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DRUGS USED FOR

ISCHEMIC HEART DISEASE

DR. CHAITALI PATTANAYAK


PROFESSOR, PHARMACOLOGY
KIMS, BHUBANESWAR
LEARNING OBJECTIVES

At the end of the class, the learner will be able to :-


• Classify the Antianginal drugs
• Write the mechanism of action, therapeutic uses,
adverse effects and contraindications of nitrates
• Write short notes on various nitrates
• Write the pharmacological basis of the use of
nitrates, CCB’s & β blockers in angina
INTRODUCTION
• Ischemic heart disease (IHD) is a common cause of
death across the world, may manifest as angina
pectoris, unstable angina & in more severe cases as
myocardial infarction
• Angina pectoris: It is the chief symptom of IHD,
characterized by sudden, severe, substernal
discomfort/pain which may radiate to the left shoulder
and along the flexor surface of the left arm
• angere=to strangulate, pectus=chest(William
Heberden)
• O2 consumption/ demand is determined by preload,
afterload & heart rate. When O2 supply to the
myocardium is insufficient for it’s needs, myocardial
ischemia develops
• Pain due to accumulation of metabolites in cardiac m.
ANGINA
• Classical / stable angina: pain is
induced by exercise or emotion,
due to myocardial O2 demand.
There is narrowing of coronary
arteries due to atherosclerosis,
cannot dilate to blood supply.
There is imbalance between
Oxygen supply and demand
• Unstable angina: factors like
myocardial O2 demand, coronary
vasospasm & platelet aggregation
may result in unstable angina,
requires immediate treatment
• Variant/Prinzmetal’s angina:
occurs at rest & is caused by
spasm of the coronary artery
ANTIANGINAL DRUGS: Drugs used to improve the
balance between O2 supply & demand by O2 supply to
the myocardium (coronary dilation) or by O2 demand
( preload / afterload/ heart rate or all of these)
CLASSIFICATION:
• Nitrates: Nitroglycerin, Isosorbide dinitrate, Isosorbide
mononitrate, Pentaerythritol tetranitrate,
Erythrityl tetranitrate
• Calcium channel blockers: Verapamil, Diltiazem, Amlodipine
Nifedipine
• β -blockers: Propranolol, Atenolol etc
• Potassium channel openers: Nicorandil, Pinacidil
• Others: Dipyridamole, Aspirin, Trimetazidine, Ranolazine,
Ivabradine
SMOOTH MUSCLE CONTRACTION
Ca+2 channels
(-) CCB’s
Ca+2 (intracellular) ATP
Calmodulin (+) β agonists
Ca+2-Calmodulin complex cAMP
+
MLCK+ Myosin-LC kinase MLCK-(PO4)2

Myosin-LC Myosin-LC – PO4 Myosin-LC


Actin phosphatase
Contraction + Relaxation
cGMP
NITRATES - MECHANISM OF ACTION
Nitrates are vasodilators :
- Nitrates converted to nitric
oxide (NO) → activate
vascular guanylyl cyclase
(GC) → synthesis of cGMP
→ dephosphorylation of
MLC →prevents Myosin-LC – PO4 Myosin-LC
interaction of actin with Actin
phosphatase
myosin → relaxation
Contraction + Relaxation
- Nitrates free cytosolic Ca+2
( Ca+2 release from SR) / cGMP
Ca+2 efflux → smooth
muscle relaxation → NITRATES NO Gyanylyl cyclase
vasodilatation
PHARMACOLOGICAL ACTIONS
1) Reduction of preload:
nitrates are predominantly
venodilators→ dilatation of
capacitance vessels →
pooling of blood in veins →
venous return → preload
→ myocardial demand
2) Reduction of afterload:
nitrates cause some arteriolar dilatation (higher doses)
→ vascular resistance → afterload → cardiac
work/demand
3) Coronary dilatation: nitrates cause some coronary
vasodilatation → coronary blood flow in a normal
person (but in presence of atherosclerotic coronary
artery disease, increase is not much)
Redistribution of coronary
Dilatation of
flow: Nitrates preferentially collaterals +
relax bigger conducting ischemic dilatation
/collateral coronary arteries of arterioles blood
flow
than resistance vessels/
arterioles → Favourable
redistribution of blood flow
to ischemic areas
Beneficial effects - in stable
angina are due to vasodilator
properties:

