Amlodipine

Pharmaceuticals

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Antihypertensives

log Kow = 3.00

3.00

3.09

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents

Pharmaceuticals

Antihypertensive medicines

Hazardous decomposition products formed under fire conditions - Carbon oxides, nitrogen oxides (NOx), sulfur oxides, hydrogen chloride gas. /Amlodipine besylate/

When heated to decomposition it emits toxic vapors of /nitric oxides/ and /hydrogen chloride/.

Mol wt 524.95. White crystals from ethyl acetate, mp 178-179 °C /Amlopidine maleate/

MW: 567.06. White crystalline powder. Slightly soluble in water; sparingly soluble in ethanol /Amlodipine benzenesulfonate/

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

P260, P264, P264+P265, P270, P273, P280, P301+P316, P305+P354+P338, P317, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P260, P264, P264+P265, P270, P273, P280, P301+P316, P302+P352, P305+P354+P338, P317, P319, P321, P330, P332+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Status: Active Update: 15-12-2008 https://echa.europa.eu/registration-dossier/-/registered-dossier/3689

Amlodipine: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amlodipine besylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amlodipine besylate/

Acute Tox. 3 (100%)

Acute Tox. 3 (100%)

Acute toxicity - category 3

Acute Tox. 3 *

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Amlodipine besylate/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Amlodipine besylate/

Keep container tightly closed in a dry and well-ventilated place. /Amlodipine besylate/

Store bottles at controlled room temperature, 59 deg to 86 °F (15 deg to 30 °C) and dispense in tight, light-resistant containers.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Amlodipine besylate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product. /Amlodipine besylate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Amlodipine besylate/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Amlodipine besylate/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Amlodipine besylate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Amlodipine besylate/

For more Preventive Measures (Complete) data for AMLODIPINE (6 total), please visit the HSDB record page.

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Amlodipine besylate/

Skin protection: Handle with gloves. /Amlodipine besylate/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Amlodipine besylate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Amlodipine besylate/

This open-label, crossover study was performed to establish if there is evidence for interaction between telmisartan, an angiotensin II antagonist, and amlodipine, a class II (dihydropyridine) calcium channel antagonist, on the basis of pharmacokinetics and safety. In a two-way crossover trial, 12 healthy Caucasian males were randomized to receive once daily for 9 days oral amlodipine 10 mg with or without oral telmisartan 120 mg. After a washout period of > or = 13 days, the subjects were switched to the other medication regimen. The geometric means of the primary pharmacokinetic parameters at steady state (day 9) for amlodipine when given alone were the following: maximum plasma concentration (Cmax) 17.7 ng/mL, area under the plasma concentration-time curve (AUC) 331 ng.hr/mL, and renal clearance 39.5 mL/min, with 8% of the total amlodipine dose being excreted. When concomitant telmisartan was given, the respective values were 18.7 ng/mL, 352 ng.hr/mL, and 43.0 mL/min, with 9.4% of the total amlodipine dose being excreted renally. The limits of the 90% confidence intervals (CIs) for the ratios of these steady-state parameters were 0.97 to 1.14 for Cmax and 0.98 to 1.16 for AUC; both were within the predefined reference range (0.8 to 1.25) for bioequivalence. The high intersubject variability in urinary amlodipine excretion resulted in bioequivalence not being demonstrated for renal clearance. Adverse effects were few, mild to moderate in intensity, and transient whether amlodipine was given alone or with telmisartan. Vital signs, except for blood pressure, and clinical laboratory values were unaffected by either medication. The findings of this study show that concomitant telmisartan and amlodipine may be administered as there is no clinically significant variation in primary pharmacokinetic parameters of amlodipine in the presence of telmisartan, and the safety of the combination is comparable to that of amlodipine alone.

