(-)-α-[3-[[2-(3,4-ジメトキシフェニル)エチル](メチル)アミノ]プロピル]-3,4-ジメトキシ-α-(1-メチルエチル)ベンゼンアセトニトリル

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

log Kow = 3.79 at pH 9.0; log Kow = 2.15 at pH 7.0

3.79

Solubility (mg/mL): water 83, ethanol (200 proof) 26, propylene glycol 93, ethanol (190 proof) >100, methanol >100, 2-propanol 4.6, ethyl acetate 1.0, DMF >100, methylene chloride >100, hexane 0.001; Freely soluble in chloroform, practically insoluble in ether /Verapamil hydrochloride/

Practically insoluble in water

Sparingly soluble in hexane; soluble in benzene, ether; freely soluble in the lower alcohols, acetone, ethyl acetate, chloroform

4.47 mg/L

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

Pharmaceuticals

Antianginal medicines

BP: 245 °C at 0.01 mm Hg

243-246 °C at 1.00E-02 mm Hg

Stable under recommended storage conditions. /Verapamil hydrochloride/

Verapamil HCl should be stored at room temperature & protected from light. Infusion soln stability studies indicate that verapamil HCl does not adsorb to glass, PVC, or polyolefin containers. It is physically compatible in soln over a pH range of 3-6 but may precipitate in solns having a pH >6 or 7.

Danger

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

P261, P262, P264, P270, P271, P280, P301+P316, P302+P352, P304+P340, P316, P321, P330, P361+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 53 reports by companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

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

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

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

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Verapamil hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. 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. /Verapamil hydrochloride/

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. /Verapamil hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. /Verapamil hydrochloride/

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. /Verapamil hydrochloride/

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. /Verapamil hydrochloride/

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. /Verapamil hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Verapamil hydrochloride/

Skin protection: Handle with gloves. /Verapamil hydrochloride/

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. /Verapamil hydrochloride/

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Verapamil hydrochloride/

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. (L1712)

Drug interactions: protein-bound drugs

Drug Interactions: beta-adrenergic blocking agents

Drug Interactions: digoxin

Drug Interactions: hypotensive agents

For more Interactions (Complete) data for Verapamil (42 total), please visit the HSDB record page.

Cardiovascular: angina pectoris, AV block (2° & 3°), atrioventricular dissociation, CHF, pulmonary edema, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive system: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and lymphatic: ecchymosis or bruising. Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special senses: blurred vision, tinnitus. Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence.

Chronic therapy with verapamil is associated with a low rate of serum aminotransferase elevations that are usually mild and may resolve even with continuation of therapy. Clinically apparent liver injury with jaundice or symptoms from verapamil is uncommon and usually presents with fatigue, weakness with or without jaundice 2 to 8 weeks after starting the drug. The pattern of injury is usually mixed or cholestatic. Acute presentation can include fever, rash, arthralgias and eosinophilia, but these immunoallergic features are rarely prominent. Rapid recurrence with rechallenge has been reported. Autoantibodies are usually not present. Most cases have been mild and self-limited. Recovery is prompt with stopping verapamil and no cases of chronic hepatitis or vanishing bile duct syndrome have been attributed to its use. At least a dozen instances of acute liver injury attributed to verapamil have been published and the nature of the reaction is probably an idiosyncratic and immunologic.

LC50; Species: Daphnia magna (Water flea) neonate; Conditions: freshwater, static, ASTM hard water; Concentration: 11330 ug/L for 48 hr /99% purity/

LC50; Species: Pimephales promelas (Fathead Minnow) age <48 hr eggs; Conditions: freshwater, renewal, 22-24 °C, pH 8.3-8.5, hardness 110-150 mg/L CaCO3, alkalinity 100-130 mg/L CaCO3, dissolved oxygen 7.5-8.0 mg/L; Concentration: 600 ug/L for 28 days post-hatch

LC50; Species: Oncorhynchus mykiss (Rainbow Trout) juvenile; Conditions: freshwater, renewal, 15 °C, pH 7.4, dissolved oxygen 7.5-8.0 mg/L; Concentration: 2720 ug/L for 96 hr (95% confidence interval: 1980-3780 ug/L) /formulation/

