Download S 10 Antianginal Drugs

Drugs used in the treatment of
Angina Pectoris
Introduction
• Angina pectoris refers to sudden, severe, pressing chest
pain radiating to the neck, jaw, back, and arms caused by
cardiac ischemia
• Occurs due to an imbalance in the myocardial oxygen
supply-demand relationship caused by:
I. An increase in myocardial oxygen demand
(determined by heart rate, ventricular contractility, and
ventricular wall tension)
II. A decrease in myocardial oxygen supply (primarily
determined by coronary blood flow)
III. Both
Heart Rate
Contractility
Preload
Afterload
Oxygen
Oxygen
=
demand
supply
>
ischemia
Coronary
blood flow
Regional
myocardial
blood flow
Introduction
Types of angina
1. Atherosclerotic or typical angina
•
The most common form of angina
•
Caused by the reduction of coronary blood flow produced
by coronary atherosclerosis
•
Symptoms of angina occurs when myocardial oxygen
demand increases, as with physical activity, emotional
excitement, or any other cause of increased cardiac
workload
Introduction
Types of angina
2. Vasopastic or variant angina:
• Occurs at rest, even during sleeping and is due to
vasospasm of large epicardial coronary vessels or
one of their major branches
• Symptoms are caused by decreased blood flow to
the heart muscles
Introduction
Types of angina
3. Unstable angina or acute coronary syndrome
• It lies between stable angina on the one hand and
myocardial infarction on the other
• Characterized by pain with increased frequency that
occurs with less and less exertion, culminating in pain at
rest
Introduction
Types of angina
3. Unstable angina or acute coronary syndrome
• Cause: abrupt reduction in blood flow, as might result from
coronary thrombosis or rupture of an atherosclerotic
plaque, with consequent platelet adhesion and
aggregation
• Requires hospital admission and more aggressive therapy
to prevent death and progression to MI
Therapeutic objectives
• The major therapeutic are aimed at:
1) Terminating or preventing an acute attack
2) Increasing the patient’s exercise capacity
• Can be achieved by:
1) Reducing overall myocardial oxygen demand
2) Increasing oxygen supply to ischemic areas
Therapeutic objectives
• Reducing myocardial O2 demand can be achieved by
decreasing heart rate/ myocardial contractility, reducing
preload/cardiac filling, reducing afterload/ arterial pressure,
& by shifting myocardial metabolism to substrates that
require less oxygen per unit of adenosine triphosphate
(ATP) produced
• Increasing O2 supply can be achieved by dilating the
coronary vasculature
Therapeutic objectives
• Drugs used in typical angina function principally by
reducing myocardial O2 demand by decreasing heart
rate, myocardial contractility, and/or ventricular wall
stress
• The principal therapeutic aim in variant angina is to
prevent coronary vasospasm by nitrate or calcium
channel-blocking vasodilators
Therapeutic objectives
• In unstable angina, vigorous measures are taken to
achieve both—increase oxygen delivery and decrease
oxygen demand
• strategies include the use of antiplatelet agents and
heparin to reduce intracoronary thrombosis, often
accompanied by efforts to restore flow by mechanical
means, including percutaneous coronary interventions
using coronary stents, or (less commonly) emergency
coronary bypass surgery
Antianginal drugs
1) Nitrates
2) Calcium channel blockers (CCBs)
3) Beta-blocking drugs
I. Nitrates
• Agents: nitroglycerine,
isosorbide dinitrate
isosorbide
mononitrate,
and
• Nitates are available as oral tablets, transdermal patches,
sublingual tablets, and intravenous infusion
• Nitrates exert their effect by intracellular conversion to
nitric oxide (NO)
• NO activates guanylate cyclase and increases the cells'
cyclic guanosine monophosphate (cGMP), which leads
smooth muscle relaxation by dephosphorylation of myosin
light chain phosphate
I. Nitrates
• Nitroglyerine:
–
–
–
–
–
Rapid onset of action (2-5 mins)
Maximal effect observed at 3 to 10 minutes
Short half-life (1-3 mins)
Significant first-pass metabolism (F < 10-20%)
Commonly administered either sublingually or via a
transdermal patch
I. Nitrates
