Telmisartan Mechanism of Action

Review the mechanism of action of telmisartan—a component of TWYNSTA, a fixed-dose ARB/CCB combining telmisartan and amlodipine for the treatment of hypertension

Review the mechanism of action of telmisartan—a component of TWYNSTA, the only ARB/CCB combining telmisartan and amlodipine for the treatment of hypertension
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3000-fold) for the AT1 receptor than for the AT2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.

References
1. Twynsta PI. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2009.
2. Data on file. Study 1235.1. Boehringer Ingelheim Pharmaceuticals, Inc.

Reductions that help patients reach their blood pressure target.1, 2

Review study results

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INDICATION

Twynsta® (telmisartan/amlodipine) tablets is an angiotensin II receptor blocker (ARB) and a dihydropyridine calcium channel blocker (DHP-CCB) combination product indicated for the treatment of hypertension, alone or with other antihypertensive agents. It may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals.

Base the choice of TWYNSTA tablets as initial therapy for hypertension on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of TWYNSTA tablets. Consider the patient's baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared with monotherapy when deciding whether to use TWYNSTA tablets as initial therapy.

IMPORTANT SAFETY INFORMATION

WARNING: AVOID USE IN PREGNANCY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue TWYNSTA as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

TWYNSTA is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis or angioedema) to telmisartan or amlodipine or any other components of this product.

Symptomatic hypotension may occur in patients with an activated renin-angiotensin system. Correct volume and/or salt depletion in patients before initiating TWYNSTA or start treatment under close supervision with a reduced dose.

Patients taking TWYNSTA should be told not to use potassium supplements or salt substitutes that contain potassium without consulting their physician. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances.

Titrate slowly in patients with hepatic or severe renal impairment and closely monitor. Initial therapy with TWYNSTA is not recommended in hepatically impaired patients.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system such as patients with severe congestive heart failure or renal dysfunction, treatment with ACE inhibitors and an ARB such as TWYNSTA has been associated with oliguria and/or progressive azotemia and, rarely, with acute renal failure and/or death. In patients with renal artery stenosis, increases in serum creatinine or blood urea nitrogen may occur. When adding an ACE inhibitor to an ARB, monitor renal function closely. Use of TWYNSTA with ramipril is not recommended.

Uncommonly, patients starting or increasing their dose of a CCB have developed increased frequency, duration, or severity of angina or acute myocardial infarction.

Monitor patients with heart failure for worsening of their condition.

In clinical trials, the most common reasons for discontinuation of therapy with TWYNSTA were peripheral edema, dizziness, and hypotension. Adverse events that occurred at a ≥2% higher incidence with TWYNSTA than with placebo were peripheral edema, dizziness, and back pain.

Please see full Prescribing Information, including boxed WARNING, for TWYNSTA.



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