TERRESTRIAL FATE: Based on a classification scheme(1), an approximated Koc value on the order of 1X10+5(SRC), derived from measured soil and sediment Kd values ranging from 1,341 to 5,876 L/kg(2), indicates that verapamil is expected to be immobile in soil(SRC). The pKa of verapamil is 8.92(3), indicating that this compound will exist mostly in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of verapamil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 8.8X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Verapamil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Utilizing method OECD 301D (Closed Bottle Test) with a municipal sewage treatment plant inoculum, verapamil showed virtually zero biodegradation within an initial 14 day incubation period and failed the ready biodegradability criteria(6). In a Zahn-Wellens test, verapamil reached 30% biodegradation in 9 days with a 7-day lag period, but no additional degradation occurred through a total of 30 days(6).

AQUATIC FATE: Based on a classification scheme(1), an approximated Koc value on the order of 1X10+5(SRC), derived from measured soil and sediment Kd values ranging from 1,341 to 5,876 L/kg(2), indicates that verapamil 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 8.8X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), a BCF range of 6.6-16.6 measured in carp (Cyprinus carpio)(6) suggests the potential for bioconcentration in aquatic organisms is low(SRC). Utilizing method OECD 301D (Closed Bottle Test) with a municipal sewage treatment plant inoculum, verapamil showed virtually zero biodegradation within an initial 14 day incubation period and failed the ready biodegradability criteria(7). In a Zahn-Wellens test, verapamil reached 30% biodegradation in 9 days with a 7-day lag period, but no additional degradation occurred through a total of 30 days(7). Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions(3).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), verapamil, which has an estimated vapor pressure of 4.2X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase the ambient atmosphere. Particulate-phase verapamil may be removed from the air by wet and dry deposition(SRC). Verapamil absorbs very weakly at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

EXPERIMENTAL: Verapamil is excreted into breast milk. A daily dose of 240 mg produced milk levels that were approx 23% of maternal serum. Serum levels in the infant were 2.1 ng/mL but could not be detected (<1 ng/mL) 38 hrs after treatment was stopped. ... In a second case, a mother was treated with 80 mg 3 times/day for hypertension for 4 wks prior to the determination of serum and milk concentrations. Steady-state concentrations of verapamil and the metabolite, norverapamil, in milk were 25.8 and 8.8 ng/mLl, respectively. These values were 60% and 16% of the concentrations in plasma. The investigators estimated that the breast-fed child received <0.01% of the mother's dose. Neither verapamil nor the metabolite could be detected in the plasma of the child. /Salt not specified/

