Metxl Trio

Indications

Metxl Trio is indicated for the treatment of hypertension

Adverse Effects

Cilnidipine General: Gastrointestinal disturbances, lethargy, increased frequency or urination, muscle aches, impotence, abnormal liver function, allergic reaction Eye: Transient blindness, eye pain Metoprolol Most common adverse reactions: tiredness, dizziness, depression, shortness of breath, bradycardia, hypotension, diarrhea, pruritus, rash.

Drug Interactions

Cilnidipine: Drugs with antihypertensive effect:It is considered to enhance the action additively or synergistically:Blood pressure may drop excessively; It is believed that rifampicin-induced hepatic drug-metabolizing enzyme (cytochrome P-450) promotes the metabolism of calcium channel blockers and increases clearance; It is considered that the azole antifungal agent inhibits the drug-metabolizing enzyme CYP3A4 of this drug Telmisartan: Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio; Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19.Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19 Metoprolol: Catecholamine-depleting drugs may have an additive effect when given with beta-blocking agents. CYP2D6 Inhibitors are likely to increase metoprolol concentration Concomitant use of glycosides, clonidine, and diltiazem and verapamil with beta-blockers can increase the risk of bradycardia. Beta-blockers including metoprolol, may exacerbate the rebound hypertension that can follow the withdrawal of clonidine

Mechanism of Action

Telmisartan: Telmisartan is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan Telmisartan does not inhibit human plasma renin or block ion channels. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse effects In human, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours Metoprolol: Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output (2) a central effect leading to reduced sympathetic outflow to the periphery (3) suppression of renin activity Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated Cilnidipine: Cilnidipine is a dihydropyridine calcium-channel blocker. Cilnidipine is the novel calcium antagonist having L-type and N-type calcium channel blocking function. It inhibits cellular influx of calcium, thus causing vasodilatation. It has greater selectivity for vascular smooth muscle. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. It has little or no action at the SA or AV nodes and negative inotropic activity is rarely seen at therapeutic doses

Pharmacokinetics

The half life of Metoprolol in Metxl Trio is 3 -7 hours; half life of Cilnidipine in Met XL trio is 7.5 hours; half life of Telmisartan in Met XL trio is more than 20 hours

Drug Use in Pregnancy

Telmisartan: Pregnancy: There are no adequate data from the use of Telmisartan in pregnant women. Studies in animals have shown reproductive toxicity Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. While there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started Exposure to angiotensin II receptor antagonist therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended Breast-feeding: Because no information is available regarding the use of Telmisartan during breast-feeding, Telmisartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant Cilnidipine: Pregnancy: Category C Animal reproduction studies have shown adverse effects on the fetus and there are no adequate and well controlled studies in humans. Cilnidipine may be used in pregnancy only if the potential benefits justify the risk Lactation: It is desirable to avoid administration to lactating women, but if it is unavoidable, stop lactation. Metoprolol: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed Nursing Mothers: Metoprolol is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Consider possible infant exposure when Metoprolol-XL is administered to a nursing woman

Drug Use in Renal Impairment

Metoprolol: Renal Impairement:Renal Impairment: The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. No reduction in dosage is needed in patients with chronic renal failure Telmisartan: Renal Impairement:Renal Insufficiency: Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild-to-moderate renal impairment (creatinine clearance of 30-80 mL/min, mean clearance approximately 50 mL/min), no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration

Drug Use in Hepatic Impairment

Metoprolol: Hepatic Impairment: Consider initiating Metoprolol therapy at low doses and gradually increase dosage to optimize therapy, while monitoring closely for adverse events Telmisartan: Hepatic Insufficiency: In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100%

Drug Use in Pediatric Population

Metoprolol: Pediatric Use: Safety and effectiveness have not been established in patients < 6 years of age. Cilnidipine: Safety has not been established for low birth weight infants, newborns, infants, toddlers or children Telmisartan:Pediatric: Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.

Drug Use in Geriatric Population

Metoprolol: Geriatrics: No notable difference in efficacy or safety vs. younger patients. Clinical studies of Metoprolol-XL in hypertension did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience in hypertensive patients has not identified differences in responses between elderly and younger patients. Of the 1,990 patients with heart failure randomized to Metoprolol-XL in the MERIT-HF trial, 50% (990) were 65 years of age and older and 12% (238) were 75 years of age and older. There were no notable differences in efficacy or the rate of adverse reactions between older and younger patients. In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Chlorthalidone: Elderly patients and patients with renal impairment: The lowest effective dose of Chlortalidone is also recommended for patients with mild renal insufficiency and for elderly patients In elderly patients, the elimination of chlortalidone is slower than in healthy young adults, although absorption is the same. Therefore, a reduction in the recommended adult dosage may be needed. Close medical observation is indicated when treating patients of advanced age with chlortalidone Chlortalidone and the thiazide diuretics lose their diuretic effect when the creatinine clearance is <30ml/min Telmisartan: Geriatric: The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years