Anti anginal drugs
Dr.V.V.Gouripur
Ischaemic Heart Disease,
• ALSO known as Coronary Artery Disease
• Angina pectoris
• Myocardial infarction
(Acute coronary syndrome)
Ischaemic Heart Disease,
• A condition that affects the supply of blood to the
heart.
• The blood vessels are narrowed or blocked due
to the deposition of cholesterol plaques on their
walls.
• This reduces the supply of oxygen and nutrients
to the heart musculature, which is essential for
proper functioning of the heart.
• This may eventually result in a portion of the
heart being suddenly deprived of its blood
supply leading to the death of that area of heart
tissue, resulting in a heart attack
Etiology
• Ischemia is secondary to coronary artery
disease in 95% of patients.
• A decreased oxygen supply from anemia,
hypotension, vasospasm, or arrhythmias or an
increase in oxygen demand secondary to
exercise, emotional stress, CHF, hypertension,
tachycardia, sepsis, etc., can lead to a
worsening of symptoms.
• Ischemia can occur in patients with normal
coronary arteries in the setting of LV
hypertrophy, aortic stenosis or insufficiency,
hypertrophic cardiomyopathy, coronary
vasospasm, or cocaine abuse.
Types of Angina
• Stable. Intensity, character, and frequency of
episodes can be predicted, and angina occurs in
response to a known amount of exercise or
other stress.
• Unstable. Intensity, frequency, or duration of
episodes is changed and can no longer be
predicted. Pain is precipitated by less exercise
or is of longer duration. This includes angina at
rest and new-onset angina.
• Variant. Pain, which may occur at rest, is
secondary to vasospasm of coronary arteries.
Etiology
• Stable angina can be caused by gradual, progressive
coronary artery stenosis associated with
hyperlipidemia and atherosclerosis.
• These stable, fixed lesions reduce coronary artery
blood flow and when myocardial workload increases
the restricted coronary flow is inadequate to meet the
increased myocardial demand.
• The resultant ischemia and anoxia can then trigger the
classic symptoms of anginal chest pain.
• With rest the myocardial demand diminishes,
adequate perfusion is restored and the chest pain
resolves.
Etiology
• Unstable angina can be defined in three
ways:
-new onset angina with frequent attacks
(greater than or equal to 3 episodes/day),
-rest angina, and
-accelerated angina.
• Indicative of worsening cardiovascular
disease
• May be associated with an unstable plaque of
the coronary arteries that can initiate
thrombus formation and total occlusion very
quickly.
• Also cause occlusion by flap dissection or
by dislodging & becoming wedged in a
smaller diameter artery.
• Is a medical emergency and does not follow
the predictable pattern of exertional pain
alleviated with rest that is often seen with
stable angina.
Etiology
• Prinzmetal's variant angina is caused by
coronary vasospasm.
• It has a variable pattern and while associated
with an overall low mortality rate, is associated
with a high degree of morbidity..
Factors that Affect Myocardial
Oxygen Demand
• The major determinants of myocardial
oxygen consumption include
• ventricular wall stress,
• heart rate, and
• inotropic state (contractility)
• Both preload and afterload affect the
stress on the ventricular wall
Preload
• Preload is the pressure that distends the
ventricular wall during diastole (ventricular-end
diastolic pressure, VEDP) and is determined by
venous return
• Peripheral venodilation increases venous
capacitance and thereby reduces venous return
and preload
• Decreasing preload also reduces ventricular enddiastolic volume (VEDV) which reduces ventricular
wall tension as described by Laplace's law
(Tension = Pressure x Radius)
• An added benefit of reducing preload is improvement in
subendocardial perfusion as a result of increasing the
pressure gradient for perfusion across the ventricular wall
Afterload
• Afterload is the impedance against which
the ventricle must pump
• Decreasing peripheral arteriolar resistance
reduces myocardial work and therefore
myocardial oxygen consumption
• A commonly used non-invasive index of myocardial
oxygen demand is the "double product"
• Heart Rate x Systolic Blood Pressure
Factors that Affect Myocardial
Oxygen Supply
• Coronary artery blood flow is the primary
determinant of myocardial oxygen supply since
myocardial oxygen extraction from the blood is nearly
complete, even at rest
• Coronary blood flow is essentially negligible during
systole and is therefore determined by perfusion
pressure (aortic diastolic pressure), duration of diastole,
and coronary resistance
• Coronary vascular resistance is determined by
numerous factors including:
– Metabolic products that vasodilate coronary arterioles
– Autonomic activity
– Extravascular mechanical compression
– Atherosclerosis, -Intracoronary thrombi
Signs and Symptoms
• 25 to 30 % of ischemic episodes may be
•
•
•
•
•
asymptomatic, :
Crushing, heavy, pressure, squeezing, tight
sensation or aching/ pain in the chest
Intensity varying from mild to intense
Location often retrosternal with radiation to
neck, ears jaw, teeth, arms (left more common
than right), shoulders or back
Numbness, tingling, paresthesias following
the above distribution
Shortness of breath Anxiety/nervousness,
palpitations"
Drugs used in angina
Organic nitrates ---- Glyceryl trinitrite (GTN)
(Nitroglycerin)
Isosorbide mononitrite
Isosorbide dinitrite
Erythrityl tetranitrite
Beta blockers- ------Atenalol
-Metopralol
Calcium channel blockers- Verapamil
-Diltiazam
-nifedepine
-Amlodepine
Nitrates
• The major beneficial effect-- is a reduction in preload
and afterload, resulting in reduction in myocardial
work and reduction of intramural pressure.
