AMLOMET 25

Indications

• Hypertension
• Angina

Dosage

Children: Children 1 month to 11 years: Initially 100–200 micrograms/kg once daily; increased if necessary at intervals of 1–2 weeks up to a maximum of 5 mg once daily.

Adults: Initially, 5 mg once daily, increased if necessary to a maximum of 10 mg once daily.

Mechanism of action

Amlodipine inhibits the influx of calcium ions into vascular smooth muscle and cardiac muscle cells, leading to vasodilation and decreased myocardial oxygen demand.

Pharmacodynamics

Amlodipine causes a reduction in systemic vascular resistance and arterial pressure, resulting in decreased workload on the heart. It has a long duration of action due to its slow onset and prolonged effects.

Pharmacokinetics

Amlodipine is well absorbed orally, with peak plasma concentrations occurring 6-12 hours after administration. It has a half-life of approximately 30-50 hours, allowing for once-daily dosing. It is extensively metabolized in the liver and excreted primarily in the urine.

Contra-indications

• Cardiogenic shock
• Aortic stenosis

Adverse effects

• Asthenia
• Constipation
• Diarrhoea
• Drowsiness
• Dyspnoea
• Gastrointestinal disturbances

Interactions

• Grapefruit juice (severe increase in exposure)
• Enzalutamide (moderate decrease in exposure)
• Apalutamide (moderate decrease in exposure)
• Dronedarone (moderate increase in exposure)
• Antifungals (azoles) (moderate increase in exposure)
• Miconazole (moderate increase in exposure)
• Cobicistat (moderate increase in exposure)
• Crizotinib (moderate increase in exposure)
• Dabrafenib (moderate decrease in exposure)
• Idelalisib (moderate increase in exposure)

Precautions

• Caution in hepatic impairment (risk of increased exposure)
• Monitor for sudden withdrawal effects, which may exacerbate myocardial ischaemia

Pregnancy

Manufacturer advises caution due to limited data on safety.

Breast-feeding

Manufacturer advises to avoid; no information available.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Amlodipine 5mg/5ml oral solution (sugar-free)
• Amlodipine 10mg/5ml oral solution (sugar-free)
• Amlodipine 5 mg tablets
• Amlodipine 10 mg tablets

Indications

• Hypertension
• Short-term treatment of supraventricular arrhythmias
• Atrial fibrillation
• Atrial flutter
• Sinus tachycardia
• Tachycardia and hypertension in the perioperative period
• Symptomatic relief in hyperthyroidism

Dosage

Children: In children, the usual dose is 1 to 2 mg/kg daily in 2 to 4 divided doses, with a maximum of 8 mg/kg daily.

Adults: 200 mg once daily, increased if necessary to 400 mg once daily.

Mechanism of action

Metoprolol tartrate selectively blocks beta-1 adrenergic receptors, which results in a decrease in heart rate and myocardial contractility. This action reduces the workload on the heart and decreases oxygen demand, thereby lowering blood pressure.

Pharmacodynamics

As a beta-1 blocker, metoprolol exhibits negative chronotropic (decreasing heart rate) and inotropic (decreasing force of contraction) effects. This results in lower cardiac output and, consequently, reduced blood pressure. The drug also has a mild effect on reducing renin release from the kidneys, contributing further to its antihypertensive effects.

Pharmacokinetics

Metoprolol is well absorbed from the gastrointestinal tract but undergoes significant first-pass metabolism in the liver, which reduces its bioavailability to approximately 50%. It has a half-life of about 3 to 7 hours, allowing for once or twice daily dosing. Metoprolol is primarily eliminated by hepatic metabolism, and renal excretion of metabolites also occurs. Dose adjustments may be necessary in patients with hepatic impairment but are generally not required for mild renal impairment.

Contra-indications

• Severe bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Uncontrolled heart failure
• Hypersensitivity to metoprolol or any component of the formulation

Adverse effects

• Dizziness
• Fatigue
• Hypotension
• Bradycardia
• Heart block
• Depression
• Insomnia
• Nausea
• Diarrhea
• Cold extremities
• Peripheral edema

Interactions

• Other antihypertensive drugs may enhance the hypotensive effect
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce antihypertensive effect
• Caution with other beta-blockers
• Concurrent use with calcium channel blockers may increase the risk of bradycardia and heart block
• Caution with drugs that affect CYP2D6 metabolism

Precautions

• Caution in patients with asthma or reactive airway disease
• Caution in patients with diabetes mellitus, as it may mask signs of hypoglycemia
• Monitor in patients with hepatic impairment
• Gradual withdrawal is advised to avoid acute tachycardia, hypertension, or ischemic symptoms

Pregnancy

Metoprolol should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consult guidelines for specific recommendations.

