Enalapril + Hydrochlorothiazide

CrCl (mL/min)	Dosage
≤30	Not recommended.

Enalapril + Hydrochlorothiazide May be taken with or without food.

Hypersensitivity to sulfonamide-derived drugs. Anuria, hereditary or idiopathic angioedema, history of angioneurotic oedema associated with previous ACE inhibitor therapy. Pregnancy. Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²). Concomitant use with or within 36 hours of switching to or from a neprilysin inhibitor (e.g. sacubitril).

Patient with volume depletion, ischaemic heart disease, heart failure, hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, cerebrovascular disease, collagen vascular disease, diabetes mellitus, renal artery stenosis, history of angioedema unrelated to ACE inhibitor therapy. Patient undergoing major surgery. Avoid use during dialysis with high-flux membranes (e.g. polyacrylonitrile) and LDL apheresis with dextran sulfate or before desensitisation with hymenoptera venom; anaphylactoid reactions may occur. Black race. Renal and hepatic impairment. Elderly. Lactation.

Significant: Symptomatic hypotension with or without syncope; non-productive cough, renal dysfunction, renal failure, haematologic effects (e.g. neutropenia, agranulocytosis, thrombocytopenia, anaemia); hyperkalaemia, hypokalaemia, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia; hypersensitivity reactions; acute transient myopia, acute angle-closure glaucoma; photosensitivity, increased risk of squamous cell carcinoma and basal cell carcinoma (prolonged use); hyperglycaemia or impaired glucose tolerance; may precipitate gout (particularly in susceptible patients).
Cardiac disorders: Tachycardia, palpitations.
Ear and labyrinth disorders: Tinnitus.
Gastrointestinal disorders: Nausea, diarrhoea, abdominal pain, vomiting, dyspepsia, constipation, xerostomia, flatulence.
General disorders and administration site conditions: Asthenia, fatigue, chest pain.
Investigations: Increased cholesterol, triglycerides, and serum creatinine.
Musculoskeletal and connective tissue disorders: Muscle cramps, back pain, arthralgia.
Nervous system disorders: Headache, dizziness, drowsiness, paraesthesia.
Psychiatric disorders: Nervousness.
Renal and urinary disorders: UTI.
Reproductive system and breast disorders: Impotence, decreased libido.
Respiratory, thoracic and mediastinal disorders: Dyspnoea.
Skin and subcutaneous tissue disorders: Rash, pruritus, diaphoresis.
Potentially Fatal: Rarely, angioedema of the tongue, glottis or larynx; cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis.

PO: D

Avoid prolonged exposure to direct sunlight and UV light; apply sunscreen or wear protective clothing when going outdoors.

Monitor blood pressure, serum creatinine, BUN and electrolytes. For patients with collagen vascular disease and/or renal impairment: Monitor CBC with differential periodically.

Symptoms: Enalapril: Marked hypotension, stupor, cough, dizziness, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, and anxiety. Hydrochlorothiazide: Electrolyte depletion (e.g. hypokalaemia, hypochloraemia, hyponatraemia) and dehydration. Management: Symptomatic and supportive treatment. Treatment measures may include induction of emesis and/or gastric lavage, administration of activated charcoal and laxative, and correction of dehydration, electrolyte imbalance and hypotension using established procedures. Enalaprilat may be removed using haemodialysis. In case of therapy-resistant bradycardia, pacemaker therapy may be used. Monitor vital signs, serum electrolytes, and creatinine concentrations continuously.

