CONCOR AMLO 10+5

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
• Angina pectoris
• Heart failure (adjunctive therapy)

Dosage

Children: Refer to BNF for Children for appropriate dosing information, as specific pediatric doses are not provided.

Adults: Initial dose: 5 mg once daily. Maintenance dose: may be increased to a maximum of 10 mg once daily depending on response and tolerability.

Mechanism of action

Bisoprolol fumarate selectively inhibits beta-1 adrenergic receptors located primarily in the heart. This results in a decrease in heart rate, myocardial contractility, and conduction velocity through the atrioventricular node, leading to reduced cardiac output and lower blood pressure. It does not significantly affect beta-2 adrenergic receptors, which are found in the lungs and vascular smooth muscle, resulting in a lower risk of bronchospasm in susceptible individuals.

Pharmacodynamics

The pharmacological effects of bisoprolol include a reduction in heart rate, myocardial oxygen demand, and blood pressure. The onset of action occurs within 1-2 hours after oral administration, with peak effects observed around 4-6 hours. The antihypertensive effect lasts for 24 hours, allowing for once-daily dosing. Bisoprolol also has a favorable safety profile compared to non-selective beta-blockers, particularly in patients with respiratory conditions.

Pharmacokinetics

Bisoprolol fumarate is well absorbed from the gastrointestinal tract, with a bioavailability of approximately 90%. It is primarily metabolized in the liver via cytochrome P450 enzymes, predominantly CYP2D6, and has a half-life of around 10-12 hours, allowing for once-daily dosing. Excretion occurs mainly through the kidneys, with approximately 50% of the drug eliminated unchanged in urine. Dosage adjustments may be necessary in patients with significant renal impairment.

Contra-indications

• Acute or decompensated heart failure requiring intravenous inotropes
• Sino-atrial block

Adverse effects

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

Interactions

• Other beta-blockers
• Calcium channel blockers
• Antiarrhythmic agents
• CYP2D6 inhibitors
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Digoxin
• Insulin or oral antidiabetic agents

Precautions

• Caution in patients with a history of bronchospasm
• Careful monitoring in patients with renal impairment
• Caution in patients with hepatic impairment
• Gradual withdrawal recommended to avoid rebound hypertension
• Assess heart failure status before initiation and during titration

Pregnancy

Bisoprolol fumarate is not recommended during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised as bisoprolol fumarate is excreted in breast milk; monitor the infant for adverse effects.

Storage

Store below 25 degrees Celsius in a dry place, away from light.

Formulations

• Bisoprolol fumarate 1.25 mg tablets
• Bisoprolol fumarate 2.5 mg tablets
• Bisoprolol fumarate 5 mg tablets
• Bisoprolol fumarate 7.5 mg tablets
• Bisoprolol fumarate solution for injection

Indications

• Hypertension
• Heart failure
• Angina pectoris
• Arrhythmias

Dosage

Children: Refer to BNF for Children for specific pediatric dosing.

Adults: Refer to BNF for specific dosing guidelines.

Mechanism of action

Though the precise mechanism of action of bisoprolol in hypertension is not fully understood, it is believed to primarily exert its therapeutic effects through the antagonism of β-1 adrenoceptors. This leads to a reduction in cardiac output by decreasing heart rate and myocardial contractility. Additionally, bisoprolol may lower renin output from the kidneys and exert some central nervous system effects that contribute to decreased sympathetic nervous system activity, further lowering blood pressure and heart rate.

Pharmacodynamics

Bisoprolol significantly decreases heart rate (chronotropy), reduces myocardial contractility (inotropy), and lowers blood pressure. Clinical studies have shown that bisoprolol can effectively reduce cardiovascular mortality and overall mortality in patients suffering from heart failure with reduced ejection fraction.

Pharmacokinetics

Bisoprolol is well absorbed from the gastrointestinal tract and has a bioavailability of approximately 80%. It is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and has an elimination half-life of about 10-12 hours, allowing for once-daily dosing. The drug is primarily excreted via the kidneys, with a small portion eliminated unchanged.

Contra-indications

• Severe bradycardia
• Second or third degree AV block
• Cardiogenic shock
• Uncontrolled heart failure
• Hypersensitivity to bisoprolol or any excipients

Adverse effects

• Fatigue
• Dizziness
• Bradycardia
• Hypotension
• Cold extremities
• Gastrointestinal disturbances
• Sleep disturbances
• Depression

Interactions

• Propafenone: Moderate (increases risk of cardiovascular adverse effects)
• Rifampicin: Unknown (decreases exposure)

Precautions

• Caution in patients with asthma or chronic obstructive pulmonary disease (COPD)
• Caution in patients with diabetes mellitus (may mask hypoglycemia)
• Caution in patients with peripheral vascular disease
• Monitor heart rate and blood pressure regularly

Pregnancy

Bisoprolol should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It may cause fetal bradycardia, hypotension, and neonatal withdrawal symptoms.

Breast-feeding

Bisoprolol is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Oral tablets: 1.25 mg, 2.5 mg, 5 mg, 10 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

Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate.

Pharmacodynamics

Bisoprolol decreases heart rate (chronotropy), decreases contractility (inotropy), and reduces blood pressure. The results of various clinical studies indicate that bisoprolol reduces cardiovascular mortality and all-cause mortality in patients with heart failure and decreased cardiac ejection fraction (EF).