Theory class of MBBS Semester II students

1. Drugs Used In Ischaemic
Heart Disease-II
Dr. Pravin Prasad
M.B.B.S, MD Clinical Pharmacology
Lecturer, Lumbini Medical College
26 June, 2018 (12 Asar, 2075), Tuesday

2. In our last class we discussed:
The term Ischaemic Heart Disease (IHD) and its
types
Classify drugs used in IHD
Pharmacological basis of following drugs in
treatment of IHD
Nitrates
Beta blockers
Potassium channel openers

3. By the end of the class, MBBS
Sem II students will be able to:
Compare the different classes of Calcium Channel
Blockers (CCBs)
Describe the pharmacological basis of other anti-
anginal drugs
Review the anti-anginal drug combinations used
in IHD
List the other drugs used in IHD

4. A new concept
Coronary steal phenomenon
Classical
angina
Coronary
steal
Maximal dilatation
of resistance arteries
in ischemic area
(adenosine
mediated)
Dilatation of conducting
arteries due to drugs
(e.g. nitrates)
Resistance arteries
of non-ischaemic
area not dilated
Resistance arteries
of non-ischaemic
area dilated by drugs
(dipyridamole)

5. Few Terminologies
Chronotropy
Inotropy
Dromotropy
GERD

6. Anti-anginal Drugs
Calcium Channel blockers:
Phenyl alkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines (-dipines):
• Nife-, Felo-, Amlo-, Nitren-, Nimo-, Laci-,
Lercani-, Beni-

7. Anti-anginal Drugs
Others:
• Trimetazidine
• Ranolazine
• Ivabradine
• Dipyridamole

8. Calcium Channel Blockers
Blocks L-type voltage gated Ca2+ channels
Multiple isoforms exists
• CCBs have differing affinities to these
isoforms
• Difference in response seen
Difference in RMP of vascular smooth muscle
and cardiac muscle

9. Calcium Channel Blockers
Mechanism of Action:
Binds to their own specific sites in L-channels
Decreased Ca2+ entry to cells
Ca2+ mediated component of action potential
(AP) inhibited
• Smooth muscle (vascular) relaxation
• Negative inotropy, chronotropy and
dromotropy seen

10. Calcium Channel Blockers
Smooth Muscle cell
MLCK-P
Myosin
Myosin-P
+ Actin
Contraction
Ca2+ + CAM
Ca2+
Stored Ca2+
Ca2+
CCBs
Relaxation

11. Calcium Channel Blockers
Smooth muscle relaxation
Marked effect on arterioles (coronary as well)
Extravascular smooth muscles also relaxed
DHPs > Verapamil > Diltiazem
Nitrendipine
• Release NO from endothelium
• Inhibit cAMP-PDEs
Anti-atherosclerotic action

12. Calcium Channel Blockers
Effect on cardiac muscle
Decreased
Intracellular Calcium
Phase II: Ca2+ moves in; releases Ca2+
from Sarcoplasmic reticulum
Negative inotropy
CCBs

13. Calcium Channel Blockers
Effect on Nodal Tissues

14. Calcium Channel Blockers
Effect of Heart
Negative inotropic action
• Verapamil, Diltiazem
Negative chronotropic and dromotropic action
• Verapamil > Diltiazem
• Not seen with DHPs

15. CCBs: Verapamil
Phenylalkylamine, hydrophilic
Dilates arteries:
Decrease t.p.r.  fall in BP
Cardio-depressant activity:
Partially offset by decreased afterload and
increased sympathetic activity on heart
Cardiac output maintained

16. CCBs: Verapamil
Coronary flow increased
Adverse effects:
Bradycardia, constipation, GERD
Precipitate CHF in patients with pre-existing
disease
Can accentuate conduction defects (C/I in 2nd
and 3rd degree heart block)
Cardiac arrest when given to patient with sick
sinus or when given i.v.

17. CCBs: Diltiazem
Benzothiazepine, hydrophilic
Dilates arteries (lesser than DHPs and verapamil):
Fall in BP (modest)
• Reflex not stimulated
Coronary arteries also dilated
Negative chronotropic and dromotropic action
similar to verapamil

18. CCBs: Diltiazem
Side effects:
Generally well tolerated
Similar to but milder than verapamil
Headache, ankle edema, hypotension,
Bradycardia, AV block

19. CCBs: Nifedipine
Prototype Dihydropyridines
Amlodipine, Benidipine, Felodipine, Lacidipine,
Lercanidipine, Nitrendipine, Nimodipine
Causes arteriolar dilatation
Decreased t.p.r. and fall in BP
Reflex tachycardia seen
Does not depress SA node and AV node

20. CCBs: Nifedipine
Side effects:
Due to arteriolar dilatation:
• Flushing, ankle edema, headache,
hypotension
Reflex tachycardia:
• Palpitation
Rx: start low dose, fraction the dose, use slow
release formulation

21. CCBs: Nifedipine
Side effects:
Paradoxical increase in frequency of angina
• Reflex tachycardia leading to increased
oxygen demand
Increased voiding difficulty (elderly males)
Worsening of Gastro-intestinal reflux disease

22. CCBs: Amlodipine
Pharmacokinetic advantages
Slow, complete oral absorption
Peak blood levels after 6-9 hrs
• Early vasodilator side effects avoided
Higher and consistent oral bioavailability
Longer t½, high Vd
• Lesser diurnal fluctuation
• Action extends over next day
S(-)
Amlodipine