May increase hypotensive effects with other antihypertensive agents. May increase the serum concentrations and toxicity of lithium. May reduce antihypertensive effects with NSAIDs (including COX-2 inhibitors). Increased risk of hypoglycaemia with insulin and oral antidiabetic drugs.
Enalapril: May increase the risk of angioedema with racecadotril, mTOR inhibitors (e.g. everolimus, sirolimus, temsirolimus). Concomitant use with NSAIDs (including COX-2 inhibitors) may result in deterioration of renal function. Increased risk of hyperkalaemia with K-sparing diuretics (e.g. spironolactone, triamterene, amiloride), K supplements, K-containing salt substitutes, and other drugs associated with increases in serum K (e.g. trimethoprim/sulfamethoxazole, heparin). May result in further blood pressure reduction with certain anaesthetic agents. Nitritoid reactions (e.g. facial flushing, nausea, vomiting, hypotension) may occur when used concurrently with injectable gold (Na aurothiomalate).
Hydrochlorothiazide: May enhance the effect of non-depolarising neuromuscular-blocking agents (e.g. tubocurarine chloride). May potentiate orthostatic hypotension with barbiturates or opioid analgesics. Reduced absorption with colestyramine and colestipol. May increase the response of the heart to toxic effects (e.g. increased ventricular irritability) of digitalis. Enhanced hypokalaemic effect with corticosteroids or ACTH. May reduce the effect of pressor amines (e.g. norepinephrine). May potentiate the myelosuppressive effects of cytotoxic drugs (e.g. cyclophosphamide, methotrexate). May increase the risk of torsades de pointes with drugs that prolong QT interval (e.g. quinidine, procainamide, amiodarone, sotalol).
Potentially Fatal: Enalapril: Increased risk of angioedema with neprilysin inhibitors (e.g. sacubitril). Concomitant use with aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure).

Hydrochlorothiazide: May enhance the hypotensive effect with alcohol.

Description:
Mechanism of Action: Enalapril acts as a prodrug of enalaprilat, which competitively inhibits angiotensin-converting enzyme (ACE) from converting angiotensin I to angiotensin II (a potent vasoconstrictor). This results in reduced levels of angiotensin II, leading to increased plasma renin activity, diminished vasopressor activity and decreased aldosterone secretion.
Hydrochlorothiazide, a thiazide diuretic, inhibits the Na reabsorption in the distal tubules, resulting in increased excretion of Na and water.
Onset: Enalapril: Approx 1 hour.
Hydrochlorothiazide: Diuresis: Approx 2 hours.
Duration: Enalapril: Approx 1 hour.
Hydrochlorothiazide: Diuresis: Approx 2 hours.
Pharmacokinetics:
Absorption: Enalapril: Rapidly absorbed. Time to peak plasma concentrations: 0.5-1.5 hours (enalapril); 3-4.5 hours (enalaprilat).
Hydrochlorothiazide: Rapidly and fairly well absorbed from the gastrointestinal tract. Bioavailability: 65-75%. Time to peak plasma concentration: Approx 1-5 hours.
Distribution: Crosses the placenta and enters breast milk.
Enalapril: Plasma protein binding: 50-60% (enalaprilat).
Hydrochlorothiazide: Plasma protein binding: Approx 40-80%.
Metabolism: Enalapril: Rapidly and extensively hydrolysed in the liver to enalaprilat (active form).
Excretion: Enalapril: Via urine (61%; 18% as unchanged drug, 43% as enalaprilat); faeces (33%; 6% as unchanged drug, 27% as enalaprilat). Elimination half-life: 2 hours (enalapril); approx 35 hours (enalaprilat).
Hydrochlorothiazide: Via urine (≥61% as unchanged drug). Elimination half-life: Approx 6-15 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5388962, Enalapril. https://pubchem.ncbi.nlm.nih.gov/compound/Enalapril. Accessed Oct. 28, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3639, Hydrochlorothiazide. https://pubchem.ncbi.nlm.nih.gov/compound/Hydrochlorothiazide. Accessed Oct. 24, 2023.

Store between 20-25°C. Protect from moisture.

ACE Inhibitors/Direct Renin Inhibitors / Diuretics

C09BA02 - enalapril and diuretics ; Belongs to the class of ACE inhibitors in combination with diuretics. Used in the treatment of cardiovascular disease.

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