Smooth Muscles

Question 1

What are the examples of nitrates drugs

Answer 1

Nitroglycerine and isosorbide mono/dinitrite

Question 2

Explain the MOA of nitrates.

Answer 2

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”.

Question 3

Explain why nitroglycerin is given sublingually?

Answer 3

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

Question 4

What are the indications for nitrates?

Answer 4

• 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

Question 5

What are the side effects of nitrates?

Answer 5

• 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”.

Question 6

How often should nitrates be taken for prophylaxis?

Answer 6

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.

Question 7

When are nitrates contraindicated?

Answer 7

• 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.

Question 8

Explain the pathophysiology of migraines.

Answer 8

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”.

Question 9

Explain the MOA of triptans.What are their side effects?

Answer 9

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”

Question 10

What other condition can be treated with triptans?What other drugs can be used for migraine prophylaxis?

Answer 10

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.

Question 11

What does COX1 and COX2 make that leads to vasodilation?

Answer 11

Prostaglandins

Question 12

Explain the use of Aloprostadil and Indomethacin.

Answer 12

“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.

Question 13

Are NSAIDS safe to use for pregnancy?

Answer 13

NSAIDs are not recommended for use during 3rd trimester pregnancy due to risk of premature ductus arteriosus closure (d/t inhibiting production of PGE2).

Question 14

What are the obstetrics effects of prostaglandins analogs?What drugs are used specifically used for this purpose?

Answer 14

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

Question 15

What is a non obstetric use of misoprostol?

Answer 15

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.

Question 16

MOA, indications and side effects of Lotanoprost and Travoprost.

Answer 16

“LA tan sandals” – Latanoprost (PGF2α)“World traveler boots” – Travoprost (PGF2α)Latanoprost and Travoprost (PGF2α) treat glaucoma by increasing outflow of aquous humor, thereby reducing occular pressure. Latanoprost and Travoprost (PGF2α) may induce brown pigmentation in the iris as a side-effect.

Question 17

What is the role of prostaglandins in pulmonary hypertyension?What drugs are used and what are their side effects?

Answer 17

• “High tension rackets” – patients with pulmonary HTN can be treated symptomatically with prostaglandin agonists. However it is important to know that there are numerous diseases that can cause pulmonary hypertension and it is important to treat it by treating the underlying cause of the disease however for patients with persistent symptoms prostaglandins can be used for symptomatic relief “dilated pro cycler” PGI2 (prostacyclin) – is a potent vasodilator and platelet inhibitor, normally synethized by COX-2 in the vascular endothelium. “iLOW & ePRO setting” – iloprost and epoprostenol (prostacyclin/ PGI2 analogs) treat pulmonary HTN. The major adverse effects of iloprost and epoprostenol (prostacyclin/ PGI2 analogs) include headache, flushing, and hypotension. “Boss man stan” – Bosentan treats pulmonary HTN by inhibiting endothelin, causing vasodilation “end of the line” “baggy red shirt”. Bosentan is associated with fatal hepatotoxicity “liver stained shirt”.

Question 18

PDE 5 inhibitors.

Answer 18

“FILL” – ‘-fill’ suffix of Phosphodiesterase Isoform 5 (PDE-5) inhibitors (e.g. sildenafil, tadalafil) increase cGMP by inhibiting its breakdown by phosphodiesterases “don’t phoster disinterest” “GruMP”. Increased cGMP causes decreased intracellular Ca2+, leading to dephosphorylation of myosin light chains and smooth muscle relaxation. PDE-5 inhibitors (e.g. sildenafil, tadalafil) can be used to treat pulmonary HTN, but are more known for their ability to treat erectile dysfunction “erect bat in poster”.

Question 19

Explain the role of histamine in the body.

Answer 19

• Histamine is sequestered inside the granules of mast cells “bee hive”.
• Allergy symptoms are caused by histamine binding to the H1 receptor. The H1 receptor is coupled to Gq protein “Q-dandelion”. H2 receptors are coupled to Gs proteins and lead to an ↑cAMP “2 S’s”. H2 histamine receptors mediate gastric acid secretion “golden gastric honey from stomach pot”.
• Activation of the H1 receptor by histamine increases nasal and bronchial mucus production and vascular permeability “dripping sap & red sap”. In the lung, H1 receptor activation by histamine causes constriction of bronchial smooth muscle “constricted lung branch”. Histamine in the brain functions as a neurotransmitter and has an affect on sleep/arousal “brain tree”.
• H1 mediates type 1 hypersensitivity reactions

Question 20

What are some of the H1 receptor antagonists and what are they used for?What is an off label use of H1 receptor antagonists?

