Calcium channel blockers

Calcium channel blockers


  • Verapamil – a phenyl alkylamine, hydrophilic papaverine derivative
  • Nifedipine – a dihydropyridine (lipophillic)
  • Diltiazem –  hydrophilic benzothiazepine

 The dihydropyridines (DHPs) are the most potent Ca2+ channel blockers. Voltage sensitive calcium channels 


L type

(long lasting current)

T type

(transient current)

N type



25 pS

8 pS

12-20 pS

Activation threshold




Inactivation rate




Location and function

Excitation contraction coupling  in cardiac and smooth muscle

SA and AV node – conductivity

Endocrine cells – hormone release

Neurons – transmitter release

SA node pacemaker activity

T current and repetitive spikes in thalamic and other neurons

Endocrine cells – hormone release

Certain arteries – constriction

Only on neurons in CNS, sympathetic and myenteric plexuses – transmitter release


Nifedipine, diltiazem, verapamil

Mibefradil, flunarizine, ethosuximide


Pharmacological actions and adverse effects ​The common property of all three subclasses of CCBs is to inhibit Ca2+ mediated slow channel component of action potential (AP) in smooth/ cardiac muscle cell.The two most important actions of CCBs are:

  1. Smooth muscle (especially vascular) relaxation
  2. Negative chronotropic, ionotropic and dromotropic action on heart

  Smooth muscle:

  • The CCBs cause relaxation by decreasing intracellular availability of Ca2+.
  • They markedly relax arterioles but have a mild effect of veins
  • Extravascular smooth muscle (bronchial, biliary, intestinal, vesical, uterine) is also relaxed.
  • The dihydropyridine (DHPs) have the most marked smooth muscle relaxant and vasodilator action; verapamil is weaker followed by diltiazem


  • CCBs have negative ionotropic effect
  • Verapamil and diltiazen results in depression of pacemaker activity and conduction
  • DHPs have no negative chronotropic/ dromotropic action
  • Channel blockade by verapamil is enhanced at higher rates of stimulation, that by nifedipine is independent of frequency while diltiazem is intermediate
  • Verapamil slows the sinus rate and AV conduction, but nifedipine does not
  • Effect of diltiazen on sinus node automaticity and AV conduction is similar to that of verapamil

 Comparative properties of representative calcium channel blockers  






Channel blocking potency





Frequency dependence of channel blockade




Channel recovery rate


Much delayed

No effect


Cardiac effects

Heart rate

↓, –


AV conduction velocity





–, ↓

↓, ↑




–, ↑

Vascular smooth muscle relaxation





Clinical use in











  • It dilates arterioles and has some α adrenergic blocking activity – decreases tpr but BP is only modestly lowered
  • The pronounced direct cardio depressant effect is partially offset in vivo by reflex effects of peripheral vasodilatation
  • The HR generally decreases, AV conduction is slowed, but CO is maintained by reflex sympathetic stimulation and reduction in aortic impedance
  • Ventricular contractility may be markedly impaired in CHF patients
  • Coronary flow is increased
  • Verapamil is extremely effective in the treatment of patients with hypertrophic cardiomyopathy. The basic physiological action of the drug may lead to serious adverse effects. (1)
  • Verapamil is ineffective and potentially hazardous in most patients with ventricular tachycardia. It should not be used to treat broad complex tachycardia unless a supraventricular origin has been established. (2)
  • Verapamil does not affect ventricular tachycardia caused by reentry and catecholamine sensitive automacity but is effective in suppressing ventricular tachycardia caused by triggered activity related to delayed after depolarizations in humans. (3)
  • Verapamil binds to and blocks open HERG channels. Tyr-652 and Phe-656, 2 aromatic amino-acid residues in the inner (S6) helix, are critical in the verapimil-binding site. (4)
  • Verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes. (5)
  • Beneficial effects are achieved in some patients when low dose verapamil is administered intraarterially in patients with cerebral vasospasm. (6)
  • Intralesional verapimil is a suitable alternative to triamcinolone in the treatment of hypertrophic scars and keloids. (7)

