RECENT ADVANCES IN ISCHEMIC HEART DISEASES

By Dr. Sachin R. ChoudhariJR 2, Dept. of PharmacologySVNGMC , Yavatmal

INTRODUCTION WHAT IS ANGINA PECTORIS ??? AVAILABLE TREATMENT OTHER ANTIANGINAL DRUGS NEED FOR NEW AGENTS RECENTS ADVANCES SUMMARY

OUTLINE…..

An imbalance between the supply of oxygen and the myocardial demand resulting in myocardial ischaemia

Most common cause of cardiovascular morbidity and mortality Peak incidence of symptomatic IHD is age 50-60 (men) and 60-70 (women) M>F MC cause of death worldwide by 2020 Consist of Angina and Myocardial Infarction

INTRODUCTION

Angina :

Stable Angina Unstable Angina Variant Angina / Vasospastic Angina

Myocardial infarction :

STEMI NSTEMI

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

What is the Angina Pectoris?

Type of Angina Pectoris

typical Stable Angina

↓coronary flow ,Occurs on

physical Exertion (five minutes or

less)

Unstable angina

Epicardial coronary spasm & formation

of non-occlusive thrombi

Can Occurs at rest Heart attack(emergency)

Variant , vasospastic or

prinzmetal angina ..

Reversible coronary

spasm .. Occurs at rest

2%

RISK FACTORS

Chest pain or discomfort (stabbing, pulsating) Pain in arms, neck, jaw, shoulder or back Nausea Fatigue Shortness of breath Anxiety Sweating Dizziness

SYPMTOMS

ACUTE ANGINA :

Rest Sublingual Nitroglycerine

CHRONIC ANGINA :

Long acting nitrates Beta blockers CCBs K+ channel opener pFOX inhibitorsCURRENT TREATMRNT STRATEGY

1. Nitrates :

a. Short acting : Glyceryl trinitrate

b. Long acting : Isosorbide dinitrateIsosorbide mononitrateErythrityl tetranitratePentaerythritol tetranitrate

2. Beta blockers : propranololMetoprololAtenolol

Antianginal drug :

3. Calcium channel blockers :

a. Phenyl alkylamine : VerapamilGallopamil

b. Benzothiazepines : Diltiazemc. Dihydropyridines : Nifedipine

FelodipineAmlodipineNitrendipineNimodipineLacidipineLercanidipineBenidipine

4. Potassium channel opener : Nicorandil

Others :

1. Dipyridamole2. Trimetazidine3. Ranolazine4. Ivabradine5. Oxyphendrine

Organic nitrates & nitrites are simple nitric & nitrous esters of glycerol.

Cause a rapid decrease in myocardial oxygen demand

Effective for all types of angina.

Activation of guanylate cyclase increases cGMP activating a cGMP kinase leading to dephosphorylation of myosin light chains decreasing contractile force.

Nitrates :

Reduced venous return(Due to dilatation of the veins)

Decrease left ventricular volume

Decrease preload

Decrease workload

Decrease oxygen consumption

1st mechanism of action

Reduction on peripheral resistance(Secondary to dilatation of aorta)

Decrease blood pressure

Decrease after load

Decrease workload

Decrease oxygen consumption

2nd mechanism of action :

Coronary artery dilatation

Decrease coronary bed resistance (Relieved coronary vasospasm)

Increase coronary blood flow

Increase oxygen supply

3rd mechanism of action :

Throbbing headache Flushing of the face Dizziness Postural Hypotension Tolerance Dependence Methemoglobinemia

Adverse effects :

Decrease oxygen demands of the myocardium by lowering the HR and contractility (decrease CO)

Reduce PVR by direct vasodilatations of both arterial & venous vessels

Reduce the frequency and severity of anginal episodes (when used in combination with nitrates)

Improve survival in post MI patients and decrease the risk of subsequent cardiac events & complications

Beta blockers :

Decrease heart rate & Contractility

Increase duration of diastole Decrease workload Increase coronary blood flow Decrease O2 consumptionIncrease oxygen supply

MOA:

Decompensated congestive heart failure

Asthma

Complete heart block

Contraindications :

Inhibit the entrance of Ca+2 into cardiac and smooth muscle cells of the coronary and systemic arterial beds

Produce some vasodilation (↓ PVR) and (-) inotropes

By acting on AV node thus serving to control cardiac rhythm

They are useful in Prinzmetal angina in conjunction with nitrates

Calcium channel blockers :

Works mainly on the arteriolar vasculature decreasing after load it has minimal effect of conduction or HR.

