1. CALCIUM CHANNEL BLOCKERS/ANTAGONISTS
February 2017

2. History
The term “calcium antagonists” was 1st coined by Fleckenstein & colleagues in 1969.
Investigating vasodilator effects of prenylamine and verapamil
Observed that they have a negative inotropic effect on the heart
Showed that the –ve inotropic effect can be antagonized by calcium

3. The term ‘calcium antagonist’ is used for drugs that block cellular entry of Ca+2 through calcium channels rather than its intracellular actions.(refer to How drugs act: cellular aspects-excitation, contraction and secretion)
Some authors use the term ‘Ca+2 entry blockers’ to make this distinction clearer.
Therapeutically important calcium antagonists act on L-type channels.

4. Classification of Ca+2 antagonists
1) Phenylalkylamines:
Verapamil, desmethoxyverapamil, tiapamil, anipamil, gallopamil, ronipamil, devapamil, terodilin
2) Benzothiazepines:
Diltiazem, fostedil

5. Classification of Ca+2 antagonists …
3) Dihydropiridines:
Nifedipine, nitrendipine, nimodipine, niludipine, niguldipine, nicardipine, nisoldipine, amlodipine, felodipine, isradipine, ryosidine, lacidipine
Piperazines:
Cinnarizine, lidoflazine, flunarizine

6. Membrane effects of Ca+2 antagonists
Free Ca+2 in the cytosol regulates a number of cellular functions
The intracellular pools of Ca+2 are replenished by Ca+2 from the ECF
The transport of Ca+2 takes place via the Ca+2 channels
Interfere with Ca+2 transport over excitable membranes in different tissues

7. Membrane effects of Ca+2 antagonists…
The channels have to be open for Ca+2 to enter the cells
opened by changes in membrane potential (Voltage-operated Ca+2 –channels)
AND
Through hormone/neurotransmitter mediated changes (receptor-operated channels)

8. Membrane effects of Ca+2 antagonists…
Calcium antagonists act on voltage operated channels which are differentiated into:
T-channels (transient):
- have small conductance and transient opening times
-activated by small depolarisations from very negative potentials
Involved in the initiation of action potentials

9. Membrane effects of Ca+2 antagonists…
Occur in neuronal, smooth muscle, cardiac, skeletal muscle cells
Do not take part in intracellular Ca+2 homeostasis
Inhibited by neurotransmitters e.g. NA & dopamine
Not affected by calcium antagonists

10. Membrane effects of Ca+2 antagonists…
N-type: neuronal channels
L-type: have a high conductance and a prolonged opening time
Play a central role in the regulation of intracellular calcium concentration
Activated by changes in membrane potential

11. Membrane effects of Ca+2 antagonists…
Also modulated by hormones and neurotransmitters
Very sensitive to calcium antagonists
Considered to be their primary receptor
Have a wide distribution
High concentrations in atria, blood vessels & skeletal muscle T-tubules

12. Vascular effects of Ca+2 antagonists
All of them dilate blood vessels
Vasodilator effect is most pronounced with dihydropyridines
Within the dihydropyridines there are marked differences of the vasodilator effect
Vasodilator effect occurs on arteries and resistance vessels

13. Vascular effects of Ca+2 antagonists…
Have negligible effect on veins
Strongly reduce coronary and skeletal vascular resistance
Insignificant effect on skin
Small effect on renal vascular resistance
Vasodilator effect is maintained during chronic therapy in hypertensive patients

14. Other effects on blood vessels
Inhibit arterial smooth muscle proliferation due to a decrease in vascular DNA synthesis
Inhibit platelet activation (platelets are a rich source of vascular growth factors)

15. Effect on renal function
Calcium antagonists are vasodilators that reduce BP without triggering renal compensatory mechanisms that lead to fluid and electrolyte retention with classical vasodilators
Renal blood flow & GFR are maintained during acute and long-term treatment with Ca+2 antagonists

16. Effect on renal function…
Have a diuretic & natriuretic effect inspite of their relative lack of effect on GFR or RBF which may suggest a tubular site of action

17. Effects on the heart Block slow Ca+2 channels
Block myocardial cellular Ca+2 uptake
Reduce the amount of Ca+2 available for interaction with troponin
Negative inotropic effect
Phenylalkyalamines & benzothiazepines > dihydropyridines

18. Effect on the heart…
The relatively strong vasodilator effects of dihydropyridines trigger a baroreflex-mediated rise in sympathetic nerve activity
Leads to a +ve rather than –ve inotropic effect
Verapamil & diltiazem: direct –ve and indirect reflexogenic inotropic effects usually cancel each other

19. Effect on AV conduction
Limited to phenylalkylamines & benzothiazepines
Slow AV node conduction & sinus pacemaker activity
Dihydropyridines & piperazines are less effective and may increase the heart rate due to baroreflex-mediated alteration of sympathetic nerve activity

20. Verapamil & diltiazem: good for treatment of supraventricular tachyarrhythmias
The coronary vasodilator effect of dihydropyridines is useful for preventing coronary spasms that are responsible for causing angina
Whereas as nitroglycerine acts predominantly on large coronary arteries calcium antagonists dilate large and small coronary arteries

21. Effects on cardiac metabolism
Cardiac ischaemia is followed by:
- a decrease in tissue ATP levels
-increase in free-radical production via xanthine oxidase pathway
-alteration in ionic homeostatis
Leading to cardiac arrhythmias and structural disorganization of the heart

22. Upon reperfusion, cells injured by the above mechanisms accumulate large amounts of Ca+2 (Ca+2-overload)
This leads to further damage of the heart
Ca+2 enters the myocardial cells via routes that can be blocked by calcium antagonists

23. They also protect the heart from post ischaemic injury by:
Coronary vasodilatation
Cardiac unloading
Effect on adenosine metabolism
Reduce cardiac hypertrophy due to chronic hypertension

24. Hemodynamic effects
Verapamil & diltiazem cause a modest lowering of BP (Blood Pressure) and TPR (Total Peripheral Resistance) with little or no depressive effect on cardiac function
Dihydropyridines (nifedipine) reduce BP via a strong fall in TPR with an early rise in CO and HR
Piperazines have insignificant short-term BP-lowering activity
(NB: BP=CO X TPR)
(CO=Stroke X volume X HR)

25. Clinical uses Angina pectoris Supraventricular tachyarrhthmias
Hypertension
migraine

26. Unwanted effects
Most of the unwanted effects of calcium antagonists are extensions of their main pharmacological actions
Short acting dihydropyridines cause flushing and headache due to their vasodilator action
Chronic use of dihydropyridines e.g. nifedipine often cause ankle swelling, related to arteriolar dilatation and increased permeability of postcapillary venules.

27. Unwanted effects…
Verapamil can cause constipation, probably because of effects on calcium channels in gastrointestinal nerves or smooth muscle.

28. Summary-Unwanted effects
Headache, constipation (verapamil), ankle oedema (dihydropyridines)
There is a risk of causing cardiac failure or heart block, especially with verapamil and diltiazem

29. H/W Read on the following: Mechanism of action of calcium antagonists
Pharmacokinetics of calcium antagonists

30. Revision-H/W
Giving examples, classify the calcium channel blockers, their clinical uses and unwanted effects
Write short notes on the following:-
Pharmacological effects of calcium channel blockers
Pharmacokinetics of calcium channel blockers
NB: Further reading