Anti anginal agents

ADVANCED PHARMACOLOGY- I
PRESENTED BY:
L A X M A N N I M B A L E
M . P H A R M A
D E P T . O F P H A R M A C O L O G Y
ANTI-ISCHAEMIC DRUGS
1
Dept. of PHARMACOLOGY

CONTENTS
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 ISCHAEMIA
 ANGINA PECTORIS
 MYOCARDIAL INFARCTION
 ISCHAEMIC STROKE
 ANTI-ANGINAL DRUGS

ISCHAEMIA
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 An inadequate blood supply to an organ or part of the
body, especially the heart muscles.
 It comprises not only insufficiency of oxygen but also
reduced availability of nutrient substrate
 Reduction in blood flow due to atherosclerotic coronary
arterial obstruction
 It is generally caused by problems with blood vessels,
with resultant damage to or dysfunction of tissue

TYPES OF ISCHAEMIA
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 Cardiac Ischemia-
Reduces the heart muscle's ability to pump blood
 Mesenteric Ischemia-
Decreased blood flow can permanently damage the
small intestine.
 Brain Ischemia-
This leads to poor oxygen supply or cerebral hypoxia
and thus leads to the death of brain tissue
or cerebral infarction / ischemic stroke.

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 Acute Limb Ischemia-
A rapid decrease in lower limb blood flow
due to acute occlusion of peripheral artery or bypass
graft, and in ALI not only limbs but also life
prognosis will be poor unless quick and appropriate
treatment is given
 Cutaneous Ischemia:
Redued blood flow to the skin layers ay results in
mottling, patchy discoloration of the skin.

ANGINA PECTORIS
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 Insufficient supply of blood to heart muscle from narrowing of
coronary artery may cause angina.
 It is not a disease but symptom of ischemic heart disease.
 ATHEROSCLEROSIS:
Athero- paste Sclerosis- hardness
 Anoxia – improper supply of O2 to cardiac muscle
 Blocking of the blood vessels by thrombosis, atherosclerosis
 Spasm of blood vessels – contraction / atherosclerosis

STABLE ANGINA
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UNSTABLE ANGINA
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Also called as variant/
prinzmetal /
vasospastic angina

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CAUSES:
 Coronary artery disease
 Blood clot
 Coronary spasm
SYMPTOMS:
 Some people have silent ischaemia
 MI with sign and symptoms-
 Chest pain
 Neck or joint pain
 Shoulder or arm pain
 Nausea and vomiting

MYOCARDIAL INFARCTION
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 MI defined as a condition which is caused by reduced
blood flow in a coronary artery due to atherosclerosis
and occlusion of an artery by thrombus formation.

TYPES
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ISCHAEMIC STROKE
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 Ischemia occurs when part of the brain results in
death of brain cells movement, sensation or emotion
controlled by affected area are lost of impaired.

TYPES OF STROKE
15

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 Ischemic Stroke :
Obstruction within a blood vessel supplying
blood to the brain.
 Hemorrhagic Stroke:
When a weakened blood vessels ruptures.
 Transient Stroke:
Area of temporarily blocked blood flow

TREATMENT
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 Statin: Decrease the liver’s production of harmful
cholesterol Eg. Lovastatin, Atorvastatin
 β-blockers: Slows heart rate and decreases blood pressure.
Eg. Propranolol , Pindolol , Acebutalol
 Antianginal: Reduce chest pain or pressure caused by
blockages in the arteries of the heart. Eg. ISD, ISM, GTN
 CCBs: Relaxes blood vessels. Eg. Amlodipine, Verapamil
 Anticoagulant: Unwanted reactions from taking drugs that
inhibit blood clotting. Eg. Heparin , Hinadin

ANTI-ANGINAL DRUGS
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 Anti- anginal drugs are those that prevent, abort or
terminate attacks of angina pectoris .
OR
 Which dilates the blood vessels are known as
vasodilator and are used in the treatment of angina
pectoris , hypertension and arrhythmia.

CLASSIFICATION
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ANTIANGINAL DRUGS
NITRATES CA++ CHANNEL
BLOCKERS
β- BLOCKERS POT. CHANNEL
OPENER
OTHER
ANTIANGINAL
DRUGS
Short acting Long acting
-Glyceryl
trinitrate
-Isosorbide
dinitrate
(sublingual)
-ISD (oral)
-ISM
-Erythrityl
tetranitrate
Propranolol
Metoprolol
Atenolol
(etc.)
Verapamil
Diltiazem
Amlodipine
(etc.)
Nicorandil
Trimetazidine
Ranolazine
Ivabradine
Dipyridamole

MOA OF ANTI-ANGINAL AGENTS
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β- blockers – To reduce heart rate
Nitrates – To reduce preload
β- blockers + CCB – To reduce contractility
Nitrate + CCB – Dilate coronary arteries
CCB – To reduce after load

NITRATES
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 Organic nitrates are rapidly de-nitrated enzymatically in
the smooth muscle cell to release the reactive free radical
NO (nitric oxide) which activates cytosolic soluble
guanylyl cyclase increased cGMP causes de-
phosphorylation of MLCK (myosin light chain kinase)
through a cGMP dependent protein kinase.
 Reduced availability of phosphorylated (active) MLCK
interferes with activation of myosin it fails to
interact with actin to cause contraction. Consequently
relaxation occurs raised intracellular cGMP may also
reduce Ca++ entry contributing to relaxation.

