Drugs listsP450 interactionsendingfunctionexampleupdown -afilerectile dysfunctionsildenafilneuro drugs are for those who act upbarbituratessulfonamides -aneinhalational general anesthetichalothanephenytoinerythromycin -azepamBDZdiazepamcarbamazepinecimetidine -zolamBDZalprazolamgriseofulvinketoconazoleinhibits enzyme -azinephenothiazine (neuroleptic, antiemetic)chlorpromazineramp uprifampinisoniazid -azoleantifungalketoconazolechronic EtOH useacute EtOH use -barbitalbarbituratephenobarbitalSt. John's Wortgrapefruit juice -cainelocal anestheticlidocainequinidineHIV protease inhibitors -cyclineprotein synth inhibiting abxtetracycline -etineSSRIfluoxetinetorsadesclass III, IA -ipramineTCAimipraminedilated CMdoxorubacin (amiodarone), daunarubicin -navirprotease inhibitorsaquinaviraplastic anemiachloramphenicol, benzene, NSAIDs, propylthiouracil, methimazole, carbamazepine -operidolbutyrophenone (neuroleptic)haloperidolhemolysis in G6PDDINH, sulfonamides, antimalarials, aspirin, ibuprofen, nitrofurantoin -oxinglycoside (inotrope)digoxinnephro-/oto-toxicaminoglycosides, cisplatin, vancomycin, loop diuretics -phyllinemethylxnthinetheophyllinedisulfiram-like rxncephalosporins, metronidazole, 1G sulfonylureas (tolbutamide, chlorpropamide), procarbazine -terol2 agalbuterol -tidineH2 antcimetidine -triptan5HT1B/1D ag (migrane)sumatriptan -triptylineTCAamitriptyline

DrugsMicroDrugClassUseMechanismSFx/OtherpenicillinB-lactamGP (not Staph), SyphBind PBP, inhibit transpeptidase cross-linking of cell wall, and activate autolytic enzymesbacteriocidal; G=IV, V=oral; can cause hypersensitivity rxn (all PCNs) or hemolytic anemia, SJSnafcillinPCNase-resistant PCN, narrow spectraS. aureus (not MRSA)Same as PCN, but bulkier R groupsame as PCNdicloxacillinmethicillin + interstitial nephritisampicillinaminoPCN, wide spectrumcertain GPs (Listeria, enterococci) and GNRs (Proteus, H. flu, E. coli, Salmonella)Same as PCN, wider spectrum, PCNase sensitive (use with clavulanic acid)pseudomembranous colitisamoxicillin + higher oral availability; rashticarcillinextended spectrum PCNPseudomonas (+AG) and GNRSame as PCN, PCNase sensitive (use with clavulanic acid)piperacillinPseudomonas (+AG) and GNRcarbenicillinPseudomonas (+AG) and GNRclavulanic acidB-lactamase inhibitorsulbactamtazobactamcefazolin1G cephGPC, Proteus, E. coli, K. pneumo (think UTI)B-lactam, but less susceptible to PCN-ases, bactericidalHypersensitivity (cross hypersensitivity with PCNs in 5-10%), vitamin K deficiency, disulfiram-like rxn with EtOH (only in some cephalosporins), increase nephrotoxicity of aminoglycosidescephalexin1G cephcefoxitin2G cephGPC, Proteus, E. coli, K. pneumo, H. flu, Enterobacter, Neisseria, Serratia (think more UTIs, gonorrhea)cefalcor2G cephcefuroxime2G cephceftriaxone3G cephH. flu meningitis, Neisseria, gonorrhea prophylaxisfor serious gram negative infxnceftazidime3G cephPseudomonascefipime4G cephPseudomonas and GPaztreonammonobactamGNRs ONLY, synergistic w/ AGsinhibits cell wall synth (binds PBP3), B-lactamase-resistant, synergistic w/ AGsno cross-allergenicity w/ PCN or cephalosporins, good in renal insufficiency; occasional GI upsetimipenem/cilastatincarbapenemGPC, GNR, anaerobes; broad spectrum, B-lactamase resistantcilastatin=renal dehydropeptidase I inhibitor, decreases inactivation of drug; seizures, GI distress, rashmeropenemcarbapenemdehydropeptidase I stable, lower risk of seizures; GI distress, skin rashvancomycinglycopeptideGPs ONLY, esp MDR (MRSA, Enterococci, and C. diff)inhibits cell wall mucopeptide formation by binding D-ala D-ala portion of precursorsrarely SFx: nephrotoxicity + ototoxicity, thrombophlebitis, "red man syndrome" (preventable by slow infusion)gentamicinAGGNR, synergistic w/ B-lactamsbind 30S, inhibit initiation complex, cause misreading of mRNA; require O2 for uptake (no anaerobes); modifying transferase enzymes (acetylation, eg) can lead to resistancenephrotoxic (especially when used w/ cephalosporins), ototoxic (especially when used w/ loop