Cordil

Uses

Cordil is used for the prevention and long-term treatment of angina pectoris.

Cordil is also used to associated treatment for these conditions: Angina Pectoris

How Cordil works

Cordil mediates its therapeutic efficacy via two main mechanisms. Cordil is an activator and opener of ATP-sensitive (ATP-dependent) potassium channels (KATP channels) that are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits. Cordil binding sites are located in the sulfonylurea receptor 2 (SUR2) in the ATP-sensitive potassium channel , which are regulatory subunits of the channel that exhibit an ATPase activitiy . There are 2 types of SUR2 subunits (2A/2B) that have identical nucleotide binding domains (NBD), where SUR2A is more predominantly expressed in skeletal and cardiac myocytes and SUR2B in smooth muscle cells . Cordil more potently activates SUR2B/Kir6.2 than SUR2A/Kir6.2 channels to cause hyperpolarization. ATP-NBD1 interaction influences the channel signalling by nicorandil, and the response of the channel to nicorandil is also facilitated and heightened by the interaction of ATP or ADP with NBD2 . Potentiated activity of ATP-sensitive channels have cardioprotective role by limiting the duration of action potentials and preventing intraceullar calcium overload . This attenuates cellular injury by preserving cellular energetics and ultimately cell survival . KATP channel-dependent membrane hyperpolarization can also lead to vasodilation via reduction in Ca2+ influx through the voltage-gated Ca2+ channels and regulation of intracellular Ca2+ mobilization in smooth muscle cells . Cordil contain a nitrate moiety in its structure, making it a good dilator of vascular smooth muscle like other nitroglycerin esters . Direct relaxation of venous vascular system arises from NO-donor mediated stimulation of guanylyl cyclase and increased levels of intracellular cyclic GMP (cGMP). Elevated levels of cGMP contributes to the total relaxing effect of nicorandil at higher concentrations of the drug .

Dosage

Cordil dosage

Adult: The usual therapeutic range is 10 to 20 mg twice daily. The usualstarting dose is 10 mg twice daily, in the morning and in the eveningpreferably, and should be titrated upwards in accordance with patients needs, response andtolerance up to 40 mg twice daily, if necessary. An even lower starting dose of 5 mg twice daily may be used in patients particularly prone to headache.

Eldery: There are nospecial dosage requirements for elderly patients, but as with all medicines the lowest effectivedose should be used. Cordil should be administered with care, using low startingdosages, in the elderly.

Children: Not recommended. Cordil should be used withcaution in patients with serious hepatic dysfunction.

Hepatic Impairment: Dose reduction may be necessary.

Side Effects

Headache (usually transitory), flushing, dizziness, nausea, vomiting and weakness. Hypotension and reflex tachycardia at high doses.

Toxicity

Common adverse effects include lethargy, back pain, chest pain, infection, feeling of weakness. In the cardiovascular system, hypotension, increased heart rate in higher doses, palpitations, worsened angina pectoris and vasodilation/flush may be observed. Dyspepsia, nausea, and vomiting may occur as gastrointestinal disorders. Headaches may arise from vasodilation. Other common side effects include myalgia, bronchitis, dyspnoea, and respiratory disorder . Cordil does not affect fertility of male or female rats, and shows no potential in carcinogenic, mutagenic or genotoxic studies . Oral LD50 values in mouse, rat and dog are 626 mg/kg, 1220 mg/kg and 62.5 mg/kg, respectively .

Precaution

Hypovolaemia, low systolic BP, acute pulmonary oedema, pregnancy. May impair ability to drive or operate machinery.

Interaction

Although no pharmacological and/or pharmacokinetic interaction has been obsen/ed in animal and human studies with Cordil associated with beta-blockers, calcium antagonists, digoxin, a combination of digoxin/furosemide, rifampicin, and cimetidine, it is not excluded that the drug may nevertheless potentiate the effect of other vasodilators, tricyclic antidepressants and antihypertensive drugs administered concurrently, especially in combination with alcohol.

Volume of Distribution

After oral (and i.v.) administration of the drug, the apparent volume of distribution is approximately 1.0-1.4 L/kg body weight .

Elimination Route

Following oral administration, nicorandil is well absorbed from the gastrointestinal tract with the oral bioavailability of 75% with the maximum peak plasma concentration (Cmax) reached within 30-60 minutes. The mean Cmax is Cmax then is approximately 300 ng/ml . Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after twice daily dosing (10 or 20mg) .

Half Life

The elimination half life is approximately 1 hour .

Clearance

The total body clearance is approximately 1.15 L/min .

Elimination Route

The main route of elimination is the kidney with more than 60% of the administered dose was eliminated in the urine 24 hours after dosing . Only approximately 1% of nicorandil is excreted unchanged in the urine, and the remaining compounds are mainly the denitrated metabolite (9%) and its derivatives (e.g. nicotinuric acid 6%, nicotinamide 1%, N-methylnicotinamide < 1% and nicotinic acid < 1%) . Less than 2% of administered dose is excreted through the biliary system .

Pregnancy & Breastfeeding use

Although animal studies have not shown any harmful effect of Cordil to the foetus, has not been studied in human pregnancy. Use in pregnant women requires that the anticipated benefit be weighed against possible hazard. It is not known whether the drug is excreted in human milk. Caution should be exercised when Cordil is administered to a nursing mother. Drug interactions: Although no pharmacological and/or pharmacokinetic interaction has been obsen/ed in animal and human studies with Cordil associated with beta-blockers, calcium antagonists, digoxin, a combination of digoxin/furosemide, rifampicin, and cimetidine, it is not excluded that the drug may nevertheless potentiate the effect of other vasodilators, tricyclic antidepressants and antihypertensive drugs administered concurrently, especially in combination with alcohol.

Contraindication

Cordil tablet is contra-indicated in patients who have shown hypersensitivity to Cordil. Use is contra-indicated with cardiogenic shock and acute myocardial infarction with acute left ventricular failure and low filling pressures, in patients with hypotension, and in patients taking phosphodiesterase-5 inhibitors because concurrent use of Cordil can lead to a serious drop in blood pressure. Warnings and precautions: Cordil should be used with caution in patients who may have blood volume depletion or in those who present with low systolic blood pressure (below 100 mm Hg). The use of the drug in patients with cardiogenic shock, or acute myocardial infarction with acute left ventricular failure and low filling pressures should be avoided. Cordil should be discontinued and appropriate measures taken if mouth ulceration, stomatitis or persistent or severe buccal ulcerations, appear. Caution is advised for the use of Cordil in patients with glaucoma. The hypotensive effect of other vasodilators, tricyclic antidepressants or alcohol can be increased by administration in combination with Cordil. Therapeutic doses of Cordil may lower the blood pressure of hypertensive patients and Cordil therefore, as with other antianginal agents, should be used with care when prescribed with antihypertensive drugs. Animal mutagenicify and carcinogenicity studies have not revealed any adverse effect of Cordil when used under experimental conditions.

Acute Overdose

ln the case of overdosage, the likely symptomatology may be peripheral vasodilation with a fall in blood pressure and reflex tachycardia. In such an event, monitoring of cardiac function and general supportive measures should be used. If not successful, circulating plasma volume should be increased by substitution of fluid. ln life-threatening situations, administration of vasopressors should be considered.

Storage Condition

Store in a cool and dry place, protected from light.

Innovators Monograph

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