GI & 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 & Gretel”: Insulin, sulfo sulfonylureas, nylureas, meglitinides, GLP -1 agon agonists, ists, 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) 3.2 – “The Natural h/o Osteoporosis”: Bisphosphonate, raloxifene, calcitonin, denosumab • All of the rx here are useful in the treatment of osteoporosis by preventing or decreasing bone resorption. Will cause a moderate increase in bone mineral density & decreased fracture risk (TA is drawing out a fresh piece of chalk to replace the fractured boneshaped piece). • Mostly directed against osteoclasts (destructive kids in class) rather than osteoblasts (don’t disturb the builders) • PTH (PhD) stimulates osteoblasts to express RANKL (Receptor activator of nuclear factor κ-Β ligand) → osteoclast activation (RANKL = crank-drill; builder giving to kid, & kids drilling out bone). • Bisphosphonates o Alendronate, pamidronate, zoledronate, others (“Donate” box for -dronate) o Actions: ▪ Have a chemical strucutre similar to pyrophosphate (2 Ⓟ coins in the box). Attach to hydroxyapatite in bone (T-rex appetite). Osteoclasts that try to latch onto bone bind instead to the bisphosphonate & are unable to adhere to bone (kid is stuck in box so cannot destroy things). ▪ decrease development & recruitment of osteoclast precursors (lady with 2 Ⓟ coins blocking next class from entering. ▪ Induce osteoclast apoptosis (popping Apatosaurus balloon). ▪ Net result: decreased bone lost and stable or increased bone mineral density. o Indications: ▪ First line treatment for osteoporosis ▪ Alendronate, zoledronate used for hypercalcemia d/t ↓bone resorption (elevated ice cream). • Especially important in hypercalcemia of malignancy, a common cause of severe hypercalcemia requiring acute treatment (fossil with lots of crabs) ▪ Paget’s disease • uncontrolled osteoclast resorption with secondary disorganized bone formation (disorganized human skeleton • Helps prevent high bone turnover, preventing pain & progressive deformity o Adverse effects ▪ Upper GI effects (e.g. acid reflux, esophagitis, esophageal ulcers). Can be avoided by drinking lots of water & staying upright after taking (corrosion of dinosaur neck) • May administer IV (much less frequent administration) with severe intolerance. ▪ Rare: osteonecrosis of the jaw (crumbling jawbone). More likely with IV administration ▪ Can cause hypocalcemia d/t inability to resorb bone (fallen ice cream cup) • Selective Estrogen Receptor Modulators (SERMs) o Estrogen receptors are found throughout bone. Activation inhibits osteoclast differentiation. Estrogen therapy can prevent & treat postmenopausal osteoporosis ( ); however, not recommended d/t increased risk of breast cancer and other adverse effects. o Instead, use SERMs, such as Raloxifene (relax sign). o SERMs have estrogen agonist activity in bone (inhibiting osteoclast differentiation [slowing down the classmates] → net resorption is decreased, slowing postmenopausal osteoporosis), CV system, & blood lipoproteins. Estrogen antagonists activity in uterus & breast (↓risk of breast cancer) • Denosumab (dino-suit) o Monoclonal antibody against RANKL (antibody shaped spines) o As effective as bisphosphonates o Used in treatment of postmenopausal osteoporosis • Calcitonin – “tones down calcium” (curator) o Peptide hormone released by thyroid parafollicular cells → ↓serum calcium & phosphate by actions in bone & kidney (curator pointing down) Not as effective as bisphosphonates, so not first line. o Inhibits osteoclasts, and thereby decreases bone resorption (curator grabbing destructive kid). o Promotes Ca excretion by the kidney by inhibiting resorption (pouring ice cream down leg). o Used in hypercalcemia of malignancy (crabs on fossil) o Useful in Paget disease (misaligned skeleton) o Adverse effects: ▪ Hypocalcemia (fallen ice cream) 3.3 - "PthD in Paleontol Paleontology": ogy": Teriparatide, Vita Vitamin min D, Cinacalcet Cinacalcet,, Sevelamer • Treat osteoporosis by increasing bone formation & bone mineral density for the duration of treatment. • Parathyroid hormone (PTH) (PthD) o Regulates bone formation & resorption. Effects: ▪ Stimulates preosteoblast maturation to osteoblasts (osteo-builders = osteoblasts; PthD teaching builders). ▪ Stimulates osteoblasts to express RANKL (receptor activator of nuclear factor κ-Β ligand) (RANKL = crank-drill; builder giving drill to kids, and kids drilling away