1) Angina pectoris is characterized by chest pain due to myocardial ischemia. There are three main types: typical (classical), variant, and unstable angina. 2) Typical angina is induced by exercise and associated with atherosclerosis. Variant angina occurs at rest and is caused by coronary vasospasm. Unstable angina involves coronary spasm and atherosclerosis with longer, worsening chest pain. 3) Treatment involves decreasing oxygen demand and increasing supply. Nitrates, calcium channel blockers, and beta blockers are commonly used either alone or in combination to relieve angina by reducing preload, afterload, heart rate, and contractility.

1. Definition of terms
Angina Pectoris – is the principal symptoms of patient
with ischemic heart disease.
Manifested by sudden, severe, pressing substernal
pain that often radiates to the left shoulder and along
the flexor surface of the left arm.
Usually precipitated by exercise, excitement or a
heavy meal.

2. Types of Angina
Typical Angina ( Classical Angina )
 pain is commonly induced by exercise, excitement or a heavy
meal
 secondary to advanced atherosclerosis of the coronary vessels
 associated with ST-segment depression on ECG
Variant Angina ( Prinzmetal Angina)
 pain is induced while at rest
 associated with ST-segment elevation on ECG
 secondary to vasospasm of the coronary vessels
Unstable angina
 may involve coronary spasm and may also have the component of
atherosclerosis
 the duration of manifestation is longer than the first two and has
the manifestation of Myocardial infarction

3. * Myocardial ischemia which produces angina
results from imbalances in myocardial oxygen
supply & demand relationship such as decreased
oxygen supply and/or increased oxygen demand.
Etiology
1. Decrease oxygen supply
2. Increase demand for oxygen

4. Determinant of Myocardial Oxygen Supply
1. Coronary blood flow
Determined by: perfusion pressure
duration of diastole
coronary bed resistance
2.Arterio-venous oxygen difference

5. Determinant of Myocardial Oxygen demand
Major Determinants
1. Wall stress
intraventricular pressure
ventricular volume
wall thickness
2. Heart rate
3. Contractility

6. Determinants of Vascular Tone
Relaxation of vascular smooth muscle by:
1. Increase cGMP
2. Decrease intracellular calcium
3. Increase cAMP
4. Stabilizing or preventing depolarization of the
vascular smooth muscle cell membrane

7. Treatment Plan:
A. decrease the risk factor like
atherosclerosis, hypertension,
smoking
B. increase oxygen supply
C. decrease oxygen demand

8. ANTIANGINAL DRUGS
I. AGENTS WHICH ↓ O2 DEMAND & ↑ O2 SUPPLY
A. NITRATES
B. CALCIUM CHANNEL BLOCKERS
II. AGENTS WHICH ↓ O2 DEMAND
C. BETA BLOCKERS

9. Treatment
Drugs Classification
Three classes of drugs, used either
alone or in combination, are
effective in treating patients with
angina.
These agents lower the oxygen
demand of the heart by affecting
blood pressure, venous return, heart
rate, and contractility.

10. Classification of Antianginal Agents
1. Nitrates:
a) Short acting (10 minutes): Glyceryl trinitrate (GTN and
Nitroglycerine) - EMERGENCY
b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide
mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate
2. Calcium Channel Blockers:
a) Phenyl alkylamine: Verapamil
b) Benzothiazepin: Diltiazem
c) Dihydropyridines: Nifedipine, Felodipine, Amlodipine,
Nitrendipine and Nimodipine
3. Beta—adrenergic Blockers: Propranolol, Metoprolol, Atenolol
and others
4. Potassium Channel openers: Nicorandil
5. Others: Dipyridamole, Trimetazidine, Ranolazine and
oxyphedrine

11. Nitrates
 All Nitrates share same action – only difference is on
Pharmacokinetic properties (duration of action)
 Hepatic first-pass metabolism is high and oral bioavailability is
low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN)
 Sublingual or transdermal administration of these agents
avoids the first-pass effect
 Isosorbide mononitrate is not subject to first-pass metabolism
and is 100% available after oral administration
 Hepatic blood flow and disease can affect the pharmacokinetics
of GTN and ISDN

12. Organic Nitrates - MOA
 All of these agents are enzymatically converted to free radical nitric oxide
(NO) in the target tissues
 NO is a very short-lived endogenous mediator of smooth muscle
contraction and neurotransmission
 Veins and larger arteries appear to have greater enzymatic capacity than
resistance vessels, resulting in greater effects in these vessels – arterioles,
veins, aorta and coronary arteries
 NO activates a cytosolic form of guanylate cyclase in smooth muscle
 Activated guanylate cyclase catalyzes the formation of cGMP which
activates cGMP-dependent protein kinase
 Activation of this kinase results in phosphorylation of several proteins
that reduce intracellular calcium and hyperpolarize the plasma
membrane causing relaxation

