Smooth Muscles Flashcards
What are the examples of nitrates drugs
Nitroglycerine and isosorbide mono/dinitrite
Explain the MOA of nitrates.
NO activates guanylyl cyclase in vascular smooth muscle causing an increase in cGMP. ↑cGMP leads to a decreased intracellular Ca2+ and a decreased activity of myosin light chain kinase, causing myosin light chain dephosphorylation, preventing the interaction of myosin with actin and causing dilation of smooth muscles “cut P lock off chain”.NOs primarily cause dilation of veins, leading to a decrease in cardiac preload, causing a decrease in cardiac filling and wall stress, which result in a reduced myocardial oxygen demand “pants, ventilator, and hose”.
Explain why nitroglycerin is given sublingually?
Oral bioavailability of nitrates is low due to rapid metabolism by the liver. Sublingual route of nitrate administration is preferred for quick acute symptom relief to minimize first pass mwtabolism by liver
What are the indications for nitrates?
- Nitrates can treat chronic stable angina, unstable angina, and variant (prinzmetal) angina.
- When nitrate therapy is needed for prophylaxis, oral preparations can be given, including isosorbide dinatrate and isosorbide mononitrate “pair of sticks, single stick”. Oral nitrate preparations require larger dosing to avoid first-pass metabolism by the liver “large pile”. IV nitroglycerine can be used in hypertensive emergency (e.g. pulmonary edema d/t ↑↑BP). Nitroglycerine can be used as acute treatment for pulmonary edema during hypertensive emergency
What are the side effects of nitrates?
- Nitrates should be avoided in patients with Right-sided MI, since nitrates reduce right ventricular preload, instead IV fluids should be given to improve flow out of the right ventricle.
- A side effect of nitrates is that it can cause orthostatic hypotension. Nitrate-induced orthostatic hypotenstion causes reflex tachycardia; but we want to reduce the work-load of the heart, so nitrates in combination with β-blockers may be helpful in these patients.
- Nitrates can cause throbbing headaches and facial flushing
- Methemoglobinemia may occur as a result of prolonged nitrate therapy – nitrates can cause Fe2+ -> Fe3+ “oxidized wheels”.
How often should nitrates be taken for prophylaxis?
Developing tolerance to nitrates is minimized by going on an every-other-day regimen. Developing tolerance to nitrates and then taking a break, followed by restarting them can cause a case of the “Mondays” where headaches and dizziness are experienced. A danger of the “Mondays” is experiencing profound orthostatic hypotension and reflex tachycardia that induce MI.
When are nitrates contraindicated?
- Right sided heart failure
- Patients with erectile dysfunction who are taking Sildenafil or other PDE-5 inhibitors
- Nitrates are also contraindicated in patients with hypertrophic obstructive cardiomyopathy.
Explain the pathophysiology of migraines.
The pain experienced in a migraine is due to the activation of the Trigeminal Nerve afferents that innervate intracranieal arteries, particularly in the meninges “tri-gems”. In migraine pathophysiology, Trigeminal afferents release vasoactive peptides (e.g. CGRP, Substance P, Neurokinin A) onto meningeal vessels, leading to vasodilation and protein extravasation causing neurogenic inflammation that stimulate pain nerve endings in the dura of the meninges “dilated sleeves”.
Explain the MOA of triptans.What are their side effects?
Triptans (e.g. sumatriptan) are an acute treatment for migraines. –Triptans are activators of 5HT-1b and 5HT-1d receptors located on the meningeal vessels, the trigeminal nerve, and the brain stem “sumo headband, hair stem, red headband, ref, & hands”. –Triptans cause vasoconstriction of cerebral and meningeal vessels.Most side effects of triptans are mild, including tingling and muscle weakness. Coronary vasospasm (prinzmetal) may arise as a side effect of triptans. Triptans are contraindicated in patients with angina or coronary artery disease. Triptans are a known trigger of Prinzmetal (variant/spastic) angina. “bottom right”
What other condition can be treated with triptans?What other drugs can be used for migraine prophylaxis?
Cluster headaches can be treated acutely with triptans “lantern cluster”. Combined use of triptans and NSAIDs for acutre treatment of migraines is more effective than use of either drug alone.
Calcium channel blockers, though of questionable efficacy, are widely used for migraine prophylaxis. Beta-blockers can also be used for migraine prophylaxis, due to their affects on BP.
Valproic acid and Topiramate (both anti-epileptics) can be used for migraine prophylaxis.
Tricyclic antidepressants (e.g. Amitriptyline) can be used for migraine prophylaxis.
What does COX1 and COX2 make that leads to vasodilation?
Prostaglandins
Explain the use of Aloprostadil and Indomethacin.
“Dill pickle” “erect bat” Alprostadil (PGE1) is a 2nd line therapy that treats erectile dysfunction – it raises that dill-pickle up in the air! As a vasodilator, Alprostadil (PGE1) can be used for both treatment of erectile dysfunction and for keeping the Ductus Arteriosus open “floppy red hoodie” “knocking open ducts”. PGE2 is a vasodilator made by COX-2 that declines after birth, allowing the ductus arteriosus to close. Like PGE2, PGE1 (e.g. alprostadil) is a vasodilator and an inhibitor of platelet aggregation.In cases of delayed closure of the ductus arteriosus, COX-2 inhibitors/ NSAIDs (e.g. indomethacin) can be used to speed up closing of the PDA by decreasing PGE2 production “guy closing the duct”. Indomethacin (NSAID) is the 1st-line agent used for speeding up the closure of the ductus arteriosus.
Are NSAIDS safe to use for pregnancy?
NSAIDs are not recommended for use during 3rd trimester pregnancy due to risk of premature ductus arteriosus closure (d/t inhibiting production of PGE2).
What are the obstetrics effects of prostaglandins analogs?What drugs are used specifically used for this purpose?
PGE analogs (e.g. misoprostol) have potent oxytocin action, having the ability to induce early labor or terminate pregnancy at any age by promoting uterine contraction “uterine bag spilling out contents”.Drugs:
- Misoprostol -Misoprostol’s use is limited due to its activation of the uterus (oxytocin action) and its activation of the GI tract (diarrhea)
- Dinoprostone (PGE2) is approved for inducing labor or abortion by stimulating contraction of the uterus and ripening the cervix (via oxytocin action).
- Carboprost (PGF2α) is used in obstetrics to promote uterine contraction in order to control postpartum hemorrhage or terminate pregnancy
What is a non obstetric use of misoprostol?
Misoprostol (PGE1) promotes protective mucus secretion by gastric mucosa. At higher doses, PGE1 analogs (e.g. misoprostol) can inhibit gastric acid production. Due to protective effects on the gastric mucosa, Misoprostol (PGE1) can prevent NSAID-induced peptic ulcers.