diuretics), teratogenic (CN VIII agenesis)amikacinAGGNR, synergistic w/ B-lactamstobramycinAGGNR, synergistic w/ B-lactamsneomycinAGbowel surgerytetracycline tetracycline Iintracellulars: B. burgdorferi, H. pylori, M. pneumo, Rickettsia, Chlamydia (no CNS penetration)binds 30S and prevents attachment of AA-tRNA; resistance by decreased uptake or increased efflux by pumps (plasmid-encoded); do not take w/ milk, antacids, or Fe (divalent cations inhibit absorption)GI distress, teratogen (teeth discoloration), bone growth inhibition in kids, hypersensitivity; expired causes Fanconi's, photosensitivitydoxycyclinetetracycline +fecally eliminated (can be used in pts w/ renal failure)demeclocyclinetetracycline +ADH antagonist (diuretic in SIADH) +diabetes insipidusminocyclinetetracycline +meningococcal prophylaxis (2nd line)erythromycinmacrolideatypical pneumonia (Legionella, M. pneumo, Chlamydia), URI, STD, cocci (GP/Neisseria)binds 23S or 50S and inhibits translocationprolonged QT, GI discomfort, acute cholestatic hepatitis (avoid in liver disease), eosinophilia, skin rashes; P450 down (increases efficacy of theophylline and oral anticoagulants)clarithromycinmacrolideazithromycinmacrolide + MAC prophylaxis (AIDS)chloramphenicolmeningitis (H. flu, N. meningitides, S. pneumo)inhibits 50S peptidyltransferase; plasmid-encoded acetyltransferase inactivates druganemia (dose dependent), aplastic anemia (dose ind), gray baby sz (in preemies because they lack UDP-glucuronyl transferase)clinda-/linco-mycinlincosamideanaerobes in aspiration pneumoniabinds 50S and inhibits translocationpseudomembranous colitis, fever, diarrheasulfa-sulfonamideGP, GN, Nocardia, ChlamydiaPABA antimetabolytes inhibit DHpteroate synthetase (DHpteroate=DHF precursor); resistance=all mechanismshypersensitivity, SJS, hemolysis (G6PDD), nephrotoxic (tubulo-interstitial nephritis), teratogen (kernicterus), photosensitive, megaloblastic anemia, P450 downSMXsulfonamide I +UTItrimethoprim +SMXUTIs (tx or prophylactic for recurrent), Shigella, Salmonella, PCP (tx/prophylaxis)bacterial DHFRase Ipancytopenia (leuko-, granulocyto-, megaloblastic anemia; may alleviate w/ supplemental folinic acid [leucovorin rescue])nitrofurantoinUTIs (esp E. coli), used in pregnancybacterial DNA damagecan be used in pregnancy, hemolysis in G6PD deficiencyciprofloxacinFQGNR (esp of UTI/GI infxn), Neisseria, some GPstopoisomerase II inhibitor; resistance=mutated DNA gyrase; do not take w/ antacidsGI upset, superinfxns, tendonitis/rupture (not for pregnant women/kids), headache, dizziness, rashenoxacinFQmetronidazoleGI protozoa (Giardia, Entamoeba), vaginal (Trichomonas, Gardnerella), anaerobesfree radical toxic metabolites that damage DNAmetallic taste, disulfiram-like effect w/ EtOH, headache, mutagenesiscolistimethanepolymyxinresistant GNsdisrupts membranes (basic cations=detergent)neurotoxic, nephrotoxic (acute tubular necrosis)dapsoneM. leprae (oral, long term), PCPhemolysis (in G6PDD), methemoglobimemia, agranulocytosisclofazimineM. leprae (added to dapsone)rifampinM. leprae (delays resistance to dapsone), prophylactic for H. flu and N. meningitides; M. TB (quad tx)DNA-dep RNA pol inhibitororange body fluids, minor hepatotoxicity, ups P450INH (isoniazid)M. TB (quad tx and prophylaxis)decreased synth of mycolic acid, activated by bacterial catalase-peroxidaseneurotoxic (seizures), hepatitis, lupus; pyridoxine (B6) can prevent neurotoxicity and lupus; hemolytic in G6PD deficiency, P450 downpyrazinamideM. TB (quad tx)ethambutolM. TB (quad tx)pentamidine (aerosolized)PCP (prophylaxis, second line, after bactrim)linezolidVREbinds 50S and inhibits translocationquinupristinstreptograminVREdalfopristinstreptograminVREamphotericin Bserious systemic mycoses: Histoplasma, Blastomyces, Coccidioides, Aspergillus, Candida, Mucorbinds ergosterol, forms pores in membrane; does not cross BBB (intrathecal for meningitis)fever/chills, hypotension, nephrotoxicity (reduced by hydration), arrhythmias, IV phlebitis, anemiaflucytosinesystemic