MAVIK

Indications

• Hypertension
• Heart failure
• Prophylaxis after myocardial infarction
• Left ventricular dysfunction

Dosage

Children: For paediatric patients, dosing should be based on

Adults: The usual starting dose for adults is 0.5 mg to 1 mg once daily, which may be adjusted based on response. The maximum recommended dose is 4 mg once daily.

Mechanism of action

Trandolaprilat, the active metabolite of trandolapril, inhibits the activity of angiotensin-converting enzyme (ACE), which is responsible for converting angiotensin I (ATI) to angiotensin II (ATII). By reducing ATII levels, trandolaprilat decreases vasoconstriction and aldosterone secretion, leading to lower blood pressure and decreased fluid retention. Additionally, the inhibition of ACE increases plasma renin activity due to the loss of ATII's feedback inhibition on renin release.

Pharmacodynamics

As a prodrug, trandolapril is metabolized to trandolaprilat, which is approximately eight times more potent as an ACE inhibitor. The drug's primary action is through the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure, fluid balance, and electrolyte homeostasis. By interfering with this system, trandolapril effectively lowers systemic vascular resistance and facilitates better cardiac output.

Pharmacokinetics

Trandolapril is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after oral administration. The bioavailability of the active form, trandolaprilat, is significantly affected by liver metabolism, leading to variable plasma levels based on hepatic function. The elimination half-life of trandolaprilat is approximately 6 to 12 hours, and it is excreted primarily via the kidneys. Dose adjustments may be necessary in patients with renal impairment.

Contra-indications

• Hypersensitivity to trandolapril or any component of the formulation
• History of angioedema associated with previous ACE inhibitor therapy
• Hereditary or idiopathic angioedema
• Severe renal impairment (creatinine clearance less than 10 mL/min)
• Pregnancy

Adverse effects

• Hypotension
• Dizziness
• Cough
• Hyperkalemia
• Angioedema
• Rash
• Fatigue
• Gastrointestinal disorders

Interactions

• Potassium-sparing diuretics and potassium supplements may lead to hyperkalemia
• Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Lithium levels may increase when used in conjunction with ACE inhibitors
• Diuretics may enhance the hypotensive effect of trandolapril

Precautions

• Monitor renal function, especially in patients with renal impairment
• Use with caution in patients with a history of heart failure or severe aortic stenosis
• Pregnancy should be avoided due to potential fetal harm
• Caution is advised in patients undergoing surgery or anesthesia

Pregnancy

Trandolapril is contraindicated during pregnancy due to the risk of fetal harm, particularly in the second and third trimesters.

Breast-feeding

Not recommended; alternative treatments with better established safety during breastfeeding should be considered.

Storage

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

Formulations

• Trandolapril 500 microgram capsules
• Trandolapril 1 mg capsules
• Trandolapril 2 mg capsules
• Trandolapril 4 mg capsules
• Trandolapril oral suspension

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. Trandolaprilat, the active metabolite of trandolapril, 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. Trandolaprilat 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

Trandolapril is the ethyl ester prodrug of a nonsulfhydryl ACE inhibitor, trandolaprilat. Trandolapril is deesterified in the liver to the diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE than its parent compound. ACE is a peptidyl dipeptidase that is part 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 via 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 further sustain the effects of trandolaprilat by causing increased vasodilation and decreased blood pressure. The blood pressure lowering effect of trandolaprilat is due to a decrease in peripheral vascular resistance, which is not accompanied by significant changes in urinary excretion of chloride or potassium or water or sodium retention.