BDS 2nd year theory class

1. Drugs Used In Ischaemic
Heart Disease
Dr. Pravin Prasad
M.B.B.S, MD Clinical Pharmacology
Asst. Prof., Maharajgunj Medical Campus
6 February, 2020 (23 Magh, 2076), Thursday

2. By the end of the class, BDS II
Year students will be able to:
Classify anti-anginal drugs
Describe the pharmacology of nitrates and their
role in treatment of Ischaemic Heart Disease (IHD)
Explain the pharmacological basis of beta blockers
in IHD
Compare the different classes of Calcium Channel
Blockers (CCBs)

3. Lets revise some concepts
What is your understanding about:
? Blood supply of heart
? Preload
? Afterload
? Factors affecting Cardiac O2 consumption
? Smooth muscle contraction
? Ischaemic Heart Disease
• What are included in it?

4. Anti-anginal Drugs:
Classification
Nitrates
Short acting:
• Glyceryl trinitrate (GTN, Nitroglycerine)
Long acting:
• Isosorbide (mono-) dinitrate
• Erythrityl tetranitrate
• Pentaerythritol tetranitrate

5. Anti-anginal Drugs:
Classification
Beta blockers
Cardioselective: Metoprolol, Atenolol
Nonselective: Propanolol
Calcium Channel blockers:
Phenyl alkylamine: Verapamil
Benzothiazepine: Diltiazem
Dihydropyridines (-dipines):
• Nife-, Felo, Amlo-, Nitren-, Nimo-, Laci-, Lercani-
, Beni-

6. Anti-anginal Drugs:
Classification
Potassium channel openers
• Nicorandil
Others:
• Trimetazidine
• Ranolazine
• Ivabradine
• Dipyridamole, Oxyphedrine

7. Nitrates
 GTN (Nitroglycerine)
Isosorbide mononitrate, Isosorbide dinitrate,
Erythrityl tetranitrate, Pentaerythritol tetranitrate
Acts by direct non-specific smooth muscle
relaxation
Organic nitrates

8. Nitrates: Mechanism of Action
Smooth
Muscle cell Nitrates
Nitric oxide
Denitrated
Guanylyl cyclase
(activated)
cyclic GMP
(cGMP)
GTP
Myosin Light Chain Kinase-P
(MLCK)-P
MLCK (active)
Myosin
Myosin-P
+ Actin
Contraction
Ca2+ + CAM
Ca2+
Stored
Ca2+
Ca2+

9. Nitrates: Mechanism of Action
Rapidly denitrated to reactive free radical nitric
oxide (NO)
Activates guanylyl cyclase
Increased cGMP levels
Inhibits phosphorylation (activation) of MLCK
interaction between myosin and actin
prevented  relaxation (vasodilatation)
Reduced Ca2+ entry inside cells

10. Nitrates: Effects
Preload reduction (venodilatation):
Relief in classical angina
Afterload reduction (arteriolar dilatation)
Moderate dose: Decrease in cardiac work
• Therapeutic
Large dose: reflex tachycardia
• Counter productive

11. Nitrates: Effects
Redistribution of coronary flow:
Dilates conducting vessels (larger coronary
arteries)
Ischaemic area resistance vessels (smaller
arterioles) already dilated
Increased blood flow to ischaemic area
Relief in variant angina

12. Nitrates: Effects
Heart and peripheral blood flow:
No direct effect on heart
Dilate cutaneous vessels: Flushing
Dilate meningeal vessels: Headache
Splanchnic and renal blood flow: 
Shifting of blood from lungs to systemic
circulation: decongestion of lungs

13. Nitrates: Pharmacokinetics
Absorption:
 Lipid soluble: well absorbed from buccal
mucosa, intestines and skin
 Oral administration: extensive and variable
first pass metabolism in liver
• Not seen with Isosorbide mononitrate
(IMN)

14. Nitrates: Pharmacokinetics
Metabolism:
Rapidly denitrated (glutathione reductase,
mitochondrial aldehyde dehydrogenase)
Partly denitrated metabolites: less active, longer t½
Duration of action depends on the site of
administration:
• Sub-lingual GTN, IDN- short acting
• Oral GTN, IDN- long acting

15. Nitrates: Adverse effects
Due to Vasodilation:
Fullness in head, throbbing headache
Flushing, weakness, sweating, palpitation,
dizziness, fainting
Methaemoglobinemia
Significant in severe anaemia
Tolerance
Dependence
Rashes: pentaerythritol tetranitrate

16. Nitrates: Tolerance
Dose/Duration dependent; weans off rapidly
Significant: continuous intra-venous infusion, oral &
transdermal administration
Cross tolerance seen
Possible mechanism:
Depleted SH radicals
Compensatory mechanism, oxidative stress
Rx: Provide nitrate free interval everyday

17. Nitrates: Dependence
Prolonged exposure  sudden withdrawal 
spasm of coronary and peripheral blood vessels
Lowering of angina threshold seen
Can lead to MI, sudden deaths
Rx:
Gradual withdrawal
Use another class of drug

