DRUGS USED IN ISCHAEMIC HEART DISEASE

PRESENTED BY

DR DHARMENDER GUPTA JR-1, DEPT OF PHARMACOLOGY

ISCHEMIC HEART DISEASE (IHD):

Can be considered in TWO BROAD CATEGORIES
1. 2.

CHRONIC CORONARY ARTERY DISEASE ACUTE CORONARY SYNDROMES

The pharmacological strategies employed to treat these distinct clinical entities differ as their pathogenesis is distinct

ISCHEMIC HEART DISEASE

CHRONIC CORONARY ARTERY DISEASE (STABLE ANGINA)

ACUTE CORONARY SYNDROMES

UNSTABLE ANGINA

ST E MI

NSTEMI

PRINCIPAL GOALS Of PHARMACOTHERAPY

IN CHRONIC CORONARY ARTERY DISEASE To maintain the balance between myocardial oxygen supply and demand IN ACUTE CORONARY SYNDROMES ---To restore and / or to maintain patency of coronary vascular lumen

RISK FACTORS

Unalterable risk factors:

gender age family history environmental influences
climate, air pollution, trace metals in drinking water

diabetes mellitus

Alterable risk factors:

smoking HTN hyperlipidemia obesity, sedentary lifestyle hyperuricemia psychosocial factors (stress, type A behavior) medications
progestins corticosteroids cyclosporine

Non-pharmacologic approach
Changes of lifestyle (nicotine, food) lowering lipids

Psychosocial factors (excercise, taking care of oneself)

NITRATES

NITROGLYCERIN-

MOAreleases nitric oxide in smooth muscle ,

which activates
guanylyl cyclase and cGMP---dephosphorylation of myosin light chain ----- relaxation of smooth muscle in

blood vessels

EFFECTSsmooth muscle

relaxation , esp. in
vessel , vasodilatation venous return heart size , may coronary flow in some areas

Pharmacological Actions
Preload Reduction Nitrates exerts prominent action on vascular smooth muscle Nitrates dilate veins more than arteries --- peripheral pooling of blood & decrease venous return i.e. preload on heart ---- , decreases cardiac work & reduces O2 consumption.

After load Reduction Nitrates also produce arteriolar dilatation -- decrease peripheral resistance & systolic BP falls more reduction in cardiac work

Redistribution of coronary flow Nitrate relax bigger conducting coronary arteries leading redistribution of blood flow to ischaemic areas in angina patients

to

Pharmacokinetics Lipid soluble, well absorbed from buccal mucosa, intestines, skin Undergo extensive First Pass Metabolism (except mononitrate) Longer t1/2

Adverse Effects: these are mostly due to vasodilatation

Fullness in head, throbbing headache

Flushing, weakness, sweating, palpitation, dizziness & fainting

Methemoglobinemia

Rashes

 1.

Uses of Nitrates .Angina Pectoris: effective in classical & variant angina (unstable angina ) SL GTN is preferred . Role of nitrates appears limited to relief of pain because no mortality benefit has been demonstrated in large RCT GSSI-3 (1994)& ISIS-

4 (1995)

2.

.CHF & acute LVF: Nitrates afford relief by reducing preload & decreasing the end diastolic volume ---- improvement in left ventricular function by Laplace law & regression of pulmonary congestion .

I.V GTN is the drug of choice but continuous hemodynamic

monitoring should be done.

CONTD
3.Myocardial Infarction: i.v. infusion of GTN is used, aiming of relieving the chest pain , pulmonary congestion &

limiting the area of necrosis by altering O2 balance in the marginal partially ischaemic zone

GTN should not be administered if :

SBP- IS < 90 mmhg RV infarction is suspected Hypotension caused by nitrate limits the administration of beta blockers which have more salutary effects. Patient has taken Sildenafil in past 24 hours

Esophageal spasm: Sublingual GTN relieves pain Nitrates before a meal facilitate feeding in esophageal achalasia

by reducing esophageal tone

.Biliary colic: due to disease or morphine induced, respond to sublingual GTN or ISDN

.Cyanide poisoning: Nitrates along with Sodium thiosulfate is used in the treatment of cyanide poisoning

TOLERANCE

Continuous use of nitrates , may develop tolerance (tachyphylaxis) when long acting preparations (oral, transdermal) or continuous IV infusions are used for long hours without interruption. Mechanism of tolerance still unknown To minimize tolerance , the minimum effective dose should be used and a minimum of 8 h each day kept drug free to restore any useful response

ISOSORBIDE MONONITRATE active metabolite of dinitrate: used orally for prophylaxis ISOSORBIDE MONONITRATE & ISOSORBIDE DINITRATE are long acting nitrates that are relatively resistant to hepatic catabolism t1/2 ~ 1 hour

BETA BLOCKERS

PROPRANOLOL

MOA

Non selective competitive antagonism at beta adrenoreceptors

EFFECTS
HR, COP, BP, Myocardial oxygen demand They also reduce PVR by direct vasodilatation of both arterial & venous vessels reducing both pre- and after load.

