Verapamil
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| Systematic (IUPAC) name |
(RS)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-
(methyl)amino}-2-prop-2-ylpentanenitrile |
| Clinical data |
| Licence data |
US FDA:link |
| Pregnancy cat. |
C (US) |
| Legal status |
℞ Prescription only |
| Routes |
Oral, Intravenous |
| Pharmacokinetic data |
| Bioavailability |
35.1% |
| Metabolism |
Hepatic |
| Half-life |
2.8-7.4 hours |
| Excretion |
Renal: 11% |
| Identifiers |
| CAS number |
52-53-9 Y |
| ATC code |
C08DA01 |
| PubChem |
CID 2520 |
| IUPHAR ligand |
2406 |
| DrugBank |
DB00661 |
| ChemSpider |
2425 Y |
| UNII |
CJ0O37KU29 Y |
| KEGG |
D02356 Y |
| ChEBI |
CHEBI:9948 Y |
| ChEMBL |
CHEMBL6966 Y |
| Chemical data |
| Formula |
C27H38N2O4 |
| Mol. mass |
454.602 g/mol |
SMILES
- N#CC(c1cc(OC)c(OC)cc1)(CCCN(CCc2ccc(OC)c(OC)c2)C)C(C)C
|
InChI
-
InChI=1S/C27H38N2O4/c1-20(2)27(19-28,22-10-12-24(31-5)26(18-22)33-7)14-8-15-29(3)16-13-21-9-11-23(30-4)25(17-21)32-6/h9-12,17-18,20H,8,13-16H2,1-7H3 Y
Key:SGTNSNPWRIOYBX-UHFFFAOYSA-N Y
|
| Y (what is this?) (verify) |
Verapamil (brand names: Isoptin, Verelan, Verelan PM, Calan, Bosoptin, Covera-HS) is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches.[1] It is also an effective preventive medication for migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class IV antiarrhythmic, more effective than digoxin in controlling ventricular rate[2] and was approved by the U.S. Food and Drug Administration (FDA) in March 1982.[3]
Contents
- 1 Mechanism and uses
- 2 Pharmacokinetic details
- 3 Side effects
- 4 Uses in cell biology
- 5 Veterinary use
- 6 Potential use in the treatment of malaria
- 7 References
- 8 External links
Mechanism and uses[edit]
Verapamil's mechanism in all cases is to block voltage-dependent calcium channels.
In cardiac pharmacology, calcium channel blockers are considered class IV antiarrhythmic agents. Since calcium channels are especially concentrated in the sinoatrial and atrio-ventricular nodes, these agents can be used to decrease impulse conduction through the AV node, thus protecting the ventricles from atrial tachyarrhythmias.
Calcium channels are also present in the smooth muscle that lines blood vessels. By relaxing the tone of this smooth muscle, calcium-channel blockers dilate the blood vessels. This has led to their use in treating hypertension and angina pectoris.
The pain of angina is caused by a deficit in oxygen supply to the heart. Calcium channel blockers like Verapamil will dilate blood vessels, which increases the supply of blood and oxygen to the heart. This controls chest pain, but only when used regularly. It does not stop chest pain once it starts. A more powerful vasodilator such as glyceryl trinitrate may be needed to control pain once it starts.
Verapamil is also used intra-arterially to treat cerebral vasospasm.[4] Verapamil has been used to treat cluster headaches,[5] but it can also cause headaches as a side effect.
Pharmacokinetic details[edit]
Given orally, 90–100% of Verapamil is absorbed, but due to high first-pass metabolism, bioavailability is much lower (10–35%). It is 90% bound to plasma proteins and has a volume of distribution of 3–5 L/kg. It is metabolized in the liver to at least 12 inactive metabolites (though one metabolite, norverapamil, retains 20% of the vasodilating activity of the parent drug). As its metabolites, 70% is excreted in the urine and 16% in feces; 3–4% is excreted unchanged in urine. This is a non-linear dependence between plasma concentration and dosage. Onset of action is 1–2 hours after oral dosage. Half-life is 5–12 hours (with chronic dosages). It is not cleared by hemodialysis. It is excreted in human milk. Because of the potential for adverse reaction in nursing infants from Verapamil, nursing should be discontinued while Verapamil is administered.