infxn along with Amphotericin Bconverted to 5-FU, inhibits DNA synthN/V/D/bone marrow suppression, nonmegaloblastic macrocytic anemianystatinCandida (thrush, diaper rash, vaginal)same as amphotericin Btopical (too toxic for oral)miconazoleazoletopical (esp tinea)inhibit fungal ergosterol synthesis by inhibiting P450 enzyme (lanosterol 14--demethylase); for systemic mycoses; ketoconazole also inhibits human enzyme desmolase (T-synth)liver dysfunction (P450 inhibitor), fever, chillsketoconazoleazoleCandida, Histoplasma, Blastomyces, PCOS (hirsutism), Coccidioides, hypercortisolism + hypocortisolism (blocks hormone synthesis in adrenals), gynecomastia, amenorrheafluconazoleazoleCryptococcal meningitis in AIDS, Candida + can cross BBBcaspofunginInvasive Aspergillosis-glucan cell wall synthesis inhibitorGI upset, flushingterbinafinedermatophytes (esp onychomycosis)squaline epoxidase I (ergosterol precursor)griseofulvinoral tx of superficial infxn, esp dermatophytes (tinea, ringworm)microtubule inhibitor, deposits in keratin-containing tissuesteratogen, carcinogen, confusion, headache, increase P450 and warfarin metabolismsuraminantiprotozoanTrypanosomes, no CNS penetrationinhibits energy metabolism enzymesmelacortinantiprotozoanTrypanosomes, CNS penetrationinhibits sulfhydryl enzymesnifurtimoxantiprotozoanT. cruziforms intracellular oxygen radicalsNa stibogluconateantiprotozoanLeishmaniasisinhibits glycolysis at PFKchloroquineantiprotozoanPlasmodiumblocks plasmodium heme polymerase (buildup of toxic hemoglobin products)hemolytic anemia in G6PD deficiencymefloquineantiprotozoanPlasmodium (resistant to chloroquine)quinineantiprotozoanchloroquine-resistant Plasmodium (+ pyrimethamine and sulfonamide); Babesiacinchonism (flushing, sweating, headache, confusion, blurred vision, vertigo, tinnitus, rash, abdominal pain, N/V/D)pyrimethamineantiprotozoanP. falciparum, + sulfadiazine=toxoinhibits plasmodial DHFRasemebendazoleantihelminthGI, neurocysticercosisinhibits glucose uptake and microtubule synthalbendazoleantihelminthEchinococcusinhibits glucose uptake and microtubule synthpyrantel pamoateantihelminthEnterobius, Ascaris, hookwormsstimulates depolarization-induced paralysis by stimulating nicotinic receptors at NMJivermectinantihelminthOnchocerca, Strongyloidesamplifies GABA-mediated inhibition leading to immobilization; doesn't cross BBB (no effect on humans)diethylcarbamazineantihelminthLoa loa, Wuchereria bancrofti, Toxocara canispraziquantelantihelminthtapeworms and flukesincreases membrane permeability to Ca (contraction, paralysis)amantidineInfluenza A (tx and prophylaxis), Parkinson's dzblocks viral penetration/uncoating (M2); also causes release of DA from intact nerves; resistance=mutated M2 (90% of flu A resistant)ataxia, dizziness, slurred speechrimantidinedoesn't cross BBB, fewer CNS SFx mzanamivirinfluenza A and Binhibit neuraminidaseoseltamivirpalivizumabRSVneutralizes F-proteinribavirinRSV, chronic hep Cinhibit IMPDH (guanine synthesis)hemolytic anemia, teratogen (severe)acyclovirHSV (tx and prophylaxis), VZV, EBVguanosine analog: monophosphorylated by viral thymidine kinase, triphosphate made in human cells; leads to chain terminationno effect on latent virus; resistance=lack of viral thymidine kinase famciclovirherpes zostergangciclovirCMV (mostly in immunocompromised)thrombocyto-/leuko-/neutro-penia, nephrotoxicfoscarnetgangciclovir-resistant CMV retinitis, acyclovir-resistant HSVviral DNA pol inhibitor, binds to PP-binding site, no activation requirednephrotoxic, hypo-Ca/PO4/K/Mg; resistance by mutated DNA polsaquiNAVIRprotease IHIVprevents cleavage of polypeptide products of pol gene, thus inhibiting virion assemblyhyperglycemia, N/D, lipodystrophy, P450 inhibitionindiNAVIRprotease IHIV + thrombocytopeniastavudine (d4T)nucleoside reverse transcriptase inhibitorHIVcompetitively inhibit nucleotide binding site on RT causing DNA chain termination; must be activated first by viral thymidine kinasebone marrow suppression (can be reversed