recent advances in ischemic heart diseases
TRANSCRIPT
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RECENT ADVANCES IN ISCHEMIC HEART DISEASES
By Dr. Sachin R. ChoudhariJR 2, Dept. of PharmacologySVNGMC , Yavatmal
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INTRODUCTION WHAT IS ANGINA PECTORIS ??? AVAILABLE TREATMENT OTHER ANTIANGINAL DRUGS NEED FOR NEW AGENTS RECENTS ADVANCES SUMMARY
OUTLINE…..
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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
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Angina :
Stable Angina Unstable Angina Variant Angina / Vasospastic Angina
Myocardial infarction :
STEMI NSTEMI
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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?
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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%
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RISK FACTORS
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Chest pain or discomfort (stabbing, pulsating) Pain in arms, neck, jaw, shoulder or back Nausea Fatigue Shortness of breath Anxiety Sweating Dizziness
SYPMTOMS
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ACUTE ANGINA :
Rest Sublingual Nitroglycerine
CHRONIC ANGINA :
Long acting nitrates Beta blockers CCBs K+ channel opener pFOX inhibitorsCURRENT TREATMRNT STRATEGY
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1. Nitrates :
a. Short acting : Glyceryl trinitrate
b. Long acting : Isosorbide dinitrateIsosorbide mononitrateErythrityl tetranitratePentaerythritol tetranitrate
2. Beta blockers : propranololMetoprololAtenolol
Antianginal drug :
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3. Calcium channel blockers :
a. Phenyl alkylamine : VerapamilGallopamil
b. Benzothiazepines : Diltiazemc. Dihydropyridines : Nifedipine
FelodipineAmlodipineNitrendipineNimodipineLacidipineLercanidipineBenidipine
4. Potassium channel opener : Nicorandil
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Others :
1. Dipyridamole2. Trimetazidine3. Ranolazine4. Ivabradine5. Oxyphendrine
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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 :
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Reduced venous return(Due to dilatation of the veins)
Decrease left ventricular volume
Decrease preload
Decrease workload
Decrease oxygen consumption
1st mechanism of action
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Reduction on peripheral resistance(Secondary to dilatation of aorta)
Decrease blood pressure
Decrease after load
Decrease workload
Decrease oxygen consumption
2nd mechanism of action :
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Coronary artery dilatation
Decrease coronary bed resistance (Relieved coronary vasospasm)
Increase coronary blood flow
Increase oxygen supply
3rd mechanism of action :
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Throbbing headache Flushing of the face Dizziness Postural Hypotension Tolerance Dependence Methemoglobinemia
Adverse effects :
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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 :
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Decrease heart rate & Contractility
Increase duration of diastole Decrease workload Increase coronary blood flow Decrease O2 consumptionIncrease oxygen supply
MOA:
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Decompensated congestive heart failure
Asthma
Complete heart block
Contraindications :
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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 :
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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:
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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 :
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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 :
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Nausea and vomiting
Dizziness
Flushing of the face
Tachycardia : Due to hypotension
Adverse effect :
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Cardiogenic shock
Recent myocardial infarction
Heart failure
Atria-ventricular block
Contraindications :
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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 :
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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 :
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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 :
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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
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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 :
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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
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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 :
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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
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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
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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 :
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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
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‘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 :
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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
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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 :
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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 ???
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Recent advances :
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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 :
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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 :
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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)
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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 :
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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
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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 :
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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 :
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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 :
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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)
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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)
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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 :
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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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Basics and clinical pharmacology-13th edition;BG Katzung & AJ Trevor
Pharmacology for MBBS – 1st edition ; S K shrivastav
Principals of pharmacology - 2nd edition ; HL sharma & KK sharma
Essential of medical pharmacology- 7th edition; KD Tripathi
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