Nimodipine

Usage

Nimodipine is primarily indicated for improving neurological outcomes in patients with subarachnoid hemorrhage (SAH) resulting from ruptured intracranial berry aneurysms. It achieves this by reducing the incidence and severity of ischemic deficits, irrespective of the patient’s post-ictus neurological condition (Hunt and Hess Grades I-V). It’s important to initiate treatment as soon as possible, ideally within 96 hours of the SAH onset.

While not FDA-approved for these uses, nimodipine is sometimes prescribed off-label for migraine prophylaxis and acute ischemic stroke.

Pharmacological Classification: Calcium Channel Blocker, specifically a dihydropyridine calcium channel blocker.

Mechanism of Action: Nimodipine acts by selectively blocking L-type voltage-gated calcium channels, predominantly in cerebral arteries. This leads to cerebral vasodilation, improved cerebral blood flow, and reduced vasospasm, thereby protecting against ischemic damage following SAH.

Alternate Names

Nimodipine is the generic name. Brand names include Nimotop and Nymalize. There aren’t widely recognized alternate names or regional variations for the generic molecule itself.

How It Works

Pharmacodynamics: Nimodipine exerts its therapeutic effect primarily through cerebral vasodilation. It has high lipophilicity, allowing it to cross the blood-brain barrier effectively and concentrate in cerebral tissues. By blocking calcium influx into smooth muscle cells of cerebral arteries, it reduces vascular tone and prevents vasospasm.

Pharmacokinetics:

• Absorption: Well-absorbed orally, reaching peak plasma concentrations within 1 hour. Food can slightly delay but doesn’t significantly affect the extent of absorption.
• Metabolism: Extensively metabolized in the liver, primarily by CYP3A4 enzymes.
• Elimination: Excreted mainly in the urine as metabolites, with a small portion eliminated in feces. The elimination half-life is approximately 8-10 hours, requiring frequent dosing (every 4 hours).

Mode of Action: Nimodipine selectively blocks L-type voltage-gated calcium channels in cerebral vascular smooth muscle. This inhibits calcium influx, preventing contraction and promoting vasodilation. This selectivity for cerebral arteries minimizes its effects on systemic blood pressure compared to other dihydropyridine calcium channel blockers.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: The primary mechanism involves the blockade of L-type calcium channels. There is no significant interaction with other receptors, enzymes, or neurotransmitters.

Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by renal excretion of metabolites.

Dosage

Standard Dosage

Adults:

• Subarachnoid Hemorrhage: 60 mg (two 30 mg capsules or 10mL of oral solution) orally every 4 hours for 21 days. Treatment should begin within 96 hours of SAH onset. If swallowing is impaired, the capsule contents can be extracted and administered via nasogastric or gastric tube, followed by a flush with normal saline.

Children:

The safety and efficacy of nimodipine in children have not been established.

Special Cases:

• Elderly Patients: Although no specific dosage adjustments are recommended, caution is advised due to age-related decline in hepatic and renal function. Initiate at the lower end of the dosing range and monitor closely.
• Patients with Renal Impairment: No specific dosage adjustment is necessary.
• Patients with Hepatic Dysfunction (Cirrhosis): Reduce the dose to 30 mg orally every 4 hours. Monitor blood pressure and heart rate closely.
• Patients with Comorbid Conditions: Consider potential drug interactions and monitor for adverse effects, especially in patients with cardiovascular disease.

Clinical Use Cases

The standard dosage described above applies to the FDA-approved indication of subarachnoid hemorrhage. The dosing for off-label uses like migraine prophylaxis and acute ischemic stroke varies and isn’t standardized. Consult specialized literature or guidelines when considering off-label use. Nimodipine is not typically administered during procedures like intubation, or as part of routine ICU care unless specifically indicated for SAH management. It’s also not used in emergency situations like status epilepticus or cardiac arrest.

Dosage Adjustments

Dose reduction is primarily considered in patients with hepatic impairment, particularly cirrhosis. Concomitant use of strong CYP3A4 inhibitors may necessitate dose reduction if hypotension occurs.

Side Effects

Common Side Effects:

• Headache
• Hypotension
• Nausea
• Dizziness
• Peripheral Edema

Rare but Serious Side Effects:

• Myocardial Infarction
• Cardiac Arrest
• Hepatic Dysfunction (elevated liver enzymes)
• Ischemic Stroke

Long-Term Effects:

Long-term effects are not typically observed as treatment is for a limited duration (21 days). However, hepatic dysfunction can occur with long-term use.