• Reduction of myocardial work results in
decreased oxygen demand; reduction of
intramural pressure allows better perfusion of
deeper layers of the myocardial tissue). Decreased
myocardial wall tension is a major determinant of
myocardial oxygen demand
• Nitrates have also been shown to have a substantial
antiplatelet effect .
• Blood is preferentially redistributed to ischemic areas
caused by an increase in coronary collateral blood flow
NITRATES
• NO is capable of dilating all blood vessels,
however, there is a greater effect on large
arteries and veins compared to arterioles.
• This means that low concentrations of GTN
dilates veins first. In order to dilate arterioles,
larger concentrations are needed.
• However, the main target to reduce preload is
the effects on the veins
• GTN dilates the veins, which causes increased
venous pooling (increased venous capacitance)
• This reduces venous return (preload) and
hence reduces the amount of blood the heart
has to pump, thus making it work less (thus
reducing the O2 demand)
• In normal individuals, GTN will also act to
dilate the coronary arterioles, thus allowing
increased perfusion to the heart.
• However, this is not the case in people
with classic angina because the arterioles
are already maximally dilated, therefore
there will be no increase in cardiac blood
flow
Systemic effects of GTN
• Little effect on arterial pressure (even though it
may cause dilation of arteries and arterioles).
Hence it is not an effective anti hypertensive
agent
• No direct effect on the myocardium
• It is possible to see a mild reflex tachycardia.
Decreased cardiac output (due to reduced
venous return)
• Flushing due to vasodilation of the facial vessels
• Headache due to cerebral vessel dilation
• Effects on extravascular smooth muscle:
• Relaxation of the smooth muscle of the
bronchus and GIT (only transient effects)
Pharmacokinetics of GTN &ISDN
• GTN is rapidly metabolised by the liver, hence it
is not given orally
• It is either given sublingually (for rapid onset,
short lasting) or transdermally (for constant slow
administration which lasts longer)
• ISDN can be given orally, although it is
metablised by the liver (not as efficiently as
GTN). It is also metabolised to an active
metabolite, which lengthens its duration
(ETN&PETN-NOT USED)
Pharmacokinetics
Nitrovasodilators
Property
GTN ISDN
• Half-life (min)
3
10
• Oral bioavailability (%) < 1 20
ISMN
280
100
Adverse Effects
• The major acute adverse effects of nitrates
are due to excessive vasodilation:
– Orthostatic hypotension
– Tachycardia
– Severe throbbing headache
– Dizziness
– Flushing
– Syncope (fainting)
NITRATES
TOLERANCE
" Decrease in the effect of a drug
when administered in a long-acting form"
Develops with all nitrates
Is dose-dependent
Disappears in 24 h. after stopping the drug
Tolerance can be avoided
- Using the least effective dose
- Creating discontinuous plasma levels
• Tolerance occurs because the enzyme
required to break down GTN (the tissue
thiols) are depleted, and so there is lack of
conversion of GTN to NO.
• After a drug free period, the enzymes
regenerate, and are ableto convert GTN to
NO again.
• The best way to overcome the tolerance is
to have a drug free period - the patient
puts on a patch in the morning and takes it
off at night (so that nighttime is their drug
free period)
NITRATES
CONTRAINDICATIONS
Previous hypersensitivity
Hypotension ( < 80 mmHg)
AMI with low ventricular filling pressure
1st trimester of pregnancy
•Constrictive pericarditis
•Intracranial hypertension
•Hypertrophic cardiomyopathy
Uses:
Acute attack
• Give GTN sublingually
In anticipation of an attack
• Take GTN sublingually before doing some
work requiring physical effort
• ISDN can be taken orally as well
• ISDN is not suitable for an acute attack
because its onset of action is much slower
Prophylaxis
• GTN transdermally or ISDN orally
Calcium Channel Blockers
• Four chemically distinct classes of calcium
channel blockers are currently used to
treat angina
• Phenylalkylamines: Verapamil (Calan)
• Benzothiazipines: Diltiazem (Cardizem)
• Dihydropyridines: Nifedipine (Procardia),
nimodipine (Nimotop), nicardipine
(Cardene)
• Diarylaminopropylamine ethers: Bepridil
(Vascor)
Mechanism of Action
• The primary action of the calcium channel
blockers is to block voltage-sensitive calcium
channels
• Dihydropyridines, verapamil, and diltiazem block
L-type calcium channels which are abundant in
cardiac myocytes, arteriole smooth muscle cells,
SA nodal tissue, and AV nodal tissue
• Bepridil blocks L-type channels, but also has
significant sodium and potassium channel
blocking activity in the heart
Mechanism of action
• Block the L type voltage operated Ca2+ channel
which is present on smooth muscle and cardiac
muscle and in lots of other tissues which
required the inflow of Ca2+.
