1. Antianginal (Anti-ischaemic) Drugs

2. Angina pectoris
Angina pectoris is a clinical syndrome characterized by episodes of chest pain.
It occurs when there is a deficit in myocardial oxygen supply (myocardial ischemia) in relation to myocardial oxygen demand.
It is most often caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm.

3. Coronary artery disease (CAD)
The development and progression of atherosclerotic plaque is called coronary artery disease (CAD).
Atherosclerotic plaque narrows the lumen, decreases elasticity, and impairs dilation of coronary arteries.
The continuum of CAD progresses from angina to myocardial infarction.

5. Ischemic heart disease
Coronary artery disease (CAD), also known as ischemic heart disease (IHD), is a group of diseases that includes:
angina,
myocardial infarction,
sudden coronary death.
A common symptom is chest pain or discomfort which may travel into the shoulder, arm, back, neck, or jaw.

6. Types of angina There are three main types of angina:
classic angina (stable, exertional)
variant angina (Prinzmetal/Vasospastic)
unstable angina 

7. Stable (exertional) angina
Attacks are predictably provoked by exercise, emotion, eating or coitus.
is relieved by taking rest and reducing the myocardial workload.
The underlying pathology is—severe arteriosclerotic affliction of larger coronary arteries (conducting vessels)
Drugs that are useful, primarily reduce cardiac work (directly by acting on heart or indirectly by reducing preload and afterload).

8. Stable angina
Classic anginal pain is usually described as substernal chest pain of a constricting, squeezing, or suffocating nature.
It may radiate to the jaw, neck, or shoulder, down the left or both arms, or to the back.
The discomfort is usually brief, typically lasting 5 minutes or less until the balance of oxygen supply and demand is restored.

10. Variant/Prinzmetal/Vasospastic angina
Attacks occur at rest or during sleep and are unpredictable.
It often occurs at the same time each day.
They are due to recurrent localized coronary vasospasm.
Drugs are aimed at preventing and relieving the coronary vasospasm.

12. Unstable angina
Unstable angina (also "crescendo angina“) this is a form of acute coronary syndrome
is defined as angina pectoris that changes or worsens.
Severe attacks is mostly due to rupture of an atheromatous plaque attracting platelet deposition and progressive occlusion of the coronary artery  (incomplete coronary arterial occlusion).
 In contrast with stable angina, unstable angina has at least one of these three features:
it occurs suddenly at rest (or with minimal exertion)
it is severe and of new onset
it occurs with a “crescendo pattern” (i.e., distinctly more severe, prolonged, or frequent than before).

16. CLASSIFICATION 1. Nitrates
(a) Short acting: Glyceryl trinitrate (Nitroglycerine)
(b) Long acting: Isosorbide dinitrate (short acting by sublingual route), Isosorbide mononitrate
2. β Blockers
Propranolol, Metoprolol, Atenolol
3. Calcium channel blockers
(a) Phenylalkylamine: Verapamil
(b) Benzothiazepine: Diltiazem
(c) Dihydropyridines: Nifedipine, Felodipine,Amlodipine
4. Potassium channel opener
Nicorandil
5. Others
Dipyridamole, Trimetazidine, Ranolazine, Ivabradine, Oxyphedrine

17. Antianginals These drugs relieve anginal pain by:
reducing myocardial oxygen demand
increasing blood supply to the myocardium.

19. NITRATES Short acting: Glyceryl trinitrate (Nitroglycerine)
Long acting: Isosorbide dinitrate,
Isosorbide mononitrate
The only major action is direct smooth muscle relaxation (vascular smooth muscle).
Nitrates dilate veins more than arteries → preload on heart is reduced → decreased cardiac work
Nitrates also produce some arteriolar dilatation → slightly decrease afterload on heart

20. Mechanisms of action
Nitrates cause venous vasodilation by their conversion to nitric oxide (NO) which are endothelium relaxing factor (ERF).
At therapeutic doses, nitrates have two major effects:
1)they cause dilation of the large veins → this diminishes preload (venous return to the heart) → reduces the work of the heart → a decrease in myocardial oxygen demand
2) Nitrates dilate the coronary vasculature → increasing in blood supply to the heart muscle.

