AMLOPRIL TABLETS

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

• Essential hypertension
• Heart failure (adjunctive treatment)
• Myocardial infarction (post-myocardial infarction management)
• Diabetic nephropathy (under expert supervision)

Dosage

Children: For children aged 12-17 years: Initially 5 mg once daily; usual maintenance 10-20 mg once daily, with a maximum of 80 mg per day. For children aged 12-17 years: Initially 2.5 mg once daily, increased in steps of up to 10 mg

Adults: Initially 10 mg once daily; usual maintenance 20 mg daily, with a maximum of 40 mg daily as needed.

Mechanism of action

Lisinopril inhibits angiotensin converting enzyme (ACE), thereby preventing the conversion of angiotensin I to angiotensin II. This inhibition results in decreased levels of angiotensin II, leading to reduced vasoconstriction and decreased aldosterone secretion, which together lower blood pressure. Additionally, increased bradykinin levels due to ACE inhibition contribute to vasodilation.

Pharmacodynamics

As an ACE inhibitor, lisinopril primarily lowers blood pressure through inhibition of the renin-angiotensin-aldosterone system. This results in reduced vasopressor activity and helps in maintaining cardiac output in heart failure. The drug has a wide therapeutic index and is effective in a range of doses from 10 to 80 mg daily, allowing for individualized treatment plans.

Pharmacokinetics

Lisinopril is well absorbed following oral administration, with peak plasma concentrations occurring within 6-8 hours. It has a long half-life, allowing for once-daily dosing. The drug is primarily excreted unchanged in the urine, and its pharmacokinetics may be altered in patients with renal impairment, necessitating dose adjustment.

Contra-indications

• History of angioedema related to previous treatment with an ACE inhibitor
• Hereditary or idiopathic angioedema
• Concomitant use with aliskiren in patients with diabetes
• Severe renal impairment (creatinine clearance less than 30 mL/min)

Adverse effects

• Cough
• Hyperkalemia
• Hypotension
• Dizziness
• Fatigue
• Headache
• Renal impairment
• Angioedema
• Rash
• Gastrointestinal disturbances

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Diuretics may potentiate the hypotensive effect
• Lithium levels may increase when used concurrently
• Other antihypertensive agents may enhance the hypotensive effect

Precautions

• Monitor renal function and serum potassium levels
• Use with caution in patients with a history of heart failure
• May cause hypotension, especially after the first dose
• Consider alternative treatments in patients with a history of angioedema
• Adjust dosage in cases of hepatic impairment

Pregnancy

Not recommended during pregnancy. Use in pregnancy may cause fetal harm, especially in the second and third trimesters.

Breast-feeding

Not recommended; alternative treatment options with better established safety during breastfeeding are available.

Storage

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

Formulations

• Tablets: 2.5 mg, 5 mg, 10 mg, 20 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

Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Lisinopril is an angiotensin converting enzyme inhibitor (ACEI), preventing the conversion of angiotensin I to angiotensin II. This action prevents myocyte hypertrophy and vascular smooth muscle cell proliferation seen in untreated patients. Increased levels of bradykinin also exhibit vasodilating effects for patients taking ACEIs. Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I. Orally active angiotensin-converting enzyme inhibitor. Lisinopril inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. The action of the angiotensin-converting enzyme (ACE) inhibitor lisinopril on the consequences of myocardial reoxygenation and oxidative damage was assessed in cultured chick embryonic ventricular cardiomyocytes. Lisinopril, 10(-8) M to 10(-6) M, produced a significant (P < 0.05) dose-dependent enhancement of the restoration of contractile frequency occurring during myocardial reoxygenation but did not alter the depression in contractile frequency during hypoxia. Lisinopril significantly (P < 0.05) shifted the dose-response relationship of ammonium persulfate-induced reduction in cardiac contractile frequency. Lisinopril significantly (P < 0.05) reduced the effect of another oxidative agent, tertbutylhydroperoxide which produced a time-dependent reduction in cardiac contractile frequency. Lisinopril did not alter cardiac contractile frequency in the absence of hypoxia or ammonium persulfate or tertbutylhydroperoxide. The viability of cardiomyocytes, assessed by trypan blue exclusion, paralleled the changes in cardiac contractile frequency. Lisinopril significantly (P < 0.05) improved viability of cardiomyocytes exposed to either ammonium persulfate or tertbutylhydroperoxide. Lisinopril did not display any antioxidant properties against the free radical alpha,alpha-diphenyl-beta-picrylhydrazyl. These data suggest that lisinopril accelerates the recovery of cardiomyocytes during reoxygenation and blunts the effects of oxidative agents through mechanisms involving the endogenous renin angiotensin system and/or a direct cellular action.

Pharmacodynamics

Lisinopril is an angiotensin converting enzyme inhibitor used to treat hypertension, heart failure, and myocardial infarction. Lisinopril is not a prodrug, and functions by inhibition of angiotensin converting enzyme as well as the renin angiotensin aldosterone system. It has a wide therapeutic index and a long duration of action as patients are generally given 10-80mg daily.