with GCSF and erythropoietin), peripheral neuropathy, lactic acidosiszalcitabine (ddC)HIVdidanosine (ddI)HIV + pancreatitiszidovudine (ZDV)HIV (tx, prophylaxis, pregnancy) + megaloblastic anemianevirapineNNRTIHIVbind to RT at site different from NRTIs, do not require phosphorylationbone marrow suppression (can be reversed with GCSF and erythropoietin), peripheral neuropathy, rash (SJS)efavirenzNNRTIHIVdelaviridineNNRTIHIVenfuvirtidefusion inhibitorHIV (used in pts w/ persistent viral replication despite HAART)bind gp41: inhibit conformational change necessary for fusion with CD4 cellshypersensitivity, increased risk of bacterial pneumoniaIFN-recombinantchronic hep B/C, Kaposi's sarcoma, leukemias, malignant melanomasynthesized by viral infected cells to block replication of DNA and RNA virusesneutropeniaIFN-recombinantMSneutropeniaIFN-recombinantNADPH oxidase deficiencyneutropeniaImmuneDrugClassMechanismUseSFx/OthercyclosporineBinds cyclophilins, inhibits calcineurin preventing IL-2 and IL-2R productionsome autoimmune disorders, suppresses organ rejectionnephrotoxic (prevented by mannitol diuretic), higher risk for viral infxn and lymphomatacrolimusBinds FK-BP, inhibits IL-2 and IL-2R production (and other cytokines)suppresses organ rejection (very strong immunosuppressant)significant: hyperglycemia, htn, nephrotoxicity, peripheral neuropathy, pleural effusionsirolimus (rapamycin)inhibits mTOR and TC response to IL-2kidney transplant (+ cyclosporine and steroids)hyperlipidemia, thrombocytopenia, leukopeniadaclizumabMAb w/ high affinity for IL-2R on activated TCkidney transplantazathioprineantimetabolite precursor to 6-MP (interferes w/ nucleic acid synth)kidney transplant, autoimmune disorders (including GN, hemolytic anemia, UC)bone marrow suppression, worsened w/ allopurinol (6-MP broken down by xanthine oxidase), nonmegaloblastic macrocytic anemiamuromonab-CD3 (OKT-3)MAb that binds CD3 (epsilon chain) on TC, blocks signal transductionkidney transplantcytokine release syndrome, hypersensitivity rxnaldesleukinrecombinantIL-2RCC, metastatic melanomaerythropoietinrecombinantepoetinanemias (esp renal failure)filgrastimrecombinantGranulocyte Colony Stimulating Factorbone marrow recoverysargramostimrecombinantGranulocyte/Macrophage-CSFbone marrow recoveryoprelvekinrecombinantIL-11thrombocytopeniathrombopoietinrecombinantthrombopoetinthrombocytopeniadigoxin immune Fabtherapeutic abantidote for digoxin intoxicationPharm/CardioDrugClassMechanismUseSFx/Othermetyrosineinhibits tyrosine hydroxylase (makes DOPA)htn from pheo (prevents catecholamine synth)guanethidineinhibits NE release (replaces it in vescicles)htnbethanecholdirect ACh agACh ag, resistant to AChEneurogenic ileus/urinary retention and postopexacerbation of COPD/asthma (M3), and peptic ulcers (M1 and M3); severe/OD on AChEI: DUMBBELS=diarrhea, urination, miosis, bradycardia, bronchospasm, excitation of CNS and skeletal mm, lacrimation, sweating, salivationneostigmineAChEIno CNS penetrationneurogenic ileus/urinary retention and postop (reversal of NMJ block), myasthenia gravisedrophoniumAChEIno CNS penetration, extremely short actingdx of myasthenia gravispyridostigmineAChEIno CNS penetration, long actingtx of myasthenia gravisphysostigmineAChEICNS penetrationglaucoma and atropine ODatropineACh antregenerates AChEcauses mydriasis and cycloplegia, tx of ACh poisoning (organophosphates)constipated, urine retention, mydriasis, cyclopegia, acute angle closure glaucoma, bronchodilation, tachycardia, disorientation, increased T, and dry eyes, skin, and mouth (hot, dry, red, blind, mad, all analogies)pralidoximeregenerates AChEwith atropine, for cholinesterase poisoningscopolamineACh antCNSmotion sicknesstx OD w/ physostigmine salicylateoxybutyninACh antGUreduce urgency in mild cystitis and reduce bladder spasmsglycopyrrolateACh anthexamethoniumnicotinic agganglionic blockerused in experiments onlysevere orthostatic hypotension, blurred vision, constipation, sexual dysfunctionepinephrineSymp