Antianginal Drugs and Other Anti-ischaemic Drugs

Department of PharmacologyNEIGRIHMS, Shillong

Learning Objectives!

• Know the Basics of the Disease of Angina Pectoris• Know the major classes of drugs used to treat angina

and their clinically important mechanisms of action• Know the basic Pharmacology of each class of

antianginal drugs• Know the major contraindications, toxicities, and

drug interactions of each class of antianginal drugs• Know the drugs of choice for treating different forms

of angina• Know which antianginal drug combinations

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, tachypnea and nausea

• The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels– This imbalance may be due to:

• a decrease in myocardial oxygen delivery• 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– Classically angina is not associated with ischemic cell death

DISCOMFORTS?

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 (aortic diastolic pressure)– Duration of diastole– Coronary vascular resistance: Coronary vascular resistance

is determined by numerous factors including:• Atherscelorosis• Intracoronary thrombi• Metabolic products that vasodilate coronary arterioles• Autonomic activity• Extravascular compression

Factors Affecting Myocardial Oxygen Demand

• The major determinants of myocardial oxygen consumption include:– Ventricular wall stress

• Both preload (end-diastolic pressure) and afterload (end-systolic pressure) affect ventricular wall stress

– Heart rate– Inotropic state (contractility)– 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”

Types of Angina

1. Classical angina: Stable Unstable

2. Variant or Prinzmetal`s angina

Myocardial infarction – what is it ?• Acute and complete occlusion of a coronary artery• Due to coronary thrombosis

Stable Angina

• Stable angina (common form) 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: Increase myocardial blood flow by dilating

coronary arteries and arterioles (increase oxygen delivery), decrease cardiac load (preload and afterload; decrease oxygen demand), decrease heart rate (decrease oxygen demand), [alter myocardial metabolism?]

Subendocardial Crunch - Image

Unstable Angina• Unstable angina is also known as:

– Preinfarction angina– Crescendo angina– 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

• Associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of angina at rest

• May be associated with myocardial infarction• Therapeutic Goal: Inhibit platelet aggregation and thrombus formation

(increase oxygen delivery), decrease cardiac load (decrease oxygen demand), and vasodilate coronary arteries (increase oxygen delivery) and Statins

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)

Coronary artery imageCoronary calibre changes in Classical and variant angina –

1. Normal2. Classical angina3. Variant angina

1.

2.

3.

Antianginal AgentsThree major classes of agents are used

individually or in combination to treat angina:1. Organic nitrates:

• Vasodilate coronary arteries• Reduce preload and aferload

2. Calcium channel blockers:• Vasodilate coronary arteries• Reduce afterload• The non-dihydropyridines (verapamil and diltiazem) also

decrease heart rate and contractility3. Beta-adrenergic blockers:

• Decrease heart rate and contractility - decrease in cardiac work and O2 consumption

• Improve myocardial perfusion due to decrease in heart rate – decreased in ventricular wall tension

• Exercise tolerance

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: Verapamilb) Benzothiazepin: Diltiazemc) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine and

Nimodipine

3. Beta—adrenergic Blockers: Propranolol, Metoprolol, Atenolol and others

4. Potassium Channel openers: Nicorandil5. Others: Dipyridamole, Trimetazidine, Ranolazine and oxyphedrine

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

NitratesPharmacokinetic comparison:

• Bioavailability:NG: Below 1%IDN: 20%ISMN: 100%• Plasma clearance:NG: 50L/minIDN: 4L/minISMN: 0.6L/min

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

Mechanism of Action of Nitrovasodilators

Nitric Oxide

activates

converts

Guanylate Cyclase*

GTPcGMP

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

Actions of Nitrates - GTN1. Preload reduction:

Dilatation of veins more than arteries – peripheral pooling of Blood – decrease venous return

Will lead to 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

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

Nitrates - ADRs• The major acute adverse effects of nitrates are

due to excessive vasodilatation– Orthostatic hypotension– Tachycardia– Severe throbbing headache– Dizziness– Flushing– Syncope

• Organic nitrates are contraindicated in patients with elevated intracranial pressure

• 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)

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

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 ointment1) 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 AMI3) Patches: Ointment and patches – at night application

Nitrates – Therapeutic Uses

1. Angina pectoris: Classical and variant Types2. Acute Coronary syndromes: Unstable angina and associated with

MI (Combination Drugs)3. Myocardial Infarction: IV administration is useful in relieving

congestions of chest and favouring blood supply to ischemic zone

4. CHF and LVF: Pooloing of blood5. Biliary colic: Sl administration6. 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)

Beta-blockers

• Though most beta-blockers do not cause coronary vasodilatation like the nitrovasodilators or calcium channel blockers, beta-blockers are important in the treatment of angina because of their effects on the heart

• Desired effects of beta-blockers– Reduce myocardial oxygen consumption by reducing

contractility and heart rate• Reducing cardiac output also reduces afterload• Some b-blockers can cause vasodilatation directly or by acting as a-

blockers

– Improve myocardial perfusion by slowing heart rate (more time spent in diastole)

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

• 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)

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

Calcium Channel Blockers• Five major classes of Ca++

channel blockers are known with diverse chemical structures:

