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Drugs used in ischaemic heart disease 2
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)
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
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
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
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
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
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