agvasoconstriction decreases aq humor production; low dose: >; high: >anaphylaxis, open angle glaucoma, asthma, hypotensionDONT use in closed angle: causes mydriasis and can block angle moreNESymp ag>1hypotension (but decreases renal perfusion)DASymp agD>>, inotropic and chronotropicshock (increases renal perfusion), CHFdobutamineSymp ag1>2, inotropicCHF, cardiac stress testingphenylephrineSymp ag1>2pupillary dilation, vasoconstriction, nasal decongestionephedrinerelease stored catecholaminesnasal decongestant, urinary incontinence, hypotensiontachyphylaxis (rebound congestion/continence[?])cocainecatecholamine reuptake inhibitor, inactivates Na channelscauses vasoconstriction, local anesthesiafetal abnormalities, fetal addiction, placental abruption, coronary vasospasm; OD: pupil dilation, hallucinations (esp tactile), paranoia, angina, tx=BDZ; withdrawal: suicidal, hypersomnolent, malaiseclonidinecentral 2 ag, decrease central adrenergic outflowhtn, esp. in renal disease (no decrease in renal blood flow), DM, 1st line in preg (+ hydralazine)-methyldopadirect Coombs-positive hemolytic anemiaergonovineperipheral alpha agonist (and DA, 5HT)dx of Prinzmetal's angina, placental deliveryergotismphenoxybenzamineirreversible nonselective -blockerpre-op on pheoorthostatic hypotension, reflex tachycardiaphentolaminereversible nonselective -blocker(praz)-osin1-blocker (smooth m relaxation)htn, urinary retention in BPH1st dose orthostatic hypotension, dizziness, headachecarvedilolnonselective - and -blockerhtn (decrease CO, decrease renin secretion [ blockade on JGA cells]), angina (decrease afterload, decrease HR and contractility [via calcium channels] causing decreased O2 consumption), MI and CHF (decrease mortality [esp carvedilol], slow progression), glaucoma (timolol, carve-dilol, betaxolol, decrease secretion of aqueous humor), antiarrhythmics (SVT, VT, AFib; decrease cAMP, Ca currents, and AV conduction velocity, increase PR); headache, essential tremor (propranolol)impotence, exacerbation of asthma, CV effects (bradycardia, AV block, CHF), CNS effects (sedation, sleep alteration), caution in DM (tx OD w/ glucagon), partial agonists (pindolol and acebutolol) contraindicated in angina; metoprolol can cause dyslipidemialabetalolnonselective - and -blockernadololnonselective -blockerpindololnonselective partial -agonistacebutolol1 partial agonist (>2)betaxololselective 1-blockerpropranololAND class II anti-arrhythmicsnonselective -blockermnemonics class II antiarrhythmics: help with Most suPrAvEnTriculars= metoprolol, propranolol, atenolol, esmolol, timolol; Partial agonists: pindolol, acebutolol; selective 1: A-M (atenolol, acebutolol, betaxolol, esmolol, metoprolol); nonselective: N-Z (nadolol, pindolol, propranolol, timolol)timololnonselective -blockeresmololselective 1-blocker, short-actingatenololselective 1-blockermetoprololselective 1-blockerhydralazinevasodilatorincreased cGMP, relaxing smooth m; arterioles>veins, afterload reductionhtn in pregnancy (1st line, with methyldopa), severe htn, CHFreflex tachycardia (contraindicated in angina/CAD, commonly given w/ -blocker), Lupus-like szverapamil (non-DHP)(L-type) CCB and type IV antiarrhythmicreduce mm contractility, ventricle>>vessels; -blocker-like antianginalhtn, angina (no unstable for DHP), Raynaud's, arrhythmias (non-DHPs; nodal arrhythmias [SVT, AFib]: slow conduction velocity, increase refractory period and PR, decrease slope of phases 1 and 2)cutaneous flushing, cardiac depression, AV block (careful in WPW), peripheral edema, dizziness, constipation, gingival hyperplasiadiltiazem (non-DHP)reduce mm contractility, ventricle=vesselsnife-/amlo-dipine (DHP)(L-type) CCBvasodilator, ventricle>TG, raise HDL a littlehepatotoxicity, rhabdomyolysisniacin (also see vitamin section)B3decreases hepatic VLDL secretion into circ, inhibit lipolysis in adipose tissuelower LDL>TG, raise HDL a bunchcutaneous flushing (esp face), hyperglycemia, acanthosis nigricans, hyperuricemiacholestyraminebile acid resinprevents