Verapamil has been reported to be effective in both short-term[6] and long-term treatment of mania and hypomania.[7] Addition of magnesium oxide to the verapamil treatment protocol enhances the antimanic effect.[8] It has on occasion been used to control mania in pregnant patients, especially in the first 3 months. It does not appear to be significantly teratogenic. For this reason, when one wants to avoid taking valproic acid (which is high in teratogenicity) or lithium (which has a small but significant incidence of causing cardiac malformation), Verapamil is usable as an alternative, albeit presumably a less effective one.
Side effects[edit]
Some possible side effects of the drug are headaches, facial flushing, dizziness, lightheadedness, swelling, increased urination, fatigue, nausea, ecchymosis, galactorrhea, and constipation.[9][10]
Verelan 300mg Extended Release Capsule
Along with other calcium channel blockers, verapamil is known to induce gingival hyperplasia. [11]
Overdose[edit]
Acute overdose is often manifested by nausea, asthenia, bradycardia, dizziness, hypotension and cardiac arrhythmia. Plasma, serum or blood concentrations of verapamil and norverapamil, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Blood or plasma verapamil concentrations are usually in a range of 50-500 μg/L in persons on therapy with the drug, but may rise to 1–4 mg/L in acute overdose patients and are often at levels of 5–10 mg/L in fatal poisonings.[12][13]
Uses in cell biology[edit]
Verapamil is also used in cell biology as an inhibitor of drug efflux pump proteins such as P-glycoprotein.[14] This is useful as many tumor cell lines overexpress drug efflux pumps, limiting the effectiveness of cytotoxic drugs or fluorescent tags. It is also used in fluorescent cell sorting for DNA content, as it blocks efflux of a variety of DNA-binding fluorophores such as Hoechst 33342. Radioactively-labelled verapamil and positron emission tomography can be used with to measure P-glycoprotein function.[15]
Veterinary use[edit]
Intra-abdominal adhesions are common in rabbits following surgery. Verapamil can be given post-operatively in rabbits who have suffered trauma to abdominal organs to prevent formation of these intra-abdominal adhesions.[16][17][18] Such effect was not documented in another study with ponies.[19]
Potential use in the treatment of malaria[edit]
Recent resistance to the anti-malarial drug chloroquine has hindered the treatment of malaria in Southeast Asia, South America and Africa. Resistance to chloroquine is caused by the parasite cell's ability to expel the drug outside of its digestive vacuole. It has been shown that verapamil, when used in combination with chloroquine, enhances the accumulation of chloroquine within a parasitic cell's digestive vacuole, rendering it incapable of detoxifying itself and making it more susceptible to death.[20][21]
References[edit]
- ^ Beck, Ellen; Sieber, William J.; Trejo, Raúl (2005). "Management of Cluster Headache". American Family Physician 71 (4): 717–24. PMID 15742909.
- ^ Srinivasan, Viswanathan; Sivaramakrishnan, H; Karthikeyan, B (2011). "Detection, Isolation and Characterization of Principal Synthetic Route Indicative Impurities in Verapamil Hydrochloride". Scientia Pharmaceutica 79 (3): 555–68. doi:10.3797/scipharm.1101-19. PMC 3163365. PMID 21886903.
- ^ "verapamil, Calan, Verelan, Verelan PM, Isoptin, Covera-HS". MedicineNet.com. Retrieved 6 October 2011.
- ^ Jun, P.; Ko, N. U.; English, J. D.; Dowd, C. F.; Halbach, V. V.; Higashida, R. T.; Lawton, M. T.; Hetts, S. W. (2010). "Endovascular Treatment of Medically Refractory Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage". American Journal of Neuroradiology 31 (10): 1911–6. doi:10.3174/ajnr.A2183. PMID 20616179.
- ^ Drislane, Frank; Benatar, Michael; Chang, Bernard S.; Acosta, Juan; Tarulli, Andrew (1 January 2009). Blueprints Neurology. Lippincott Williams & Wilkins. pp. 71–. ISBN 978-0-7817-9685-9. Retrieved 14 November 2010.