PHARMACOLOGIACAL ACTIONS
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 Nitroglycerin is the prototype drug. Nitrates have
no direct action on the heart.
 VASCULAR SMOOTH MUSCLE:
Nitroglycerin quickly relieves anginal pain by
decreasing the O2 requirement and increasing O2
delivery to the myocardium.
 ACUTE ANGINA: Nitroglycerin is commonly
administered sublingually with an initial dose of 0.5
mg that usually relieves pain in 2-3 minutes.

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 Prophylaxis of Angina: Oral nitrates are used for
long term prophylaxis of angina pectoris. Eg.
Isosorbide mononitrate, isosorbide dinitrate,
nitroglycerin.
 Variant Angina: It is due to coronary vasospasm.
These are treated with nitrates; for prophylaxis,
nitrates and CCBs ( amlodipine, nifedipine SR and
diltiazem) are effective. Addition of CCBs with
nitrates produce better efficacy in variant angina.

Nitrates Used In The Treatment Of Angina
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Drug Dosage Routes Duration of
action
Glyceryl tri-nitrate
(nitroglycerin)
0.5 mg
0.4 mg
5-10 mg
5-15 mg
Sublingual
Lingual spray
Transdermal patch
Oral
10-30 mins
10-30 mins
Upto 24 hours
(TDP should be
removed for few
hours each day to
avoid development
of tolerance )
Isosorbide
dinitrate
2.5 mg
5-40 mg
Sublingual
Oral
20-60 mins
6-8 hours
Isosorbide
mononitrate
20-40 mg Oral 6-10 hours

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 MI: Intravenous infusion of nitroglycerin is useful
for persistent or ischemic pain.
 Biliary colic : Sublingual nitroglycerin can be used to
relieve biliary spasm and associated spasm.
ADVERSE EFFECT:
Hypotension
Flushing
Constipation
Throbbing headache

Ca++ Channel Blockers
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 These are the drugs that protect tissue by inhibiting
the entry of calcium ions into cardiac and smooth
muscle cells of coronary and systemic arterial bed.
Ca++ Channel Blockers
Phenylalkylamine Benzothiazepine Dihydropyridines
-Verapamil -Diltiazem -Nifedipine
-Amlodipine
-Nimodipine
-Felodipine
-Benidipine

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 Three types of Ca++ channels have been described in
smooth muscles as they;
a) Voltage sensitive channels
b) Receptor operated channels
c) Leak channel or Stretch sensitive channel.
Voltage sensitive channels are 3 types as they;
L-type
T-type
N-type

MOA OF CCBs
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CCBs block voltage sensitive L-type Ca++ channels
by binding to α1- subunit
Prevent entry of Ca++ into the cell
No excitation- contraction coupling in
the heart and vascular smooth muscle

PHARMACOLOGICAL ACTIONS
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 Produce vasodilation in heart muscle Eg. verapamil
(inj. 2.5mg/mL, tab. 40/80/120mg every 8 hrs, caps.
100/120/180/200mg), diltiazem
 Relax vascular smooth muscle Eg. Dihydropyridines
(caps. 2.5/5mg tab. 5/10mg every 12hrs.)
 Extarcellular smooth muscle like bronchial, biliary,
intestinal, vescal and uterine is also relaxed.

ADVERSE EFFECT
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 Swelling of legs
 Excess lowering of heart rate and blood pressure
 Depressing heart muscle.

β-BLOCKERS
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 These are drugs that the inhibit adrenergic responses
mediated through the β- receptors
 All β- blockers are competitive antagonists,
propranolol blocks β1 & β2 receptors but has weak
activity on β3 subtype.

MOA
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 β- blockers decreases the heart rate, force of
contraction and cardiac output
 Cardiac work and O2 consumption are reduced as
the product of heart rate and aortic pressure
decreases.
 Central action reducing sympathetic outflow

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β- blockers β- receptor of heart
Heart rate and force of
myocardial contraction
Cardiac work
Myocardial O2
consumption
(Propranolol
Metoprolol
Atenolol
Timolol)
blocks

PHARMACOKINETICS
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 PROPRANOLOL: Well absorbed after oral
administration but has low bioavailability due to high
first pass metabolism in liver. 10-30 mg taken 3-4
times/day before meals and at bedtime.
 It is lipophilic and penetrates into brain easily.
 Metabolism is dependent on hepatic blood flow
 Excreted in urine, mostly as glucouronides. More than
90% of propranolol is bound to plasma protein

ADVERSE EFFECT
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 Bradycardia- slow heart rate
 Peripheral vascular disease- atherosclerosis (is a sign of
fatty deposite & calcium building up in the walls of the
arteries.
 Bronchospasm- airway go into spasm and contract
 Cardiac failure- in which the heart does not pump blood as
well as it should.
 Arrhythmias- Improper breathing of the heart whether
irregular/ too fast/ too slow.

CONTRAINDICATION
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 Asthmatics: Propranolol worsens (make/worse)
chronic obstructive lung disease (COLD), can
precipitate life threatening attack of bronchial
asthma.
 Variant angina: Occurs due to coronary
vasospasm (coronary artery has α1 and β2
adrenergic receptor ).
 β–blockers can be counteracted by combining
them with nitrates

K+ CHANNEL OPENER
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 K+ channels are membrane proteins that allows
rapid and selective flow of K+ ions across the cell
membrane and thus generate the electrical signals in
cells.

MOA OF K+ CHANNEL OPENER
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 Eg. Nicorandil
- well absorbed orally
- metabolized in liver
- excreted in urine
- t ½ is 1 hour in initial phase and later slow phase
t1/2 is 12 hours.

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 SIDE EFFECTS:
- Flushing
- Palpitation
- Weakness
- Headache
- Nausea and vomiting

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 Uses:
- Ischemic heart disease, angina and MI
- Hypertension
- Peripheral vascular disease

Anti anginal agents

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