Antihypertensive – Antianginal
Action And Clinical Pharmacology: Amlodipine is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). Amlodipine is a member of the dihydropyridine class of calcium antagonists.
Mechanism of Action: The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The contractile processes of these tissues 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. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound and its kinetic interaction with the calcium channel receptor is characterized by the gradual association and dissociation with the receptor binding site. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites.
Hypertension: The mechanism by which amlodipine reduces arterial blood pressure involves direct peripheral arterial vasodilation and reduction in peripheral vascular resistance.
Angina: The precise mechanism by which amlodipine relieves angina has not been fully delineated. Amlodipine is a dilator of peripheral arteries and arterioles which reduces the total peripheral resistance and, therefore, reduces the workload of the heart (afterload). The unloading of the heart is thought to decrease ischemia and relieve effort angina by reducing myocardial energy oxygen consumption and oxygen requirements.
Pharmacokinetics and Metabolism: After oral administration of therapeutic doses of amlodipine, absorption occurs gradually with peak plasma concentration reached between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not altered by the presence of food.
Amlodipine is metabolized through the cytochrome P450 system, mainly via CYP 34 isoenzyme.
Amlodipine is extensively (about 90%) converted to inactive metabolites (via hepatic metabolism) with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 35 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Plasma concentrations in the patients with moderate to severe renal failure were higher than in the normal subjects. Accumulation and mean elimination half-life in all patients were within the range of those observed in other pharmacokinetic studies with amlodipine in normal subjects.
In elderly hypertensive patients (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.
Following single oral administration of 5 mg of amlodipine, patients with chronic mild-moderate hepatic insufficiency showed about 40% increase in AUC of amlodipine as compared to normal volunteers. This was presumably due to a reduction in clearance of amlodipine as the terminal elimination half-life was prolonged from 34 hours in young normal subjects to 56 hours in the elderly patients with hepatic insufficiency.
Following oral administration of 10 mg amlodipine to 20 male volunteers, pharmacokinetics of amlodipine were similar when amlodipine was administered with and without grapefruit juice. Geometric mean Cmax of amlodipine was 6.2 ng/mL when the drug was administered with grapefruit juice and 5.8 ng/mL when administered with water. Mean Tmax of amlodipine was 7.6 hours with grapefruit juice and 7.9 hours with water. Geometric mean AUC0 was 315 ng/hr/mL with grapefruit juice and 293 ng/hr/mL with water. Geometric mean bioavailability of amlodipine was 85% when administered with grapefruit juice and 81% when administered with water.
Pharmacodynamics: Hemodynamics: Following administration of recommended doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by any significant change in heart rate or plasma catecholamine levels with chronic dosing. With chronic once daily oral administration (5 and 10 mg once daily), antihypertensive effectiveness is maintained throughout the 24 hours dose interval with minimal peak to trough differences in blood pressure reduction. Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of amlodipine. In normotensive patients with angina amlodipine has not been associated with any clinically significant reductions in blood pressure or changes in heart rate.
Negative inotropic effects have not been observed when amlodipine was administered at the recommended doses to man, but has been demonstrated in animal models. Hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in angina patients with normal ventricular function have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction.
Electrophysiologic Effects: Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals, or man. In patients with chronic stable angina, i.v. administration of 10 mg of amlodipine and a further 10 mg of amlodipine after a 30 minute interval produced peripheral vasodilation and afterload reduction, but did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients, amlodipine as monotherapy did not alter electrocardiographic intervals.
Indications And Clinical Uses: Hypertension: The treatment of mild to moderate essential hypertension. Amlodipine should normally be used in those patients in whom treatment with diuretics or beta-blockers was found ineffective or has been associated with unacceptable adverse effects.
Amlodipine can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Combination of amlodipine with a diuretic, a beta-blocking agent or an angiotensin converting enzyme inhibitor has been found to be compatible and showed additive antihypertensive effect.
Chronic Stable Angina: For the management of chronic stable angina (effort-associated angina) in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents.
Amlodipine may be tried in combination with beta-blockers in chronic stable angina in patients with normal ventricular function. When such concomitant therapy is introduced, care must be taken to monitor blood pressure closely since hypotension can occur from the combined effects of the drugs.
Contra-Indications: Patients with hypersensitivity to the drug or other dihydropyridines and in patients with severe hypotension (less than 90 mmHg systolic). tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Outflow Obstruction (Aortic Stenosis): Amlodipine should be used with caution in a presence of fixed left ventricular outflow obstruction (aortic stenosis).
Patients with Impaired Hepatic Function: There are no adequate studies in patients with liver dysfunction and dosage recommendations have not been established. In a small number of patients with mild to moderate hepatic impairment given single dose of 5 mg, amlodipine half-life has been prolonged (see Pharmacology, Pharmacokinetics and Metabolism). Amlodipine should, therefore, be administered with caution in these patients and careful monitoring should be performed. A lower starting dose may be required (see Dosage).
