|
|
| Line 1: |
Line 1: |
| __NOTOC__
| | #REDIRECT [[Metoprolol tartrate#Pharmacology]] |
| {{Metoprolol}}
| |
| {{CMG}}
| |
| | |
| ===Pharmacodynamics===
| |
| | |
| Relative [[beta1]] selectivity is demonstrated by the following: (1) In healthy subjects, Lopressor is unable to reverse the [[beta2]]-mediated [[vasodilation|vasodilating]] effects of [[epinephrine]]. This contrasts with the effect of nonselective ([[beta1]] plus [[beta2]]) [[beta blocker]]s, which completely reverse the [[vasodilation|vasodilating]] effects of [[epinephrine]]. (2) In [[asthmatic]] patients, Lopressor reduces [[FEV1]] and [[FVC]] significantly less than a nonselective [[beta blocker]], [[propranolol]], at equivalent [[beta1]]-receptor blocking doses.
| |
| | |
| Lopressor has no [[intrinsic sympathomimetic activity]], and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Animal and human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction.
| |
| | |
| Significant beta-blocking effect (as measured by reduction of exercise [[heart rate]]) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise [[systolic blood pressure]] was evident at 12 hours. When the drug was infused over a 10-minute period, in normal volunteers, maximum beta blockade was achieved at approximately 20 minutes. Equivalent maximal beta-blocking effect is achieved with oral and [[intravenous]] doses in the ratio of approximately 2.5:1.
| |
| | |
| There is a linear relationship between the log of plasma levels and reduction of exercise [[heart rate]]. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of [[antihypertensive]] activity to dose, selection of proper dosage requires individual titration.
| |
| | |
| In several studies of patients with [[acute myocardial infarction]], [[intravenous]] followed by oral administration of Lopressor caused a reduction in [[heart rate]], [[systolic blood pressure]] and [[cardiac output]]. [[Stroke volume]], [[diastolic blood pressure]] and pulmonary artery end diastolic pressure remained unchanged.
| |
| | |
| In patients with [[angina pectoris]], plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50-400 mg. Exercise [[heart rate]] and [[systolic blood pressure]] are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose.
| |
| | |
| ===Pharmacokinetics===
| |
| | |
| ====Absorption====
| |
| | |
| The estimated oral bioavailability of immediate release metoprolol is about 50% because of pre-systemic metabolism which is saturable leading to non-proportionate increase in the exposure with increased dose.
| |
| | |
| ====Distribution====
| |
| | |
| Metoprolol is extensively distributed with a reported volume of distribution of 3.2 to 5.6 L/kg. About 10% of metoprolol in plasma is bound to serum [[albumin]]. Metoprolol is known to cross the [[placenta]] and is found in breast milk. Metoprolol is also known to cross the [[blood brain barrier]] following oral administration and CSF concentrations close to that observed in plasma have been reported. Metoprolol is not a significant [[P-glycoprotein]] substrate. | |
| | |
| ====Metabolism====
| |
| | |
| Lopressor is primarily metabolized by [[CYP2D6]]. Metoprolol is a racemic mixture of R- and S- enantiomers, and when administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. [[CYP2D6]] is absent (poor metabolizers) in about 8% of Caucasians and about 2% of most other populations. Poor [[CYP2D6]] metabolizers exhibit several-fold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity thereby decreasing Lopressor’s cardioselectivity.
| |
| | |
| ====Elimination====
| |
| | |
| Elimination of Lopressor is mainly by biotransformation in the liver. The mean elimination half-life of metoprolol is 3 to 4 hours; in poor CYP2D6 metabolizers the half-life may be 7 to 9 hours. Approximately 95% of the dose can be recovered in urine. In most subjects (extensive metabolizers), less than 5% of an oral dose and less than 10% of an intravenous dose are excreted as unchanged drug in the urine. In poor metabolizers, up to 30% or 40% of oral or [[intravenous]] doses, respectively, may be excreted unchanged; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity. The renal clearance of the stereo-isomers does not exhibit stereo-selectivity in renal excretion.
| |
| | |
| ===Special populations===
| |
| | |
| ====Geriatric patients====
| |
| | |
| The geriatric population may show slightly higher plasma concentrations of metoprolol as a combined result of a decreased metabolism of the drug in elderly population and a decreased hepatic blood flow. However, this increase is not clinically significant or therapeutically relevant.
| |
| | |
| ====Renal impairment====
| |
| | |
| The systemic availability and half-life of Lopressor in patients with [[renal failure]] do not differ to a clinically significant degree from those in normal subjects.
| |
| | |
| ====Hepatic Impairment====
| |
| | |
| Since the drug is primarily eliminated by hepatic metabolism, [[hepatic impairment]] may impact the pharmacokinetics of metoprolol. The elimination half-life of metoprolol is considerably prolonged, depending on severity (up to 7.2 h).<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = LOPRESSOR (METOPROLOL TARTRATE) TABLET [NOVARTIS PHARMACEUTICALS CORPORATION] | url =http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bb05420c-fd24-4672-9f62-fdd313819287 | publisher = | date = | accessdate = }}</ref>
| |
| | |
| ==References==
| |
| | |
| {{Reflist}}
| |
| | |
| {{FDA}}
| |
| | |
| [[Category:Antianginals]]
| |
| [[Category:Antiarrhythmic agents]]
| |
| [[Category:Antihypertensive agents]]
| |
| [[Category:Antimigraine drugs]]
| |
| [[Category:Beta blockers]]
| |
| [[Category:Cardiovascular Drugs]]
| |