Anti-Anginal

drugs
Angina pectoris
• Acute chest pain that
occurs when
myocardial oxygen
supply is less than
the demand.
 IHD– progressive insufficiency of coronary circulation

Acute – unstable angina pectoris

acute myocardial infarction

Chronic – asymptomatic IHD

angina pectoris - after excercise
- variant
- Prinzmetal´s
state after MI
chronic heart failure

Not every ischaemia is accompanied with pain

–
silent ischaemia (only at ECG – depression of
 Differences between Angina pectoris and myocardial infarction

Angina pectoris
Pain due to reduction in the blood
supply of cardiac muscle fibers
because of narrowing of the coronary
artery by atherosclerosis. This is a
reversible process and there is no
permanent damage to the muscle.
Myocardial infarction
Ischemic necrosis due to total
occlusion of coronary artery by a
thrombus complicating atheromatous
lesion. The changes in muscle are
irreversible.
• Angina pectoris is a characteristic
sudden severe pressing chest pain
or heaviness radiating to the neck,
jaw, back and arms.
• It is often associated with
tachypnea and nausea.
• The discomfort abates when supply
becomes adequate for demand.
• Typically angina lasts for seconds to
minutes, up to 15 minutes.
• Classically angina is not associated
with ischemic cell death, anginal
symptoms lasting longer than 60
minutes indicates myocardial death.
What is Angina & Why Does it Happen?

• Oxygen demand depends on heart work

• Coronary artery partial obstruction (due to
atherosclerosis) limits blood supply to part of the
myocardium
• Coronary circulation can meet oxygen demands of
myocardium at rest, but not when heart work
increased by exercise, etc.
• Ischaemia (O2 deficiency) causes pain:
“angina”
• Triggers: emotional stress, extreme temperatures,
heavy meals, alchohol, strenuous exercise,
cigarette smoking
 Types of Angina

 Atherosclerotic angina
(also called classic or effort angina)
↑ O2 demand - fixed supply

 Vasospastic angina
(also called Prinzmetal’s or variant angina)
↓ O2 supply - unchanged demand
- ie. at rest, coronary spasm (PGs?)

 Unstable angina
(also called preinfarction or crescendo angina)
• People with stable angina have episodes of chest
discomfort that are usually predictable, such as
on exertion or under stress (Treatment: Nitrates,
β-blockers).
frequency, intensity and duration

• Variant angina is also called Prinzmetal's angina.

Unlike typical angina, it nearly always occurs
when a person is at rest, and does not follow
physical exertion or emotional stress. Variant
angina is due to coronary artery spasm
(Treatment: Nitrates, Ca++ channel blockers).
vasospasm, elevation of ST segment on ECG