Beta-blocker Withdrawal: Amlodipine gives no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker.
Precautions: Patients With Congestive Heart Failure: Although generally calcium channel blockers should only be used with caution in patients with heart failure, it has been observed that amlodipine had no overall deleterious effect on survival and cardiovascular morbidity in both short-term and long-term clinical trials in these patients. While a significant proportion of the patients in these studies had a history of ischemic heart disease, angina or hypertension, the studies were not designed to evaluate the treatment of angina or hypertension in patients with concomitant heart failure.
Hypotension: Amlodipine may occasionally precipitate symptomatic hypotension. Careful monitoring of blood pressure is recommended, especially in patients with a history of cerebrovascular insufficiency, and those taking medications known to lower blood pressure.
Peripheral Edema: Mild to moderate peripheral edema was the most common adverse event in the clinical trials (see Adverse Effects). The incidence of peripheral edema was dose-dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg dose range. Care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
Pregnancy: Although amlodipine was not teratogenic in the rat and rabbit some dihydropyridine compounds have been found to be teratogenic in animals. In rats, amlodipine has been shown to prolong both the gestation period and the duration of labor. There is no clinical experience with amlodipine in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
Lactation: It is not known whether amlodipine is excreted in human milk. Since amlodipine safety in newborns has not been established, amlodipine should not be given to nursing mothers.
Children: The use of amlodipine is not recommended in children since safety and efficacy have not been established in that population.
Geriatrics: In elderly patients (Â³65 years) clearance of amlodipine is decreased with a resulting increase in AUC (see Pharmacology, Pharmacokinetics and Metabolism). In clinical trials the incidence of adverse reactions in elderly patients was approximately 6% higher than that of younger population.
Interaction With Grapefruit Juice: Published data indicate that through inhibition of the cytochrome P450 system, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel blockers. Following oral administration of 10 mg amlodipine to 20 male volunteers, pharmacokinetics of amlodipine were similar when amlodipine was administered with and without grapefruit juice (see Pharmacology, Pharmacokinetics).
Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via CYP 3A4 isoenzyme. Coadministration of amlodipine with other drugs which follow the same route of biotransformation may result in altered bioavailability of amlodipine or these drugs. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered amlodipine to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.
Amlodipine has a low (rate of first-pass) hepatic clearance and consequent high bioavailability, and thus, may be expected to have a low potential for clinically relevant effects associated with elevation of amlodipine plasma levels when used concomitantly with drugs that compete for or inhibit the cytochrome P450 system.
Cimetidine, Warfarin, Cyclosporin, Digoxin: Pharmacokinetic interaction studies with amlodipine in healthy volunteers have indicated: cimetidine did not alter the pharmacokinetics of amlodipine; amlodipine did not change warfarin-induced prothrombin response time; amlodipine does not significantly alter the pharmacokinetics of cyclosporin; amlodipine did not change serum digoxin levels or digoxin renal clearance.
Antacids: Concomitant administration of Maalox had no effect on the disposition of a single 5 mg dose of amlodipine in 24 subjects.
Beta-blockers: When beta-adrenergic receptor blocking drugs are administered concomitantly with amlodipine, patients should be carefully monitored since blood pressure lowering effect of beta-blockers may be augmented by amlodipine’s reduction in peripheral vascular resistance.
Adverse Reactions: Amlodipine has been administered to 1 714 patients (805 hypertensive and 909 angina patients) in controlled clinical trials (vs placebo alone and with active comparative agents). Most adverse reactions reported during therapy were of mild to moderate severity.
Hypertension: In the 805 hypertensive patients treated with amlodipine in controlled clinical trials, adverse effects were reported in 29.9% of patients and required discontinuation of therapy due to side effects in 1.9% of patients. The most common adverse reactions in controlled clinical trials were: edema (8.9%) and headache (8.3%).
The following adverse reactions were reported with an incidence of ³0.5% in the controlled clinical trials program (n=805): Cardiovascular: edema (8.9%), palpitations (2.0%), tachycardia (0.7%), postural dizziness (0.5%).
Skin and Appendages: pruritus (0.7%).
Musculoskeletal: muscle cramps (0.5%).
Central and Peripheral Nervous System: headache (8.3%), dizziness (3.0%), paresthesia (0.5%).
Autonomic Nervous System: flushing (3.1%), increased sweating (0.9%), dry mouth (0.7%).
Psychiatric: somnolence (1.4%).
Gastrointestinal: nausea (2.4%), abdominal pain (1.1%), dyspepsia (0.6%), constipation (0.5%).
General: fatigue (4.1%), pain (0.5%).
Angina: In the controlled clinical trials in 909 angina patients treated with amlodipine, adverse effects were reported in 30.5% of patients and required discontinuation of therapy due to side effects in 0.6% of patients. The most common adverse reactions reported in controlled clinical trials were: edema (9.9%) and headache (7.8%).