13. Mechanism of Action of Nitrovasodilators
Nitric Oxide
activates
converts
Guanylate Cyclase*
GTP
cGMP
activates
cGMP-dependent protein kinase
Activation of PKG results in phosphorylation
of several proteins that reduce intracellular calcium
causing smooth muscle relaxation
Nitrates become denitrated by glutathione S-transferase
to release

16. Actions of Nitrates - GTN
1. Preload reduction:
 Dilatation of veins more than arteries – peripheral pooling of Blood –
decrease venous return
 Will lead to reduction in preload – decrease in fibre length
 Less wall tension to develop for ejection (Laplace`s law) – less oxygen
consumption and reduction in ventricular wall pressure
2. Afterload reduction:
 Some amount of arteriolar dilatation – Decrease in peripheral
Resistance (afterload reduction) – reduction in Cardiac work (also fall
in BP)
 Standing posture – pooling of Blood in legs – reflex tachycardia
(prevented by lying down and foot end raising)
 However in large doses opposite happens – marked fall in BP – reflex
tachycardia – increased cardiac work – precipitation of angina

17. Actions of Nitrates - contd.
3. Increased Myocardial Perfusion:
 Dilatation of bigger conducting coronary arteries all over the
heart + dilatation of autoregulatory ischemic vessels due to
ischaemia + normal tone of non-ischaemic zone vessels –
Redistribution of blood in Myocardium to ischemic zone
 However total blood flow in coronary vessels is almost
unchanged with Nitrates
4. Mechanism of angina relief:
 Variant angina – coronary vasodilatation
 Classical angina – reduction in Cardiac load
 Increased exercise tolerance
5. Other actions: Cutaneous vasodilatation (flushing occurs),
meningeal vessels dilatation (headache) and decreased renal
blood flow

18. ROUTES OF ADMINISTRATION
1. Sublingual route – rational and effective for the
treatment of acute attacks of angina pectoris. Half-life
depend only on the rate at which they are delivered to
the liver.
2. Oral route – to provide convenient and prolonged
prophylaxis against attacks of angina
3. Intravenous Route – useful in the treatment of
coronary vasospasm and acute ischemic syndrome.
4. Topical route – used to provide gradual absorption
of the drug for prolonged prophylactic purpose.

19. Drug Usual single dose Route of
administration
Duration of action
Short acting
Nitroglycerin
0.15-1.2 mg sublingual 10 - 30 min
Isosorbide dinitrate 2.5-5 mg sublingual 10 – 60 min
Amyl nitrite 0.18 – 3 ml inhalation 3 – 5 min
Long acting
Nitroglycerin sustained
action
6.5 – 13 mg q 6-8 hrs oral 6 – 8 hrs
Nitroglycerin 2%
ointment
1 – 1.5 inches q hr topical 3 – 6 hrs
Niroglycerin slow
released
1 –2 mg per 4 hrs Buccal mucosa 3 – 6 hrs
Nitroglycerin slow
released
10 – 25 mg /24hrs (one
patch/day}
transdermal 8 –10 hrs
Isosorbide dinitrate 2.5 – 10 mg per 2 hrs sublingual 1.5 – 2 hrs
Isosorbide dinitrate 10 –60 mg per 4-6 hrs oral 4 – 6 hrs
Isosorbide dinitrate
chewable
5 – 10 mg per 2-4 hrs oral 2 – 3 hrs
Isosorbide mononitrate 20 mg per 12 hrs oral 6 –10 hrs

20. Adverse Effects
1. Throbbing headache
2. Flushing of the face
3. Dizziness – especially at the beginning of treatment
4. Postural Hypotension – due to pooling of blood in the
dependent portion of the body
Contraindication
1. Renal ischemia
2. Acute myocardial infarction
3. Patients receiving other antihypertensive agent

21. B-Blockers
Hemodynamics Effects
1. Decrease heart rate
2. Reduced blood pressure and cardiac
contractility without appreciable decrease in
cardiac output

22. B-Blockers
Decrease heart rate & Contractility
Increase duration of diastole
Decrease workload
Increase coronary blood flow
Decrease O2 consumption
Increase oxygen supply

23. Beta-blockers – contd.
 Benefits:
 Decreased frequency and severity of attacks
 Increased exercise tolerance (classical angina) – cardioselectives
are preferred
 Routinely used in UA and with MI
 ADRs and CI:
 May exacerbate heart failure
 Contraindicated in patients with asthma
 Should be used with caution in patients with diabetes since
hypoglycemia-induced tachycardia can be blunted or blocked
 May depress contractility and heart rate and produce AV block in
patients receiving non-dihydropyridine calcium channel blockers
(i.e. verapamil and diltiazem)

