ENRIL 20H

Indications

• Hypertension
• Heart failure
• Prophylaxis of symptomatic heart failure after renal impairment
• Myocardial infarction in clinically stable patients with left ventricular dysfunction
• Diabetic nephropathy in type 1 diabetes mellitus

Dosage

Adults: Initially 2.5 mg

Mechanism of action

Enalapril maleate functions as an ACE inhibitor, blocking the enzyme that converts angiotensin I to angiotensin II. This reduction in angiotensin II levels leads to decreased vasoconstriction, lower levels of aldosterone secretion, and ultimately results in reduced blood pressure and decreased workload on the heart. Additionally, it promotes diuresis by reducing fluid retention.

Pharmacodynamics

The pharmacodynamics of enalapril involve the reduction of peripheral vascular resistance, resulting in decreased blood pressure. It also reduces preload and afterload on the heart, making it beneficial for patients with heart failure. The onset of action typically occurs within one hour after oral administration, with peak effects seen at 4 to 6 hours. The duration of action can extend up to 24 hours, allowing for once-daily dosing in most cases.

Pharmacokinetics

Enalapril is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 hour. It undergoes hepatic conversion to enalaprilat, which is responsible for its pharmacological effects. The elimination half-life of enalaprilat ranges from 11 to 30 hours, allowing for effective blood pressure control with once-daily dosing. Renal impairment can significantly affect the clearance of enalaprilat; therefore, dose adjustments may be necessary based on the patient's renal function. Enalapril is primarily excreted by the kidneys, and care should be taken in patients with renal impairment.

Contra-indications

• History of hypersensitivity to enalapril or any ACE inhibitor
• Angioedema related to previous ACE inhibitor therapy
• Pregnancy
• Severe renal impairment (creatinine clearance less than 10 mL/min)
• Aortic stenosis
• Uncontrolled heart failure

Adverse effects

• Hypotension
• Hyperkalemia
• Cough
• Dizziness
• Fatigue
• Nausea
• Diarrhea
• Renal impairment
• Angioedema
• Rash
• Gynaecomastia
• Sleep disorders
• Aplastic anemia (rare)

Interactions

• Diuretics may enhance the hypotensive effect of enalapril
• Potassium-sparing diuretics may increase the risk of hyperkalemia
• NSAIDs may reduce the antihypertensive effect
• Lithium levels may increase when used concurrently
• Other antihypertensives may have additive effects

Precautions

• Monitor renal function and potassium levels during treatment
• Caution in patients with renal artery stenosis
• Caution in patients with a history of angioedema
• Gradual dose adjustments recommended in renal impairment
• Use with caution in patients with hepatic impairment

Pregnancy

Enalapril is contraindicated during pregnancy as it may cause fetal harm, including renal dysfunction and skull malformation.

Breast-feeding

Avoid in the first few weeks postpartum, particularly in preterm infants due to the risk of profound neonatal hypotension. Can be used in breastfeeding mothers if essential, but infant's blood pressure should be monitored.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Enalapril 2.5 mg tablets
• Enalapril 5 mg tablets
• Enalapril 10 mg tablets
• Enalapril 20 mg tablets
• Enalapril 25 mg tablets
• Enalapril oral solution

Indications

• Hypertension
• Heart failure
• Left ventricular dysfunction following myocardial infarction
• Diabetic nephropathy

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing guidelines.

Adults: For the treatment of hypertension, the initial dose is typically 5 mg daily, which can be adjusted based on blood pressure response. The maximum dose is usually 40 mg per day.

Mechanism of action

Enalapril works by inhibiting the angiotensin-converting enzyme (ACE), which prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This results in vasodilation, reduced peripheral vascular resistance, and decreased blood pressure. Additionally, it reduces the reuptake of norepinephrine and promotes sodium and water reabsorption, contributing to its antihypertensive effects.

Pharmacodynamics

Enalapril effectively lowers blood pressure in all grades of essential and renovascular hypertension and does so without increasing heart rate. Its antihypertensive effects last for at least 24 hours, and with continuous use, a steady-state response may develop over several weeks. In patients with congestive heart failure, enalapril improves cardiac output and reduces both preload and afterload, resulting in enhanced clinical outcomes.

