At the most basic level, angina is chest pain that is associated with an imbalance between oxygen demand by the heart and oxygen supply to the heart.  As the former increases and/or the latter decreases, areas of ischaemia will develop, resulting in pain.  The imbalance may be caused by increased demand such as exercise/overexertion or eating (both of which divert blood flow from the heart to the whole body or stomach, respectively).  Alternately, supply may be limited by constriction or occlusion of coronary vessels as discussed below.

Typical Angina -- The pain of angina generally begins beneath the sternum as a vague pain.  It may proceed to a severe, crushing (pressure in the chest), or intense pain that may radiate to the left shoulder, down the arm, to the back, throat, or even the jaws and teeth.  Typical angina is often associated with atherosclerosis; which, with the accompanying plaque formation in the coronary vessel, occludes blood flow to the myocardium.  Consequently, even a small increase in demand by the heart may result in an anginal attack.  (Recall that vessels with large amounts of plaque may loose their ability to constrict and/or dilate effectively.)  Typical angina may also occur following an MI (note that is may also precipitate an MI).  ECG changes associated with typical angina include ST depression.  Typical angina may be further subdivided into stable or unstable angina.

Stable Angina -- May occur for many years, but somewhat predictably (following exertion, a meal, et c.).
Unstable Angina -- Typical stable angina that has become unpredictable.  There is usually an increase in the frequency and intensity of pain.  Unstable angina often presents as a medical emergency.
 
Atypical (Variant, Prinzmetal's, Vasospastic) Angina -- This type of angina is often not exercise-induced nor is it associated with atherosclerosis.  It often occurs during rest (even at night during sleep) and often occurs at about the same time of day.  As the name implies, it is caused by sudden and intense coronary vasoconstriction that results in impeded blood flow to the myocardium.  ECG changes associated with atypical angina include ST elevation.

Since in either type of angina there are problems with getting needed blood and oxygen to the heart, a review of the control of coronary blood flow (specifically vasoconstriction and vasodilatation) is warranted.  Basically there are two pathways which may result in vascular constriction (and reduce blood flow) and two pathways that allow relaxation (and subsequent dilatation, increasing blood flow).
Vasoconstriction -- Constriction may result from either alpha adrenergic receptor activation or calcium influx without alpha involvement.
The alpha receptor is coupled to a G protein that activates the phospholipase C cascade.  This activates various protein kinases that ultimately result in phosphorylation of myosin and subsequent muscle fibre contraction-coupling.

Calcium influx will initiate a Ca-calmodulin mediated cascade event that also results in phosphorylation of myosin light chain via the specific enzyme myosin light chain kinase.  Again, this permits myosin/actin interaction and contraction coupling.


Vasodilatation --

Beta-2 receptor activation results in activation of the second messenger adenylyl cyclase/cAMP.  This pathway also activates protein kinases that phosphorylate myosin light chain kinase (the enzyme that allows contraction in the Ca-calmodulin pathway).  This phosphorylation INACTIVATES myosin light chain kinase, thus preventing any contraction that would be induced by the Ca-calmodulin pathway.

The endothelium of the vessel may release a local vasodilator (endothelium derived relaxation factor -- identified as nitric oxide, NO).  NO will interact with and activate the guanylyl cyclase/cGMP  second messenger system.  This pathway results in dephosphorylation of phosphorylated myosin light chain, thus ending the contractile process initiated by either of the contraction pathways.  NO therefore stops contraction, allowing passive vasodilatation.

Organic Nitrates & Nitrites

The nitrates (esters of nitrous acid) and nitrites (esters of nitric acid) entered the realm of medicine with the synthesis of nitroglycerin in 1846.  It was not until 1857 that a nitrite was used medically (amyl nitrite by Brunton) and nitroglycerin was first used in 1879.  Current agents used include:
Amyl nitrite -- inhalational
Nitroglycerin -- oral, topical (paste, patches), sublingual, and parenteral
Isosorbide dinitrate -- oral, sublingual
Isosorbide mononitrate -- oral
Erythrityl tetranitrate -- oral, sublingual
Pentaerythritol tetranitrate -- oral
Mechanism of Action -- These agents are all prodrugs.  There are converted in vivo to NO or a NO agonist to act at the endogenous G-coupled receptor for NO.  This in turn activates the GC second messenger ultimately causing dephosphorylation of myosin light chain, ending the contractile process, thus resulting in vasodilatation.