bones). RANKL binds to RANK on osteoclasts, increasing osteoclast proliferation & differentiation. Appropriately activated, osteoclasts increase bone resorption & turnover and release phosphate & calcium from bone, allowing bone development & systemic metabolic function (destructive class kids = osteoclasts; kids releasing both Ⓟ shaped shell fossils and calcified bones). Note that this activation is indirect. ▪ Net effect of endogenous PTH: ↑bone resorption o PTH increases kidney calcium resorption and phosphate excretion (PthD is gathering calcified bones and dropping P-shaped fossils at kidney-shaped pit). Net effect: ↑calcium levels & ↓phosphate levels o PTH increases activity of 1-α-hydroxylase in the kidney →↑production of 1,25-dihydroxy-vitamin D (calcitriol) (Calci-TRON robot = calcitriol; robot head with 1 antenna = 1-α-hydroxylase; PthD is activating robot) o High serum Ca feeds back to parathyroids, inhibiting PTH production and release via calcium-sensitive receptors (calcium backup on conveyer belt blocking the PthD from the field). • Vitamin D o Two forms: D2 (ergocalciferol) from plants (earth friendly battery under tree). D3 (cholecalciferol) is obtained from sun or dairy products (solar calciferol cart being pulled by dairy cow). Either form can be administered therapeutically. o Activated by: ▪ 1) Liver hydroxylates vitamin D to 25-hydroxy-vitamin D (robot body added to D battery in liver-barrow) ▪ 2) In kidney, 1-α-hydroxylase converts to 1,25-dihydroxy-vitamin D (calcitriol) (#1 on head to remind that’s the last step). o Activated vitamin D functionally acts as a steroid (lipophilic, intracellular receptor). Has a number of downstream effects: ▪ Calcitriol increases phosphate & calcium resorption in the kidney (robot picking up bones & phosphate shells at kidney pit) ▪ Potent stimulant of intestinal calcium & phosphate absorption (robot picking up bones & phosphate shells at colonic truck) ▪ Stimulates maturation of osteoblasts → ↑bone formation (robot teaching osteo-builders), and stimulates osteoblast production of RANKL → activation of osteoclasts. Potent stimulator of both; net effect is bone turnover (robot delivering crank drills to class). ▪ Inhibits PTH production (rolling over tent, trapping PTH) o Indications for exogenous administration ▪ Osteoporosis ▪ Topical treatment can be given for psoriasis (kidney worker with pads) ▪ Can be used for long-term management of hypocalcemia (robot stabilizing seizing scientist) • Hypocalcemia can cause seizures, paresthesias, muscle cramps, trismus, tetany (shaking structure, clenched fist) • Commonly caused by hypoparathyroidism (falling PhD badge; undone bowtie for thyroid surgery damage to PTH glands). Vitamin D will be less effective d/t decreased activation of kidneys o Note that inactivated vitamin D will be ineffective in kidney failure d/t inability to activate (cracked kidney tower). In this case, give as calcitriol (robot stabilizing kidney shaped water tower). o Deficiency ▪ Osteomalacia in adults, rickets in children (robot stabilizing rickety tower) ▪ May see in chronic renal failure, dietary deficiency, ↓sunlight exposure. o Adverse effects ▪ Teriparatide & Vitamin D therapy can both cause hypercalcemia (raised calci-yum ice cream) • Teriparatide (TA) o Recombinant PTH. Effects include: ▪ Net effect when given in low-intermittent doses increases bone formation (in contrast with the effects of endogenous PTH). • Stimulations maturation & increases anabolic function of osteoblasts (TA teaching osteo-builders). • Does not activate osteoclasts (TA not dealing with classmates) ▪ Increases kidney resorption of calcium, dumping phosphate (TA is gathering calcified bones and dropping P-shaped fossils at kidney-shaped pit). ▪ Increases calcitriol production (TA helping build robot o Used in treatment of osteoporosis (fresh piece of calcified chalk) o Adverse effects: ▪ Teriparatide & Vitamin D therapy can both cause hypercalcemia (raised calci-yum ice cream) • Cinacalcet (worker calculating calcium) o Calcimimetic; activates calcium sensing receptor in parathyroid gland → ↓PTH production. Useful to treat hypercalcemia d/t primary or secondary hyperparathyroidism (cinacalcet worker calculating the bone buildup going into the parathyroid tent). • Sevelamer (shoveler) o Non-absorbable phosphate binding polymer that binds Ⓟ in the GI tract, decreasing phosphate absorption (shoveler in truck) o Used to treat hyperphosphatemia