Metabolized in the liver and excreted in both the urine & the feces

Causes less flushing, headache, hypotension and peripheral edema

Induces less reflex sympathetic stimulation

DHP other than Nifedipine:

Main effect on cardiac conduction decreasing HR and thereby O2 demand

It has much more (-) inotropic effect than other Ca+2 channel blockers

It is a weak vasodilator

Because of its focused myocardial effects it is not used as an antianginal unless there is a tachyarrhythmia

It interferes with digoxin levels causing elevated plasma levels

Verapamil :

This agent function similarly to Verapamil however it is more effective against Prinzmetal angina

Dilates coronaries

It has less effect on HR

It has similar metabolism and side effects as Verapamil

Diltiazem :

Nausea and vomiting

Dizziness

Flushing of the face

Tachycardia : Due to hypotension

Adverse effect :

Cardiogenic shock

Recent myocardial infarction

Heart failure

Atria-ventricular block

Contraindications :

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

Combination therapy :

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

Calcium channel blockers +beta blockers :

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

Calcium channel blocker + nitrates :

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

Triple drugs: Nitrates + calcium channel blockers + beta blocker

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

Potassium Channel Openers :

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

Dipyridamole :

Powerful coronary dilator dilates resistance vessels and abolishes autoregulation , but has no effect

on larger conducting coronary vessels pharmacological success but therapeutic failure : coronary steal

phenomenon By potentiating PGI2 and increasing cAMP in platelets, it enhances

antiaggregatory influences Not useful as an antianginal drug Employed for prophylaxis of coronary and cerebral thrombosis in post-

MI and post stroke patients

Other antianginal drugs :

Labelled as pFOX (fatty acid oxidation pathway) inhibitor

Inhibiting mitochondrial long chain 3-ketoacyl-CoAthiolase (LC3-KAT)

Reduces fatty acid metabolism and increases glucose metabolism in myocardium

Since oxidation of fatty acid requires more O2, shift back of substrate to glucose would reduce O2 demand

Limiting intracellular acidosis and Na+, Ca2+ accumulation during ischaemia

Protecting against Oxygen free radical induced membrane damage.

Trimetazidine

No effect on HR and BP , both at rest as well as during exercise

Absorbed orally, partly metabolized and largely excreted unchanged in urine

t ½ : 6 hr.

Widely used in France, Spain, some other European countries and India, but not in the UK or USA

Mostly an add on medication to conventional therapy

Side effects : gastric burning, dizziness, fatigue and muscle cramps

Acts by inhibiting a late Na+ current (late INa) in the myocardium which indirectly facilitates Ca2+ entry through Na+/Ca2+ exchanger

Decrease calcium level decreases contractility (cardioprotective effect)

Sparing of fatty acid oxidation

No effect on HR and BP, but prolongs exercise duration in angina patient

Side effects : dizziness, weakness, constipation, postural hypotension, headache and dyspepsia

Ranolazine :

Several trial : Aim : To see efficacy in decreasing frequency of anginal

attacks and in prolonging exercise duration 1. MARISA : (2004)2. CARISA : (2004)3. ERICA : (2005)4. MERLIN TIMI 36 : (2007)

It is metabolized in liver by CYP3A4 and excreted in urine

‘Pure’ heart rate lowering antianginal drug (alternative to β blockers.)

Significant action : Blockade of cardiac pacemaker (sino-atrial) cell ‘f’ channels, which are ‘funny’ cation channels

Resulting inward current (If) determines the slope of phase 4 depolarization

results in heart rate reduction without any other electrophysiological or negative inotropic effect

HR reduction decreases cardiac O2 demand and prolongation of diastole tends to improve myocardial perfusion (O2 supply)

Ivabradine :

40% bioavailable due to first pass metabolism; degraded by CYP3A4 and excreted in urine

Side effects : Excess bradycardia , visual disturbance

Indicated in chronic stable angina in patients with sinus rhythm who are intolerant to β blockers

Contraindications : HR < 60/min , AF

claimed to improve myocardial metabolism so that heart can sustain hypoxia better

Its efficacy and status in coronary artery disease is not defined

Can diminish or alter taste sensation.

