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Antianginal Drugs

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It is often associated with diaphoresis, tachypnea and nausea. Angina is caused by coronary flow that is insufficient to meet oxygen demands of ... – PowerPoint PPT presentation

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Title: Antianginal Drugs


1
Antianginal Drugs
  • 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 diaphoresis, tachypnea and nausea.
  • Angina is caused by coronary flow that is
    insufficient to meet oxygen demands of the
    myocardium. Angina can be precipitated by any
    activity/process that creates an imbalance in O2
    supply and demand.
  • 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.
  • Three classes of agents are effective in treating
    angina
  • organic nitrates,
  • ß-blockers
  • Ca2 channel blockers.
  • These agents lower the O2 demand by affecting
    BP, HR and contractility.
  • Angina is modifiable by altering life style and
    risk factors associated with CHD.

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3
Types of Angina
  • Angina occurs in three overlapping patterns
  • Stable angina
  • Unstable angina
  • Prinzmetal (variant) angina

4
Stable Angina
  • The experience of angina is quite variable, often
    described as chest pain it is frequently
    associated with adjectives indicating a
    compressive tightness that is often quite
    debilitating. Unfortunately the presentation of
    angina can be quite variable between patients but
    tends to be somewhat episodically consistent for
    a particular patient. Angina indicates that
    myocardial oxygen demand is exceeding supply.
    Stable indicates the reproducible nature of the
    angina the same activity at the same intensity
    faithfully produces symptoms. Typically this
    type of angina is relieved by rest or acute use
    of nitroglycerin.

5
Unstable Angina
  • Unstable angina occurs when anginal symptoms
    occur with less cardiac demand previously
    tolerated activities elicit symptoms, of great
    concern is angina at rest. These episodes are
    less or un-responsive to nitroglycerine or rest.
    Crescendo angina describes a rapid progression of
    myocardial ischemia often heralding infarction.

6
Prinzmetal (variant) Angina
  • This is a relatively uncommon pattern of
    myocardial ischemia usually occurring at rest and
    often in young individuals (particularly women)
    lacking classic risk factors or significant
    demonstrable coronary disease.
  • The anginal attacks in PVA tend to have a
    circadian rhythm and generally occur in the early
    morning hours.
  • These attacks can be triggered by alcohol,
    drinking iced drinks, rapid eye movement sleep,
    ergonovine, atrial pacing, cocaine, nicotine,
    acetylcholine, and hyperventilation.
  • It is induced by coronary artery vasospasm it
    generally responds promptly to vasodilators. PVA
    has been associated with other vasospastic
    disorders such as migraine headaches and
    Raynauds phenomena. Endothelial dysfunction has
    been considered as primarily responsible for PVA.
  • The risk of both ventricular bradyarrthymias is
    markedly increased during spastic events, sudden
    cardiac death is not uncommon.

7
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.
  • 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. He began treating patients with small
    doses in 1878, and it was soon adopted into
    widespread use after he published his results in
    The Lancet in 1879. The medical establishment
    used the name "glyceryl trinitrate" or
    "trinitrin" to avoid alarming patients who
    associated nitroglycerin with explosions.

8
  • 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.

9
Nitroglycerine
10
ORGANIC NITRATES
  • Organic nitrates nitrites are simple nitric
    nitrous esters of glycerol. These agents cause a
    rapid decrease in myocardial oxygen demand
    leading to rapid resolution of symptoms. Nitrates
    are effective for all types of angina.

Requires normal vascular endothelium
Diffuses to local vascular smooth muscle
11
Mechanism of Action
  • Nitrates decrease myocardial oxygen demand
  • The primary effect is a reduction in venous tone
    which results in venous pooling decreasing venous
    return (decreased preload).
  • Arteriolar tone is less effectively reduced
    resulting in a decrease in PVR (decreased
    afterload ) and decreased blood pressure.
  • s 1 2 decrease myocardial wall stress reducing
    O2 demand.
  • Dilation of coronary vessels or exerts a minor
    effect on increasing O2 supply.

12
Pharmacokinetics
  • The difference between nitrate preparations is
    mainly in time of onset of action.
  • Nitroglycerin suffers marked 1st pass metabolism
    so administration is sublingual (rapid absorbtion
    and onset (lt1 minute). 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. Nitro-Bid is an oral or
    topical preparation which saturates the hepatic
    catabolic pathways allowing a prolonged level of
    nitroglycerinegt
  • Isosorbide mononitrate isosorbide dinitrate are
    long acting nitrates that are relatively
    resistant to hepatic catabolism.