24. Calcium Channels
1. Voltage Sensitive Channels (-40mV)
2. Receptor operated Channel (Adr and
other agonists)
3. Leak channel (Ca++ATPase)
o Voltage sensitive Calcium
channels are heterogenous
(membrane spanning
funnel shaped):
o L-Type (Long lasting
current) – SAN, AVN,
Conductivity, Cardiac
and smooth muscle
o T-Type (Transient
Current) – Thalumus,
SAN
o N-Type (Neuronal) –
CNS, sypmathetic and
myenteric plexuses

25. Calcium Channel Blockers
 Five major classes of Ca+2 channel blockers are known
with diverse chemical structures:
1) Benzothiazepines: Diltiazem
2) Dihydropyridines: Nicardipine, nifedipine,
nimodipine, amlodipine, and many others
 There are also dihydropyridine Ca+2-channel
activators (Bay K 8644, S 202 791)
3) Phenylalkylamines: Verapamil
4) Diarylaminopropylamine ethers: Bepridil
5) Benzimidazole-substituted tetralines: Mibefradil

26. Ca Channel Blockers
Coronary artery dilatation
Decrease coronary bed resistance
(Relieved coronary vasospasm)
Increase coronary blood flow
Increase oxygen supply
Reduction on peripheral
resistance
(Secondary to dilatation of aorta)
Decrease blood pressure
Decrease after load
Decrease workload
Decrease oxygen consumption

27. Effects on Vascular Smooth Muscle
 Ca+2 channel blockers inhibit mainly L-type
 Little or no effect on receptor-operated channels or on release of
Ca+2 from SR.
 “Vascular selectivity” is seen with the Ca+2 channel blockers
 Decreased intracellular Ca+2 in arterial smooth muscle results
in relaxation (vasodilatation) -> decreased cardiac afterload
(aortic pressure)
 Little or no effect of Ca++-channel blockers on venous beds ->
no effect on cardiac preload (ventricular filling pressure)
 Specific dihydropyridines may exhibit greater potencies in
some vascular beds (e.g.- nimodipine more selective for
cerebral blood vessels, nicardipine for coronary vessels)
 Little or no effect on nonvascular smooth muscle

28. CCBs – Therapeutic Uses
1. Angina Pectoris:
 Reduce frequency and severity of Classical and Variant angina
 Classical angina
 reduction in cardiac work by reducing afterload
 Increased exercise tolerance
 Coronary flow increase – less significant (fixed arterial block)
 But: short acting DHPs cause Myocardial Ischaemia – WHY? - due to
decreased coronary blood flow secondary to fall in mean BP, reflex
tachycardia and coronary steal
 Verapamil/Diltiazem are better (reduce O2 consumption by direct effect)
 MI - Verapamil/Diltiazem as alternative to β-blockers
 Variant angina: Benefited by reducing the arterial spasm
2. Hypertension
3. Cardiac arrhythmia
4. Hypertrophic Cardiomyopathy: verapamil

29. Unwanted effect
 Nausea and vomiting
 Dizziness
 Flushing of the face
 Tachycardia – due to hypotension
Contraindications
 Cardiogenic shock
 Recent myocardial infarction
 Heart failure
 Atrio-ventricular block

30. Combination Therapy
1. Nitrates and B-blockers
* The additive efficacy is primarily a result of one drug blocking the adverse
effect of the other agent on net myocardial oxygen consumption
* B-blockers – blocks the reflex tachycardia associated with nitrates
* Nitrates – attenuate the increase in the left ventricular end diastolic volume
associated with B-lockers by increasing venous capacitance
2. Ca channel blockers and B-blockers
* useful in the treatment of exertional angina that is not controlled adequately
with nitrates and B-blockers
* B-blockers – attenuate reflex tachycardia produce by nifedipine
* These two drugs produce decrease blood pressure
3. Ca channel blockers and Nitrates
* Useful in severe vasospastic or exertional angina (particularly in patient with
exertional angina with congestive heart failure and sick sinus syndrome)
* Nitrates reduce preload and after load
* Ca channels reduces the after load
* Net effect is on reduction of oxygen demand

31. 4. Triple drugs – Nitrate + Ca channel blockers + B-blockers
*Useful in patients with exertional angina not controlled by the
administration of two types of anti-anginal agent
* Nifidipine – decrease after load
Nitrates – decrease preload
B-blockers – decrease heart rate & myocardial contractility

32. Type of
Angina
Other Names Description Drug Therapy
STABLE Classic
Exertional
Fixed
Atherosclerotic
Obstruction
coronary artery
Nitrates
CCB
B-blockers
VARIANT Prinzmetal’s
Vasospasmic
Vasospasm at
any time
Nitrates
CCB
UNSTABLE Crescendo Combined effect
Pre= MI
Nitrates
CCB