Amlodipine

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Amlodipine quick reference

Amlodipine
Amlodipine general drug information
 Pronunciation am LOE di peen (.wav file)
 Trade Name(s) Norvasc
 How Supplied Tablets: 2.5 mg, 5 mg, 10 mg
 Generic Availability Yes, all strengths
 Patent Expiry Date n/a
 Classification calcium channel blocker
 Schedule Rx
 Pregnancy Category C
 Breast-feeding No known information. It is recommended that breast-feeding be discontinued during administration.
Amlodipine chemical information
 IUPAC Name 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-

chlorophenyl)-1,4-dihydro-6-methyl-3,5- pyridinedicarboxylate benzenesulfonate[1]

 Empirical Formula (C20H25C1N2O5)•C6H6O3S
 Molecular Weight 567.1 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Amlodipine besylate is an oral long-acting dihydropyridine calcium channel blocker. It is indicated for the treatment of hypertension, chronic stable angina, vasospastic angina (Prinzmetal’s or variant angina) and angiographically documented coronary artery disease.[2][3]

At therapeutic drug levels in patients with hypertension, amlodipine produces a reduction of supine and standing blood pressures. The magnitude of the reduction of blood pressure is related to the level of the pretreatment blood pressure. Patients with moderate hypertension (diastolic pressure 105-114 mm Hg) experienced a 50% greater response rate than patients with mild hypertension (diastolic pressure 90-104 mmHg).[4]

Mechanism of Action

Amlodipine selectively inhibits the transmembrane influx of calcium ions into the vascular smooth and cardiac muscle. A decrease in intracellular calcium inhibits the contractility of the myocardial smooth muscle cells. This results in the dilation of coronary and systemic arteries with a greater pharmacological effect on the vascular smooth muscle than the cardiac muscle. The ultimate effect of amlodipine is a reduction in peripheral vascular resistance and reduction in blood pressure.

Amlodipine does not significantly affect sinus node function, cardiac conduction, or have negative inotropic effects at clinical doses. The gradual pharmacological effect of amlodipine does not produce tachycardia caused by other peripheral vasodilators. Serum calcium levels are unaffected by amlodipine.

In patients with angina, the exact mechanism of action has not been fully explained. In patients that experience exertion angina, amlodipine decreases the total peripheral resistance or afterload which decreases the myocardial oxygen demand when a person is exercising.

Amlodipine inhibits coronary spasms of Prinzmetal’s or variant angina by blocking and restoring blood flow in coronary arteries and arterioles.[2][4]

Time Required for Therapeutic Response

  • Initial: about 7 days [5]
  • Maximum: about 14 days [5]

Pharmacokinetics

Absorption
Oral absorption of a therapeutic dose produces a peak concentration between 6 and 12 hours and absolute bioavailability is estimated to be between 64 and 90%. Co-administration with food does not affect the bioavailability of amlodipine.[4]

Distribution
Approximately 93% of the circulating drug is bound to plasma protein in hypertensive patients. After 7 to 8 days of consecutive daily dosing, plasma steady state is achieved. Volume of distribution is 21 L/kg.[4][6]

Metabolism
About 90% of amlodipine is converted to inactive metabolites via hepatic metabolism. Metabolism is mostly through the CYP 3A4 isoenzyme. Amlodipine is moderately inhibited by CYP 1A2 isoenzyme with a weaker inhibition by 2A6, 2B6, 2C8/9, 2D6 and 3A4.[4][6]

Excretion
The mean terminal half-life of amlodipine is about 30-50 hours. Amlodipine is eliminated from the plasma by a biphasic mechanism. 10% of the parent compound and 60% of the metabolites are excreted in the urine.[4][6]

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Special Population Pharmacokinetics