1) Benzothiazepines: Diltiazem2) Dihydropyridines: Nicardipine,

nifedipine, nimodipine, amlodipine, and many others• There are also dihydropyridine

Ca++-channel activators (Bay K 8644, S 202 791)

3) Phenylalkylamines: Verapamil4) Diarylaminopropylamine ethers:

Bepridil5) Benzimidazole-substituted

tetralines: Mibefradil

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• “Vascular selectivity” is seen with the Ca++ channel

blockers– Decreased intracellular Ca++ 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

Effects on Cardiac Cells

• Magnitude and pattern of cardiac effects depends on the class of Ca++channel blocker• Negative inotropic effect (myocardial L-type channels)

– Reduced inward movement of Ca++ during action potential plateau phase

– Dihydropyridines have very modest negative inotropic effect– Mibefradil (T-type) has no negative inotropic effect

• Negative chronotropic/dromotropic effects (L- and T-type channels)– Verapamil, diltiazem, and mibefradil depress SA node and AV

conduction– Dihydropyridines have minimal direct effects on SA node and AV

conduction (but they can cause reflex tachycardia)

Individual Drugs – Verapamil

• Arteriolar dilatation and alpha blocking action – decrease in t.p.r – but modest lowering of BP

• Direct Cardiac depressant action (countered by reflex effects of above)

• Overall, decrease in HR, slowed AV conduction and increased coronary flow

• Available as 40, 80, 120 etc. tabs and also injections• Drug Interactions:

– Verapamil and beta blockers – sinus depression and conduction defects (asystole)

– Gigoxin – digitalis toxicity (by decreasing excretion)– Quinidine – Cardiac depresion

Relative Cardiovascular Effects of Calcium Channel Blockers - (Goodman & Gilman)

Verapamil ++++ ++++ +++++ +++++Diltiazem +++ ++ +++++ ++++Nifedipine +++++ + + 0Nicardipine +++++ 0 + 0

Compound Coronary vasodilatation

Suppression of cardiac

contractility

Suppression of

SA node

Suppression of

AV node

Adverse effects• Adverse effects are typically direct extensions of their therapeutic

effects and are relatively rare– Minor adverse effects

• Nausea , constipation and bradycardia (Verapamil)• Hypotension, dizziness, edema, flushing (more with DHPs)

– Major adverse effects:• Depression of contractility and exacerbation of heart failure• AV block, bradycardia, and cardiac arrest – ppt of CCF

• Patients with ventricular dysfunction, SA node or AV conduction disturbances, WPW syndrome, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem

• Immediate-release forms of dihydropyridines (Nifedipine) may increase mortality in patients with myocardial ischemia – longer acting Nifedipine is used– Also cause increase in angina frequency– Cerebral Ischaemia – rapid bringing down of BP– Bladder relaxation – voiding difficulty– Decrease in Insulin release

CCBs - Pharmacokinetics• High oral absorption, but high first pass metabolism (except amlodipine) –

individual variation and highly plasma protein bound• Extensively distributed in tissues and metabolized in liver and excreted in

urine, eliminated in 22-6 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

Desired Therapeutic Effects of Calcium Channel Blockers for Angina

• Improve oxygen delivery to ischemic myocardium– Vasodilate coronary arteries– May inhibit platelet aggregation– 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)

CCBs – Therapeutic Uses1. 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. Hypertension3. Cardiac arrhythmia4. Hypertrophic Cardiomyopathy: verapamil5. Nifedipine – Preterm labour (?) and Raynaud`s disease; Verapamil - migraine

and nocturnal leg cramps

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 • Acute Prophylaxis: GTN 15 minutes before a period of increased activity – exercise, sexual

activity etc. – lasts for upto 2 Hrs

2. 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)• When Two Drugs fails – go for all above 3 drugs

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

Additional Measures

1. Hyperlipidemia, Diabetes and Hypertension - Statins

2. Dietary Restriction – saturated fats3. Smoking cessation4. Lifestyle change – obesity reduction5. Physical exercise6. Daily intake of Vit. C and Vit. E7. Antiplatelete Drugs – Aspirin etc.

Potassium Channel Openers – Nicorandil, Pinacidil• Minoxidil and Diazoxide – older Drugs used in hypertension• 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

• 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

Pharmacotherapy of MI1. Aim:

Emergency life saving management of the patient (ICU) Subsequent Treatments

2. Pain, anxiety and apprehension: Morphine, Pethidine parenteral3. Oxygenation: assisted respiration4. Maintenance of Blood Volume, tissue perfusion and microcirculation: slow

IV fluid with saline5. Correction of acidosis: Sodibicarb IV6. Prevention of Arrhythmia: Beta blockers early (arrhythmia and infarct size)7. Pump Failure: Furosemide, GTN IV/Nitroprusside and Dobutamine8. Prevention of Thrombus extension and thrombo-embolism9. Thrombolysis and reperfusion: Streptokinase, urokinase etc.10. Prevention of future attacks: beta-blockers, aspirin, anti-hyperlipidemia

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:

– Non-haemorrhagic stroke– Intermittent claudication– Trophic leg ulcers– TIA– To improve memory, vertigo and tinnitus etc. after CVA

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

Khublei Shibun/Thank You