Module 44 Flashcards
What is known about the mechanism of tolerance to nitrates?
- Nitroglycerine has been used for more than a century for the treatment of angina. It works by releasing NO, which is a vasodilator.
○ NO works by activation of soluble guanylate cyclase leading to an increase in cGMP. Actually, it appears that is not really NO, but some other NO-related molecule that activates guanylate cyclase. It works very rapidly, but when administered repeatedly, tolerance develops quickly, and it is no longer effective.
The mechanism of this tolerance has been the focus of research for >30 years without much progress until recently. It now appears that the mechanism by which nitroglycerine releases NO involves catalysis by mitochondrial aldehyde dehydrogenase. If you remember from PHM 144, there is a thiol at the active site of aldehyde dehydrogenase. Nitroglycerine also stimulates the production of reactive oxygen species (especially superoxide) in mitochondria, and this leads to oxidation of the aldehyde dehydrogenase thiol to a disulfide, which inactivates the enzyme. In addition, nitroglycerine causes nitrosation of soluble guanylate cyclase, which may also play a role in the tolerance. Not all nitrates are bioactivated by aldehyde dehydrogenase, and therefore tolerance to different nitrates is different. For example, isosorbide mononitrate and dinitrate are activated by a different enzyme, probably P450. Furthermore, pentaerythrityl tetranitrate does not appear to induce tolerance. It is very complex and not completely understood. No good prospective studies have been performed, but there are retrospective studies that suggest that chronic nitrate use worsens cardiac prognosis.
What is the mechanism of action of sidenafil (Viagra), and how was it discovered? One of the contraindications is the concurrent use of nitrates. In addition, it causes visual disturbances. What does the visual disturbances say about the selectivity of this agent for the desired receptor?
- Sidenafil is a phosphodiesterase inhibitor that was developed for treating congestive heart failure. As with other agents designed to increase the force of cardiac contraction, sidenafil did not decrease cardiac mortality, but it had a side-effect that made Pfizer a lot of money.
- By inhibiting phosphodiesterase it decreases the hydrolysis of cGMP, while nitrates produce an increase in the production of cGMP. When combined, there is a synergistic increase in cGMP that causes a marked decrease in blood pressure. There are 7 different phosphodiesterases. The phosphodiesterase that is responsible for the major pharmacological effect of sidenafil is type 5, while type 6 is in photoreceptors in the eye. Therefore, the fact that sidenafil causes visual disturbances means that it also inhibits phosphodiesterase type 6 to some degree.
In a large clinical trial of various treatments for hypertension called the MRFIT trial (Multiple Risk Factor Intervention Trial), it appeared that the use of diuretics, especially at high dose, might have been associated with a higher mortality than some other treatments. If this is true, and the evidence is not that clear, speculate on possible mechanisms.
- Electrolyte disturbances, especially hypokalemia and hypomagnesemia, increase the risk of serious cardiac arrhythmias. This is especially a risk in patients who have had a heart attack.
What are the choices for treatment of diuretic-induced hypokalemia, and what are the advantages and disadvantages of each?
- The major treatments are potassium supplements and potassium-sparing diuretics such as amiloride. Potassium supplements have two major problems. The first is that they are not very effective because the kidney can eliminate potassium so rapidly that it is very difficult to keep up with the potassium loss.
In addition, potassium supplements do nothing to replace the loss of other elements caused by thiazides such as magnesium and selenium. Therefore, in my opinion, potassium-sparing diuretics are a better choice for treatment of thiazide-induced hypokalemia. ACE inhibitors also increase potassium levels
By what mechanism do thiazide diuretics help to prevent kidney stones?
- Thiazide diuretics decrease calcium excretion by the kidney. The mechanism is not exactly clear, at least not to me. Most kidney stones are calcium oxalate; therefore, this decreases the risk of kidney stones. Thiazide diuretics also appear to decrease the risk of osteoporosis by decreasing calcium excretion.
The chairman of medicine of a teaching hospital was treating himself for hypertension. He developed joint pain and started to take an NSAID. A few months later he had a massive stroke and died (It was a hypertensive/thrombotic stroke not a hemorrhagic stroke). How might the use of an NSAID contributed to the occurrence of the stroke?
- Although NSAIDs do not cause a significant increase in blood pressure in most patients, patients who are started on chronic NSAID therapy should have their blood pressure checked. It is especially true of patients with decreased renal perfusion because of hypovolemia or vascular dysfunction. In these patients there is a prostaglandin response (prostacyclin and PGE2) to increase renal blood flow. If this is blocked by an NSAID, there is an increase in sodium and water retention, and this increases blood pressure. In addition to the renal effects, there are also direct effects on blood vessels
- the bottom line is that the effect is much greater in patients that already have hypertension. Different NSAIDs appear to have different effects, and naproxen appears to cause more of an increase in blood pressure than aspirin or COX-2 selective agents.
Spironolactone was demonstrated to improve survival in patients with congestive heart failure in a clinical trial. This led to an increase in its use for congestive heart failure. What type of toxicity resulted, and why was it not detected in the clinical trial?
After the clinical trial there was a large increase in the use of spironolactone for patients with heart failure. Unfortunately, this led to many cases of hyperkalemia with some deaths. This is because in the clinical trial co-treatment with other drugs that increase potassium were prohibited, and potassium levels were monitored. This did not happen in the “real world”.
How are the mechanisms of action of nitroprusside and nitrates related? Why are the clinical effects of these agents so different?
- Both nitroprusside and nitroglycerine lead to the release of NO, but the location is different.
- The major effect of nitroglycerine is on veins because the major site of bioactivation is in veins. Vasodilation of veins leads to blood pooling and a decrease in cardiac preload (the amount of blood that needs to be pumped), and this appears to be the major mechanism by which nitroglycerine decreases angina, although it also causes dilation of coronary arteries.
- In contrast, the release of NO from nitroprusside is nonenzymatic, and its major effect is on arteries leading to a decrease in blood pressure and a decrease in afterload, i.e. the pressure against which the heart has to pump. The effect on blood pressure is immediate and profound. Therefore, extreme care must be taken not to lower blood pressure too much.
