HYTEL CM

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
• Heart failure
• Chronic kidney disease
• Diabetic nephropathy

Dosage

Children: For paediatric patients, refer to the BNF for Children for appropriate dosing guidelines.

Adults: The usual starting dose is 40 mg once daily, which may be adjusted based on blood pressure response. The maximum recommended dose is 80 mg per day.

Mechanism of action

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT1 receptor by selectively binding to these receptors in vascular smooth muscle and the adrenal gland. This blockage leads to reduced systemic vascular resistance and lower blood pressure. Telmisartan is not an ACE inhibitor and does not affect other hormone receptors or ion channels. It may also enhance carbohydrate and lipid metabolism via its PPARγ activity.

Pharmacodynamics

Telmisartan exhibits high affinity for the AT1 receptor subtype, making it an effective angiotensin II antagonist. It plays a significant role in lowering blood pressure by preventing vasoconstriction and aldosterone release. The potential PPARγ agonistic properties suggest additional metabolic advantages, including improved glucose and lipid metabolism.

Pharmacokinetics

Telmisartan is administered orally and has a high bioavailability. It is extensively bound to plasma proteins and undergoes hepatic metabolism, primarily via glucuronidation. The drug has a long half-life, allowing for once-daily dosing. Excretion occurs mainly through the feces, with minimal renal elimination.

Contra-indications

• Hypersensitivity to telmisartan or any of the excipients
• Severe hepatic impairment
• Severe renal impairment or patients on dialysis

Adverse effects

• Dizziness
• Fatigue
• Hypotension
• Hyperkalemia
• Renal impairment
• Angioedema

Interactions

• Other antihypertensives
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Lithium
• Potassium-sparing diuretics
• Renin-angiotensin-aldosterone system (RAAS) inhibitors

Precautions

• Monitor renal function, particularly in patients with renal artery stenosis
• Caution in patients with a history of angioedema
• Use with caution in patients with diabetes
• Monitor potassium levels in patients at risk for hyperkalemia

Pregnancy

Telmisartan is not recommended during pregnancy, particularly in the second and third trimesters, due to potential harm to the fetus.

Breast-feeding

The effects of telmisartan on breastfed infants are unknown; caution should be exercised.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 20 mg, 40 mg
• Combination tablets with hydrochlorothiazide: 20 mg/12.5 mg, 40 mg/12.5 mg

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

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.

Mechanism of action

Telmisartan interferes with the binding of angiotensin II to the angiotensin II AT₁-receptor by binding reversibly and selectively to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Telmisartan does not inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels. Studies also suggest that telmisartan is a partial agonist of PPAR&gamma;, which is an established target for antidiabetic drugs. This suggests that telmisartan can improve carbohydrate and lipid metabolism, as well as control insulin resistance without causing the side effects that are associated with full PPAR&gamma; activators. Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-gamma-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARgamma in this context. CD4-positive lymphocytes express both the AT1R and PPARgamma. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1+/-3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6+/-0.7-fold induction at 10 mumol/L of telmisartan (P<0.01 compared with SDF-1-treated cells; n=22). Three different PPARgamma activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPARgamma-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPARgamma small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARgamma. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPARgamma-activating properties. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Block

Pharmacodynamics

Telmisartan is an orally active nonpeptide angiotensin II antagonist that acts on the AT₁ receptor subtype. It has the highest affinity for the AT₁ receptor among commercially available ARBs and has minimal affinity for the AT₂ receptor. New studies suggest that telmisartan may also have PPAR&gamma; agonistic properties that could potentially confer beneficial metabolic effects, as PPAR&gamma; is a nuclear receptor that regulates specific gene transcription, and whose target genes are involved in the regulation of glucose and lipid metabolism, as well as anti-inflammatory responses. This observation is currently being explored in clinical trials. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Telmisartan works by blocking the vasoconstrictor and aldosterone secretory effects of angiotensin II.