The following adverse reactions occurred at an incidence of ³0.5% in the controlled clinical trials program (n=909): Cardiovascular: edema (9.9%), palpitations (2.0%), postural dizziness (0.6%).
Skin and Appendages: rash (1.0%), pruritus (0.8%).
Musculoskeletal: muscle cramps (1.0%).
Central and Peripheral Nervous System: headache (7.8%), dizziness (4.5%), paresthesia (1.0%), hypoesthesia (0.9%).
Autonomic Nervous System: flushing (1.9%).
Psychiatric: somnolence (1.2%), insomnia (0.9%), nervousness (0.7%).
Gastrointestinal: nausea (4.2%), abdominal pain (2.2%), dyspepsia (1.4%), diarrhea (1.1%), flatulence (1.0%), constipation (0.9%).
Respiratory: dyspnea (1.1%).
Special Senses: vision abnormal (1.3%), tinnitus (0.6%).
General: fatigue (4.8%), pain (1.0%), asthenia (1.0%).
Amlodipine has been evaluated for safety in about 11 000 patients with hypertension and angina. The following events occurred in 0.1% of patients in comparative clinical trials (double-blind comparative vs placebo or active agents; n=2 615) or under conditions of open trials or marketing experience where a causal relationship is uncertain.
Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension.
Central and Peripheral Nervous System: hypoesthesia, tremor, vertigo.
Gastrointestinal: anorexia, constipation, dysphagia, vomiting, gingival hyperplasia.
General: asthenia back pain, hot flushes, malaise, rigors, weight gain.
Musculoskeletal: arthralgia, arthrosis, myalgia.
Psychiatric: sexual dysfunction (maleand female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
Skin and Appendages: pruritus rash erythematous, rash maculopapular, erythema multiforme.
Special Senses: conjunctivitis, diplopia, eye pain, tinnitus.
Urinary: micturition frequency, micturition disorder, nocturia.
Autonomic Nervous System: dry mouth, sweating increased.
Metabolic and Nutritional: thirst.
hese events occurred in less than 1% in placebo controlled trials, but the incidence of these side effects was between 1 and 2% in all multiple dose studies.
The following events occurred in 0.1% of patients: cardiac failure, skin discoloration, urticaria, skin dryness, Stevens-Johnson syndrome, alopecia, twitching, ataxia, hypertonia, migraine, apathy, amnesia, gastritis, pancreatitis, increased appetite, coughing, rhinitis, parosmia, taste perversion, and xerophthalmia.
Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty.
In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) in some cases severe enough to require hospitalization have been reported in association with use of amlodipine.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage can cause excessive peripheral vasodilation with marked and probably prolonged hypotension and possibly a reflex tachycardia. In humans, experience with overdosage of amlodipine is limited. When amlodipine was ingested at doses of 105 to 250 mg some patients remained normotensive with or without gastric lavage while another patient experienced hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who took 70 mg of amlodipine with benzodiazepine developed shock which was refractory to treatment and died. In a 19 month old child who ingested 30 mg of amlodipine (about 2 mg/kg) there was no evidence of hypotension but tachycardia (180 bpm) was observed. Ipecac was administered 3.5 hours after ingestion and on subsequent observation (overnight) no sequelae were noted.
Treatment: Clinically significant hypotension due to overdosage requires active cardiovascular support including monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor (such as nonrepinephrine) may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit. I.V. calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Clearance of amlodipine is prolonged in elderly patients and in patients with impaired liver function. Since amlodipine absorption is slow, gastric lavage may be worthwhile in some cases.
Dosage And Administration: Dosage should be individualized depending on patient’s tolerance and responsiveness.
For both hypertension and angina, the recommended initial dose is 5 mg once daily. If necessary, dose can be increased after 1 to 2 weeks to a maximum dose of 10 mg once daily.
Geriatrics or Patients with Impaired Renal Function: The recommended initial dose in patients over 65 years of age or patients with impaired renal function is 5 mg once daily. If required, increasing in the dose should be done gradually and with caution (see Precautions).
Patients with Impaired Hepatic Function: Dosage requirements have not been established in patients with impaired hepatic function. When amlodipine is used in these patients, the dosage should be carefully and gradually adjusted depending on patients tolerance and response. A lower starting dose of 2.5 mg once daily should be considered (see Warnings).
Availability And Storage: 5 mg: Each white, octagonal tablet, scored, debossed on one face as NRV 5 with Pfizer on the opposite face, contains: amlodipine besylate equivalent to amlodipine 5 mg. Nonmedicinal ingredients: dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. White plastic (high density polyethylene) bottles of 100 and 250.
10 mg: Each white, octagonal tablet, debossed on one face as NRV 10 with Pfizer on the opposite face, contains: amlodipine besylate equivalent to amlodipine 10 mg. Nonmedicinal ingredients: dibasic calcium phosphate anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. White plastic (high density polyethylene) bottles of 100 and 250.
Store at 15 to 30°C. Protect from light.
NORVASC Pfizer Amlodipine Besylate Antihypertensive – Antianginal
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