Adverse Drug Reactions (ADR):

Serious ADRs like cardiac arrest, cardiovascular collapse, and severe hypotension require immediate intervention. Parenteral administration (IV) is contraindicated and has resulted in fatal outcomes.

Contraindications

• Hypersensitivity to nimodipine.
• IV administration or other parenteral routes.

Drug Interactions

Nimodipine is metabolized by CYP3A4.

• CYP3A4 Inhibitors: Concomitant use of strong or moderate CYP3A4 inhibitors (e.g., azole antifungals, macrolide antibiotics, grapefruit juice) can increase nimodipine plasma levels and risk of adverse effects, particularly hypotension. Dose reduction may be required.
• CYP3A4 Inducers: Strong CYP3A4 inducers (e.g., rifampin, carbamazepine) can decrease nimodipine plasma levels and efficacy. Avoid concomitant use if possible or monitor for loss of effect and consider dose adjustments.
• Other interactions include those with antihypertensives (additive hypotensive effects) and other medications metabolized by CYP3A4.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Breastfeeding: It is unknown whether nimodipine is excreted in human milk. Due to the potential for adverse effects in nursing infants, breastfeeding is not recommended during nimodipine therapy.

Drug Profile Summary

• Mechanism of Action: Selective blockade of L-type calcium channels in cerebral arteries, leading to vasodilation and improved cerebral blood flow.
• Side Effects: Headache, hypotension, nausea, dizziness, peripheral edema. Serious but rare: myocardial infarction, cardiac arrest, hepatic dysfunction.
• Contraindications: Hypersensitivity, IV administration.
• Drug Interactions: CYP3A4 inhibitors and inducers, antihypertensives.
• Pregnancy & Breastfeeding: Category C; use with caution in pregnancy. Breastfeeding is not recommended.
• Dosage: 60 mg orally every 4 hours for 21 days for SAH. Dose reduction for hepatic impairment.
• Monitoring Parameters: Blood pressure, heart rate, liver function tests.

Popular Combinations

Nimodipine is typically used as monotherapy for SAH. Combinations with other agents are based on individual patient needs and the management of other conditions. For example, antihypertensives may be needed to manage blood pressure, but careful monitoring for excessive hypotension is crucial.

Precautions

• General Precautions: Monitor blood pressure, heart rate, and liver function. Screen for hepatic impairment before initiating therapy.
• Specific Populations: Use with caution in elderly patients. Dose adjustment for hepatic impairment. Avoid use during pregnancy/breastfeeding if possible. Safety and efficacy in children haven’t been established.
• Lifestyle Considerations: Alcohol may potentiate the hypotensive effects. No specific restrictions on smoking or diet, other than avoiding grapefruit juice. Advise patients against operating machinery if experiencing dizziness or other CNS side effects.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Nimodipine?

A: For SAH in adults, 60mg orally every 4 hours for 21 days. For hepatic impairment (cirrhosis), reduce to 30mg every 4 hours.

Q2: Can Nimodipine be given intravenously?

A: No. Intravenous administration is contraindicated and can be fatal. Only oral, nasogastric, or gastric tube administration is permitted.

Q3: When should Nimodipine be started after SAH?

A: As soon as possible, and within 96 hours of SAH onset.

Q4: What are the most serious side effects of Nimodipine?

A: Cardiac arrest, cardiovascular collapse, severe hypotension, myocardial infarction, and hepatic dysfunction.

Q5: How does Nimodipine interact with grapefruit juice?

A: Grapefruit juice inhibits CYP3A4, increasing nimodipine plasma levels and the risk of side effects like hypotension. Avoid concurrent use.

Q6: Is Nimodipine safe in pregnancy?

A: Nimodipine is Pregnancy Category C. Use with caution only if the potential benefit outweighs the risk to the fetus.

Q7: Does Nimodipine require dose adjustment in renal failure?

A: No. No dose adjustment is needed in renal impairment.

Q8: Can Nimodipine be used for migraine prevention?

A: While sometimes used off-label for migraine prophylaxis, its efficacy for this purpose is not robustly established. Consult specialized literature if considering off-label use.

Q9: What should be monitored during Nimodipine therapy?

A: Closely monitor blood pressure and heart rate, especially during initial therapy and after dose adjustments. Monitor liver function tests periodically to assess for hepatotoxicity.