intestinal reabs of bile acids, liver uses chlsl to make morelower LDL, slightly raise HDL and TGpts hate it: tastes bad, constipation, decreased abs of fat soluble vitamins, chlsl gallstonescolesevelamezetimibeprevents chlsl reabs at small intestine brushlower LDLrare increase in LFTgemfibrozilfibrateupregulate LPL causing increased TG Cl.lower TG>>>LDL, raise HDL a littlemyositis, hepatotoxicity (LFT), chlsl gallstonesdigoxincardiac glycosideinhibition of Na/K ATPase causes indirect inhibition of Na/Ca exchanger, increases [Ca]i, positive inotropy; stimulates vagus (suppresses AV node)CHF (decrease morbidity, not mortality), AFib (depresses SA node, slow AV nodal conduction); 75% bioavailable, 20-40% protein bound, t1/2=40h, urinary excretiongynecomastia, cholinergic (N/V/D), blurry yellow vision, ECG (high PR, low QT, scooping, inverted-T, arrhythmia), hyperK; OD worse w hypoK, renal failure, and quinidine (decreased clearance); tx OD w/ digoxin immune Fab, slowly normalize K, lidocaine, cardiac pacer, Mgclass I antiarrhythmicsNa ch blockersaffect on AP: phase 1=BAC (B is unchanged); phase 3=BCA (C is unchanged)mnemonic: Double Quarter Pounder, Lettuce Tomato Mayo, Extra/More Fries Pleasetoxicity increased w/ hyperkalemiadisopyramideclass IA anti-arrhythmicsincrease AP duration, effective refractory period, and QT; big gap in phase 3 from normal; intermediate dissociation speedgood for atrial and ventricular arrhythmias, especially reentrant and ectopic SVT, and VTquinidineTorsades, cinchonism (tinnitus, headache), thrombocytopeniaprocainamideLupus-like szmexiletineclass IB anti-arrhythmicsdecrease AP duration (no effect on QRS), preferentially target ischemic/depolarized Purkinje/ventricular tissue; fast dissociationacute ventricular arrhythmias (esp post-MI) and digitalis-induced arrhythmias (lidocaine)CNS stimulation/depression, CV depressionlidocainetocainidemoricizine/encainideclass IC anti-arrhythmicsno effect on AP duration, slow dissociation, so significantly prolongs refractory period in AV nodeVT (esp that go to VFib), intractible SVT, last resort in refractory tachyarrhythmias, only in pts w/o structural abnormalitiesproarrhythmic, esp post MI (contraindication)flecainidepropafenonesotalolclass III anti-arrhythmics: K-channel blockersincrease AP duration, increased effective refractory period, and increased QT interval; big gap in phase 3 from normal; sotalol is also mild beta blockerused when other arrhythmics fail; amiodarone has class I, II, III, and IV effects bc it alters the lipid membraneTorsades, excessive -blockibutilidetorsadesbretyliumnew arrhythmias, hypotension (emergency use only)dofetilideamiodaronepulmonary fibrosis, hepatotoxicity, thyroid dysfunction (40% I by wt), hypersensitivity, corneal deposits, photodermatitis, blue/gray skin deposits, CNS effects, constipation, CV effects (bradycardia, heart block, CHF, NOT TORSADES)adenosineantiarrhythmictransient AV block (A1R=Gq); endothelial dependent smooth m relaxationdx/tx of SVT, dx of CAD, very short acting (~15s)cutaneous flushing, hypotension, chest pain (blocked by theophylline)Kantiarrhythmicdepress ectopic pacemakers in hypokalemiadigoxin toxicityMgantiarrhythmictorsades and digoxin toxicityEndocrineDrugClassMechanismUseSFX/otherbromocriptineDA ag, inhibits PRL secretionPRLoma, Parkinsons, neuroleptic malignant szcabergolineDA ag, inhibits PRL secretionPRLomamethimazoleinhibits peroxidase-coupling of MIT/DIT and thyroid hormone synthesishyperthyroidismskin rash, aplastic anemia, agranulocytosis (rare)propylthiouracil + hepatotoxicityoctreotidesomatostatin analog (in stomach, inhibit ECL cell secretion of histamine)GHoma, NET, gastrinoma, glucagonoma, acute variceal bleed, VIPoma, carcinoid tumornausea, cramps, steatorrheadesmopressin (ddAVP)ADH analog; releases endothelial vWF storecentral DI, von Willebrand's dzgiven intranasal for DIlisprorapid-acting insulin (SPeedy)bind insulin receptor; liver: increased glycogen synthesis; muscle: increased glycogen