GI and Endocrine

GI & Endocrine 1. Gastroin Gastrointestinal testinal 2. Diabetes 3. Thyroid, parathyroid, & adrena adrenals ls 4. Hypotha Hypothalamic lamic & Pitu Pituitary itary 1.1 – “Stadium Vo Vomitorium”: mitorium”: AntiAnti-emetics emetics – Ondansetron, metoclopra metoclopramide, mide, H1 receptor anta antagonists, gonists, scopolam scopolamine, ine, aprepitant • The Nucleus Tractus Solitarius (NTS, or vomiting center), located in the medulla, receives inputs from the GI tract (white lines connecting stomach to track), vestibular system (semi-circular canal running outside the track), & area postrema. NTS neurons project to other medullary nuclei to coordinate vomiting response (vomiting on track directly in front of NTS sign). o The stomach communicates directly with the NTS via vagal stimulation (white lines run underneath “Vegas” sign). GI irritation for any reason (e.g. infection, chemo, distention) causes mucosal serotonin release (stomach competitor throwing serotonin smiley face weights). Serotonin activates 5-HT-3 receptors on vagus afferents, relaying signal to NTS (1-2-3 sign). o Vestibulocochlear system is responsible for vertigo & motion sickness (vestibular nausea); CN VIII communicates directly with NTS (seasick sailors racing vest-wearers; semicircular canal directly behind NTS track). o Area postrema is the chemoreceptor trigger zone, located outside the BBB in the 4 th ventricle, immediately adjacent to the NTS. Responds to emetogenic substances including chemo agents (gymnast doing “extreme postures” on exposed pommel horse immediately adjacent to NTS track). Contains D2 dopamine receptors (gymnast on two D-rings). Triggered by Neurokinin 1 receptors bringing substance P (plaNK1 pommel horse bound by competitors; competitors must first have their pee checked). ▪ Antagonized by Aprepitant (participants). Crosses BBB. Often combined with serotonergic Rx. No impact on dopamine, serotonin, muscarinic receptors, limiting adverse effects compared with other antiemetics. This is a very new drug, so side effect profile is not well-established. Antiemetics • Ondansetron (out-of-bounds dancer) o locks vagal afferent 5HT-3 receptors in the GI tract (distracting from the accurate throw of serotonin hammer). o Highly effective in post-op or chemo-induced nausea/vomiting. Used off-label for other n/v; effective for any cause involving vagal stimulation. o Side effects: ▪ Constipation (hammer wrapping around runner’s stomach, tightening gut) ▪ Headache, dizziness (hammer hitting head) ▪ Rarely: QT interval prolongation, increasing risk of torsades des pointes (dancer with twisting ribbon) ▪ Rarely: Serotonin syndrome; usually only occurs if combined with other serotonergic agents (pile of smiley-face hammers seems like an overload) • Antihistamines o Histamines are involved in vestibular system, specifically H1-receptors coupled to GqPCR (allergenic dandelions shaped like Qs along canal). Histamine receptor blockers (bee swatters) effective to treat motion sickness (sailor uniforms) include diphenhydramine, meclizine. Also Africanized bees add adventure to the race! o Side effects a result of crossing BBB ▪ Sedation ▪ Antimuscarinic properties (recall the tea party sketch) d/t M1 receptor antagonism (motorcycle parked in spot M1) • Scopolamine – a muscarinic agonist – can be used to minimize these effects (telescope) ▪ Other effects of antihistamines are described in respective sketches • Metoclopramide (cheating tickling gymnast – me tickle -pyramid) o D2 receptor antagonist in the area postrema; used for treatment of chemo induced vomiting (cheater is antagonizing gymnast on two D-rings). Also has upper GI prokinetic effects, useful for treatment gastroparesis & delayed gastric emptying post- surgically or d/t diabetes (second gymnast has fallen off D-rings onto stomach-shaped cushion). Can