  • Renal insufficiency: Pharmacokinetics of amlodipine are not significantly affected by decreased renal function. Patients should receive a lower initial therapeutic dose in hypertension.[4]
  • Hepatic insufficiency: Hepatic dysfunction decreases the clearance of amlodipine by increasing the AUC by about 40 to 60%.[4] The elimination half-life of patients with cirrhosis is significantly prolonged to about twice the time compared to healthy individuals.[3] A decreased initial dose of amlodipine may be required.
  • Hemodialysis: Amlodipine is not eliminated by hemodialysis or peritoneal dialysis.[4]
  • Geriatric: A decrease in clearance of amlodipine in the elderly results in about a 40 to 60% increase in the AUC.[4]
  • Pediatric: Pharmacokinetic values such as clearance and volume of distribution were similar to values in adults when adjusted for weight.[4]
  • Gender: No dosage adjustment is needed.

Indications and Dosages

FDA Approved Indications

Treatment of hypertension alone or in combination with other hypertensive agents[4]

  • Starting dose (adults and pediatric patients aged 6-17):[2]
    • 5 mg once daily
  • Maintenance dose (adults and pediatric patients aged 6-17):
    • Recommended maximum maintenance dose is 10 mg once daily.
  • Titration schedule (adults): Dose may be adjusted to the patient’s response and titration of dose should proceed slowly by an increase in 2.5 mg increments over 7 to 14 days to a maximum of 10 mg once a day. If there is a clinical need for a high dose, titration may occur more rapidly.
  • Titration schedule (pediatric patients aged 6-17): Slowly titrate based on clinical response.

Symptomatic treatment of chronic stable angina alone or in combination with other antianginal therapies[4]

  • Starting dose (adults):
    • 5-10 mg once daily
  • Maintenance dose (adults):
    • Recommended maximum maintenance dose is 10 mg once daily.

Treatment of confirmed or suspected vasospastic angina (Prinzmetal's or variant angina) alone or in combination with other antianginal therapies[4]

  • Starting dose (adults):
    • 5-10 mg once daily
  • Maintenance dose (adults):
    • Recommended maximum maintenance dose is 10 mg once daily.

Treatment of patients with recently documented CAD by angiography and without heart failure and an ejection fraction <40%[4]

  • Starting dose (adults):
    • 5-10 mg once daily
  • Maintenance dose (adults):
    • Recommended maximum maintenance dose is 10 mg once daily.

Non-FDA Approved Indications

None known.

Dosage Adjustment

Renal insufficiency: Starting dose for hypertension should be reduced to 2.5 mg once daily.
Hepatic insufficiency: Starting dose for hypertension should be reduced to 2.5 mg once daily and 5 mg daily for chronic stable or vasospastic angina.
Hemodialysis: unknown
Geriatric: Starting dose for the elderly population is 2.5 mg once daily.

Dosage Limits

  • Adults: 10 mg once daily
  • Elderly: 10 mg once daily
  • Adolescents and children 6-17 years: 10 mg once daily
  • Children < 6 years: unknown


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Administration

  • Route: Oral[4]
  • Method:
    • Take with a full 8 ounce glass of water. Tablet can be taken any time during the day but at the same time each day.
    • Add extra bullet points if necessary

Monitoring Parameters

  • blood pressure and heart rate
  • ECG
  • hepatic and renal laboratory tests[2]
  • reduction of chest pain in treatment of angina
  • signs and symptoms of peripheral edema[7]

Contraindications/Precautions

Warning: In patients with severe obstructive coronary artery disease, there has been reported increased frequency, duration, and/or severity of angina or acute myocardial infarction when starting calcium channel blocker therapy or at any increase in dose. The mechanism of this effect has not been studied.[4]

Contraindications

  • Amlodipine is contraindicated in patients with previous sensitivity reactions.[4]

Precautions

  • Caution should be exercised in patients with severe aortic stenosis when initiating amlodipine.[4]
  • Calcium channel blockers should be used with caution in patients with heart failure.[4]

Pregnancy indications

Category C [4]

Animal reproduction studies have been shown to have adverse effects on the fetus. There have not been any adequate and well-controlled studies in pregnant women. Amlodipine may be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Breast-feeding indications

