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. CHRONIC CORONARY ARTERY DISEASE

2. 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

NSTEMI

ST E MI UNSTABLE ANGINA

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-

MOA-

releases nitric oxide

in smooth muscle ,

which activates

guanylyl cyclase

and cGMP----

dephosphorylation

of myosin light

chain ----- relaxation

of smooth muscle in

blood vessels

EFFECTS-

smooth 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 to redistribution of

blood flow to ischaemic areas in angina patients

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

Uses of Nitrates

1. .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.

CONTD3.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

COPDDRUG INTERACTION Cimetidine, Furosemide, Chlorpromazine – potentiate the

antihypertensive effect of Propranolol Barbiturates Phenytoin and Rifampicin – mitigate its effect

β1 antagonists (Atenolol, Metoprolol and Acebutolol) reduce the frequency and severity of anginal episodes particularly when used in

combination with nitrates. β1 antagonists have been shown to improve survival

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

β-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

Reducing the dose / discontinuation may be needed if the side effects develop and persist

Sudden discontinuation can intensify ischemia , the doses should be tapered over 2 weeks

Beta blockers with β1 –receptor specificity (atenolol, metoprolol and acebutolol) may be preferable in patients with mild bronchial obstruction and IDDM

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 –

MOA-Block 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)

Prinzmetal’s angina responds well to CCB(Dihydropyridine)

PHARMACOKINETICS-

Metabolized 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 raynaud’s phenomenon

BENEFICIAL COMBINATIONS

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

Tachycardia due to nitrate is blocked by β-blocker

The tendency of β-blocker to cause ventricular dilatation is

counteracted by nitrate

The tendency of β-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 TG’s (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 ACTION1. Inhibition of TXA A2 formation through prostaglandin pathway

– inhibition of COX-1 (ASA)

2. Inhibition of TXA A2 formation through increasing level of

cAMP in thrombocyte – inhibition of phosphodiesterase

(dipyridamole)

- stimulation of adenylatecyclase (prostacyclin)

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 etc induce platelet aggregation

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

The important advantages of LMWH-

1. better SC availability

2. once daily administration

3. Since aPTT/ clotting factors are not prolonged lab monitoring is not needed,

4. 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. Recent trauma

2. Surgery

3. Biopsies

4. Hemorrhagic stroke

5. Peptic ulcer s

6. Severe hypertension

7. Aneurysm

8. Bleeding disorders

9. Acute pancreatitis

10. 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) ACUTE CORONARY

SYNDROMES

Add Heparin, GPIIp/IIIa inhibitor

clpopidogrel

ST E MI UNSTABLE ANGINA/ NSTEMI

Aspirin Beta antagonists Nitrates

Calcium channel blockers ACE

inhibitors Ranolazine

Post MI

Angioplasty

Thrombolysis

Add -Thrombolytic

agent , heparin , clopidogrel

Add Heparin, GPIIp/IIIa inhibitor

clpopidogrel

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