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Micardis(R) - Micardis Plus(R) - Pharmakologie (14 Abbildungen)




Abbildung
 
FÜR ÖSTERREICH: Weitere Informationen: Merck Gesellschaft mbH, Zimbagasse 5, 1147 Wien, Tel.: 01/576 00-0
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Pharmakologie
Abbildung 1


Keywords: Pharmakologie
 
 
Angiotensin-II-Antagonisten
Abbildung 2: Telmisartan, a potent and highly selective AT1 receptor antagonist, displays a novel bis-benzimidazole structure. This unique feature of telmisartan accounts for both its high receptor affinity and its excellent pharmacokinetic properties.1 This slide shows the active metabolites of losartan, candesartan and olmesartan. The chemical structures of valsartan, irbesartan and eprosartan are also shown. 1. Ries UJ, et al. 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure–activity relationships. J Med Chem 1993; 36: 4040–4051.


Keywords: Chemische StrukturformelTelmisartan
 
 
Telmisartan - Röntgenstruktur
Abbildung 3: X-ray crystallography of telmisartan shows that it adopts a triangular configuration closely resembling the proposed conformations of ideal receptor-bound AT1 antagonists. The heteroaromatic substituent in the structural conformation of telmisartan may account for its high receptor affinity.


Keywords: RöntgenstrukturTelmisartan
 
 
Angiotensin-I-Rezeptor
Abbildung 4: In vivo studies show that telmisartan is a potent and long-acting antagonist of the hypertensive effects of exogenously administered angiotensin II. In the rabbit aorta, the maximal contractile response to angiotensin II was dose-dependently decreased by 40% to 50% across a dose range of 10 to 1000 nM. No agonist activity was detected at any concentration.1 Even high concentrations of angiotensin II were unable to overcome the receptor blockade, demonstrating that telmisartan manifests an insurmountable AT1 receptor antagonism. 1. Wienen W, et al. Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277. Br J Pharmacol 1993; 110: 245–252.


Keywords: Angiotensin-I-RezeptorTelmisartan
 
 
Plasma-Halbwertzeit
Abbildung 5: Telmisartan has a 24-h plasma half-life, which is the longest any ARB.1,2 The long plasma half-life ensures that the antihypertensive efficacy is maintained for the full 24-h dosing interval, including into the early morning hours. 1. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000; 355: 637–645. 2. Brunner HR. The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview. J Hum Hypertens 2002;16 (Suppl 2): S13–S16.


Keywords: Angiotensin-I-RezeptorHalbwertzeitplasma
 
 
Angiotensin-I-Rezeptorblocker - Verteilungsvolumina
Abbildung 6: Telmisartan also has the largest volume of distribution of any ARB.1 A large volume of distribution signifies that telmisartan penetrates the tissue compartment, ensuring that local as well as systemic RAAS is blocked. Because the AT1 receptor has pathological effects that include cell hypertrophy and fibrosis, blocking AT1 at the tissue level may help to reduce target-organ damage. 1. Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001; 36: 487–499.


Keywords: Angiotensin-I-RezeptorblockerDiagramm
 
 
Telmisartan - PPAR-Gamma
Abbildung 7: PPAR-g agonists can improve insulin sensitivity, reduce triglyceride levels and decrease the risk for atherosclerosis. This study examined the ability of different ARBs to activate PPAR-g in a cell-based transient transfection assay.1 This assay eliminates interference from endogenous nuclear receptors. In the results shown here, each ARB was applied at 10 mmol/L. Telmisartan was the only ARB to show strong (27-fold) activation, although irbesartan showed a slight activation (two- to three-fold). By comparison, full PPAR-g agonists show ~140-fold activation in this assay.1 Telmisartan was also the only ARB that activated PPAR-g when tested at lower concentrations that can be achieved physiologically (1–5 mmol/L).1 Telmisartan therefore acts as a partial agonist of PPAR-g. 1. Benson SC, Pershadsingh HA, Ho CI et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARg-modulating activity. Hypertension 2004; 43: 993–1002.


Keywords: DiagrammPPAR-gammaTelmisartan
 
 
SBD - DBD
Abbildung 8: The trough:peak ratio is a method for assessing the duration of effect of an antihypertensive.1 The mean 24-h ambulatory blood pressure is considered the gold standard for testing the duration of antihypertensive effect, although trough:peak ratios can still provide valuable guidance.2 Losartan provides a trough:peak ratio of 35% SBP and 51% DBP.3 Telmisartan once daily provides clinically significant reductions in trough (i.e., 24 h after last dose) SBP and DBP that are comparable to the peak reductions.4 The trough:peak ratio for the 40 mg dose is around 66% (SBP) and 100% (DBP), and around 92% (SBP) and 100% (DBP) for the 80-mg dose. 1. Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157: 2413–2446. 2. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Principles for clinical evaluation of new antihypertensive drugs. 2000. Available at: http://www.fda.gov/cder/guidance/3774dft.htm 3. Stergiou GS, et al. Comparison of the smoothness index, the trough : peak ratio and the morning : evening ratio in assessing the features of the antihypertensive drug effect. J Hypertens 2003; 21: 913–920 4. Neutel JM. Ambulatory blood pressure monitoring to assess the comparative efficacy and duration of action of a novel new angiotensin II receptor blocker—telmisartan. Blood Press 2001; 10 (Suppl 4): 27–32.


