Transcript Antianginal Drugs

Antianginal Drugs
Dr. Kaukab Azim. MBBS, PhD
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Drug List
Nitrates and nitrites
Amyl nitrite
Nitroglycerine
Isosorbide mononitrate
Beta Blockers
Propranolol
Metoprolol
Atenolol
Calcium Channel Blockers
Nifedipine
Nicardipine
Diltiazem
Verapamil
Note: More drugs have been mentioned in other slides
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Angina Pectoris
Definition
• A clinical syndrome due to myocardial ischemia characterized by episodes
of precordial discomfort or pressure, typically precipitated by exertion or
stress and relieved by rest or drugs.
Types
• Exertional angina, (or angina of effort) which is typically triggered by
physical activity, persists few minutes and subsides with rest (this form
constitutes about 90% of angina cases).
• Vasospastic angina (or Prinzmetal’s angina, or variant angina) which
tends to occur regularly at certain times of the day and is characterized by
pain at rest.
Evolution
• Stable, when its characteristics are constant for a given individual.
• Unstable (also called crescendo angina, acute coronary insufficiency,
preinfarction angina or intermediate syndrome), when there is an
increased frequency, intensity or duration of attacks, or changes in
precipitating factors. It must be treated as a medical urgency.
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Pathophysiology of Angina
Angina pectoris occurs when the O2 needs of the heart are not met.
Heart O2 needs are high because:
• The O2 consumption of myocardial tissue is the highest of all
tissues (9.7 mL/100 g/min, at rest)
[the "double product" (heart rate x systolic blood pressure) is an
indirect measure of myocardial oxygen consumption]
The myocardial O2 demand increases when there is an increase in:
• heart rate
• myocardial contractility
• peripheral resistance
• ventricular volume
• ejection time
(all the above mentioned factors increase the intramyocardial fiber
Tension)
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Pathophysiology of Angina
Increased myocardial O2 demand in the normal heart can be met only by augmenting
coronary blood flow.
Coronary blood flow is related to:
• a) the perfusion pressure.
• b) coronary vascular bed resistance.
• c) the duration of diastole
Angina pectoris occurs when the coronary blood flow cannot meet the myocardial
O2 demand.
• Angina is mainly due to:
• a) a critical coronary artery obstruction caused by atherosclerosis (exertional
angina)
• b) a large vessel spasm (variant angina).
• The pain of angina (like the pain of skeletal muscle contracting with insufficient
blood supply) is due to chemical factors released by the ischemic muscle.
• Possible candidates for these pain-producing substances include adenosine, K+,
H+, bradykinin, histamine, serotonin and prostaglandins.
• Sensory end-plates of the intracardiac sensory nerves appear to be particularly
sensitive to these pain-producing substances.
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Nitrates and nitrites available for
clinical use
Generic Name
Amyl nitrite
Nitroglycerine
Isosorbide mononitrate
Duration of Action
3 - 5 mins
From 10 mins to 10 hours
(Depending upon route of
administration)
6 – 10 hours
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Mechanism of action of nitrates and
congeners
Nitrates are denitrated (by glutathione S-transferase), thereby releasing free
nitrite ions (this reaction requires -SH groups).
• Nitrite ion is converted to nitric oxide (NO), which activates a cytosolic
form of guanylyl-cyclase (this reaction requires -SH groups).
• cGMP synthesis is increased in smooth muscle.
This increase in turn triggers the following cascade of events:
Activation of protein kinase G………….leading to Increased dephosphorylation
of myosin light chain………….leading to relaxation of smooth muscle
Two consequences of this mechanism of action are:
1) NO stimulates guanylyl-cyclase in platelets as in smooth muscle.
2) A decreased availability of tissue -SH groups reduces the action of
nitrates (at least partially).
