Mistel Mechanism of Action

Pharmacology: Mechanism of Action: 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 (>3,000 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.
Pharmacodynamics: In normal volunteers, a dose of Telmisartan 80 mg inhibited the pressor response to an intravenous infusion of angiotensin II by about 90% at peak plasma concentrations with approximately 40% inhibition persisting for 24 hours.
Plasma concentration of angiotensin II and plasma renin activity (PRA) increased in a dose-dependent manner after single administration of Telmisartan to healthy subjects and repeated administration to hypertensive patients. The once-daily administration of up to 80 mg Telmisartan to healthy subjects did not influence plasma aldosterone concentrations. In multiple dose studies with hypertensive patients, there were no clinically significant changes in electrolytes (serum potassium or sodium), or in metabolic function (including serum levels of cholesterol, triglycerides, HDL, LDL, glucose, or uric acid).
In 30 hypertensive patients with normal renal function treated for 8 weeks with Telmisartan 80 mg or Telmisartan 80 mg in combination with hydrochlorothiazide 12.5 mg, there were no clinically significant changes from baseline in renal blood flow, glomerular filtration rate, filtration fraction, renovascular resistance, or creatinine clearance.
Pharmacokinetics: Telmisartan is rapidly absorbed from the gastrointestinal tract; the absolute oral bioavailability is dose-dependent and is about 42% after a 40-mg dose and 58% after a 160-mg dose. Peak plasma concentrations of Telmisartan are reached about 0.5 to 1 hour after an oral dose. Telmisartan is over 99% bound to plasma proteins. It is excreted almost entirely in the faeces via bile, mainly as unchanged drug. The terminal elimination half-life of Telmisartan is about 24 hours.