Nimodipine, sold under the brand name Nimotop among others, is
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 and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or de ...
secondary to
subarachnoid hemorrhage
Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain. Symptoms may include a severe headache of rapid onset, vomiting, decreased level of consci ...
(a form of
cerebral hemorrhage
Intracerebral hemorrhage (ICH), also known as cerebral bleed, intraparenchymal bleed, and hemorrhagic stroke, or haemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. It is one kind of bleed ...
). It was originally developed within the calcium channel blocker class as it was used for the treatment of
high blood pressure
Hypertension (HTN or HT), also known as high blood pressure (HBP), 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. Long-term high bl ...
, but is not used for this indication.
It was patented in 1971 and approved for medical use in the US 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 vasospasm
Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or de ...
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 wi ...
, a complication of
subarachnoid hemorrhage
Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain. Symptoms may include a severe headache of rapid onset, vomiting, decreased level of consci ...
(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 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 "blood pressure" r ...
drops by over 5%, dosage is adjusted. There is still controversy regarding the use of intravenous nimodipine on a routine basis.
A 2003 trial (Belfort ''et al.'') found nimodipine was inferior to magnesium sulfate
Magnesium sulfate or magnesium sulphate (in English-speaking countries other than the US) 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, ...
in preventing seizures in women with severe preeclampsia
Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...
.
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
Amygdalohippocampectomy is a surgical procedure for the treatment of epilepsy. It consists of the removal of the hippocampus, which has a role in memory, spatial awareness, and navigation, and the amygdalae, which have a role in the processing and ...
.
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 nutrie ...
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 oesophagus, and down into the stomach. Orogastric intubation is a similar process involving the inserti ...
is an alternative.
Contraindications
Nimodipine is associated with low blood pressure
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
, flushing and sweating, edema, nausea and other gastrointestinal problems, most of which are known characteristics of calcium channel blockers
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 ...
. It is contraindicated
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
in unstable angina
Unstable angina (UA), also called crescendo angina, is a type of angina pectoris that is irregular. It is also classified as a type of acute coronary syndrome (ACS).
It can be difficult to distinguish unstable angina from non-ST elevation (non-Q ...
or an episode of myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
more recently than one month.
While nimodipine was occasionally administered intravenously in the past, the FDA released an alert in January 2006, warning that it had received reports of the approved oral preparation being used intravenously, leading to severe complications; this was despite warnings on the box that this should not be done.
Side-effects
The 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, gastrointestinal hemorrhage, thrombocytopenia, neurological deterioration, vomiting, diaphoresis
Perspiration, also known as sweating, is the production of fluids secreted by the 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 distribut ...
, congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, deep vein thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
.[
]
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 whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
. The dihydropyridine ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
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.
The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. These genes e ...
). 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 th ...
(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.
Mode 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 chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the 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
An antimineralocorticoid, also known as a mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is ofte ...
.
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 to ...
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 ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s. The pharmaceutical drug is a racemate
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts 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 racemates. ...
, 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.]
References
Further reading
*Pharmacology: R. Towart, S. Kazda, Br. J. Pharmacol. 67, 409P (1979).
*Use as cerebral vasodilator: H. Meyer et al., ; eidem, (1979, 1983 to Bayer
Bayer AG (, commonly pronounced ; ) is a German multinational corporation, multinational pharmaceutical and biotechnology company and one of the largest pharmaceutical companies in the world. Headquartered in Leverkusen, Bayer's areas of busi ...
).
*Effect on associative learning in aging rabbits: R. A. Deyo et al., Science 243, 809 (1989).
External links
*
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