Answer 20

“dragonfly fairy” Diphenhydramine and dimenhydrinate are 1st generation H1 receptor blockers. “Color fairy” – chlorpheniramine is a 1st generation H1 receptor blocker. “fairy cuiSINE” – ‘-ZINE’ suffix – hydroxyzine, meclizine, and promethazine are 1st generation H1 receptor blockers
Uses:
* 1st generation H1-blockers can treat vestibular nausea or motion sickness because they are lipophilic -> so they can cross the BBB -> and act on the vestibular system and brainstem.
* 1st generation H1-blockers can treat insomnia by causing drowsiness, because they are lipophilic -> so they can cross the BBB -> leading to central effects.
Off label use:The blockage of muscurinic receptors by 1st generation H1-blockers (antihistamines) means that they can be used to acutely suppress the extrapyramidal side effects of antipsychotics (by reestablishing dopamine:cholinergic balance), antipsychotics can inhibit the release of dopamine and lead to symptoms as that seen in parkinson’s disease.

Question 21

What are the adverse effects of 1st generation antihistamine drugs?

Answer 21

• An adverse effect of 1st generation antihistamines is that they can antagonize peripheral and central muscurinic receptors (e.g. causing pupillary dilation, dry mouth, urinary retention, constipation, exacerbation of glaucoma, and delirium similar to atropine).
• 1st generation H1 blockers can stimulate appetite and cause weight gain by antagonizing serotonin receptors in the CNS.
• 1st generation H1 blockers can cause dizziness and hypotenstion due to α-1 receptor antagonism.
• H1 receptor antagonists can also antagonize α-1 receptors, serotonin receptors, and muscurinic receptors.
• Cognitive impairment due to 1st generation H1-blockers are more common in the elderly.

Question 22

2nd generation antihistamine drugs.

Answer 22

“Fox, Satyr, and Rat” – Fexofenadine, Cetirizine, and Loratadine are 2nd generation H1-receptor blockers.2nd generation H1-receptor blockers (e.g. Fexofenadine, Cetirizine, and Loratadine) are less lipophilic, so they cannot cross the BBB and are less sedating and have less antimuscurinic, less antiserotonergic, and less anti-alpha1 activity than 1st generation H1-blockers.

Question 23

Explain what happens in asthma short term and long term.

Answer 23

Cross-linking IgE on mast cells result in their degranulation and allergic response which causes local smooth muscle contraction & vascular leakage.If asthma is uncontrolled, chronic airway constriction leads to remodeling and thickening of the bronchiole wall, as well as hyperplasia of the bronchiole vasculature, smooth muscle, and secretory glands & goblet cells.It is important to know that asthma therapy consists of controlling 2 components of the disease: bronchoconstricition that happens immediately after exposure to allergens and the ensuing inflammatory response that has a delayed onset

Question 24

Asthma treatment that involves short acting beta agonists (SABA)

Answer 24

• “Dilated beta-2 tuba” Selective β-2 agonists (e.g. albuterol) treat bronchoconstriction in asthma. Selective β-2 agonists are preferred over non-selective β agonists due to less cardiac stimulation.
• “-Rol rollcall sheet” Most β-2 agonists have a ‘-rol’ suffix (e.g. albuterol, pirbuterol)
• “do not disturb” – terbutaline is a selective β-2 agonist that treats bronchoconstriction in asthma.
• β-2 agonists are available as metered dose inhalers for acute symptom relief (‘rescue inhalers’).
• “balloon” Inhaled corticosteroids (e.g. beclomethasone, budesonide, fluticasone) can be added as daily maintenance therapy for persistent asthma symptoms. Side effect of these is oropharyngeal candidiasis

Question 25

Explain the role of leukotrienes in the development of asthma.