Amlodipine is a representative calcium channel blocker that is frequently prescribed for the treatment of hypertension. In this study, the possibility of drug-drug interactions between amlodipine and coadministered antibiotics (ampicillin) was investigated in rats; thus, changes in the metabolic activities of gut microflora and the consequent pharmacokinetic pattern of amlodipine following ampicillin treatment were characterized. In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls. These results showed that antibiotic intake might increase the bioavailability of amlodipine by suppressing gut microbial metabolic activities, which could be followed by changes in therapeutic potency. Therefore, coadministration of amlodipine with antibiotics requires caution and clinical monitoring.

1. The antinociceptive effects of amlodipine, administered subcutaneously (sc), intracerebroventricularly (icv) and intrathecally (it) were examined with the acetic acid writhing and tail-flick tests in mice. Amlodipine was also tested in combination with morphine and ketorolac. Isobolographic analyses were used to define the nature of functional interactions between amlodipine and morphine or ketorolac. 2. The s.c. (0.1, 1.25, 2.5, 5 and 10 mg/kg), icv (2.5, 5, 10 and 20 ug/mice) and it (2.5, 5, 10 and 20 ug/mice) administration of amlodipine exhibited a dose-dependent antinociceptive effect in the writhing test but had no effect on the tail-flick latency. Isobolographic analyses revealed an additive interaction between amlodipine and morphine or ketorolac in the writhing test. 3. These results suggest that amlodipine induces antinociception and increases antinociceptive action of morphine and ketorolac, possibly through a decrease in cellular calcium availability.

...The purpose of this study was to investigate drug interactions between amlodipine and simvastatin. Eight patients with hypercholesterolemia and hypertension were enrolled. They were given 4 weeks of oral simvastatin (5 mg/day), followed by 4 weeks of oral amlodipine (5 mg/day) co-administered with simvastatin (5 mg/day). Combined treatment with simvastatin and amlodipine increased the peak concentration (C(max)) of HMG-CoA reductase inhibitors from 9.6 +/- 3.7 ng/mL to 13.7 +/- 4.7 ng/mL (p < 0.05) and the area under the concentration-time curve (AUC) from 34.3 +/- 16.5 ng h/mL to 43.9 +/- 16.6 ng h/mL (p < 0.05) without affecting the cholesterol-lowering effect of simvastatin. ...

For more Interactions (Complete) data for AMLODIPINE (13 total), please visit the HSDB record page.

Chronic therapy with amlodipine is associated with a low rate of serum enzyme elevations at rates that are similar to matched control populations. The enzyme elevations are usually mild, transient and asymptomatic and may resolve even during continued therapy. Clinically apparent liver injury from amlodipine is rare and described only in isolated case reports. In the few idiosyncratic cases reported, the latency period to onset of liver injury was usually 4 to 12 weeks, but examples with prolonged latency have also been published (10 months and several years). The latency period is shorter with recurrence on reexposure, including several instances of recurrence after liver injury due to other calcium channel blockers. The pattern of serum enzyme elevations is usually mixed or cholestatic. Rash, fever and eosinophilia have not been described and autoantibodies are not typical.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine is expected to have slight mobility in soil(SRC). Volatilization of amlodipine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(4) suggests that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3200(SRC), determined from a structure estimation method(2), indicates that amlodipine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.9X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 44(SRC), from its log Kow of 3.00(6) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). A biodegradation of 3% in 28 days using an aqueous ready biodegradability test(7) suggests that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amlodipine, which has an estimated vapor pressure of 1.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase amlodipine may be removed from the air by wet and dry deposition(SRC). Amlodipine contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The significant adverse effects of amlodipine include peripheral edema, heart failure, pulmonary edema, flushing, dizziness, headache, drowsiness, skin rash, nausea, abdominal pain, and constipation. Researchers observed edema, dizziness, flushing, and palpitations in controlled clinical trials in a dose-dependent manner. For example, at a dose of 10 mg, the incidence of edema, dizziness, flushing, and palpitations was 10.8%, 3.4%, 2.6%, and 4.5%, respectively. The incidence of headaches, fatigue, nausea, and abdominal pain was 7.3%, 4.5%, 2.9%, and 1.6%, respectively.

