calcium channel blockers

1. Calcium Channel Blockers
Dr. Anisha Pamarthi
JR 1
Dept of Pharmacology
GMC, Nagpur

2. Overview
 Introduction
 Types of calcium channels
 Classification of CCBs
 Mechanism of action
 Pharmacological actions
 Pharmacokinetics
 Uses
 Adverse effects
 Recent advances
 Summary

3. Introduction
 Calcium is involved in several vital processes
 final intracellular messenger
 activation of several key enzymes of the
cell
Calcium antagonist : A drug that alters the
cellular function of calcium by inhibiting its
entry and/or its release and/or by interfering
with one of its intracellular actions

4. History
1960 - Godfraind coined the term “calcium
antagonist”
1962 - Hass and Hartfelder reported verapamil
possessed negative inotropic and chronotropic
effects
1967- Albrecht Fleckenstein reported that the –ve
ionotropic effect of calcium antagonist was due to
inhibition of excitation contraction coupling
1972 - Kolhardt showed that Gallonamil blocks the
movement of calcium through the slow channel
1975- Japanese pharmacologists introduced diltiazem

5. Types of Calcium Channels
 4 types of Calcium channels
Voltage sensitive
Receptor operated
Leak or stretch operated
Na + -Ca 2+ Exchange

6. Voltage – sensitive calcium channel
 Existence of VDCCs first reported by Hagiwara in
1975 using egg cell membrane of starfish
Activation threshold of
VDCCs
High
L, N, P/Q
R(Occasionaly
IVA)
Low
T

7. Structure & Function
 L-TYPE Ca+2 CHANNEL
Location: cardiac & smooth
muscle, SA node, AV node
Function: regulate excitation cont-
raction coupling,pacemaker activity,
Conduction velocity
Blockers: Verapamil, Nifedipine,
Diltiazem

8. N-Type Ca+2 Channel
• It is purified from the rat
brain
• It is composed of 4 subunits:
1 , 2 ,  , & 
• role - neurotransmitter
release.

9. P/Q-Type Ca+2 Channel
 It is composed of 1, 2,  &  subunits
 Neurotransmitter release
 Location: Cerebellar & Purkinje neurons
T-Type Ca+2 Channel
 Responsible for neuronal oscillatory activity, involved in
sleep / wakefulness regulation & motor coordination
Also involved in pacemaker activity

10. Receptor – Operated Channels
( Ligand – Gated Ion Channels)
 These channels increase calcium influx in response
to various hormones and neuro-hormones
 Independent of membrane depolarization
 found on plasma membrane

11. Stretch operated channels:
leaky ca+2 channels
 Small amount of Ca+2 leak into resting cell &
pumped out by Ca+2 ATPase
 Mechanical stretch promotes inward movement of
Ca+2 occurring through activation of leaky
channels

12. Classification of CCBs
Nayler classification
Fleckenstein Classification
By Chemical structure

13. Nayler classification
Verapamil
Gallopamil Nifedipine
Niludipine Nimodipine
Amlodipine Isradipine
Nicardipine Nitrendipine
Diltiazem Prenylamine
Fendiline
Organic Blockers
Inorganic Blockers
Co, Na, Mn
Energy dependent
Blockers
cyanide,
dinitrophenol

14. Fleckenstein Classification
Highly potent & Specific substances
Verapamil, Diltiazem, Nifedipine
Less specific substances
Prenylamine, Fendiline, Perhexiline
Non Specific Substances
Phenytoin, Chlorpromazine, Indomethacin

15. By Chemical Structure

16. Classification of CCBs
Dihydropyridines
1.Ultra short acting:
Clevidipine
2.Short acting:
Nifedipine,
Nicardipine
3. Intermediate:
Nislodipine,
Isradipine
4. Long acting :
amlodipine
Non-Dihydropyridines
Short acting:
Verapamil, Diltiazem
Long acting:
Bepridil

17. MECHANISM OF ACTION OF CCBs
 Block calcium entry into cardiac and vascular smooth
muscle at œ-1 subunit of the L-type VDCC
 Increase Ca 2+ channels closed time
 Relaxation of arterial smooth muscle but not
much effect on venous smooth muscle
 Significant reduction in afterload but not preload

19. Pharmacological actions
1. In vascular smooth muscle
cytosolic calcium
binds to form calcium calmodulin complex
Activates MLCK , causes interaction between actin & myosin
Contraction of smooth muscle
Depolarition
of membrane
VGC open
EC calcium
moves into
cell
Hydrolysis of membrane
phosphotidyl inositol
Formation of IP3
Release of calcium from SR
Influ x of EC calcium
Receptor
operated
channel
Stimulated
by NE , 5 HT
histamine
ccb