Preload & afterload →


myocardial workload/
myocardial O2 demand
coronary vasodilatation→
myocardial O2 supply
- in variant angina: coronary vasodilatation → relief
from coronary vasospasm
4) Other vasculature: cause dilatation of blood vessels
in the skin(face & neck) → flushing, dilatation of the
meningeal vessels → headache
5) Other smooth muscles: nitrates relax the bronchial,
gastrointestinal (biliary ducts & sphincter of oddi) &
genitourinary smooth muscles (uterine) – for short
period.
6) Platelets: nitrates converted to NO → activates
vascular guanylyl cyclase → synthesis of cGMP →
platelet aggregation is inhibited, may be helpful in
patients with unstable angina
PHARMACOKINETICS
• Nitrates are well absorbed orally from buccal
mucosa, intestines & skin (good lipid solubility),
undergo extensive first pass metabolism, except
Isosorbide mononitrate
• Rapidly denitrated by a glutathione reductase &
mitochondrial aldehyde dehydrogenase → less
active metabolites with longer t1/2
• Nitroglycerin, Isosorbide dinitrate, Isosorbide
mononitrate, Pentaerythritol tetranitrate used in
angina
• Isosorbide mononitrate is longer acting (given BD),
100% bioavailability( no 1st pass metabolism)
• Amyl nitrite used in cyanide poisoning
PREPARATIONS
• Nitrates available for oral, sublingual, parenteral use, as
ointment and transdermal patches for topical use
• Topical preparations are used for the prevention of nocturnal
episodes of angina
• Risk of development of tolerance with topical & slow release
preparations
DRUG DOSE & ROUTE DURATION OF ACTION
- Nitroglycerin → 0.5 mg SL 15-40mins
(GTN/NTG) 5mg oral 4-8hrs
2% skin ointment 4-6hrs
- Isosorbide → 5-10 mg SL 20-40mins
dinitrate 10-20mg oral 2-3hrs
- Isosorbide → 10-20mg oral 6-8hrs
mononitrate
ADVERSE EFFECTS
• Headache – common (due to meningeal vessel vasodilatation)
• Sweating, flushing, palpitations, weakness, postural
hypotension & rashes
• Tolerance to vascular effects develops on repeated long term
use ( due to plasma levels)
• Pt. must be free of nitrates for at least 8 hours of the day to
prevent the development of tolerance/ twice or thrice daily
schedule
• Monday morning disease/sickness: seen in workers working
in explosive factories experience headache, flushing,
palpitations on joining duty on Monday morning due to
development of tolerance
• Dependence: sudden withdrawal after prolonged exposure
→coronary spasm & peripheral vasoconstriction → MI &
sudden death, so withdrawal should be gradual
THERAPEUTIC USES
1) Stable/Exertional angina:-
- Acute episode: S/L nitroglycerin(NTG/GTN) is the
drug of choice for acute anginal attacks, relieves
pain in 2-5 mins. If pain is not relieved→ dose may
be repeated upto 3 tablets in 15mins
Isosorbide dinitrate may be used though it is slower
acting than S/L NTG
- Prophylaxis: NTG can be used for acute/chronic
prophylaxis. Nitrates used orally for the prophylaxis
