Felodipine

Felodipine is an antihypertensive agent belonging to the Calcium Channel Blocker class.

Felodipine is a calcium channel blocker used to treat hypertension.

Felodipine is completely absorbed from the gastrointestinal tract after oral administration. The systemic bioavailability of Felodipine is approximately 20%. Mean peak concentrations following the administration of Felodipine are reached in 2.5 to 5 hours. The plasma protein binding of felodipine is approximately 99%. It is bound predominately to the albumin fraction. Felodipine is extensively metabolized in the liver, predominantly by cytochrome P-450 CYP 3A4. After 72 hours, approximately 70% of a given dose is excreted as metabolites in the urine and 10% is secreted in the feces. Less than 0.5% of a dose is recovered unchanged in the urine. Six metabolites, which account for 23% of the oral dose, have been identified: none has significant vasodilating activity.

Felodipine shows common side effects Headache, flushing, dizziness or light-headedness, weakness, fast heartbeat, heartburn, Constipation, enlargement of gum tissue around teeth, etc.

Felodipine is available in the form of Oral Tablets.

Felodipine is available in India, US, UK, Canada, Russia China, Japan and Australia.

Felodipine belonging to the Calcium Channel Blockers acts as an antihypertensive agent.

Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension.

The Onset of action of Felodipine occurs within 2-5 hours.

The Duration of Action for Felodipine in the body is approximately 24 hours.

The Tmax was found within 2.5-5 hours following the administration of Felodipine.

Felodipine is available in the form of Oral Tablet.

Felodipine tablet taken by mouth. Usually once a day.

Felodipine is a prescription medicine used to treat the symptoms of High Blood Pressure (Hypertension). Felodipine may be used alone or with other medications. Felodipine belongs to a class of drugs called Calcium Channel Blockers; Calcium Channel Blockers, Dihydropyridine. Patients are advised to follow a strict exercise and diet regimen along with this medicine to get the best possible effect. This medicine may cause swelling of gums; this can be avoided with good dental care.

Felodipine is an antihypertensive agent belonging to Calcium Channel Blockers. It inhibits calcium ions from entering the “slow channels” or select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization, producing a relaxation of coronary vascular smooth muscle and coronary vasodilation; increases myocardial oxygen delivery in patients with vasospastic angina.

Felodipine is approved for use in the following clinical indications

• Adult Hypertension

Felodipine is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including felodipine.

• Pediatric Hypertension

Felodipine is also indicated for the treatment of Pediatric hypertension.

Although not approved, there have been certain off-label indications. These include

• Chronic stable angina

A beta-blocker is the preferred initial therapy; if there are ongoing symptoms on beta-blocker therapy, a calcium channel blocker (typically a dihydropyridine [eg, felodipine]) may be added; felodipine may be used as an alternative therapy if there are contraindications or unacceptable adverse effects with beta-blockade.

• Hypertension

Adult Dose

Initial dose: 5 mg orally once a day

Maintenance dose: 2.5 to 10 mg orally once a day.

Pediatric Dose

Children ≥6 years and Adolescents

Initial: 2.5 mg once daily; may increase as needed at 2-week intervals.

maximum dose: 10 mg orally once a day.

Geriatric Dose

Initial dose: 2.5 to 5 mg orally once a day

Maintenance dose: 2.5 to 10 mg orally once a day.

Comments: If needed, dose adjustments should generally occur at intervals of at least 2 weeks.

• Chronic stable angina (alternative agent) (off-label use):

Oral: Initial: 5 to 10 mg once daily; if initiated at 5 mg, increase dose to 10 mg once daily as tolerated after 2 to 4 weeks.

Felodipine is available in various strengths as 2.5mg, 5mg and 10mg.

Felodipine is available in the form of Oral Tablet.

May be taken with a small meal that is low in fat and carbohydrates.

Felodipine is contraindicated in patients with

● Patients with a known hypersensitivity to felodipine or any other components of Felodipine.

● Patients with a known hypersensitivity to other dihydropyridines.

● In women of childbearing potential, in pregnancy, and during lactation. Fetal malformations and adverse effects on pregnancy have been reported in animals.

• Hypotension

Felodipine, like other calcium antagonists, may occasionally precipitate significant hypotension and, rarely, syncope. It may lead to reflex tachycardia which in susceptible individuals may precipitate angina pectoris.

