Blood and Inflammation Part 2

3.1 – “NSAID “NSAIDss in the outfield outfield”” Physiology • Arachidonic acid is the precursor molecule for prostanoids & leukotrienes (AA next to dugout; dugout players are the precursors). It is a membrane bound polyunsaturated fatty acid that must be released from the membrane prior to metabolism to prostaglandins. • Injury (chemical or physical) → ↑intracellular Ca → activation of Ca dependent translocation of phospholipase A2 (PLA2) (play ball) which hydrolyzes arachidonic acid membrane bonds. • Free arachidonic acid is metabolized to various inflammatory compounds (prostaglandins, thromboxane, and prostacyclin) by cyclooxygenases COX-1 or COX-2 (Head Coach Cox 1, Assistant Coach Cox 2). • COX-1 is constitutively active in many cell types and is responsible for housekeeping prostanoids (coach 1 constitutively active on the field),: o Prostaglandins (pro-slugger): maintain gastric mucus (pro-slugger protecting gastric-garbed umpire) ▪ Hence why COX-1 inhibition causes gastric ulcers o synthesized to TXA2 (batter’s box), which stimulates platelet aggregation. Is also a potent vasoconstrictor (twisting red hat) • COX-2 is expressed in vascular endothelial & smooth muscle cells, mainly in the setting of inflammation, and is responsible for many vascular effects (vascular endothelium pattern on wall of dugout) o markedly upregulated in inflammatory processes (assistant coach is running from fire). This is the main target of NSAIDS. o Prostacyclin (PGI-2) causes vasodilation & inhibits platelet aggregation (pro-cycler pitching machine; dilated cone; kids with plates being dispersed). Maintains non-thrombogenic vascular endothelial surfaces. ▪ NSAIDS that excessively blocks COX-2 can thus cause a hypercoagulable state. o prostaglandins → ↑vascular permeability (leaky sprinkler activated by pro-slugger), increase pain sensibility (pro slugger with painful inflamed foot), & induce fever (pro-slugger with flaming head) • COX-1 + COX-2 help maintain normal renal function. Produced in glomerular endothelium → afferent arteriolar dilation (prosluggers at the afferent tunnel). Activity is especially important in the situation of hypotension & ↓renal perfusion; in this case, prostaglandin maintains perfusion and limits ischemia. NSAIDs • Non-steroidal anti-inflammatory agents (NSAIDs) (fire extinguisher) decrease production of the prostaglandins that cause fever, edema, & pain associated with inflammation. Directly inhibiting cyclooxygenases COX-1 (constitutively expressed) & COX-2 (expressed in inflammation) (coach 1 constitutively active on the field; assistant coach 2 on fire). Various NSAIDs have differing affinities for the cyclooxygenases; most are non-selective (fire extinguisher dowsing both Cox coaches). • Include aspirin; ibuprofen; diclofenac & ketorolac (black sox) - ketorolac specifically is used mainly as an analgesic; indomethacin (indigo Sox) - used to accelerate closure of patent ductus arteriosus; meloxicam & piroxicam (Sox Cam) - meloxicam has some preference for COX-2; naproxen (approximately 110 mph) • Shared Adverse effects: ▪ D/t COX-1 inhibition o Inhibition of COX-1 → ↓ production of gastric mucus, even at low NSAID concentrations. Can result in gastritis, erosions, ulcerations (burning catcher). ▪ Can change anti-inflammatories or add a gastric acid inhibitor o Are the number one cause of GI bleeds (ketchup on GI pads). o inhibition of thromboxane production → ↓ platelet aggregation. Long-term use can increase risk of hemorrhagic stroke & other bleeding. ▪ Inhibition of COX-1 can prolong bleeding time (ketchup on clock) ▪ Contraindicated in patients with preexisting platelet defects o Pseudo-allergic reactions can be elicited by COX-1-inhibiting NSAID; likelihood is related to the strength with which that drug inhibits COX-1. Reactions usually seen in patients with one of the following comorbidities: the combination of asthma and chronic rhinosinusitis with nasal polyposis or chronic urticaria. Reactions can be divided into four types: ▪ Type 1 – NSAID-induced asthma and rhinosinusitis ▪ Type 2 – NSAID-induced urticaria/angioedema in patients with chronic urticaria ▪ Type 3 – NSAID-induced urticaria/angioedema in otherwise asymptomatic individuals ▪ Type 4 – Blended (mixed respiratory and/or cutaneous) reactions in otherwise asymptomatic individuals ▪ D/t COX-2 inhibition o COX inhibition in the kidney → ↓sodium excretion → ↑BP (exploding fire extinguisher). Occurs in both normotensive & hypertensive patients. Usually mild. o Can cause acute interstitial nephritis (baseballs in blue kidney shaped container = acute leukocyte infiltrate). May have eosinophilia, casts in urine, systemic dysfunction. o AKI d/t afferent arteriolar constriction (constricted proximal end of fire extinguisher hose) →↓GFR. use should be minimized in patients at high risk for AKI (fire extinguisher behind cracked kidney glass by emergency exit) ▪ May cause renal papillary necrosis (sloughing off cleat spikes) o Reduced GFR →↓excretion of renally excreted drugs ▪ e.g. lithium (lithium balloons – “liftium”) can lead to ↑serum lithium & lithium toxicity o Aplastic anemia (rare) (bone balloon); indomethacin specifically. o Neutropenia (all NSAIDs) o ↓ renal prostaglandin synthesis → ↓renin →↓aldosterone → decreased K excretion. ▪ Hypoaldosteronism (depleted mineral mine) ▪ Hyperkalemia (K shaped board) o Contraindicated in 3rd trimester d/t risk of premature closure of the ductus arteriosus (indomethacin & ibuprofen are highest risk) (pregnant lady bounding toward emergency exit) Aspirin (ASA on coat) • Irreversibly acetylates COX-1 & COX-2 in existing platelets, preventing TXA2 synthesis until new platelets are formed (ASA referee is blowing acetylation whistle at Coach Cox for cheating, expelling him from the field until the end of the game, permanently). All other NSAIDs are reversible. Thromboxane production doesn’t begin again until platelets are reborn (~1 week) • Indications (nowadays used less as an anti-inflammatory & more as an antiplatelet): o Reduces CV events & angina in patients with arterial disease o Used as a preventative measure for ischemic stroke o Used post-MI o Used as part of dual antiplatelet therapy (ASA + ADPRI) to prevent coronary stent thrombosis o Used as an anti-inflammatory in Kawasaki’s disease, the most common vasculitis syndrome of childhood (Kid on ATV). ▪ Characterized by systemic inflammation manifesting as fever, erythema of lips & oral mucosa, cervical lymphadenopathy, rash, & conjunctivitis. ▪ Tx with high-dose aspirin during acute phase of illness. Generally transitioned to low dose ASA when fever subsides. • Side effects: o Can cause Reye’s syndrome when given to children with viral infection (rays on shirt). ▪ Presents as rapidly progressive encephalopathy (confusion, vomiting, seizures, coma) (brain cap) with hepatic dysfunction (hepatic steatosis, hepatomegaly) (liver spotted goat) o Anion gap metabolic acidosis (Mud pile). ▪ Stimulates respiratory center directly → initial respiratory alkalosis before metabolic acidosis sets in (blowing bubbles on pitcher mound) ▪ MUD PILES – causes of anion-gap metabolic acidosis: methanol, uremia, DKA, propylene glycol, iron OD or isoniazid, lactic acidosis, ethylene glycol, salicylates o Tinnitus (tin cans). Common with acute poisoning or chronic intoxication o Poisoning ▪ Activated charcoal can be used in setting of acute toxicity; indicated in all patients appearing within 2 hours of acute toxicity (dark paint under eyes) ▪ Alkalization of urine with sodium bicarb since salicylate is weak acid (hose is loading bases). Increasing urine to pH 8 from normal of ~5 can increase excretion 5x COX-2 selective inhibitors (coxibs) • Celecoxib (celebrating catcher) o No inhibition of COX-1, so no effects on platelet aggregation, thus minimizing bleeding risk. ▪ ↓ risk of GI bleed (happy colonic catcher) o Cause reduced synthesis of prostacyclin, decreasing smoothness of endothelial surface ▪ may increase risk of ischemic CV disease (blood cubes). Relatively contraindicated in ACS. o Sulfa drug (sulfa eggs) • Acetaminophen (paracetamol) o Equivalent for use as an antipyretic & analgesic, but lacks anti-inflammatory effects (icy medicine spray) o Used in treatment of mild to moderate pain when anti-inflammatory effect is less desirable (e.g. Osteoarthritis) o Poisoning is common. ▪ Metabolized by liver, with small percentage metabolized to the toxic metabolite NAPQI by CYP450. Generally NAPQI is conjugated to glutathione; at toxic levels, NAPQI is produced in excess and depletes available glutathione (hepatic goat [goat-a-thione] scared by icy spray) ▪ Toxic metabolites can cause widespread hepatocyte injury ▪ TX: • N-acetylcysteine given IV or oral (N-flower seeds). Probably restores glutathione stores (glutathione goat eating seeds) • Oral activated charcoal can be given within 4 hours of OD (dark paint under eyes). 