Answer 25

• “lacrosse coach Lox” “curly lox” 5-Lipoxygenase (LOX) produces leukotrienes from AA. Leukotrienes LTB4, C4, D4, and E4 are important regulators of inflammation.
• “LTB4 attracts first responders” LTB4 is a chemoattractant for inflammatory cells (first-responders e.g. neutrophils).
• “gripping lacrosse stick w/ lung-nets” – LTC4, D4, and E4 cause bronchoconstriction, mucus production, and increase airway vascular permeability.
• LTD4 is the most potent bronchoconstrictor.
• “inhibiting coach COX” – ASA inhibition of COX shifts AA metabolism to the LOX leukotriene pathway, which can cause ASA-induced asthma and systemic allergic effects.

Question 26

Explain the role of leukotrience inhibitors in controlling asthma.

Answer 26

• Although they are less effective than inhaled corticosteroids, LT inhibitors can be used for mild-moderate asthma.
• “Lacrosse goal CysLT1” CysLT1 is the receptor for LTD4 (the most potent bronchoconstrictor)
• “Monte the broadcaster” “blocked D4 shot” - Montelukast and Zafirlukast (-‘kast’ suffix) are LTD4 receptor antagonists. Montelukast and Zafirlukast (LTD4 receptor antagonists) are an alternative therapy for mild persistent asthma due to their ability to inhibit bronchoconstriction. LTD4 receptor antagonists (Montelukast and Zafirlukast) block LTD4 receptors, causing bronchodilation “dilated scarf”.
• The main advantage of LTD4-receptor antagonists (Montelukast and Zafirlukast) is that they are taken orally.
• “godzilla falling on coach Lox” – Zileuton is an alternative therapy for mild persistant asthma that works as a direct lipoxygenase inhibitor, preventing the production of leukotrienes. Zileuton has a small risk for hepatoxicity, requiring assessment of liver function and is not recommended for chronic use for asthma.

Question 27

Explain the role of LABA drugs for controlling asthma.When is a patient put on LABA exactly?

Answer 27

• For mild asthma, patients are usually started on a short-acting β-agonist (SABA) inhaler to be used as needed. If asthma is still persistent, they then have daily inhaled corticosteroids added to their regimen. If therapy needs to be stepped up again, the next step may be the addition of a long-acting β-agonist (LABA).
• “salute & formation chart” Long-acting β2-agonists (LABA) (e.g. salmeterol and formoterol) are used to treat moderate to severe persistent asthma.
• “salute & formation chart” Long-acting β2-agonists (LABA) (e.g. salmeterol and formoterol) have a long duration of action due to their high lipid solubility.
• LABAs (e.g. salmeterol and formoterol) can be given as a daily inhaler and are always combined with inhaled corticosteroids.
• Besides LABA, an increased dose of inhaled corticosteroids can treat moderate to severe persistent asthma.

Question 28

Methylxanthine

Answer 28

“Xanthine energy drink” “flyin’”– Methylxanthines (e.g. theophylline) are an alternative therapy for mild to severe persistent asthma. Methylxanthines (e.g. theophylline) are related to caffeine. Theophylline (a methylxanthine) works to increase cAMP by inhibiting its breakdown by phosphodiesterases, aiding in bronchosmooth muscle relaxation, as well as the inhibition of cytokine release. “don’t phoster… go camping”. Of the Xanthines, Theophylline is the most effective bronchodilator. Theophylline is not used much anymore due to a narrow therapeutic index and numerous side effects. Methylxanthines (e.g. theophylline) have CNS side effects including nervousness & tremor and cardiac side effects such as tachycardia and ionotropy. Methylxanthines are metabolized by the CYP450 enzyme.

Question 29

Omalizumab

Answer 29

“IgE gun” – Ag cross-linking IgE on mast cells causes degranulation and release of inflammatory mediators (e.g. histamine).“limousine” – omalizumab is an anti-IgE monoclonal IgG Ab that targets the Fc portion of IgE. Omalizumab is an anti-IgE Ab used as an adjunctive therapy for moderate to sever persistent asthma.

Question 30

Cromolyn sodium

Answer 30

“Chrome Lynn’s bee control” Cromolyn sodium inhibits mast cell degranulation (preventing the release of histamine)

Question 31

How is an acute asthmatic attack such as status asthmaticus controlled?

Answer 31

• “emergency” “guy floating away” – SABAs (e.g. albuterol) are used to treat an acute severe asthma exacerbation along with IV corticosteroids.
• “catepillar” Nebulized ipratropium bromide (anticholinergic) can be added to SABAs to treat an acute severe asthma exacerbation.
• “EPIC” Subcutaneous or intramuscular epinephrine can be used to treat an acute severe asthma exacerbation