Adverse effects:

Nauseao Constipationo Verapamil given in infants with supraventricular tachycardia causes life threatening bradycardia and hypotension. (8)o Flushing, headache and ankle edema are less commono Hypotension is occasionalo Tachycardia is absento Polymorphous ventricular tachycardia. (9)o It can accentuate conduction defects (contraindicated in 2nd and 3rd degree AV block)o Precipitate CHF in patients with preexisting disease 

Drug interactions:

Should not be given with β blockerso Increases plasma digoxin level by decreasing its excretion, toxicity can developo Should not be used along with other cardiac depressants like quinidine and disopyramideo Verapamil significantly increases the serum digoxin concentration. The process is dose dependent and is due to reduced renal excretion without reduction in glomerular filteration. (10)o Chronic renal failure predispose patients to verapamil toxicity. Drugs that inhibit cytochrome P450 metabolism should be avoided in patients with renal failure who receive treatment with verapimil. (11)o Verapamil potentiate doxorubicin cardiotoxicity. (12)   Diltiazem

  • Less potent vasodilator than nifedipine and verapamil and has modest direct negative ionotropic action
  • Direct depression of SA node and AV conduction are equivalent to verapamil
  • Usual clinical doses produce consistent fall in BP with little change or decrease in HR
  • Large dose or iv injection decreases tpr markedly which may elicit reflex cardiac effects  
  • Diltiazem dilates coronaries
  • Diltiazem is safe and effective in the management of rapid ventricular rate in atrial fibrillation. Rate control effect is earleir and percentage decrease in ventrcular rate is higher with diltiazem. (13)
  • The pharmacokinetics of diltiazem in patients with artrial fibrillation or atrial flutter is non linear with an apparent dose dependent decrease in systemic clearance with increasing infusion rate. There is a strong relation between plasma diltiazem concentration and percent heart rate reduction. The plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem are low and are not expected to contribute significantly to the pharmacodynamics of intravenous diltiazem. (14)
  • Diltiazem and verapamil exert similar suppressive effect on the AV node and are useful for treating and preventing AV nodal reentrant tachycardia. They may sometimes worsen AV conduction, especially in patients with conduction disturbances. (15)
  • DIltiazem is more effective than nifedipine in reducing angina and the episodes of ST segment depression on the ambulatory monitor. Exercise duration is increased and resting heart rate is reduced. Both drugs reduce the resting blood pressure and rate pressure product. (16)
  • In patients with chronic atrial fibrillation, diltiazem controls the ventricular rate response through exercise without attenuating blood pressure or exercise capacity. (17)
  • Hyperinsulinaemia-euglycaemia and lipid emulsion is efefctive in the treatment of severe diltiazem poisoning. (18)
  • Diltizem treatment leads to a significant increase in IL-10 concentrations in the patients of unstable angina. (19)
  • Diltiazem has antidepressant activity like imipramine and venlafaxine. (20)
  • Diltiazem is useful in resuscitation from recurrent ventricular fibrillation. (21)
  • Diltiazen should not be given to patients with preexisting sinus, AV nodal or myocardial disease

Adverse effects:

o Side effects are milder

o Side effects are similar to verapamil

o It increases plasma digoxin level

o Diltiazem toxicity presents with dysrrhythmias and heart block. The risk factors include advanced age and impaired renal function. (22) Nifedipine

  • It is the prototype DHP with a rapid onset and short duration of action
  • The overriding action of nifedipine is arteriolar dilatation –  tpr decreases, BP falls.
  • The direct depressant action on heart requires much higher dose, but a weak negative ionotroic action can be unmasked after β blockade
  • It does not depress SA node or AV conduction
  • Reflex sympathetic stimulation of heart predominates producing tachycardia, increased contractility and CO
  • No decrease in venous return along with lowering of afterload aids increase in CO
  • Coronary flow is increased
  • Nifedipine is superior to β2-adrenergic receptor agonists and magnesium sulphate for tocolysis in women with preterm labor. (23)
  • Oral nifedipine is effective in the management of severe hypertension in pregnancy, controls hypertension more rapidly and is associated with a significant increase in urinary output. (24)
  • Nifedipine improves the smooth muscle function in esophageal motility disorders like achalasia and diffuse esophageal spasm. (25)