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Pharmacodynamics of nitrates and
congeners
Cardiovascular actions
1) After therapeutic doses:
Marked relaxation of large veins (the main effect) which leads to:
a. Decreased preload and cardiac output (in the absence of cardiac failure).
b. Decreased blood pressure (slightly).
c. Improved perfusion of subendocardial regions (due to the lowering of
left ventricular end-diastolic pressure, which reduces subendocardial
compression)
Relaxation of large arteries (less pronounced than vein relaxation) which
leads to increased blood flow in:
a. the skin (face and thorax) and the brain.
b. large epicardial vessels (autoregulation in small vessels is not impaired)
c. large collateral vessels (perfusion of ischemic regions is increased)
2) After higher doses:
Relaxation of all segment of the vascular system which leads to:
a. Reflex tachycardia and reflex increase in cardiac contractility
b. Postural hypotension
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Pharmacodynamics of nitrates and
congeners
Other actions
Relaxation of smooth muscle of:
1. the bronchi (small effect)
2. the biliary system (rapid reduction of biliary pressure)
3. the gastrointestinal tract (sphincteral and non sphincteral)
4. the genitourinary tract (small effect)
• Decreased platelet aggregation (likely due to the increase in
cGMP)
• Increased methemoglobin formation (with nitrites, not with
therapeutic doses of nitrates) due to the formation of nitrite ion
that can oxidize the ferrous ion of hemoglobin to the ferric state.
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Pharmacokinetics of nitrates and
congeners
ABSORPTION
• Bioavailability:
• Oral: generally low (but isosorbide mononitrate > 95%)
• Sublingual: 10-60 %
• Transdermal: 50-90 %
DISTRIBUTION
• In all body tissues including brain.
BIOTRANSFORMATION
• > 99%, mainly in liver (by a high capacity nitrate-reductase).
Half-life: very variable
• sublingual nitroglycerin: 2-3 min
• oral isosorbide mononitrate: 4-5 hours
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Nitrates Tolerance and Dependence
• Frequently repeated exposures to nitrates leads to a
decrease in most of their pharmacological effects.
• Tolerance to a nitrate results in tolerance (at least partial)
to all other compounds of the class.
• The amount of tolerance is a function of the dosage and
the frequency of administration, and it exhibits a very high
individual variability.
• Since tolerance appears rapidly (24 hours) and disappears
rapidly (6-10 hours), brief periods of no therapy (hours of
overnight) can be sufficient to permit recovery.
• Nitrate can cause dependence. In fact sudden death or
myocardial infarction have occurred after a few days' break
in long-term exposure to an organic nitrate.
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Duration of antianginal effect of
nitrates
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Adverse effects of Nitrates
Central nervous system
• Throbbing headache (> 50%, can be severe)
• Dizziness, vertigo, lightheadedness (5%)
• Syncope (. 4%, with high doses).
Cardiovascular system
• Flushing of the face (common, with rapid-acting preparations, likely due to
the local production of prostaglandins).
• Palpitations (with high doses).
• Postural hypotension (frequent).
• Profound hypotension (if taken concomitantly with sildenafil, a specific
cGMP phosphodiesterase-5 inhibitor. The interaction can be lifethreatening).
Other systems
• Skin rashes, contact dermatitis (rare)
• Methemoglobinemia (with nitrite, or with toxic doses of nitrates) (very
rare)
• Withdrawal reactions (digital vasospasm, coronary spasms, myocardial
ischemia, myocardial infarction)
• Drug abuse (with amyl nitrite)
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Nitrates: Contraindications and
Precautions
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Angina due to hypertrophic Cardiomyopathy
Constrictive pericarditis
Increased intracranial pressure
Severe hypotension (systolic < 90 mm Hg)
Hypovolemic states
Hyperthyroidism
Severe hepatic disease
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Therapeutic uses of nitrates
Angina pectoris
a) Treatment (or prevention) of the acute attack.
Nitroglycerin (sublingual route) or amyl nitrite (inhalant route). [pain is
relieved; protection lasts 30-40 min].
b) Chronic prophylaxis
Nitroglycerin (oral, transdermal), other nitrates (oral) [attacks are reduced
or eliminated].
Main mechanisms of antianginal effects:
a) In exertional angina: decreased myocardial O2 demand
b) In variant angina: increased myocardial O2 supply (they are not the
treatment of choice)
c) In unstable angina: The main mechanism is still uncertain (decreased
myocardial O2 demand, increased myocardial O2 supply, and decreased
platelet aggregation, all might contribute to the therapeutic efficacy).
High doses may cause undesirable effects due to:
reflex tachycardia
reflex increase in cardiac contractility
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Therapeutic uses of Nitrates
Heart failure
Unlike in normal subjects, nitrates can increase stroke volume
and cardiac output in patients with systolic heart failure (the
decreased preload lowers the ventricular filling pressure, so
allowing a more efficient ventricular contraction).