- ^ Giannini, AJ; Houser Jr, WL; Loiselle, RH; Giannini, MC; Price, WA (1984). "Antimanic effects of verapamil". The American Journal of Psychiatry 141 (12): 1602–3. PMID 6439057.
- ^ Giannini, AJ; Taraszewski, R; Loiselle, RH (1987). "Verapamil and lithium in maintenance therapy of manic patients". Journal of clinical pharmacology 27 (12): 980–2. doi:10.1002/j.1552-4604.1987.tb05600.x. PMID 3325531.
- ^ Giannini, A.James; Nakoneczie, Ann M.; Melemis, Stephen M.; Ventresco, James; Condon, Maggie (2000). "Magnesium oxide augmentation of verapamil maintenance therapy in mania". Psychiatry Research 93 (1): 83–7. doi:10.1016/S0165-1781(99)00116-X. PMID 10699232.
- ^ "Verapamil". PubMed Health. Retrieved 10 Jan 2012.
- ^ "“verapamil, Calan, Verelan, Verelan PM, Isoptin, Covera-HS (cont.)". MedicineNet.com. Retrieved 10 Jan 2012.
- ^ Steele, RM; Schuna, AA; Schreiber, RT (1994). "Calcium antagonist-induced gingival hyperplasia". Annals of internal medicine 120 (8): 663–4. PMID 8135450.
- ^ Wilimowska, Jolanta; Piekoszewski, Wojciech; Krzyanowska-Kierepka, Ewa; Florek, Ewa (2006). "Monitoring of Verapamil Enantiomers Concentration in Overdose". Clinical Toxicology 44 (2): 169–71. doi:10.1080/15563650500514541. PMID 16615674.
- ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. pp. 1637–9.
- ^ Bellamy, W T (1996). "P-Glycoproteins and Multidrug Resistance". Annual Review of Pharmacology and Toxicology 36: 161–83. doi:10.1146/annurev.pa.36.040196.001113. PMID 8725386.
- ^ Luurtsema, Gert; Windhorst, Albert D.; Mooijer, Martien P.J.; Herscheid, Jacobus D.M.; Lammertsma, Adriaan A.; Franssen, Eric J.F. (2002). "Fully automated high yield synthesis of (R)- and (S)-[11C]verapamil for measuring P-glycoprotein function with positron emission tomography". Journal of Labelled Compounds and Radiopharmaceuticals 45 (14): 1199–207. doi:10.1002/jlcr.632.
- ^ Elferink, Jan G.R.; Deierkauf, Martha (1984). "The effect of verapamil and other calcium antagonists on chemotaxis of polymorphonuclear leukocytes". Biochemical Pharmacology 33 (1): 35–9. doi:10.1016/0006-2952(84)90367-8. PMID 6704142.
- ^ Azzarone, Bruno; Krief, Patricia; Soria, Jeannette; Boucheix, Claude (1985). "Modulation of fibroblast-induced clot retraction by calcium channel blocking drugs and the monoclonal antibody ALB6". Journal of Cellular Physiology 125 (3): 420–6. doi:10.1002/jcp.1041250309. PMID 3864783.
- ^ Steinleitner, Alex; Lambert, Hovey; Kazensky, Carol; Sanchez, Ignacio; Sueldo, Carlos (1990). "Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit". Journal of Surgical Research 48 (1): 42–5. doi:10.1016/0022-4804(90)90143-P. PMID 2296179.
- ^ Baxter, Gary M.; Jackman, Bradley R.; Eades, Susan C.; Tyler, David E. (1993). "Failure of Calcium Channel Blockade to Prevent Intra-abdominal Adhesions in Ponies". Veterinary Surgery 22 (6): 496–500. doi:10.1111/j.1532-950X.1993.tb00427.x. PMID 8116206.
- ^ Martin, S.; Oduola, A.; Milhous, W. (1987). "Reversal of chloroquine resistance in Plasmodium falciparum by verapamil". Science 235 (4791): 899–901. doi:10.1126/science.3544220. PMID 3544220.
- ^ Krogstad, D.; Gluzman, I.; Kyle, D.; Oduola, A.; Martin, S.; Milhous, W.; Schlesinger, P. (1987). "Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance". Science 238 (4831): 1283–5. doi:10.1126/science.3317830. PMID 3317830.