of angina. Longer acting nitrates preferred (patients
develop tolerance). NTG ointment applied over
chest to control angina at night. Transdermal patch
delivers NTG constantly for 24 hrs
2) Vasospastic angina: NTG relieves pain by relieving
coronary vasospasm
3) Unstable angina: IV NTG helps to relieve pain,
cardiac workload & causes vasodilatation, NTG
started in a dose of 5-10μg/min, gradually titrated
upto 20μg/min depending on the requirement.
Aspirin, Clopidogrel, Heparin are primary measures
4) Cardiac failure: NTG given S/L or IV helps pts. with
acute LVF by preload → cardiac workload.
Constant monitoring is required
5) Myocardial infarction: IV NTG is used to cardiac
workload, dose adjusted to avoid tachycardia &
hypotension
6) Cyanide poisoning: cyanide Haemoglobin
rapidly binds to cytochrome
nitrites
oxidase & other vital enzymes
→ inhibition of cellular Methemoglobin + cyanide
respiration, blocks O2
utilization→ immediate tt. Cyanmethaemoglobin
- Amylnitrite is given by reacts with
Inhalation & Sodium nitrite by IV Sodium thiosulphate
(10ml of 3% solution)
- Sodium thiosulphate IV is given Thiocyanate + Sodium
(50ml of 25% solution) sulphate
7) Oesophageal spasm: S/L NTG
taken just before meals Excreted by kidneys
8) Biliary colic: S/L NTG is given
CALCIUM CHANNEL BLOCKERS (CCB’s)
- CCB’s relax the arterioles → Calcium channel blockers
PVR & afterload
- DHP’s → reflex tachycardia Bind L type Ca+2 channels
- Verapamil & Diltiazem
myocardial contractility → Prevent entry of Ca+2 into cell
HR & FOC → cardiac
workload, O2 consumption
Arteriolar Myocardial
- CCB’s dilate coronaries →
Dilatation contractility
coronary blood flow
- used for the prophylaxis of
exertional angina, can be PVR HR, FOC
combined with β blockers
(except Verapamil) Myocardial workload
- useful in vasospastic angina
CCB’s in Ischemic Heart Disease:
a) Angina pectoris: In chronic stable angina, Verapamil &
Diltiazem are used for prophylaxis. They myocardial
O2 demand by a mild –ve inotropic effect & afterload.
They also inhibit exercise induced tachycardia & cause
coronary vasodilatation. Among DHPs, Amlodipine
may be combined with β blockers
b) Vasospastic angina: CCB’s are coronary vasodilators &
relieve pain → DOC in variant angina ( Verapamil &
Amlodipine commonly used)
c) Unstable angina: Verapamil may be used alongwith
other lines of treatment ( Antiplatelets, β blockers,
nitrates etc)
β BLOCKERS
• β blockers the frequency & β blockers
severity of attacks of angina
• β blockers prevent angina by Block cardiac β1 receptors
blocking increased HR, FOC, BP
due to exercise, emotion
FOC, HR, BP
• β blockers improve exercise
tolerance
• Used for long term prophylaxis Myocardial O2 demand
of classical angina, may be during exercise
combined with nitrates
• Also useful in unstable angina Cardioselective β1 blockers
• Dose should be tapered after preferred over nonselective
prolonged use β blockers
LEARNING OBJECTIVES