They are not used routinely in heart failure but can be used
when:
① symptoms of pulmonary congestion predominate
(redistribution of blood volume away from the chest
relieves the congestion. This improves exercise tolerance
even when cardiac output is not increased)
② pulmonary edema occurs or is impending.
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Therapeutic uses of Nitrates
Myocardial infarction
• It has been shown that IV infusion of nitrates lead
only to a minor reduction in short-term mortality.
• Therefore they are not recommended for routine
use, but it is reasonable to use IV nitroglycerin in
more complicated patients, such as those with
impending heart failure or hypertension.
Cyanide poisoning
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Beta blockers
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Beta-blockers in Angina
1) Therapeutic doses of beta-blockers are effective in angina because:
a) They decrease cardiac O2 demand (the main mechanism) by:
reducing heart rate
reducing cardiac contractility
lowering blood pressure
b) They increase myocardial perfusion in certain parts of the heart (mainly
subendocardial regions) due to an augmented diastolic perfusion time.
Therefore:
a) They are effective in chronic prophylaxis of exertional angina and in the acute
treatment of unstable angina.
b) They are not effective in variant angina (where instead they may be dangerous,
by causing coronary vasoconstriction).
2) High doses may cause undesirable effects due to:
increased end diastolic volume
increased ejection time
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Beta-blockers in Myocardial Infarction
Beta-blockers without sympathomimetic activity have been clearly
demonstrated to reduce mortality in myocardial infarction. They should be
given early and continued indefinitely.
The mortality reduction is likely due to the following reasons:
1) They decrease myocardial oxygen demand (by decreasing heart
contractility and rate)
2) They decrease the risk of ventricular fibrillation (by decreasing heart
conduction and automaticity).
3) They limit the infarct size (so decreasing the risk of myocardial rupture)
4) They reduce myocardial remodeling (which is enhanced by
catecholamines and angiotensin II).
Warning! withdrawal effects after chronic use of beta blockers in ischemic
heart disease are well documented. In risk patients abrupt withdrawal may
cause hypertension, angina, myocardial infarction, and sudden death.
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Calcium Channel
Blockers
To understand the rest of the
lecture, you must know the role of
calcium in muscle contraction and
relaxation
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The Calcium Channels
There are two types of calcium channels
a) Ligand-gated (or "receptor-operated"): they
are coupled to excitatory receptors either
directly or via G proteins and open when the
receptor is activated.
b) Voltage-gated (or "potential-operated"): they
open when the cell is depolarized.
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Voltage Gated Calcium Channels
Type
Location
Properties of Ca++ current
L (long-lasting) Smooth muscle, heart,
neurons
Long, high threshold
T (Transiently
opening)
Heart, neurons
Short, low threshold
N
Neurons
Short, high threshold
P
Purkinje
Long, high threshold
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Classification of Ca++ Channel
Blocking Drugs
Dihydropyridines
Drug
Vascular
Selectivity
Others
Drug
Vascular
Selectivity
Nifedipine
High
Verapamil
Low
Nicardipine
Very High
Diltiazem
Low
Bepridil
Absent
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Pharmacodynamics
Mechanism of action
• Calcium channel blockers bind to the voltagegated Ca++ channel of L-type from the inner side
of the membrane.
• Verapamil and diltiazem block Ca++ channels both
in the heart and in the vessels.
• Dihydropyridines block Ca++ channels in the
vessels only.
• Blockade can be reversed (at least partially) by
drugs that increase transmembrane flux of Ca++,
such as beta-1 agonists.
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Cardiac and Vascular Actions
Cardiac actions
(Only verapamil and diltiazem can cause these effects)
• Decreased conduction (in "slow fibers").
• Increased refractoriness (markedly, but only in "slow fibers" or in fibers
that fire frequently and are incompletely polarized at rest).
• Decreased automaticity (mainly in ischemic zones, by preventing Ca++
overload).
• Dose-dependent decrease of cardiac contractility.
Vascular actions
(All Ca++ channel blockers can cause these effects)
• Vasodilation (mainly in arterioles, where the calcium-dependent tone of
the smooth muscle is more pronounced).
