A power point presentation on “Antianginal drugs and drugs used in ischaemia” suitable for undergraduate level MBBS students

1. Antianginal Drugs
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. What is angina?
• Angina pectoris is a syndrome characterized by
sudden severe pressing substernal chest pain or
heaviness radiating to the neck, jaw, back and
arms. It is often associated with diaphoresis,
tachypnoea and nausea
• Primary cause: imbalance between myocardial
oxygen demand and oxygen supplied by coronary
vessels
– This imbalance may be due to:
1. a decrease in myocardial oxygen delivery
2. an increase in myocardial oxygen demand, or both
• The discomfort abates when supply becomes
adequate for demand. Typically angina lasts for
seconds to minutes, up to 15 minutes

3. Factors affecting Myocardial
Oxygen Delivery
• Coronary artery blood flow is the primary determinant of
oxygen delivery to the myocardium
– Myocardial oxygen extraction from the blood is nearly
complete, even at rest
• Coronary blood flow is essentially negligible during systole
and is therefore determined by:
– Perfusion pressure during diastole
– Duration of diastole
– Coronary vascular resistance: determined by numerous factors:
• Atherscelorosis
• Intracoronary thrombi
• Metabolic products that vasodilate coronary arterioles
• Autonomic activity
• Extravascular compression

4. Factors Affecting
Myocardial Oxygen Demand
• The major determinants of myocardial oxygen
consumption include:
1. Ventricular wall stress
• Both preload (end-diastolic pressure) and afterload (end-
systolic pressure) affect ventricular wall stress
2. Heart rate
3. Myocardial metabolism (glucose vs fatty acids)
• A commonly used non-invasive index of
myocardial oxygen demand is the “double
product”:
– [Heart rate] X [Systolic blood pressure]
– Also known as the “rate pressure product”

5. Types of Angina
1. Classical angina:
 Stable
2. Variant or Prinzmetal`s angina
 Unstable
Myocardial infarction – what is it ?
• Ischaemic necrosis of a portion of myocardium due to
acute and complete occlusion of a coronary artery -
due to coronary thrombosis

6. Stable Angina
• Common form and is also known as - exertional angina/typical or classic
angina/angina of effort/atherosclerotic angina
– The underlying pathology is usually atherosclerosis (reduced oxygen delivery)
giving rise to ischemia under conditions where the work load on the heart
increases (increased oxygen demand)
– Anginal episodes can be precipitated by exercise, cold, stress, emotion, or
eating
– Subendocardial crunch developes
• Therapeutic goals:
– Increasing myocardial blood flow by dilating coronary arteries and arterioles
(increase oxygen delivery)
– Decreasing cardiac load (preload and afterload: decrease oxygen demand)
– Decreasing heart rate (decrease oxygen demand)

7. Unstable Angina
• Unstable angina is also known as:
– Preinfarction angina/Crescendo angina/angina at rest
• Associated with a change in the character, frequency, and
duration of angina in patients with stable angina, and
episodes of angina at rest
• Caused by recurrent episodes of small platelet clots at the
site of a ruptured atherosclerotic plaque which can also
precipitate local vasospasm
• May be associated with myocardial infarction
• Therapeutic Goal: Inhibiting platelet aggregation and
thrombus formation (increase oxygen delivery), decreasing
cardiac load (decrease oxygen demand), and vasodilate
coronary arteries (increase oxygen delivery)

8. Vasospastic
Angina
• Vasospastic angina (uncommon form) is also known as:
– Variant angina/Prinzmetal's angina
• Caused by transient vasospasm of the coronary vessels
• Attack occurs even at rest or during sleep
• Usually associated with underlying atheromas, abnormally
reactive or hypertrophied segments in coronary artery
• Chest pain may develop at rest
• Therapeutic rationale: Decrease vasospasm of coronary
vessels (calcium channel blockers are efficacious in >70% of
patients; increase oxygen delivery)

9. Coronary
artery image
• Coronary calibre
changes in Classical
and variant angina
1. Normal
2. Classical angina
3. Variant angina
1.
2.
3.