IDENTIFICATION AND USE: Amlodipine is calcium channel blocker used as antihypertensive and vasodilator agent. HUMAN EXPOSURE AND TOXICITY: One patient ingested 250 mg amlodipine and was asymptomatic. Another patient ingested 120 mg, underwent gastric lavage, and remained normotensive. A third patient took 105 mg and had hypotension (90/50 mmHG), which normalized following plasma expansion. A 19-month old ingested 30 mg (2 mg/kg) and had no evidence of hypotension but had a heart rate of 180 bpm. Children who ingested > 10 mg were 4.4 times more likely to develop clinically important responses than those ingesting < or = 5 mg. Hypotension may occur in children with amlodipine doses as low as 2.5 mg. ANIMAL STUDIES: Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed no evidence of a carcinogenic effect of the drug. Amlodipine has been shown to prolong the duration of labor in rats. No evidence of teratogenicity or other embryo/fetal toxicity was observed in rats or rabbits given up to 10 mg/kg during periods of major organogenesis. However, the number of intrauterine deaths increased about five-fold, and rat litter size was decreased by 50%. Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.

Signs and Symptoms of Overdose

Using a structure estimation method based on molecular connectivity indices(1), the Koc of amlodipine can be estimated to be 3200(SRC). According to a classification scheme(2), this estimated Koc value suggests that amlodipine is expected to have slight mobility in soil. Amlodipine has the potential to adsorb to wastewater treatment plant biosolids(3).

/SIGNS AND SYMPTOMS/ In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

/SIGNS AND SYMPTOMS/ Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of Norvasc is limited.

/CASE REPORTS/ A 35-year-old woman with a 9-year history of Grave's disease delivered a male infant weighing 2,210 g at 32 weeks of gestation by cesarean section. The neonate developed thyrotoxicosis and, at the age of 24 hr, was treated with oral carbimazole (500 ug every 8 hr) and propranolol (2 mg/kg/day in two divided doses). He subsequently developed hypertension on day 4, which required therapy with amlodipine (0.1 mg once daily). Severe hypotension developed within 24 hr and required discontinuation of amlodipine, with initiation of intravenous inotropic support with dopamine and dobutamine (at a rate of 20 ug/kg/min). The blood pressure rapidly normalized, and both dopamine and dobutamine infusions were stopped within 36 hr. A Naranjo assessment score of 6 was calculated, indicating that the severe hypotension was a probable adverse drug reaction caused by the combination of amlodipine and propranolol therapy.

/CASE REPORTS/ Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.

For more Human Toxicity Excerpts (Complete) data for AMLODIPINE (26 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

amlodipine

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 44 was calculated in fish for amlodipine(SRC), using a log Kow of 3.00(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Henry's Law constant for amlodipine is estimated as 2.9X10-17 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that amlodipine is expected to be essentially nonvolatile from water and moist soil surfaces(2). Amlodipine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-9 mm Hg(SRC), determined from a fragment constant method(3).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including amlodipine besylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amlodipine besylate/

C08CA01

C - Cardiovascular system

QC - Cardiovascular system

C08CA01

**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 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 was inhibited by amlodipine in a concentration-dependent manner and was significantly decreased at a concentration of 10 umol/L. IL-1beta production was also inhibited by 30 umol/L amlodipine. In contrast, neither diltiazem nor nifedipine inhibited the production of these cytokines. The unique property of amlodipine to inhibit the production of IL-1alpha, IL-1beta and IL-6 may contribute to its beneficial effects in heart failure patients.

