PH1.28 Describe the mechanisms of action, types, doses, side effects, indications and contraindications of the drugs used in ischemic heart disease (stable, unstable angina and myocardial infarction), peripheral vascular disease

1. PH1.28 Describe the mechanisms of action, types,
doses, side effects, indications and
contraindications of the drugs used in ischemic
heart disease (stable, unstable angina and
myocardial infarction), peripheral vascular disease
Dr Pankaj Kumar Gupta, MD
Assistant Professor,
Department of Pharmacology,
ESIC Medical College & Hospital,
Faridabad (HARYANA) INDIA

2. Ischemic Heart Disease

3. Objectives
• Definition of Myocardial Ischemia
• Definition, Pathophysiology & types of Angina
• Anti-anginal drugs Pharmacology
 Nitrates
 B-blockers
 Calcium Channel blockers
• Newer drugs for Angina
• Drug therapy in myocardial infarction
• Drug therapy in Peripheral Vascular Disease (PVD)

4. Myocardial ischemia
• Myocardial ischemia is a condition
when blood flow to heart is
reduced, preventing the heart
muscle from receiving enough
oxygen.
• The reduced blood flow is usually
the result of a partial or complete
blockage of coronary arteries.
• A sudden, severe blockage of
coronary artery can convert
myocardial ischemia to myocardial
infarction.

7. Angina
• Angina (an-JIE-nuh or AN-juh-
nuh) is a type of chest pain
caused by reduced blood flow
to the heart.
• Angina is a symptom of
coronary artery disease.
• Angina is also called angina
pectoris.
• Angina pain is often described
as squeezing, pressure,
heaviness, tightness or pain in
the chest. It may feel like a
heavy weight lying on the
chest.
https://www.mayoclinic.org/diseases-conditions/angina/symptoms-causes/syc-20369373

8. Pathophysiology of Angina/IHD
• Chest pain/discomfort related to a decrease
in oxygen-rich blood flow
• Usually due to coronary artery disease (CAD)
• Atherosclerosis
– Build up of plaque over time that narrows the
internal diameter of the vessel
• Arteriosclerosis
– Stiffening of vessels over a period of time which
makes them less pliable
8

9. • Plaque
formation
• Angina serves as
a warning that
something is
going on
9
Pathophysiology of Angina/IHD

10. Types of Angina
• Classic angina
• Variant angina
• Unstable angina

11. Stable Angina
• Most common form
• Pain occurs when oxygen
demand is greater than
the supply during
periods of increased
workload of the heart
• Usually treated with rest
and medication (i.e.
nitroglycerin)
11

12. Unstable Angina
• Pain that is unpredictable
and can occur at rest
• May not stop with rest
and/or medication
• Event to be taken
seriously
– May be predicting an
imminent acute MI in
the near future
12

13. Variant Angina
• Occurs when vessel is in spasm
• Very painful
• Often occurs at night
• Controlled with medication
13

14. Anti-Anginal drugs Classification

15. NITRATES
MODE OF ACTION
• Acts directly on vascular smooth muscle to
produce arterial and venous dilatation
EFFECT DURING ANGINA
• Reduces myocardial oxygen demand (lowers pre-
load and after load)
• Increases myocardial oxygen supply (coronary
vasodilatation)

16. Nitrates Preparations
Drug Dose & route Duration of
action
Brands
1 GTN (Nitroglycerine) •0.5 mg SL
•0.4-0.8 mg SL Spray
•5-15 mg SR Oral
•Patch-14-16 hr/day
•IV 5-20 µg/min
•10-30 min
•10-30 min
•4-8 hr
•24 hrs
•Till infused
•Tab Angised 0.5 mg
•Nitrolingual GTN Spray 0.4 mg/spray
•Tab Nitrocontin
•Nitroderm TTS Patch
•Inj Nitroject
2 Isosorbide dinitrate •5 mg SL
•10-20 mg Oral
•10-40 mg SR Oral
•20-40 min
•2-4 hr
•6-10 hr
Tab Sorbitrate 5/10 mg
Tab Isorbid 10 mg
Tab Dinitrate SR 20/40 mg
3 Isosorbide-5-
mononitrate
•10-40 mg Oral
•10-40 mg SR Oral
•6-10 hr Tab Monotrate 10/20/40 mg
Tab Monotrate 25/50 mg SR
4 Erythrityl-tetranitrate •15-60 mg Oral •4-6 hrs Tab Cardilate 5/15 mg
5 Pentaerythritol-
tetranitrate
•10-40 mg Oral
•80 mg SR Oral
•3-5 hrs
•8-12 hrs
Tab Peritrate 10 mg
Tab Peritrate SR 80 mg SR