At the end of the class, the learner will be able to :-


• Write short notes on Potassium channel openers,
Dipyridamole,
• Explain the drug therapy & management of
myocardial infarction
• Write the pharmacological basis of the use of
various drug combinations in angina
POTASSIUM CHANNEL OPENERS
• Nicorandil, Pinacidil, Cromakalin Nicorandil
are potassium channel openers
• Nicorandil is an arterial & Opens ATP sensitive K+
venous dilator
channels
• In addition, acts through nitric
oxide (like nitrates)
• preload, afterload, causes hyperpolarization & relaxation
coronary vasodilatation of vascular smooth muscle
• Relaxes other smooth muscles
like the bronchi & uterus Preload, Afterload,
• Used in angina when other drugs coronary vasodilatation
do not afford significant benefit S/E: headache, flushing,
or as an alternative to nitrates palpitation, dizziness, painful
• More expensive than nitrates apthous ulcers, hypotension,
OTHER ANTIANGINAL DRUGS
• DIPYRIDAMOLE: coronary
vasodilator, coronary flow by
preventing uptake &
degradation of adenosine.
Dilates resistance vessels in
non ischaemic zone as well,
diverts blood from ischemic
zone, no effect on larger
conducting coronary vessels
→’coronary steal’
phenomenon, not beneficial
• It inhibits platelet aggregation
for which it is used in post MI
& post-stroke patients for
prevention of coronary &
cerebral thrombosis,
• 25-100mg TDS
• ASPIRIN: inhibits platelet aggregation → prevents MI in
patients with angina, long term administration of low
dose aspirin recommended to prevent MI
• TRIMETAZIDINE: Calcium channel blocker, having a
protective effect on the ischemic myocardium,
maintains left ventricular function → modulates
metabolism of myocardium
- pFOX (Partial inhibitor of Fatty acid OXidation)
inhibitor, inhibits the enzyme involved in fatty acid
oxidation pathway in the myocardium
- Also inhibits the superoxide induced cytotoxicity
- Protects the myocardium from ischemic damage
- Orally effective, well tolerated, used as add-on drug
along with other anti anginal drugs in the treatment of
angina pectoris
• IVABRADINE: blocks sino-atrial ‘f’ Na+ channels, funny
cation channels in early part of phase 4 depolarization
→ HR(direct bradycardia), may be used to HR as an
alternative to β blockers
• RANOLAZINE: recently introduced Trimetazidine
congener with a unique mechanism of action, inhibits
late sodium current( INa) in the myocardium which
indirectly facilitates Ca+2 entry.
- Prevents Ca+2 overload in the myocardium during
ischemia, O2 demand.
- Approved for prevention of angina as add-on therapy in
patients who do not respond to 1st line drugs
- orally effective, prolongs QT interval, should be avoided
with other drugs prolonging QT interval
PHARMACOTHERAPY OF ANGINA
• STABLE ANGINA: coronary angioplasty with insertion of
stent is the preferred treatment in presence of
significant coronary artery narrowing,
pharmacotherapy may be an alternative
- Acute attack: S/L nitroglycerin is the DOC, if the pain
does not subside in 5 minutes, repeat dose. Discard
tablet after relief of pain
- Acute prophylaxis: S/L nitroglycerin given 15 minutes
before exertion (walking uphill) can prevent the attack,
effect lasts for 30 mins
- Chronic prophylaxis: long acting nitrates / β blockers
(preferred) / CCB’s can be used. Given orally. If 1 drug is
not effective, a combination of drugs may be used
COMBINATION OF DRUGS IN ANGINA
• Nitrates + β blockers: reflex tachycardia due to nitrates
countered by β blockers, ventricular dilatation due to β
blockers opposed by nitrates, very effective in
exertional angina
• CCB’s + β blockers: anti anginal effects are additive.
Reflex tachycardia due to CCB’s countered by β blockers
• Nitrates + CCB’s: nitrates preload, CCB’s afterload,
combination cardiac workload
• CCB’s + Nitrates + β blockers: if angina is not controlled
by 2 drug combinations, 3 drugs can be used. Nitrates
preload, CCB’s afterload & coronary flow, β blockers
HR, combination useful in severe angina
• Verapamil & Diltiazem avoided in combinations
• VASOSPASTIC ANGINA: S/L nitroglycerin &
Nifedipine are effective in preventing & treating
vasospastic episodes
• UNSTABLE ANGINA: pts. are at a high risk of
developing MI/sudden death, need hospitalization
& rigorous tt. for it’s prevention. Drugs used are:-
- Aspirin: low dose (75-300mg daily) prevents
platelet aggregation, can prevent MI
- Heparin: in high risk pts. IV/SC heparin pain
- Nitrates: IV nitroglycerin cardiac workload,
relieves pain
- Others: β blockers, CCB’s, Abciximab, Eptifibatide,
Tirofiban
DRUGS USED IN MYOCARDIAL INFARCTION
• Coronary artery disease is the most important cause of
premature death due to rupture of an atheromatous
plaque in the coronary artery resulting in an occlusive
thrombus leading to acute MI
• Symptoms: severe substernal pain radiating to the left
shoulder, nausea, vomiting, sweating, palpitation
• Process of infarction gradually develops over 6-8hrs →
cell death in the infarcted area
• Coronary angioplasty with a stent inserted to recanalise
the coronary artery is the preferred option
• Immediate objective of treatment is to limit the
myocardial ischemia & consequent cell death
PATHOPHYSIOLOGY & SITES OF ACTION OF DRUGS
Myocardial ischaemia
Analgesics (Morphine/Pethidine)
cardiac pain