Haemodynamic Response -- This class of drugs relaxes smooth muscle of arteries, veins, and non-vascular smooth muscle.  It exhibits preferential dilatation of venous beds (possibly due to more EDRF control in veins than arteries).  This venous dilatation will result in hypotension, decreased ventricular end diastolic pressure (due to decreased preload), slight reflex tachycardia, and little change in overall peripheral resistance (due to minor effect in large arteries).  Facial arteriolar and meningeal arterial dilatation contribute to the side effects of flushing and headache seen with organic nitrates/nitrites.

Efficacy in Angina

Effects on Coronary Flow (Supply) -- Recall that atherosclerotic plaques cannot constrict or dilate to as great an extent as vessels with no plaque.  Therefore coronary flow might not increase as much as anticipated.  However, dilatation of larger vessels within the heart may result in some slight increase in blood flow to ischaemic areas.

Myocardial Oxygen Requirements (Demand) -- The vasodilation that is produced by organic nitrates will decrease afterload (some, due to slight arterial dilatation) and preload (greater, due to preferential venous dilatation).  This will decrease the workload on the heart, thus decreasing the myocardial oxygen demand.  This is the primary benefit of the organic nitrates/nitrites.
 

Other and Adverse Effects -- Relaxation of bronchiolar, gall bladder, biliary duct, and gastro-intestinal smooth muscle may occur but does not contribute to any side effects.  The primary side effects encountered with organic nitrates/nitrites are headache, flushing, dry mouth, dizziness, and nausea (mild and relatively uncommon).  Higher concentrations may cause hypotension, reflex tachycardia.  Toxic concentrations may cause methaemaglobinaemia (which may proceed through cyanosis, acidosis, coma, and seizures to death).

Tolerance develops rapidly to these drugs (there is also cross-tolerance within the class).  However, brief drug holidays (as little as overnight or one day skipped) will allow the tolerance to disappear, and drug efficacy to return.

Dihydropyridines (Nifedipine, Nicardipine, Nimodipine, Isradipine, Felodipine, Amlodipine)
Benzothiazepines (Diltiazem)
Phenylalkylamines (Verapamil)
Miscellaneous (Bepridil)

Mechanism of Action -- All of these drugs block calcium influx by blocking the calcium channel.  There is some specificity for particular calcium channels.
 
Review of calcium channels -- There are currently six (6) identified calcium channels.  In general, calcium channels may be opened (activated) by one of three mechanisms.
1) Receptor-mediated (ligand-gated) channels, open via neurohumoral control
2) Voltage-gated channels, open in response to changes in membrane potential
3) Stretch-gated channels, open in response to vasodilatation
Each channel is composed of five (5) subunits (2 alpha subunits and 1 each beta, gamma, and delta subunit).  It has been shown that the dihydropyridine class of calcium antagonists binds to the alpha-1 subunit.  it is presumed that other agents also bind here.  The specific calcium channels and agents that block them are summarised below:
L Type -- These are found in vascular smooth and myocardial muscle.  Their activation will result in excitation contraction-coupling, causing contraction.  They are voltage dependent with slow activation at high (more positive) voltage and produce a long lasting calcium current (stay open for a longer period of time, relative to other calcium channels).  L channels are blocked by all the currently available calcium antagonists.

N Type -- These are found primarily on neurones.  Activation will cause the release of neurotransmitters.  The N channel is blocked by the snail venom omega-conotoxin.  The calcium antagonists have no efficacy at this channel.

P Type -- These channels are dispersed body wide.  Their specific function has not been determined.  They are blocked by the funnel web spider venom atraxatoxin but not by the agents used in medicine.

Q Type -- Recently discovered and poorly characterised.

R Type -- Recently discovered and poorly characterised.