Breast-feeding

Manufacturers advise avoidance during breastfeeding due to potential adverse effects on the infant.

Storage

Store below 25°C, protect from light and moisture. Keep out of reach of children.

Formulations

• Metoprolol tartrate 25 mg tablets
• Metoprolol tartrate 50 mg tablets
• Metoprolol tartrate 100 mg tablets

Indications

• Hypertension
• Angina pectoris
• Heart failure
• Arrhythmias
• Myocardial infarction prevention

Dosage

Children: Paediatric dosing of metoprolol is not provided in the BNF text supplied. It is essential to refer to the BNF for Children for appropriate paediatric dosing recommendations.

Adults: The typical dose of metoprolol for adults varies based on the specific indication and patient factors. For hypertension, the initial dose is often 50 mg once daily, which may be adjusted based on response. For angina, the usual starting dose is also 50 mg, taken twice daily. It is recommended to refer to the BNF for specific dosing guidelines.

Mechanism of action

Metoprolol selectively inhibits beta-1-adrenergic receptors in cardiac cells, leading to negative chronotropic and inotropic effects. It reduces automaticity, decreases conduction velocity, and enhances refractoriness in accessory pathways. By blocking adrenergic stimulation, metoprolol lowers heart rate and myocardial contractility, contributing to its antihypertensive effects.

Pharmacodynamics

Administration of metoprolol results in a dose-dependent decrease in heart rate and cardiac output. It reduces cardiac excitability and myocardial oxygen demand, improving outcomes in patients with arrhythmias by suppressing atrioventricular conduction. Clinical trials indicate that metoprolol significantly reduces mortality and reinfarction risk in post-myocardial infarction patients.

Pharmacokinetics

Metoprolol is rapidly absorbed and undergoes extensive first-pass metabolism in the liver, leading to variable bioavailability. Peak plasma concentrations occur approximately 1-2 hours post-administration. The drug is primarily excreted by the kidneys, with a half-life of around 3-7 hours. Individual pharmacokinetic profiles may vary based on genetic factors and co-administered medications.

Contra-indications

• Severe bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Uncontrolled heart failure
• Hypersensitivity to metoprolol or any component of the formulation

Adverse effects

• Bradycardia
• Hypotension
• Fatigue
• Dizziness
• Depression
• Cold extremities
• Gastrointestinal disturbances
• Shortness of breath
• Sleep disturbances

Interactions

• dacomitinib+metoprolol: Severe (increases exposure)
• eliglustat+metoprolol: Moderate (increases exposure)
• fedratinib+metoprolol: Moderate (increases exposure)
• panobinostat+metoprolol: Moderate (increases exposure)
• abiraterone+metoprolol: Unknown (increases exposure)
• propafenone+metoprolol: Unknown (increases exposure)
• bupropion+metoprolol: Unknown (increases exposure)
• cinacalcet+metoprolol: Unknown (increases exposure)
• mirabegron+metoprolol: Unknown (increases exposure)
• snris+metoprolol: Unknown (increases exposure)

Precautions

• Use with caution in patients with asthma or chronic obstructive pulmonary disease due to potential for bronchoconstriction at high doses
• Monitor heart rate and blood pressure regularly
• Caution in patients with diabetes as it may mask hypoglycemic symptoms
• Taper dose gradually to avoid rebound hypertension

Pregnancy

Metoprolol is classified as a category C drug. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Metoprolol is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 25 mg, 50 mg, 100 mg