Adverse effects:

o Palpitation

o Flushing

o Ankle edema

o Hypotension

o Headache

o Short acting nifedipine markedly increases the risk of stroke. (26)

o Drowsiness

o Nausea

o Relaxant action on bladder can increase urine voiding difficulty in elderly males

o Gastroesophageal reflux may be worsened due to relaxation of lower esophageal sphincter

o Hamper diabetes control by decreasing insulin release Other dihyropyridines

  • Felodipine
  • Amlodipine
  • Nitrendipine
  • Lacidipine
  • Nimodipine
  • Lercanidipine
  • Benidipine

 Pharmacokinetic characteristics of calcium channel blockers 

DrugBioavailabilityVd (L/Kg)CL (L/hr/Kg)Active metaboliteElimination t ½ (hr)


1. Angina pectoris

  • All CCBs are effective in reducing frequency and severity of classical as well as variant angina
  • Benefit in classical angina is primarily due to reduction in cardiac work: mainly as a result of reduced afterload and the BP × HR product

2. Hypertension 

3. Cardiac arrhythmias 

  • Verapamil and diltiazem are highly effective in PSVT and for control of ventricular rate in supraventricular arrhythmias

4. Hypertrophic cardiomyopathy

  • The negative ionotropic action of verapamil can be salutary in this condition

5. Other uses

  • Nifedipine is an alternative drug for premature labor
  • Verapamil has been used to suppress nocturnal leg cramps
  • The DHPs reduce severity of Raynaud’s episodes