cause diarrhea for same reason (mud beyond the gastric cushion). o Contraindicated in small bowel obstruction d/t stimulation of motility (“do not obstruct” sign by ring-set) o Side effects: ▪ d/t central D2 blockade ▪ Drowsiness (sleeping judge) ▪ Depression (crying coach) ▪ Extrapyramidal effects, including dystonia, akathisia, Parkinsonian features (judge wearing a pyramid shaped “EXTRA” hat). With chronic use, may cause tardive dyskinesia (judge sticking out tongue). Long term used should be avoided, especially in the elderly. ▪ Neuroleptic malignant syndrome (judge eating “Now More Spicy!” chicken); symptoms include fever (man is flushed), rigidity, mental status changes, autonomic instability, rhabdomyolysis (bite out of drumstick). Usually seen with higher potency D2 blockers, but may occasionally be seen here too ▪ Elevated prolactin → galactorrhea, gynecomastia, menstrual disruption (judge laughing so hard, milk is coming out his nose) ▪ Prolonged QT (twisted torsades streamers) 1.2 – “Gastroesopha “Gastroesophageal geal Re Refund”: fund”: Acid control therapy with H2 receptor blockers & PPIs Physiology • Parietal cells in the gastric mucosa are responsible for gastric acid production, secreting acid into the gastric lumen (“Pour-it-all” lemonade, with lemonade spilling into the lumen-like sidewalk). Acid is secreted via Na-K-ATPase pump, maintaining electrolyte balance to secrete H+ ions into the lumen (Lemonade pump on the side of the stand is secreting acidic lemonade; mom is adding a potassium-laden banana to mix it up a bit; operated by 3 Ⓟ batteries). • Gastrin (gas cans) stimulates parietal cells, primarily by way of stimulating Enterochromaffin-like (ECL) cells (tree with the “Enter Carefully” sign) → release of H2 (gas driven leaf blower has disturbed histamine bees on the ECL tree) → activation of H2 receptors (GsPCR) (kid holding honey pot with S-shaped handles is attracting bees) → stimulation of parietal cells (honey-pot boy is knocking over lemonade pitchers, spilling onto sidewalk). Gastrin has a much smaller direct stimulatory effect on the parietal cells. Gastrin is released from G-cells in response to vagal stimulation via cholinergic M3 receptors using gastrin-releasing peptide (GRP) (truck is releasing gas tanks, in response to GRP lever being pulled. Parked next to motorcycle with “Vegas” sticker in M3 spot). • Zollinger-Ellison syndrome is seen with gastrinoma, where excess gastrin production over-activates ECL cells (jumbo gas tank on the cancer crab lawnmower is over activating bees). Results in heartburn, diarrhea, GI bleed Rx • H2 blockers o cimetidine, ranitidine, famotidine, nizatidine (tie-dye shirts for -tidine suffix; 2 bee swatters for H2 blockers). o Reversibly bind to H2-receptors, inhibiting acid secretion from parietal cells. H2 receptor blockers have a strong effect on nocturnal acid secretion, but minimal effect on prandial secretion. Fast action & short duration make this class suitable for symptomatic relief. o Indications ▪ Can be used to treat GERD and ulcers (gastric & duodenal), although PPIs are preferred for both (girl gurgling lemonade while standing on a cracked sidewalk). o Adverse effects ▪ Cimetidine is notorious for adverse effects (tie-dyed kid in the cement) ▪ CYP450 inhibitor (beating up the car with the CYP-450 plates) ▪ Antiandrogen effects: Hyperprolactinemia (kid laughing milk out nose), gynecomastia (kid holding lids to his chest), impotence & decreased libido (floppy honey wand) ▪ Can cross BBB → confusion, dizziness, headaches, especially in the elderly ▪ Crosses placenta ▪ Cimetidine & ranitidine both →↓Crt secretion (although have no actual negative effects on GFR) • Proton pump inhibitors (PPIs) o omeprazole, lansoprazole, esomeprazole, pantoprazole, dexlansoprazole (“prize” sounds a bit like -prazole). o Form a covalent disulfide