Undergradute Level

1. Dr Htet Htet
MBBS, MMedSc (Pharmacology)
CVS Pharmacology (I)
Calcium channel blockers

2. Learning objectives
• At the end of the lecture, students should be able to
• Classify calcium channel blockers.
• Describe
• mechanism of action
• pharmacological action
• therapeutic uses
• adverse effects
• drug interactions
• pharmacokinetics of calcium channel blockers.

3. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

6. Normal physiological role of calcium channels in vessels
L type calcium
channel
Calcium + calmodulin
MLCK
MLCK-P
MLCK
MLCK
Actin-
myosin
cross
bridge

8. Normal physiological role of calcium channels in heart

9. Calcium channel blockers
• Effects – on vessels & heart
• Nitrates – mainly venodilator
• CCB – arterial dilator

10. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

11. Mechanism of action of CCB
• In vascular smooth muscles,
• Entry of Ca2+ through L-type calcium channels lead to activation of myosin light chain kinase,
which then leads to phosphorylation of light chain myosin, finally resulting actin-myosin cross
bridging – and contraction of vascular smooth muscle – resulting in vasoconstriction.
• CCB blocks calcium channels – resulting – vasodilation – predominantly arteriolar smooth
muscle.
• In cardiac myocytes,
•  calcium entry through L-type calcium channels – leads to decrease in myocardial contractility,
SA node pace maker rate, AV conduction velocity.

12. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

13. Pharmacological action/effects on organs of CCBs
• Effects on vascular smooth muscle
• Vasodilation of systemic arterial smooth muscle →  systemic blood pressure
• Vasodilation of coronary arterial smooth muscle →  blood supply to cardiac
muscles.
• Cardiac muscle
• SA node → rate of nodal discharge
• AV node → AV conduction
•  heart rate
•  myocardial contractility
• conduction

14. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

15. Classification of CCBs
1. Dihydropyridines (Nifedipine, amlodipine, felodipine, clevidipine)
2. Benzothiazepines (diltiazem)
3. Phenylalkylamines (verapamil)
antidysrhythmic
antihypertensive
Antianginal
Generally

16. Overall Therapeutic uses of different CCBs
1. Systemic hypertension
2. Arrhythmia
3. Angina.

17. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

18. Status of different CCB in different conditions
• Dihypyridine group
• Nifedipine, amlodipine – significantly more arteriolar vasodilation, little effect on
cardiac tissue. More used in systemic hypertension. Nifedipine has more
vasodilation effect which can even lead to reflex tachycardia – and can precipitate
angina (coronay steal syndrome).
• Amlodipine is more useful – antihypertensive agent.
• Celvidipine – recently approved – only IVI – management of hypertensive
emergency.

19. Status of different CCB in different conditions
• Verapamil & Diltiazem
• Have more effect on heart than in vascular smooth muscle.
• Causes decrease automaticity of heart, decrease conduction velocity, decrease
contractility.
• Useful for arrhythmia & angina
(due to cardiac depressant action.)

20. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

21. Pharmacokinetics of CCBs
• Absorption – typically oral form, but verapamil & diltiazem – also have IV
formulation.
nifedipine, verapamil & diltiazem – all possess significant first
pass metabolism.
• Metabolism & excretion – nifedipine & verapamil – excreted by kidney.
verapamil – excreted by liver.

22. Amlodipine or nifedipine?
Amlodipine Nifedipine
Bioavailability Higher Lower
Onset of action Slow Rapid
Chance of reflex
tachycardia
Less Higher chance
Plasma half life Longer (about 40 hrs) Shorter
Dosing Once a daily dosing Frequent dosing
But extended release/slow release formulation
available.

23. Coronary steal syndrome by nifedipine
• Rapid onset of action <20 min
• Produces brisk precipitous fall in BP
• Drug induced hypotension – can activate severe reflex tachycardia,which can
worsen the myocardial ischaemia by increasing the myocardial oxygen demand
and decrease myocardial oxygen demand (by decreasing the diastolic oxygen
filling time)

24. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

25. Therapeutic uses of verapamil & Diltiazem
1. Exertional angina , Unstable angina , Angina due to coronary spasm
(Prinzmetal angina or variant angina)
2. Systemic Hypertension
3. Atrial fibrillation, flutter , Paroxysmal supraventricular tachycardia.

26. Therapeutic uses of DHP groups
1. Exertional angina , Unstable angina , Coronary spasm
2. Hypertension
3. Raynaud’s phenomenon
4. Pre-eclampsia.

27. Other therapeutic uses of CCBs
• Cerebral vasospasm and infarct following subarachnoid haemorrhage
• Nicardipine
• High affinity for cerebral vessels
• Reduce morbidity after SAH
• IVI or intraarterial infusion to prevent cerebral vasospasm associated with stroke.
• Uterine relaxant
• To prevent premature labor

28. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

29. Adverse effects
• Extension of pharmacological actions.
• Flushing (common with nifedipine)
• Constipation (common with verapamil – excessive smooth muscle relaxation in
GI smooth muscle)
• Bradycardia, atrioventricular block, heart failure (extension of negative
chronotropic and inotropic effects).

30. Learning outline
1. Normal physiological role of calcium channels ‘
2. Mechanism of action of CCB
3. Pharmacological actions
4. Classification
5. Status of CCB indifferent clinical conditions
6. Pharmacokinetics
7. Therapeutic uses
8. Adverse effects
9. Drug interactions

31. Drug interaction
• CCB + beta receptor blockers – cardio-depressant action, dangerous
combination.

32. References