IDENTIFICATION AND USE: Verapamil is the drug of choice for prevention and treatment of paroxysmal supraventricular tachycardia. Verapamil has been shown to be effective in the treatment of angina pectoris. Verapamil may be used as an alternative treatment for mild or moderate hypertension. HUMAN STUDIES: Verapamil has a vasodilating action on the vascular system. Toxic effects occur usually after a delay of 1 to 5 hours following ingestion. After IV injection, symptoms appear after a few minutes. The main cardiovascular symptoms are: bradycardia and atrioventricular block (in 82% of cases) hypotension and cardiogenic shock (in 78% of cases) cardiac arrest (in 18% of cases). Pulmonary edema may occur. Impairment of consciousness and seizures may occur and are related to a low cardiac output. Nausea and vomiting may be observed. Metabolic acidosis due to shock and hyperglycemia may occur. Verapamil is a calcium channel blocker and inhibits the entry of calcium through calcium channels into cardiovascular cells. Verapamil reduces the magnitude of the calcium current entry and decreases the rate of recovery of the channel. Verapamil decreases peripheral vascular and coronary resistance but it is a less potent vasodilator than nifedipine. In contrast, its cardiac effects are more prominent than those of nifedipine. At doses necessary to produce arterial vasodilatation, verapamil has much greater negative chronotropic, dromotropic and inotropic effects than nifedipine. At toxic doses, calcium channel inhibition by verapamil results in three principal effects: hypotension due to arterial vasodilatation, cardiogenic shock secondary to a negative inotropic effect, bradycardia and atrio-ventricular block. The therapeutic effects of verapamil on hypertension and angina pectoris are due to arterial systemic and coronary vasodilatation. The antiarrhythmic activity of verapamil is due to a delay in impulse transmission through the AV node by a direct action. Toxicity may occur after ingestion of 1 g. Verapamil was tested on human peripheral lymphocytes in vitro using micronucleus (MN) test. The MN frequencies showed increase after all treatment. The results of FISH analysis suggest that verapamil, separately or combined with ritodrine, shows to a larger extent aneugenic than clastogenic effect. ANIMAL STUDIES: Verapamil promotes atrial fibrillation in normal dogs. In swine, verapamil toxicity, as defined by a mean arterial pressure of 45% of baseline, was produced following an average verapamil infusion dose of 0.6 +/- 0.12 mg/kg. This dose produced an average plasma verapamil concentration of 728.1 +/- 155.4 ug/L. Hypertonic sodium bicarbonate reversed the hypotension and cardiac output depression of severe verapamil toxicity in a swine model. ECOTOXICITY STUDIES: Effects of long-term exposure of verapamil on mutagenic, hematological parameters and activities of the oxidative enzymes of Nile tilapia, Oreochromis niloticus were investigated for 60 days exposure at the concentrations of 0.29, 0.58 and 1.15 mg/L in the fish liver. The exposure resulted in significantly high micronuclei induction of peripheral blood cells. The indices of oxidative stress biomarkers (lipid peroxidation and carbonyl protein) showed elevated level. There was increase in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST). In other experiments, exposure to sub-lethal concentrations of verapamil (0.14, 0.29 and 0.57 mg/L) for period of 15, 30, 45 and 60 days, led to inhibition of acetylcholinesterase activities in the brain and muscle of the fish. Transcription of catalase (CAT), superoxide dismutase (SOD) and heat shock proteins 70 (hsp70) were up-regulated in both the tissues after the study period. In Carassius auratus, the behavioral alterations were observed in the form of respiratory difficulty and loss of body balance confirming the cardiovascular toxicity caused by verapamil at higher doses. In addition to affecting the cardiovascular system, verapamil also showed effects on the nervous system in the form of altered expression of parvalbumin. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae of common carp (Cyprinus carpio). In the D. magna chronic toxicity test, several parameters, such as the survival percentage, the body length of D. magna, the time of first reproduction, and the number of offspring per female, were adversely affected during the exposure to 4.2 mg/L verapamil. During the 24-hr short-term exposure, verapamil caused a downregulated expression of the CYP4 and CYP314 genes. During the 21-day long-term exposure, verapamil significantly reduced the expression level of the Vtg gene, a biomarker of the reproduction ability in an oviparous animal.

Like all calcium channel blockers, an overdose of verapamil can lead to negative inotropic and chronotropic effects, dilation of arterial vasculature, and hypotension. Additionally, verapamil’s blockade of slow calcium channels in pancreatic beta cells can lead to inhibited insulin release, thereby causing hyperglycemia. If a patient experiences bradycardia with hypotension/metabolic acidosis and hyperglycemia is indicative of verapamil toxicity. The most serious complications from a verapamil overdose are bradycardia and hypotension, as both can lead to death if the patient is left untreated.

Verapamil inhibits voltage-dependent calcium channels. Specifically, its effect on L-type calcium channels in the heart causes a reduction in ionotropy and chronotropy, thuis reducing heart rate and blood pressure. Verapamil's mechanism of effect in cluster headache is thought to be linked to its calcium-channel blocker effect, but which channel subtypes are involved is presently not known.