17. BETA BLOCKERS
MODE OF ACTION
• Lowers myocardial oxygen demand by
A. Reducing heart rate
B. Reducing blood pressure
C. Reducing myocardial contractility

18. • All β- blockers except those with intrinsic
sympathomimetic activity are equally effective in
decreasing frequency & severity of attacks & in
increasing exercise tolerance in classical angina but
the cardio-selective are preferred over non-selective
blockers.
• Commonly used β- blockers:
• Atenolol 50-200 mg daily
• Metoprolol SR 50-200 mg daily
• Bisoprolol 5-10 mg daily

20. Limitations of β blockers
• Can exacerbate symptoms of peripheral vascular disease.
• May provoke bronchospasm in patients with obstructive
airway disease e.g asthma.
• Non-selective beta blockers may aggravate coronary
vasospasm (variant angina) by blocking the coronary artery β-
2 receptors & due to unopposed α receptor mediated
vasoconstriction.
• β-blockers should not be withdrawn abruptly because of the
possibility of a rebound effect and the risk of precipitating
arrhythmias, worsening angina or causing myocardial
infarction (the ‘beta-blocker withdrawal syndrome).

21. Calcium Channel Blockers
MODE OF ACTION
• Decreases myocardial oxygen demand by reducing blood
pressure and myocardial contractility
TYPES
A. Dihydropyridine CCBs:
• Often cause reflex tachycardia
• best used in combination with beta blocker
• Eg. Nifedipine, Nicardipine
B. Phenylalkylamine-Verapamil
C. Benzothiazepine- Dilitiazem
• Both suitable for patients who are not receiving beta blockers as
they decrease the heart rate (dangerous additive effect)
• May reduce myocardial Contractility to a degree that can aggravate
or precipitate Heart failure

22. Status of CCBs in Angina
• All the CCBs have been used for treating angina. However, the most
commonly used for this purpose are the longer-acting forms of
Diltiazem and Verapamil, Amlodipine, or Felodipine.
• Nifedipine, especially its short-acting forms, should be avoided in
people with angina since the pronounced blood vessel dilation
produced by this drug can increase in adrenaline, leading to a more
rapid HR, and consequently an increase in cardiac oxygen
requirements which led to worsen cardiac ischemia.
• CCBs should be tried in patients who cannot tolerate beta-blockers.
• CCBs should be added to beta-blockers in patients who have
insufficient relief of symptoms with beta-blockers.
https://www.verywellhealth.com/calcium-channel-blockers-for-treating-angina-1745910

23. POTASSIUM CHANNEL ACTIVATORS: NICORANDIL
Mode of action 1. Dilates arteries and veins
2. Does not exhibit tolerance seen with nitrates
Mechanism of
action
1. This a novel anti-anginal drug activates ATP sensitive K+
channels leading to hyperpolerization of vascular smooth
muscle.
2. It also acts as a NO donor and relaxes blood vessels by
increasing cGMP.
2. Coronary blood flow is increased, dilatation of both
epicardial conducting vessels and deeper resistance vessel.
3. Mitochondrial K+ ATP channel opening exert myocardial
protection by preconditioning which appears to reduce
myocardial stunning, arrhythmias and infarct size.
Side effect 1. Flushing, palpitation, weakness, headache, dizziness
2. Large painful aphthous ulcers of mouth.
Dose 1. Nicorandil Dose- 5-20 mg BD (NIKORAN)

24. RANOLAZINE
Mode of action 1. ↓ myocardial contractility
2. Cardioprotective effect
Mechanism of
action
1. Act mainly by reducing a late, prolonged sodium current in
myocardial cells. (Late INa)
2. The decrease in intracellular sodium causes an increase in
calcium expulsion via the Na/Ca transporter and a reduction in
cardiac force and work.
3. By inhibiting LC3KAT Spare fatty acid oxidation during
ischemia & ↑ O2 efficient carbohydrate oxidation.
4. Ranolazine is moderately effective in angina prophylaxis.
Pharmacokinetics 1. Oral absorption- slow (4-6 hrs), BA-30-50%
2. Metabolism CYP3A4, t1/2- 7 hrs
3. Excretion-urine
Side effect 1. Dizziness, weakness, constipation, postural hypotension,
headache, dyspepsia
Dose 1. 0.5- 1 g BD (RANOZEX)