External links[edit]
- MedlinePlus DrugInfo medmaster-a684030
- "Verapamil" in Drugs.com
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Antiarrhythmic agents (C01B)
|
|
| Channel blockers |
|
class I
(Na+ channel blockers)
|
|
class Ia (Phase 0→ and Phase 3→)
|
- Ajmaline
- Disopyramide
- Lorajmine
- Prajmaline
- Procainamide#
- Quinidine#
- Sparteine
|
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class Ib (Phase 3←)
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- IV (Lidocaine#)
- enteral (Aprindine
- Mexiletine
- Tocainide)
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class Ic (Phase 0→)
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- Encainide‡
- Ethacizine
- Flecainide
- Indecainide‡
- Lorcainide
- Moracizine‡
- Propafenone
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|
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class III
(Phase 3→, K+ channel blockers)
|
- Amiodarone
- Bretylium
- Bunaftine
- Dofetilide
- Dronedarone
- E-4031†
- Ibutilide
- Nifekalant
- Sotalol
- Tedisamil
- Vernakalant
|
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class IV
(Phase 4→, Ca2+ channel blockers)
|
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Receptor agonists
and antagonists |
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class II
(Phase 4→, β blockers)
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- Nadolol
- Pindolol
- Propranolol
- cardioselective (Acebutolol
- Atenolol
- Esmolol
- Metoprolol)
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A1 agonist
|
- Adenosine
- Benzodiazepines
- Barbiturates
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M2
|
- muscarinic antagonist: Atropine
- Disopyramide
- Quinidine
muscarinic agonist: Digoxin
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α receptors
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- Amiodarone
- Bretylium
- Quinidine
- Verapamil
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| Ion transporters |
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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noco/cong/tumr, sysi/epon, injr
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proc, drug (C1A/1B/1C/1D), blte
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Channel blockers
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|
| Calcium (Ca2+) |
|
|
| Potassium (K+) |
- 3,4-Diaminopyridine
- 4-Aminopyridine
- Amiodarone
- Bretylium
- Bunaftine
- Charybdotoxin
- Conotoxins
- Dofetilide
- Dronedarone
- E-4031
- Ibutilide
- Linopirdine
- Maurotoxin
- Nifekalant
- Paxilline
- Sotalol
- Tedisamil
- Tetraethylammonium
- Vernakalant
|
|
| Sodium (Na+) |
- Antiarrhythmics: Ajmaline
- Aprindine
- Disopyramide
- Dronedarone
- Encainide
- Flecainide
- Lidocaine
- Lorajmine
- Lorcainide
- Mexiletine
- Moricizine
- Phenytoin
- Pilsicainide
- Prajmaline
- Procainamide
- Propafenone
- Quinidine
- Sparteine
- Tocainide
- Anticonvulsants: Carbamazepine
- Eslicarbazepine acetate
- Ethotoin
- Fosphenytoin
- Licarbazepine
- Mephenytoin
- Oxcarbazepine
- Oxitriptyline
- Phenytoin
- Rufinamide
- Topiramate
- Sodium valproate
- Valnoctamide
- Valproate pivoxil
- Valproate semisodium
- Valproic acid
- Valpromide
- Diuretics: Amiloride
- Benzamil
- Triamterene
- Local anesthetics: pFBT
- Amylocaine
- Articaine
- Benzocaine
- Bupivacaine (Levobupivacaine, Ropivacaine)
- Butacaine
- Butamben
- Chloroprocaine
- Cinchocaine
- Cocaine
- Cyclomethycaine
- Dimethocaine
- Diphenhydramine
- Etidocaine
- Hexylcaine
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- Mepivacaine
- Meprylcaine
- Metabutoxycaine
- Orthocaine
- Piperocaine
- Prilocaine
- Procaine
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- Proxymetacaine
- Risocaine
- Tetracaine
- Trimecaine
- Toxins: Conotoxins
- Neosaxitoxin
- Saxitoxin
- Tetrodotoxin
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| Other |
- Uncategorized: Ethadione
- Paramethadione
- Phenacemide
- Pheneturide
- Trimethadione
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