bond with Na-K-ATPase. By blocking the final common pathway to acid production, these are the most effective treatment for acid production, regardless of the etiology (girl scouts are blocking the lemonade pump). o Indications ▪ First line agents in GERD, with both erosive & non-erosive esophagitis (gargling girl) ▪ duodenal &, to a less extent, gastric ulcers (cracked sidewalk) ▪ Zollinger-Ellison syndrome ▪ stress ulcer treatment ▪ Part of routine H. pylori triple therapy (helicopter hat on girl scout). ▪ Clinically, often used for unexplained dyspepsia o Side effects: ▪ Up to 3x increased risk of C. diff infection (chocolate fountain). ▪ Increased risk of respiratory infections/PNA, both nosocomial & community acquired (dark lung shaped chocolate spots on scouts tee). Possibly d/t ↑levels of upper GI bacteria. Note that the evidence for this in the literature is relatively weak. ▪ Decreased absorption of calcium, magnesium, and iron, as all three rely on an acidic environment (electrolyte medals on wagon), all easily treated by supplementation. If untreated, may result in : • Exacerbation/cause of osteoporosis (termite-eaten wagon) • ↑risk of osteoporotic fractures (broken bone-shaped axel) • Hypomagnesemia (falling magnets) • Vitamin B12 deficiency • Octreotide (exogenous SST) o Endogenous somatostatin (SST) inhibits gastrin release (G-cells) & histamine (ECL cells). can be administered to manage some cases of excess acid production, notably in SST-sensitive gastrinoma (octagonal stop sign blocking irritation of bees). 1.3 – “Relaxatives”: Laxative agents (lactulose, magnesium, polyethylene glycol, docusate, Senna, psyllium, lopera loperamide, mide, diphenoxylate) & antidiarrhea antidiarrheals ls Laxatives • Alternatively, eat enough fiber, exercise, and stay hydrated; that’ll be enough for most folks, and has far fewer adverse effects! • Note that laxatives ≠ prokinetics (those would be the muscarinic agonists, metoclopramide, erythromycin). Laxatives work on the stuff that comes out, and may indirectly stimulate peristalsis by increasing stool volume → luminal distension. Osmotic laxatives • Nonabsorbable substances draw water into the intestinal lumen(bubbling spa water). Serves to loosen stool, as well as distending the lumen → stimulating peristalsis. Can cause rapid movement of water and rapid action (rapid relaxation by hanging out in the water filled tub). Can result in dehydration d/t water loss (water spilling down drain). OTC availability leads to potential for abuse, as in eating disorders. • magnesium hydroxide & magnesium citrate (magnets) act rapidly, resulting in large volumes of water and consequent high volume of stool. Can result in hypermagnesemia, especially in patients with kidney disease • Polyethylene glycol (PEG) is used for endoscopy prep (peg used as a drain plug). Usually combined with electrolytes to keep balanced • Sodium polystyrene sulfonate (Kayexalate) used occasionally as a laxative. Used as well to manage hyperkalemia. • Lactulose o Non-absorbable sugar (“relaxulose” tub additive). Used occasionally as laxative, but causes severe gas and cramps (bubbling tub). o More often used in cases of hepatic encephalopathy (liver and brain-shaped corals in fish tank). Gut flora degrade lactulose into lactic acid & acetic acid, driving down the pH of the intestinal lumen (fish gobbling up lactulose; acid meter on side of tank). This in turn favors NH4+ (non-absorbable) over NH3 (absorbed form), favoring excretion of the excess ammonia (tank cleaner guy has ammonia cleaner is his belt, and is drawing NH4 out of tank). o May be combined with rifaximin to eradicate ammonia-producing gut bacteria in the case of hyperammonemia (fisherman is removing fish altogether) Bulk forming laxatives • Psyllium, methylcellulose (bulky seaweed). Works as a hydrophilic colloid, absorbing water in