Angina pectoris

Angina pectoris
Chest pain due to ischemia of heart muscles

Weak relationship between severity of pain and degree of oxygen supply- there can be severe pain with minimal disruption of oxygen supply or no pain in severe cases
Four types:
Stable angina
Unstable angina
Microvascular angina
Prinzmetal’s angina

Stable angina:
Also called “Effort Angina”
Discomfort is precipitated by activity
Minimal or no symptoms at rest
Symptoms disappear after rest/cessation of activity

Unstable angina:
Also called “Crescendo angina”
Acute coronary syndrome in which angina worsens
Occurs at rest
Severe and of acute onset
Crescendo pain- pain increases every time

Microvascular angina:
Also called Syndrome X
Cause unknown
Probably due to poor functioning of the small blood vessels of the heart, arms and legs
No arterial blockage
Difficult to diagnose because it does not have arterial blockage
Good prognosis

Prinzmetal’s angina
Prinzmetal’s angina is a variant form of angina with normal coronary vessels or minimal atherosclerosis
It is probably caused by spasm of coronary artery

Symptoms
What is the cause of ischemia ?
either ↑ oxygen demand or ↓ oxygen supply
Inadequate blood supply and decreased oxygen supply are directly related to blockade or narrowed vessels

Treatment:
Aims:
Relief of symptoms
Slowing progression of the disease
Reduction of future events like myocardial infarction

Drugs:
1. For treatment of acute attacks:
Organic nitrates/nitrites
2. For prophylaxis:
Organic nitrates
Beta blockers
Calcium channel blockers
Ranolazine
K+ channel opener- Nicorandil

↑ Heart rate
↑ Contractility
↑ Preload
↑ Afterload
↓ Coronary flow
↓ Regional myocardial blood flow
↑ O2
Dema n d
↓ O2
S u p p l y
β-Blockers/Ca2+ channel blockers
Nitrates/Ca2+ channel blockers
Nitrates/Ca2+ channel blockers/antithrombotics/ statins
HEART

Organic nitrates
Pro drugs release NO
↑ Levels of intracellular cGMP
Dephosphorylation of mysosin light chain
↓ Cytosolic calcium
Relaxation of smooth muscle
EDRF –endothelium derived relaxing factor is NO

Relaxation of vascular smooth muscles- vasodilatation
NO-mediated guanylyl cyclase activation inhibits platelet aggregation
Relaxation of smooth muscles of bronchi and GIT

L-Arginine
NO
NO Synthases
Neurotransmission
Vasomotor
effects
Immunomodulation
Endogenous NO pathway
nNOS
eNOS
iNOS

Three different forms of NO synthase are found in humans:
1. Neuronal NOS (nNOS or NOS1)- found in nervous tissue, skeletal muscle- involved in cell communication
2. Inducible NOS (iNOS or NOS2) found in immune system and cardiovascular system- involved in immune defense against pathogens
3. Endothelial NOS (eNOS or NOS3 or cNOS) found in endothelium- responsible for vasodilation

CVS Effects:
Vasodilatation- low concentrations preferably dilate veins
Venodilatation→ decreases venous return to heart
Decreased chamber size and end-diastolic pressure of ventricles
Systemic vascular resistance changes minimally
Systemic BP may fall slightly
Dilatation of meaningeal vessels can cause headache

HR-unchanged or may increase slightly (reflex tachycardia)
Cardiac output slightly reduced
Even low doses can cause dilatation of arterioles of face and neck causing flushing
Higher doses may cause fall in systemic BP due to venous pooling and decreased arteriolar resistance
Reflex tachycardia and peripheral arteriolar constriction occur which tend to restore the systemic BP

Coronary blood flow may initially increase transiently
Subsequently, due to decreased BP, may decrease
Nitrates have dilating effect on large coronary vessels
Increase collateral flow to ischemic areas
Tend to normalize blood flow to subendocardial regions of heart- redistribution of blood
Dilate stenoses and reduce vascular resistance in ischemic areas

Reduction in myocardial O2 consumption is caused by:
Peripheral pooling of blood- reduced preload
Arteriolar dilatation- reduced afterload
↓ in end diastolic volume and LV filling pressure
In platelets increases cGMP: inhibits aggregation
Strongest factor for nitrate effect is peripheral pooling
Nitrates infused into coronary artery- no effect
Sublingual- produces effect
Venous phlebotomy mimics effect of nitrates

How myocardial O2 consumption can be determined?
Double product: HR × systolic BP- approximate measure of myocardial O2 consumption
Triple product: Aortic pressure × HR × Ejection time- roughly proportional to myocardial O2 consumption
Angina occurs at the same value of triple product with or without nitrates, therefore;
The beneficial effects of nitrates appear to be due to decrease in oxygen consumption rather than increase in oxygen supply
Relax all smooth muscles-GIT, biliary, bronchial etc

Pharmacokinetics:
Orally ineffective because of high first pass metabolism
Administered sublingually to avoid first pass matabolism
Tolerance:
Repeated doses lead to tolerance
Dose spacing is necessary
Reasons for tolerance:
↓ Capacity of vascular smooth muscle to convert nitrates to NO – called true vascular tolerance
Pseudotolerance- due to other reasons

ADRs:
Headache- may be severe
May disappear after continued use or,
Decrease dose
Transient episodes of dizziness, weakness, pallor etc- symptoms of postural hypotension
Rash
PDE5 inhibitor (sildenafil) and nitrates given simultaneously can produce severe hypotension
Uses: Angina pectoris, CHF, MI

Administration of nitrates:
Sublingual
Oral: For prophylaxis, require high doses due to first pass metabolism, isosorbide dinitrate (20 mg or more) every 4 h or mononitrate (20 mg or more) OD or BD
Cutaneous:
Ointment (2%) applied to 2.5-5 cm patch of skin

Transdermal nitrogycerine discs impregnated with nitroglycerine polymer- gradual absorption and 24 h plasma nitrate concentration
Onset is slow
Peak concentration in 1-2 h
Interrupt therapy for at least 8 h a day to prevent tolerance

Ca2+ antagonists:
↓ Ca2+ influx
Negative iono and chronotropic effects
Peripheral vasodilatation
Used in variant angina (spasm), exertional angina, unstable angina, MI, hypertension, antiarrhythmic

β-Blockers:
Effective in reducing severity and frequency of exertional angina
May worsen vasospastic angina- contraindicated
Reduce myocardial O2 demand by reducing cardiac work (-ve iono and chrono effects; decrease in BP during rest and exercise)
All β-blockers are equally effective

Ranolazine:
Reserve agent for treatment of chronic, resistant angina
Inhibits cardiac late Na+ current
Effects the Na+ dependent Ca2+ channels and prevents Ca2+ overload that causes cardiac ischemia
Decreases cardiac contractility
No change in HR, BP
Prolongs QT interval so it is contraindicated with drugs that increase QT interval