20. 2. In cardiac cells
 Negative ionotropic effect
cardiac myocyte
calcium binds to troponin
CCB
Inhibitory effect of troponin on contractile apparatus is
relieved
Actin myosin interacts
contraction

21.  SA node , AV node & Atria
Negative Chronotropic
Negative Dromotropic
 Purkinje Fibres:
suppression of electrical activity

22. Relaxation
of arteriolar
smooth
muscle
Relaxation
of coronary
blood flow
Cerebral
vasodilation

23. Differential effects of different
CCBs on CV
AV
SN
AV
SN
Potential reflex
increase in
HR, myocardial
contractility
and O2 demand
Coronary
VD
Dihydropyridines: Selective
vasodilators
Non -dihydropyridines: effect on
cardiac tissue and vasculature
Heart rate
moderating
Peripheral
and coronary
vasodilation
Reduced
inotropism
Peripheral
vasodilation

24. Pharmacokinetics of important CCBs

25. Effect Verapamil Diltiazem Nifedipine
Peripheral
vasodilatation
  
Coronary
vasodilatation
  
Preload 0 0 0/
Afterload   
Contractility  0/ / *
Heart rate 0/  /0
AV conduction   0
Hemodynamic Effects of CCBs

26. Nifedipine
 Prototype DHP
 Rapid onset & short acting
 Arteriolar dilatation BP HR & Oxygen
demand
 ER formulation of nifedipine developed
 Additional intrinsic natriuretic effect
uses: HT & Exertional angina
Dose : 20 – 40 mg BD orally

27. Amlodipine
 Less lipid soluble
 Slow smooth onset , long duration of action
 Day time fluctuations in blood level are minimal
Uses: Exertional angina , hypertention
Dose: 5 – 10 mg OD orally

28. Nicardipine
 More pronounced coronary dilatation
 lesser effect on cardiac contractility as compared
to nifedipine
Uses: angina and HT
Dose: 30-60 mg BD
Nimodipine: selective for cerebral blood vessels &
reduces mortality following a SAH
Dose : 60 mg 6 hourly x 21 days
Nitrendipine ,isradipine, nisoldipine and
lacidipine are vasoselective intermediate acting
nifedipine derivative

29. Clevidipine
 Ultra short acting L type CCB
 t half < 15 min
 More effective than sodium nitroprisside &
glyceryl trinitrate
Uses: HT, Control of perioperative & postoperative
HT

30. Verapamil
 Peripheral vasodilator effect with cardiac depressant
effect like decrease in HR, conduction velocity &
contractility
 Direct negative chronotropic effect blunts reflex
tachycardia
 Possesses alpha adrenergic blocking action which
contributes to peripheral vasodilation
 Inhibit P glycoprotein which is responsible for
extrusion of many anticancer drugs out of cancer cells
Uses: Angina,
supraventricular tachyarrythmia,
post infarct protection,
mild – moderate hypertension

31. Diltiazem
 Diltiazem is less potent vasodilator than
nifedipine and verapamil
 Equivalent to verapamil in effect on AV node and
SA node ,Cardiodepression is < than verapamil but
>nifedipine
 Reflex tachycardia is minimal
 Also inhibit platelet aggregation

32. Bipridil
 Inhibit both inward ca current and
fast inward Na current
 Used for severe stable angina pectoris
Mibefradil
 Block T type calcium channel
 It is proarrthymatic and hence
withdrawn

33. Therapeutic uses of CCB
Prinzmetals Variant Angina
 Diltiazem, amlodipine and
nifedipine– are effective
 Effective prophylactically
Cardiovascular

35. Unstable Angina
 CCB should be used as
third line therapy in
unstable angina in patients
with continuing symptoms
on nitrates & beta blockers
 Initial doses should be low

36. Atrial Fibrillation &
Flutter
 Verapamil reduces ventricular
rate during AF by prolonging
AV nodal conduction.
 In atrial flutter IV Verapamil
increases AV block thus
converting flutter into
Fibrillation with
 controlled Ventricular
response.

37. Hypertrophic Cardiomyopathy &
Congestive Cardiac Failure
 CCBs have limited role in both these conditions.
 They are indicated when there is associated
angina or systemic hypertension.

38. Supra-ventricular
Tachycardia(SVT)

39. Systemic Hypertension
CCBs are effective anti-hypertensive drugs as they
produces
 Peripheral Vasodilatation.
 Antiadrenergic & Natriuretic actions.
 Direct Negative Inotropic actions.
 They reduces both systolic & diastolic pressure
with minimum side effects.