25. DIPYRIDAMOLE
Mode of action 1. Coronary dilator
2. Adjuvant anti-platelet drug
Mechanism of action 1. It is a powerful coronary dilator
2. ↑ total coronary flow by preventing uptake and
degradation of adenosine. (local mediator involved in auto-
regulation)
3. It dilates resistance vessels (both in ischemic & non-
ischemic zone vessels) and abolishes auto-regulation. So, fails
to relieve anginal symptoms & avert ECG changes. (Coronary
steal phenomena- pharmacological success but therapeutic
failure)
4. Not useful as an anti-anginal drug but used for prophylaxis
of Coronary and cerebral thrombosis in post-MI and post stoke
patients.
5. Inhibit platelet aggregation. (PGI2 potentiation)

26. Diagrammatic representation of coronary haemodynamics.
A—in classical angina,
B — Selective nitrate action on conducting vessels,
C—Dipyridamole action on all resistance vessels increases blood flow to non-ischaemic zone

27. TRIMETAZIDINE
Mode of action 1. pFOX inhibitor (fatty acid oxidation pathway)
2. Anginal frequency is reduced and exercise capacity is increased.
Mechanism of action 1. Improve cellular tolerance to ischemia by
• Inhibiting mitochondrial long chain 3-ketoacyl-CoA- thiolase
(LC3-KAT) a key enzyme in fatty acid oxidation
• Increasing glucose metabolism in myocardium. (oxidation of fatty
acid requires more more O2 to glucose for same amount of ATP
generation)
• Limiting intracellular acidosis and Na+ and Ca++ accumulation
during ischemia.
• Protecting against O. free radical induced membrane damage
Pharmacokinetics 1. Oral absorption
2. Partial metabolism
3. Excretion in urine-unchanged, t1/2- 6 hrs
Side effect 1. Well tolerated
2. Gastric burning, dizziness, fatigue, muscle cramps
3. Reversible parkinsonism
Dose & use 1. 20 mg TDS (FLAVEDON)
2. Used as an add-on medication to conventional therapy in angina,
post-MI patients.

28. IVABRADINE
Mode of action 1. This is a‘pure’ heart rate lowering antianginal drug.
Mechanism of action 1. It blocks the cardiac pacemaker (sino-atrial) cell ‘f’ channels,
which are ‘funny’ cation channels that open during early part of
slow diastolic (phase 4) depolarization.
2. The resulting inward current (If) determines the slope of phase 4
depolarization, thus decreasing heart rate.
3. Heart rate reduction decreases cardiac O2 demand and
prolongation of diastole tends to improve myocardial perfusion
(O2 supply).
Pharmacokinetics 1. Well absorbed orally, BA-40%
2. Metabolism by CYP3A4
3. Excretion in urine, t1/2-2 hrs
Side effect 1. Excess bradycardia, visual disturbance, extrasystoles, prolongation
of P-R interval, headache, dizziness and nausea.
Dose & use 1. Initially 5 mg BD, increase to 7.5 mg BD (IVABRAD)

29. DRUG COMBINATIONS
I. β blocker + long-acting nitrate combination
II. slow acting DHP (in place of nitrate) with β blocker.
III. Nitrates and CCBs
IV. All 3 classes

30. DRUG THERAPY IN MYOCARDIAL
INFARCTION

31. Acute Coronary Syndromes (ACS)
•According to severity, the acute coronary syndrome (ACS)
may be graded into:
•Unstable Angina (UA)
•Non-ST segment Elevation Myocardial Infarction (NSTEMI)
•ST segment Elevation Myocardial Infarction (STEMI)
•Myocardial Infarction (MI) is ischaemic necrosis of a
portion of the myocardium due to sudden occlusion of a
branch of coronary artery.
•Ischemia means the absence of blood flow to the organ or
body tissues, while Infarction implies the death of tissues
due to reduced blood supply.

32. Acute Coronary Syndromes (ACS)
Unstable Angina (UA)
NSTEMI
(Non-ST segment
Elevation Myocardial
Infarction)
STEMI
(ST segment Elevation
Myocardial Infarction)
1 Vascular obstruction is
incomplete
Vascular obstruction is
incomplete, but occlusion &
micro-embolization has
started
Vascular obstruction is
complete (complete
occlusion)
2 Myocardial necrosis is
absent
Smaller area of myocardial
necrosis
Full thickness of ventricular
wall & larger area of
myocardium is necrosed
3 Biochemical biomarkers
of ischemia (myoglobin,
CK-MB, Troponin-I) do not
appear in blood
Biochemical biomarkers of
ischemia appear in blood
Biochemical biomarkers of
ischemia appear in blood
prominently
4 ST segment not elevated
in ECG
ST segment not elevated in
ECG
ST segment is elevated in
ECG

