Flunarizine

Synonyms :
1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine, Flunarizina, Flunarizinum

Status : approved

Category

Anticonvulsants

Therapeutic Classification

ANTIVERTIGO PREPARATIONS

NERVOUS SYSTEM
OTHER NERVOUS SYSTEM DRUGS
ANTIVERTIGO PREPARATIONS
Vasodilator Agents

Description

Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity. It is effective in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.

Used

Used in the prophylaxis of migraine, occlusive peripheral vascular disease, vertigo of central and peripheral origin, and as an adjuvant in the therapy of epilepsy.

Mechanism Of Action

Flunarizine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores by physically plugging the channel. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.

Dosage

Form Route Strength
Capsule oral 5 mg

Pharmacodynamics

Flunarizine is a selective calcium entry blocker with calmodulin binding properties and histamine H1 blocking activity.

Toxic Effect

-Flunarizine should be used with care in patients with depression or those being prescribed other agents, such as phenothiazines, concurrently, which may cause extrapyramidal side-effects.
-Acute overdosage has been reported and the observed symptoms were sedation, agitation and tachycardia.
-Treatment of acute overdosage consists of charcoal administration, induction of emesis or gastric lavage, and supportive measures. No specific antidote is known.

Metabolism

Hepatic, to two metabolites via N-dealylation and hydroxylation.

Absorption

85% following oral administration.

Half Life

18 days

Protein Binding

99% bound to plasma proteins

Chemical Classification

This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.

Diphenylmethanes

Organic compounds

Benzenoids

Benzene and substituted derivatives

Diphenylmethanes

Salt : Flunarizine dihydrochloride

Chemical Name

1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine

Brands

name Dosage form Country
Flunarizine capsule Canada
Novo-flunarizine – Cap 5mg capsule Canada
Sibelium Cap 5mg capsule Canada