/AQUATIC SPECIES/ The influx of pharmaceutical drugs and their metabolites have been reported to cause negative impact on aquatic biota. In this study, effects of long-term exposure of verapamil on mutagenic, hematological parameters and activities of the oxidative enzymes of Nile tilapia, Oreochromis niloticus were investigated for 60 days exposure at the concentrations of 0.29, 0.58 and 1.15 mg/L in the fish liver. The exposure resulted in significantly high (p<0.05) micronuclei induction of peripheral blood cells at the peak on day 30 at 1.15 mg/L. Compared with the control, there was significant increase (p<0.05) in white blood cell counts and red blood cell distribution width (RDW), with a reduction in hemoglobin (Hb), red blood cell counts (RBCs), mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) level as the concentration of the drug increased. The indices of oxidative stress biomarkers (lipid peroxidation and carbonyl protein) showed elevated level, depicting a positive correlation with both time and concentration. More so, the activity of energy-related parameter (Na+-K+- ATPase) in the tissue was significantly inhibited (p<0.05) at the end of 60 days exposure period. Further, the activity of catalase (CAT) was inhibited while reduced glutathione (GSH) level was decreased in the liver tissue. There was increase in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) after 30 days at 0.29 mg/L. The study demonstrated that prolonged exposure to verapamil at sublethal concentration can result in mutagenic effects and oxidative dysfunctions in O. niloticus.

/AQUATIC SPECIES/ Pharmaceutical drugs and their metabolites are detected in aquatic ecosystems and have been reported to cause ecotoxicological consequences to resident aquatic organisms. The study investigated the effects of acute and long-term exposure to verapamil on activities of acetylcholinesterase and antioxidant enzymes as well as mRNA expression of stress-related genes in brain and muscle tissues of Nile tilapia, Oreochromis niloticus. The 96 hr LC50 of verapamil to O. niloticus was 2.29 mg/L. Exposure to sub-lethal concentrations of verapamil (0.14, 0.29 and 0.57 mg/L) for period of 15, 30, 45 and 60 days, led to inhibition of acetylcholinesterase activities in the brain and muscle of the fish. The activities of the oxidative enzymes such as the catalase, superoxide dismutase and glutathione peroxidase were also inhibited in both the tissues while there was an increase in the activities of glutathione-S-transferase and reduced glutathione in the muscle after 15 days at 0.29 mg/L. Lipid peroxidation and carbonyl protein showed elevated level, indicating a positive correlation with both time and concentration. The activities of energy-related biomarker (Na+-K+-ATPase) in both the tissues were significantly inhibited (p<0.05) compared with the control. Transcription of catalase (cat), superoxide dismutase (sod) and heat shock proteins 70 (hsp70) were up-regulated in both the tissues after the study period. Prolonged exposure to sub-lethal verapamil can result in oxidative stress, up-regulation of stress-related genes and neurotoxicity in O. niloticus.

/AQUATIC SPECIES/ The influx of calcium ions (Ca(2+)) is responsible for various physiological events including neurotransmitter release and synaptic modulation. The L-type voltage dependent calcium channels (L-type VDCCs) transport Ca(2+) across the membrane. Calcium-binding proteins (CaBPs) bind free cytosolic Ca(2+) and prevent excitotoxicity caused by sudden increase in cytoplasmic Ca(2+). The present study was aimed to understand the regulation of expression of neuronal CaBPs, namely, calretinin (CR) and parvalbumin (PV) following blockade of L-type VDCCs in the CNS of Carassius auratus. Verapamil (VRP), a potent L-type VDCC blocker, selectively blocks Ca(2+) entry at the plasma membrane level. VRP present in the aquatic environment at a very low residual concentration has shown ecotoxicological effects on aquatic animals. Following acute exposure for 96 hr, median lethal concentration (LC50) for VRP was found to be 1.22 mg/L for goldfish. At various doses of VRP, the behavioral alterations were observed in the form of respiratory difficulty and loss of body balance confirming the cardiovascular toxicity caused by VRP at higher doses. In addition to affecting the cardiovascular system, VRP also showed effects on the nervous system in the form of altered expression of PV. When compared with controls, the pattern of CR expression did not show any variations, while PV expression showed significant alterations in few neuronal populations such as the pretectal nucleus, inferior lobes, and the rostral corpus cerebellum. Our result suggests possible regulatory effect of calcium channel blockers on the expression of PV.