• Isosorbide mononitrate owes its improved
bioavailability and long duration of action to its
stability against hepatic breakdown
• Oral isosorbide dinitrate undergoes denitration to
two mononitrates, both of which possess antianginal
activity
Time to peak effect and duration of action for some common organic
nitrate preparations
Onset of action
Duration of action
Key:
Isosorbide dinitrate
Nitroglycerin
Sublingual
tablet or spray
2 min
25 min
Oral,
sustainedrelease
35 min
4-8 hrs
Transdermal
30 min
8-14 hrs
5 min
1hr
Sublingual
Oral, slowrelease
30 min
8 hrs
Isosorbide mononitrate
Oral, extendedrelease
30 min
12 hrs
I. Nitrates & nitrites
Cardiovascular effect
•
•
•
•
Nitrovasodilators promote vascular smooth muscle
relaxation
Low concentrations of nitroglycerin preferentially dilate the
veins more than the arterioles (gradient response)
This result in marked relaxation of veins with increased
venous capacitance, decreased venous return to the heart,
and reduces the work of the heart (decreases myocardial
oxygen consumption)
Nitroglycerin dilates the coronary vasculature, providing an
increased blood supply to the heart muscle, but concentric
atheromas can prevent significant dilation
I. Nitrates
Action on platelets
•
•
•
Nitric oxide released from nitroglycerin stimulates
guanylyl cyclase in platelets as in smooth muscle
The increase in cGMP that results is responsible for a
decrease in platelet aggregation
Unfortunately, recent prospective trials have established
no survival benefit when nitroglycerin is used in acute
myocardial infarction
I. Nitrates
Other effects
• Nitrite ion reacts with hemoglobin (which contains ferrous
iron) to produce methemoglobin (which contains ferric
iron)
• Because methemoglobin has a very low affinity for
oxygen, large doses of nitrites can result in
pseudocyanosis, tissue hypoxia, and death
• The plasma level of nitrite resulting from even large doses
of organic and inorganic nitrates is too low to cause
significant methemoglobinemia in adults
I. Nitrates
Other effects
• In nursing infants, the intestinal flora is capable of
converting significant amounts of inorganic nitrate, eg,
from well water, to nitrite ion
• Thus, inadvertent exposure to large amounts of nitrite ion
can occur and may produce serious toxicity
I. Nitrates
Clinical uses
•
•
•
•
•
Nitrates are used to treat acute anginal attacks and as a
prophylaxis against recurrent attacks
There are effective in stable, variant, and unstable angina
pectoris
All nitrates are effective, but they differ in their onset of
action and rate of elimination
Sublingual nitroglycerin is the DOC for prompt relieve of
ongoing attack of precipitated by exercise or emotional
stress
Nitrates are frequently given in combination with βblockers and CCBs
I. Nitrates
Clinical use of nitrates
•
•
•
Sublingual nitroglycerin: is the most frequently used agent for the
immediate treatment of angina b/c of its rapid onset of action (1–3
minutes). Because its duration of action is short (not exceeding 20–
30 minutes), it is not suitable for maintenance therapy
IV nitroglycerine: has a rapid onset of action of intravenous
nitroglycerin (minutes), but its hemodynamic effects are quickly
reversed when the infusion is stopped. Clinical application of
intravenous nitroglycerin is therefore restricted to the treatment of
severe, recurrent rest angina
Slowly absorbed preparations of nitroglycerin: such as buccal
form, oral preparations, and several transdermal forms have been
shown to provide blood concentrations for long periods but, this leads
to the development of tolerance
I. Nitrates
Adverse effects
•
Extensions of therapeutic vasodilation: orthostatic
hypotension, tachycardia, and throbbing headache (3060% of patients)
•
Sildenafil potentiates the action of the nitrates. To
preclude the dangerous hypotension and inadequate
perfusion of critical organs that may occur, this
combination is contraindicated
•
Methemoglobinemia at high blood concentration
I. Nitrates
Tolerance
• Repeated and frequent exposure to organic nitrates is
accompanied by the development of tissue tolerance:
the blood vessels become desensitized to the