Mechanism of action

**Mechanism of action on blood pressure** Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both _dihydropyridine_ and _nondihydropyridine_ binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure. **Mechanism of action in angina** The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold: Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Recent studies have suggested that cytokines are capable of modifying cardiovascular function and that drugs used in the treatment of heart failure have various modulating properties on the production of cytokines. More recently, we have found that ouabain induces the production of cytokines. This study was performed to examine the effects of calcium channel blockers on the production of cytokines induced by a cardiac glycoside. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers. PBMC were cultured in 0.1, 1, 10, and 30 umol/L amlodipine, diltiazem, and nifedipine in presence of 1 umol/L ouabain. After 24 hr of incubation, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were measured in the culture supernatants by enzyme-linked immunosorbent assay. Ouabain induced the production of IL-1alpha, IL-1beta and IL-6, but not of TNF-alpha. Induction of IL-1beta was most prominent. The production of IL-1alpha, and IL-6 wa

Pharmacodynamics

**General pharmacodynamic effects** Amlodipine has a strong affinity for cell membranes, modulating calcium influx by inhibiting selected membrane calcium channels. This drug's unique binding properties allow for its long-acting action and less frequent dosing regimen,. **Hemodynamic effects** After the administration of therapeutic doses of amlodipine to patients diagnosed with hypertension, amlodipine causes vasodilation, which results in a reduction of supine and standing blood pressure. During these blood pressure reductions, there are no clinically significant changes in heart rate or plasma catecholamine levels with long-term use. Acute intravenous administration of amlodipine reduces arterial blood pressure and increases heart rate in patients with chronic stable angina, however, chronic oral administration of amlodipine in clinical studies did not cause clinically significant alterations in heart rate or blood pressures in patients diagnosed with angina and normal blood pressure. With long-term, once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. **Electrophysiologic effects** Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in animals or humans. In patients who were diagnosed with chronic stable angina, the intravenous administration of 10 mg of amlodipine did not cause clinically significant alterations A-H and H-V conduction and sinus node recovery time after cardiac pacing. Patients administered amlodipine with concomitant beta-blockers produced similar results. In clinical trials in which amlodipine was given in combination with beta-blockers to patients diagnosed with hypertension or angina, no adverse effects on electrocardiographic parameters were noted. In clinical studies comprised of angina patients alone, amlodipine did not change electrocardiographic intervals or produce high degrees of AV block. **Effects on angina** Amlodipine relieves the symptoms of chest pain associated with angina. In patients diagnosed with angina, daily administration of a single amlodipine dose increases total exercise time, the time to angina onset, and the time to 1 mm ST-segment depression on ECG studies, decreases anginal attack frequency, and decreases the requirement for nitroglycerin tablets.

Mechanism of action

Metoprolol is a beta-1-adrenergic receptor inhibitor specific to cardiac cells with negligible effect on beta-2 receptors. This inhibition decreases cardiac output by producing negative chronotropic and inotropic effects without presenting activity towards membrane stabilization nor intrinsic sympathomimetics. Beta-adenoreceptor blocking property the amount of beta1 and beta2 effect depends on the cardioselectivity of the drug. Decreased automaticity. Reduced conduction velocity and increased refractoriness in accessory bundles (Wolff- Parkinson-White syndrome). /Class II- beta-Blocking Agents/ At low doses, metoprolol is a selective inhibitor of beta 1-adrenergic receptors. Like propranolol, metoprolol inhibits response to adrenergic stimuli by competitively blocking b1-adrenergic receptors within the myocardium. Unlike propranolol, however, metoprolol blocks b2-adrenergic receptors within bronchial and vascular smooth muscle only in high doses. The precise mechanism of metoprolol's hypotensive action has not been determined. It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. In the management of angina pectoris, the mechanism of action of metoprolol is thought to be blockage of catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, which results in a net decrease in myocardial oxygen consumption. For more Mechanism of Action (Complete) data for METOPROLOL (7 total), please visit the HSDB record page.

Pharmacodynamics

Administration of metoprolol in normal subjects is widely reported to produce a dose-dependent reduction on heart rate and cardiac output. This effect is generated due to a decreased cardiac excitability, cardiac output, and myocardial oxygen demand. In the case of arrhythmias, metoprolol produces its effect by reducing the slope of the pacemaker potential as well as suppressing the rate of atrioventricular conduction. The Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) trial showed a significant improvement in sudden cardiac death and myocardial infarction when patients were given with metoprolol as compared with diuretics. As well, in clinical trials performed in 1990, metoprolol reduces mortality and re-infarction in 17% of the individuals when administered chronically after an episode of myocardial infarction.