Nimodipine, sold under the brand name Nimotop among others, is a

calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

used in preventing

vasospasm Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia (insufficient blood flow) and tissue death (necrosis). Along with physical resistance, vasospasm is a main cause of ischemi ...

secondary to

subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid (brain), arachnoid membrane and the pia mater surrounding the human brain, brain. Symptoms may include a thunderclap headache, severe heada ...

(a form of

cerebral hemorrhage Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain (i.e. the parenchyma), into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stro ...

). It was originally developed within the calcium channel blocker class as it was used for the treatment of

high blood pressure Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...

, but is not used for this indication. It was patented in 1971 and approved for medical use in the United States in 1988. It was approved for medical use in Germany in 1985.

Medical use

Because it has some selectivity for cerebral vasculature, nimodipine's main use is in the prevention of cerebral

and resultant

ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

, a complication of

(a form of cerebral bleed), specifically from ruptured intracranial berry aneurysms irrespective of the patient's post-ictus neurological condition. Its administration begins within 4 days of a subarachnoid hemorrhage and is continued for three weeks. If

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

drops by over 5%, dosage is adjusted. There is still controversy regarding the use of intravenous nimodipine on a routine basis. A 2003 trial found nimodipine was inferior to

magnesium sulfate Magnesium sulfate or magnesium sulphate is a chemical compound, a salt with the formula , consisting of magnesium cations (20.19% by mass) and sulfate anions . It is a white crystalline solid, soluble in water but not in ethanol. Magnesi ...

in preventing seizures in women with severe

preeclampsia Pre-eclampsia is a multi-system disorder specific to pregnancy, characterized by the new onset of high blood pressure and often a significant amount of protein in the urine or by the new onset of high blood pressure along with significant end- ...

. Nimodipine is not regularly used to treat

head injury A head injury is any injury that results in trauma to the skull or brain. The terms ''traumatic brain injury'' and ''head injury'' are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of inju ...

. Several investigations have been performed evaluating its use for traumatic subarachnoid hemorrhage; a systematic review of 4 trials did not suggest any significant benefit to the patients that receive nimodipine therapy. There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy.

Dosage

The regular dosage is 60 mg tablets every four hours. If the patient is unable to take tablets orally, it was previously given via

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

at a rate of 1–2 mg/hour (lower dosage if the body weight is <70 kg or blood pressure is too low), but since the withdrawal of the IV preparation, administration by

nasogastric tube Nasogastric intubation is a medical process involving the insertion of a plastic tube (nasogastric tube or NG tube) through the nose, down the esophagus, and down into the stomach. Orogastric intubation is a similar process involving the insertion ...

is an alternative.

Contraindications

Side effects

The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) has classified the side effects into groups based on dosages levels at q4h. For the high dosage group (90 mg) less than 1% of the group experienced adverse conditions including

itching An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

, gastrointestinal hemorrhage,

thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

, neurological deterioration,

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

diaphoresis Perspiration, also known as sweat, is the fluid secreted by sweat glands in the skin of mammals. Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distributed over much of the ...

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...

hyponatremia Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...

, decreasing platelet count,

disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking Microvessel, small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems ...

, and

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

Pharmacokinetics

Absorption

After oral administration, it reaches peak plasma concentrations within one and a half hours. Patients taking enzyme-inducing anticonvulsants have lower plasma concentrations, while patients taking sodium valproate were markedly higher.

Metabolism

Nimodipine is metabolized in the

first pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

. The

dihydropyridine 1,4-Dihydropyridine (DHP) is an organic compound with the formula CH2(CH=CH)2NH. The parent compound is uncommon, but derivatives of 1,4-dihydropyridine are important commercially and biologically. The pervasive cofactors NADH and NADPH are deriv ...

ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

isoform 3A (

CYP3A Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice. These genes encode monooxygenases which catalyze many reactions involved in the synthesis of cholesterol, steroids and other ...

). This can be completely inhibited however, by

troleandomycin Troleandomycin (TAO for short) is a macrolide antibiotic. It was sold in Italy (branded Triocetin) and Turkey (branded Tekmisin). It is no longer sold in Italy as of 2018. The drug's mode of action is to bind to the ribosome, specifically in the ...

(an antibiotic) or ketoconazole (an antifungal drug).

Excretion

Studies in non-human mammals using radioactive labeling have found that 40–50% of the dose is excreted via urine. The residue level in the body was never more than 1.5% in monkeys.

Mechanism of action

Nimodipine binds specifically to L-type voltage-gated calcium channels. There are numerous theories about its mechanism in preventing vasospasm, but none are conclusive. Nimodipine has additionally been found to act as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

, or as an

antimineralocorticoid A mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which receptor antagonist, antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive t ...

Synthesis

The key acetoacetate (2) for the synthesis of nimodipine (5) is obtained by alkylation of sodium acetoacetate with 2-methoxyethyl chloride,

Aldol condensation An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties (of aldehydes or ketones) react to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), and this is then followed by dehydration t ...

of ''meta''-nitrobenzene (1) and the subsequent reaction of the intermediate with enamine (4) gives nimodipine.

Stereochemistry

Nimodipine contains a stereocenter and can exist as either of two

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s. The pharmaceutical drug is a

racemate In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

, an equal mixture of the (''R'')- and (''S'')- forms.Rote Liste Service GmbH (Hrsg.): ''Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte)''. Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, , S. 204.