Amlodipine

Amlodipine is an antihypertensive agent belonging to the Calcium Channel Blocker class.

Amlodipine is a Calcium Channel Blocker used to treat Hypertension and Angina.

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food. The plasma protein binding of Amlodipine is approximately 98%. Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine.

Amlodipine shows common side effects swelling of the hands, feet, ankles, or lower legs, headache, upset stomach, nausea, stomach pain, dizziness or light-headedness, drowsiness, excessive tiredness, flushing, etc.

Amlodipine is available in the form of Oral Tablet, Oral Solution and Oral Suspension.

Amlodipine is available in India, US, UK, Canada, Russia, China, Japan, Korea, Singapore, and South Africa.

Amlodipine belonging to the Calcium Channel Blockers acts as an antihypertensive agent.

Mechanism of action on Hypertension

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 non-dihydropyridine 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 (Prinz metals or variant angina) and reduces coronary vasoconstriction caused by smoking.

The Onset of action of Amlodipine is not clinically established.

The Duration of Action for Amlodipine in the body is approximately 24 hours.

The Tmax was found within 6-12 hours following the administration of Amlodipine.

Amlodipine is available in the form of Oral Tablet, Oral Solution and Oral Suspension.

Amlodipine tablet, solution and suspension taken orally. Usually once a day.

Amlodipine is a medicine used for the treatment of high blood pressure. This medicine works by relaxing the blood vessels which make the blood flow easily, thus lowering the blood pressure. This will reduce your risk of heart attack or a stroke by making it easier for your heart to pump blood around your body.

Amlodipine is an antihypertensive agent belonging to Calcium Channel Blockers. It inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina. Amlodipine directly acts on vascular smooth muscle to produce peripheral arterial vasodilation reducing peripheral vascular resistance and blood pressure.

Amlodipine is approved for use in the following clinical indications

• HYPERTENSION

Amlodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Amlodipine.

• CORONARY ARTERY DISEASE (CAD)

Chronic Stable Angina

Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents.

Vasospastic Angina (Prinz metals Or Variant Angina)

Amlodipine is indicated for the treatment of confirmed or suspected vasospastic angina. Amlodipine may be used as monotherapy or in combination with other antianginal agents.

Angiographically Documented CAD

In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, Amlodipine is indicated to reduce the risk of hospitalization for angina and to reduce the risk of a coronary revascularization procedure.

• Hypertension

Adult Dose

Initial dose: 5 mg orally once a day

Maintenance dose: 5 to 10 mg orally once a day

Maximum dose: 10 mg/day

Pediatric Dose (6 to 17 years)

Maintenance dose: 2.5 to 5 mg orally once a day

Maximum dose: 5 mg/day

Pediatric dose (<6 years)

Limited data available:

Oral: Initial: 0.1 mg/kg/dose once daily; titrate based on clinical response.

Maximum daily dose: 0.6 mg/kg/day or 5 mg/day

Geriatric Dose

Initial dose: 2.5 mg orally once a day

Maintenance dose: 2.5 to 10 mg orally once a day

Maximum dose: 10 mg/day

• Angina Pectoris

Adult Dose

Maintenance dose: 5 to 10 mg orally once a day

Maximum dose: 10 mg/day

Geriatric Dose

Initial dose: 5 mg orally once a day

Maintenance dose: 5 to 10 mg orally once a day

Maximum dose: 10 mg/day

• Coronary Artery Disease

Maintenance dose: 5 to 10 mg orally once a day

Maximum dose: 10 mg/day

Amlodipine is available in various strengths as 2.5mg, 5mg, 10mg and 1mg/mL(150mL).

Amlodipine is available in the form of Oral Tablet, Oral Solution and Oral Suspension.

Avoid grapefruit juice while taking Amlodipine.

Amlodipine is contraindicated in patients with known sensitivity towards Amlodipine.

• Hypotension

Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely.

• Increased Angina or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Amlodipine, particularly in patients with severe obstructive coronary artery disease.

• Patients with Hepatic Failure

Because Amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t 1/2) is 56 hours in patients

No information is available.

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Avoid grapefruit juice while taking Amlodipine.

• Common Adverse effects

Peripheral edema, Flushing, palpitations, Pruritus, skin rash, Abdominal pain, nausea, Male sexual disorder, Asthenia, dizziness, drowsiness, Muscle cramps, Dyspnea.

• Rare Adverse effects

Peripheral ischemia, sinus tachycardia, syncope, vasculitis, Diaphoresis, erythema multiforme, Hot flash, hyperglycemia, weight gain, weight loss, Anorexia, constipation, dysphagia, flatulence, gingival hyperplasia, pancreatitis, vomiting, xerostomia, Difficulty in micturition, female sexual disorder, nocturia, urinary frequency, Leukopenia, purpuric disease, thrombocytopenia, Angioedema, hypersensitivity reaction, Abnormal dreams, anxiety, depersonalization, depression, hypoesthesia, insomnia, malaise, pain, paresthesia, peripheral neuropathy, rigors, tremor, vertigo, Arthralgia, back pain, myalgia, osteoarthritis, Conjunctivitis, diplopia, eye pain, Tinnitus, Epistaxis.

• CYP3A Inhibitors

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.

• CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

• Sildenafil

Monitor for hypotension when sildenafil is co-administered with amlodipine.

• Simvastatin

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

• Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate.

The common side effects of Amlodipine include the following

• Common
  

Swelling of the hands, feet, ankles, or lower legs, headache, upset stomach, nausea, stomach pain, dizziness or light-headedness, drowsiness, excessive tiredness, flushing.

• Rare

More frequent or more severe chest pain, rapid, pounding, or irregular heartbeat, fainting.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (respectively, 8 times2 and 23 times2 the maximum recommended human dose of 10 mg on a mg/m2 basis) during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

• Nursing Mothers

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while Amlodipine is administered.

• Pediatric Use

Effect of Amlodipine on blood pressure in patients less than 6 years of age is not known.

• Geriatric Use

Clinical studies of Amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required.

• Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Amlodipine is limited.
• Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
• If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As Amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Pharmacodynamic

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.

Pharmacokinetics

• Absorption

Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food.

• Distribution

The plasma protein binding of Amlodipine is approximately 98%.

• Metabolism and Excretion

Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine. Ex vivo studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Characteristics that add to amlodipine's unique pharmacologic profile include nearly complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic breakdown. Approximately 10% of a given dose is excreted in the urine.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019787s047lbl.pdf
• https://www.uptodate.com/contents/amlodipine-drug-information
• https://go.drugbank.com/drugs/DB00381
• https://www.drugs.com/amlodipine.html
• https://medlineplus.gov/druginfo/meds/a692044.html
• https://reference.medscape.com/drug/katerzia-norvasc-amlodipine-342372
• https://www.rxlist.com/consumer_amlodipine_norvasc/drugs-condition.htm