Nimodipine

Nimodipine is an antihypertensive agent belonging to Calcium Channel Blocker.

Nimodipine is a calcium channel blocker used to improve neurological outcomes in patients with subarachnoid hemorrhage due to a ruptured intracranial aneurysm.

Nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. Bioavailability is 100% following intravenous administration and 3-30% following oral administration due to extensive first-pass metabolism. Crosses blood-brain barrier but concentrations in CSF are lower than those in plasma. Plasma protein binding: >95%. The metabolism of nimodipine is mediated by CYP3A4. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug.

Nimodipine shows common side effects like Low blood pressure (feeling light-headed), nausea, upset stomach, slow heartbeats, and muscle pain, etc.

Nimodipine is available in the form of Oral Capsule and Oral Suspension.

Nimodipine is available in India, US, UK, Ireland, Canada, Japan and China.

Nimodipine belonging to the Calcium Channel Blocker acts as an antihypertensive agent.

Nimodipine blocks intracellular influx of calcium through voltage-dependent and receptor-operated slow calcium channels across the membranes of myocardial, vascular smooth muscle, and neuronal cells. By specifically binding to L-type voltage-gated calcium channels, Nimodipine inhibits the calcium ion transfer, resulting in the inhibition of vascular smooth muscle contraction. Evidence suggests that the dilation of small cerebral resistance vessels, with a resultant increase in collateral circulation, and/or a direct effect involving the prevention of calcium overload in neurons may be responsible for nimodipine's clinical effect in patients with subarachnoid hemorrhage.

The Data of the Onset of action and Duration of Action of Nimodipine is not available.

The Tmax was found within 0.25-1.05 hours of the administration of Nimodipine.

Nimodipine is available in the form of Oral capsules and Oral solutions.

Nimodipine is taken orally every 4 hours for 21 consecutive days.

Nimodipine is used to treat and prevent brain damage due to a subarachnoid hemorrhage, a life-threatening condition that occurs due to the rupture of a blood vessel in the brain causing bleeding in the space surrounding the brain. This medicine is not recommended for use in children below 18 years of age.

Nimodipine is an antihypertensive agent belonging to Calcium Channel Blocker.

Nimodipine has a greater effect on cerebral arterials than other arterials; this increased specificity may be due to the drug's increased lipophilicity and cerebral distribution as compared to nifedipine; which inhibits calcium ion from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization.

Nimodipine is approved for use in the following clinical indications

• Subarachnoid hemorrhage

Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).

• Subarachnoid hemorrhage

Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. For all routes of administration, begin Nimodipine within 96 hours of the onset of Subarachnoid Hemorrhage. Administer one hour before a meal or two hours after a meal for all routes of administration.

Administration By Oral Route

The recommended oral dosage is 10 mL (60 mg) every 4 hours for 21 consecutive days.

Administration Via Nasogastric or Gastric Tube

Using the supplied prefilled oral syringe labeled “For Oral Use Only”, administer 10 mL (60 mg) every 4 hours into a nasogastric or gastric tube for 21 consecutive days. For each dose, refill the syringe with 10 mL of 0.9% saline solution and then flush any remaining contents from the nasogastric or gastric tube into the stomach.

Nimodipine is available in various strengths as Oral Capsule (30 mg) and Oral Solutions (30 mg/10 mL; 30 mg/5 mL; 60 mg/10 mL; 60 mg/20 mL)

Do not drink grapefruit juice or eat grapefruit while you are taking Nimodipine.

Nimodipine is contraindicated in patients with

● Hypersensitivity to Nimodipine or any component of the formulation.

● Concomitant use with phenobarbital, phenytoin, carbamazepine, or Rifampin.

● Concomitant use with strong CYP3A4 inhibitors (eg, clarithromycin, telithromycin, delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, and nefazodone).

• Angina/MI

Increased angina and/or MI have occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade.

• Gastrointestinal events

Intestinal pseudo-obstruction and ileus have been reported (rarely) during therapy.

• Hypotension/syncope

Symptomatic hypotension with or without syncope can occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Monitor blood pressure closely during treatment.

• Peripheral edema

Peripheral edema is a common adverse event; occurs within 2-3 weeks of starting therapy.

• Hepatic impairment

Use with caution in patients with cirrhosis due to the increased plasma concentrations of nimodipine and an increased risk of adverse reactions; a lower dose and close monitoring of blood pressure and heart rate are required.

• Hypertrophic cardiomyopathy with outflow tract obstruction

Use with caution in patients with hypertrophic cardiomyopathy with outflow tract obstruction.

Consumption of alcohol is not recommended while receiving Nimodipine as it may increase the risk of adverse effects like dizziness, fainting, lightheadedness, headache, etc.

Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, nursing mothers are advised not to breastfeed their babies when taking the drug.

