TREXEVA PLUS 5/ 1,25

Indications

• Essential hypertension
• Management of fluid retention

Dosage

Adults: For adult patients, the usual dose is 2.5 mg once daily, which should be taken in the morning. In cases where a modified-release formulation is used, the dose may

Mechanism of action

Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter. This inhibition leads to reduced sodium reabsorption, causing sodium and water to remain in the nephron lumen for urinary excretion. Consequently, this results in decreased plasma volume, venous return, and cardiac output, ultimately lowering blood pressure. Additionally, indapamide may decrease responsiveness to pressor agents and reduce peripheral resistance, although these mechanisms require further investigation.

Pharmacodynamics

Indapamide is classified as a sulfonamide diuretic and is recognized for its efficacy in managing hypertension and preventing target organ damage. It induces water and electrolyte loss, with higher doses correlating with increased diuresis. Indapamide can cause significant electrolyte disturbances, such as hypokalemia, which may lead to QTc prolongation. It also influences plasma levels of renin and aldosterone while decreasing calcium excretion. Importantly, studies indicate that indapamide does not significantly alter glucose tolerance in hypertensive patients, although long-term metabolic effects remain to be fully elucidated.

Pharmacokinetics

Indapamide is absorbed orally and has a bioavailability that can be affected by food. It is extensively metabolized in the liver, with metabolites primarily excreted in urine. The drug has a half-life of approximately 14 to 18 hours, allowing for once-daily dosing. Renal function can influence the pharmacokinetics of indapamide, necessitating caution in patients with renal impairment due to the risk of hyperkalaemia.

Contra-indications

• Hypersensitivity to sulfonamides
• Severe renal impairment

Adverse effects

• Hypokalemia
• Dehydration
• Electrolyte disturbances
• Hypotension
• Dizziness
• Dry mouth
• Fatigue
• Restlessness
• Angina pectoris
• Arrhythmias
• Arthralgia
• Asthenia
• Chest pain
• Confusion
• Severe cutaneous adverse reactions
• Vision disorders
• Rhabdomyolysis
• QT interval prolongation

Interactions

• Potassium-sparing diuretics
• Thiazide diuretics
• Pressor agents
• Other antihypertensives

Precautions

• Caution in diabetes mellitus
• Caution in elderly patients
• Monitor electrolytes regularly
• Caution in patients with a history of acute porphyrias
• Caution in hepatic disorders

Pregnancy

No information available; use with caution and consult healthcare professional.

Breast-feeding

Avoid; no information regarding safety in breast milk.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• 2.5 mg immediate-release tablet
• 1.5 mg modified-release tablet

Indications

• Hypertension
• Heart failure
• Prevention of cardiovascular events in patients with coronary artery disease

Dosage

Adults: The usual

Mechanism of action

Perindoprilat, the active metabolite of perindopril, binds to and inhibits the activity of the somatic isoform of angiotensin-converting enzyme (ACE), particularly the C-domain, which plays a crucial role in blood pressure regulation. By inhibiting ACE, perindoprilat decreases the levels of angiotensin II (ATII), thereby reducing blood pressure and promoting vasodilation. Additionally, the inhibition of ATII leads to increased plasma renin activity due to the loss of feedback inhibition.

Pharmacodynamics

Perindopril is a nonsulfhydryl prodrug that undergoes first-pass metabolism and systemic hydrolysis to produce perindoprilat. This active form lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS), which is involved in regulating blood pressure and fluid balance. By inhibiting the actions of ATII, perindoprilat reduces aldosterone secretion, leading to decreased sodium and water reabsorption in the kidneys. This results in increased urine output and a decrease in blood volume, further contributing to its antihypertensive effects.

Pharmacokinetics

After oral administration, perindopril is rapidly absorbed, with a bioavailability of approximately 62%. It undergoes extensive first-pass metabolism in the liver to form its active metabolite, perindoprilat, which has a half-life of about 17 hours. Perindoprilat is primarily excreted by the kidneys, and its pharmacokinetics may be altered in patients with renal impairment. The peak plasma concentration of perindoprilat is reached within 3 to 4 hours after administration.

Contra-indications

• History of hypersensitivity to perindopril or any other ACE inhibitor
• History of angioedema associated with previous ACE inhibitor therapy
• Hereditary or idiopathic angioedema
• Severe renal impairment (creatinine clearance less than 30 mL/min)
• Pregnancy

Adverse effects

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

Interactions

• Potassium supplements or potassium-sparing diuretics may increase the risk of hyperkalemia
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect of perindopril
• Lithium levels may increase when used concurrently with perindopril
• Other antihypertensive agents may have additive effects leading to hypotension

Precautions

• Monitor renal function before and during treatment
• Use with caution in patients with aortic stenosis or hypertrophic cardiomyopathy
• Consider monitoring potassium levels in at-risk populations
• Caution in patients with a history of angioedema

Pregnancy

Perindopril is contraindicated during pregnancy due to potential harm to the fetus, particularly in the second and third trimesters.

Breast-feeding

Caution is advised as perindopril is excreted in breast milk; consult a healthcare professional before use.

Storage

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

Formulations

• Tablets: 2 mg, 4 mg, 8 mg

Indications

• Hypertension
• Heart failure
• Diabetic nephropathy

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations in paediatric patients.

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

Mechanism of action

Tosilate selectively inhibits the binding of angiotensin II to the AT1 receptor, which is found in various tissues including blood vessels and the adrenal gland. By blocking this receptor, tosilate prevents the vasoconstrictive and aldosterone-secreting effects of angiotensin II, leading to dilation of blood vessels and reduced blood volume, ultimately decreasing blood pressure.

Pharmacodynamics

Tosilate exhibits dose-dependent antihypertensive effects. The maximum effect is generally observed within 6 to 8 hours after administration, with a sustained reduction in blood pressure lasting up to 24 hours. The drug also improves endothelial function and has been shown to have protective effects on the heart and kidneys, particularly in patients with diabetes or heart failure.

Pharmacokinetics

Tosilate is well absorbed after oral administration, with peak plasma concentrations typically occurring within 1 to 3 hours. It has a bioavailability of approximately 60-70%. The drug is extensively metabolized in the liver, primarily via cytochrome P450 enzymes, and its metabolites are excreted primarily in the urine. The elimination half-life of tosilate ranges from 8 to 12 hours, allowing for once-daily dosing in most cases.

Pregnancy

The safety of tosilate during pregnancy has not been established. Use only if potential benefits justify the potential risks to the fetus.

Breast-feeding

Tosilate may pass into breast milk. Caution is advised when administering to breastfeeding women.

Storage

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

Mechanism of action

Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure. Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes. Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle.

Pharmacodynamics

Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients.

Mechanism of action

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

Pharmacodynamics

Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure.