Anti-anginal DrugsAngina 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: 1. organic nitrates, 2. β-blockers 3. Ca+2 channel blockers.

• These agents lower the O2 demand by affecting: Blood Pressure (BP), Heart rate (HR) and contractility.

• Angina is modifiable by altering life style and risk factors associated with Coronary Heart Disease (CHD).

Types of Angina

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

angina

Stable AnginaThe 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.

Unstable AnginaUnstable 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.

Prinzmetal (Variant) AnginaThis 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 tends 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. Prinzmetal Variant Angina (PVA) has been associated with other vasospastic disorders such as migraine headaches and Raynaud’s phenomena. Endothelial dysfunction has been considered as primarily responsible for Prizmental Variant Angina (PVA).

The risk of both ventricular & bradyarrthymias is markedly increased during spastic events, sudden cardiac death is not uncommon.

Prinzmetal Variant Angina (PVA)

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.

• Alfred Nobel in 1851 recognized the potential of Nitro glycerin (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.

Nitroglycerine

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

Mechanism of Action

Nitrates decrease myocardial oxygen demand:1. The primary effect is a reduction in venous tone which

results in venous pooling decreasing venous return (decreased preload).

2. Arteriolar tone is less effectively reduced resulting in a decrease in Peripheral Vascular resistance(PVR) (decreased afterload ) and decreased blood pressure.

3. #s 1 & 2 decrease myocardial wall stress reducing O2 demand.

4. Dilation of coronary vessels or exerts a ~minor effect on increasing O2 supply.

Pharmacokinetics:The difference between nitrate preparations

is mainly in time of onset of action.1. Nitroglycerin suffers marked 1st pass

metabolism so administration is sublingual (rapid absorption and onset (<1 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 nitroglycerine**>

2. Isosorbide mononitrate & isosorbide dinitrate are long acting nitrates that are relatively resistant to hepatic catabolism t1/2 ~ 1 hour.

Adverse effects:1. 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.

2. Postural hypotension & syncope particularly with sublingual use. 3. Tachycardia induced by decreased PVR may itself induce anginal

symptoms especially with unstable symptoms. 4. Methemaglobinemia can occur with chronic use of long term

agents, this may occur when sublingual use is combined with long acting agents.

5. Withdrawal symptoms may occur (an indication of tolerance) when nitrate agents are tapered or discontinued, this may precipitate anginal attacks.

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.

β-Blockers

• β-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 β1 receptors, selective β1 antagonists (atenolol, metoprolol and acebutolol) lose their selectivity at high doses and at least partially block β2 receptors (a concern for bronchospastic disease).

• β1 antagonists reduce the frequency and severity of anginal episodes particularly when used in combination with nitrates. β1 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 β blockers: asthma, diabetes, bradycardia, PVD & COPD.

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

Ca+2 Channel BlockersCa+2 channel blockers protect tissue by inhibiting the entrance of Ca+2

into cardiac and smooth muscle cells of the coronary and systemic arterial beds.

All Ca+2 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.

Agents 1. Nifedipine: This Ca+2 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.

2. 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 Ca+2 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.

3. 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, Nitroglycerin (NTG) taken at intervals after tadalafil