• In people with unstable angina, the chest pain is

unexpected and usually occurs while at rest. The
discomfort may be more severe and prolonged
than typical angina (Treatment: Nitrates).
sudden beginning, longer duration of pain
 Drug Treatment of Angina:
Limiting Heart Work
 (1)Decease myocardial oxygen consumption
 (2)Increase myocardial blood and oxygen supply
 (3)antiplatelet 、 antithrombosis
• Reduce heart rate and contractility
–  adrenoceptor blockers
– Ca2+ channel blockers (verapamil and diltiazem)
• Dilate resistance vessels
– Ca2+ channel blockers (nifedipine, felodipine, amlodipine)
– Nitrates
Anti anginal drugs
Antianginal drugs relieve cardiac ischemia
but do not alter coronary artery pathology
 NITRATES
Short acting : Sublingual : GTN (nitroglycerine),
Isosorbide dinitrate
Long acting : Oral : Isosorbide dinitrate, Isosorbide
mononitrate , Nitroglycerine, Erythrityl tetranitrate,
pentaerythritol tetranitrate
 BETA BLOCKERS
 CALCIUM CHANNEL BLOCKERS
 POTASSIUM CHANNEL OPENERS- nicorandil ,
pinacidil, minoxidil, cromakalim, diazoxide
 OTHERS : Trimetazidine, ranolazine, Dipyridamole
 Nitrates
• It was known from the time of its discovery in 1847 that
the tasting or close handling of nitroglycerin could cause
sudden intense headaches, which indicated some form
of vasodilation effect. “Nitrate handlers headache”,
severe on Monday but not so bad by Friday.
• he noted two curious syndromes among his workers,
who came in contact with the dynamite factory's
nitroglycerin.
– First, on Monday mornings, these laborers often complained
of pounding headaches, which disappeared over the
weekends.
– Second, workers who suffered from angina pectoris - heart
failure - often experienced relief from the anginal chest pains
during the work week - but they recurred on weekends
• Following discoveries that amyl nitrite helped to alleviate
chest pain, Doctor William Murrell experimented with the
use of nitrogylcerin to alleviate angina pectoris and reduce
blood pressure.
• Alfred Nobel in 1851
recognized the potential
of NG. He began
manufacturing NG in
Sweden, overcoming
handling problems with
his patented mixture of
NG & diatomaceous earth
(dynamite). Nobel
suffered acutely from
angina and was later to
refuse NG as a treatment.
Nobel named the new product dynamite ( from Greek dynamis, "power")
The merchant of death
Nobel himself, however, remains a figure of paradoxes and contradictions: a brilliant
man, who invented the powerful explosives used in modern warfare but also
established the world's most prestigious prizes for intellectual services rendered to
humanity.
Mechanism of Action of Nitrovasodilators
Nitrates become denitrated by glutathione S-transferase
to release

Nitric Oxide
activates

Guanylate Cyclase*

converts

GTP
cGMP
activates

cGMP-dependent protein kinase

Activation of PKG results in phosphorylation

of several proteins that reduce intracellular calcium
causing smooth muscle relaxation
 Anti anginal drugs

Requires normal vascular

endothelium
• It was originally believed that nitrates and nitrites
dilated coronary blood vessels, thereby
increasing blood flow to the heart.

• It is now believed that atherosclerosis limits

coronary dilation and that the benefits of nitrates
and nitrites are due to dilation of arterioles and
veins in the periphery.

• The resultant reduction in preload, and to a

lesser extent in afterload, decreases the
workload of the heart and lowers myocardial
oxygen demand.
 Pharmacological action
 (1) decrease myocardiac oxygen consumption
dilate venous------ decrease blood returning to heart --------- decrease
ventricular end-diastolic volume and pressure (veins more generation NO)

(large dose) dilate arterial --------decrease peripheral resistance

-------decrease afterload
reflex symp activity- tachycardia, increased contractility,
 (2) increase blood supply to ischemia area (vasodilation of
epicardial vessels, improved subendocardial perfusion)
 (3) redistribution of coronary blood flow –
dilatation of epicardial vessels, dilatation of collaterals, improved perfusion
of ischemic subendocardial region
 (4) flushing, headache, decongest lungs,
 (5)Inhibit platelet aggregation, increase the
release of PGI2
 (6) Bronchi, biliary tract, esophagus relaxed
 Antianginal Agents: Nitrates
Available forms:
Sublingual Ointments
Buccal Transdermal patches
Chewable tablets Inhalable sprays
Capsules Intravenous solutions
To apply nitroglycerin ointment,
 use the special paper to measure the dose.
 Place the ointment on a nonhairy part of
the body, and apply with the applicator paper.
 Cover the area with plastic wrap or tape.
 Rotate application sites and
 wipe off previous ointment before applying
a new dose.
 Nitrates
Formulations
• Sublingual, buccal GTN for immediate relief of
angina