and protein synthesis, K uptake; fat: aids TG storageDM, gestational DM, life-threatening hyperkalemia, stress-induced hyperglycemiahypoglycemia, hypersensitivity (very rare)aspartinsulinNPHintermediateglarginelong-acting insulindetemirtolbutamide1G sulfonyl-ureaclose K-channel in -cell membrane, causes cell depolarization and triggers Ca influx and insulin releaseT2DM (stimulates endogenous release of insulin, need some -cell function, so useless in T1DM)disulfiram-like effect w/ EtOH, hypoglycemiachlorpropamideglyburide2G sulfonyl-ureahypoglycemiaglimepirideglipizidemetforminbiguanidedecreases gluconeogenesis, increase glycolysis and peripheral glucose uptakeoral, can be used in pts w/o islet function (T1 or 2DM)lactic acidosis (contraindicated in renal failure)pioglitazonethiazolidine-dionesincrease peripheral insulin sensitivity, binds PPAR-T2DM (monotherapy or combo)weight gain, edema, hepatotoxicity, CV toxicityrosiglitazoneacarbose-glucosidase inhibitorinhibit intestinal brush border enzymes, delays sugar hydrolysis/absorptionT2DM (monotherapy or combo)diarrheamiglitolpramlintideamylin mimeticdecrease glucagonT2DMhypoglycemia, N/DexenatideGLP-1 analogincrese insulin, decrease glucagonT2DMN/V, pancreatitislevothyroxinethyroxine replacementhypothyroidism, myxedematachycardia, heat intolerance, tremors, arrhythmiastriiodothyronineGHhormone replacementGH deficiency, Turner'soxytocinhormone replacementstimulates labor, uterine contractions, milk let-down, controls uterine hemorrhagehydrocortisonesynthetic glucocorticoidinhibits virtually all cytokines by inactivating NF-B (TNF- transcription factor)Addison's, inflammation, immune suppression (Crohn's), asthma (1st line for chronic)iatrogenic Cushing's (incl. osteoporosis [contraindication], peptic ulcers, and DM), adrenal insufficiency when drug stopped after chronic usebeclomethasonedexamethasone + dx of Cushing's dz (suppression test)prednisone + triggers apoptosis + CLL, HodgkinsGIDrugClassMechanismUseSFX/othermethscopolamineACh antblock M1R on ECL cells (decrease histamine) and M3R on parietal cells (decrease H secretion)peptic ulcers (rarely used)tx OD w/ physostigmine salicylate; tachycardia, dry mouth, difficulty focusing eyespirenzepineACh antpropanthelineACh antfamoTIDINEreversible block of H2R on gastric parietal cells causes decreased H secretion (cimetidine=also antiandrogenic)PUD, gastritis, mild esophageal refluxnone (most H2 blockers); cimetidine: P450 down, gynecomastia (antiandrogenic, PRL release, impotence, decreased libido), can cross BBB (confusion, dizziness, headaches); ranitidine and cimetidine: decrease renal excretion of creatinineraniTIDINEcimeTIDINEnizaTIDINEomeprazolePPIirreversibly inhibit H/K ATPase in parietal cellsPUD, gastritis, esophageal reflux, Zollinger-Ellison Sz, H. pylori (+ clari, metro/amoxi)lansoprazolebismuthbind to ulcer base, provides physical protection, allows HCO3 secretionimproved ulcer healing, traveller's diarrhea, + metronidazole + amoxicillin (or tetracycline) for H. pyloriblack tongue, stoolsucralfatemisoprostolPGE1 analog, increased production of gastric mucous, decreased H+ productionprevention of NSAID-induced ulcer, induce labor, maintenance of ductus arteriosusdiarrhea, abortifacient Al(OH)3antacidcan affect absorption, bioavailability, and excretion of other drugs (alters pH or delaying gastric emptying)all cause hypokalemiaconstipation, hypophosphatemia, mm weakness, osteodystrophy, seizureMg(OH)2diarrhea, hyporeflexia, hypotn, cardiac arrestCaCO3hyperCa, rebound acid level, chelates other drugs sulfasalazinesulfa- antibiotic + 5-aminosalicylate (anti-inflammatory), activated by bacteriaUC, Crohn'smalaise, nausea, sulfa, reversible oligospermiaetanerceptrecombinantform of TNF-R (sequesters TNF)Crohn's, RA, psoriatic arthritisadalimumabtherapeutic abanti-TNF-Crohn's, RA, psoriatic arthritisinfliximabtherapeutic abanti-TNF-Crohn's, RA, psoriatic arthritis, ankylosing spondylitisrespiratory infxn (reactivation of latent TB bc TNF- maintains