Pharmacokinetics

Enalapril is administered orally and is rapidly converted to its active metabolite, enalaprilat, which is responsible for its pharmacological effects. It has a bioavailability of approximately 60%, with peak plasma concentrations occurring within 1 hour. The drug is primarily excreted by the kidneys, necessitating dose adjustments in patients with renal impairment. Its half-life is approximately 11 hours, allowing for once-daily dosing in most cases.

Adverse effects

• Cough
• Hyperkalemia
• Hypotension
• Dizziness
• Fatigue
• Angioedema
• Renal impairment

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia.
• NSAIDs may reduce the antihypertensive effect of enalapril.
• Other antihypertensive agents may have additive effects on blood pressure.
• Lithium levels may increase when used concurrently with enalapril.

Precautions

• Monitor renal function before and during treatment.
• Use with caution in patients with a history of angioedema.
• Discontinue if signs of angioedema occur.
• Consider risk of hyperkalemia in patients with renal impairment.

Pregnancy

Enalapril is contraindicated during pregnancy as it may cause injury or death to the developing fetus, particularly in the second and third trimesters.

Breast-feeding

Enalapril should be used with caution during breastfeeding as it is excreted in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg

Indications

• Hypertension
• Edema associated with heart failure
• Edema associated with liver cirrhosis
• Edema associated with renal disorders
• Nephrolithiasis due to idiopathic hypercalciuria

Dosage

Children: Refer to the BNF for Children for appropriate dosing information in pediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on individual patient needs and conditions.

Mechanism of action

Hydrochlorothiazide inhibits the sodium-chloride symporter in the distal convoluted tubule of the nephron, leading to increased excretion of sodium and chloride in the urine. This diuretic effect results in decreased reabsorption of water, leading to increased urine output and reduced blood pressure.

Pharmacodynamics

The pharmacodynamic effects of hydrochlorothiazide include a reduction in peripheral vascular resistance, primarily due to decreased blood volume and changes in vascular smooth muscle reactivity. The onset of diuretic effect typically occurs within 1 to 2 hours after oral administration, with peak effects seen at approximately 4 to 6 hours. The duration of action can last up to 12 hours.

Pharmacokinetics

Hydrochlorothiazide is well absorbed from the gastrointestinal tract, with an oral bioavailability of approximately 60-80%. It is primarily eliminated through the kidneys, with around 60-70% of an administered dose excreted unchanged in the urine. The half-life of hydrochlorothiazide ranges from 6 to 15 hours, depending on the dose and individual patient factors. It is minimally metabolized in the liver.

Contra-indications

• Anuria
• Hypersensitivity to hydrochlorothiazide or any component of the formulation
• Severe renal impairment
• Electrolyte imbalance, particularly hypokalemia

Adverse effects

• Hypokalemia
• Hyponatremia
• Hypercalcemia
• Hyperuricemia
• Dizziness
• Headache
• Gastrointestinal disturbances, such as nausea and vomiting
• Skin rash or other allergic reactions

Interactions

• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the diuretic effect
• Corticosteroids can exacerbate hypokalemia
• Lithium levels may increase, leading to toxicity
• Antidiabetic agents may require dosage adjustment due to changes in glucose tolerance
• Digoxin toxicity risk may increase with hypokalemia

Precautions

• Use with caution in patients with renal impairment
• Monitor electrolyte levels regularly, especially potassium
• Can cause dehydration, monitor fluid intake and output
• Consider potential for gout attacks due to increased uric acid levels

Pregnancy

Hydrochlorothiazide is not recommended during pregnancy, especially in the first trimester, due to potential risks to the fetus. Consult a healthcare provider for alternatives.