23. CCBs: Uses
Angina Pectoris
Reducing frequency and severity
Short acting DHP – may aggravate ischemia
• Fall in mean BP and reflex tachycardia 
decreased coronary flow
• Unlikely with Verapamil, Diltiazem, slow and
long acting DHPs
Non-DHPs reduce reinfarction and mortality in MI
patients

24. CCBs: Uses
Myocardial Infarction:
NOT TO BE USED
Secondary prophylaxis when beta blockers are
contraindicated
Unstable Angina
Add on therapy to nitrates

25. CCBs: Uses
Hypertension
Cardiac arrhythmias
Hypertrophic cardiomyopathy
Other uses:
Premature labour: Nifedipine
Nocturnal leg cramps: Verapamil
Raynaud’s episodes: DHPs

26. Other Anti-anginal Drugs
Trimetazidine (pFOX inhibitor)
Mechanism of Action- Improves cellular
tolerance to ischemia by:
• Inhibiting mitochondrial long chain 3-
ketoacyl-CoA-thiolase (LC3-KAT)
• Limit intracellular acidosis and Na+, Ca2+
accumulation during ischemia
• Protecting against O- free radical induced
membrane damage

27. Other Anti-anginal Drugs
Trimetazidine (pFOX inhibitor)
Pharmacokinetics:
• Absorbed orally
• Partly metabolised
• Excreted unchanged in urine
• t½ 6 hrs

28. Other Anti-anginal Drugs
Trimetazidine (pFOX inhibitor)
Side effects:
• Generally well tolerated
• Gastric burning, dizziness, fatigue and
muscle cramps
• Reversible Parkinsonism in elderly
Use: Add on therapy in angina and post-MI
patients

29. Other Anti-anginal Drugs
Ranolazine
Mechanism of Action:
• Inhibits late inward Na+ current in
myocardium during depolarization
Na+/Ca2+ exchanger inhibited Decreased
intracellular Ca2+
• Inhibits LC3-KAT
Decreases frequency of angina, prolongs
exercise duration

30. Other Anti-anginal Drugs
Ranolazine
Pharmacokinetics:
• Slow oral absorption
• Bioavailability 30-50%
• Metabolised by CYP3A4
• Excretion- urine
• t½ 7 hrs

31. Other Anti-anginal Drugs
Ranolazine
Side effects:
• Dizziness, weakness, hypotension
• Headache
• Constipation, dyspepsia

32. Other Anti-anginal Drugs
Ivabradine (pure heart rate lowering agent)
Mechanism of action:
• Blockade of funny channels/current slow
phase 4 depolarization  decreased firing
and heart rate
• Decreased O2 demand and prolonged
diastole improves perfusion

33. Other Anti-anginal Drugs
Ivabradine
Pharmacokinetics:
• Well absorbed orally; 40 % bioavailability
• Metabolism CYP3A4
• Excreted in urine

34. Other Anti-anginal Drugs
Ivabradine
Side effects:
• Bradycardia, visual disturbance
• Extra-systoles, prolonged PR interval
• Headache, dizziness, nausea

35. Other Anti-anginal Drugs
Ivabradine
Uses:
• Chronic stable angina with sinus rhythm
• Beta blocker intolerant or contraindicated
patients
• Inappropriate sinus tachycardia

36. Other Anti-anginal drugs
Dipyridamole:
Mechanism of action:
• Increases availability of adenosine (powerful
vasodilator)
• Resistance vessels of ischaemic as well as
non-ischaemic regions dilated
• Leads to coronary steal phenomenon

37. Other Anti-anginal drugs
Dipyridamole:
Mechanism of action:
• Venous return not reduced
• BP minimally affected
• NO IMPROVEMENT IN ANGINA
Inhibits platelet aggregation
• PGI2, cAMP

38. Other Anti-anginal Drugs
Dypridamole
Uses:
• Prophylaxis of coronary and cerebral
thrombosis in post-MI and post stroke
patients
• Prevent thrombosis in patients with
prosthetic heart valves

39. Drug Combination in Angina
Terminate the attack:
GTN
Modify disease Course and provide cardio-
protection:
Antiplatelet drugs: Aspirin, Clopidogrel
Statins: Atorvastatin
ACE inhibitors: Enalapril
Beta-blocker: Metoprolol

40. Drug Combination in Angina
Initially Monotherapy
Any one drug from Nitrates, Beta blockers or
CCBs
Similar anti-anginal efficacy and tolerability
If not adequately controlled add other drugs

41. Drug Combinations in Angina
Beta blocker + Long acting nitrates (or slow acting
DHPs)
Tachycardia of nitrate blocked
Ventricular dilatation by beta blocker checked
Reduction in total coronary flow by nitrate
opposed
Additional benefit with DHPs in coronary
vasospasm
DO NOT COMBINE VERAPAMIL/DILTIAZEM WITH BETA
BLOCKERS

42. Drug Combinations in Angina
Nitrates + CCBs
Preload reduced by nitrates
Afterload reduced by CCBs
Coronary flow increased by CCBs
Additive effect seen for:
• Cardiac work
• Coronary perfusion

43. Drug Combinations in Angina
Nitrates + CCBs + Beta blockers
Supra-additive effect seen
Drug Class Primary action
Nitrates Decrease Preload
CCBs (DHPs) Reduce afterload + increase
coronary flow
Beta blockers Direct action on heart

44. Conclusion
CCBs act by blocking L-type voltage gated Ca2+
channels
DHPs are vaso-selective as compared to Non-
DHPs
DHPs mainly vary in their pharmacokinetic
properties
Dypridamole shows coronary steal phenomenon
Verapamil and diltiazem not to be combined with
beta blockers

45. Questions??
Thank you!