• Nitrate ointments and patches for transdermal

delivery but patch must be removed at night to
avoid tolerance

• Intravenous GTN used in the setting of unstable

angina or acute MI

• ISDN and ISMN are available as oral tablets

 Pharmacokinetics:
The difference between nitrate
preparations is mainly in time of
onset of action.
1. Nitroglycerin suffers marked 1st
pass metabolism so administration
is sublingual
(rapid absorption and onset (<1 minute),
t1/2 ~10 min. Occasionally as nitroglycerin
is metabolized anginal symptoms will
return.
Transdermal administration either
as patch or paste provides a depot
of agent for a steady availability.
2. Isosorbide mononitrate &
isosorbide dinitrate are long acting
nitrates that are relatively resistant
to hepatic catabolism t1/2 ~ 1 hour.
3. Lipid soluble, rate of absorption &
rate of metabolism
 Nitrates :Side Effects
• throbbing headache
Usually diminish in intensity and frequency
with continued use.
lack of headache often indicates degradation of agent with a loss of therapeutic effect.

• Flushing, weakness, sweating, palpitation,

fainting---------lying, standing
• Tachycardia, postural hypotension & syncope
particularly with sublingual use
• Methemoglobinemia, occur with chronic use of
long term agents
• rash
• Tolerance may develop-to hemodynamic, antiischemic
effect, drug free interval, higher doses-more
• Dependance- gradual withdrawl
 Tolerance
• Tolerance to the actions of nitrates develops rapidly for their
vasodilatory effects.
• blood vessels become desensitized to vasodilation
• Sustained treatment with nitroglycerin in vivo is associated with
reduced biotransformation of nitrate to NO by endothelial
mitochondrial enzyme aldehyde dehydrogenase-2 ,
• daily “nitrate-free interval” - Avoid continuous exposure
to nitrates
• typically 10 to 12 hours, usually at night, because demand on the
heart is decreased at that time
• variant angina worsens early in the morning, perhaps due to
circadian catecholamine surges
• Avoidance of nitrate tolerance
Use smallest effective dose
Administer the fewest possible doses per day
Avoid continuous exposure to nitrates
Provide a nitrate-free interval of > 10 hrs/day
 Nitrates : USES:
• Angina – 3 min 75%
• CCF and LVF
• Myocardial infarction
• Biliary colic
• Esophageal spasm
• Cyanide poisoning
Nitrates in CCF
• Types
• Pathology
• Drugs
• Nitrrate-
» MOA
» Pharmacological actions
» Uses
» Side effects
– Tolerance
– Dependance
» dose
 b-Adrenergic Blockers in
the Treatment of Angina
 Though most beta-blockers do not cause coronary
vasodilation like the nitrovasodilators or calcium channel
blockers, beta-blockers are important in the treatment of
angina because of their effects on the heart
 Desired effects of beta-blockers
– Reduce myocardial oxygen consumption by reducing contractility
and heart rate
 Reducing cardiac output also reduces afterload
 Some b-blockers can cause vasodilation directly
– Improve myocardial perfusion by slowing heart rate (more time
spent in diastole)
 β-adrenoceptor blocking drugs
1. decrease myocardial oxygen consumpation block β-
adrenoceptor inhibit myocardial contractility and
heart rate & mean BP
(1) improve blood and oxygen supply to ischamia area
(subendocardial area)
(2) lower heart rate, prolong diastolic perfusion time,
increase endocardium flow
(3) gradual reduction of tpr i.e. mean BP, CO
(4) RS, Metabolism, muscles, local anaesthetic

Favourable
redistribution
Inotropic
HR Mean of coronary
state
BP blood flow
 Antianginal Agents: Beta Blockers
 Decrease the HR, resulting in decreased myocardial
oxygen demand & increased oxygen delivery to
heart
 Decrease myocardial contractility, helping to
conserve energy or decrease demand
 More reduction of BP & HR during exercise, anxiety
 Do not dilate coronaries
 Propranolol is the prototype: not cardioselective
 metoprolol or atenolol, are preferred
 All β-blockers are nonselective at high doses and
can inhibit β2 receptors.
 Important in asthmatics
 May worsen variant angina
contraindication
 Asthma
 Diabetes
 severe bradycardia
 peripheral vascular disease
 chronic obstructive pulmonary disease.
 Partial or complete heart block

 Do not discontinue β-blocker therapy abruptly.