21. Pharmacokinetics
The time to onset of action varies from one minute for nitroglycerin to more than one hour for isosorbide mononitrate.
Significant first-pass metabolism of nitroglycerin occurs in the liver.
Therefore, it is  common to give the drug either sublingually or via a transdermal patch.

22. NITRATES
Short-acting nitrates are used to abort angina attacks that have occurred.
Longer-acting nitrates are used in the prophylactic management of the angina pectoris.
For prompt relief of an ongoing attack of angina precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin  is the drug of choice.
Used to relieve both exertional and vasospastic angina 

23. Indications 1. Angina pectoris
2. Acute coronary syndrome (include unstable angina and non-ST segment elevation myocardial infarction)
3. Myocardial infarction
4. CHF and acute LVF
5. Esophageal spasm
6. Cyanide poisoning

24. Adverse effects
These are mostly due to vasodilatation:
The most common adverse effect of all nitrates is throbbing headache(60 % of patients).
Postural hypotension
Facial flushing
Tachycardia
Tolerance develops rapidly on continued use.
The most practical way to prevent nitrate tolerance is to provide nitrate free intervals everyday. This interval is typically hours usually at night because there is decreased demand on the heart at that time.

25. Glyceryl trinitrate (Nitroglycerine)
The sublingual route – for prompt relief of an attack of angina (the drug of choice!!!!)
It acts within 1–2 min (peak blood level in 3–6 min)
t½ - 2 min
A sublingual spray formulation acts more
rapidly than sublingual tablet.
Intravenous infusion of GTN provides rapid, steady plasma concentration. It has been successfully used for:
unstable angina,
coronary vasospasm,
LVF accompanying MI,
hypertension.

26. Nitroglycerine
Nitroglycerin is indicated for the prophylaxis, treatment and management of patients with angina pectoris.
One tablet should be dissolved under the tongue at the first sign of an anginal attack.  
The dose may be repeated approximately  every five minutes until relief is obtained.
If the pain persists after a total  of 3-tablets in a 15-minute period,  it could be a symptom of the MI.

27. Long-acting nitrates Isosorbide dinitrate
is used to reduce the frequency and severity of acute anginal episodes.
Sublingually it acts in 2 minutes, and its effects last 2 to 3 hours.
Therapeutic effects last about 4 hours after oral administration.
Isosorbide mononitrate 
It is well absorbed after oral administration and almost 100% bioavailable.
t½ - 5 hours.
It is used only for prophylaxis of angina; it does not act rapidly enough to relieve acute attacks.

28. Choice of Drug
For relief of acute angina and prophylaxis before events that cause acute angina, nitroglycerin (sublingual tablets or translingual spray) is the primary drug of choice.
Sublingual tablets of isosorbide dinitrate also may be used.
For long-term prevention or management of recurrent angina, oral or topical nitrates, beta-adrenergic blocking agents, or calcium channel blocking agents are used.
Clients taking one or more long-acting antianginal drugs should carry a short-acting drug as well, to be used for acute attacks.

30. Beta blockers
Beta blockers are used in the long-term management of stable (exertional) angina by reducing the myocardial oxygen demand.
Not for acute treatment!
A slower heart rate improves coronary blood flow to the ischemic area. Beta blockers also reduce blood pressure, which in turn decreases myocardial workload and oxygen demand.
Long term β blocker therapy clearly lowers risk of sudden cardiac death among ischaemic heart disease patients.
They are contraindicated in:
variant angina (they produce vasospasm)
heart failure
severe asthmatics

31. Calcium channel blockers
As a result:
myocardial contractility is decreased, and the conduction system is depressed
coronary and peripheral arteries are dilated
Act on :
contractile and conductive tissues of the heart
vascular smooth muscle.

32. Calcium channel blockers
Are used in the treatment of :
chronic stable angina,
most effectively in the treatment of variant angina (directly preventing coronary artery vasospasm)
Hypertension
Cardiac arrhythmias
They are not used in the treatment of unstable angina .
They dilate the coronary and peripheral arteries → decreasing afterload → reducing heart rate
Dihydropyridines are vasodilators → more effective in angina

33. CALCIUM CHANNEL BLOCKERS
Nifedipine  –functions mainly as an arteriolar vasodilator. This drug has no effect on heart rate. The vasodilation effect of nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.
ADR: flushing, headeache, hypotension, and peripheral edema as side effects of its vasodilation activity. The drug may cause reflex tachycardia.
Verapamil slows cardiac conduction directly → decreases heart rate and oxygen demand. 
ADR: depressed cardiac function, CHF, AV block.
Diltiazem  effects are similar to those of verapamil and nifedipine