the lumen → distention & peristalsis. Cause bloating & gas in some patients. • Surfactants (stool softeners, emollients) • Docusate & glycerin, given PO or as enema. Work by allowing water & lipids to penetrate stool (canoe on the dock is filling with water). Not known for being especially effective. • Stimulant laxatives, a.k.a. cathartics • Senna and others. Work by direct stimulation of enteric nervous system → electrolyte & fluid secretion. MOA is not entirely understood. (Guy tanning in sun, with masseuse rubbing oil into skin, stimulating stomach). Chronic use of Senna may cause benign brown pigmentation of the colon called melanosis coli (brown stomach) Antidiarrhea Antidiarrheals ls (muddy slipper slippers) s) • ONLY use in cases where there is neither infection nor hemorrhage (red stool outside of the massage parlor). In either of those situations, need to treat the underlying cause. • Most of these are opioid agonists which act on μ-receptors, present in high density in the GI tract (“Utopia μ-ssage”). Like all opioids, these are notorious for causing constipation (clogged bathroom) o Loperamide increases colonic transit time by increasing colonic phasic segmenting activity, pushing colonic juju back and forth more (lop-eared rabbits hopping back and forth across person’s back). Does not cross BBB, so has no analgesic or addiction potential. o Diphenoxylate increases colonic transit time by the same mechanism (two dolphins). At high doses, typically higher than prescribed, can cross BBB. To prevent abuse, typically combined with atropine such that doses high enough to cross BBB will cause miserable atropine adverse effects. • VIPomas & carcinoid tumors cause secretory diarrhea along with other systemic symptoms (“VIP customers” crab sign). If unable to fully resect, can use octreotide to limit (octagonal stop sign). Can also use octreotide for other causes of secretory diarrhea (e.g. Chemo) 2.1 – “Langerhan “Langerhansel sel & Grete Gretel”: l”: Insul Insulin, in, sulfo sulfonylureas, nylureas, meglitinides, GLP -1 agonists, DPP-4 inh inhibitors ibitors • Insulin is a major storage and anabolic hormone of the body, and “invites” fat & carbs into cells (“welcome inside” mat for creepy high carb house). Produced pancreatic β-cells in the islets of Langerhans. Release is stimulated by glucose (most potent), or direct sympathetic activation of β-cells (holding candy; β bugler). o 1) When glucose enters into circulation from GI tract, resultant hyperglycemia increases intracellular ATP levels. ↑ATP stimulates closure of ATP-gated K+ channels (closed garden gate). o 2) Closed K channels → ↓K efflux and increased intracellular K concentration → membrane depolarization (elevated bananas in garden). Membrane depolarization leads to opening of voltage gated calcium channels → Calcium influx, which stimulates insulin release from secretory granules (Gretel riding a calcium ice cream flower to carry the candy out of the cell). o 3) Insulin binds receptor tyrosine kinase insulin receptors (tyrosine tire swing). Downstream has a number of effects: ▪ Increases GLUT4 glucose transporter expression in the cell membrane (#4 door) ▪ Increase hepatic glycogenesis (candies in liver-shaped container) ▪ Increased glycogen storage & protein synthesis in skeletal muscles (ham with glycogen glaze) ▪ ↑storage of triglyceride in adipocytes (jar of donuts) ▪ ↓serum K+ by enhancing Na-K-ATPase in skeletal muscle (witch holding eaten banana candy). • Prior to release from β cells, C-peptide is cleaved from proinsulin in the secretory granule; endogenous insulin release is accompanied by equimolar release of C-peptide (Candy wrappers on the ground). • Note that insulin is cleared by both kidneys and liver. Injectable ins insulin ulin prepara preparation tion & analo analogs gs • Used in Type 1 Diabetes mellitus (T1DM). May be