3.2 – “Confe “Confessions ssions of a knit knit--wit”: Gout drugs (allopurinol, febuxostat, probenecid, peglotica pegloticase) se) Physiology • Purine metabolism: Nucleic acids broken down to nucleotides (purine-shaped collection plate). Purine is broken down into hypoxanthine by Xanthine oxidase (XO letter from hypo kid) → Xanthine (larger kid). Xanthine is broken down into uric acid by Xanthine oxidase, sent to kidney for excretion. • Uric acid is a poorly soluble product of purine metabolism that is generally excreted in the urine (yellow aisle = tubular lumen). Overproduction or underexcretion will result in hyperuricemia; underexcretion is more common. o Causes of increased urate production: idiopathic primary gout; myeloproliferative & lymphoproliferative disorders; tumor lysis syndrome; Lynch syndrome (HGPRT deficiency) o Causes of decreased clearance: CKD; thiazide & loop diuretics. • Gout is a metabolic disease characterized by deposits of uric acid. o Most often an initial attack of gout will occur in a single joint, classically a knee or the big toe (priest with flaming toe). Crystal precipitate induces local activation of prostaglandins & lysosomal enzymes, attracting neutrophils & increasing inflammation. o Over time, uric acid crystals can precipitate in the joints and skin, resulting in formation of tophi. o Uricemia can precipitate uric acid renal calculi, or even interstitial nephritis o Uric acid crystals are needle shaped & negatively birefringent under polarized light (knitting needles) • CPPD disease aka pseudo-gout o Calcium pyrophosphate crystal deposition disease o Presents like uric acid induced gout, but results from deposition of calcium pyrophosphate (it’s lying in looking like gout – hence “thou shall not lie”). Differentiated by microscopy: calcium pyrophosphate crystals are rhomboid-shaped & positively birefringent (blue rhomboid censor). o Deposition triggers an inflammatory response much like that seen in gout o Acute treatment is very similar to gout • Uric acid crystals can form in tumor lysis syndrome (cancer crab stained glass shattered into crystals); o most commonly occurs in treatment of aggressive lymphomas & acute lymphoblastic leukemia (white T-cell crusaders). o Allopurinol used preventatively. • Lesch-Nyhan syndrome o Deficiency of HGPRT results in excess uric acid production. o Skin and lips are common sites of deposition for uric acid crystals → pain (may be the stimulus for the self-injurious behavior) (kid poked in flesh with knitting needle) Treatment of ac acute ute gout (tr (tripping ipping over yarn) • All also suitable for CPPD • NSAIDs are first response; mediate inflammation (kid with fire extinguisher) • Glucocorticoids can be used in Tx of severe, systematic gout, depending on the level of pain (moon face). • Colchicine (chorus) o First line for acute gout. o Administered orally to relieve gout within 12-24 h o Binds intracellular tubulin, preventing polymerization into tubulin ( palm fronds; kid binding fronds in hands). Disrupts cytoskeletal function, including phagocytosis, degranulation, and neutrophil migration (blocked first responders) o Brush border cells in GI tract are sensitive → diarrhea (muddy shoes) o N/V, Abd pain Manageme Management nt of chronic gout • Goal is to prevent recurrent of episodes and to minimize risk of urate nephrolithiasis • Allopurinol (pure nun) o First line for chronic management o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Febuxostat (XO -stopped) o Inhibits XO, ↓uric acid in the body (nun grabbing XO notes) o Adverse effects ▪ May precipitate acute attack after initiating therapy. Often started with concurrent NSAID or colchicine therapy. ▪ Can interfere with breakdown of purine analogs (e.g. 6-MP, azathioprine) → increased risk of toxicity (purine rosaries) ▪ Rashes. Risk of SJS/TEN (tengu mask) ▪ DRESS syndrome, with eosinophilia (eo-slingshot, eosinophilic dress) • Probenecid (Cid the probation officer) o Uricosuric agent used to manage underexcretion. Second line agents for underexcretion o Inhibits organic anion transporter, site of active transport sites of reabsorption & secretion in the PCT (preventing punk kid grabbing yarn) o Adverse effects: ▪ Increase in uric acid in urine increases risk of uric acid stones (lots of yellow yarn balls) ▪ Can inhibit the excretion of many drugs (e.g. penicillin, anionic agents, antibiotics) (penicillin pencil) ▪ Can precipitate an acute attack. Must be started 2-3 weeks after resolution of an acute attack ▪ Sulfa drug (kid throwing stinky eggs) • Aspirin (ASA umpire) o At high doses prevents reabsorption of uric acid (ump blocking yarn collector); at low doses, can block urinary excretion (kid catching yarn) o d/t need for high dosing, should never be used as treatment for hyperuricemia. • Pegloticase o Urate oxidase enzyme that converts uric acid to more water soluble allantoin (holy water – just in case) o Used in refractory gout. o Used to prevent gout symptoms in patients at high risk for tumor lysis syndrome. o Adverse effects: ▪ Can cause hemolysis in G6PD deficiency (G6PD watermelon with bite) o Can cause anaphylaxis (kid suffocating). Seen in 6-15% of patients. Must be administered IV in an inpatient setting by a qualified provider d/t high risk of severe Adverse effects (ivy around door)