There is no known information if amlodipine is excreted in human milk. It is recommended that breast-feeding be discontinued during administration of amlodipine.[4]

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Drug-Drug, -Food, -Herb Interactions

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Adverse Reactions/Side Effects

Amlodipine Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Peripheral edema (2-15%, dose-related), pulmonary edema (15% from PRAISE trial CHF population)
1-10% CNS Weakness (0-4%), dizziness
Cardiovascular Flushing (1-3%), palpitations (1-4%)
Dermatologic Rash (1-2%), pruritus (1-2%)
Endocrine Male sexual dysfunction (1-2%)
GI Nausea (3%), abdominal pain (1-2%), dyspepsia (1-2%)
Neuromuscular/skeletal Muscle cramps (1-2%)
Respiratory Dyspnea (1-2%)
<1% All abnormal dreams, abnormal vision, allergic reaction, angioedema, anorexia, anxiety, arrhythmia (including ventricular tachycardia and atrial fibrillation), arthralgia, arthrosis, asthenia, back pain, bradycardia, chest pain, conjunctivitis, constipation, depersonalization, depression, diarrhea, diplopia, dry mouth, dysphagia, epistaxis, erthema multiforme, eye pain, flatulence, gingival hyperplasia, hyperglycemia, hypoesthesia, hypotension, insomnia, leukopenia, malaise, micturition disorder, micturition frequency increased, muscle cramps, myalgia, nervousness, neuropathy (peripheral), nocturia, pain, pancreatitis, paresthesia, peripheral ischemia, postural dizziness, postural hypotension, purpura, rash erythematous, rash maculopapular, rigors, sweating increased, syncope, tachycardia, thirst, thrombocytopenia, tinnitus, tremor, vasculitis, vertigo, vomiting, weight decrease, weight gain

Overdosage Measures

Overdose symptoms may include excessive peripheral vasodilation with marked hypotension and a reflex tachycardia.
Treatment:[4]

  • In a suspected overdose, active cardiac monitoring, blood pressure, and respiratory monitoring should be instituted.
  • In the event of hypotension, cardiovascular support should include elevating the extremities and administration of fluids.
  • If the hypotension is unresponsive, vasopressors such as phenylephrine can be administered.
  • Additional administration of intravenous calcium gluconate may reverse the effects of calcium entry blockade.
  • Hemodialysis is not a treatment option in amlodipine overdose because amlodipine is highly protein bound.
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
2.5 mg tablet white diamond NORVASC/2.5
5 mg tablet white octagon NORVASC 5
10 mg tablet white round NORVASC 10
  • Inactive ingredients for tablets: dibasic calcium phosphate anhydrous, microcrystalline cellulose, magnesium stearate, sodium starch glycolate.[2]

Patient Information

  • Take tablet at the same time each day.
  • If a dose is missed, skip the dose for the day and do not double the dose the following day.
  • Do not significantly alter the amount of grapefruit or grapefruit juice you intake after starting on this medication. It may be advisable to refrain from intaking grapefruit and grapefruit juice after starting this medication.
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References

  1. ↑ Amlodipine monograph.(database available on internet):Wikipedia.(cited 2006 Jan) Available from http://en.wikipedia.org/wiki/Norvasc
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Amlodipine monograph(database on the internet).Rx list(cited 2006 Jan.) Available from: http://www.rxlist.com/cgi/generic/amlod2.htm
  3. ↑ 3.0 3.1 Amlodipine Monograph.Clinical Pharmacology (database on the internet) Available at www.clinicalpharmacolgy.com
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 Norvasc(Amlodipine besylate) package insert,Canada;Pfizer:2006 http:/ www.pfizer.com/pfizer/download/uspi_norvasc.pdf
  5. ↑ 5.0 5.1 Amlodipine monograph.Facts and Comparison(database on internet. (cited 200 Jan) Available from www.factandcomparison.com
  6. ↑ 6.0 6.1 6.2 Lexi-Comp(2006)Drug Information Handbook. 14th ed.Hudson, Lexi-Comp. 2006
  7. ↑ Micromedex: Amlodipine monograph Available at www.micromedex.com