40. Non Cardiovascular Uses
Migraine Prophylaxis:
 In CNS CCB prevents
vasoconstriction by inhibition of Ca
influx via voltage & receptor channels
 reduction in both severity &
frequency of attacks
 Verapamil, flunarizine

41. Sub - Arachnoid Hemorrhage
(SAH)
 Vasospasm following SAH is the major cause of
morbidity due to resulting cerebral ischemia.
 Nimodipine had showed efficacy in reducing the
severity of post SAH vasospasm & its resultant
morbidity
 Nimodipine reduces the frequency & severity of
ischemic defects, penetrate BBB effectively

42. Gastrointestinal Uses
Spasmolytic action on
smooth muscle cells,
they are beneficial in
lowering lower
esophageal sphincter
pressure
Nifedipine is used
Achalasia
Spasmolytic action on
smooth muscle cells,
they are beneficial in
relieving esophageal
spasm
Nifedipine is used
Diffuse esophageal
spasm

43. Hiccups
 Nifedipine is useful in resistant hiccups
 Dosage- 20mg thrice a day
Reynaud's Phenomenon
 Nifedipine is the drug of choice.
Significant reduction in vasospastic attack
 Verapamil is not so effective

44.  Nocturnal cramps
 Spasmodic dysmennorhoea- Nifedipine
 PIH -Nifedipine
 Urinary urgency- Nifedipine
 To reverse resistance to chemotherapeutic
agents(verapamil)

45. Ca+2 Channel in anaesthetics
MECHANISM OF ACTION
 Inhalational anesthetics inhibit inward currents
through VDCCs in a dose-dependent manner
 I.V anesthetics thiopental, ketamine & propofol all
inhibited inward ca+2 currents through L- type VDCCs
of porcine tracheal smooth muscle cells

46. Local anesthetics
 Lidocaine at clinically relevant conc. inhibit inward ca+2
currents in ganglionic neurons
 Lidocaine, tetracaine & bupivacaine also inhibit VDCC
activity of cardiac myocytes in the chick, guinea pig &
hamster, respectively

47. As Antiepileptic
Valproic acid (Na valproate) Ethosuximide
Absence seizures, GTCS, CPS
Juvenile myoclonic epilepsy,
Lennox-Gastaut syndrome,
second-line treatment of status
epilepticus,
post-traumatic epilepsy.
Absence seizures
Anorexia, vomiting drowsiness,
ataxia
Hypersensitivity rashes, blood
dyscrasias.
•Blocks voltage-gated sodium
channels & T-type calcium channels
•Affect the function of the
neurotransmitter GABA
•Inhibitor of the enzyme histone
deacetylase 1
Reduced low-threshold Ca2+ currents
in T-type Ca2+ channels in thalamic
neuron

48. Adverse effects

49. Contraindications:
 Prolonged QT syndrome
 Overt CCF
 Hepatic dysfunction
Use with Caution
 Digitalised patient
 Relative low BP
Safe in:
 Asthama
 Hyperlipidemia
 DM
 Renal dysfunction

50. Interaction
Digoxin
Carbamazepine
Cyclosporine
Theophyline
Rifampin
Barbiturates
Cimetidine

51. Recent advances
Imagabalin
 acts on α2δ subunit of the voltage-dependent
calcium channel
 It has demonstrated preclinical efficacy
of anxiolytic, analgesic,hypnotic,
and anticonvulsant-like activity
 Currently in phase III clinical trials for
treatment of generalized anxiety disorder

52. Ziconotide (SNX-111; Prialt)
 Atypical analgesic agent for severe and chronic
pain.
 Derived from Conus magus (Cone Snail), it is
the synthetic form of an ω-conotoxin peptide.
 FDA Approved December 2004
 Selective N-type voltage-gated calcium
channel blocker

53.  Inhibits release of glutamate, calcitonin gene-
related peptide (CGRP), and substance P in brain
and spinal cord, resulting in pain relief
 Most common S/E
Dizziness, confusion, nystagmus & headache.
Abnormal vision, somnolence,
Urinary retention, diarrhea, nausea, vomiting,

54. Summary
 Calcium ions -vital in many biologic processes
 Calcium antagonists affect physiological
processes.
- secretion of hormones, muscle contraction,
platelet function and neurotransmitter
release
 Calcium channels divided into 3 groups
Voltage- sensitive, Receptor operated,
Stretch operated

55.  T and L Channels- cardiac and vascular
smooth muscles
N- channels -only in nerves.
 CCBs used in cardiovascular conditions
like angina, HTN, AF PSVT
 Non cardiac uses- Local and iv
anaesthetic, migraine prophylaxis,
epilepsy, gastrointestinal diseases etc

56. References
 Basic and clinical pharmacology, Katzung :13th
edition
 H . L. Sharma, K. K. Sharma ;chapter 7
Pharmacodynamics; Principles of Pharmacology ;
2nd edition
 Pharmacology : H.P Rang, M.M. Dale 7th edition
 Seth S., Seth S. NoTitle. Indian J Physiol Pharmacol.
1991;35(4):217–31.
 Papadakis M, McPhee S, editors. CMDT 2017. 56th ed.
McGraw Hill; 2017.