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. Actions of Nitrates - GTN
1. Preload reduction:
 Dilatation of veins more than arteries – peripheral pooling of Blood –
decrease venous return
 Reduction in preload – decreased end diastolic size – decrease in
fibre length
 Less wall tension to develop for ejection (Laplace`s law) – less oxygen
consumption and reduction in ventricular wall pressure (crunch
abolished)
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

12. Actions of Nitrates - contd.
3. Increased Myocardial Perfusion:
 Redistribution of coronary blood flow – facilitates entry of
blood to Ischaemic area
 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),
meningeal vessels dilatation (headache) and decreased
splanchnic and Renal blood flow (compensatory)

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

14. Pharmacokinetics - Nitrates
• All Nitrates share same action – only Pharmacokinetic differences
• All are highly lipid soluble and absorbed well from bccal mucosa, orally
and skin
• Rapidly denitrated by glutathione reductase and mitochondrial aldehyde
dehydrogenase
• Hepatic first-pass metabolism is high and oral bioavailability is low for
nitroglycerin (GTN) and isosorbide dinitrate (ISDN)
– Sublingual or transdermal administration - 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

15. GTN ISDN 5-ISMN
Half-life (min) 3 10 280
Plasma clearance (L/min) 50 4 0.1
Apparent volume of distribution (L/kg) 3 4 0.6
Oral bioavailability (%) < 1 20 100
Property
Comparison of
Pharmacokinetic
Properties of Nitrates

16. Nitrates - ADRs
• Due to excessive vasodilatation - Orthostatic
hypotension, Tachycardia, Severe throbbing
headache, Dizziness, Flushing and Syncope
• Methaemoglobinemia
• Rashes - rare
• Contraindicated in patients with elevated
intracranial pressure
• Drug Interaction: Sildenafil (Viagra) and other PDE-5
inhibitors used for erectile dysfunction can
potentiate the actions of nitrates because they
inhibit the breakdown of cGMP (they should not be
taken within 6 hours of taking a nitrovasodilator)

17. Nitrate Tolerance
• Continuous or frequent exposure to nitrates can
lead to the development of complete tolerance
• The mechanism of tolerance is not completely
understood:
– May be related to the enzymes involved in converting
the nitrates to NO
– or to the enzyme that produces cGMP
• Industrial (occupational) exposure to organic
nitrates has been associated with “Monday
disease” and physical dependence manifest by
variant angina occurring 1-2 days after
withdrawal

18. Nitrates – Individual agents
• Glyceryl trinitrate (GTN, Nitroglycerine):
– Rendered nonexplosive by adsorbing in inert matrix of a
tablet
– Stored in a tightly closed Glass container
• Formulations: Oral, SL, IV and ointment
1) SL (0.5 mg) – to terminate an Ongoing attack
• Crushed under the tongue and spread over the buccal mucosa
• Action starts within 1-2 minutes
• Effects disappear within minutes but its metabolite – dinitrate
stays (1 hr)
2) IV transfusion: in acute AMI
3) Patches: Ointment and patches – at night application

19. Nitrates – Therapeutic Uses
1. Angina pectoris: Classical and variant Types
2. Acute Coronary syndromes: Unstable angina and associated with
MI (Combination Drugs)
3. Myocardial Infarction: In evolving MI : IV administration is useful
in relieving – 3 things: chest pain, congestions of chest and
reducing the infarct size favouring blood supply to ischemic zone
4. CHF and LVF: Pooling of blood
5. Biliary colic: Sl administration
6. Oesophageal spasm: Reduction in oesophageal tone (achalasia)
7. Cyanide Poisoning: Nitrates counter cyanide by producing
Methaemoglobin – then Cyanomethaemoglobin (Sod. Thiosulfate
is given to form Sod. Thiocyanate)

20. Role of Beta-blockers
• No coronary vasodilatation like the
nitrovasodilators or calcium channel blockers -
beta-blockers are important in the treatment of
angina
• Instead coronary flow reduced – beta2 effect
• But, Coronary flow to ischaemic area not
reduced:
– Redistribution and decrease in ventricular wall
tension
• Improve myocardial perfusion by slowing heart rate (more
time spent in diastole)
• less O2 consumption (decreased HR, Inotropy and mean BP)

21. Role of Beta-blockers – contd.
• Benefits:
– Decreased frequency and severity of attacks
– Increased exercise tolerance (classical angina) – cardioselectives are
preferred (coronary spasm due to alpha-blockade)
– Lowers sudden cardiac death
– Routinely used in UA and with MI – pretreatment with Nitrates or CCB
– Avoid abrupt withdrawal
• ADRs and CI:
– May exacerbate heart failure
– Contraindicated in patients with asthma
– Precaution in 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)

22. 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

23. Calcium Channel Blockers
1) Phenylalkylamines:
Verapamil
2) Dihydropyridines:
• 1st generation: Nifedepine
• 2nd generation: Nicardipine,
nimodipine, Felodipine,
Isradipine
• 3rd generation: Amlodipine
3) Benzothiazepines: Diltiazem
4) Diarylaminopropylamine
ethers: Bepridil
5) Benzimidazole-substituted
tetralines: Mibefradil