PUBMED References

Efficacy Trial Articles

  1. Efficacy and safety of amlodipine: a comparative study of hypertensive patients treated at primary- and specialised-care centres.
  2. Antihypertensive therapy and regression of coronary artery disease: insights from the Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) and Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation (NORMALISE) trials.
  3. Incidence and predictors of angioedema in elderly hypertensive patients at high risk for cardiovascular disease: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
  4. Population pharmacokinetics of amlodipine in hypertensive children and adolescents.
  5. Preliminary experience with amlodipine in the pediatric population.
  6. Hypertension control in the elderly with amlodipine
  7. Abernethy DR, Gutkowska J, Winterbottom LM. Effects of amlodipine, a long-acting dihydropyridine calcium antagonist in aging hypertension: pharmacodynamics in relation to disposition. Clin Pharmacol Ther 1990;48(1):76-86.
  8. Taylor SH. Usefulness of amlodipine for angina pectoris. Am J Cardiol 1994;73(3):28A-33A.
  9. Valcarcel Y, Jimenez R, Hernandez V, Aristegui R, Gil A. Efficacy and safety of amlodipine: a comparative study of hypertensive patients treated at primary- and specialised-care centres. Clin Drug Investig 2006;26(3):125-33.
  10. Islim IF, Watson RD, Ihenacho HN, Ebanks M, Singh SP. Amlodipine: effective for treatment of mild to moderate essential hypertension and left ventricular hypertrophy. Cardiology 2001;96 Suppl 1:10-8
  11. Chahine RA, Feldman RL, Giles TD, Nicod P, Raizner AE, Weiss RJ, et al. Randomized placebo-controlled trial of amlodipine in vasospastic angina. Amlodipine Study 160 Group. J Am Coll Cardiol 1993;21(6):1365-70.
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Therapeutic Class Comparison Articles

  1. Impact of therapy initiation with amlodipine or losartan on hemodynamic endpoints and JNC-VI blood pressure stage.
  2. Comparison of monotherapy with irbesartan 150 mg or amlodipine 5 mg for treatment of mild-to-moderate hypertension.
  3. Amlodipine versus angiotensin II receptor blocker; control of blood pressure evaluation trial in diabetics (ADVANCED-J.
  4. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.
  5. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.
  6. Bernink PJ, de Weerd P, ten CF, Remme WJ, Barth J, Enthoven R, et al. An 8-week double-blind study of amlodipine and diltiazem in patients with stable exertional angina pectoris. J Cardiovasc Pharmacol 1991;17 Suppl 1:S53-6.
  7. Opie LH. Calcium channel antagonists should be among the first-line drugs in the management of cardiovascular disease. Cardiovasc Drugs Ther 1996;10(4):455-61.
  8. Stone PH. Calcium antagonists for Prinzmetal's variant angina, unstable angina and silent myocardial ischemia: therapeutic tool and probe for identification of pathophysiologic mechanisms. Am J Cardiol 1987;59(3):101B-115B.
  9. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. Jama 2004;292(18):2217-25.

Pharmacokinetics Articles

  1. The pharmacokinetic profile of amlodipine.
  2. Population analyses of amlodipine in patients living in the community and patients living in nursing homes.
  3. Pharmacokinetics of amlodipine in hypertensive patients undergoing haemodialysis.
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Drug Interaction Articles

  1. Can combining different risk interventions into a single formulation contribute to improved cardiovascular disease risk reduction? Rationale and design for an international, open-label program to assess the effectiveness of a single pill (amlodipine/atorvastatin) to attain recommended target levels for blood pressure and lipids (The JEWEL Program).
  2. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist

Adverse Effects Articles

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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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