T Type -- These are found primarily in the SA node (and to a lesser extent, the AV node).  They are low voltage activated channels that produce a short calcium current (open and close relatively quickly).  T channels are blocked by verapamil and to a lesser extent by bepridil and diltiazem.  They are NOT blocked by the dihydropyridines.
 

All calcium channels are time-delayed and must close and assume resting conformation before they may be opened again.  Additionally, the pharmacodynamic response of calcium channel activation is always related to some action of calcium following its influx.  In vascular smooth and myocardial muscle this is manifested as muscle contraction.
 
Haemodynamic Effects -- These agents cause the preferential vasodilatation of arterial beds.  They have little effect on venous beds.  They will reduce peripheral resistance, afterload, and blood pressure.  They will also exert negative inotropic effects, decreasing cardiac output.  The decrease in blood pressure may cause reflex tachycardia.  This is a common side effect with the dihydropyridines.  Note, however that this does not occur with the other calcium antagonists.  This is due to their ability to block not only L type but also T type channels.  Therefore, the increased sympathetic tone that produces reflex tachycardia is not transmitted through the SA node and does not occur.

Efficacy in Angina

Blood Flow -- Calcium antagonists, through their direct vasodilatation, may increase coronary blood flow slightly.

Myocardial Oxygen Demand -- This is probably the primary source of the beneficial effects of calcium antagonists.  By virtue of their ability to decrease afterload and peripheral resistance, cardiac workload is decreased and therefore myocardial oxygen demand is decreased.

Adverse Effects -- These agents have been discussed previously.  Please consult previous notes for the adverse effects of calcium antagonists.

Propranolol (non-selective with membrane stabilising action)
Nadolol (non-selective with membrane stabilising action)
Atenolol (selective beta-1 blocker)
Metoprolol (selective beta-1 blocker with membrane stabilising action)
 
Mechanism of Action -- These agents are competitive antagonist for the beta receptors.  Non-selective blockers will antagonise both beta-1 and beta-2 receptors, however at higher doses, even beta-1 "selective" antagonists may show beta-2 blockade.  Consequently they inhibit the normal action of noradrenaline at these receptors.

Haemodynamics -- Blockade of beta-2 receptors will inhibit vasodilatation (or allow vasoconstriction to occur).  This is not the therapeutic effect that is beneficial in angina (in fact it could be detrimental and worsen an attack of angina -- for this reason beta blockers are NEVER used in vasospastic angina, which is directly caused by intense vasoconstriction).   They also block beta-1 receptors to produce negative inotropic and negative chronotropic effects on the heart.  This in turn causes a reduction in CO with subsequent decrease in peripheral resistance.

Efficacy in Angina

Blood Flow -- These agents do not increase blood flow to ischaemic areas.

Myocardial Oxygen Demand -- The efficacy of beta blockers in angina is due solely to their ability to decrease oxygen demand by decreasing the workload of the heart (by their negative ino- and chrono-tropic effects).
 

Adverse Effects --  These agents have been discussed previously.  Please consult previous notes for the adverse effects of beta antagonists.

Mechanism of Action -- Dipyridamole inhibits adenosine uptake and also inhibits phosphodiesterase 3.  Therefore it has a dual mechanism, both of which may cause vasodilatation.  Adenosine is a vasodilator, therefore inhibition of uptake will prolong its action.  Additionally, since cAMP mediates the vasodilating effects of beta-2 receptors, inhibition of its metabolism (by inhibition of PDE₃) will prolong  its action.

Haemodynamic Effects --

Blood Flow -- Through its vasodilatatory effects, dipyridamole may decrease coronary vascular resistance and therefore increase blood flow/oxygen delivery to oxygen-starved myocardium.  This has not been proven definitively, but is an acceptable theory for its clinical usefulness in angina.  NOTE that the FDA has withdrawn approval of dipyridamole for chronic treatment of angina.  This does not prevent is prescription by physicians for that purpose and its use may be encountered in the clinic.

Myocardial Oxygen Demand -- Dipyridamole probably has minimal effect on this parameter, although peripheral vasodilatation could, again theoretically, lower total peripheral resistance and thus decrease cardiac workload.
 

Adverse Effects -- Dizziness and abdominal distress may occur with initiation of therapy, however, they usually do not persist.