Keywords: BlutdruckDBDSBD
 
 
Normaldosierung
Abbildung 9: Telmisartan produces substantial antihypertensive efficacy with a dose of 40 mg, and so this is the recommended starting dose.1,2 Further blood pressure reductions can be achieved with the 80 mg dose.1,2 If additional blood-pressure lowering power is needed, telmisartan can be given in fixed-dose combination with the diuretic HCTZ. Blood pressure reductions are achieved smoothly but quickly, with most of the response apparent within 2 weeks.1,2 1. Micardis Prescribing Information. Available at http://www.bidocs.com/renetnt:/Prescribing+Information/PIs/Micardis+Tabs/MICARDIS20-40-80 mg.PDF 2. Micardis Summary of Product Characteristics. Available at http://www.emea.eu.int/humandocs/Humans/EPAR/Micardis/Micardis.htm


Keywords: DosierungTelmisartan
 
 
Dosierung - Alter - Geschlecht
Abbildung 10: The pharmacokinetics of telmisartan in the elderly (≥65 years) is similar to that in younger patients, with no accumulation.1 This indicates that changes in hepatic function with increasing age do not affect the clearance of telmisartan. Although plasma concentrations of telmisartan are higher in women, this does not affect the antihypertensive effect nor does it increase the risk for adverse events.1,2 1. Stangier J, et al. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 2000; 28: 149–167. 2. Smith DHG, et al. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol 2000; 40: 1380–1390.


Keywords: AlterDosierungGeschlechtTelmisartan
 
 
Telmisartan - Harnausscheidung
Abbildung 11: Unlike other ARBs, only 1% of a telmisartan dose in excreted by the kidney.1 Up to 50% of the dose of other ARBs is excreted by the kidney.1 Renal impairment is unlikely to affect the pharmacokinetics of telmisartan. 1. Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001; 36: 487–499.


Keywords: Angiotensin-I-RezeptorblockerDiagrammHarnausscheidung
 
 
Dosierung - Nephropathien
Abbildung 12: Because telmisartan is 99.5% bound to serum protein, it is not dialysable, and as a result there is no requirement for post-dialysis supplementation.1 Valsartan and eprosartan show notably lower binding (95 % and 90 %, respectively).1 Telmisartan has been shown to reduce blood pressure in patients with renal disease in the Efficacy and Safety in Patients with Renal Impairment treated with Telmisartan (ESPRIT) study.2 ESPRIT was a 12-week, open-label study of telmisartan 40–80 mg in 82 patients with hypertension (DBP 90–109 mmHg) and chronic mild/moderate (GFR 30–74 ml/min/1.73 m2) or severe renal impairment (GFR <30 ml/min/1.73 m2), or requiring maintenance haemodialysis. There was greater effect in patients with greater renal impairment (a common finding in this patient population). 1. Song JC, White CM. Olmesartan medoxomil (CS-866). An angiotensin II receptor blocker for treatment of hypertension. Formulary 2001; 36: 487-499. 2. Sharma AM, et al. Telmisartan in patients with mild/moderate hypertension and chronic kidney disease. Clin Nephrol 2005; 63: 250–257.


Keywords: DosierungNephropathieTelmisartan
 
 
Telmisartan - Wechselwirkung
Abbildung 13: Telmisartan is not metabolized by cytochrome P450, an enzyme that is important for the oxidative metabolism of a number of other drugs. Therefore, the potential for interaction with drugs metabolized by this pathway is low.1 Telmisartan is primarily metabolized by glucuronidation.2 Other drugs metabolized by glucuronidation include paracetamol (acetaminophen) and ibuprofen. There is no effect of telmisartan on the pharmacokinetics of these drugs.3 Telmisartan has been assessed for interaction with a number of other drugs that are likely to be used concomitantly, with no evidence of a significant effect.4–7 Telmisartan can result in elevated serum digoxin in some patients. However, clinical trials and post-marketing surveillance has revealed no evidence of a clinically significant interaction.8 1. Wienen W, et al. A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardiovasc Drug Rev 2000; 18: 127–156. 2. Stangier J, et al. Absorption, metabolism and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers. J Clin Pharmacol 2000; 40: 1312–1322. 3. Stangier J, et al. Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers. J Clin Pharmacol 2000; 40: 1338–1346. 4. Stangier J, Su CAPF. Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers. J Clin Pharmacol 2000; 40: 1338–1346. 5. Heuer HJ, et al. Influence of repeated oral doses of telmisartan on the clinical pharmacology of glibenclamide in healthy volunteers. Eur J Clin Pharmacol 1998; 54: A12 (abstract 38). 6. Stangier J, et al. Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy volunteers. J Clin Pharmacol 2000; 40: 1331–1337. 7. Dunselman PHJM, and the replacement of angiotensin converting enzyme inhibition (REPLACE) investigators. Effects of the replacement of the angiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patients with congestive heart failure. Int J Cardiol 2001; 77: 131–138. 8. Unger T, Kaschina E. Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives. Drug Safety 2003; 26: 707–720.


Keywords: medikamentöse Wechselwirkung
 
 
Pharmakologie: Zusammenfassung
Abbildung 14


Keywords: Pharmakologie
 
 
 
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