used in the case of severe insulin resistance or severe pancreatic insufficiency in late stages of T2DM. • Long acting for basal control, short acting for control of post-prandial glucose spike. Intermediate acting formulations were the earliest produced, less used now. (note the shape of the house mimics the graph of insulin onset & duration) • Rapid acting, short duration o Include insulin glulisine, insulin aspart, & insulin lispro formulations (Girls & lads sign on tower). “Do not LAG” o Amino acid modifications → slower onset o Rapid onset & short duration of action (onset of 15 minutes, peak 45-75 minutes) (high peaked tower). Used for postprandial spike; mimics endogenous postprandial insulin (Birds pecking away). • Intermediate acting o Regular & neutral protamine Hagedorn (NPH) (Rest Now sign) o Delayed onset & intermediate duration of acting d/t formation of dimers & hexamers, which take time to break down, similar to endogenous insulin (low-peaked gable). NPH is somewhat slower onset. o Regular insulin can be administered IV (ivy). ▪ Particularly useful in DKA (diabetic key). Administer in conjunction with glucose & K. ▪ Monitor potassium, as insulin in the setting of DKA can precipitate hypokalemia. ▪ Should never use subcutaneous insulin in DKA. o IV regular insulin also useful in hyperkalemia. o NPH is less predictable with delayed onset within 2 hours. Not used as much clinically nowadays. • Long acting o Insulin detemir & glargine (“Don’t Go”) o Long duration with steady basal level of insulin (flat roof). Glargine is longest acting, 24h activity with no distinct peak • Adverse effects o Hypoglycemia risk with tachycardia palpitations, sweating, nausea, hunger (ANS hyperactivity, both SNS &PNS). May progress to convulsions & coma if untreated. Falling candies = falling glucose levels ▪ Treat with IM glucagon (glucagon when glucose is gone), or glucose by PO or IM Other agent agentss All of the following function of endogenous β cells or external insulin sensitivity. Note that is only works with T2DM. Will see increase C-peptide levels with increases endogenous production. • Sulfonylureas (swan/Mother goose) o Upregulate endogenous insulin release. Binds ATP dependent K+ channel in β cells → release of endogenous insulin by the mechanisms described above (geese in intracellular garden). o First generation: ▪ Include tolbutamide, chlorpropamide, others (mother Goose in maid outfit = -amide) ▪ Longer acting, rarely used nowadays ▪ Some, including chlorpropamide, may cause disulfiram-like reaction when combined with alcohol (“Do not drink” sign) o 2nd generation: ▪ Include glyburide, glipizide, glimepiride (gosling riding on mother’s back for -ride) ▪ Smaller dosing, longer duration of action (goslings are smaller) • Glipizide has shortest duration of action (Z’s in water). So has a lower risk of hypoglycemia o Adverse effects ▪ Is a sulfa drug (sulfa eggs). ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • Meglitinides o Include repaglinide, nateglinide (Gliding goose for -glinide) o Similar MOA to sulfonylureas. Bind ATP dependent K+ channel in β cells (geese in intracellular garden) o Non-sulfa drugs so can be used in allergy to sulfa drugs. o Adverse effects ▪ Risk of hypoglycemia (falling candies). Increased risk with renal failure. ▪ Weight gain (lady under tree) • GLP analogs o endogenous glucagon-like peptide (GLP) (old lady eliciting gulp from tuba player). GLP is secreted from intestinal L-cells in response to food intake. Acts in opposition to glucagon; binds GLP-1 receptor ▪ Induces satiety ▪ ↓gastric emptying (full stomach shaped water container) ▪ ↓glucagon release (empty glucagon packets) ▪ ↑insulin release from β cells ▪ Combine to decrease serum glucose levels o GLP effects are glucose dependent, so agonists do not cause hypoglycemia (candies not falling from tree) o GLP-1 