Smooth Muscle

Smooth Muscle 1. Vasoact Vasoactive ive drugs 2. Allergy & Pulmonary drugs 1.1 – “The Bal Ballad lad of Johnny Nitro”: Nitrates Physiology • Angina results from an imbalance in oxygen demand & delivery → ischemia (rock looks like anvil). For acute treatment of symptoms, need to immediately have vasodilator to ↑oxygen delivery (blasting open obstruction). o Prinzmetal angina is d/t coronary vasospasm (John Henry wearing angina medal) • Phosphorylation of myosin light chain in vascular smooth muscle cells allows myosin interaction with actin → muscular contraction & consequent vasoconstriction (chain around legs & arms of chain gang = myosin light chain; P locks [= phosphate groups] allowing chain to constrict prisoners’ legs; baggy blue pants & red shirts constricted at cuffs = arterial & venous constriction). • Nitric oxide (NO) is produced endogenously by endothelial NO synthase (eNOS) in response to platelet-derived factors, shear stress, acetylcholine, and cytokines. NO increases cGMP in vascular smooth muscle cells (grumpy man controlling steam drill) → ↓Ca. Decreased calcium decreases activity of myosin light chain kinase, resulting in myosin dephosphorylation, preventing myosin interaction with actin (P locks being removed, preventing chains from working & decreasing constriction of prisoners’ legs; freed prisoner). • cGMP cases venous dilation & ↑venous capacitance; veins are most sensitive → ↓preload (Preload tank with ↓↓ arrows). Results in ↓cardiac filling & wall stress, ↓pulmonary vascular pressure, ↓CO, which combined add up to decreased myocardial oxygen demand (blacksmith has removed O2 mask). Have some vasodilation of larger arteries → mild ↓SVR Nitrates • Exogenous nitrates include nitroglycerin, isosorbide mononitrate (single stick of dynamite), & isosorbide dinitrate (double stick of dynamite) • Organic nitrates are metabolized in vascular smooth muscle cells → release of gaseous NO (white NO exhaust emanating from steam drill). Act analogously to endogenously synthesized NO →→ Decreased myocardial O2 demands • Oral bioavailability is low. Sublingual is preferred to avoid first pass metabolism for acute symptom relief. Duration of action is very short, and is not suitable for prophylaxis or maintenance therapy • Indications: o Given orally for maintenance therapy in chronic stable angina (anvil rock; dynamite being thrown into mouth-shaped cave). Isosorbide mononitrate & dinitrate are oral formulations. Doses much higher for sufficient levels to survive first pass metabolism o Sublingual formulations for acute symptoms of either Prinzmetal or “angina of effort” (folded shoe tongue on anvil) o Acute coronary syndrome (ACS) (broken string guitar). Symptomatic treatment only; no mortality benefit in ACS. ▪ ACS includes: unstable angina (episodes of angina at rest, increase in severity, frequency, or duration of chest pain in patients with previously stable angina), NSTEMI, STEMI. o Acute treatment of pulmonary edema (guy with lung-shaped sweat stains on shirt), as seen in a hypertensive crisis o Lowering BP in HTN crisis (involving the presence of end organ damage) (emergency shut off switch) • Adverse effects o Orthostatic hypotension, up to syncope d/t venous blood pooling in lower extremities (fainting gal) ▪ ↓BP can lead to reflex tachycardia (doc with reflex hammer). To maintain low levels of heart stress, may combine with a β-blocker in some patients to prevent this occurrence (β bugler blocking doctor). o Throbbing headaches, flushing d/t vasodilation (guy holding his head, looking a bit sunburned) o Prolonged infusion of high dose nitrate may cause methemoglobinemia (rusty wheels on dynamite cart) o May develop tolerance to nitrate effects over time (tachyphylaxis) (“We will not tolerate” protester). May be d/t decreased metabolism over time in vascular endothelium (tachycardia, ↓contractility, salt & water retention) ▪ Avoid with nitrate free intervals of one day (“We will not tolerate 24h days!”) ▪ Seen more with continuous exposure as in workplace – may see loss of tolerance over weekends, causing headache & dizziness to recur on Mondays; hence the name Monday Disease (Monday clock). o Contraindications ▪ Do not coadminister with sildenafil (coal filling