Telmisartan

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Telmisartan
Telmisartan.svg
Systematic (IUPAC) name
2-(4-{[4-Methyl-6-(1-methyl-1H-1,3-benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]methyl}phenyl)benzoic acid
Clinical data
Trade names Micardis
AHFS/Drugs.com Monograph
MedlinePlus a601249
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
Oral
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability 42–100%
Protein binding >99.5%
Metabolism Minimal hepatic (glucuronidation)
Biological half-life 24 hours
Excretion Faecal 97%
Identifiers
CAS Number 144701-48-4 YesY
ATC code C09CA07 (WHO)
PubChem CID 65999
IUPHAR/BPS 592
DrugBank DB00966 YesY
ChemSpider 59391 YesY
UNII U5SYW473RQ YesY
KEGG D00627 YesY
ChEBI CHEBI:9434 YesY
ChEMBL CHEMBL1017 YesY
Chemical data
Formula C33H30N4O2
Molar mass 514.617 g/mol
  (verify)

Telmisartan (INN) /tɛlmɪˈsɑːrtən/ is an angiotensin II receptor antagonist (angiotensin receptor blocker, ARB) used in the management of hypertension. It was discovered by Boehringer Ingelheim and launched in 1999 as Micardis.[1][dead link]

In January 2014, Actavis as generic version of Micardis got appoval from FDA.[2]

Medical uses[edit]

Telmisartan is indicated in the treatment of essential hypertension.[3][4]

Contraindications[edit]

Telmisartan is contraindicated during pregnancy. Like other drugs affecting the renin-angiotensin system (RAS), telmisartan can cause birth defects, stillbirths, and neonatal deaths. It is not known whether the drug passes into the breast milk.[5] Also it is contraindicated in bilateral renal artery stenosis in which it can cause renal failure.

Side effects[edit]

Side effects are similar to other angiotensin II receptor antagonists and include tachycardia and bradycardia (fast or slow heartbeat), hypotension (low blood pressure), edema (swelling of arms, legs, lips, tongue, or throat, the latter leading to breathing problems), and allergic reactions.[5]

Interactions[edit]

Due to its mechanism of action, telmisartan increases blood potassium levels. Combination with potassium preparations or potassium-sparing diuretics could cause hyperkalaemia (excessive potassium levels). Combination with NSAIDs, especially in patients with impaired kidney function, has a risk of causing (usually reversible) kidney failure.[6]

Pharmacology[edit]

Mechanism of action[edit]

Telmisartan is an angiotensin II receptor blocker that shows high affinity for the angiotensin II receptor type 1 (AT1), with a binding affinity 3000 times greater for AT1 than AT2.

In addition to blocking the RAS, telmisartan acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPAR-γ), a central regulator of insulin and glucose metabolism. It is believed that telmisartan’s dual mode of action may provide protective benefits against the vascular and renal damage caused by diabetes and cardiovascular disease (CVD).[7]

Telmisartan's activity at the peroxisome proliferator-activated receptor delta (PPAR-δ) receptor has prompted speculation around its potential as a sport doping agent as an alternative to GW 501516.[8] Telmisartan activates PPAR-δ receptors in several tissues.[9][10][11][12]

Pharmacokinetics[edit]

The substance is quickly but to varying degrees absorbed from the gut. The average bioavailability is about 50% (42–100%). Food intake has no clinically relevant influence on the kinetics of telmisartan. Plasma protein binding is over 99.5%, mainly to albumin and alpha-1-acid glycoprotein.[6] It has the longest half-life of any ARB (24 hours)[3][7] and the largest volume of distribution among ARBs (500 liters).[13][14] Less than 3% of telmisatran is inactivated by glucuronidation in the liver, and over 97% are eliminated in unchanged form via bile and faeces.[4][6]

Clinical trials[edit]

ONTARGET[edit]

The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was one of the largest ARB clinical studies ever undertaken;[15] 25,620 patients from 733 centres in 41 countries were randomised for 5.5 years of treatment of either telmisartan, the ACE inhibitor ramipril or a combination of the two. The study aimed to investigate the role of telmisartan in cardiovascular (CV) protection through the primary composite outcome of death from CV causes, myocardial infarction, stroke or hospilization for heart failure, in high CV risk patients.

