This document discusses drugs used to treat ischemic heart disease. It begins by classifying anti-anginal drugs into nitrates, beta blockers, calcium channel blockers, and potassium channel openers. It then provides details on the pharmacology of nitrates, including their mechanism of action, effects, pharmacokinetics, uses, and adverse effects like tolerance and dependence. Beta blockers are described as improving blood supply and being more effective for exercise or emotion-related angina. The document concludes by noting nitrates donate nitric oxide to cause vasodilation, beta blockers have a better prognosis for classical angina, and nicorandil benefits ischemic heart disease through its dual mechanism of action.

1. Drugs Used In Ischaemic
Heart Disease
Dr. Pravin Prasad
M.B.B.S, MD Clinical Pharmacology
Asst Prof, Maharajgunj Medical Campus
7 April, 2020 (25 Chatira 2076), Tuesday

2. By the end of the class, MBBS 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
Explain the role of potassium channel blockers in
IHD

3. Lets revise some concepts
What is your understanding about:
? Types of blood vessels 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
(MLCK)
MLCK-P
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):
 End diastolic size and pressure reduced
 Decreased cardiac work
 Sub endocardial crunch abolished
Laplace law:
T = P x R
Relief in classical angina
T= Wall tension
P= Intraventricular Pressure
R= Intraventricular Radius

11. Nitrates: Effects
Afterload reduction (arteriolar dilatation):
Total peripheral resistance decreases (fall in BP,
systolic>diastolic)
Aortic impedance decreases
Cardiac work decreases

12. Nitrates: Effects
Afterload reduction (arteriolar dilatation):
Large doses/ significant fall in mean BP
Reflex sympathetic stimulation
Tachycardia, increased cardiac work, angina
precipitated
• Fainting and cold sweat (cerebral ischemia)
• Rx: lying down and raising the foot end

13. 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

14. 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

15. Nitrates: Effects
Other smooth muscles:
Bronchi, Biliary tract, Esophagus: mild
relaxation
Intestine, ureter, uterus: variable and
insignificant
Platelets:
Mild antiaggregatory effect (valuable in
unstable angina)

16. 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))

17. 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

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

19. 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

20. 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

21. 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

22. 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

23. 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

24. Nitrates: Isosorbides
Dinitrate:
Solid form
Available for oral as well as sub lingual
administration
• Variable and high first pass metabolism on
oral administration
• t½ 40 mins; sustained release formulation
effective for 6-10 hrs
Last dose before 6 pm

25. Nitrates: Isosorbides
Mononitrate:
Active metabolite
Little first pass metabolism on oral
administration
Longer acting (t½ 4-6 hrs)
Last dose in afternoon
Sustained release formulation- once daily
administration

26. Nitrates: Others
Erythrityl tetranitrate, Pentaerythritol tetranitrate
Longer acting nitrates
Suitable for chronic prophylaxis
High doses saturates first pass metabolism in
liver
• Haemodynamic effects lasting for 4-6 hrs
seen

27. Nitrates: Uses
Angina pectoris
Terminating attack: GTN, IDN
Chronic prophylaxis: Longer acting
formulations
• Prognosis better with CCBs

28. Nitrates: Uses
Acute Coronary Syndrome
GTN, sublingually, 1 tablet, repeat in 5 mins if not
improved up to 3 tablets
• Start i.v. infusion of GTN
Other drugs/modalities:
• Antiplatelet drugs
• Beta blockers
• CCBs
• Revascularization (pharmacological or surgical)

29. Nitrates: Uses
Myocardial Infarction:
GTN, i.v. infusion, titrated according to response
Avoid hypotension and tachycardia
DO NOT ADMINISTER IF:
• Systolic BP < 90 mmHg
• HR <50 or >100 bpm
• RV infarction suspected
• Patient has taken sildenafil in the past 24 hrs

30. 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

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

32. 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
Use cautiously in variant angina

33. 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

34. Potassium Channel Openers
Minoxidil, Diazoxide
Marked compensatory reflexes activated
Diazoxide: reduced insulin secretion
Nicorandil, Pinacidil, Cromakalim
Beneficial for both classical and vasospastic
angina

35. Potassium Channel Openers
Mechanism of action:
Opens K+
ATP channels (smooth muscles)
• Hyperpolarization of cells and relaxation of
vessels
Also acts as NO donor
• cGMP mediated activity
Decreased preload, afterload and increased
coronary flow

36. Potassium Channel Openers
Mechanism of action:
Stimulates ischaemic preconditioning
• Activates mitochondrial KATP channels
• Exerts cardioprotective action

37. Potassium Channel Openers
Pharmacokinetics:
Well absorbed orally
Metabolised in liver
Excreted in urine
Biphasic elimination:
• Initial t½ 1 hour
• Later t½ 12 hours

38. Potassium Channel Openers
Side effects:
Due to vasodilatation:
• Flushing, palpitation, weakness, headache,
dizziness
Apthous ulcer
• Reversible
Possible interaction with sildenafil

39. 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
Nicorandil benefits by dual mechanism in IHD

40. Questions??
Thank you!