Anxiety & apprehension

Sympathetic stimulation β blockers


Antiarrhythmics
cardiac work
Vasodilators
Worsen myocardial ischaemia
Fibrinolytics, vasodilators,
Cell death oxygen
DRUGS USED IN MYOCARDIAL INFARCTION

β-blockers

Anti-
arrhythmics

Antiplatelet
drugs & Anti-
coagulants

Inotropics
Nitrates - Analgesics Thrombo- ACE inhibitors/ARB’s
preload lytics - afterload
DRUGS USED IN MYOCARDIAL INFARCTION
• Immediate treatment:
1) Analgesics & antianxiety drugs: pain in MI → anxiety &
apprehension → sympathetic over activity →
deleterious to the heart
- Morphine 10mg / Pethidine 50mg IV relieves pain →
reduce anxiety, sympathetic over activity
- Diazepam can also be given for sedation & to anxiety
2) Thrombolytics: can limit the extent of damage &
mortality, should be started at the earliest (6-12hrs)
- Streptokinase 1.5 million units infusion over 1 hr or
- Urokinase / Alteplase 15mg bolus & 0.5mg/kg over
the next 90 mins
- Anistreplase is long acting, can be used as a single IV
injection
3) Antiplatelet drugs: 300mg soluble Aspirin given
orally immediately at the onset of symptoms →
mortality & the effect of thrombolysis. Aspirin
should be continued for a long term (75-150mg/
day) even after the patient recovers from MI.
Pts allergic to Aspirin given oral Clopidogrel
4) Anticoagulants: Heparin may be given to prevent
extension of thrombus & to prevent DVT
5) Oxygen: high flow should be given by inhalation
6) Vasodilators: Nitroglycerin / Sodium nitroprusside
may be used as IV infusion to cardiac workload &
mortality.
7) Other drugs:
i. β-blockers: IV Atenolol 5-10mg over 5mins/
Metoprolol 5mg over 2 mins given at the earliest
unless C/I. Limit the infarct size, incidence of
arrhythmias, mortality. Later oral β-blockers
ii. ACE inhibitors/ ARB’s: should be started within
24hrs, prevent ventricular remodelling &
progression of heart failure, continued for long
periods
iii. Inotropic drugs: Dobutamine/Dopamine may be
given to pumping action of heart
iv. Antiemetics: Pheniramine 25mg IV
v. Furosemide: cardiac preload
vi. Antiarrhythmics: depending on arrhythmia
LONG TERM TREATMENT
Certain drugs are recommended for prevention of
further ischemic events:-
• Stool softener to avoid straining at stools
• Long term administration of low dose aspirin,
β-blocker, ACE inhibitor useful in reducing long term
mortality
RISK FACTOR MANAGEMENT
• Smoking should be stopped
• Hyperlipidemia should be controlled
• Reduction of body weight
• Regular moderate exercises
• Adequate control of diabetes & hypertension
TREATMENT OF PERIPHERAL VACULAR DISEASES

Peripheral vascular diseases (PVD) result from


blood supply to the lower limbs due to:-
• Organic occlusion (thrombus)- drugs not helpful
• Vasospasm ( thromboangitis obliterans, Raynaud’s
phenomenon, frost bite, vascular complications of
Diabetes mellitus)
Obstruction to the blood flow in the peripheral
circulation due to any cause can result in ischemia
of the area distal to it with it’s related
consequences
DRUGS USED IN PVD
• Vasodilators:
- CCB’s – Nifedipine
- Adrenergic blockers – Prazosin, Tolazoline
- β adrenergic agonists - Isosxuprine
• Anticoagulants & antiplatelet drugs: Heparin,
warfarin, Aspirin, Clopidogrel
• Other drugs: Hypolipidemics (Statins),
Pentoxiphylline, Naftidofuryl oxalate, Cilostazol,
Cyclandelate, Xanthinol nicotinate