 The dose should be gradually tapered off over 5 to
10 days to avoid rebound angina or hypertension.
 To be taken on regular basis. & not SOS
Side effects

 Bradycardia
 Worsening of COPD
 Exacerbate Variant angina
 Impaired GTT
 Hyperlipidemia
 Nightmares, forgetfulness
 Ca Channel Blockers
2+

• Cardioselective • Vascular selective

– verapamil – dihydropyridines
• Nifedipine
• amlodipine
• Non-selective • nimodepine
– diltiazem • Nitredepine
• Felodipine
• lacidepine

voltage-gated channels have been divided into three

subtypes, L, N, and T, based upon their conductances
and voltage sensitivities
NB: only the L-type is sensitive to listed calcium
channel blockers
 Drugs acting on Calcium
Channels
Calcium Channel Blockers

L-type Ca channel N-type Ca channel T-type Ca channel

blocker (long blocker (neuronal) blocker (transient
lasting current) • Gabapentin current)
• Verapamil • Pimozid
• Diltiazem • Mibefradil
• Nifedipine • ethosuximide
• Phenytoin
 Ca2+ Channel Blockers
• Myocardial selective:
– Reduce cardiac contractility
– Negative inotropic, chronotropic
– Also reduce heart rate (action on heart rhythm)
–  BP,  heart work
• Vascular smooth muscle selective
– Reduce vascular resistance, arteriole more
–  BP,  heart work
– Also relaxes extravascular smooth muscle
– DHP
– nifedepine > verapamil > diltiazem
 calcium antagonists
 mechanism of antiangina
 (1) dilate coronary arterial
 (2) reduction in peripheral vascular resistance
afterload
 (3) negative chronotropic and inotropic,
decrease myocardiac oxygen consumpation
 (4) antiatherosclrosis
 Nifedipine
 a dihydropyridine derivative: CCB
 works mainly on the arteriolar vasculature decreasing afterload
(arteriolar vasodilator)
 it has minimal effect of conduction or HR.
 No effect on conduction -SAnode, AV conduction
 Reflex tachycardia
A reflex tachycardia associated with the vasodilation may elicit
myocardial ischemia in tenuous patients, as such it is generally
avoided in non-hypertensive coronary artery disease.
 Oral : Usually: extended-release tablets.
 Hepatic metabolism
 Eliminate in both urine and the feces
 S/E- palpitation, flushing, hypotension, ankle oedema,
headache, drowsiness
 has some slowing effect on the GI musculature - constipation.
 Can be given with B blockers
 Felodepine- greater vascular
selectivity, long half life
 Amlodepine- complete & slow oral
absorption, long half life
 Nitrndepine- release NO, retard
atherosclerosis
 Lacidepine- high vasoselectivity
 Nimodepine- penetrate BBB,
cerebroselective
 Verapamil
 Slows AV conduction
 The agents has its main effect on cardiac conduction
decreasing HR & thereby O2 demand.
 It also has much more (-) inotropic effect than other
Ca+2 channel blockers. It is a weak vasodilator.
Because of its focused myocardial effects it is not used as an antianginal
unless there is a tachyarrhythmia.
 contraindicated in patients with preexisting depressed
cardiac function or AV conduction abnormalities
 s/e- nausea,constipetion, bradycardia, flushing,
headache,ankle oedema, hypotension, AV block
 It interferes with digoxin levels causing elevated plasma
levels; caution and monitoring of drug levels are necessary
wit concomitant use.
Diltiazem
 slow AV conduction
 decrease the rate of firing of the
sinus node pacemaker
 It has less effect on HR.
 metabolized by the liver
 It has similar metabolism and side
effects as Verapamil.
Side Effects
 Flushing
 Headache due to vasodilation
 dizziness
 Hypotension
 peripheral edema
 all calcium-channel blockers are with
constipation is a problem
 Gingival hypertrophy
 Tachycardia with depins
 Bradycardia with verapamil, diltiazem
Uses