station) or other PDE5 inhibitors (synergism ↑risk of severe hypotension). Nitrates should be avoided in patients who have taken such rx in last 24 hours d/t risk of hypotension ▪ ↓preload should be avoided in hypertrophic obstructive cardiomyopathy (as ↑preload will cause ↑outflow tract obstruction) & R-sided MI d/t decreased RV preload (want the latter to be enhanced) (large heart-shaped smokestack on train with right side painted white) 1.2 – “Pounding at the Sumo Festival”: Triptans & migraine migrainess • Classic migraine consists of aura of variable duration ± n/v visual scotomas, speech abnormalities, followed by severe, throbbing unilateral headache that lasts for a few hours up to a few days (throbbing bell). Common migraine is similar but sans aura. Pathology is unknown. Pain is d/t activation of trigeminal nerve afferents that innervate intracranial arteries, particularly in the meninges (three gems on protective meningeal hat). Trigeminal afferents release vasoactive peptides (e.g. CGRP, substance P, neurokinin A) onto meningeal vessels → vasodilation & protein extravasation → neurogenic inflammation (dilated sleeves). Mechanical stretch by perivascular edema may be the immediate cause of neurogenic pain. • NSAIDs can be used for migraine as well. Combined with triptan seems to be more effective than either alone. Triptans • Sumatriptan and others (sumo wrestlers) • Acute treatment for migraines. o Triptans + inhaled oxygen are acute treatment for cluster headache (lantern cluster) • Combat neurogenic pain, but MOA is not entirely understood. Act as selective agonists for 5HT-1B & 5HT-1D receptors in trigeminal nerves, meningeal vessels & brainstem (smiley face headband; b & d shaped fingers). o Activates receptors directly on meningeal & cerebral → vasoconstriction, and may reduce pressure/stretch sensitive pain receptors (red constricting headband) o Acts on 5HT-1B & 5HT-1D on the trigeminal nerve, preventing release of vasoactive peptides promoting vasoconstriction (taking out ref in 5 gem hat) o Causes 5HT receptors in brain stem, inhibiting pain pathways • Adverse effects o Mostly mild. Include tingling, dizziness, muscle weakness. o Chest discomfort or pain, likely d/t vasospasm. Contraindicated in CAD (tiny coronary crown), known trigger of Prinzmetal angina (tiny anvils) Long term m migraine igraine proph prophylaxis ylaxis (long term fans) • Calcium channel blockers (Calci-yum ice cream), although questionable efficacy • Triptans • β blockers (ref with bugle) • Valproic acid can be used (festival pro sign) • Topiramate (toupee) • Tricyclic antidepressants, e.g. amitriptyline (tricycle) 1.3 – “Pro “Pro--Slugger Sporting Good Goods”: s”: Pro Prostaglandins, staglandins, prostacyclin, bosentan, PDE PDE--5 inhibitors • Prostaglandin R is an important mediator of vasoconstriction & inflammation. Recall arachidonic acid pathways, produced by Cox-1 & COX-2 (coaches in the back). Numerous prostaglandins are synthesized endogenously, and may be administered exogenously in certain clinical scenarios with effects on smooth muscle of GI,, vascular, genitourinary tracts. • PGE1 & PGE2 (Extreme Sports) o Alprostadil = synthetic PGE1 (dill pickle themed board). ▪ Acts as a vasodilator ▪ Indications • ED therapy (erect pro-slugger bat). Second line treatment, either monotherapy or in combination therapy. Works because PGE1 is a vasodilator with potent smooth muscle relation effects. • Maintains patency of fetal ductus arteriosus (knocking air duct open with bat). PGE2 acts locally in the womb on fetal vasodilatory receptors. After birth, PGE2 levels fall, causing closure of the PDA. In conditions where maintaining patency is important (as in certain congenital heart diseases), may administer PGE1 via continuous infusion. o This closure is why NSAID/prostaglandin use is not recommended in third trimester o when PDA doesn’t close after birth, which may induce respiratory failure in preemies, can give indomethacin – an NSAID – to promote closure. o Misoprostol = synthetic PGE1 analog (kid in front missing the ball) ▪ Indications • Cytoprotective in the GI tract at low doses, ↑secretion of gastric mucosa. Protects against NSAID-induced peptic ulcers (kid knocking over fire extinguisher) • Potent oxytocic