drugsused in ihd
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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
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