Breast-feeding

Hydrochlorothiazide is excreted in breast milk. Caution is advised when administering to breastfeeding mothers, as it may affect milk production.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Combination formulations with other antihypertensives or diuretics

Mechanism of action

The renin-angiotensin-aldosterone system (RAAS) is a signaling pathway that works in synergism with the sympathetic system to regulate blood pressure and fluid and electrolyte homeostasis. Activation of this system upon stimulation by different factors, such as low blood pressure and nerve impulses, leads to increased release of norepinephrine (NE) from sympathetic nerve terminals and effects on the vascular growth, vasoconstriction, and salt retention in the kidneys. Renin is released from Renin acts on the precursor prottein angiotensinogen, which is a plasma globulin synthesized from the liver, to produce cleaved peptide hormone angiotensin I. Angiotensin I then can be further cleaved by ACE to produce angiotensin II, a vasoconstrictive peptide hormone. Present in different isoforms, angiotensin converting enzyme (ACE) is peptidyl dipeptidase enzyme expressed in various tissues, including the vascular tissues, such as the heart, brain, and kidneys. ACE also plays a role in inactivation of bradykinin, a potent vasodepressor peptide. Angiotensin II mediates various actions on the body by working on its G-protein coupled receptors, AT1 and AT2. It causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of NE thereby increasing available levels, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium ions and water by promoting proximal tubular reabsorption, stimulates synthesis and release of aldosterone from the adrenal cortex, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes. Enalapril is a pharmacologically inactive prodrug that requires hepatic biotransformation to form [enalaprilat], its active metabolite that works on the RAAS to inhibit ACE. Biotransformation is critial for the therapeutic actions of the drug, as enalapril itself is only a weak inhibitor of ACE. ACE inhibition results in reduced production and plasma levels of angiotensin II, increased plasma renin activity due to the loss of feedback inhibition by angiotensin II, and decreased aldosterone secretion. However, plasma aldosterone levels usually return to normal during long-term administration of enalapril. Decreased levels of angiotensin II subsequently leads to the dilatation of peripheral vessles and reduced vascular resistance which in turn lower blood pressure. While inhibition of ACE leading to suppression of RAAS is thought to be the primary mechanism of action of enalapril, the drug was shown to still exert antihypertensive effects on individuals with low-renin hypertension. It is suggested that enalapril may mediate its pharmacological actions via other modes of action that are not fully understood. As ACE is structurally similar to kininase I, which is a carboxypeptidase that degrades bradykinin, whether increased levels of bradykinin play a role in the therapeutic effects of enalapril remains to be elucidated. Enalapril maleate is a prodrug of enalaprilat and has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. ... Enalapril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) through inhibition of angiotensin-converting enzyme (ACE). The drug competes with physiologic substrate (angiotensin I) for the active site of ACE; the affinity of enalaprilat for ACE is approximately 200,000 times greater than that of angiotensin I. In vitro on a molar basis, the affinity of enalaprilat for ACE is 300-1000 or 2-17 times that of enalapril or captopril, respectively. However, in vitro on a molar basis, the ACE-inhibitory effect of enalapril was shown to be similar to that of enalaprilat in rat plasma and kidneys, because these tissues extensively hydrolyze enalapril to form enalaprilat. The drug apparently does not inhibit brain ACE in animals.

Pharmacodynamics

Enalapril is an antihypertensive agent that exhibits natriuretic and uricosuric properties. Enalapril lowers blood pressure in all grades of essential and renovascular hypertension, and peripheral vascular resistance without causing an increase in heart rate. Individuals with low-renin hypertensive population were still responsive to enalapril. The duration of hypertensive effect in the systolic and diastolic blood pressure persists for at least 24 hours following initial administration of a single oral dose, and repeated daily administration of enalapril confers an additional reduction in blood pressure and a steady-state antihypertensive response may take several weeks. In patients with severe congestive heart failure and inadequate clinical response to conventional antihypertensive therapies, treatment with enalapril resulted in improvements in cardiac performance as observed by a reduction in both preload and afterload, and improved clinical status long-term. Furthermore, enalapril was shown to increase cardiac output and stroke volume while decreasing pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. In clinical studies, enalapril reduced left ventricular mass, and did not affect cardiac function or myocardial perfusion during exercise. Enalapril is not highly associated with the risk of bradycardia unlike most diuretics and beta-blockers and it does not produce rebound hypertension upon discontinuation of therapy. Enalapril is not reported to produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. In the kidneys, enalapril was shown to increase renal blood flow and decrease renal vascular resistance. It also augmented the glomerular filtration rate in patients with a glomerular filtration rate less than 80 mL/min. When used in combination, enalapril was shown to attenuate the extent of drug-induced hypokalemia caused by hydrochlorothiazide and the antihypertensive effects of both drugs were potentiated.