Agonists ▪ Include exenatide, liraglutide (TIDE detergent) ▪ GLP-1 agonists function as exogenous agonists of the GLP-1 receptor ▪ May increase risk of pancreatitis (pancreas sponge). o DPP-4 inhibitors (gliptins) (dripping laundry) ▪ Include sitagliptin, saxagliptin, linagliptin (clipped in laundry for -gliptin) ▪ Dipeptidyl peptidase-4 (DPP-4) breaks down GLP. Inhibition increases endogenous GLP availability (witch gulping) ▪ Can cause increased risk of nasopharyngitis & URIs (witch with clothespin on her nose) 2.2 – “Rosiglitazones are Red, Pioglitazone Pioglitazoness Thiazolidinedi Thiazolidinediones, ones, Pramlint Pramlintide, ide, SGLT2 inh inhibitors ibitors are Blue…”: Metformi Metformin, n, • Drugs that lower glucose levels by a variety of means can be used in Type 2 diabetes (2nd grade); require functional β cells. Unlike the sulfonylureas, meglitinides, & GLP analogs, these drugs act outside the pancreas →↓serum glucose • Metformin (kneeling kid reciting metaphors) o First line oral agent for T2DM. o Decreases serum glucose by poorly understood mechanisms. The only biguanide used clinically. ▪ Inhibits mitochondrial glycerophosphate dehydrogenase, the first step in hepatic gluconeogenesis, decreasing glucose production (girl eating candy, but distracted by serenade so is not taking candy out of liver-shaped bag) ▪ Activates AMP-activated protein kinase (AMPK) (AMP Kandy), decreasing liver gluconeogenesis (friend stopping candy release from bag). ▪ Increasing peripheral insulin sensitivity, resulting in increased peripheral glucose uptake & utilization, by enhancing glucose mediated insulin utilization (“Inside” notice on mailbox) ▪ Decreased intestinal glucose absorption. o Excreted by kidney as active drug (kidney shaped lunch tray) o ↓ risk of hypoglycemia o Adverse effects ▪ Lactic acidosis d/t lactate inability to enter gluconeogenesis(spilled sour milk). Rare. More likely to occur in conditions of renal failure or tissue hypoxia (kidney shaped lunch tray is broken). ▪ GI adverse effects anorexia, nausea/V, diarrhea (girl looks sick) ▪ Can cause modest weight reduction or stabilization (thin physique). • Thiazolidinediones (aka glitazones) o Include rosiglitazone, pioglitazone (“Roses are red” card filled with glitter) o Oral agents. Because these drugs affect gene transcription, take days to weeks for improvements. o Increase glucose utilization & decrease glucose production in adipose tissue, liver, & muscle. o Thiazolidinediones are ligands of peroxisome proliferator-activated receptor γ (PPAR-γ) (PPAR-γ on kid’s shirt). PPAR-γ receptors are intracellular nuclear receptors found in muscle, fat, & liver; part of the steroid & thyroid family of intranuclear receptors. ▪ Regulated genes include those affecting lipid & glucose metabolism, insulin signal transduction, adipocyte differentiation. ▪ One of the more important genes: adiponectin, which is low in patients with T2DM, obesity (turtleneck). Increases insulin sensitivity & fatty acid oxidation; increases differentiation & number of adipocytes (elevated donut jar). ▪ Increased availability of adipocytes increases triglyceride storage combined with increased fatty acid oxidation → ↓circulating TG levels ▪ Upregulate GLUT4 in peripheral tissue →↑glucose uptake (door to mailbox) o Adverse effects ▪ Weight gain d/t increased triglyceride storage — a little “extra glit in your zone” (fat kid) • May be exacerbated when coadministered with sulfonylurea ▪ ↑sodium resorption can cause fluid retention & peripheral edema (kid wearing baggy sweatpants • Contraindicated in HF d/t risk of exacerbation (balloon!) in ▪ Increased risk of atypical extremity fractures in women d/t decreased bone mineral density (fractured chair leg). Exact mechanism unknown, possibly d/t ↓osteoblast activity • Amylin analogues (twins Amy & Lynn) o Pramlintide o Analog of