/AQUATIC SPECIES/ Verapamil is a pharmaceutical that belongs to a group of calcium channel blockers and is mainly used as a treatment of angina pectoris and arterial hypertension. Verapamil has been detected in aquatic environments in concentrations ranging from ng/L to ug/L. In the present study, a series of acute toxicity tests of verapamil on various developmental stages of common carp (Cyprinus carpio) were conducted. As a result, 96 hr LC50 values of verapamil were estimated at 16.4+/-9.2, 7.3+/-1.5 and 4.8+/-0.2 mg/L for embryos (E5-E9) and common carp larvae L2 and L5, respectively. Lethal concentrations of verapamil decreased with an increase in the age of the fish. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae. In an embryo-larval toxicity test (sub-chronic exposure), the bioconcentration, depuration, and toxic effects of verapamil were assessed in common carp. The fish were exposed to verapamil in a concentration of 0.463 (environmentally relevant), 4.63, 46.3 and 463 ug/L. Verapamil had no effect on the accumulated mortality, hatching, condition factor, growth or ontogeny of the fish in any of the tested concentrations. In carp exposed to 463 and 46.3 ug/L of verapamil, significantly higher occurrences of malformations and edemas were observed compared to the control. The bioconcentration factor of verapamil in whole fish homogenates ranged between 6.6 and 16.6 and was therefore below the critical value for hazard substances (BCF>500). The half-life and the 95% depuration time for the tested compound were estimated to be 10.2+/-1.6 days and 44.2+/-8.6 days, respectively. No effects of verapamil on the studied endpoints were observed at environmentally relevant concentrations.

For more Ecotoxicity Excerpts (Complete) data for Verapamil (10 total), please visit the HSDB record page.

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

C08DA01

C08DA01

C - Cardiovascular system

QC - Cardiovascular system

C08DA01

Verapamil is an L-type calcium channel blocker with antiarrhythmic, antianginal, and antihypertensive activity. Immediate-release verapamil has a relatively short duration of action, requiring dosing 3 to 4 times daily, but extended-release formulations are available that allow for once-daily dosing. As verapamil is a negative inotropic medication (i.e. it decreases the strength of myocardial contraction), it should not be used in patients with severe left ventricular dysfunction or hypertrophic cardiomyopathy as the decrease in contractility caused by verapamil may increase the risk of exacerbating these pre-existing conditions.

Verapamil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit,Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Verapamil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus. Verapamil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina. Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia. Verapamil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type). Verapamil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors.

Calcium antagonists inhibit excitation-contraction coupling in myocardial and smooth muscle by blocking the transmembrane carrier of calcium. This results in decreased myocardial contractility and in vasodilatation. ... /Salt not specified/

Verapamil has been shown to be neuroprotective in several acute neurotoxicity models due to blockade of calcium entry into neurons. However, the potential use of verapamil to treat chronic neurodegenerative diseases has not been reported. Using rat primary mesencephalic neuron/glia cultures, we report that verapamil significantly inhibited LPS-induced dopaminergic neurotoxicity in both pre- and post-treatment experiments. Reconstituted culture studies revealed that the presence of microglia was essential in verapamil-elicited neuroprotection. Mechanistic studies showed that decreased production of inflammatory mediators from LPS-stimulated microglia underlay neuroprotective property of verapamil. Further studies demonstrated that microglial NADPH oxidase (PHOX), the key superoxide-producing enzyme, but not calcium channel in neurons, is the site of action for the neuroprotective effect of verapamil. This conclusion was supported by the following two observations: 1) Verapamil failed to show protective effect on LPS-induced dopaminergic neurotoxicity in PHOX-deficient (deficient in the catalytic subunit of gp91(phox)) neuron/glia cultures; 2) Ligand binding studies showed that the binding of (3)H-verapamil onto gp91(phox) transfected COS7 cell membranes was higher than the non-transfected control. The calcium channel-independent neuroprotective property of verapamil was further supported by the finding that R(+)-verapamil, a less active form in blocking calcium channel, showed the same potency in neuroprotection, inhibition of pro-inflammatory factors production and binding capacity to gp91(phox) membranes as R(-)-verapamil, the active isomer of calcium channel blocker. In conclusion, our results demonstrate a new indication of verapamil-mediated neuroprotection through a calcium channel-independent pathway and provide a valuable avenue for the development of therapy for inflammation-related neurodegenerative diseases.

Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours.

The pharmacokinetics of verapamil and its metabolite, norverapamil, were studied in 10 patients (ages 19-69 yr) with portal hypertension and in 6 healthy subjects (ages 21-69 yr) who received an oral dose of 80 mg verapamil hydrochloride (Isoptin). The terminal phase half-life of verapamil was 210 hr in controls and 1384 hr in patients.

A toxicokinetic study performed in two cases showed plasma half lives of 7.9 and 13.2 hours, total body clearances of 425 and 298 mL/min. ...

Verapamil is extensively metabolized by the liver, with up to 80% of an administered dose subject to elimination via pre-systemic metabolism - interestingly, this first-pass metabolism appears to clear the S-enantiomer of verapamil much faster than the R-enantiomer. The remaining parent drug undergoes O-demethylation, N-dealkylation, and N-demethylation to a number of different metabolites via the cytochrome P450 enzyme system. Norverapamil, one of the major circulating metabolites, is the result of verapamil's N-demethylation via CYP2C8, CYP3A4, and CYP3A5, and carries approximately 20% of the cardiovascular activity of its parent drug. The other major pathway involved in verapamil metabolism is N-dealkylation via CYP2C8, CYP3A4, and CYP1A2 to the D-617 metabolite. Both norverapamil and D-617 are further metabolized by other CYP isoenzymes to various secondary metabolites. CYP2D6 and CYP2E1 have also been implicated in the metabolic pathway of verapamil, albeit to a minor extent. Minor pathways of verapamil metabolism involve its O-demethylation to D-703 via CYP2C8, CYP2C9, and CYP2C18, and to D-702 via CYP2C9 and CYP2C18. Several steps in verapamil's metabolic pathway show stereoselective preference for the S-enantiomer of the given substrate, including the generation of the D-620 metabolite by CYP3A4/5 and the D-617 metabolite by CYP2C8.

Metabolites: The main metabolite is norverapamil which has an elimination half-life very similar to that of the parent compound, ranging from 4 to 8 hours. Verapamil undergoes an extensive hepatic metabolism. Due to a large hepatic first-pass effect, bioavailability does not exceed 20 - 35% in normal subjects. Twelve metabolites have been described. The main metabolite is norverapamil and the others are various N- and 0-dealkylated metabolites. Elimination by route of exposure: Kidney: About 70% of the administered dose is excreted in urine within 5 days as metabolites, of which 3-4% is excreted as unchanged drug. Feces: About 16% of the ingested dose is excreted within 5 days in feces as metabolites. Breast milk: Verapamil may appear in breast milk.

Verapamil yields in the dog: 5-(3,4-dimethoxyphenethylamino)-2 -(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile; 2-(3,4-dimethoxyphenyl)-5 -(n-(4-hydroxy-3-methoxyphenethyl)methylamino)-2-isopropylvaleronitrile, and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-methylaminovaleronitrile. The latter was also found in rats. /From table/ /salt not specified/

Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240 mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.

The biotransformation pathway of verapamil, a widely prescribed calcium channel blocker, was investigated by electrochemistry (EC) coupled online to liquid chromatography (LC) and electrospray mass spectrometry (ESI-MS). Mimicry of the oxidative phase I metabolism was achieved in a simple amperometric thin-layer cell equipped with a boron-doped diamond (BDD) working electrode. Structures of the electrochemically generated metabolites were elucidated on the basis of accurate mass data and additional MS/MS experiments. We were able to demonstrate that all of the most important metabolic products of the calcium antagonist including norverapamil (formed by N-demethylation) can easily be simulated using this purely instrumental technique. Furthermore, newly reported metabolic reaction products like carbinolamines or imine methides become accessible. The results obtained by EC were compared with conventional in vitro studies by conducting incubations with rat as well as human liver microsomes (RLMs, HLMs). Both methods showed good agreement with the data from EC/LC/MS. Thus, it can be noted that EC is very well-suited for the simulation of the oxidative metabolism of verapamil. In summary, this study confirms that EC/LC/MS can be a powerful tool in drug discovery and development when applied complementary to established in vitro or in vivo approaches.