vasodilating action of nitrates
• The magnitude of tolerance is a function of dosage
and frequency of use
I. Nitrates
Tolerance
• Tolerance may result from:
1) True vascular tolerance: reduced capacity of the
vascular smooth muscle to convert nitroglycerin to NO
resulting from depletion of tissue thiol compounds
2) Pseudotolerance: as a result of activation of
mechanisms extraneous to the vessel wall. Initially,
significant sympathetic discharge occurs and after one or
more days of therapy with long-acting nitrates, retention
of salt and water may reverse the favorable
hemodynamic changes normally caused by nitroglycerin
I. Nitrates
Tolerance
•
Tolerance can be avoided by:
1) Daily “nitrate-free interval” to restore sensitivity to the
drug. This interval is typically 10 to 12 hours, usually at
night, because demand on the heart is decreased at
that time
2) Nitroglycerin patches are worn for 12 hours then
removed for 12 hours
Other nitro vasodilators
•
Nicorandil is a nicotinamide nitrate ester that has
vasodilating properties in normal coronary arteries but
more complex effects in patients with angina
• It displays a dual mechanism of action:
a) It opens up ATP-sensitive K+ channels, thereby
causing dilatation of peripheral and coronary resistant
arterioles
b) It contains an NO2-moiety, which dilates systemic
veins and epicardial coronary arteries
II. Calcium channel blockers
Mechanism of action
•
Ca2+ channel antagonists, also called Ca
blockers, inhibit Ca2+ channel function
•
Voltage-sensitive Ca2+ channels (L-type or slow
channels) mediate the entry of extracellular Ca2+ into
smooth muscle and cardiac myocytes and sinoatrial (SA)
and atrioventricular (AV) nodal cells in response to
electrical depolarization
•
Voltage-sensitive channels consists of α1, α2, γ, and δ
subunits
2+
entry
II. Calcium channel blockers
Mechanism of action
•
All the Ca2+ channel blockers bind to the α1 subunit of
the L-type Ca2+ channel, which is the main pore-forming
unit of the channel
•
CCBs bind more effectively to open channels and
inactivated channels
II. Calcium channel blockers
Mechanism of action
•
Binding of the drug reduces the frequency of opening in
response to depolarization
•
This result is a marked decrease in transmembrane
calcium current, which in turn results in smooth muscle
with a long-lasting relaxation and in cardiac muscle with a
reduction in contractility throughout the heart and
decreases in sinus node pacemaker rate and AV node
conduction velocity
II. Calcium channel blockers
• Vascular smooth muscle appears to be the most sensitive,
but similar relaxation can be shown for bronchiolar, GIT,
and uterine smooth muscle
•
In the vascular system, arterioles appear to be more
sensitive than veins. Therefore, orthostatic hypotension is
not a common adverse effect
• Important differences between the available CCBs arise
from the differences in their relative smooth muscle versus
cardiac effects
II. Calcium channel blockers
1. Diphenylalkylamines
(e.g.Verapamil):
is the least
selective of any CCBs and has significant effects on both
cardiac and vascular smooth muscle cells
2. Benzothiazepines (e.g. diltiazem): it affects both cardiac
and vascular smooth muscle cells; however, it has a less
pronounced negative inotropic effect on the heart compared to
that of verapamil
3. Dihydropyridines:
nifedipine, amlodipine, felodipine,
isradipine ,nicardipine , and nisoldipine. They have a much
greater affinity for vascular calcium channels than for calcium
channels in the heart
II. Calcium channel blockers
Organ system effects
1. Smooth muscle
• All the Ca2+ channel blockers approved for clinical use
decrease coronary vascular resistance and increase
coronary blood flow
• The dihydropyridines (e.g. nifedipine) are more potent
vasodilators and have a greater ratio of vascular smooth
muscle effects relative to cardiac effects than do diltiazem
and verapamil
• The dihydropyridines may cause reflex tachycardia if
peripheral vasodilation is marked
II. Calcium channel blockers
Organ system effects
2. Cardiac muscle
• In the SA and AV nodes, depolarization largely depends
on the movement of Ca2+ through the slow channel.
