Clinical data | |
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Trade names | Nimotop, Nymalize, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a689010 |
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Routes of administration | Intravenous, by mouth |
Drug class | Dihydropyridine calcium channel blocker |
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Pharmacokinetic data | |
Bioavailability | 13% (by mouth) |
Protein binding | 95% |
Metabolism | Hepatic |
Elimination half-life | 8–9 hours |
Excretion | Feces and Urine |
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ECHA InfoCard | 100.060.096 |
Chemical and physical data | |
Formula | C21H26N2O7 |
Molar mass | 418.446 g·mol−1 |
3D model (JSmol) | |
Melting point | 125 °C (257 °F) |
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Nimodipine, sold under the brand name Nimotop among others, is a calcium channel blocker used in preventing vasospasm secondary to subarachnoid hemorrhage (a form of cerebral hemorrhage). It was originally developed within the calcium channel blocker class as it was used for the treatment of high blood pressure, but is not used for this indication.
It was patented in 1971 [3] and approved for medical use in the US in 1988. [4] It was approved for medical use in Germany in 1985. [5]
Because it has some selectivity for cerebral vasculature, nimodipine's main use is in the prevention of cerebral vasospasm and resultant ischemia, a complication of subarachnoid hemorrhage (a form of cerebral bleed), specifically from ruptured intracranial berry aneurysms irrespective of the patient's post-ictus neurological condition. [6] Its administration begins within 4 days of a subarachnoid hemorrhage and is continued for three weeks. If blood pressure drops by over 5%, dosage is adjusted. There is still controversy regarding the use of intravenous nimodipine on a routine basis. [7] [8]
A 2003 trial (Belfort et al.) found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia. [9]
Nimodipine is not regularly used to treat head injury. 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. [10] There was one report case of nimodipine being successfully used for treatment of ultradian bipolar cycling after brain injury and, later, amygdalohippocampectomy. [11]
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 at a rate of 1–2 mg/hour (lower dosage if the body weight is <70 kg or blood pressure is too low), [7] but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative.
Nimodipine is associated with low blood pressure, flushing and sweating, edema, nausea and other gastrointestinal problems, most of which are known characteristics of calcium channel blockers. It is contraindicated in unstable angina or an episode of myocardial infarction more recently than one month.[ citation needed ]
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. [12]
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, congestive heart failure, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, deep vein thrombosis. [6]
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. [13]
Nimodipine is metabolized in the first pass metabolism. The dihydropyridine ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by cytochrome P450 isoform 3A (CYP3A). This can be completely inhibited however, by troleandomycin (an antibiotic) or ketoconazole (an antifungal drug). [14]
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.[ citation needed ]
Nimodipine binds specifically to L-type voltage-gated calcium channels. There are numerous theories about its mechanism in preventing vasospasm, but none are conclusive. [15]
Nimodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. [16]
The key acetoacetate (2) for the synthesis of nimodipine (5) is obtained by alkylation of sodium acetoacetate with 2-methoxyethyl chloride, Aldol condensation of meta-nitrobenzene (1) and the subsequent reaction of the intermediate with enamine (4) gives nimodipine.
Nimodipine contains a stereocenter and can exist as either of two enantiomers. The pharmaceutical drug is a racemate, an equal mixture of the (R)- and (S)- forms. [18]
Enantiomers of nimodipine | |
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(R)-Nimodipine CAS number: 77940-92-2 | (S)-Nimodipine CAS number: 77940-93-3 |
An intracranial aneurysm, also known as a cerebral aneurysm, is a cerebrovascular disorder characterized by a localized dilation or ballooning of a blood vessel in the brain due to a weakness in the vessel wall. These aneurysms can occur in any part of the brain but are most commonly found in the arteries of the circle of Willis. The risk of rupture varies with the size and location of the aneurysm, with those in the posterior circulation being more prone to rupture.
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 medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.
Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism.
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina, and supraventricular tachycardia. It may also be used for the prevention of migraines and cluster headaches. It is given by mouth or by injection into a vein.
Nifedipine, sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. It is a calcium channel blocker of the dihydropyridine type. Nifedipine is taken by mouth and comes in fast- and slow-release formulations.
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 consciousness, fever, weakness, numbness, and sometimes seizures. Neck stiffness or neck pain are also relatively common. In about a quarter of people a small bleed with resolving symptoms occurs within a month of a larger bleed.
