PLENDIL 10MG

Indications

• Essential hypertension
• Chronic stable angina

Dosage

Children: Refer to the BNF for Children for paediatric dosing guidance.

Adults: The usual adult dosage for hypertension is 5 mg once daily, which may be increased to 10 mg depending on clinical response.

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 dihydropyridine calcium channel blockers for binding sites in vascular smooth muscle, leading to reduced contractile activity and vasodilation.

Pharmacodynamics

Felodipine belongs to the dihydropyridine class of calcium channel blockers, primarily targeting L-type calcium channels in muscle cells. It also inhibits T-type calcium channels and calmodulin-dependent calcium release, although these interactions appear to have minor pharmacologic significance. Its vasodilatory effects contribute to lowering blood pressure and improving blood flow.

Pharmacokinetics

Felodipine is well absorbed following oral administration, with peak plasma concentrations occurring about 2-5 hours after dosing. It undergoes extensive hepatic metabolism and has a long half-life, allowing for once-daily dosing. Its bioavailability is affected by food, particularly grapefruit juice, which can significantly increase plasma levels.

Contra-indications

• Severe hypotension
• Cardiogenic shock
• Unstable angina
• Severe aortic stenosis

Adverse effects

• Peripheral edema
• Headache
• Flushing
• Palpitations
• Dizziness
• Nausea
• Abdominal pain

Interactions

• Grapefruit juice: Severe (increases exposure)
• Enzalutamide: Moderate (decreases exposure)
• Apalutamide: Moderate (decreases exposure)
• Dronedarone: Moderate (increases exposure)
• Antifungals (azoles): Moderate (increases exposure)
• Miconazole: Moderate (increases exposure)
• Cenobamate: Moderate (decreases exposure)
• Cobicistat: Moderate (increases exposure)
• Crizotinib: Moderate (increases exposure)
• Dabrafenib: Moderate (decreases exposure)

Precautions

• Use with caution in patients with hepatic impairment
• Monitor blood pressure regularly
• Consider the risk of hypotension in patients on other antihypertensives

Pregnancy

Felodipine should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. Consult specific guidelines for use during pregnancy.

Breast-feeding

Felodipine is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and light. Keep out of reach of children.

Formulations

• Felodipine 2.5 mg tablets
• Felodipine 5 mg tablets
• Felodipine 10 mg tablets
• Felodipine extended-release 2.5 mg tablets
• Felodipine extended-release 5 mg tablets
• Felodipine extended-release 10 mg tablets

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.

Pharmacodynamics

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.