actions. Used to increase uterine smooth muscle tone to facility labor or terminate pregnancy (uterus shaped bags expelling contents). Hence is a pregnancy category X drug. ▪ Adverse effects • Abdominal discomfort, diarrhea (flooded bathroom) o Dinoprostone = PGE2 analog (kid in a dino helmet) ▪ Stimulates contraction of uterus throughout pregnancy. May be used to induce abortion. ( open uterus bag) ▪ Directly affects cervix, promoting softening. May be applied locally for cervical ripening in preparation for labor induction • PGF2a (footwear section) o Carboprost = PGF2a analog (cardboard box) ▪ Used in obstetrics to increase uterine tone. May be used to induce abortion or to control refractory post-partum hemorrhage (uterus bags) o Latanoprost & travoprost (La Tan Sandals, Traveler boots) ▪ Stable, long-acting prostaglandin agents used in the management of glaucoma (leaky eyeball containers). Increase aqueous humor outflow → ↓IOP (cleaner flowing off of glasses) ▪ Causes increased iris pigmentation. Most commonly seen in green-brown eyes (brown sunglasses) Pulmonary hyp hypertension ertension manage management ment • Narrow and fibrosed pulmonary arteries result from long-term untreated HTN. Idiopathic pulmonary HTN specific classically manifests as dyspnea & exercise intolerance in women aged 20-40. All treatments have direct vasodilatory effects on pulmonary vasculature (high tension lung-shaped rackets). For most patients with pulmonary HTN, treat underlying conditions. • Prostacyclin (PGI2) analogs o Prostacyclin is a potent vasodilator and platelet inhibitor produced by COX-2 at the vascular endothelium (pro-cycler pitching machine) o Epoprostenol & iloprost (iLOW – ePRO setting). Epoprostenol is first line as has been shown to improve symptoms, prolong survival, & delay need for lung transplant. However, must be given as continuous IV infusion. o Major adverse effects include flushing, headache, hypotension (fainted girl) • Endothelin R antagonists o Bosentan (boss man stan) o Endothelin is a potent vasoconstrictor & promotes endothelial proliferation (end o’ the line). Bosentan inhibits endothelin → vasodilation (untucked shirt) o Adverse effects ▪ Associated with fatal hepatotoxicity (liver shaped spot). Calls for monthly LFTs. ▪ Can cause hypotension. (fainted girl) • PDE-5 inhibitors o Sildenafil, tadalafil (ball FILL) o Potent vasodilation o Inhibit PDE breakdown of cGMP, increasing intracellular levels (Don’t Phoster Disinterest = inhibiting phosphodiesterase; grumpy employee). ↑cGMP → dephosphorylation of myosin light chains → vasodilation. o Also used to treat ED (erect bat in photo) 2.1 – “A Midsum Midsummer mer Night’s D Diphenhydramine iphenhydramine iphenhydramine”: ”: Antihistam Antihistamines ines • Histamine is a biologically active amine that plays an important role in gastric acid secretion, functions as a NT, and mediates allergic inflammation. Most tissue histamine is stored in mast cells & basophils. Once mast cells are exposed to IgG, they wi ll burst open at exposure to specific antigens (like an irritated beehive). • H1 receptor is involved in allergic response. o coupled to GqPCR (one Q-shaped dandelion). o Mediates type 1 allergic reaction → hives & allergic rhinitis (fairy dust making Hermia sneeze and break out in hives) ▪ ↑nasal & bronchial mucus production (dripping nose) ▪ Endothelia H1 receptors stimulate extravasation of fluid. Mediate pain, puritis, vasodilation, seen in allergies. Urticaria results from increased vascular permeability (bloody sap) o Causes constriction of bronchial smooth muscle (constricting lung branch). ▪ Asthma is in part a hypersensitivity to this effect. • Non-mast cell associated histamine functions as a neurotransmitter, acting via CNS H1 receptors to regulate sleep & arousal, neuroendocrine & CV regulation (brain shaped tree). • H2 receptors are coupled to GsPCR →↑cAMP (2 S-shaped handles on honeypot). Located on gastric principal cells and activate gastric acid secretion (stomach shaped honey pot leaking yellow honey) Antihis Antihistamines tamines (Hermia swatting away bees) • Antihistamines work at the H1 receptor, located in vascular endothelial cells, bronchial airways, and CNS. • First generation: Diphenhydramine & dimenhydrinate (diphenhydramine salt) (dragonfly fairy), chlorpheniramine (colored beetle, Queen Tatiana), hydroxyzine, cylizine, promethazine (cuisine) o Indications ▪ Used as initial treatment for type 1 allergic reactions. Blockade of H1 prevents type 1 responses. ▪ Treat vestibular nausea/motion sickness. Are lipophilic so easily enter CNS, acting on H1 receptors in the vestibular system and brainstem (sailor outfitted fairies riding current in front of brain tree) ▪ As an extension of antimuscarinic effects, can acutely suppress anti-pyramidal effects cause by antipsychotics (e.g. dystonia, drug induced parkinsonism) (parking cone) i.e. Help reestablish dopaminergic/cholinergic balance. (Antipsychotics interfere with dopaminergic transmission via nigrostriatal tract.) o Adverse effects ▪ Cause drowsiness (Lysander sleeping). Sufficiently potent as to treat insomnia. ▪ antagonize many other Rs in the periphery & CNS, including muscarinic Rs → significant antimuscarinic effects (Mad Hatter’s Tea Party) • Urinary retention, dry mouth, pupillary dilation, constipation, exacerbation of glaucoma, & delirium ▪ Anti-serotonergic effects: antagonize serotonin R in the CNS, stimulating appetite & causing weight gain (chubby fairy asleep on branch) ▪ Antagonize α1 receptors → dizziness & hypotension (α candle & passed out fairy) ▪ Can cause cognitive impairment in the elderly d/t central antihistamine & antimuscarinic effects (delirious Egeus) • Second generation: fexofenadine, cetirizine, loratadine (fox, satyr, and rat respectively) o Less lipophilic, so do not cross the BBB and are generally less sedating (trio standing far away from brain tree). Also less antimuscarinic, anti-serotonergic, and anti-adrenergic activity. o Can be used to treat allergic rhinitis or urticaria with significantly fewer adverse effects. 2.2 – “Fa “Fant nt nt--asthmic Parade Parade”: ”: Asthma treat treatment ment (β-2 selective agonists, leuk leukotriene otriene inhibitors, methy methylxanthines, lxanthines, cromo cromolyn, lyn, sulfate oomalizumab) malizumab) • Asthma involves two processes: o Widespread reversible narrowing of bronchial airways and increased responsiveness to inhaled allergens o Eosinophilic and lymphocytic inflammation of bronchial mucosa o Both bronchodilation therapy & anti-inflammatory therapy are important in asthma management. The level of control depends on the level of disease. • Classic allergic asthma is mediated by IgE produced in response to exposure to foreign antigens (dust, dander, pollen). IgE binds to high affinity mast cell receptors in airway mucosa, stimulating degranulation and release of histamine, tryptases, PGs, leukotrienes, all of which stimulate bronchoconstriction and vascular leakage (guy shooting mast cell beehive with IgE shaped gun) • Leukotrienes are involved in aspirin induced asthma. In 5-10% of patients with asthma, even small doses of aspirin or other NSAIDs can causes profound vasoconstriction and systemic inflammation. Thought to be d/t inhibition of COX pathway, shifting Arachidonic acid metabolism from prostaglandin synthesis toward leukotriene synthesis (ASA ump on balcony with Cox blocking activity) Manageme Management nt • Chronic or more severe is associated with more severe SSx (especially at night) with long-term constriction of airways → thickening of bronchial wall & remodeling, hyperplasia of secretory glands & goblet cells, SM, bronchial vasculature. Management is critical to prevent chronic irreversible loss of pulmonary function. Therapy is stepwise until appropriate management of symptoms is obtained. Dose or number of rx is increased as necessary until control is achieved. • Selective β2 agonists o albuterol, metaproterenol, pirbuterol o counter bronchoconstriction (dilated β2 bugles; -rol Roll Call sheet). o β2 selective are preferred d/t lack of CV activation. Terbutaline also (“Do not disturb” sign in window) o Available as metered dose inhalers – short acting β-agonists (SABAs). Rescue inhalers (tuba player with inhaler). o In mild asthma, symptoms only occur intermittently and may be managed with only SABAs. • low-dose inhaled corticosteroids o beclomethasone, budesonide, fluticasone o With persistent symptoms, may be used as daily maintenance therapy. o