• Some dihydropyridines have a relative vascular selectivity (nicardipine for
cerebral and coronary vessels)
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Other Actions
Other actions
• Relaxation of bronchiolar, gastrointestinal and
uterine smooth muscle (modest).
• Inhibition of insulin release (verapamil,
nifedipine, after very high doses)
• Inhibition of platelet aggregation (in vitro)
• Blockade of P-glycoprotein which is a multidrug
transporter associated with the development of
drug resistance in cancer cells (verapamil).
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Pharmacokinetics
ABSORPTION
Oral bioavailability: variable (verapamil: 30% ) (amlodipine: 80%)
Oral Tmax: 30-60 min.
DISTRIBUTION
In all tissues including brain.
BIOTRANSFORMATION
> 99% in liver and other organs. Some metabolites are active.
EXCRETION
< 1 % excreted by the kidney.
Half-life: very variable
(Diltiazem: . 3 hours; amlodipine . 40 hours)
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Adverse Effects
Central Nervous System
• Headache (up to 20%)
• Dizziness, lightheadedness (up to 20%), weakness (up to 10%).
Cardiovascular System
• Flushing (nifedipine up to 25%).
• Peripheral edema (nifedipine, up to 50%)
• Profound hypotension (mainly with immediate-release nifedipine)
• Tachycardia, palpitations (nifedipine, . 5%).
• A-V block, bradycardia, arrhythmias (verapamil, diltiazem, .2%).
• Ventricular fibrillation (verapamil, diltiazem, in patients with accessory AV
pathways)
• Aggravation of myocardial ischemia (nifedipine .10%).
Other systems
• Constipation (verapamil, up to 40%), gingival hyperplasia (verapamil up to
19%) nausea, heart burn, abdominal pain (up to 10%).
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Contraindications and Precautions
• Hypotension
• Cardiogenic shock, systolic heart failure (verapamil,
diltiazem)
• SA and AV block, sick sinus syndrome (verapamil, diltiazem)
• Arrhythmias associated with Wolff-Parkinson-White
syndrome (verapamil, diltiazem)
• Ventricular tachycardia (verapamil, diltiazem)
• Myocardial ischemia (dihydropyridines)
• Digoxin overdose
• GERD, constipation, fecal impaction, intestinal obstruction,
hemorrhoids
(you must remember the ones in blue)
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Therapeutic Uses
Angina pectoris
a) Exertional angina mainly because they decrease myocardial O2
demand (due to decreased afterload, heart rate and contractility)
Verapamil and diltiazem are the preferred drugs.
High doses may cause undesirable effects due to:
increased end diastolic volume
the increased ejection time
b) Variant angina mainly because they increase myocardial O2 supply (due
to coronary vasodilation)
All calcium channel blockers are considered drugs of choice:
High doses of dihydropyridines may cause undesirable effects due to:
reflex tachycardia
reflex increase in cardiac contractility
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Therapeutic Uses
Unstable angina and myocardial infarction
• During myocardial ischemia, an increase in Ca++ influx
(due to membrane depolarization) can trigger a
secondary cellular damage.
• A cytoprotective effect, due to a decrease in the
amount of necrosis in the heart tissue, has not been
consistently supported by clinical studies, but these
drugs can reduce the rate of reinfarction and death in
patients without heart failure.
Cardiac arrhythmias
Hypertension
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Therapeutic Uses
Hypertrophic cardiomyopathy and diastolic heart failure
• Diltiazem (alone or in combination with beta-blockers) improves diastolic
compliance by reducing myocardial contractility.
Subarachnoid hemorrhage
• Dihydropyridines (especially nicardipine) dilate cerebral vessels at doses that have
little effects in the periphery. Therefore they inhibit delayed reactive vasospasm
arising from hemorrhage.
Raynaud's phenomenon
• They are drugs of choice for relieving peripheral vasospasm.
Migraine
• They are sometimes used for migraine prophylaxis (mechanism not established).
Neuropsychiatric disorders
• Various neuropsychiatric disorders (rapid-cycling bipolar disorder, Tourette’s
disease, Huntington’s disease). Long term-efficacy in these disorders remains to be
established.
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Antianginal Drug interactions
CI = Clinical importance
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Combination Therapy
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