18. Nitrates: GTN
Volatile liquid
Should be stored in a tightly closed glass container
Sublingual tablet/spray:
To terminate attack
Crush the tablet under the teeth  spread over
buccal mucosa
Acts within 1-2 mins
Anginal pain relieved  spit or swallow the
remaining tablet

19. Nitrates: GTN
Sustained release capsules
For chronic prophylaxis
Cutaneous application:
Ointment: effects in 4-6 hrs
Transdermal patch:
• Effects seen in 60 mins
• Tolerance, Dependence seen
Transmucosal dosage (Gum):
• Acts in 5 mins, for 4-6 hrs

20. Nitrates: GTN
Intravenous infusion
Rapid, steady, titratable plasma concentration
Begin with 5mcg/min, titrate as required
Unstable angina, coronary vasospasm, LVF with
MI, hypertension during cardiac surgery

21. Nitrates: Uses
Angina pectoris
Terminating attack: GTN, IDN
Chronic prophylaxis: Longer acting
formulations
Acute coronary syndrome
Myocardial infarction

22. Nitrates: Uses
Congestive Heart Failure and Acute Left
Ventricular failure
Biliary Colic
Esophageal spasm
Achalasia cardia
Cyanide Poisoning
Sod. nitrite
Haemoglobin
Methaemoglobin
Cyanomethaemoglobin
Methaemoglobin + Sod. thiocyanate
Sodium nitrite
Sodium thiosulfate
Cyanide

23. Beta Blockers
Improves blood supply by:
Decreased heart rate, inotropic state and mean
BP
• Reduced cardiac work and O2 consumption
Cardio-selective agents preferred
Atenolol, Acebutolol, Bisoprolol, Metoprolol,
Nebivolol

24. Beta Blockers
More effective in exercise, emotion related angina
(classical angina)
High dose may precipitate angina
To be taken on a regular schedule
Dose has to be individualised
Do not discontinue abruptly
• May precipitate angina, MI
Long term therapy: reduced cardiac deaths in IHD
Not suitable for variant angina

25. Beta Blockers
Acute Coronary Syndrome
Routinely used
• If coronary vasospasm- After administering
nitrates +/- CCBs
Benefits by:
• Reducing O2 demand
• Reducing risk of impending MI/ sudden
cardiac death

26. 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

27. 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

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

29. Calcium Channel Blockers
Smooth muscle relaxation
Marked effect on arterioles
DHPs > Verapamil > Diltiazem
Effect of Heart
Negative inotropic action
Negative chronotropic and dromotropic action
• Not seen with DHPs

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

31. Calcium Channel Blockers
Effect on Nodal Tissues

32. CCBs: Verapamil
Dilates arteries:
Decrease t.p.r.  fall in BP
Coronary flow increased
Cardio-depressant activity:
Counter balanced by reflex increased
sympathetic activity on heart
Cardiac output maintained

33. CCBs: Verapamil
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.

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

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

36. 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

37. CCBs: Nifedipine
Side effects:
Due to arteriolar dilatation:
• Flushing, ankle edema, headache,
hypotension
Reflex tachycardia:
• Palpitation

38. 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

39. CCBs: Uses
Angina Pectoris
Reducing frequency and severity
• Verapamil, Diltiazem, slow and long acting
DHPs
Non-DHPs reduce reinfarction and mortality in
MI patients
Unstable Angina
Add on therapy to nitrates

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

41. Conclusion
Nitrates acts by donating nitric oxide and increasing
cGMP
Always be alert for tolerance and dependence on
nitrates
Beta blockers are has better prognosis in classical
angina
Not suitable for variant angina
CCBs act by blocking L-type voltage gated Ca2+
channels
DHPs are vaso-selective as compared to Non-DHPs

42. Questions??
Thank you!

43. Pharmacotherapy for
Myocardial Infarction
Objectives Drug
Pain, anxiety and apprehension GTN- 3 doses, 5 mins apart
Morphine/ pethidine
Diazepam
Prevention of thrombus
extension, embolism and
thrombosis
Aspirin (162-325 mg)
Heparin
Correction of acidosis Sodium bicarbonate
Thrombolysis and reperfusion Streptokinase, Urokinase
Prevent/Treat arrhythmias Tachyarrhythmia- lidocaine,
procainamide, amiodarone
Bradycardia- atropine, electrical
pacing

44. Pharmacotherapy for
Myocardial Infarction
Objectives Drug
Maintenance of blood volume,
tissue perfusion and
microcirculation
Saline
LMW dextran
Pump failure Furosemide, GTN,
dopamine/dobutamine
Prevention of remodeling and
subsequent CHF
ACE inhibitors, ARBs
Prevention of future attacks Platelet inhibition: Aspirin,
clopidogrel
Reduce risk of infarction, CHF,
mortality: Beta blockers
Control hyperlipidemia: statins