d/t CKD 3.4 – “The C Court ourt of Sone He Henge”: nge”: Gluc Glucocorticoids ocorticoids • Cortisol (endogenous glucocorticoid), aldosterone (mineralocorticoid), & DHEA (androgen) all released from adrenal (head druid wearing adrenal cap). Here we focus on effects of glucocorticoids, either endogenous or exogenous (moon face). Exogenous formulations include dexamethasone, fludrocortisone, prednisone, budesonide (-sone suffix, hence sone henge) • Effects are mediated by widely distributed cytosolic glucocorticoid receptor (receptor scepter in outer scepter); enters the nucleus & acts as transcription factor at glucocorticoid receptor elements (GREs) (activated scepter in the inner circle, representing the nucleus; has many effects, pictured as blue squiggles). Effects include: o Upregulate inhibitor of PLA2 (inhibited A-frame catapult A2). ▪ PLA2 releases arachidonic from cell membranes → metabolism to several inflammatory compounds. By inhibiting this, GCs block COX (prostaglandin synthesis) (bat) & LOX (leukotriene synthesis) (lacrosse stick) o Inhibits NFκB (nuclear factor kappa-Β), inhibiting activation of lymphocytes by inhibiting proinflammatory cytokines (inhibited N-Flame Krossbow). ▪ End effect: ↓recruitment & activation of T & B cells (blocked T-cell knight and antibody archer). ▪ Decreased neutrophil recruitment by causing demargination & ↓synthesis adhesion molecules. Results in circulating neutrophilia (i.e. an acute rise in WBC count) (congregation of neutrophilic first responders). This will present as apparent elevation of white counts, but will increase risk of infection. o Rapidly reduce peripheral lymphocytes by ↓Ig synthesis, stimulation of apoptosis, & redistribution into spleen, lymph nodes, & bone marrow (T-cell knit, helper T-cell squire, & antibody archer, eosinophil slingshot dropping into chasm). ▪ Hence utility as immunosuppression (transplant rejection prevention, autoimmune disorders) (eclipsed inflammatory sun), ▪ inflammatory conditions (gout, RA, asthma, IBD) (cracked antibodies on standing stone). ▪ Eosinophil decrease; useful in atopic conditions (eosinophil slingshot dropping into chasm) o Metabolic effects ▪ Recall that glucocorticoids are essentially the body’s stress hormones. As such, will upregulate the systems needed to maintain metabolic & circulatory function in times of stress. ▪ Can cause hyperglycemia (elevated candy jar held by statue) • Peripheral antagonism of insulin, i.e. insulin resistance (locked welcome mat). • Stimulate gluconeogenesis via production of gluconeogenesis enzymes (liver shaped bag producing candy). • Increase glycogen synthesis → increased glycogen storage (candy filled liver-shaped candy jar) ▪ Will not see these homeostatic effects in adrenal insufficiency (fainted druid with cracked moon face on ground). Can see collapse of circulatory function, leading to shock and even death, with even minor noxious stimuli. • Exogenous glucocorticoids must be given to treat acute adrenal insufficiency (extra moon face being extended). May also prevent in cases of primary adrenal insufficiency (e.g. Addison’s disease). • Chronic exogenous glucocorticoid use causes adrenal cortical atrophy d/t negative feedback on the pituitary →↓ACTH production (secondary adrenal insufficiency) (shriveled adrenal hat on fallen man) o Note: oral budesonide often given in a delayed release preparation targeting the ilium; especially useful in Chron’s because it has high topical potency & fewer systemic adverse effects than other glucocorticoids d/t high first pass metabolism. o Adverse effects (altar and moon statue) ▪ ↓overall white counts → immunosuppression; ↑risk of infection • Reactivation of latent infections ▪ Promote peripheral catabolism, proteolysis in skeletal muscle, lipolysis. (falling ham & donuts). ▪ Cushing’s syndrome can occur with chronic glucocorticoid use (cushion; demonstrated in moon statue) • Results in adipose redistribution with central adiposis (fat stomach) • Myopathy, muscle wasting, proximal weakness (scrawny arms) • Inhibit fibroblast proliferation → weakened skin, capillary damage (fine cloth with purple striae) • Direct inhibition of osteoblasts → osteoporosis & fractures (osteoporotic altar). Chronic, can cause osteonecrosis, classically aseptic necrosis of the hip. o Chronic users should take supplementary calcium & vitamin D • Psychosis: hypomania, confusion, hallucinations (cracked and cross-eyed moon