Beta blockers
PHARMACOKINETICS Oral and Parenteral- 4-6 h duration
CONTRAINDICATIONS Asthma, Diabetes, Bradycardia,

Peripheral vascular disease

COPD DRUG INTERACTION

Cimetidine, Furosemide, Chlorpromazine potentiate the antihypertensive effect of Propranolol Barbiturates Phenytoin and Rifampicin mitigate its effect

1 antagonists (Atenolol, Metoprolol and Acebutolol) reduce the frequency and severity of anginal episodes particularly when used in

combination with nitrates.

1 antagonists have been shown to improve survival in post MI patients and decrease the risk of subsequent cardiac events & complications.

-Blockers in combination with nitrates can be quite effective

 Esmolol

-an ultra short acting beta-blocker administered as continuous iv infusion ,its rapid action makes it an attractive agent to be used in patients with relative C/I to beta blockers the dose / discontinuation may be needed if the side effects develop and persist

Reducing

Sudden

discontinuation can intensify ischemia , the doses should be tapered over 2 weeks
blockers with 1 receptor specificity (atenolol, metoprolol and acebutolol) may be preferable in patients with mild bronchial obstruction and IDDM

Beta

Calcium channel blocker Miscellaneous

VERAPAMIL , DILTIAZEM
MOA
Nonselective blocker of L- type of calcium channels in vessels and heart APPLICATIONS Prophylaxis of angina , hypertension PHARMACOKINETICS Oral / IV DURATION 4-8 h

TOXICITY
AV block , acute heart failure , edema Have an additive effect with other cardiac depressants and hypotensive drugs

EFFECTS

vascular resistance

cardiac rate

cardiac force

there by

myocardial oxygen

demand

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

weak vasodilator.
Because of its focused myocardial effects it is not used as an antianginal unless there is a tachyarrhythmia. Metabolized in the liver. Interferes with digoxin levels causing elevated plasma levels; caution and monitoring of drug levels are necessary with concomitant use .

Diltiazem:
can be combined with beta blocker in patient with normal ventricular function and no conductance abnormality.

more effective against Prinzmetal angina.

It has less effect on HR. It has similar metabolism and side effects as Verapamil

Calcium channel blocker Dihydropyridine

NIFEDIPINE MOABlock of vascular L- type calcium channels > cardiac channels works mainly on the arteriolar vasculature decreasing after load , it has minimal effect of conduction or HR.

APPLICATIONS
Prophylaxis of angina , hypertension (first line drugs) Prinzmetals angina responds well to CCB(Dihydropyridine) PHARMACOKINETICSMetabolized in the liver and excreted in both the urine & the feces. TOXICITY Causes flushing, headache, hypotension and peripheral edema. It also has

some slowing effect on the GI musculature resulting in constipation.

Contd-
A reflex tachycardia associated with the vasodilatation may elicit myocardial

ischemia in tenuous patients, as such it is generally avoided in non-hypertensive

coronary artery disease.

The slower and long acting DHP induce less sympathetic stimulation .

Tachycardia , propensity to

increase cardiac work , flushing , headache ,

dizziness are subdued

They are currently favored among post MI patients as mortality, been reported

with regular short acting nifedipine formulation

OTHER USES

CARDIAC ARRHYTHMIAS
verapamil and diltiazem are highly effective in PSVT and for control of ventricular rate in supraventricular arrhythmias

HOCM
negative inotropic action of verapamil can be salutary in this condition

DHP
reduce severity of raynauds phenomenon

BENEFICIAL COMBINATIONS
Beta-Blocker + Long acting nitrate combination - rationale in Classical angina

Tachycardia due to nitrate is blocked by -blocker The tendency of -blocker to cause ventricular dilatation is counteracted by nitrate

The tendency of -blocker to reduce total coronary flow is

opposed by nitrate

 Nitrates with Nifedipine

Advocated for patients of exertional angina with heart failure or

sick sinus syndrome or AV nodal conduction defect but excessive

tachycardia can be observed

Nitrates primarily decrease preload CCBs mainly reduce after load + increases coronary flow

 Amlodipine and beta blocker have a complementary action on coronary blood flow and myocardial oxygen demand , the former decreases BP and dilates coronary arteries , the latter slows heart rate and decreases contractility.