endogenous islet amyloid peptide (i.e. amylin) usually present in insulin secretory granules. ▪ Decreases glucagon secretion (glucagon packets) ▪ slows gastric emptying (closed stomach shaped water cooler) ▪ Appetite suppressant o Used for glycemic control. Can be used to manage postprandial hyperglycemia in either T1DM or T2DM (peaked cupcakes). Injected immediately before eating o Adverse effects ▪ Can cause hypoglycemia (knocking over candy jar) ▪ GI SSx (n/v, anorexia) (kid is nauseated) • Alpha-glucosidase inhibitors o Include acarbose & miglitol (box of A-carb wigglers in corner) o Intestinal α-glucosidase normally converts disaccharides in the intestines into absorbable monosaccharides. Blocking this enzyme decreases absorption of dietary sugars at the intestinal brush border, delaying carbohydrate absorption (“Monosaccharide FREE” box label; brush border flags; delayed access to wiggles) o Can be used to blunt postprandial serum glucose spike by as much as 30-50% (peaky cupcakes). Can be administered regularly through the day. o Side effects generally limit use. GI adverse effects (diarrhea, flatulence, abdominal pain, etc.) result from fermentation of undigested carbs by gut bacteria (leaky bathroom) • SGLT2 inhibitors o Include canagliflozin, dapagliflozin (flossing). Are the newest class. o Sodium-glucose cotransporter 2 (SGLT2) is a low affinity, high capacity transporter responsible for resorbing 90% of glucose in the PCT (Salty Glucose peanuts; pro-cart track poster). Inhibition causes significant glucose loss in the urine. o 2nd or 3rd line for diabetes management. Usually added to existing oral regimen o Side effects are mostly d/t glucosuria: ▪ UTI (bladder cup) ▪ Yeast infections (snowball in the crotch) ▪ Increased osmotic diuresis can cause symptomatic hypotension in some patients, especially elderly & those on diuresis (kid diuresing pants & falling over) ▪ Contraindicated in renal insufficiency d/t ↓ efficacy, ↑ risk of Adverse effects (cracked kidney tray) 3.1 – “Iodine is Forever”: Propy Propylthiouracil, lthiouracil, meth methimazole, imazole, levothyr levothyroxine oxine Physiology • Thyroid hormones are T3 (triiodothyronine) & T4 (thyroxine). They are involved in most metabolic functions (like a secret criminal organization). Both contain iodine (anionic form: iodide). • Synthesis: o Iodide is transported into thyroid follicular cells (follicu-LAIR) via a sodium-iodide symporter (peanut box with iodide smuggled). This concentrates iodide; is an energy dependent process. o Iodide is oxidized to iodine by thyroid peroxidase (TPO) (transport with rusty truck). o TPO further catalyzes iodine biding to tyrosine to form iodotyrosine molecules; this process is organification (Organic Food truck with tyrosine tires) o iodotyrosine molecules are stored in the thyroid lumen bound to thyroglobulin (Thyro-Global). While bound, the mono- & di-iodotyrosine molecules couple; mono + di forms T3, di + di forms T4 (vegetables in logo are coupled). • Release & effects: o thyroglobulin is drawn into parafollicular cells, where T3 & T4 are cleaved off (bombs). T3 is the more potent form (activated bomb), T4 produced in greater quantities in the thyroid gland (more bombs with 4:00 timers in the lair) o In the peripheral tissues, T4 is de-iodinated to T3 by 5’-deiodinase (T4 detonator). o T3 enters the nucleus, acting as a transcription factor. Some effects: ▪ Increased sensitivity to SNS catecholamine-mediated stimulation by increasing β 1 receptors (catfish; dead man sensitive to catfish). Increased SNS sensitivity mediates many of the SSx of hyperthyroidism, including hypermetabolic & hyperadrenergic SSx (nervous henchmen with big bowtie) Hyperthyroi Hyperthyroidism dism • Presents with hypermetabolic & hyperadrenergic SSx (e.g. tachycardia, palpitations, insomnia, tremor, anxiety, heat intolerance, weight