Telmisartan ((IUPAC 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)) is an angiotensin II receptor antagonist (also known as angiotensin receptor blocker, or ARB ), of the sartan family, used in the management of essential hypertension and sold under the name of Micardis© by Boheringer and Pritor© by Bayer.
Pharmacokinetics
Telmisartan has got important bioavailability and binding to serum proteins (99%). It has an half-life of around 24 hours, which make it administrable once a day. It has high volume of distribution, it reaches easily cells’ cytoplasm and good concentrations in it. It’s completely excreted by the liver, which make it not recommended for hepatopatic patients. The dose of administration is 40-80 mg per day.
Angiotensin II receptor, which is bound by telmisartan blocking its transduction potential, is a G-protein associated peripheral receptor expressed in different cell types, which mediates effects as vasoconstriction, aldosterone synthesis and secretion, increased vasopressin secretion, augmentation of peripheral noradrenergic activity, vascular smooth cells proliferation and feedback renal renin inhibition. As a result of vasoconstriction and increase of noradrenergic sympathetic activity, vascular resistance increases and blood pressure with it. As a result of increase production of aldosterone, there is an increase of renal sodium (and water with it) retention, which increase the circulating fluid amount. Increase of vasopressin/ADH leads to selective water retention in the collective tubules, and further increase of circulating fluid. Angiotensin II is produced from Angiotensin I due to Angiotensin I-Converting Enzyme (ACE ) process, which is a free-circulating enzyme, secreted by pulmonary and endothelial cells. Furthermore, Angiotensin I is produced from Angiotensinogen by Renin, which is secreted by juxtaglomerular apparatus in kidney after loss of blood pressure in the afferent glomerular arterioles.
There aren’t many studies on pregnant women, but Telmisartan, as other sartans, is highly not recommended in pregnancy for its various teratogenic effects. (Differential clinical profile of candesartan compared to other angiotensin receptor blockers,2011)
Further highly-interesting mechanisms
In 2004, it was observed an interesting structural resemblance between telmisartan, and pioglitazone, a thiazolidinedione used in therepy of diabetes. So telmisartan was shown to act on a pathway different from the well know RAAS, activating peroxisome proliferator-activated receptor-gamma (PPARgamma): a crucial cellular and metabolic switch that regulates many physiologic and disease processes. Due to its peculiar structure, different from other ARBs, Telmisartan is the only ARB able to act as a partial agonist of PPARgamma. (Identification of Telmisartan as a Unique Angiotensin II Receptor Antagonist With Selective PPARγ–Modulating Activity,2004, Telmisartan: just an antihypertensive agent? A literature review,2011)
PPAR gamma is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, regulating the expression of target genes involved in carbohydrate and lipid metabolism. PPAR gamma plays essential roles in the regulation of cellular differentiation, development, metabolism, and tumorigenesis.
Activated PPAR gamma forms a heterodimer with the retinoic acid receptor RXRA called adipocyte-specific transcription factor ARF6, and binds to a promoter element in the gene for acyl-CoA oxidase and activates transcription of target genes, increased or decreased, depending on the gene. The RXRA also forms a heterodimer with a number of other receptors (e.g., vitaminD and thyroid hormone). Endogenous ligand include PGJ2 (a prostaglandin).
PPAR gamma interacts with :
* NCOA6 coactivator, leading to a strong increase in transcription of target genes.
* Coactivator PPARBP, leading to a mild increase in transcription of target genes.
* FAM120B.
* PRDM16 by similarity.
* NOCA7 in a ligand-inducible manner.
* NCOA1 LXXLL motifs.
* DNTTIP2, MAP2K1/MEK1, PRMT2 and TGFB1I1.
* PDPK1
- Glucose and lipids metabolism effects
PPAR gamma is an established target in the treatment of insulin resistance, diabetes and metabolic syndrome, whose activation is also correlated to anti-inflammatory and, finally, anti-atherosclerotic properties.
Telmisartan has shown to be able to reduce fasting plasma glucose level and to increase adiponectin level, as well as to reduce fasting plasma insulin level and HOMA-IR, thus suggesting a beneficial effect of telmisartan in improving insulin sensitivity in hypertensive patients with insulin resistance or diabetes.
It's clear how far the effects of telmisartan on PPAR gamma could go, reaching rather distant biochemical pathways, with deep pleiotropic effects. So far, everybody seems to be enthusiastic with its anti-atherosclerotic properties, and the perspectives in the treatment of insulin resistance, diabetes and metabolic syndrome. (Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes,2011)
Furthermore, activation of PPAR gamma can reduce vasoconstriction, vascular remodeling and inflammation, and thrombosis. It has the potential to regulate a complex variety of pathways that are involved in remodeling of the pulmonary vasculature. For instance, PPAR gamma increases endothelial NO release by reducing the inhibitory interaction between eNOS and caveolin, increasing interactions between eNOS and the molecular chaperone, hsp90, and enhancing phosphorylation of eNOS on serine 1177, all post-translational modifications associated with enhanced eNOS activity. As well, PPAR can increase NO bioavailability by blunting the degradation of inducible nitric oxide synthase (iNOS) and by decreasing serum levels of asymmetric dimethylarginine (ADMA), the endogenous inhibitor of NOS . Nevertheless, safety concerns are raised for instance regarding the cardiac safety profile of PPAR agonists particularly for inducing lipotoxicity and precipitating or worsening heart failure. Cardiac pathways are involved in PPAR activation, and their potential regulation of maladaptive pathways are involved in heart failure.
