Felodipine

3.86

3.8

19.7

7.15e-03 g/L

145

145 °C

Warning

H302 (93.2%): Harmful if swallowed [Warning Acute toxicity, oral]；H361 (22%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]；H373 (22%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]；H410 (15.3%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

P203, P260, P264, P270, P273, P280, P301+P317, P318, P319, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 59 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The adverse effects of felodipine are classified as either dose-dependent or dose-independent.；* The common dose-dependent adverse effects of felodipine include peripheral edema, flushing, palpitations, and headaches. The most common clinical side effect of Felodipine use is peripheral edema. The frequency of peripheral edema is higher in individuals taking a higher dose of felodipine and elderly individuals. The incidence of peripheral edema is about 30% in elderly patients taking 20 mg of felodipine daily. Felodipine selectively dilates the arterioles, which increases intra-capillary pressure, causing extravasation of fluid into the interstitial space and resulting in peripheral edema. ACE inhibitors or angiotensin receptor blockers can prevent peripheral edema. Flushing and headaches also occur because of the vasodilatory effects of felodipine. Palpitations may occur because of reflex tachycardia.；* In older adults with hypertension, initiating CCBs like felodipine frequently triggers a prescribing cascade, resulting in the subsequent unnecessary prescription of diuretics. Evaluating whether the edema is attributed to an underlying medical condition or is a result of Felodipine use is a risk mitigation strategy.；* The dose-independent adverse effects of felodipine include fatigue, nausea, and gingival hyperplasia. Gingival hyperplasia occurs in less than 1% of patients and is more common in individuals with poor dental hygiene. The mechanism of gingival hyperplasia is overexpression of growth factors due to high concentrations of calcium ions, leading to fibroblast proliferation and chronic inflammatory cell infiltration. Gingival hyperplasia is usually reversible on discontinuation of felodipine.；Drug-Drug Interactions；Cytochrome P450 3A4 metabolizes felodipine.；* The plasma level of felodipine increases when used in conjunction with CYP 3A4 inhibitors such as azole antifungals (Itraconazole and Ketoconazole), macrolide antibiotics (Clarithromycin and Azithromycin), HIV protease inhibitors, immunosuppressants (Cyclosporine), Cimetidine, or grapefruit juice.；* The plasma level and efficacy of felodipine decrease when co-administered with CYP3A4 inducers such as anticonvulsants (Phenytoin and Carbamazepine), St John’s wort, or rifampicin.；* When Metoprolol is subsequently administered with a conventional Felodipine formulation to treat essential hypertension, the plasma concentration of Metoprolol increases while that of felodipine remains unchanged.；* If felodipine is co-administered with Theophylline, it results in a decrease in the plasma concentration of Theophylline.；* CCBs and statins are frequently prescribed in patients with cardiovascular risk factors. In a study, acute kidney injury, hyperkalemia, acute myocardial infarction, and acute ischemic stroke were increased due to interaction between CYP3A4-metabolized statins and CCBs that inhibit CYP3A4, like Felodipine.

A mild-to-moderate overdose of felodipine can result in hypotension secondary to peripheral vasodilation and reflex tachycardia. However, a severe overdose of felodipine can cause life-threatening profound hypotension and bradycardia. Case fatality due to profound, refractory circulatory collapse overdose has been reported in the literature. The risk of overdose increases in elderly individuals, patients with liver impairment, and concomitant administration of felodipine with beta blockers. Overdose symptoms can include lightheadedness, syncope, altered mental status, and shock secondary to profound hypotension. The insulin release from the pancreas depends on calcium influx through the L-type channels. Felodipine blocks these calcium channels and results in hyperglycemia because of decreased insulin release.；The first step in managing Felodipine overdose is maintaining a patent airway. Patients who have consumed an excess of felodipine ER tablets but have not yet developed any symptoms should be started on gastrointestinal decontamination with whole bowel irrigation if they present within 6 to 8 hours of drug ingestion. Patients with hypotension should undergo resuscitation with IV fluids. However, caution is necessary for individuals with congestive heart failure and pulmonary edema. Vasopressor therapy with dopamine or norepinephrine is an as-needed option for hypotension. IV calcium gluconate or calcium chloride (given via central line) are also options in treating Felodipine overdose.；In patients with severe overdose, atropine should be administered IV for bradycardia. The vital signs, serum electrolytes, especially potassium, blood glucose, urine output, and ECG, should be monitored regularly. Hyperinsulinemia-euglycemia therapy is also an established treatment for CCB overdose. This therapy helps mobilize glucose from the peripheral tissue to serve as an alternative energy source for the myocardium.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Felodipine

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation；Because no information is available on the use of felodipine during breastfeeding, an alternate drug may be preferred.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

C08CA02

C - Cardiovascular system；C08 - Calcium channel blockers；C08C - Selective calcium channel blockers with mainly vascular effects；C08CA - Dihydropyridine derivatives；C08CA02 - Felodipine

QC - Cardiovascular system；QC08 - Calcium channel blockers；QC08C - Selective calcium channel blockers with mainly vascular effects；QC08CA - Dihydropyridine derivatives；QC08CA02 - Felodipine

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 channe

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.

OL961R6O2C

FELODIPINE

Mechanisms of Action [MoA] - Calcium Channel Antagonists

Established Pharmacologic Class [EPC] - Dihydropyridine Calcium Channel Blocker

Chemical Structure [CS] - Dihydropyridines

Felodipine is a Dihydropyridine Calcium Channel Blocker. The mechanism of action of felodipine is as a Calcium Channel Antagonist.

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Drugs used to cause dilation of the blood vessels.

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.

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.

10 L/kg

0.8 L/min [Young healthy subjects]