indication

For the treatment of mild to moderate essential hypertension.

pharmacology

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.

mechanism of action

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.

toxicity

Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD₅₀ is 1050 mg/kg.

biotransformation

Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified.

absorption

Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food.

half life

17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers.

route of elimination

Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.

drug interactions

Amobarbital: The barbiturate, amobarbital, decreases the effect of felodipine.

Aprobarbital: The barbiturate, aprobarbital, decreases the effect of felodipine.

Butabarbital: The barbiturate, butabarbital, decreases the effect of felodipine.

Butalbital: The barbiturate, butalbital, decreases the effect of felodipine.

Butethal: The barbiturate, butethal, decreases the effect of felodipine.

Carbamazepine: Carbamazepine may increase the metabolism of felodipine. Monitor for changes in the therapeutic and adverse effects of felodipine if carbamazepine is initiated, discontinued or dose changed.

Dihydroquinidine barbiturate: The barbiturate, dihydroquinidine barbiturate, decreases the effect of felodipine.

Erythromycin: Erythromycin increases the effect of felodipine

Ethotoin: The hydantoin decreases the effect of felodipine

Fosphenytoin: The hydantoin decreases the effect of felodipine

Heptabarbital: The barbiturate, heptabarbital, decreases the effect of felodipine.

Hexobarbital: The barbiturate, hexobarbital, decreases the effect of felodipine.

Itraconazole: Itraconazole may increase the therapeutic and adverse effects of felodipine.

Josamycin: Erythromycin increases the effect of felodipine

Mephenytoin: The hydantoin decreases the effect of felodipine

Methohexital: The barbiturate, methohexital, decreases the effect of felodipine.

Methylphenobarbital: The barbiturate, methylphenobarbital, decreases the effect of felodipine.

Nelfinavir: Nelfinavir increases the effect and toxicity of felodipine

Oxcarbazepine: Oxcarbazepine decreases the levels of felodipine

Pentobarbital: The barbiturate, pentobarbital, decreases the effect of felodipine.

Phenobarbital: The barbiturate, phenobarbital, decreases the effect of felodipine.

Phenytoin: The hydantoin decreases the effect of felodipine

Primidone: The barbiturate, primidone, decreases the effect of felodipine.

Quinidine barbiturate: The barbiturate, quinidine barbiturate, decreases the effect of felodipine.

Quinupristin: This combination presents an increased risk of toxicity

Secobarbital: The barbiturate, secobarbital, decreases the effect of felodipine.

Tacrolimus: Felodipine increases tacrolimus levels

Talbutal: The barbiturate, talbutal, decreases the effect of felodipine.

Telithromycin: Telithromycin may reduce clearance of Felodipine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Felodipine if Telithromycin is initiated, discontinued or dose changed.

Thiopental: The CYP3A4 inducer, Thiopental, may increase the metabolism and clearance of Felodipine, a CYP3A4 substrate. Monitor for changes in the therapeutic/adverse effects of Felodipine if Thiopental is initiated, discontinued or dose changed.

Tipranavir: Tipranavir, co-administered with Ritonavir, may alter the concentration of Felopidine. Monitor for efficacy and adverse/toxic effects of Felopidine.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Tretinoin: The moderate CYP2C8 inhibitor, Felopidine, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Felopidine is initiated, discontinued to dose changed.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of felodipine by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of felodipine if voriconazole is initiated, discontinued or dose changed.