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cGMP mediated smooth muscle vasodilators

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cGMP mediated smooth muscle vasodilators

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cGMP mediated smooth muscle vasodilators

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Cyanide toxicity is associated with high doses of the vasodilator .

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A 62-year-old female with hypertension develops drug-induced lupus secondary to hydralazine therapy. You take a biopsy of a lesion on her face and send it to pathology. Which of the following histopathologic findings in the basal layer of the epidermis is consistent with this diagnosis?


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cGMP-mediated smooth muscle vasodilators, as their name implies, are medications that promote dilation of blood vessels by potentiating the effect of cyclic guanosine monophosphate, or cGMP for short.

These medications are mainly used to treat hypertension, heart failure, and angina pectoris, which is a pain caused by reduced blood flow to the heart muscle.

Alright, first, let’s focus on the structure of blood vessels.

Blood vessels have three layers, also called “tunics,” or coverings, that surround the vessel lumen, the hollow part of the vessel that contains the blood.

The innermost tunic is the tunica intima, which includes the endothelial cells; the next one is the tunica media, or middle tunic, which is mostly made of smooth muscle cells and sheets of elastin protein; and finally, there’s the tunica externa, or outside tunic, which is made up of loosely woven fibers of collagen.

Moreover, the tunica media can contract, causing vasoconstriction, where the lumen gets a lot smaller; or it can relax, or vasodilate, causing the lumen’s diameter to increase, allowing for more blood flow.

Now, within endothelial cells of the tunica intima, there’s an enzyme called nitric oxide synthase, which uses the amino acid L-arginine and molecular oxygen to synthesize nitric oxide or NO for short.

Once synthesized, nitric oxide diffuses to adjacent smooth muscle cells in the tunica media, where it binds and activates an enzyme guanylyl cyclase.

This enzyme converts guanosine triphosphate, GTP, into cyclic guanosine monophosphate, cGMP, which is a second messenger that induces relaxation of smooth muscle cells in vessel walls.

Alright, now moving on to pharmacology. cGMP-mediated smooth muscle vasodilators are subdivided into two main groups: antianginal medications, which are used to treat anginal pain, when oxygen delivery to the heart is inadequate for normal heart function; and antihypertensive medications, which are used to treat high blood pressure.

First, let’s start with antianginal medications, also known as nitrates.

These medications are actually prodrugs, meaning that they need to be converted into their active form, called nitric oxide, before they can produce the desired effect.

Once converted, nitric oxide diffuses to surrounding smooth muscle cells and stimulates guanylyl cyclase, thereby increasing the concentration of cGMP.

Ultimately, this results in vasodilation of both veins and arteries. But, even though they affect both, nitrates dilate veins and venules more than they dilate arteries and arterioles.

Moreover, vasodilation of small veins and venules result in peripheral pooling of the blood and decreased return of the venous blood to the heart.

This way nitrates predominantly reduce preload, which is the volume of blood that the heart must eject with each contraction.

On the other hand, vasodilation of small arteries and arterioles lowers the systemic vascular resistance, so nitrates will also reduce afterload, which is the pressure that the heart must work against to eject the blood.

Ultimately, by reducing preload and afterload, nitrates reduce the amount of work the heart has to do, and eventually decreasing the heart’s oxygen consumption; but, at the same time, they increase oxygen delivery to heart tissue by dilating coronary arteries to a small degree.

Common medications in this class include nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate (the active metabolite of isosorbide dinitrate).

Nitroglycerin can be administered sublingually, intravenously, or transdermally.

The sublingual form of nitroglycerin has a rapid onset, causing a vasodilatory effect within the first 3 minutes after administration that lasts approximately up to 25 minutes.

This makes sublingual nitroglycerin useful for the treatment and short-term prevention of an acute anginal pain.

On the other hand, intravenous nitroglycerin is reserved for individuals who don't respond to sublingual nitroglycerin; while transdermal nitroglycerin is indicated for the long-term prevention of angina pectoris.

In contrast to nitroglycerin, isosorbide dinitrate and isosorbide mononitrate are taken peroral, but they have a longer onset of action of 15-30 minutes and duration of action of 6-10 hours, which makes them useful for the long-term prevention of angina pectoris.

Common side effects of nitrates include flushing, headache, orthostatic hypotension, and reflex tachycardia, which is treated by co-administration of beta blockers.

Interestingly enough, workers in the construction and demolition industries who are regularly exposed to nitroglycerin or isosorbide dinitrate at their job can develop “Monday disease.”

This is characterized by building up tolerance throughout the workweek and then losing that tolerance during the weekend.

When they re-expose themselves to the nitrates the following monday, they experience tachycardia, dizziness, and headaches until they develop tolerance again.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Hurst's the Heart, 14th Edition: Two Volume Set" McGraw-Hill Education / Medical (2017)
  5. "Formation of Nitric Oxide by Aldehyde Dehydrogenase-2 Is Necessary and Sufficient for Vascular Bioactivation of Nitroglycerin" Journal of Biological Chemistry (2016)
  6. "Inhibition of sustained smooth muscle contraction by PKA and PKG preferentially mediated by phosphorylation of RhoA" American Journal of Physiology-Gastrointestinal and Liver Physiology (2003)