  1. SE Epstein, DR Rosing. Verapamil: its potential for causing serious complication in patients with hypertrophic cardiomyopathy. Circulation. 1981;64:437-441. 
  2. Andrew C Rankin, ALan P Rae, Stuart M Cobbe. MIsuse of intravenous verapamil in patients with ventricular tachycardia. The Lancet. 1987;330(8557):472-474. 
  3. RJ Sung, WA Shapiro, EN Shen, F Morady, J Davis. Effects of verapamil on ventricular tachycardias possibly caused by reentry, automacity and triggered activity. J Clin Invest. 1983;72(1):350-360. 
  4. Jing-jing Duan, Ji-hua Ma, Pei-hua Zhang, XIan-pei Wang, An-rou Zou, Dan-na Tu. Verapamil blocks HERG channel by the helix residue Y652 and F 656 in the S6 transmembrane domain. Acta Pharmacologica Sinica. 2007;28:959-967. 
  5. Nasir Afzal, Pallab K Ganguly, Ken S Dhalla, Grant N Pierce, Pawan K Singal, Naranjan S Dhalla. Beneficial effects of verapamil in diabetic cerdiomyopathy. Diabetes. July 1988;37(7):936-942. 
  6. Lei Feng, Brian Fred Fitzsimmons, William L Young, Mitchell F Berman, Erwin Lin, Beverly DL Aagaard, Hoang Duong, John Pile Spellman. Intrarterially administered verapimil as adjunct therapy for cerebral vasospasm: Safety and 2 year experience. American Journal of Neuroradiology. 2002;23:1294-1290. 
  7. FX Margaret Shanthi, Kalpana Ernest, Prema Dhanraj. Comparison of intralesional verapimil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian Journal od dermatology, venereology and leprology. 2008;74(4):343-348.
  8. D Radford. Side effects of verapamil in infants. Arch Dis Child. Jun 1983;58(6):465-466. 
  9. Stephen L Winters, Paul Schweitzer, Joel Kupersmith, Joseph A Gomes. Verapamil induced polymorphous ventricular tachycardia. Journal of the American College of Cardiology. July 1985;6(1):257-259. 
  10. HO Klein, R Lang, E Weiss, E Di Segni, C Libhaber, J Guerrero, E Kaplinsky. The influence of verapamil on serum digoxin concentration. Circulation. 1982;65:998-1003. 
  11. Steven J Rosansky. Verapamil toxicity and renal failure. Arch Intern Med. 1992;152(9):1925.
  12. Hajime Akimoto, Nicholas A Bruno, Doris L Slate, Margaret E Billingham, Suzy V Torti, FRank M Torti. Effect of verapimil on doxorubicin cardiotoxicity: Altered muscle gebe expression in cultured neonatal rat cardiomyocytes. Cancer Res. Oct 1993;53:4658.
  13. C Demircan, H Cikriklar, Z Engindeniz, H Cebicci, N Atar, V Guler, E Unlu, B Ozdemir. Comparison of the effectiveness of intravenous diltiazem and metoprolol in the management if the rapid ventricular rate in atrial fibrillation. Emerg Med J. June 2005;22(6):411-414. 
  14. The VC Dias, SJ Weir, KA Ellenbogen. Pharmacokinetics and pharmacodynamics of intravenous diltiazem in patients with atrial fibrillation or atrial flutter. Circulation. 1992;86:1421-1428.
  15. C Kawai, T Konishi, E Matsuyama, H Okazaki. Comparativ effects of three calcium antagonists, diltiazem, verapamil and nifedipine on the sinoatrial and atrioventricular nodes. Experimentala nd clinical studies. Circulation 1981;63:1035-1042. 
  16. W Frishman, S Charlap, B Kimmel, M Teicher, J Cinnamon, L Allen, J Strom. Diltiazem, nifedipine and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance and the ambulatory electrocardiographic ST segment. Circulation. 1988;77:774-786. 
  17. J Edwin atwood, Jonathan N Myers, Michael J Sullivan, Susan M Forbes, William F Pewen, Victor F Froelicher. Diltiazem and exercise performance in patients with chronic atrial fibrillation. Chest. 1988;93(1):20-25. 
  18. Nadine Monteiro, Joana Silvestre, Joao Goncalves-Pereira, Camila Tapadinhas, Vitor Mendes, Pedro Povoa. Severe diltiazem poisoning treated with hyperinsulinaemia-Euglycaemia and lipid emulsion. Case reports in critical care. 2013. Article ID 138959, 4 pages. 
  19. L Dubey, Z Hesong. Anti-inflammatiry action of diltiazem in patients with unstable angina. Postgrad Med J 2006;82:594-597. 
  20. Rajesh Komma, Seema Bhalerao, PS Worlikar, Nikhil Vijay, Pavitra Raj Dewda. A study to evaluate the effect of diltiazem on the antidepressant action of imipramine and venlafaxine using forced swim test in-vivo in rats. Am J PharmTech Res. 2012;2(2). 
  21. Kishikawa Kazuhiro, Kumeta Yukihiro Kumeta, Kuhihara Chieko, Endo Hideko, Namiki Akiyoshi. Diltiazem for ventricular fibrillation. Anesthesiology. Sept 1997;87(3):709. 
  22. Jorge A Brenes, Yong-Mei Cha. Diltiazem-induced transient complete atriventricular block in an elderly patient with acute in chronic renal failure. The Open Cardiovascular Medicine Journal. 2013;7:23-27. 
  23. Agustin Conde Aqudelo, Roberto Romero, Juan Pedro Kusanovic. Nifedipine in the management of preterm labor: a systematic review and metaanalysis. American Journal of Obstetric & Gynecology. Feb 2011;204(2):134.e1-134.e20
  24. Badal Dhali, Shritanu Bhattacharya, Rajendra Prasad Ganguly, Shrirupa Bandyopadhyay, Mousumi Mondal, Mousumi Dutta. Int J Reprod Contracept Obstet Gynecol. 2012;1(1):42-46. 
  25. Keith Berger, Richard W McCallum. Nifedipine in the treatment of achalsia. Ann Intern Med. 1982;96(1):61-62. 
  26. Ferdinando S Buonanno, J David Spence. Short-acting nifedipine and risk of stroke. Neurology Sept 2011;77(13):1216-1217.