loss) (nervous henchmen with big bowtie) • Causes may include toxic adenoma, toxic multinodular goiter, thyroiditis • Most common cause is Graves’ disease. o Associated with Graves Ophthalmopathy (bulging infrared goggles). Activation of T-cells → lymphocytic infiltration of retroorbital space → cytokine production → fibroblast secretion of hydrophilic glycosaminoglycans → osmotic muscle swelling, muscle inflammation, and increased adipocyte count → exophthalmos. Note that chronic ophthalmopathy doesn’t necessarily correlate to treatment of thyroid levels; may decrease, may not. • Management: o In the US, patients with can be treated with ablative doses of radioactive iodine (I-131). This is done particularly with Graves’s disease. ▪ Can cause hypothyroidism in as many as 80% of patients (undone bowtie burned by radioactive vial) ▪ Can cause transient hyperthyroidism d/t dumping of excess thyroid hormone (anxious radioactive henchman). Particularly in those who are more susceptible (elderly, those with severe thyrotoxicosis), may treat with thioamide drug prior to radioablation to prevent. ▪ Can cause transient exacerbation of ophthalmopathy for unknown reasons; relatively contraindicated in patients with preexisting ophthalmopathy (bulging radioactive goggles) o thioamides ▪ Propylthiouracil (PTU) (secret agent with gunshot “PTU” sounds) • Inhibits TPO and 5’-deiodinase (shooting at bomb detonator). Acts centrally & peripherally. • Use generally limited to those with reactions to methimazole, in the first trimester of pregnancy, or treatment of acute thyrotoxicosis • Adverse effects: o Use limiting reaction: severe hepatotoxicity (mounted liver beaker). o Maculopapular pruritic rash o agranulocytosis (neutrophil <500). o drug-induced lupus (lupus wolf). May see ANCA-associated vasculitis. Usually asymptomatic, but may occasionally develop arthralgias & glomerulonephritis o bone marrow suppression & aplastic anemia (rare) (chew bones) ▪ Methimazole: • Inhibits TPO. Unlike PTU, does not have peripheral effects • Methimazole is 10x more potent that PTU and is the drug of choice for managing hyperthyroidism. • Adverse effects o agranulocytosis (neutrophil <500). o drug-induced lupus (lupus wolf). o bone marrow suppression & aplastic anemia (rare) (chew bones) o Methimazole is a first trimester teratogen. Use PTU instead. (pregnant lady drawing a spider on chalkboard) o β-blockers (blocked bugles being used to stick ‘em up) ▪ can be used to treat hyperadrenergic symptoms; also block 5-deiodinase. ▪ Should be started at the time of diagnosis o Glucocorticoids (moon face coasters) ▪ Treat hyperthyroidism by inhibiting 5’-deiodinase. ▪ Less effective than β-blockers, but have benefit of treating graves ophthalmopathy (knocking goggles off henchman’s face) Thyrotoxico Thyrotoxicosis, sis, aka thyrotoxic ccrisis, risis, aka thyro thyroid id storm • Life-threatening syndrome (Dr Storm) • May occur after acute precipitant or spontaneously in the situation of untreated thyroid disease • Management: o block sympathetic effects on organs using β blockers:. o Block thyroid TH synthesis. PTU preferred. o Block peripheral conversion of T3 to T4 (PTU, β blockers, & glucocorticoids) Hypothyroid • May present with dry & brittle hair (unkempt bartender), cold intolerance (ice cubes), weight gain (chubby), lethargy, fatigue, weakness, decreased basal metabolic rate, & myxedema • Untreated, can lead to myxedema coma (mixing cold drinks): progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, death. • Treat by giving levothyroxine (synthetic T4). • Side effects may mimic hyperthyroidism Radiation expo exposures sures • In the case of accidental radioactive iodine exposure, anions such as perchlorate, pertechnetate, & thiocyanate competitively inhibit the sodium-iodide transporter (obstructive box of anions with spy)