24. Effects on Vascular Smooth Muscle
• Ca++ channel blockers inhibit mainly L-type
• Little or no effect on receptor-operated channels or on
release of Ca++ from SR
1. Decreased intracellular Ca++ in arterial smooth muscle results
in relaxation (vasodilatation) -> decreased cardiac afterload
(aortic pressure)
2. Little or no effect on venous beds -> no effect on cardiac
preload (ventricular filling pressure)
DHPs have the highest vascular SM relaxant action
3. Additional Mechanism: Release of NO – inhibit cAMP PDE –
increased SM cAMP
• 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 except
bronchial, uterine, biliary, vesical and intestinal

25. Effects on
Cardiac Cells
• Negative Inotropic, Chronotropic and Dromotropic
• Negative inotropic effect (myocardial L-type channels) –
WMC and ventricular fibres
• Negative chronotropic /dromotropic effects (L- and T-type
channels)
• Verapamil and diltiazem shows such effects but not DHPs
• Verapamil, diltiazem, and mibefradil depress SA node and AV
conduction – depression of pacemaker and conduction
• Dihydropyridines have minimal direct effects on SA node
and AV conduction – more selective for vascular smooth
muscles
• Magnitude and pattern of cardiac effects depends on
the class of Ca++channel blocker
Recovery
Resting Activated Inactivated
Nonconducting of C++ conducting Ca++ NC Ca++

26. Relative Cardiovascular Effects of Calcium
Channel Blockers - (Goodman & Gilman)
Verapamil ++++ ++++ +++++ +++++
Diltiazem +++ ++ +++++ ++++
Nifedipine +++++ + + 0
Nicardipine +++++ 0 + 0
Compound Coronary
vasodilatation
Suppression
of cardiac
contractility
Suppression
of
SA node
Suppression
of
AV node

27. Adverse effects
• Verapamil:
– Nausea, constipation and bradycardia
– Headache, flushing and oedema – less common
– Hypotension and tachycardia - less common
– Precipitation of CHF in pre-existing patients
– Increase in plasma digoxin level
– Contraindicated in 2nd and 3rd degree heart block
• Diltiazem: Same as Verapamil

28. Adverse effects – contd.
• DHP – immediate release forms e.g. Nifedepine:
– Palpitation, flushing ankle oedema, hypotension, headache
and drowsiness
– Diuresis
– Higher incidence of frequency of angina
– Higer incidence of mortality
– Voiding difficulty (relaxed bladder Vs increased urine)
• Nifedipine may increase mortality in patients with
myocardial ischemia
– Cause increase in angina frequency (myocardial
Ischaemia)
– Cerebral Ischaemia – rapid bringing down of BP
– Bladder relaxation – voiding difficulty
– Decrease in Insulin release

29. CCBs - Pharmacokinetics
• High oral absorption, but high first pass metabolism (except amlodipine) –
inter and intra individual variation and highly plasma protein bound
• Extensively distributed in tissues and highly metabolized in liver and
excreted in urine, eliminated in 2 - 6 Hrs (except amlodipine)
Drug Bioavailability
%
Vd (L/kg) Active
metabolite
Elim half life(hr)
Verapamil 15-30 5.0 Y 4-6
Diltiazem 40-60 3.0 Y 5-6
Nifedepine 30-60 0.8 M 2-5
Felodipine 15-25 10.0 None 12-18
Amlodipine 60-65 21.0 None 35-45

30. Desired Therapeutic Effects of Calcium
Channel Blockers for Angina
• Improve oxygen delivery to ischemic
myocardium
– Vasodilate coronary arteries
– Particularly useful in treating vasospastic angina
• Reduce myocardial oxygen consumption
– Decrease afterload (no effect on preload)
– Non-dihydropyridines also lower heart rate and
decrease contractility
– (* Dihydropyridines may aggravate angina in some
patients due to reflex increases in heart rate and
contractility)

31. 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 a reduce O2 consumption by direct effect –
do not aggravate angina
 MI - Verapamil/Diltiazem as alternative to β-blockers
 Variant angina: Benefited by reducing the arterial spasm

32. CCBs – Therapeutic Uses – contd.
2. Hypertension
3. Cardiac arrhythmia
4. Hypertrophic Cardiomyopathy: verapamil
5. Nifedipine – Preterm labour (?) and
Raynaud`s disease; Verapamil - migraine and
nocturnal leg cramps