head) • immunosuppression (cane). o May reactivate latent infections, e.g. TB (TB cacti with reactivation in upper lobes) • Hypokalemia d/t mineralocorticoid cross reactivity (banana peel) 4.1 - "JAK Stat and the Beanstalk": Growth Hor Hormone, mone, Meca Mecasermin, sermin, Octreot Octreotide, ide, Pegvisomant Physiology • Growth hormone (GH) is an anterior pituitary secreted peptide (beans spilling from front of burlap pituitary sack). Secreted with prolactin, which has significant homology. • Effects: o enters circulation and binds GH receptor → Dimerization and recruitment of receptor-associated JAK tyrosine kinase → intracellular JAK/STAT pathway (Tire swing for tyrosine; JAK/STAT “jacks up cell growth”) o Effects on carbohydrate, protein, & lipid metabolism, mainly mediated through IGF1 produced in the liver (rock).– acts similar to insulin with similar tyrosine kinase receptor (“welcome Inside” mat). In contrast with insulin, which stimulates sugar and fat storage, IGF1 is responsible for long bone growth (mat getting lifted by lanky bean sprout). ▪ High circulating levels with pubertal growth spurt (mat growing up). ▪ Required in childhood and adolescence for normal adult size & proper lean body mass & bone density () o GH has anabolic effects in muscle directly → muscle mass (striated muscle leaf on bulky vine). Catabolic effects in adipose tissues. Essentially shifts mass from fat to muscle (dumping donut jar for adipocyte lipolysis). • Excess serum GH most commonly seen in hormone secreting pituitary adenoma. Most commonly seen in adults → acromegaly (characterized by deep voice, Large hands and feet, Increased risk of colorectal polyps/cancer, Coarse facial features, impaired glucose tolerance or insulin resistance). Seen less commonly in children; before closure of growth plates, can cause gigantism. First line treatment is trans-sphenoidal resection. Rx • Somatotropin (exogenous GH) o Indications ▪ GH deficiency • Abnormal height increase + abnormal serum GH levels with appropriate stimulation (short kid holding up bean). • May be primary (genetic, developmental) or acquired (pituitary trauma, intracranial tumors, infection, radiation). ▪ Idiopathic short stature. Somewhat controversial. $$$ ▪ Increasing growth in Prader Willi syndrome (Padre Willi – missing father gene) →↓body fat and ↑lean muscle mass ▪ Increasing growth in Turner’s syndrome (turning X girl) o GH reduces insulin sensitivity, but IGF-1 exerts insulin like effects so the effects usually balance out. • Mecasermin(sermon) o recombinant IGF-1 o Indications ▪ Small number of children have growth failure d/t deficiencies in the IGF-1 rather than growth hormone. ▪ patients who are unable to respond to GH d/t resistance (e.g. anti-GH antibodies, receptor mutations). o May see hypoglycemia d/t exerting insulin effects (falling candy) • octreotide o Indications (generally counteract secretory effects of many hormone secreting tumors): ▪ Medical therapy for gigantism/acromegaly by inhabiting secretion of GH (octagon stop sign held up to giant). ▪ VIPoma & serotonin-secreting carcinoid tumors as well (crab sign over stop sign for “VIP customers only”). Generally used to reduce secretory diarrhea in these conditions, especially in incomplete resections. ▪ glucagonoma (ridiculously huge giant glucagon packet). Usually presents was weight loss & necrolytic migratory erythema ▪ insulinoma (big “welcome inside” mat – from excess). Fasting hypoglycemia ▪ Gastrinoma, with Zollinger-Ellison syndrome (massive gas tank) ▪ Can control bleeding of esophageal varices (decreased portal blood flow & variceal pressure). MOA poorly understood (exposed variceal pipes) o Adverse effects ▪ GI adverse effects (N/V, abdominal pain), steatorrhea d/t decreased pancreatic secretions & decreased gallbladder secretion (ill looking townsperson standing on yellow stool) • Cabergoline & bromocriptine o D2 receptor agonists o treat acromegaly by inhibiting secretion of GH from the pituitary (burglar with broomstick, climbing down two dope ropes). Also inhibit prolactin release (more effective than GH inhibition) (sac holding magic beans). • Pegvisomant: o GH Receptor antagonist; inhibits GH receptor preventing downstream effects ( ants picking up beans off tire swing). May increase GH secretion d/t lack of feedback, and provoke adenoma growth. 