The study showed telmisartan was as effective as ramipril but with lower rates of cough and angioedema, which led to fewer discontinuations. The combination group experienced similar efficacy, but with increased risk of hypotensive symptoms. Moreover, in a patient population selected to tolerate ACE inhibitors, telmisartan was shown to be better tolerated and associated with higher treatment compliance than ramipril.[16]

TRANSCEND[edit]

As part of the ONTARGET study, patients who could not tolerate ACE inhibitors were randomly assigned to receive either telmisartan or placebo as part of the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) study. An accompanying editorial comments: "Overall, data supporting use of angiotensin-receptor blockers to prevent vascular events in various cardiovascular groups, other than heart failure, are incomplete. TRANSCEND's results challenge the non-inferiority shown in ONTARGET and suggest no more than a modest effect, if any at all."[17]

PRoFESS[edit]

The Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) study investigated therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years. This treatment did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes.[18]

Research[edit]

Cancer[edit]

Telmisartan has been found to have activity against a variety of cancers in vitro, including prostate,[19] renal,[20] colon,[21] leukemia,[22] and ovarian cancer.[23] The mechanisms of telmisartan's anti-cancer activity have been found to include up-regulation of proliferator-activated-receptor (PPAR) pathway, Bcl-2, and caspase activation.

Diabetes type II[edit]

According to a study with 18 patients, telmisartan can replace valsartan and candesartan for hypertensive patients with have also diabetes type II because telmisartan has additional advantages of insulin sensitivity and antiatherosclerosis through probably its effects on PPAR-y.[24]

See also[edit]

References[edit]

