cGMP mediated smooth muscle vasodilators

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cGMP mediated smooth muscle vasodilators

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A 25-year-old woman, gravida 1, para 0, presents to the emergency department at 25 weeks gestation with a severe headache and epigastric pain for the past few hours. She has had no chronic problems, and her pregnancy was uneventful until now. She does not smoke or use alcohol or illicit drugs. Family history is noncontributory. Temperature is 37.33°C (99.2°F), pulse is 58/minute, respirations are 18/min, and blood pressure is 180/100 mm Hg. On physical examination, the patient is uncomfortable and has mild epigastric tenderness. 3+ pitting edema is present in bilateral legs. Fetal heart sounds are normal. Dipstick urine shows 3+ protein. After stabilization, which medications should be administered for blood pressure control in this patient?  

External References

First Aid

2024

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2021

Afterload

hydralazine p. 323

β -blockers p. 245

hydralazine and p. 323

cGMP (cyclic guanosine monophosphate)

hydralazine and p. 323

Headache p. 532

hydralazine p. 323

Heart failure p. 316

hydralazine for p. 320

Hydralazine p. 323

gestational hypertension p. 322, 660

heart failure p. 316

Lupus-like syndrome

hydralazine p. 323

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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. All right, 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, which is 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. All right, 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.

Summary

cGMP, or cyclic guanosine monophosphate, is a second messenger that mediates smooth muscle relaxation in response to various vasoactive agents such as nitric oxide (NO). cGMP-mediated smooth muscle vasodilators, are drugs that promote vasodilation by increasing the effect of cGMP. These drugs include hydralazine and nitroprusside, used to treat hypertension, and nitrates used to treat angina pectoris.

Sources

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  2. "Rang and Dale's Pharmacology" Elsevier (2019)
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  5. "Formation of Nitric Oxide by Aldehyde Dehydrogenase-2 Is Necessary and Sufficient for Vascular Bioactivation of Nitroglycerin" Journal of Biological Chemistry (2016)
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