CALCIUM CHANNEL BLOCKERS/ANTAGONISTS

1. CALCIUM CHANNEL BLOCKERS/ANTAGONISTS February, 2011

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. • Some authors use the term ‘Ca+2 entry blockers’ to make this distinction clearer.

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

5. Classification… 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. 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. 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. 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. 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. 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 • 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. 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

21. Whereas as nitroglycerine acts predominantly on large coronary arteries calcium antagonists dilate large and small coronary arteries

22. 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

23. 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

24. 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

25. 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)

26. Clinical uses • Angina pectoris • Supraventricular tachyarrhthmias • Hypertension • migraine

27. 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.

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

29. 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

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