34. DRUG THERAPY IN MYOCARDIAL
INFARCTION
1 Pain, anxiety and
apprehension
•GTN, Morphine, Diazepam
2 Oxygenation
3 Maintenance of blood
volume
•Slow IV infusion of saline/dextrose
4 Correction of acidosis •Due to lactic acid production
•IV Sodium bicarbonate infusion
5 Prevention and
treatment of
arrhythmias
Beta blockers, Lidocaine
•Arrythmias- Prophylactic Metoprolol (IV/Oral) &
continued for few days ↓ incidence of arrhythmias,
mortality & infarct size
•Tachyarrhythmias- IV
Lidocaine/Procainamide/Amiodarone
•Bradycardia/Heart block- Atropine/Electrical Pacing

35. DRUG THERAPY IN MYOCARDIAL
INFARCTION
6 Pump failure •The objective is to increase c.o. and/or decrease
filling pressure without unduly increasing cardiac work
or lowering BP.
•Vasodilators (GTN slow IV)
•Inotropic agents (Dopamine/dobutamine IV infusion)
•Diuretics (Furosemide if pulmonary wedge pressure
>20 mm Hg)
7 Prevention of thrombus
extension, embolism,
venous thrombosis
•Aspirin (162–325 mg), then continued at 80–160
mg/day
8 Thrombolysis and
reperfusion
•Fibrinolytic agents: Plasminogen activators—
streptokinase/ urokinase/alteplase/ PCI
9 Prevention of remodeling
and subsequent CHF
•ACE inhibitors/ARBs

36. DRUG THERAPY IN MYOCARDIAL
INFARCTION
10 Prevention of future
attacks
• Platelet inhibitors: aspirin/clopidogrel on long
term basis
• β blockers: ↓ risk of re-infarction, CHF and
mortality, all pts should be on suitable β blocker
for at least 2 years
• Statins: for control of hyperlipidaemia
• ACE-I/ARBs: ↓vascular remodeling & BP

37. Approach to a patient with Acute Corornary Syndromes

38. Peripheral Vascular Disease (PVD)
• A slow and progressive circulation disorder.
• Narrowing, blockage, or spasms in a blood vessel can
cause PVD.
• Primarily due to atherosclerosis.
• The atherosclerotic process may gradually progress to
complete occlusion of medium-sized and large
arteries.
• The legs and feet are most commonly affected. It has
the potential to cause loss of limb or even loss of life.
https://emedicine.medscape.com/article/761556-overview
https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-vascular-disease

40. Drugs Properties
Cyclandelate •Papaverine like general smooth muscle relaxant
•MOA: ↑ cutaneous, skeletal & cranial blood flow
•Uses: In PVD- minor role, restricted to vasospastic PVD
•ADR: flushing, palpitation, headache
•Dose: 200-400 mg TDS (CYCLOSPASMOL)
Xanthinol
Nicotinate
•A compound of xanthine & nicotinic acid (both are vasodilators)
•Uses: Promoted for cerebrovascular disorders & PVDs
•Therapeutic benefits are insignificant
•Dose: 300-600 mg TDS Oral, 300 mg IM/slow IV (COMPLAMINA)
Pentoxiphylline •An analogue of theophylline
•Weak phosphodiesterase inhibitor
•Rheological action (property of flow- ↓blood viscosity & ↑flexibility
of RBCs) is responsible for therapeutic benefit
•ADRs: Well tolerated, in some- nausea, vomiting, dyspepsia, bloating
•Uses: intermittent claudication due to occlusion, trophic leg ulcers,
TIAs, chronic cerebrovascular insufficiency
•Overall benefits are minimal
•Dose: 400 mg BD/TDS, 300 mg/15 ml for slow IV (TRENTAL,
FLEXITAL)

41. Drug Properties
Cilostazol •MOA: PDE-3 inhibitor- ↑ intracellular cAMP in platelets &
vascular smooth muscle cells- antiplatelet & vasodilator effect
•↑walking distance in intermittent claudication pts
•More effective than Pentoxyphylline
•PK: metabolized by CYP3A4/CYP2C19
•ADRs: headache, palpitation, dizziness, nausea, vomiting,
weakness, ↑ventricular ectopic
•Use: Intermittent claudication in patient with no rest pain or
heart failure
•Dose: 100 mg BD 30 min before/2 hr after food

42. References
• Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee
Brothers Medical.
• https://www.mayoclinic.org/diseases-conditions/angina/symptoms-causes/syc-
20369373
• https://www.verywellhealth.com/calcium-channel-blockers-for-treating-angina-
1745910
• https://emedicine.medscape.com/article/761556-overview
• https://www.hopkinsmedicine.org/health/conditions-and-diseases/peripheral-
vascular-disease

44. Thanks