Proliferation of vascular smooth muscle cells (VSMC) contributes to the progression of atherosclerotic plaques. Calcium channel blockers have been shown to reduce VSMC proliferation, but the underlying molecular mechanism remains unclear. p21(Waf1/Cip1) is a potent inhibitor of cell cycle progression. Here, /investigators/ demonstrate that amlodipine (10(-6) to 10(-8) M) activates de novo synthesis of p21(Waf1/Cip1) in vitro. /Investigators/ show that amlodipine-dependent activation of p21(Waf1/Cip1) involves the action of the glucocorticoid receptor (GR) and C/EBP-alpha. The underlying pathway apparently involves the action of mitogen-activated protein kinase or protein kinase C, but not of extracellular signal-related kinase or changes of intracellular calcium. Amlodipine-induced p21(Waf1/Cip1) promoter activity and expression were abrogated by C/EBP-alpha antisense oligonucleotide or by the GR antagonist RU486. Amlodipine-dependent inhibition of cell proliferation was partially reversed by RU486 at 10(-8) M (58%+/-29%), antisense oligonucleotides targeting C/EBP-alpha (91%+/-26%), or antisense mRNAs targeting p21(Waf1/Cip1) (96%+/-32%, n=6); scrambled antisense oligonucleotides or those directed against C/EBP-beta were ineffective. The data suggest that the anti-proliferative action of amlodipine is achieved by induction of the p21 (Waf1/Cip1) gene, which may explain beneficial covert effects of this widely used cardiovascular therapeutic drug beyond a more limited role as a vascular relaxant.

Calcium channel blockers (CCBs) are widely used in the therapy of cardiovascular diseases. Recent studies have shown that several CCBs exerted distinct anti-inflammatory effect in myocardial dysfunction models. The purpose of the present study was to evaluate therapeutic effect and possible mechanism of action of amlodipine, one of the widely used CCBs, on rat cardiac dysfunction during sepsis induced by lipopolysaccharide (LPS). Pretreatment of the rats with amlodipine (10 or 30 mg/kg, i.v.) delayed the fall of mean arterial blood pressure caused by LPS. Amlodipine also significantly inhibited the elevation of plasma tumor necrosis factor alpha (TNF-alpha) and decreased levels of inducible nitric oxide synthase (iNOS) in response to LPS challenge. To investigate the mechanism of the action of amlodipine, neonatal rat cardiomyocytes were used as a model. Amlodipine concentration-dependently decreased the release of TNF-alpha and iNOS protein expression, and suppressed the degradation and phosphorylation of inhibitor of kappaB-alpha (IkappaB-alpha) in LPS-activated neonatal rat cardiomyocytes. Further studies revealed that amlodipine markedly activated phosphatidylinositiol 3-kinase (PI3K) and Akt, downstream of the PI3K signal cascade. Application of PI3K inhibitors, wortmannin and LY294002 attenuated the depression of TNF-alpha and iNOS expression by amlodipine in LPS-induced cardiomyocytes. These findings may explain some cardioprotective effects of amlodipine in LPS-mediated sepsis and suggest that the inhibition of TNF-alpha and iNOS expression by amlodipine is, at least in part, dependent on PI3K/Akt signaling pathway.

The terminal elimination half-life of about 30–50 hours. Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment.

Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours.

... Following oral administration, /amlodipine has/ a terminal elimination half-life of 40 to 50 hr. ....

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.

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.

Metabolism of the dihydropyridine calcium antagonist (R,S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbony l-5- methoxycarbonyl- 6 -methyl- 1,4-dihydropyridine (amlodipine) has been studied in animals and man using (14)C-labelled drug. The metabolite patterns are complex; 18 metabolites have been isolated from rat, dog and human urine. Based on chromatographic and mass-spectral evidence, structures have been proposed for the main metabolites and confirmed by synthesis of unambiguous reference compounds. Comparison of all reference compounds and isolated metabolites was made by gas chromatography-mass spectrometry pressure liquid chromatography on-line thermospray-mass spectrometry of underivatised compounds directly in urine. The metabolites are largely pyridine derivatives. The methods used in structure designation are presented, along with the proposed route of metabolism, which indicates that the metabolic pattern for amlodipine in man has features in common with those of both rat and dog.

... Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans.