34. DRUG COMBINATIONS IN ANGINA
I. β blocker + long-acting nitrate combination is rational in classical angina because:
(a) Tachycardia due to nitrate is blocked by β blocker.
(b) The tendency of β blocker to cause ventricular dilatation is counteracted by nitrate.
(c) The tendency of β blocker to reduce total coronary flow is opposed by nitrate.
II.Slow acting DHP + β blocker
III. Nitrates (decrease preload)+ CCBs (effect on afterload) This combination may be especially valuable in severe vasospastic angina, and when β blockers are contraindicated.
IV. In the more severe and resistant cases of classical angina, combined use of all the three classes is indicated:
Nitrates (decrease preload) + DHP (reduce afterload) + β blockers (decrease cardiac work)

35. POTASSIUM CHANNEL OPENERS
Nicorandil
Arterial dilatation is coupled with venodilatation.
No cardiac effects.
Use:
in stable angina
in vasospastic angina
ADR;
flushing,
palpitation,
headache,
Dizziness
Large painful aphthous ulcers in the mouth

36. OTHER ANTIANGINAL DRUGS
Dipyridamole
It is a powerful coronary dilator
BUT !!!! It fails to relieve anginal symptoms
The pharmacological success but therapeutic failure of dipyridamole has been explained on the basis of ‘coronary steal’ phenomenon. By dilating resistance vessels in nonischaemic zone as well, it diverts the already reduced blood flow away from the ischaemic zone.

37. Trimetazidine The first cytoprotective anti-ischemic agent
Use just as an additional treatment of angina pectoris in patients not adequately controlled by first-line antianginal therapies (nitrate/β blocker/CCB)
Optimizing cellular energy processes → maintaining proper energy metabolism during ischaemia (preserving energy metabolism in cells exposed to hypoxia or ischaemia)
Anginal attacks frequency is reduced and exercise capacity is increased
For ischaemic heart disease, it is widely used in France, Spain, some other European countries and India, but not in the UK or USA.

38. Ivabradine
‘Pure’ heart rate lowering antianginal - an alternative to β blockers.
The only significant action is blockade of cardiac pacemaker (sino-atrial)
Heart rate reduction decreases cardiac O2 demand
To improve exercise tolerance in stable angina and reduce angina frequency.
ADR:
excess bradycardia,
important adverse effect is visual disturbance.
Ivabradine is indicated in chronic stable angina in patients with sinus rhythm who are intolerant to β blockers or when they are contraindicated.

39. DRUG THERAPY IN MYOCARDIAL INFARCTION
Myocardial infarction (MI) is ischaemic necrosis of a portion of the myocardium due to sudden occlusion of a branch of coronary artery.
An acute thrombus at the site of atherosclerotic obstruction is the usual cause.
About ¼ patients die before therapy can be instituted.
The remaining are best treated in specialized coronary care units with continuous monitoring of the haemodynamic parameters, biochemical markers and ECG to guide the selection of drugs and dosage.

41. 1. Pain
After pain is not relieved by 3 doses of GTN given 5 min apart, an opioid analgesic (morphine/pethidine) is administered parenterally.
2. Oxygenation
3. Prevention and treatment of arrhythmias -i.v. Lidocaine or amiodarone
4. Reduce the infarct size -β blockers
5. Bradycardia and heart block - atropine or electrical pacing
6. Pump failure
(a) Furosemide: indicated if pulmonary wedge pressure is > 20 mm Hg. It decreases cardiac preload.
(b) Vasodilators: venous or combined dilator like GTN (i.v.), or nitroprusside have been mainly used.
(c) Inotropic agents: dopamine or dobutamine i.v.
7. Prevention of thrombosis - Aspirin

42. Prevention of future attacks
Platelet inhibitors—aspirin or clopidogrel given on long-term basis are routinely prescribed
β blockers—reduce risk of reinfarction, CHF and mortality. All patients not having any contraindication are put on a β blocker for at least 2 years.
Control of hyperlipidaemia—dietary substitution with unsaturated fats, hypolipidemic drugs especially statins