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

Do not drink grapefruit juice or eat grapefruit while you are taking Nimodipine.

• Common Adverse effects

Reductions in systemic blood pressure, Headache, Rash, Diarrhoea, and abdominal discomfort.

• Rare Adverse effect

Edema, EKG abnormalities, tachycardia, bradycardia, depression, acne, nausea, hemorrhage, hepatitis, muscle cramps/pain, dyspnea, itching, GI hemorrhage, thrombocytopenia, anemia, palpitations, vomiting, flushing, diaphoresis, wheezing, lightheadedness, dizziness, rebound vasospasm, jaundice, hypertension, hematoma, neurological deterioration, congestive heart failure, hyponatremia, disseminated intravascular coagulation, deep vein thrombosis.

• Blood Pressure Lowering

Drugs Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives such as diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, other calcium channel blockers, α-adrenergic blockers, PDE5 inhibitors, and α-methyldopa. In Europe, nimodipine was observed to occasionally intensify the effect of antihypertensive drugs taken concomitantly by hypertensive patients; this phenomenon was not observed in North American clinical trials. Blood pressure should be carefully monitored, and dose adjustment of the blood pressure lowering drug(s) may be necessary.

• CYP3A4 Inhibitors

Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong CYP3A4 inhibitors. As a consequence, the blood pressure lowering effect may be increased. Therefore, the concomitant administration of NIMODIPINE and strong CYP3A4 inhibitors should generally be avoided. Strong CYP3A4 inhibitors include some members of the following classes: - macrolide antibiotics (e.g., clarithromycin, telithromycin,), - HIV protease inhibitors (e.g. indinavir, nelfinavir, ritonavir, saquinavir), - HCV protease inhibitors (e.g., boceprevir, telaprevir), - azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), - conivaptan, delaviridine, nefazodone Nimodipine plasma concentration can also be increased in the presence of moderate and weak inhibitors of CYP3A4. If nimodipine is concomitantly administered with these drugs, blood pressure should be monitored, and a reduction of the nimodipine dose may be necessary. Moderate and weak CYP3A4 inhibitors include alprozalam, ameprenavir, amiodarone, aprepitant, atazanavir, cimetidine, cyclosporine, diltiazem, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalforpristin, valproic acid, and verapamil. A study in eight healthy volunteers has shown a 50% increase in mean peak nimodipine plasma concentrations and a 90% increase in mean area under the curve, after a one-week course of cimetidine at 1,000 mg/day and nimodipine at 90 mg/day. This effect may be mediated by the known inhibition of hepatic cytochrome P-450 (CYP) by cimetidine, which could decrease first-pass metabolism of nimodipine. Grapefruit juice inhibits CYP3A4. Ingestion of grapefruit/grapefruit juice is not recommended while taking nimodipine.

• CYP3A4 Inducers

Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore, concomitant use of NIMODIPINE with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort) should generally be avoided. Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inducers include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirnenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone, rufinamide, and vemurafenib.

The common side effect of Nimodipine include the following

• Common

Low blood pressure (feeling light-headed), nausea, upset stomach, slow heartbeats, and muscle pain.

• Rare

Hives, difficulty breathing, swelling of the face, lips, tongue, or throat, lightheadedness, fast or slow heart rate, and swelling of the ankles or feet.

• Pregnancy

Pregnancy Category C.

Nimodipine has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted fetuses were increased at oral doses of 1 and 10 mg/kg/day administered (by gavage) from day 6 through day 18 of pregnancy but not at 3.0 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted fetuses was seen at 1.0 mg/kg/day but not at higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses, in Long Evans rats at 100 mg/kg/day administered by gavage from day 6 through day 15 of pregnancy. In two other rat studies, doses of 30 mg/kg/day nimodipine administered by gavage from day 16 of gestation and continued until sacrifice (day 20 of pregnancy or day 21 post partum) were associated with higher incidences of skeletal variation, stunted fetuses and stillbirths but no malformations. There are no adequate and well controlled studies in pregnant women to directly assess the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, nursing mothers are advised not to breast feed their babies when taking the drug.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Clinical studies of Nimodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

There have been no reports of overdosage from the oral administration of nimodipine. Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly. Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmacodynamic

Nimodipine belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured congenital aneurysms who are in good neurological condition post-ictus (e.g., Hunt and Hess Grades I-III). The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier.

Pharmacokinetics

• Absorption

Nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. Bioavailability is 100% following intravenous administration and 3-30% following oral administration due to extensive first-pass metabolism.

• Distribution

Crosses blood-brain barrier but concentrations in CSF are lower than those in plasma. Plasma protein binding: >95%.

• Metabolism and Excretion

The metabolism of nimodipine is mediated by CYP3A4. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug

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