Nifedipine
Nifedipine (brand names Adalat, Nifediac, Nifedical, and Procardia) is a dihydropyridinecalcium channel blocker. Its main uses are as an antianginal (especially in Prinzmetal's angina) and antihypertensive, although a large number of other indications have recently been found for this agent, such as Raynaud's phenomenon, premature labor, and painful spasms of theesophagus in cancer and tetanus patients. It is also commonly used for the small subset ofpulmonary hypertension patients whose symptoms respond to calcium channel blockers.
Dosing
Nifedipine rapidly lowers blood pressure, and patients are commonly warned they may feel dizzy or faint after taking the first few doses. Tachycardia (fast heart rate) may occur as a reaction. These problems are much less frequent in the sustained-release preparations of nifedipine (such as Adalat OROS). A more novel release system is GITS (Gastro-Intestinal Therapeutic System), which - according to Bayer - provides 24-hour continuous release through an osmotic push system. Recent trials with GITS include INSIGHT (for blood pressure) and ACTION (for angina).
Extended release formulations of nifedipine should be taken on an empty stomach, and patients are warned not to consume anything containing grapefruit or grapefruit juice, as they raise blood nifedipine levels. There are several possible mechanisms, including the lowering of CYP3A4activity.
Uses
Approved uses
The approved uses for nifedipine are the long-term treatment of hypertension (high blood pressure) and angina pectoris. In hypertension, recent clinical guidelines generally favourdiuretics and ACE inhibitors, although calcium channel antagonists, along with thiazide diuretics, are still favoured as primary treatment for over 55's and black patients.
Sublingual nifedipine has previously been used in hypertensive emergencies. This was found to be dangerous, and has been abandoned. Sublingual nifedipine causes blood-pressure lowering through peripheral vasodilation. It can cause an uncontrollable decrease in blood pressure, reflex tachycardia, and a steal phenomenon in certain vascular beds. There have been multiple reports in the medical literature of serious adverse effects with sublingual nifedipine, including cerebral ischemia/infarction, myocardial infarction, complete heart block, and death. As a result of this, the FDA reviewed all data regarding the safety and efficacy of sublingual nifedipine for hypertensive emergencies in 1995, and concluded that the practice should be abandoned because it was neither safe nor efficacious.
Off-label uses
Nifedipine has been used frequently as a tocolytic (agent that delays premature labor). A Cochrane review has concluded that it is comparable with magnesium sulfate and beta-agonists (such as ritodrine) with fewer side-effects. Its role vis à vis atosiban is not established.
Raynaud's phenomenon is often treated with nifedipine. A 2005 meta-analysis showed modest benefits (33% decrease in attack severity, 2.8-5 reduction in absolute number of attacks per week); it does conclude that most included studies used low doses of nifedipine.
Topical nifedipine has been shown to be as effective as topical nitrates for anal fissures.
Nifedipine is also used in high-altitude medicine to treat high altitude pulmonary edema.
Oral nifedipine has also been found to cause iron loss in the urine of small animals. A NIH NIDDK study] is currently seeing if the drug can increase the removal of iron into the urine in humans as well, thus becoming a possible treatment for iron overload.
]Overdosage
A number of persons have developed toxicity due to acute overdosage with nifedipine, either accidentally or intentionally, and via either oral or parenteral administration. The adverse effects include lethargy, bradycardia, marked hypotension and loss of consciousness. The drug may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients or to assist in a medicolegal death investigation. Analytical methods usually involve gas or liquid chromatography and specimen concentrations are usually in the 100-1000 μg/L range.
History
Nifedipine (initially BAY a1040) was developed by the German pharmaceutical company Bayer, with most initial studies being performed in the early 1970s.
The use of nifedipine and related calcium channel antagonists was much reduced in response to 1995 trials that mortality was increased in patients with coronary artery disease who took nifedipine. This study was a meta-analysis, and demonstrated harm mainly in short-acting forms of nifedipine (that could cause large fluctations in blood pressure) and at high doses of 80 mg a day and more.
Nicardipine
icardipine hydrochloride (Cardene) is a medication used to treat high blood pressure andangina. It belongs to the class of calcium channel blockers.