33. Pharmacotherapy of Angina Pectoris
• Aim: 1. Relief and prevention of Individual attack; 2. Chronic Prophylaxis; 3.
Measures to prevent Progression
1. Prevention of Individual attack:
• Short acting Nitrate as and when required basis
• GTN is the drug of Choice in all kinds of angina
• Dose: 0.3 – 0.6 mg SL
• If symptoms not relieved quickly – additional tabs at 5 min. interval (not more than 3 tabs at 5
minutes interval)
• Discard the remnant tab soon relieved – hypotension
2. Acute Prophylaxis: GTN 15 minutes before a period of increased activity –
exercise, sexual activity etc. – lasts for upto 2 Hrs
3. Chronic Prophylaxis:
• Monotherapy with either of the 3 groups of Drugs – depends on stage and associated
cardiac disease
• May be Nitrates/Ca++ blockers /beta-blockers – beta blockers are preferred
• When Monotherapy fails: Go for combination of those Drugs (two drugs)
• Beta blocker + nitrates or slow acting DHP + beta blocker (no diltiazem or verapamil)
• CCB + Nitrates
• In severe cases - nitrates+ CCBs + beta blockers

34. Combination Therapy of Angina
• Use of more than one class of antianginal agent can reduce specific
undesirable effects of single agent therapy
Nitrates Alone
Reflex Increase
Decrease
Decrease
Reflex increase
Decrease
Beta-Blockers or
Channel Blockers
Alone
Decrease*
Decrease
Increase
Decrease*
Increase
Nitrates Plus
Beta-Blockers or
Channel Blockers
Decrease
Decrease
None or decrease
None
None
Undesireable effects are shown in italics
* Dihydropyridines may cause the opposite effect due to a reflex increase
in sympathetic tone
Heart Rate
Afterload
Preload
Contractility
Ejection time
Effect

35. Potassium Channel Openers –
Nicorandil
• Minoxidil and diazoxide
• MOA:
– Activation of ATP sensitive K+ channel – hyperpolarization of vascular
smooth muscle – relaxation of Smooth muscle
– Also acts as NO donor and increases cGMP – Arterio-venous relaxation
– Dilatation of all types of coronary vessels – epicardial and deep
• Benefits in angina (equipotent to nitrates, beta blockers and Ca++
channel blockers)
– Reduced angina frequency
– Increased exercise tolerance
– Ischaemic preconditioning for Myocardial stunning , arrhythmia and
infarct size (Mitochondrial K+ATP channel opening)
• ADRs: Flushing, palpitation, nausea, vomiting, aphthous ulcer
• Dose: available as 5, 10 mg tabs and also injection

36. Pharmacotherapy
of MI
1. Aim:
 Emergency life saving management of the patient (ICU)
 Subsequent Treatments
2. Pain, anxiety and apprehension: Morphine, Pethidine parenteral
3. Oxygenation: assisted respiration
4. Maintenance of Blood Volume, tissue perfusion and microcirculation: slow IV
fluid with saline
5. Correction of acidosis: Sodibicarb IV
6. Prevention of Arrhythmia: Beta blockers early (arrhythmia and infarct size)
7. Pump Failure: Furosemide, GTN IV/Nitroprusside and Dobutamine
8. Prevention of Thrombus extension and thrombo-embolism: Aspirin and oral
anticoagulants
9. Thrombolysis and reperfusion: Streptokinase, urokinase etc.
10. Prevention of Remodelling
11. Prevention of future attacks: beta-blockers, aspirin, anti-hyperlipidemia

37. Peripheral Vascular Disease –
Pentoxiphylline (Trental) -
• Analogue of Theophylline – PDE inhibitor
• Action:
– Reduction of whole blood viscosity by improving the flexibility of RBCs
– Improvement of passage of blood through microcirculation
– No vasodilatation but improved circulation
– Less chance of steal phenomenon
• Kinetics: Well absorbed in the GI tract, Metabolized in liver and via erythrocytes -
some metabolites are active. Undergoes extensive 1st pass metabolism, excreted
in urine
• Available in tabs – 400 mg form and also injection
• Uses: 1) Non-haemorrhagic stroke 2) Intermittent claudication 3) Trophic leg
ulcers 4) TIA 5) To improve memory, vertigo and tinnitus etc. after CVA

38. What is Important?
• Mechanism of action, therapeutic uses and
ADRs of Nitrates
• Role of Nitrates in Angina Pectoris
• Role of Beta-blockers and Ca++ channel
blockers in Angina Pectoris
• Pharmacotherapy of Angina Pectoris
• Pharmacotherapy of Myocardial Infarction
• Potassium Channel Openers – short question