  1. ^ History of Boehringer Ingelheim
  2. ^ "TELMISARTAN ..Actavis' Generic Version of Micardis Receives FDA Approval". Retrieved September 28, 2016. 
  3. ^ a b Pritor prescribing information
  4. ^ a b Drugs.com: Telmisartan
  5. ^ a b Drugs.com: Micardis
  6. ^ a b c Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. 
  7. ^ a b Benson, S. C.; Pershadsingh, H.; Ho, C.; Chittiboyina, A.; Desai, P.; Pravenec, M.; Qi, N.; Wang, J.; Avery, M.; Kurtz, T. W. (2004). "Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist with Selective PPAR -Modulating Activity". Hypertension. 43 (5): 993–1002. doi:10.1161/01.HYP.0000123072.34629.57. PMID 15007034. 
  8. ^ Sanchis-Gomar, F.; Lippi, G. (2011). "Telmisartan as metabolic modulator: A new perspective in sports doping?". Journal of Strength and Conditioning Research. 26 (3): 1. doi:10.1519/JSC.0b013e31824301b6. PMID 22130396. 
  9. ^ Cytoplasmic and Nuclear Receptors: Advances in Research and Application: 2011 Edition. ScholarlyEditions. 2012. pp. 21–. ISBN 978-1-464-93110-9. Retrieved 2 April 2013. 
  10. ^ Feng, X.; Luo, Z.; Ma, L.; Ma, S.; Yang, D.; Zhao, Z.; Yan, Z.; He, H.; Cao, T.; Liu, D.; Zhu, Z. (2011). "Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway". Journal of Cellular and Molecular Medicine. 15 (7): 1572–1581. doi:10.1111/j.1582-4934.2010.01085.x. PMID 20477906. 
  11. ^ He, H.; Yang, D.; Ma, L.; Luo, Z.; Ma, S.; Feng, X.; Cao, T.; Yan, Z.; Liu, D.; Tepel, M.; Zhu, Z. (2010). "Telmisartan Prevents Weight Gain and Obesity Through Activation of Peroxisome Proliferator-Activated Receptor- -Dependent Pathways". Hypertension. 55 (4): 869–879. doi:10.1161/HYPERTENSIONAHA.109.143958. PMID 20176998. 
  12. ^ Li, L.; Luo, Z.; Yu, H.; Feng, X.; Wang, P.; Chen, J.; Pu, Y.; Zhao, Y.; He, H.; Zhong, J.; Liu, D.; Zhu, Z. (2012). "Telmisartan Improves Insulin Resistance of Skeletal Muscle Through Peroxisome Proliferator-Activated Receptor- Activation". Diabetes. 62 (3): 762–774. doi:10.2337/db12-0570. PMC 3581229free to read. PMID 23238297. 
  13. ^ Department of Pharmacokinetics and Drug Metabolism, Biberach an der Riss, Boehringer Ingelheim Pharma KG, Biberach, Germany (July 2000). "Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients." (PDF). Journal of International Medical Research. Retrieved 18 January 2014. 
  14. ^ Philippe Gosse (September 2006). "A Review of Telmisartan in the Treatment of Hypertension: Blood Pressure Control in the Early Morning Hours". Vasc Health Risk Manag. Retrieved 18 January 2014. 
  15. ^ Ontarget, I.; Yusuf, S.; Teo, K.; Pogue, J.; Dyal, L.; Copland, I.; Schumacher, H.; Dagenais, G.; Sleight, P.; Anderson, C. (2008). "Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events". New England Journal of Medicine. 358 (15): 1547–1559. doi:10.1056/NEJMoa0801317. PMID 18378520. 
  16. ^ Bayer Healthcare: Telmisartan approved by the European Commission to reduce the risk of cardiovascular (CV) morbidity in a broad spectrum of at risk patients
  17. ^ Ripley, T. L.; Harrison, D. (2008). "The power to TRANSCEND". The Lancet. 372 (9644): 1128–30. doi:10.1016/S0140-6736(08)61243-X. PMID 18757086. 
  18. ^ Clinical trial number NCT00153062 for "PRoFESS - Prevention Regimen For Effectively Avoiding Second Strokes" at ClinicalTrials.gov
  19. ^ Wu, T. T. L., Niu, H. S., Chen, L. J., Cheng, J. T., & Tong, Y. C. (2016). Increase of human prostate cancer cell (DU145) apoptosis by telmisartan through PPAR-delta pathway. European journal of pharmacology, 775, 35-42.
  20. ^ de Araújo Júnior, Raimundo Fernandes, et al. "Telmisartan induces apoptosis and regulates Bcl-2 in human renal cancer cells." Experimental Biology and Medicine (2014): 1535370214546267.
  21. ^ Lee, Lucas D., et al. "Antiproliferative and apoptotic effects of telmisartan in human colon cancer cells." Oncology letters 8.6 (2014): 2681-2686.
  22. ^ Kozako, Tomohiro, et al. "Angiotensin II type 1 receptor blocker telmisartan induces apoptosis and autophagy in adult T‐cell leukemia cells." FEBS Open Bio 6.5 (2016): 442-460.
  23. ^ Pu, Z., Zhu, M., & Kong, F. (2016). Telmisartan prevents proliferation and promotes apoptosis of human ovarian cancer cells through upregulating PPARγ and downregulating MMP‑9 expression. Molecular Medicine Reports, 13, 555-559. http://dx.doi.org/10.3892/mmr.2015.4512
  24. ^ Yoshitaka Miura, MD, PHD, Naoki Yamamoto, MD, Shin Tsunekawa, MD, Seiko Taguchi, MD, Yoko Eguchi, MD, PHD, Nobuaki Ozaki, MD, PHD and Yutaka Oiso, MD, PHD. "Replacement of Valsartan and Candesartan by Telmisartan in Hypertensive Patients With Type 2 Diabetes". Retrieved September 20, 2016.