Last updated on June 16, 2019 at 20:35
As we saw in pathophysiology is increasing the coronary blood flow the only way for myocardium to receive more oxygen. Recall also that most of the coronary blood flow occurs during diastole. An increase in end-diastolic pressure would decrease coronary blood flow as the pressure would compress the coronary vessels.
The coronary blood flow depends on the difference in pressure between the aorta and the coronary sinus, so we can either decrease it by increasing the aortic pressure or by decreasing the pressure in the coronary sinus.
The endocardium receives the least perfusion due to its location furthest away from the coronaries.
The coronary circulation is regulated by autoregulation and not by autonomic innervation. Metabolites like adenosine, CO2, H+ and endothelial substances like NO and prostaglandins vasodilate coronaries.
The term “collateral circulation” means the alternate circulation “pathway” the blood can take around a blocked artery or vein. The myocardium has some collateral circulation that the blood can use when an artery is blocked. Collateral circulations are often smaller vessels that are close to the blocked vessel.
The most common reason for decreased coronary blood flow is atherosclerosis of the coronary arteries, a condition called coronary artery disease (CAD).
The oxygen supply of the myocardium depends on:
- The coronary resistance, i.e.:
- The degree of vasodilation of the coronaries
- The degree of atherosclerosis of the coronaries
- The pressure gradient between the aorta and the coronary sinus
- The duration of diastole
- The oxygen transport capacity of the blood
The oxygen demand of the myocardium depends on:
- The heart rate
- The contractility
- The strain of the myocardium
Stable angina is the condition where anginal pain only occurs during exercise. In this disease is the coronary oxygen supply sufficient in rest but not when exercising. This occurs when there is obstruction of 70% of the coronary lumen due to atherosclerosis.
Unstable angina is the worse condition, where anginal pain occurs not only during exercise but at rest as well. This is usually due to a loose plaque in the coronaries that sometimes obstructs the lumen and sometimes has thrombi growing on it. Unstable angina is often a precursor for myocardial infarction.
Acute myocardial infarction is what occurs when the occlusion is so severe that the perfusion of the myocardium decreases enough to cause ischaemia and necrosis. If there is transmural infarction is there ST elevation, if there is only subendocardial infarction is there no ST elevation.
Prinzmetal angina, also called vasospastic angina, occurs when there is a spasm of a subepicardial coronary artery. This angina may occur in rest and is often seen in relation to drug use, smoking and migraine-treating drugs. Atherosclerotic plaques may also be in the background, as atherosclerotic coronaries have an increased tendency for spasming.
Angina can be managed by either decreasing the heart’s oxygen demand, by increasing the heart’s oxygen supply, or both.
Organic nitrates are drugs that are converted into NO inside the body. These drugs release NO when metabolised.
Angina pectoris, hypertensive crisis.
Short acting nitrates are used to treat acute symptoms of angina, while long acting nitrates are used for angina prophylaxis.
Mechanism of action:
The metabolism of organic nitrates consumes -SH groups from molecules like glutathione. NO stimulates soluble guanylyl cyclase inside smooth muscle cells, causing them to produce more cGMP. The increased cGMP levels activate protein kinase G, which causes dephosphorylation of myosin light chains, which again causes smooth muscle relaxation.
When the smooth muscle inside vessels walls relax is vasodilation induced. Organic nitrates induce much more vasodilation in veins and large coronary arteries than in other arteries. This quickly reduces preload significantly. The result is that the work of the heart is decreased, which also decreases the myocardial oxygen demand.
Organic nitrates are also useful when there is coronary spasming, as is the case in Prinzmetal angina. Coronary vasodilation opposes coronary spasming.
NO not only has vascular effects, but it also prevents platelet aggregation, which is also beneficial to prevent thrombosis.
By reducing the myocardial load and improving the coronary circulation do organic nitrates treat anginal pain efficiently. For this reason are they the first-line treatment of acute anginal symptoms, while they are not preferred for maintenance treatment of angina.
These drugs are prone to development of tolerance, probably due to the depletion of available -SH groups for the drugs to react with. Significant tolerance develops after 24 hours of continuous administration. The tolerance is normally counteracted by taking patients off the nitrates for 6-8 hours every 24 hours.
There are some types of organic nitrate drugs. Let’s look at them.
Glycerol trinitrate (GTN), previously known as nitro-glycerine, is the most famous organic nitrate. It’s well absorbed from the intestine, oral mucous membrane and even the skin, so there are many possibilities of administration.
Due to its rapid onset of action, it’s often used as to treat acute symptoms of angina.
It can be administered IV, as a sublingual spray, as a transdermal patch or as a buccal tablet. In all administrations except transdermal patch does the effect occur within 1 minute. The effect of transdermal patch occurs within 1 hour.
Glycerol trinitrate is given as a transdermal patch for maintenance treatment of angina, or for chronic treatment of congestive heart failure if standard therapy fails. The patch is only worn for 12 hours to prevent tolerance.
The first-pass metabolism in the liver has significant individual differences, so oral bioavailability may vary from 20-100% depending on the individual. Because of this is oral administration not really preferred.
The half-life of glycerol trinitrate is just 1-3 minutes. It’s eliminated renally.
- Orthostatic hypotension
- Combination with PDE5 inhibitors like sildenafil, tadalafil, vardenafil
Isosorbide mono and dinitrate
Isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are two organic nitrates that are related. They’re both metabolised by the liver and are used for acute treatment or chronic maintenance of angina.
ISDN has large and variable first-pass metabolism and is therefore not preferred for oral administration. It can be given sublingually or IV for acute cases.
ISMN has 100% oral bioavailability and is therefore preferred for chronic maintenance treatment of angina by giving it orally.
They’re both contraindicated in hypotension and in combination with PDE5 inhibitors.
Ranolazine inhibits late sodium current in myocardial cells. The exact mechanism of action is unknown.
It’s indicated in stable angina if beta blockers and calcium channel blockers aren’t tolerated or ineffective.
Calcium channel blockers
Calcium channel blockers, are also used in the maintenance treatment of stable angina. These drugs improve anginal symptoms by causing coronary and peripheral vasodilation and reducing myocardial contractility.
Beta blockers relieve anginal symptoms by reducing heart rate and contractility, thereby reducing the oxygen demand. They should not be used in Prinzmetal’s angina. They’re used for maintenance treatment of stable angina.
Many other drugs can also be used in angina, but they’re lesser used now. These include molsidomine, nicorandil, ivabradine, trapidil and trimetazine.
So many drugs have been introduced, it’s hard to keep track of which drugs should be used in which case. Let’s sum it up. As you can see from this the organic nitrates are the most important new drug group from this topic.
- Acute symptoms
- Sublingual GTN or ISDN
- Maintenance therapy with antianginals
- Beta blockers are first choice
- Organic nitrates with prolonged effect or calcium channel blockers can be used together with beta blockers if satisfactory effect is not reached
5. Drugs used to treat congestive heart failure
7. Antihypertensive drugs