Therefore, low-response, or calcium-dependent, action
potentials—may be reduced or blocked by all of the
calcium channel blockers
•
Verapamil and diltiazem reduce cardiac contractility &
oxygen requirement in a dose-dependent fashion
II. Calcium channel blockers
Organ system effects
3. Other effects
• Verapamil has been shown to inhibit insulin release in
humans, but the dosages required are greater than those
used in management of angina
• CCBs may interfere with platelet aggregation in vitro and
prevent or attenuate the development of atheromatous
lesions in animals. Clinical studies have not established
their role in human blood clotting and atherosclerosis
II. Calcium channel blockers
Organ system effects
• Verapamil & other CCBs have been shown to block the Pglycoprotein responsible for the transport of many foreign
drugs out of cancer (and other) cells .Verapamil has been
shown to partially reverse the resistance of cancer cells to
many chemotherapeutic drugs in vitro
II. Calcium channel blockers
Clinical uses of CCBs
•
CCBs are effective in both effort angina (reduction in
myocardial oxygen consumption) and vasopastic angina
(relaxation of coronary arteries)
•
The choice of a particular calcium channel-blocking agent
should be made with knowledge of its specific potential
adverse effects as well as its pharmacologic properties
II. Calcium channel blockers
Clinical uses of CCBs
•
Dihydroperidines (e.g. nifedipine) have a much greater
affinity for vascular calcium channels than for calcium
channels in the heart. Therefore can be used more safely
than verapamil or diltiazem in the presence of AV
conduction abnormalities and depressed cardiac function
•
Verapamil and diltiazem produce less hypotension than
dihydropyridines which can cause further deleterious
lowering of pressure in patients with relatively low blood
pressure
II. Calcium channel blockers
Clinical uses of CCBs
•
In patients with a history of atrial tachycardia, flutter, &
fibrillation, verapamil and diltiazem provide a distinct
advantage b/c of their antiarrhythmic effect
•
Nimodipine & nicardipine, dihydropyridines, have a high
affinity for cerebral blood vessels and appears to reduce
morbidity after a subarachnoid hemorrhage
•
Nicardipine is used by intravenous and intracerebral
arterial infusion to prevent cerebral vasospasm
associated with stroke
II. Calcium channel blockers
Adverse effects
• Excessive inhibition of calcium influx can cause serious
cardiac depression, including cardiac arrest, bradycardia,
atrioventricular block, and heart failure
• Minor toxicities include flushing, dizziness, nausea,
constipation, and peripheral edema
• Constipation is particularly common with verapamil
• Patients receiving β-blocking drugs are more sensitive to
the cardio-depressant effects of calcium channel blockers
III. Beta-blockers
•
The β-adrenergic–blocking agents decrease the oxygen
demands of the myocardium by blocking β1 receptors,
and they reduce the work of the heart by decreasing heart
rate, contractility, cardiac output, and blood pressure
•
The demand for oxygen by the myocardium is reduced
both during exertion and at rest
•
β-blockers are the DOC to treat exercise-induced angina,
but are ineffective and should not be used against
vasospastic angina
Novel antianginal drugs
Metabolic modulation (pFOX): Trimetazidine
• Trimetazidine is metabolic modulator that does not reduce
oxygen demand or increase blood supply
•
It act by shifting myocardial metabolism to substrates that
require less oxygen per unit of ATP produced
•
•
ADRs: GIT disturbance, dizziness, and headache.5
Trimetazidine use can result in movement disorders such as
parkinsonian symptoms (tremor, akinesia, hypertonia), gait
instability, and restless legs
Metabolic modulation (pFOX): Trimetazidine
Myocytes
FFA
Glucose
Acyl-CoA
Pyruvate
β-oxidation
O2 requirement of glucose •
pathway is lower than FFA
pathway
During ischemia, oxidized FFA •
levels rise, blunting the glucose
pathway
Trimetazidine
Acetyl-CoA
Energy for contraction
MacInnes A et al. Circ Res. 2003;93:e26-32.
pFOX = partial fatty acid oxidation
Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
FFA = free fatty acid
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
Newer antianginal drugs
Sodium channel blocker: Ranolazine
• It reduces contractility resulting from the blockade of a late
sodium current (late INa) in myocaridla cells that facilitates
calcium entry via the sodium-calcium exchanger
•
The decrease in intracellular sodium causes and increase in
calcium expulsion via the Na-Ca+2 exchanger
•
ADRs tend to be mild to moderate in severity and often develop
within the first two weeks of treatment
•
The most common ADRs are constipation, nausea, and
weakness
Late Sodium Channel
2 Ca++
3 Na+
Na+
Cardiac ischemia
Reactive O2 species
Ischemic metabolites
2 Ca++
3 Na+
Na+
Ranolazine: Mechanism of action
Ischemia
↑ Late INa
Ranolazine
inhibits the late inward
Na current
Na+ overload
Ca2+ overload
Diastolic relaxation failure
(increased diastolic tension)
Extravascular compression
Newer antianginal drugs
Sinus node inhibition: Ivabradine
• Ivabradine blocks I(f) channel in the pacemaker cells of the
sinoatrial (SA) node
• This slows the heart rate without affecting myocardial
contractile function or peripheral vascular resistance (bronchial
and GIT smooth muscles)
• Adverse effects include visual “flashing lights” known as
phosphenes in up to 16% of patients, which are usually only
mild to moderate in intensity and transient