Antianginal drugs.pptx

Treatment of ischemic heart disease (antianginal drugs)
DR AWAIS IRSHAD

Learning Objective
1. Define Angina pectoris, its type and causes
2. Explain mechanism of action of Nitrates, calcium channel blockers and
Beta Blockers?
3. Describe the clinical uses and adverse effects of anti Anginal drugs
4. Explain why the combination of a nitrate with a beta blocker or a calcium
blocker may be more effective than either alone

A clinical syndrome of chest pain (varying in
severity) due to ischemia of heart muscle
What is angina pectoris?
Pain is caused either by obstruction
Or spasm
Pain is due to (accumulation of metabolites
K+, PGs, Kinins, Adenosine….) secondary to
the ischemia

What is Basic mechanism of angia pectoris?
What are the determinants of oxygen demand and supply?

Myocardial oxygen demand is determined
by:-
Myocardial oxygen demand is diminished
by:-
Reducing contractility
Reducing heart rate
Reducing the preload
Reducing the afterload

Myocardial oxygen supply is determined
by:-
Myocardial oxygen supply is enhanced
by:-
Reducing coronary vascular
resistance
Prolonging diastolic period
Reducing external compression
Dilating collateral vessels
Optimizing hemoglobin & RBCs

Treatment of angia pectors
1-Agents that improve symptoms & ischemia

Treatment of angia pectors
2-Agents that improve prognosis
Aspirin / Other antiplatelets
-AD blockers
ACE Inhibitors
Statins

Mechanism of action
Nitric oxide binds to guanylate cyclase in
vascular smooth muscle cell to form cGMP.
cGMP activates PKG to produce relaxation
Organic nitrates
Short acting Nitroglycerin
Long acting Isosorbide mononitate

Ref: Basic and clinical pharmacology 14th ed pp 197 BG Katzung

Ref: Pharmacology Examination and Board Review 12th ed pp 107 Katzung & Trevor’s

Hemodynamic effects of nitrates
Venous vasodilatation
Preload
Coronary vasodilatation
Arterial vasodilatation
Myocardial perfusion
Afterload
Shunting of flow from normal area to ischemic
area by dilating collateral vessels With
Nitrates

pharmacokinetics
Significant first pass metabolism occurs in
the liver (10-20%) bioavailability
Given sublingual or via transdermal patch, or parenteral
Nitroglycerin [GTN]
Oral isosorbide dinitrate & mononitrate
Very well absorbed . Mononitrate, 100% bioavailability
The dinitrate undergoes denitration to two
mononitrates both possess antianginal activity
(t1/2 1-3 hours)
Further denitrated metabolites conjugate to glucuronic acid
in liver. Excreted in urine.

Indications
IN STABLE ANGINA;
Acute symptom relief  sublingual GTN
IN VARIANT ANGINA sublingual GTN
CHF  Isosorbide mononitrate + hydralazine
[ if contraindication to ACE Is]
AMI IV GTN
IN UNSTABLE ANGINA  IV GTN
Refractory AHF  IV GTN
Prevention; Persistant prophylaxis  Isosorbide mono or dinitrate
Prevention; Situational prophylaxis  sublingual GTN
Heart Failure

contraindications
Known sensitivity to organic nitrates
Glaucoma; nitrates  aqueous humour formation
Head trauma or cerebral haemorrhage , Increase intracranial pressure.
Uncorrected hypovolemia
Concomitant administration of PDE5 Inhibitors
Sildenafil + nitrates Severe hypotension & death

Adverse drug reactions
Flushing in blush area
Throbing headache
Tachycardia & palpitation
Postural hypotension, dizziness & syncope
Rarely methemoglobinema

Preparations
Oral or bucal sustained release
I.V. Preparations
Nitroglycerin
Sublingual tablets or spray
Transdermal patch

Preparations
Isosorbide dinitrate
Dinitrate Sublingual tablets
Dinitrate Oral sustained release
Infusion Preparations
Mononitrate Oral sustained release

Nitrates tolerance
Mechanism
Loss of vasodilator response of nitrates on use of long-
acting preparations (oral, transdermal) or continuous
intravenous infusions, for more than a few hours without
interruption.
1-Compensatory neurohormonal counter-regulation
2-Depletion of free-SH groups

Nitrate tolerance can be overcome by:
Smaller doses at increasing intervals (Nitrate free
periods twice a day).
Giving drugs that maintain tissue SH group e.g.
Captopril.