• Heart Failure

Although acute hemodynamic studies in a small number of patients with NYHA Class II or III heart failure treated with felodipine have not demonstrated negative inotropic effects, safety in patients with heart failure has not been established. Caution, therefore, should be exercised when using Felodipine in patients with heart failure or compromised ventricular function, particularly in combination with a beta blocker.

• Patients with Impaired Liver Function

Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of Felodipine; therefore, a starting dose of 2.5 mg once a day is recommended. These patients should have their blood pressure monitored closely during dosage adjustment of Felodipine.

• Peripheral Edema

Peripheral edema, generally mild and not associated with generalized fluid retention, was the most common adverse event in the clinical trials. The incidence of peripheral edema was both dose and age dependent. Frequency of peripheral edema ranged from about 10% in patients under 50 years of age taking 5 mg daily to about 30% in those over 60 years of age taking 20 mg daily. This adverse effect generally occurs within 2–3 weeks of the initiation of treatment.

Information is not available.

It is not known whether this drug is secreted in human milk and because of the potential for serious adverse reactions from felodipine in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

May be taken with a small meal that is low in fat and carbohydrates.

• Common Adverse effects

Peripheral edema, Headache, Flushing, and tachycardia.

• Rare Adverse effects

Chest pain, facial edema, flu-like illness, myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia, premature beats, abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid, regurgitation, gynecomastia, anemia, arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain, insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido, dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection, contusion, erythema, urticaria, visual disturbances, impotence, urinary frequency, urinary urgency, dysuria, polyuria, gingival hyperplasia, flushing, palpitations, nausea, constipation, dizziness, paresthesia’s.

• CYP3A4 Inhibitors

Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken.

• Itraconazole

Co-administration of another extended-release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.

• Erythromycin

Co-administration of Felodipine with erythromycin resulted in approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of felodipine.

• Cimetidine

Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the Cmax, of felodipine.

• Beta-Blocking Agents

A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and Cmax of metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical trials, however, beta blockers including metoprolol were concurrently administered with felodipine and were well tolerated.

• Digoxin

When given concomitantly with Felodipine the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.

• Anticonvulsants

In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin, carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.

• Tacrolimus

Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, the tacrolimus blood concentration should be followed, and the tacrolimus dose may need to be adjusted.

• Other Concomitant Therapy

In healthy subjects there were no clinically significant interactions when Felodipine was given concomitantly with indomethacin or spironolactone.

The common side effects of Felodipine include the following

• Common
  

Headache, flushing, dizziness or light-headedness, weakness, fast heartbeat, heartburn, Constipation, enlargement of gum tissue around teeth.

• Rare

Swelling of the face, eyes, lips, tongue, arms, or legs, difficulty breathing or swallowing, fainting and rash.

• Pregnancy

Pregnancy Category C

Teratogenic Effects: Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3, and 4.6 mg/kg/day (from 0.8 to 8 times** the maximum recommended human dose on a mg/m2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine. There are no adequate and well-controlled studies in pregnant women. If felodipine is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery and on the mammary glands of pregnant females.

• Nursing Mothers

It is not known whether this drug is secreted in human milk and because of the potential for serious adverse reactions from felodipine in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Geriatric Use

Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Pharmacokinetics, however, indicate that the availability of felodipine is increased in older patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

• Symptoms

Overdosage can cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.

• Treatment

In the case of known overdosage, activated charcoal may be used. If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The intravenous administration of fluids may be used to treat hypotension. Plasma volume may be increased by infusion of a plasma volume expander. When accompanied by bradycardia, atropine 0.5-1 mg should be administered intravenously. Sympathomimetic drugs predominantly affecting the α1-adrenoceptor may be given if the above-mentioned measures are considered insufficient. Removal of felodipine from the circulation by hemodialysis has not been established.

Pharmacodynamic

Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells.

Pharmacokinetics

• Absorption

Felodipine is completely absorbed from the gastrointestinal tract after oral administration. The systemic bioavailability of Felodipine is approximately 20%. Mean peak concentrations following the administration of Felodipine are reached in 2.5 to 5 hours.

• Distribution

The plasma protein binding of felodipine is approximately 99%. It is bound predominately to the albumin fraction.

• Metabolism and Excretion

Felodipine is extensively metabolized in the liver, predominantly by cytochrome P-450 CYP 3A4. After 72 hours, approximately 70% of a given dose is excreted as metabolites in the urine and 10% is secreted in the feces. Less than 0.5% of a dose is recovered unchanged in the urine. Six metabolites, which account for 23% of the oral dose, have been identified: none has significant vasodilating activity.

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