In the present study, the metabolic profile of amlodipine, a well-known calcium channel blocker, was investigated employing liquid chromatography-mass spectrometric (LC/MS) techniques. Two different types of mass spectrometers - a triple-quadrupole (QqQ) and a quadrupole time-of-flight (Q-TOF) mass spectrometer - were utilized to acquire structural information on amlodipine metabolites. The metabolites were produced by incubation of amlodipine with primary cultures of rat hepatocytes. Incubations from rat hepatocytes were analyzed with LC-MS/MS, and 21 phase I and phase II metabolites were detected. Their product ion spectra were acquired and interpreted, and structures were proposed. Accurate mass measurement using LC-Q-TOF was used to determine the elemental composition of metabolites and thus to confirm the proposed structures of these metabolites. Mainly phase I metabolic changes were observed including dehydrogenation of the dihydropyridine core, as well as reactions of side chains, such as hydrolysis of ester bonds, hydroxylation, N-acetylation, oxidative deamination, and their combinations. The only phase II metabolite detected was the glucuronide of a dehydrogenated, deaminated metabolite of amlodipine. /Investigators/ propose several in vitro metabolic pathways of amlodipine in rat, based on our analysis of the metabolites detected and characterized.

1J444QC288

AMLODIPINE

Mechanisms of Action [MoA] - Calcium Channel Antagonists

Established Pharmacologic Class [EPC] - Dihydropyridine Calcium Channel Blocker

Established Pharmacologic Class [EPC] - Calcium Channel Blocker

Chemical Structure [CS] - Dihydropyridines

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Drugs used to cause dilation of the blood vessels.

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.

Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing. Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure,.

21 L/kg,.

Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers,. Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required.

/MILK/ The aims of this study were to evaluate the plasma concentration of amlodipine and its passage into breast milk in lactating women with pregnancy-induced hypertension and to estimate the risk for breastfeeding infants. Thirty-one lactating women receiving oral amlodipine once daily for pregnancy-induced hypertension were enrolled. Pre-dose plasma and milk concentrations of amlodipine were determined at day 6 or later after starting the medication. Relative infant dose (RID) as an infant risk for breastfeeding was calculated by dividing the infant dose via milk by the maternal dose. The mean maternal dose of amlodipine was 6.0 mg. The medians of the plasma and milk concentrations of amlodipine were 15.5 and 11.5 ng/mL, respectively. Interindividual variation was observed in the amlodipine dose and body weight-adjusted milk concentrations (interquartile range [IQR], 96.7-205 ng/mL per mg/kg). The median and IQR of the amlodipine concentration ratio of milk to plasma were 0.85 and 0.74 to 1.08, respectively. The medians of infant birth weight and daily amlodipine dose via milk were 2170 g and 4.2 ug/kg, respectively. The median of the RID of amlodipine was 4.2% (IQR, 3.1%-7.3%). Lactating women with pregnancy-induced hypertension had higher plasma concentrations of amlodipine during the early postpartum period. Oral amlodipine transferred into breast milk at the same level as that of plasma. However, the RID of amlodipine in most patients was less than 10%.

After oral administration of therapeutic doses of Norvasc, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Norvasc is not altered by the presence of food.

MEDICATION (VET)

MEDICATION

Antihypertensive Agents; Calcium Channel Blockers; Vasodilator Agents

Use (kg; approx.) in Germany (2009): >7500

... 2-Chlorobenzaldehyde can be reacted with methyl acetoacetate to afford methyl 2-(2-chlorobenzylidene) acetoacetate, which upon reaction with the enamine, prepared by heating ethyl 4-(2-azidoethoxy)acetoacetate with ammonium acetate in ethanol under reflux, yields the desired intermediate of amlodipine.

Preparation: S.F. Campbell et al., European Patent Office patent 89167; eidem, United States of America patent 4572909 (1983, 1986 both to Pfizer).

Table: Amlodipine Besylate Preparations [Table#6696]

Table: Amlodipine Besylate Combinations Preparations [Table#6697]

Table: Amlodipine Besylate Combinations Preparations [Table#6698]