Nicardipine is a dihydropyridine calcium-channel blocking agent used for the treatment of vascular disorders such as chronic stable angina, hypertension, and Raynaud's phenomenon. It is available in oral and intravenous formulations. Its mechanism of action and clinical effects closely resemble those of nifedipine and the other dihydropyridines (amlodipine, felodipine), except that nicardipine is more selective for cerebral and coronary blood vessels. Furthermore, nicardipine does not intrinsically decrease myocardial contractility and may be useful in the management of congestive heart failure. Nicardipine also has a longer half-life than nifedipine. Nicardipine was approved by the FDA in December 1988. The patent for both Cardene and Cardene SR expired in October 1995.
It has been used in percutaneous coronary intervention.
Nicardipine must be used with caution in patients with renal failure because of possible kidney shutdown.
Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect.
Amlodipine
Amlodipine (as besylate, mesylate or maleate) is a long-acting calcium channel blocker(dihydropyridine class) used as an anti-hypertensive and in the treatment of angina. Like other calcium channel blockers, amlodipine acts by relaxing the smooth muscle in thearterial wall, decreasing total peripheral resistance and hence reducing blood pressure; in angina it increases blood flow to the heart muscle.
Indications
Contraindications
§ aortic stenosis: amlodipine causes vasodilation, which can result in reduced cardiac output in patients with severe aortic stenosis.
Cautions
§ hepatic impairment
Adverse effects
Adverse side effects of the use of amlodipine may be:
§ Very often: peripheral edema in 8.3% of users, fatigue in 4.5% of users
§ Often: dizziness; palpitations; muscle-, stomach- or headache; dyspepsia; nausea - in 1 in 100 users
§ Sometimes: blood disorders, development of breasts in men (gynecomastia), impotence,depression, insomnia, tachycardia, gingival enlargement - in 1 in 1,000 users,
§ Very rarely: hyperglycemia, tremor, Stevens-Johnson syndrome - in 1 in 100,000 users
Mechanism of action
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:
Exertional angina
In patients with exertional angina, amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus lowers myocardial oxygen demand, at any given level of exercise.
Vasospastic angina
Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine in vasospastic (Prinzmetal's or variant) angina.
Interactions
§ In patients with severe coronary artery disease, amlodipine can increase the frequency and severity of angina or actually cause a heart attack on rare occasions. This phenomenon usually occurs when first starting amlodipine, or at the time of dosage increase.
§ Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking another blood pressure lowering medication. In rare instances, congestive heart failure has been associated with amlodipine, usually in patients already on a beta blocker.
Dose
The recommended starting dose for adults is 5 mg once daily, up to a maximum dose of 10 mg once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 2.5 mg once daily.[4] The recommended starting dose for pediatric patients is 2.5 mg to 5 mg once daily. Doses in excess of 5 mg daily have not been studied in pediatric patients.[4] Amlodipine is available as 2.5 mg, 5 mg, and 10 mg tablets.
Nimodipine
Nimodipine (marketed by Bayer as Nimotop) is a dihydropyridine calcium channel blocker originally developed for the treatment of high blood pressure. It is not frequently used for this indication, but has shown good results in preventing a major complication ofsubarachnoid hemorrhage (a form of cerebral hemorrhage) termed vasospasm; this is now the main use of nimodipine.
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 at a rate of 1–2 mg/hour (lower dosage if the body weight is <70 kg or blood pressure is too low),[1] but since the withdrawal of the IV preparation, administration by nasogastric tube is an alternative.
Usage
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.[2] 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.
A 2003 trial (Belfort et al.) found nimodipine was inferior to magnesium sulfate in preventing seizures in women with severe preeclampsia.
While nimodipine is not used in head injury currently, it has shown promise in clinical studies. A 2009 study found that patients with severe head trauma who were given nimodipine, via peripheral vein injection, along with the standard procedures had significantly higher cerebral perfusion pressure and jugular venous oxygen saturation, whileintracranial pressure, jugular lactate and jugular glucose were lower. The study concluded that Glasgow
Pharmacokinetics
Absorption
In humans, it is administered primarily orally and 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 dihydropyridine ring of the nimodipine is dehydrogenated in the hepatic cells of the liver, a process governed by Cytochrome P-4503A (CYP3A). This can be completely inhibited however, by troleandomycin (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. There were some metabolites of the drug found in the milk of lactating rat subjects.
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.
Contraindications
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.
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, congestive heart failure, hyponatremia, decreasing platelet count, disseminated intravascular coagulation, deep veinthrombosis.
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Others drug include:
Nisoldipine
Nitradipine.
Isradipine
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