 Angina
 HT
 Arrythmia-PSVT
 HOCM
 Premature lebour, migraine,
nocturnal leg cramp, raynaud’s
disease, malaria
 Drugs acting on potassium
Channels
Potassium Channel Openers

Vascular relaxation Promotes hair Lower Blood

growth pressure
• Minoxidil

Dizoxide, nicorandil, pinacidil, cromakalim,

• K channel opening – Hyperpolarization
- relaxation of vascular smooth muscle
• Nicorandil- NO donor
• s/e- palpitation, flushing, headache, dizziness,
painful apthous ulcers
• Uses-
• Angiana, Ht, CHF, MI, alopecia, PVD, premature
labour, erectile dysfunction
NICORANDIL
 Dual anti anginal action
- Nitrate like action
- Potassium channel opening
 Does not have any adverse haemodynamic effects
- On heart rate
- Conduction of cardiac impulse
- Myocardial contractility
 Achieves Cardio protection by Ischemic preconditioning
 Useful in recovery of myocardial stunning
 Useful for no-Reflow during PTCA
 No nitrate tolerance
 Nicorandil : mode of action

• Nicorandil dual action

• Nitrate-like action • K+ channel opener ATP

• Dilates epicardial• Venodilatation • Dilates • Dilates

• Coronary arteries peripheral coronary
• arterioles • Resistance
• Decreased • Decreased vessels
• Preload • afterload

• ↑ coronary • ↓ Myocardial O2 • ↓ Myocardial O2 • ↑ coronary

• blood flow • requirement • requirement • blood flow
Trimetazidine, Ranolazine
• Metabolic modulator.
• Has no haemodynamic effects
• Influence metabolism of cardiomyocytes & improves
cellular tolerance to ischemia
• Inhibit LC3-KAT enzyme of Fatty acid oxidation .
• Increases glucose metabolism
• pFOX inhibitor
• Recommended only as add on drugs

Dipyridamole
•Prevent uptake & degradation of adenosine
•No effect on larger conducting coronay vessels
•Coronary steal phenomenon
 In Aerobic Condition

Glucose (10-40%) Fatty Acid (60-90%)

Pyruvate Palmitate

Palm-Co A
Pyruvate
Acetyl Co A
Acetyl Co A
TCA Cycle
TCA Cycle

ATP ATP Mitochondria

Mitochondria
Myocytes Myocytes
 In Ischemic Conditions

Glucose Fatty Acid

Pyruvate Glycogen Palmitate

ADP ATP

LactateH+ Palm-Co A
Pyruvate
Acetyl Co A
Acetyl Co A
TCA Cycle TCA Cycle

ATP Mitochondria ATP Mitochondria

Myocytes Myocytes

Fatty acid oxidation out-competes glucose oxidation for the energy production
If channel inhibitor
• New anti-anginal - Ivabradine
• Blocks If (ionic funny channel) – an mixed
Na-K inward current activated by
hyperpolarization and autonomic nervous
system - lowers pacemaker activity in the
SA-node
• Slows heart rate – different mechanism from
beta-blockers
• Adverse effects: Luminous phenomena
(retinal Ih channels similar to If channels) –
self-limiting
• Indications: Angina
Type of Other Names Description Drug Therapy
Angina
STABLE Classic Obstruction Nitrates
Exertional / effort coronary artery CCB
Fixed B-blockers
Atherosclerotic

VARIANT Prinzmetal’s Vasospasm at Nitrates

Vasospastic any time CCB
No beta blocker
UNSTABLE Crescendo Combined effect Nitrates
preinfarction Pre= MI CCB
Thank You
Questions?
 Angina Drugs
• Organic nitrates
– Nitroglycerin
• Nitrate converted to nitric oxide
• Calcium Channel Blockers
– Diltiazem, Nifedipine
• Β-Blockers
– Propranolol Ca++
Nifedipine

cGMP Propranolol
Nitrate NO

Pi

Myosin Light Chain