Antianginal Drugs

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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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Types of Angina

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

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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.

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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.

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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.

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Prinzmetal (Variant) Angina
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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. Why?
• 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.

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• 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.

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Nitroglycerine
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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.
• Activation of guanylate cyclase increases cGMP
  activating a cGMP kinase leading to
  dephosphorylation of myosin light chains
  decreasing contractile force.

Requires normal vascular endothelium
Diffuses to local vascular smooth muscle
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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.

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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 absorption
  and onset (lt1 minute), t1/2 10 minutes.
  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 t1/2 1 hour.

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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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• Tolerance
• Tolerance to the actions of nitrates develops
  rapidly for their vasodilatory effects. Sustained
  treatment with nitroglycerin in vivo is
  associated with reduced biotransformation of
  nitrate to NO by endothelial mitochondrial enzyme
  aldehyde dehydrogenase-2 , 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.

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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.
• ß-Blockers in combination with nitrtates can be
  quite effective.

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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 these are (-) inotropes.
• They are useful in Prinzmetal angina in
  conjunction with nitrates.

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• 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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• 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

Tadalafil taken at time 0, NTG taken at intervals
after tadalafil