Drug Drug Interactions

  •  Amobarbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Atracurium besylate  : May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
  •  Buprenorphine  : CNS Depressants may enhance the CNS depressant effect of Buprenorphine.
  •  Butabarbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Butalbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Calcium Acetate  : Calcium Salts may diminish the therapeutic effect of Calcium Channel Blockers.
  •  Calcium carbonate  : Calcium Salts may diminish the therapeutic effect of Calcium Channel Blockers.
  •  Calcium Chloride  : Calcium Salts may diminish the therapeutic effect of Calcium Channel Blockers.
  •  Carbamazepine  : May decrease the serum concentration of Flunarizine.
  •  Cimetidine  : Cimetidine may increase the serum concentration of Calcium Channel Blockers.
  •  Cisatracurium besylate  : May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
  •  Clarithromycin  : Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers.
  •  Clopidogrel  : May diminish the therapeutic effect of Clopidogrel.
  •  Doxazosin  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Doxylamine  : May enhance the CNS depressant effect of CNS Depressants.
  •  Dronabinol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Dronabinol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Droperidol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Efavirenz  : Efavirenz may decrease the serum concentration of Calcium Channel Blockers.
  •  Erythromycin  : Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers.
  •  Fluconazole  : Fluconazole may increase the serum concentration of Calcium Channel Blockers.
  •  Fosphenytoin  : May decrease the serum concentration of Flunarizine.
  •  Hydrocodone  : CNS Depressants may enhance the CNS depressant effect of Hydrocodone.
  •  Hydroxyzine  : May enhance the CNS depressant effect of CNS Depressants.
  •  Itraconazole  : Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, Itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs.
  •  Ketoconazole  : Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs.
  •  Magnesium hydroxide  : May enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Magnesium oxide  : May enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Magnesium salicylate  : May enhance the adverse/toxic effect of Magnesium Salts. Magnesium Salts may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Magnesium Sulfate  : May enhance the CNS depressant effect of CNS Depressants.
  •  Mefloquine  : Mefloquine may diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants.
  •  Methohexital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Methotrimeprazine  : CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants.
  •  Metyrosine  : CNS Depressants may enhance the sedative effect of Metyrosine.
  •  Minocycline  : May enhance the CNS depressant effect of CNS Depressants.
  •  Mirtazapine  : CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
  •  Nabilone  : May enhance the CNS depressant effect of CNS Depressants.
  •  Nafcillin  : Nafcillin may increase the metabolism of Calcium Channel Blockers.
  •  Nitroprusside  : May enhance the hypotensive effect of Nitroprusside.
  •  Orlistat  : Orlistat may decrease the serum concentration of Anticonvulsants.
  •  Orphenadrine  : CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
  •  Pancuronium  : May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
  •  Paraldehyde  : CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
  •  Pentobarbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Perampanel  : May enhance the CNS depressant effect of CNS Depressants.
  •  Phenobarbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Phenoxybenzamine  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Phentolamine  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Phenytoin  : May decrease the serum concentration of Flunarizine.
  •  Posaconazole  : Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs.
  •  Pramipexole  : CNS Depressants may enhance the sedative effect of Pramipexole.
  •  Prazosin  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Rifabutin  : Rifamycin Derivatives may decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers.
  •  Rifampicin  : Rifamycin Derivatives may decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers.
  •  Rifapentine  : Rifamycin Derivatives may decrease the serum concentration of Calcium Channel Blockers. This primarily affects oral forms of calcium channel blockers.
  •  Rocuronium  : May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
  •  Ropinirole  : CNS Depressants may enhance the sedative effect of Ropinirole.
  •  Rotigotine  : CNS Depressants may enhance the sedative effect of Rotigotine.
  •  Rufinamide  : May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
  •  Secobarbital  : Barbiturates may increase the metabolism of Calcium Channel Blockers.
  •  Silodosin  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Sodium oxybate  : May enhance the CNS depressant effect of CNS Depressants.
  •  Sulfisoxazole  : Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers.
  •  Suvorexant  : CNS Depressants may enhance the CNS depressant effect of Suvorexant.
  •  Tamsulosin  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Tapentadol  : May enhance the CNS depressant effect of CNS Depressants.
  •  Telithromycin  : Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers.
  •  Terazosin  : Alpha1-Blockers may enhance the hypotensive effect of Calcium Channel Blockers.
  •  Thalidomide  : CNS Depressants may enhance the CNS depressant effect of Thalidomide.
  •  Vecuronium  : May enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing).
  •  Voriconazole  : Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs.
  •  Zolpidem  : CNS Depressants may enhance the CNS depressant effect of Zolpidem.

Food Interactions

  • Avoid alcohol., Take without regard to meals.

Calculated Property

kind Value Source
logP 5.3 ALOGPS
logS -5.4 ALOGPS
Water Solubility 1.68e-03 g/l ALOGPS
logP 6.17 ChemAxon
IUPAC Name 1-[bis(4-fluorophenyl)methyl]-4-[(2E)-3-phenylprop-2-en-1-yl]piperazine ChemAxon
Traditional IUPAC Name flunarizine ChemAxon
Molecular Weight 404.4948 ChemAxon
Monoisotopic Weight 404.206405252 ChemAxon
SMILES FC1=CC=C(C=C1)C(N1CCN(CC=CC2=CC=CC=C2)CC1)C1=CC=C(F)C=C1 ChemAxon
Molecular Formula C26H26F2N2 ChemAxon
InChI InChI=1S/C26H26F2N2/c27-24-12-8-22(9-13-24)26(23-10-14-25(28)15-11-23)30-19-17-29(18-20-30)16-4-7-21-5-2-1-3-6-21/h1-15,26H,16-20H2/b7-4+ ChemAxon
InChIKey InChIKey=SMANXXCATUTDDT-QPJJXVBHSA-N ChemAxon
Polar Surface Area (PSA) 6.48 ChemAxon
Refractivity 120.3 ChemAxon
Polarizability 44.2 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 2 ChemAxon
H Bond Donor Count 0 ChemAxon
pKa (strongest basic) 7.6 ChemAxon
Physiological Charge 1 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Voltage-dependent T-type calcium channel subunit alpha-1G : in Human
  • Voltage-dependent T-type calcium channel subunit alpha-1H : in Human
  • Voltage-dependent T-type calcium channel subunit alpha-1I : in Human
  • Histamine H1 receptor : in Human
  • Calmodulin : in Human