Module 16 Flashcards
The use of ACE inhibitors is associated with cough in about 10% of patients and serious angioedema in about 0.1%. How might the mechanism by which ACE inhibitors reduce blood pressure be related to these side effects? Under what clinical circumstances would you be concerned that this effect (the effect mediated by the mechanism that probably causes cough and angioedema) could lead to serious consequences? What treatment is based on this hypothesis and how effective is it? If you had a patient who is intolerant to ACE inhibitors because of cough or angioedema, what would be a good alternative that works by a related mechanism?
ACEi inhibit the hydrolysis of angiotensin I, which converts it to angiotensin II. But the ACE inhibitors are not totally specific, and they also inhibit the hydrolysis of kinins, in particular bradykinin, which leads to its inactivation.
- This off-target effect results in an increase in bradykinin and can lead to cough (incidence 5-35%) and angioedema (incidence as high as 0.7%). This appears to be more frequent when the pollen count is high.
- Angioedema can also occur in the small bowel. Although the reaction is not usually life-threatening, it can be, and it is especially dangerous in patients with asthma.
It would be expected that a direct renin inhibitor such as aliskiren would be safe in such patients, and although it is much safer with respect to angioedema, there have been cases of angioedema in ACE sensitive patients treated with aliskiren
What is aliskiren? What has been reported with the combination of it with ACE inhibitors?
- Aliskiren is the first in class of the nonpeptide renin inhibitor. Renin is upstream of the angiotensin I to angiotensin II conversion; therefore, it works on the same pathway as the ACE inhibitors. In patients with diabetes and in combination with ACE inhibitors there is an increase in the risk of kidney impairment, low blood pressure, and hyperkalemia; therefore, a new contraindication was added to the product label to reflect this risk.
What effects does vasoactive intestinal polypeptide (VIP) have on the intestine and other organs?
- This hormone was named because of its effects on the intestine, but it has a wide range of effects in other organs. There are tumors, usually benign, that secrete VIP (called VIPomas). They are in the differential diagnosis of unexplained diarrhea.
- Effects in the GI tract include relaxation of smooth muscle including that in the lower esophageal sphincter, stomach, and gall bladder, an increase in flow and water content of intestinal secretions, an increase in pancreatic bicarbonate and pepsinogen secretion, and an increase in bile flow, a decrease in gastric acid secretion, an increase in intestinal motility, and an increase in pepsinogen secretion.
- In the brain it affects circadian timing and prolactin secretion.
- In the heart it causes coronary vasodilation and has positive inotropic and chronotropic effects on the heart, which may be useful for the treatment of heart failure.
- It increases vaginal lubrication in women and stimulates growth hormone secretion.
- In the lung it has antiinflammatory and airway dilatory effects that may be useful for the treatment of asthma, chronic obstructive lung disease, and pulmonary arterial hypertension.
- the major point is that it has such pleotropic effects, and you should know that it can cause diarrhea.
What is sumatriptan, and why is it and related drugs contraindicated in patients with significant cardiovascular disease?
- Sumatriptan and related drugs are serotonin agonists (5-HT1D and 5-HT1b).
- They cause vasoconstriction of arteries in the brain and a decrease in activity of the trigeminal nerve. They are useful for the treatment of migraine and cluster headaches. However, they can also cause coronary artery vasospasm and precipitate a heart attack.
What type of antidepressant can cause drug interactions with sumatriptan, and what is the mechanism?
a major metabolic pathway for sumatriptan is oxidation by monoamine oxidase A; therefore, it should not be used in patients taking an MAO inhibitor.
What is the evidence that feverfew is active for the treatment of migraine headaches? What is thought to be the active agent? What is thought to be the mechanism by which feverfew works? What adverse reactions have been associated with the use of feverfew? Identify the two chemically reactive structures in the molecule. From the structure of the active agent what type of toxicity might you be concerned with? Have any chronic toxicity studies been done in animals or humans? Does commercial feverfew always contain what is considered the active agent?
- The evidence does not support the efficacy of feverfew for the treatment of migraine headaches. The theory is that parthenolide, an ingredient of feverfew, inhibits platelet aggregation and serotonin secretion.
Parthenolide has two reactive sites, an epoxide and a Michael acceptor (the double bond conjugated to the ketone. Because of its intrinsic chemical reactivity and low water solubility, its oral bioavailability is quite low. In addition, because of its chemical reactivity, it probably has a very short shelf life so that even if the original product contained parthenolide, the product often does not when it is purchased. Furthermore, its chemical reactivity may make it a carcinogen, although careful studies have not been performed. Like other chemically reactive chemicals it can cause contact hypersensitivity.
