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Pharmacological particulars
Pharmacological properties
Pharmacotherapeutic group: Agents acting on the renin-angiotension system, angiotensin II antagonists, plain.
ATC vet code: QC09CA07
Pharmacodynamics properties
Telmisartan is an orally active and specific angiotensin II receptor (subtype AT1) antagonist which causes a dose-dependent decrease in mean arterial blood pressure in mammalian species, including the cat. In a clinical trial in cats with chronic kidney disease, a reduction in proteinuria was seen within the first 7 days after the start of treatment with 1 mg/kg. In a further clinical trial in cats with hypertension a reduction in mean systolic blood pressure was achieved with a dose of 2 mg/kg. Due to the combination of these pharmacodynamic properties, telmisartan is an appropriate treatment for cats with concomitant hypertension and CKD.
Telmisartan displaces angiotensin II from its binding site at the AT1 receptor subtype. Telmisartan selectively binds to the AT1 receptor and does not show affinity for other receptors, including AT2 or other less characterised AT receptors. Stimulation of the AT1 receptor is responsible for pathologic effects of angiotensin II in the kidney and other organs associated with angiotensin II such as vasoconstriction, retention of sodium and water, increased aldosterone synthesis and organ remodelling. Effects associated with stimulation of the AT2 receptor such as vasodilatation, natriuresis and inhibition of inappropriate cell growth are not suppressed. The receptor binding is long lasting due to the slow dissociation of telmisartan from the AT1 receptor binding site. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor.
Hypokalaemia is associated with CKD, however telmisartan does not affect potassium excretion, as shown in the clinical field trial in cats.
Pharmacokinetic particulars
Following oral administration of telmisartan to cats, plasma-concentration-time curves of the parent compound are characterised by rapid absorption, with maximum plasma concentrations (Cmax) achieved after 0.5 hours (tmax). For both, Cmax-values, and AUC-values, a dose proportional increase over the dose range from 0.5 mg/kg to 3 mg/kg was observed. As determined by AUC, food consumption does not affect the overall extent of absorption of telmisartan.
Telmisartan is highly lipophilic and has rapid membrane permeability kinetics, which facilitates easy distribution into tissue. No significant gender effect was seen.
No clinically relevant accumulation was observed following multiple dose administration once daily for 21 days. The absolute bioavailability after oral administration was found to be 33%.
In vitro studies in human, dog, mouse and rat plasma showed a high plasma protein binding (>99.5%), mainly to albumin and α-1-acid glycoprotein.
Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate. From in vitro and ex vivo studies with feline liver microsomes it can be concluded that telmisartan is effectively glucuronidated in the cat. The glucuronidation resulted in the formation of the 1-O-acylglucuronide metabolite of telmisartan.
The terminal elimination half-life (t1/2) ranged from 7.3 hours to 8.6 hours, with mean value 7.7 hours. After oral administration, telmisartan is almost exclusively excreted in the faeces mainly as the unchanged active substance.