After immediate inflammation of asthma attack, there is a delayed response with influx of inflammatory cells into bronchial mucosa; cytokines produced by these infiltrating cells → mucus production & recruitment of further inflammatory cells. Corticosteroids block cytokine production (moon eclipsing inflammatory sun). o Daily maintenance inhalers (controllers). ↓bronchial hypersensitivity and ↓frequency of exacerbations. o Inhalation avoids systemic adverse effects of glucocorticoid use. o Adverse effects: Inhaled corticosteroids can result in oropharyngeal candidiasis (Canadian snow cone). Prevent by gargling water after each use. • Leukotriene inhibitors o LTA activity results from action of 5-lipoxygenase (LOX) on arachidonic acid (AA lacrosse league with coach LOX); synthesized by many airway inflammatory cells including mast cells, macrophages, eosinophils. ▪ Leukotrienes are important regulation of inflammation and include LT-B4, C4, D4, & E4 (lacrosse players in flaming jerseys) ▪ LTB4 is a chemoattractant for inflammatory cells including neutrophils (B4 fallen off truck and attracting neutrophil first responders) ▪ C4 & D4 are potent bronchoconstriction; increase vascular permeability, & mucus conduction (clamping down on airwayesque lacrosse sticks with lung-shaped nets) o Inhibitors can be used clinically in mild or moderate asthma, although less marked decrease in reactivity than corticosteroid. Two mechanisms: ▪ Include montelukast, zafirlukast (monte the broadcaster). ▪ Direct inhibition of binding of LTD4 (most potent LT) to CysLt1 receptor (lacrosse net being guarded) → dilate airways (bronchodilator scarf). ▪ Taken orally, so fewer issues with compliance than inhaled therapies (broadcaster popping pills). o Other approach to interrupting this pathway involves inhibition of lipoxygenase, preventing leukotriene synthesis. Include zileuton (Godzilla balloon falling on Coach Lox). ▪ Small risk of hepatotoxicity; monitor of LFTs (liver spot). Not recommended for routine use in asthma. • Long-acting β agonists (LABAs) (β bugle formation) o Salmeterol & formoterol (salute formation) o High lipid solubility → long duration of action (long tapering flag). Can last for 12+ hours. o Can be given as a daily control regimen. Always given in combination with inhaled corticosteroids. o This step-up therapy may involve increased dose of inhaled corticosteroids as well (elevated moon balloon in formation) • Methylxanthines (xanthine energy drink) o Theophylline (“you’ll be flying”) o Alternative therapy for mild to severe persistent asthma. Reduces severity of SSx in chronic asthma and can act acutely decrease airflow obstruction. Administered orally. o PDE inhibitors; increase intracellular cAMP → smooth muscle relaxation. Inhibit of cytokine release (“don’t phoster disinterest! Go Camping!” sign in background) o Adverse effects ▪ Not used as much anymore d/t safer, more effective treatment. ▪ Very narrow therapeutic index. Toxicity can be fatal & levels must be monitored ▪ CNS effects include nervousness & tremor (shaky kid) ▪ CV effects include tachycardia (heart watch) ▪ CYP450 metabolism (car with chrome bumper) • Omalizumab (limousine) o Adjunctive therapy for moderate or severe persistent asthma o Monoclonal activity directed against Fc potion of IgE, prevents mast cell sensitization (limo driver with IgG-shaped gun binding to Fc portion of IgE gun) o Limited to patients with evidence of allergic sensitization (e.g. demonstrated by skin test) • Cromolyn sodium (Lynn’s Bee Control chrome smoke dispenser) o Inhibits mast cell degranulation (preventing beehive degranulation) o Once widely used as a prophylactic, particularly in pediatric allergic asthma. Now, used much less widely d/t increased efficacy of the inhaled rx. Emergent tre treatment atment of acute aasthma sthma exacerbat exacerbation ion • Inhaled short acting β2 agonists (β2 tuba) • Systemic corticosteroids if no evidence of rapid improvement, or ASAP if patient has h/o severe asthma (ivy for IV) • Nebulized ipratropium bromide anticholinergic to treat acute severe exacerbation (caterpillar balloon) • Subcutaneous or intramuscular E can be used to treat severe exacerbation, especially with absence of rapid improvement (EPIC! Sign)