in renal impairment, diuretic use, or volume depletion), titrate to 20 to 40 mg daily based on response.

For heart failure: start at 2.5 mg daily, titrate to target of 20 to 35 mg daily at minimum 2-week intervals.

For post-MI: 5 mg within 24 hours, then 5 mg at 24 hours, 10 mg at 48 hours, then 10 mg daily for 6 weeks.

For diabetic nephropathy: 10 to 20 mg daily.

Side effects of Zestril

Common side effects

Dry cough (5 to 15%), dizziness (5 to 6%), headache (3 to 6%), fatigue, and diarrhoea. First-dose hypotension is more likely in patients who are volume-depleted, on diuretics, or have heart failure.

Uncommon side effects

Skin rash, altered taste (dysgeusia), hyperkalaemia, raised serum creatinine, and muscle cramps. Hypotension and renal impairment are more common in patients with heart failure, bilateral renal artery stenosis, or concurrent diuretic use.

Rare but serious side effects

Angioedema (0.1 to 0.5%, more common in people of African or Caribbean descent) is potentially life-threatening if it involves the larynx or tongue.

Agranulocytosis and neutropenia are very rare, primarily in patients with collagen vascular disease or concurrent immunosuppressant therapy. Hepatotoxicity (cholestatic jaundice, hepatitis) is very rare.

Pancreatitis has been reported rarely. Report suspected adverse reactions to the MHRA at yellowcard.mhra.gov.uk .

Warnings and precautions

Pregnancy and breastfeeding

ACE inhibitors are contraindicated from the second trimester of pregnancy.

Exposure during the second and third trimesters causes renal tubular dysgenesis, oligohydramnios (from fetal oliguria), limb contractures, pulmonary hypoplasia, skull ossification defects, and neonatal renal failure.

First-trimester use is associated with a possible small increase in the risk of congenital cardiovascular and central nervous system malformations.

Women of childbearing potential should be on effective contraception.

If pregnancy is confirmed, stop Zestril immediately and switch to a safe alternative (labetalol or nifedipine for hypertension in pregnancy).

Lisinopril is excreted in breast milk; breastfeeding is not recommended.

Renal impairment and monitoring

Lisinopril is eliminated entirely by the kidneys.

Dose reduction is required in renal impairment: creatinine clearance 31 to 80 mL/min, start at 5 to 10 mg; creatinine clearance 10 to 30 mL/min, start at 2.5 to 5 mg; creatinine clearance below 10 mL/min (or on haemodialysis), start at 2.5 mg.

Monitor renal function and potassium closely.

Bilateral renal artery stenosis is a contraindication because ACE inhibition in this setting removes the angiotensin II-mediated efferent arteriolar tone that maintains glomerular filtration, potentially causing acute renal failure.

Drug interactions

NSAIDs (including over-the-counter ibuprofen and naproxen) reduce the blood pressure-lowering effect of ACE inhibitors and increase the risk of renal impairment and hyperkalaemia.

Potassium-sparing diuretics (spironolactone, eplerenone, amiloride), potassium supplements, and trimethoprim increase the risk of hyperkalaemia. Lithium levels are increased by ACE inhibitors; monitor lithium levels closely.

Aliskiren is contraindicated with ACE inhibitors in patients with diabetes or eGFR below 60.

How to get Zestril in the UK

Zestril is available on NHS prescription from your GP or an authorised online prescriber registered with the General Pharmaceutical Council (GPhC).

In practice, most NHS prescriptions are dispensed as generic lisinopril, which is bioequivalent and significantly less expensive.

The standard NHS prescription charge in England is 9.90 pounds per item; prescriptions are free in Scotland, Wales, and Northern Ireland.

Sources

• Zestril 20 mg, Summary of Product Characteristics (EMC)
• Lisinopril, British National Formulary (BNF)
• NICE NG136: Hypertension in adults
• NICE NG106: Chronic heart failure in adults
• Hypertension, NICE CKS
• Lisinopril, NHS
• MHRA Yellow Card Scheme