Calcium channel blockers
Benzthiazepines:-
Verapamil
Phenylalkylamines:-
Nifedipine, Nicardipine, Amlodepine
Dihydropyridines:
-
Diltiazem
2-Selectivity
Nifedipine ,
Verapamil
Diltiazem
Vascular smoothmuscle
Cardiomyocytes
Intermediate
Classification 1-Chemecal
structure

Mechanism of Action
entry of Ca   Ca release from internal stores 
No Stimulus-Contraction Coupling  RELAXATION
Binding of calcium channel blockers [CCBs] to the L-type
Ca channels  their frequency of opening
in response to depolarization

Antianginal Action
 Cardiomyocyte Contraction  cardiac work through
their –ve inotropic & chronotropic action (verapamil &
diltiazem)  myocardial oxygen demand
VSMC Contraction   After load  cardiac work 
myocardial oxygen demand
Coronary dilatation  myocardial oxygen supply

Therapeutic Uses
IN VARIANT ANGINA
 Attacks prevented (> 60%) /
sometimes variably aborted
Seldom added in refractory cases
IN UNSTABLE ANGINA;
IN STABLE ANGINA; Regular prophylaxis
Short acting dihydropyridine should be avoided ??
Can be combined to -AR blockers???
Can be combined with nitrates???
Dihydropyridenes useful antianginal if with CHF??

Beta Adrenoceptor Blockers
Examples Atenolol, Bisoprolol, Metoprolol (1 –
Selective )
Antianginal Mechanism

Indications in angina
In stable angina
First choice for chronic use?
Regular prophylaxis, selective are prefered?
Can be combined with nitrates?
Can be combined with dihydropyridine
CCB?
In variant angina
Contraindicated?
Verapamil
?

Indications in angina
In Unstable angina
→reduce O2 demand
Halts progression to MI, improve survival
Reduce infarct size
Reduce morbidity & mortality
In Myocardial infarction
→reduce arrhythmias

- blockers should be withdrawn gradually?
Given to diabetics with ischemic heart disease?

Potassium channel openners
Mechanism
Nicorandil
It has dual mechanism of
action;
1. Opens KATP channels (>
arteriolar dilator)
2. NO donner as it has a
nitrate moiety (> venular
dilator
L

Pharmacodynamic Effects
As K channel openner
On vascular smooth muscles opening of K channels
hyperpolarization  vasodilatation
On cardiomyocytes opening of K channels repolarization
 cardiac work
As nitric oxide donor
NO  cGMP/PKG  vasoditation

Indications
Prophylactic 2nd line therapy in stable angina & refractory
variant angina
ADRs
Flushing, headache,
Hypotension, palpitation, weakness
Mouth & peri-anal ulcers, nausea and vomiting.

Ranolazine And Trimetazidine.
A new strategy to attempts to increase the efficiency of
oxygen utilization by shifting the energy substrate
preference of the heart from fatty acids to glucose.
Drugs that may act by this mechanism are termed partial
fatty acid oxidation inhibitors (pFOX inhibitors).

Ranolazine
Act mainly by reducing a late, prolonged sodium current in
myocardial cells. The decrease in intracellular sodium causes
an increase in calcium expulsion via the Na/Ca transporter and
a reduction in cardiac force and work.
As noted previously, it may also alter cardiac metabolism.
Ranolazine is moderately effective in angina prophylaxis.

Ivabradine
Ivabradine reduces slope of depolarization, slowing
HR,reducing myocardila work & O2 demand
If current is an inward Na+/K+ current that
activates pacemaker cells of the SA node
Ivabradine Selectively blocks If
Used in treatment of chronic stable angina in
patients with normal sinus rhythm who cannot
take ß-blockers
ADR:- luminous phenomena

NON PHARMACOLOGIC THERAPY
Myocardial revascularization by coronary artery bypass grafting
(CABG) and percutaneous transluminal coronary angioplasty
(PTCA) are extremely important in the treatment of severe
angina. These are the only methods capable of consistently
increasing coronary flow in atherosclerotic angina.

References:
1. Katzung & Trevor’s pharmacology
Examination & Board Review, 12th ed pp 103-111
2. Basic and Clinical Pharmacology Katzung 14th ed pp 194-211
3. Lippincott illustrate reviews pharmacology 7th ed

Antianginal drugs.pptx

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