13
Adverse effects
  • The most common side effect of nitrates is
    headache due to veno-dilation, patients whom
    intermittently used nitrate preparation should be
    asked about headaches after nitrate use lack of
    headache often indicates degradation of agent
    with a loss of therapeutic effect.
  • Postural hypotension syncope particularly with
    sublingual use.
  • Tachycardia induced by decreased PVR may itself
    induce anginal symptoms especially with unstable
    symptoms.
  • Methemaglobinemia can occur with chronic use of
    long term agents, this may occur when sublingual
    use is combined with long acting agents.
  • Withdrawal symptoms may occur (an indication of
    tolerance) when nitrate agents are tapered or
    discontinued, this may precipitate anginal
    attacks.

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15
  • Tolerance
  • Tolerance to the actions of nitrates developes
    rapidly for their vasodilatory effects. Sustained
    treatment with nitroglycerin in vivo is
    associated with reduced nitroglycerin
    biotransformation of nitrate to NO by endothelial
    mitochondrial enzyme aldehyde dehydrogenase-2 and
    that this abnormality in nitrate
    biotransformation is associated with increased
    mitochondrial formation of free radical oxygen
    species.
  • Tolerance can be avoided by providing a nitrate
    free interval daily for most angina patients
    this is a night when myocardial demand is low.

16
ß-Blockers
  • ß-Blockers decrease O2 demands of the myocardium
    by lowering the heart rate and contractility
    (decrease CO) particularly the increased demand
    associated with exercise. They also reduce PVR
    by direct vasodilation of both arterial venous
    vessels reducing both pre- and after load. These
    effects are caused by blocking ß1 receptors,
    selective ß1 antagonists (atenolol, metoprolol
    and acebutolol) lose their selectivity at high
    doses and at least partially block ß2 receptors
    (a concern for bronchospastic disease).
  • ß1 antagonists reduce the frequency and severity
    of anginal episodes particularly when used in
    combination with nitrates. ß1 antagonists have
    been shown to improve survival in post MI
    patients and decrease the risk of subsequent
    cardiac events complications. There are a
    number of contraindications for ß blockers
    asthma, diabetes, bradycardia, PVD COPD.

17
Ca2 Channel Blockers
  • Ca2 channel blockers protect tissue by
    inhibiting the entrance of Ca2 into cardiac and
    smooth muscle cells of the coronary and systemic
    arterial beds.
  • All Ca2 channel blockers produce some
    vasodilation (? PVR) and (-) inotropes.
  • Some agents also slow cardiac conduction
    particularly through the AV node thus serving to
    control cardiac rhythm.
  • Some agents have more effect on cardiac muscle
    than others but all serve to lower blood
    pressure.
  • CHF patients may suffer exacerbation of their
    failure as thes are (-) inotropes.
  • They are useful in Prinzmetal angina in
    conjunction with nitrates.

18
  • Agents
  • Nifedipine This Ca2 channel blocker works
    mainly on the arteriolar vasculature decreasing
    afterload it has minimal effect of conduction or
    HR. It is metabolized in the liver and excreted
    in both the urine the feces. It causes
    flushing, headache, hypotension and peripheral
    edema. It also has some slowing effect on the GI
    musculature resulting in constipation. 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.
  • Verapamil The agents has its main effect on
    cardiac conduction decreasing HR and thereby O2
    demand. It also has much more (-) inotropic
    effect than other Ca2 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.
    It is metabolized in the liver. It interferes
    with digoxin levels causing elevated plasma
    levels caution and monitoring of drug levels are
    necessary wit concomitant use.
  • Diltiazem This agent function similarly to
    Verapamil however it is more effective against
    Prinzmetal angina. It has less effect on HR. IT
    has similar metabolism and side effects as
    Verapamil.

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21
  • Mean Maximal Change in Blood Pressure (Tadalafil
    Minus Placebo, Point Estimate with 90 CI) in
    Response to Sublingual Nitroglycerin at 2 (Supine
    Only), 4, 8, 24, 48, 72, and 96 Hours after the
    Last Dose of Tadalafil 20 mg or Placebo
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