Another warning comes from Hypoxia-Inducible Factor (HIF)1a and PPAR gamma, jointly upregulated in hypertrophic cardiomyopathy, cooperating to obtain key changes in cardiac metabolism. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Activation of the HIF1a -PPAR gamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease. (Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?,2011)
Also the metabolism of bones and calcium is involved in the PPAR gamma pathway, in fact emerging evidences reveal that PPAR gamma is also a key modulator of skeletal remodeling. PPAR? activation not only suppresses osteoblastogenesis, but also activates osteoclastogenesis, thereby decreasing bone formation while sustaining or increasing bone resorption, resulting in increasing fracture rates. The pro-osteoclastogenic effect is mediated by a transcriptional network comprised of PPAR gamma, PPAR gamma coactivator 1ß, and estrogen-related receptor a, which promotes both osteoclast differentiation and mitochondrial activation.
As a matter of fact, the increasing use of PPAR gamma agonists for the treatment of type 2 diabetes mellitus ,poses a significant concern for health care providers, being coupled with the potential for fractures in the aging population, and has shown to have detrimental effects on bone health, as measured by reduced bone mineral density. This concern is based on many reports of postapproval adverse musculoskeletal effects, particularly bone changes and fractures. (PPARγ in bone homeostasis,2010, Bone loss and fracture risk associated with thiazolidinedione therapy,2010, Rosiglitazone decreases bone mass and bone marrow fat,2011)
- Anti-angiogenic (and anti-oncogenic) effects
It was discovered that PPAR gamma modulates function and inflammation of endothelial and vascular smooth muscular cells: this is indirectly important blocking tumor progression, along with effects on tumor-associated macrophages. The molecular mechanism underlying this anti-angiogenic effect seems to be the repression of VEGF production by tumor cells. Furthermore, there’s apoptosis induction of endothelial tumor cells, which can be mediated by p53 or by opening Ca2+-activated K+ channels, which induce the increase of pro-apoptotic Bax. It seems that increase of eNOS production induce high levels of NO which, in tumoral microenvironment, causes endothelial cells lysis. As well, It was demonstrated that PPAR gamma is expressed in a large variety of human tumors, and PPAR gamma agonists seem to block their growth in murine model. (PPARγ and Agonists against Cancer: Rational Design of Complementation Treatments,2008)
It has been reported that PPARs suppress inflammation by inhibiting the activity of transcription factors as AP-1 and NF-kB. In particular, PPAR gamma attenuates macrophage activity (The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation,1998)antagonizing AP-1, NF-?B, and STAT1 (A Retrospective on Nuclear Receptor Regulation of Inflammation: Lessons from GR and PPARs,2011). And along with these results, another study highlighted that IFN/STAT1 pathway is significantly overexpressed in drug-resistant and colonizing tumor cells: it was demonstrated that cells overexpressing this pathway produced more metastatizing colonies than not-overexpressing cells. (STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy,2009)
- Suspect tumor-inducing effects
Over the previous result, from which we can reasonably suspect that decrease of IL production and leucocytes function could result in a deficit of mytogenic products lympho-suppression, recent studies reveal the tumor-promoting and pro-angiogenic PPAR gamma activities; even though PPAR gamma agonists seemed to have anti-tumoral effect, both direct and anti-angiogienic, hepatic carcinogenesis and liposarcomas promoting action was discovered for troglitazone , a PPAR gamma agonist no longer available due to these side-effects. (PPARγ and Agonists against Cancer: Rational Design of Complementation Treatments,2008)
Conclusion
Telmisartan has been sold since 1999 and the first research that found its PPAR gamma –related effects was published 5 years later. The larger part of these PPAR gamma –related effects should still be tested in Telmisartan users, but it seems to be reasonable that its PPAR gamma activity should involve all aspects (or most of them) of its transcription downwards pathway. The only PPAR gamma –related side effect highlighted was the ‘positive’ metabolic one, that is also the one well associated with its license of drug against hypertension. (Could it be just a marketing reason lying underneath?) A review over the role of Pharmacovigilance should be raised, moving towards a deeper meaning of it, that includes the biochemical wide activity that a single molecule can exert, as the case of telmisartan testifies.
This is what literature suggests about PPAR gamma; and what we know about it nowadays it's maybe only a fragment of the whole picture. For this reason, it's warmly recommended that in the future, an independent research could obtain a broader look in the signal-net headed by PPAR gamma, deeply understanding it, especially regarding to the connections with other important pathways and related exerted effects.
For us the relation between telmisartan and PPAR gamma is surely an interesting example of how the introduction of an exogenous molecule, in the complex system of protein pathways of a biological organism, could have unexpected effects, even far away from the reason for whom the drug has been administrated.
Edoardo Gagliardi
Alberto Modini