STATINS

The treatment of dyslipidemia is central in aiming for long term relief of angina and other forms of IHD

Reduce the need for revascularization Reduce chances of MI & death

Dyslipidemia can be achieved by combination of diet low in saturated fatty

acid , exercise and weight loss

HMG CoA reductase inhibitors lovastatin , simvastatin , pravastatin , atorvastatin , rosuvastatin are required

these lower LDL cholestrol (25-50%), raise HDL cholestrol (5-9%) , lower TGs (5-30%)

A dose dependent effect is seen with statins HMG CoA reductase inhibitors- activity is max. at night there fore are to be administered at night to obtain max. effectiveness

Contd -

ADVERSE EFFECTS All statins are well tolerated Headache , nausea, bowel upset , rashes Sleep disturbances Rise in serum transaminases , but liver damage is rare Myopathy is the only serious reaction but is rare Muscle tenderness and rise in CPK levels occur infrequently

Fibric acid derivatives

These are isobutyric acid derivatives CLOFIBRATE not used now a days as evidence showed it does not prevent atherosclerosis GEMFIBROZIL

Lowers plasma TG level by enhancing breakdown and suppression of hepatic

synthesis of TG

The Helsinki Heart Study showed that men without known CAD treated with gemfibrozil had 34% reduction in fatal & nonfatal MI , though overall mortality was

not affected .

It also decreases the level of clotting factor VII phospholipid complex also promotes fibrinolysis , which may contribute to antiatherosclerotic effect. Common side effects are epigastric discomfort , loose motions

Gemfibrozil + statin increase risk of myopathy

c/I in pregnancy. Other drugs are bezafibrate , fenofibrate

DRUGS INHIBITING PLATELET AGGREGATION

Antiaggregatory

therapy

decreases

risk

of

complications (MI, sudden heart death) by 23 % among patients with angina pectoris( AP )

DRUGS INHIBITING PLATELET AGGREGATION ACCORDING TO MECHANISM OF ACTION

1.

Inhibition of TXA A2 formation through prostaglandin pathway inhibition of COX-1 (ASA) Inhibition of TXA A2 formation through increasing level of cAMP in thrombocyte inhibition of phosphodiesterase
(dipyridamole) - stimulation of adenylatecyclase (prostacyclin)

2.

3.

Inhibition of fibrinogen bridges formation between thrombocytes - inhibition of receptor for ADP on thrombocyte membrane
(thienopyridines ticlopidine, clopidogrel)

- inhibition of receptor for fibrinogen on thrombocyte membrane

glycoprotein IIb/IIIa (fibans, abciximab)

ASPIRIN

Antiaggregatory effect is given by irreversible blockade of COX-1 (thromboxane A2 is missing)

Optimal dose is between 1 mg/kg daily

IND.- manifested IHD, AP, silent ischaemia CI allergy, ulcer, GIT bleeding

TICLOPIDINE

Inhibition of platelet activation, mediated with adenosindiphosphate, starting after several days

2 times per day 250 mg Risk of leukopenia

CLOPIDOGREL

Newer congener of ticlopidine Acts similar to ticlopidine, ability to inhibhit platelet function and therapeutic efficacy

More safer and better tolerated (CLASSICS study)

The CAPRIE trial says that clopidogrel recipients have a slightly lower annual risk of primary ischaemic event than aspirin recipients.

Bleeding is the serious side effect .

Lower frequency of neutropenia ,thrombocytopenia , and other bone marrow toxicity as that of ticlopidine

Clopidogrel + aspirin - effective in stented patients 50% absorbed Action lasts up to 7 days

PRASUGREL

Newest member of the thienopyidine class Prodrug, requires metabolic activation Rapid onset of action Produces greater inhibition of ADP- induced platelet aggregation Because of irreversible binding to receptor P2Y12 these drugs have prolonged effect after discontinuation

incidence of

myocardial infarction , cardiovascular deaths

was

significantly lower with prasugrel than clopidogrel

Incidence of stent thrombosis was also reduced with prasugrel

Contraindicated with patient having cerebrovascular disease

DIPYRIDAMOLE

Vasodilator Inhibits PDE and blocks uptake of adenosine to increase cAMP which potentiates PGI 2 interfering aggregation

Alone not recommended because of low antiaggregatory effect and making worse IHD steal phenomenon

Combination of dipyridamole with retarded release 200 mg and 30 mg ASA is used in neurology in prevention of stroke

NEWER ANTI PLATELET AGENTS

These agents are in advanced stage of their development include Cangrelor Ticagrelor Directly acting reversible P2Y12 antagonist

Sch 530348
E5555

GP IIb /IIIa RECEPTOR ANTAGONIST

New class potent platelet aggregatory inhibitors Act by blocking the receptor integrin (GP IIb /IIIa RECEPTOR ) for fibrinogen and vWF through which agonists like collagen , thrombin aggregation etc induce platelet

ABCIXIMAB

It is the Fab fragment of chimeric monoclonal antibody against GP IIb /IIIa Given with aspirin + heparin during PCI markedly reduces incidence of restenosis , subsequent MI and death

After bolus dose anti aggregatory effect remains 12-24 h

T1/2 10- 30 min it is nonantigenic , hemorrahage is main risk, Thrombocytopenia can be seen , constipation , ileus and arrhythmias can occur

very expensive , used in unstable angina and adjuvant to coronary thrombolysis

and PCI with stent replacement.