Oxyphedrine :

1. Non selectivity

2. Affect hemodynamic parameters

3. Do not protect heart from stress induced adrenergic effects

4. Beneficial effect is short-lived

5. Tolerance

Need for new drugs ???

Recent advances :

It’s a CCB and similar to verapamil

It reduces AV conduction

Can be used as adjuvant for prophylaxis of angina

Did not find much favor for clinical use

Side effect : Dyguesia

Ladoflazine :

A Rho-kinase inhibitor

Rho kinase, an intracellular signaling molecule involved in the vascular smooth muscle contractile response to agonists such as acetylcholine, angiotensin II, endothelin, norepinephrine, platelet-derived growth factor, and serotonin

In phase 2 dose-finding trials : in Japanese patients : increased maximum exercise time and time to the onset of > 1 mm ST-segment depression compared with baseline

Well tolerated

Minimal effects on blood pressure or heart rate at rest or during exercise

FASUDIL :

A new class of CAs, which selectively blocks T-type of Ca2+ channels

Trial shows : statistically significant but clinically modest improveinent in total ETT duration

Decreases all hemodynamic parameters

Associated with a significantly larger reduction in the number of weekly anginal attacks

Combination of mibefradil 50 mg and long-acting nitrates was well tolerated

Mibefradil : (phase 2)

A new generation of CCBs

A more vascular selective action than currently available agents

A potent vasodilator in peripheral, coronary, and cerebral arterial beds and has substantially less myocardial depressant effect than nifedipine

Acute administration : resulted in a larger increase in coronary blood flow and myocardial oxygen supply

In acute studies, it appears to increase the myocardial oxygen supply to demand ratio

Nicardipine :

First dehydropyridine available in both oral and intravenous dosage forms

No or minimal effect on hemodynamic parameters

Minimal negative inotropic or dromotropic effects even in patients with existing left ventricular dysfunction

May be useful for the treatment of angina in patients with coexisting left ventricular dysfunction or borderline heart failure

Inhibitory effect on SA node leads to decrease HR

It has negative chronotropic effect but little effect on AV node

Causes less reflex tachycardia

Slow onset of action and for longer duration

Isradipine :

New DHP CCB with rapid onset of action but ultra short action

It has selectivity for arterial smooth muscle as compared to vein or myocardium

Useful for controlling severe HT

Need to be evaluated more antianginal drugs

Clevidipine :

It’s a CCB that blocks L and N type of calcium channels

It dilates both arterioels and venules and thus reduces capillary pressure & reduces reflex tachycardia

Used for HT

Also reduces platelet activation

Side effect : peripheral oedema

Cilnidipine :

New second generation dihydropyridine calcium antagonist

Causes very similar hemodynamic changes at rest and during exercise

Marked decrease in systemic vascular resistance, which was accompanied by an increase in cardiac index and stroke volume

Major MOA is lowering of systemic vascular resistance

Improves systolic cardiac function in patients with chronic stable angina

Data also suggest an improvement in coronary blood flow during exercise

Elgodipine : (phase 1)

New sydnonimine compound in clinical development

As a prodrug, it is transformed into a nitric oxide releasing metabolite in vivo

In human study :Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change

pirsidomine is an effective anti ischemic and antianginal agent

Safety and efficacy need to be evaluated in large population

Pirsidomine: (phase 2)

IHDs : Most common cause of cardiovascular morbidity and mortality

Nitrates, CCB and Beta blockers are widely used agents for the Rx of Angina

Currently available drugs are associated with many adverse effects

In past 20 years , treatment strategies are not much changed since non availability of new drugs

We need newer effective drugs which are specific in action with less adverse effects

Summary :

Fkishman et al. Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Concomitantly Treated with Long-Acting Nitrates for Chronic Stable Angina Pectoris. Clin.Cardiol. 2000;Vol 21:483-490

Kuhn A , Carlsson J, Miketic S, Tebbe U. Hemodynamic and anti ischemic effects of intravenous elgodipine, a new dihydropyridine calcium channel blocker, in patients with chronic stable angina. Cardiovasc Drugs Ther. 1995 Aug;9(4):595-600.

C. pepine. Nicardipine, A New Calcium Channel Blocker: Role for Vascular Selectivity. Clin. Cardiol. 12, 240-246 (1998)References :

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