Mechanism-based inactivation (MBI) of cytochrome P450 (CYP) 3A by verapamil and the resulting drug-drug interactions have been studied in vitro, but the inhibition of verapamil on its own metabolic clearance in clinic, namely auto-inhibition of verapamil metabolism, has never been reproduced in vitro. This paper aimed to evaluate the utility of gel entrapped rat hepatocytes in reflecting such metabolic auto-inhibition using hepatocyte monolayer as a control. Despite being a similar concentration- and time-dependent profile, auto-inhibition of verapamil metabolism showed apparent distinctions between the two culture models. Firstly, gel entrapped hepatocytes were more sensitive to such inhibition, which could be largely due to their higher CYP3A activity detected by the formation rates of 6-beta-hydroxy testosterone and 1'-hydroxy midazolam. Furthermore, the inhibitory effect of ketoconazole and verapamil on CYP 3A activity as well as the reduction of verapamil intrinsic clearance (CL(int)) by ketoconazole was only observed in gel-entrapped hepatocytes. In this respect, the involvement of CYP3A in auto-inhibition of verapamil metabolism could be illustrated in gel-entrapped hepatocytes but not in hepatocyte monolayer. All of these results indicated that hepatocytes of gel entrapment reflected more of verapamil metabolic auto-inhibition than hepatocyte monolayer and could serve as a suitable system for investigating drug metabolism.

CJ0O37KU29

VERAPAMIL

Mechanisms of Action [MoA] - Calcium Channel Antagonists

Established Pharmacologic Class [EPC] - Calcium Channel Blocker

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

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

Drugs used to cause dilation of the blood vessels.

More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. Tmax) between 1-2 hours following administration, whereas sustained-release formulations tend to have a Tmax between 6 - 11 hours. AUC and Cmax values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC0-24h and Cmax values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively. Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state.

Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug.

Verapamil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer.

Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil.

/MILK/ Breast milk: Verapamil may appear in breast milk.

/MILK/ Verapamil is excreted into breast milk. A daily dose of 240 mg produced milk levels that were approx 23% of maternal serum. Serum levels in the infant were 2.1 ng/mL but could not be detected (<1 ng/mL) 38 hr after treatment was stopped. ... In a second case, a mother was treated with 80 mg 3 times/day for hypertension for 4 wk prior to the determination of serum & milk concns. Steady-state concentrations of verapamil and the metabolite, norverapamil, in milk were 25.8 and 8.8 ng/mL, respectively. These values were 60% and 16% of the concns in plasma. The investigators estimated that the breast-fed child received <0.01% of the mother's dose. Neither verapamil nor the metabolite could be detected in the plasma of the child.

Anti-Arrhythmia Agents; Calcium Channel Blockers; Vasodilator Agents

MEDICATION

Use (kg) in Switzerland (2009): >1000

Drug used for the treatment of hypertension, angina, and cluster headache prophylaxis.

Preparation: Belgium patent 615861; Dengel, United States of America patent 3261859 (1962, 1966 both to Knoll).

Veratryl chloride + isopropyl bromide + homoveratrylamine + 1-bromo-3-chloroporpane (dehydrobromination/methylation/amine formation/dehydrochlorination)

Trade Names: Isoptin (Knoll), Securon (Knoll Ltd.), Calan (Searle), Cardibeltin (Pharma Schwarz), Cordilox (Abbott); all preparations contain verapamil hydrochloride.

Table: Verapamil Hydrochloride Preparations [Table#4670]

Table: Verapamil Hydrochloride Combinations [Table#4671]

Pharmaceuticals -> Cardiovascular system -> Calcium channel blockers -> Selective calcium channel blockers with direct cardiac effects -> Phenylalkylamine derivatives -> Calcium antagonists

Pharmaceuticals

Available commercially as the free base or hydrochloride

Ca2+ channel antgonist which is unrelated chemically to nifedipine and nitrendipine.