Eptifiatide and Terirofiban are other alternatives.

HEPARINS
Other options available for addition to aspirin and clopidogrel Unfractionated heparin (UFH) MAIN STAY OF THE TERAPY LMWH ,( ENOXAPARIN ) in several studies have been shown superior to UFH in

reducing recurrent cardiac events

FONDAPARIUNX the indirect factor Xa inhibitor has a lower risk of major bleeding , equivalent to enoxaparin in efficacy BIVALIRUDIN direct thrombin inhibitor , similar to efficacy to UFH/ LMWH among

paitent treated with GP IIb /IIIa inhibitor Use of bivalirudin alone causes less bleeding than combination of heparin & GPIIb/ IIIa inhibitor in patient with UA/NSTEMI under going cathetrization / PCI
1.

The important advantages of LMWHbetter SC availability

2.
3. 4.

once daily administration

Since aPTT/ clotting factors are not prolonged lab monitoring is not needed, dose is calculated on body weight basis

THROMBOLYTICS

Streptokinase Urokinase Alteplase (tPA) Reteplase (r-PA) Tenecteplase (TNK t-PA)

STEPTOKINASE

Combines with circulating plasminogen to form an activator complex which then causes limited proteolysis of other plasminogen molecules to plasmin .

A loading dose is necessary in beginning

t1/2 is 30-80 min

It is antigenic , causes hypersensitivity and anaphylaxis Fever is uncommon , arrhythmias , hypotension are reported . Being least expensive still widely used in India and other developing countries.

For MI 7.5-15 lac IU infused iv over 1 hour

RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR (rt-PA)

cultured from human tissue Activates gel phase plasminogen already bound to fibrin Has little effect on circulating plasminogen . Rapid hepatic metabolism , t1/2 4- 8 min For MI 15 mg i.v. bolus , 50 mg over 30 min , then 35 mg over next 1 hour Often requires heparin co administration Non antigenic , hypotension , fever may occur it is expensive Reteplase (rt-PA) - longer acting , less specific for fibrin bound plasminogen , Tenecteplase (TNK t-PA)- has higher fibrin selectivity , longer duration of action

CONTRAINDICATIONS
1. 2. 3. 4. 5. 6. 7. 8.

Recent trauma Surgery Biopsies Hemorrhagic stroke Peptic ulcer s Severe hypertension Aneurysm Bleeding disorders

9.
10.

Acute pancreatitis
Its use in retinal vein occlusion has been abandoned

OTHER THERAPIES

De spite of various drugs , some patients with IHD continue to experience angina , and additional medical therapy is now available to alleviate their symptoms RANOLAZINE piperazine derivative Inhibits late sodium current in heart

Also modifies fatty acid oxidation

Reduces cardiac oxygen demand used in prophylaxis of chronic angina C/I hepatic impairment With drugs or conditions associated with QTc prolongation With drugs that inhibit CYP3A metabolic system

Contd

NICORANDIL Opens ATP sensitive potassium channels in myocytes Leading to reduction of free intracellular calcium channels

administered orally in a dose of 20 mg twice daily for prevention

angina

ISCHEMIC HEART DISEASE CHORNIC CORONARY ARTERY DISEASE (STABLE ANGINA) Aspirin Beta antagonists Nitrates Calcium channel blockers ACE inhibitors Ranolazine Add Heparin, GPIIp/IIIa inhibitor clpopidogrel

ACUTE CORONARY SYNDROMES

UNSTABLE ANGINA/ NSTEMI Thrombol ysis Add -Thrombolytic agent , heparin , clopidogrel

ST E MI

Angioplas ty
Add Heparin, GPIIp/IIIa inhibitor clpopidogrel

Post MI Possible addition of Statin ACEinhibitors, Aldosterone receotor antagonist,

All patients with STEMI are candidates for reperfusion therapy best results are obtained if perfusion can be achieved within 1st hour of MI ( GOLDEN HOUR )

THROMBOLYSIS favored within 1-2 hours of onset after 3 hours PCI is favored , latter has lower chances of bleeding risk , higher grade of flow in the reperfused artery and reduction in rate of non fatal MI as compared to thrombolysis

presence of risk factor also favors PCI Overall 6 month mortality has not been found to be differ in either mode of reperfusion

THERAPEUTIC OUTCOMES

Angina symptom improvement

Improved cardiac performance

Risk factor reduction

Increased exercise capacity

May use coronary angiography to assess extent of stenosis or

re-stenosis after angioplasty or CABG