• By blocking these channels, Ca2+ is prevented
from entering and causing smooth muscle
contraction.
• Nifedipine is used as a vasodilator
• It is used to decrease TPR (and hence
afterload), by decreasing the tone of the
arterioles and arteries.
• Verapamil is used to decrease contractility of the heart, reducing the
force and rate of contraction byinhibiting the entry of Ca2+ into the
cardiac muscle
Pharmacological Effects
• All CCBs dilate coronary arterioles and
reduce afterload, but each class has
different effects on heart rate and cardiac
contractility
– Verapamil, diltiazem, and bepridil have direct
negative inotropic, chronotropic, and
dromotropic effects
– The dihydropyridines have negligible direct
effects on heart rate or contractility, but reflex
increases in sympathetic tone (due to
decreased arterial pressure) can increase
heart rate and contractility which may
aggravate angina
• The CCBs have little effect on preload
• CCBs may inhibit platelet aggregation
• The desired therapeutic effects of CCBs in
treating angina are to:
– Reduce myocardial oxygen consumption by
reducing afterload
– Reduce myocardial oxygen consumption by
reducing heart rate and contractility (except for the
dihydropyridines which have minimal effects on
contractility)
– Improve oxygen delivery to ischemic myocardium by
vasodilating coronary arteries and by reducing heart
rate (increased time spent in diastole)
– May also inhibit platelet aggregation
Pharmacokinetics
• The calcium channel blockers are orally active
• The calcium channel blockers exhibit high firstpass metabolism and high protein binding
• Most of the channel blockers used to treat
angina are active within about 30 minutes after
oral administration and have plasma half-lives of
several hours
– Bepridil and the newer dihydropyridines have longer
half-lifes (24-50 hours)
Adverse Effects
• The major adverse effects of calcium channel blockers
are typically direct extensions of their therapeutic actions
and are relatively rare:
– Depression of contractility and heart failure
– Bradycardia
– AV block
– Cardiac arrest
• Short-acting dihydropyridines have been associated with
an increased incidence of sudden death (cardiac
arrhythmia), perhaps by increasing sympathetic tone
• Minor toxicities include:
– Hypotension ,Dizziness .Edema ,Flushing
Contraindications
• Verapamil, diltiazem, and bepridil can
worsen cardiac performance in patients
with overt heart failure
• Verapamil, diltiazem, and bepridil may
depress contractility and produce AV block
in patients receiving beta-blockers
• Verapamil may increase serum digoxin
levels in digitalized patients
Uses:
• Prophylaxis for angina-The choice of
drug depends on the patients underlying
cardiovascular problems. E.g.
• If angina + hypertension use nifedipine
• If angina + arrhythmia use verapamil
• Anthypertensives
• Antiarrhythmic
Beta blockers
• Propranalol
• Atanalol
• Metaprolol
Mechanism of action
• Competitive beta adrenergic receptor
blockers
• By blocking beta1 receptors at heart
decrease cardiac contractility (decrease
force and rate) there by reduce oxygen
demand.
• Decreased arterial pressure (decrease
afterload)
Uses:
• Prophylaxis of classic angina(stable
angina)
• Antihypertensives
• Antiarrhythmic
ß-ADRENERGIC BLOCKERS
CONTRAINDICATIONS
Hypotension: BP < 100 mmHg
Bradycardia: HR < 50 bpm
Chronic bronchitis, ASTHMA
Severe chronic renal insufficiency
Variant angina
Therapy of variant angina
• It is necessary to relieve the coronary
vasospasm
• Acute treatment:· GTN sublingually
GTN relieves the spasm
• Prophylaxis: · Ca2+ channel antagonists
(Reduce Ca2+ entry into the smooth muscle around the coronary
vessels, hence preventing theirconstriction)
• Beta antagonists are never used- they can
cause a rare adverse effect whereby they
can actually cause coronary vasospasm.
THE END