A penetrating head injury, or open head injury, is a head injury in which the dura mater, the outer layer of the meninges, is breached. Penetrating injury can be caused by high-velocity projectiles or objects of lower velocity such as knives, or bone fragments from a skull fracture that are driven into the brain. Head injuries caused by penetrating trauma are serious medical emergencies and may cause permanent disability or death.
Papaverine is an opium alkaloid antispasmodic drug, used primarily in the treatment of visceral spasms and vasospasms, occasionally in the treatment of erectile dysfunction and acute mesenteric ischemia. While it is found in the opium poppy, papaverine differs in both structure and pharmacological action from the analgesic morphine and its derivatives.
Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.
Alteplase, sold under the brand name Activase among others, is a biosynthetic form of human tissue-type plasminogen activator (t-PA). It is a thrombolytic medication used to treat acute ischemic stroke, acute ST-elevation myocardial infarction, pulmonary embolism associated with low blood pressure, and blocked central venous catheter. It is given by injection into a vein or artery. Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis.
Phenylephrine, sold under the brand names Neosynephrine and Sudafed PE among numerous others, is a medication used as a decongestant for uncomplicated nasal congestion, used to dilate the pupil, used to increase blood pressure, and used to relieve hemorrhoids. It can be taken by mouth, as a nasal spray, given by injection into a vein or muscle, applied to the skin, or as a rectal suppository.
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 delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.
Lercanidipine is an antihypertensive drug. It belongs to the dihydropyridine class of calcium channel blockers, which work by relaxing and opening the blood vessels allowing the blood to circulate more freely around the body. This lowers the blood pressure and allows the heart to work more efficiently.
Osmotherapy is the use of osmotically active substances to reduce the volume of intracranial contents. Osmotherapy serves as the primary medical treatment for cerebral edema. The primary purpose of osmotherapy is to improve elasticity and decrease intracranial volume by removing free water, accumulated as a result of cerebral edema, from brain's extracellular and intracellular space into vascular compartment by creating an osmotic gradient between the blood and brain. Normal serum osmolality ranges from 280 to 290 mOsm/kg and serum osmolality to cause water removal from brain without much side effects ranges from 300 to 320 mOsm/kg. Usually, 90 mL of space is created in the intracranial vault by 1.6% reduction in brain water content. Osmotherapy has cerebral dehydrating effects. The main goal of osmotherapy is to decrease intracranial pressure (ICP) by shifting excess fluid from brain. This is accomplished by intravenous administration of osmotic agents which increase serum osmolality in order to shift excess fluid from intracellular or extracellular space of the brain to intravascular compartment. The resulting brain shrinkage effectively reduces intracranial volume and decreases ICP.
Amlodipine/valsartan, sold under the brand name Exforge among others, is a blood pressure lowering combination drug. It contains amlodipine, as the besilate, a dihydropyridine-type calcium channel blocker, and valsartan, an angiotensin II receptor antagonist. This combination is usually well tolerated and effective for the reduction of blood pressure.
Clevidipine is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this drug to lower blood pressure. It has a half-life of approximately one minute. It is rapidly inactivated by esterases.
Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.
Reversible cerebral vasoconstriction syndrome is a disease characterized by a weeks-long course of thunderclap headaches, sometimes focal neurologic signs, and occasionally seizures. Symptoms are thought to arise from transient abnormalities in the blood vessels of the brain. In some cases, it may be associated with childbirth, vasoactive or illicit drug use, or complications of pregnancy. If it occurs after delivery it may be referred to as postpartum cerebral angiopathy.
Cerebral vasospasm is the prolonged, intense vasoconstriction of the larger conducting arteries in the subarachnoid space which is initially surrounded by a clot.
A pseudosubarachnoid hemorrhage is an apparent increased attenuation on CT scans within the basal cisterns that mimics a true subarachnoid hemorrhage. This occurs in cases of severe cerebral edema, such as by cerebral hypoxia. It may also occur due to intrathecally administered contrast material, leakage of high-dose intravenous contrast material into the subarachnoid spaces, or in patients with cerebral venous sinus thrombosis, severe meningitis, leptomeningeal carcinomatosis, intracranial hypotension, cerebellar infarctions, or bilateral subdural hematomas.
Nimodipine (...) approved for the treatment of high blood pressure (...)