4.2 - "Wat "Water er Hazard": Posterior pituitary regulation (ADH, DDAVP, ADH Receptor Antagonists) ADH (aka vasop vasopressin) ressin) • responsible for regulating tonicity of plasma by regulating free water absorbed by the nephron ( water hazard). • Collecting duct is the site of ADH action & water resorption, as well as mineralocorticoid action & Na resorption (ADH boy). ADH released by posterior pituitary (water jug on posterior). ADH has antidiuretic properties and vasopressor properties. Act via two subtypes of receptors o V1 receptors are responsible for vasopressor activity. GqPCR, activates PLC → IP3 + DAG →↑intracellular Ca2+ (V1 hole on Q shaped green). Found in vascular smooth muscle cells → vasoconstriction & increased BP (angry golfer constricting golf club) o V2 receptors are GsPCR → activation of adenylyl cyclase →↑cAMP (V2 hole on S shaped green). Found on basolateral membrane of the collecting duct (location). Causes translocation of aquaporin 2 to the apical membrane of luminal cells → increased water permeability → reabsorption of free water (water boy at collecting duct translocating pure water). o There are extrarenal V2 receptors found in the vascular endothelium (endothelial tile). Activation →↑ release of coagulation factor VIII and vWF from endothelial cell Weibel-Palade bodies → increased platelet aggregation (8 ball on von Wille brand pool table). ADH activation of V2 stimulates factor 8. • Administered exogenously, directly constricts mesenteric arterioles, which can be useful in the management of esophageal variceal bleeding d/t reduction in portal pressure (bulging mucosal colored golf bag with blue veiny golf clubs) • DDAVP (desmopressin acetate) o Long acting synthetic analog of ADH (saving desert mobile). o High specificity for V2 receptor, which means minimal pressor activity (V2 engine). o Indications: ▪ Activity at vascular V2 Rs can be used to increase vWF release from vascular endothelium, useful for treating von Willebrand deficiency (scratched felt on pool table). • Von Willebrand disease will often present with increased bruising & mucosal bleeding (e.g. GI, oropharyngeal, uterine) (cue ball beating up player) ▪ Factor 8 deficiency (hemophilia A) (missing 8 ball & A-frame). • Usually presents with intramuscular bleeding, prolonged bleeding, hemarthrosis (bleeding knee) ▪ Night enuresis d/t ↓urine production (wet mattress) o May cause hyponatremia (falling peanuts) Diabetes insip insipidus idus • inability to concentrate urine (endless insipid trickle of a fountain shaped like a urinator) • Central (not producing sufficient ADH) (brain shaped dehydrating sand traps). Can be caused by number of processes (radiation, tumor, AI process) (crawling thirsty golfer). o Can administer DDAVP • nephrogenic (not responding to ADH) (brain & kidney shaped dehydrating sand traps). Usually d/t blockade by pharm agents, occasionally genetic (frustrated golfer ignoring water boy). Lithium is a common cause of nephrogenic DI (“lift-ium” balloons). Generally resolves with discontinuation of drugs. o Thiazide diuretic (pasty thigh guy) → volume reduction → proximal resorption of sodium & water, decreasing dependence on collecting duct activity. Treats polyuria & polydipsia. However, diuretics can decrease lithium clearance, increasing risk of toxicity. o Amiloride (K+ sparing diuretic) (almond snack cart) can treat lithium-induced nephrogenic DI. Blocks lithium entry into CD cells. o NSAIDs (fire extinguisher) Decrease PG production that normally antagonize ADH. SIADH (syndro (syndrome me of inappropri inappropriate ate ADH) • Overproduction of ADH resulting in excess water retention & hyponatremia (inappropriate water boy). May result from CNS disorders, traumas, ectopic production in lung cancer, or certain pharmacologic agents. • Treat with V2 receptor antagonisms, including conivaptan, tolvaptan (Vaporizer model water gun for -vaptan suffix). o Promote free water excretion by inhibiting aquaporin translocation. Can be used in conjunction with hypertonic saline & free water restriction. • Be careful in correcting hyponatremia too rapidly. May cause hypernatremia or, in severe cases, central pontine myelinolysis (osmotic demyelination syndrome) → irreversible CNS damage (salty peanuts being thrown at head) o Maximum rates of correction: less than 10 mEq/L at 24h and less than 18 mEq/L at 48 hours. Monitor sodium levels closely • Demeclocycline – a tetracycline – can be used to treat SIADH by interfering with V2 receptor activity. MOA not known. Not first line.