granulomas), fever, hypotensionondansetron5HT3 ant, powerful central antiemeticdecrease vomiting (post-op, chemo)headache, constipationmetoclopramideD2R ant causes increased LES tone, motility, contractility, decreased pyloric S toneantiemetic, gastroparesis (DM or post-surgery), does not influence colon transport timeParkinsonian, restlessness, drowsiness, depression, N/D; interacts w/ digoxin and diabetic agents; contraindicated in SI obstructionHeme/OncDrugClassMechanismUseSFX/otherheme and glucoseinhibits ALA synthase (RLS of heme synth)acute intermittent porphyriavitamin A (xs)for PML: inhibits retinoic acid receptor causing promyelocyte differentiationacne, measles, PML (AML M3)teratogen (spontaneous abortion, cleft palate, cardiac abnormalities); when txing PML, can release Auer rods and cause DICheparinactivates antithrombin, acts most on Xa and thrombin; very short t1/2; watch PTTimmediate anticoagulation: PE, CVA, acute coronary sz, MI, DVT; safe for pregnancyfollow PTT; bleeding, thrombocytopenia/clotting (HITT, binds PF4 [platelet factor 4, natural CXCR4L]), osteoporosis; antidote= protamine sulfate (positive, binds)enoxaparinLMW heparinacts more on Xa, better bioavailability, longer t1/2; subQ, fine if unmonitorednot easily reversible, similar sfx(bival)-IRUDINhirudindirectly inhibit thrombinheparin alternative in pts w/ hx of HITwarfarininhibit activation (-carboxylation) of vit K-dependent facotrs (II, VII, IX, X, proteins C and S)chronic anticoagulation, oralmonitor PT, metabolized by P450; antidote=vitamin K; for more rapid reversal, give FFP; skin/tissue necrosis; teratogen (bone deformities, fetal hemorrhage, abortion)tPAconvert plasminogen to plasmin, which degrades fibrinogen and fibrinearly MI, early ischemic strokebleeding, treat toxicity with aminocaproic acid or tranexamic acid (plasminogen activation inhibitors)urokinasestreptokinasebind w/ plasminogen, activate plasminogenanistreplasestreptokinase bound to plasminogenclopidogrelbinds ADPR on platelets, inhibits GpIIb/IIIa expression, inhibits fibrinogen bindingacute coronary sz, coronary stenting, decrease risk of thrombotic stroketiclopidineneutropeniaabciximabtherapeutic abGpIIb/IIIa Ab for activated plateletsprevent cardiac ischemia in unstable angina and in pts txed w/ percutaneous coronary intervention, acute coronary szbleeding, thrombocytopeniamethotrexate (MTX)antimetabolite (all work on S-phase)folic acid analog, inhibits DHFR, decreasing dTMP and DNA/protein synthleukemia, lymphoma, chorioca, sarcomas; abortion, ectopic pregnancy, RA, psoriasismyelosuppression (leucovorin rescue), macrovescicular fatty liver, mucositis (aphthous ulcer), teratogenic; tx OD by alkalinizing urine5-FUpyrimidine analog, activated to 5F-dUMP, covalently binds DHFR, which inhibits thymidylate synthase, decreasing dTMPsolid tumors, topical for basal cell ca, synergistic w/ MTXmyelosuppression (non-megaloblastic microcytic anemia, thymidine rescue), photosensitivity6-MPpurine analog, inhibits de novo purine synth, activated by HGPRTleukemia or lymphoma (not CLL or HL), UCnonmegaloblastic macrocytic, GI, liver; increased toxicity w/ allopurinol6-thioguanine (6TG)ALLmarrow depression, can be given w/ allopurinolcytarabine (ara-C)pyrimidine analog, inhibits DNA PolAML, ALL, high grade NHLleukopenia, thrombocytopenia, megaloblastic anemiadactinomycinantitumor abx (mostly G2)intercalates in DNAEwing's sarcoma, rhabdomyosarcoma, childhood tumors (Wilm's)myelosuppressiondoxorubicin (adriamycin)anthracyclines: noncovalently intercalate in DNA causing breaks; generate free radicalsHodgkins, myelomas, sarcomas, solid tumorscardiotoxicity (dilated CM, protected by dexrazoxane [Fe-chelation]), myelosuppression, alopecia; toxic to tissues with extravasationdaunorubicinbleomycinfree radical formation, breaks DNAtesticular and Hodgkinspulmonary fibrosis, skin changes, minimal myelosuppression(eto)-POSIDE (VP-16)inhibits topoisomerase II (S and G2)SCC of lung/prostate, testicularmyelosuppression, GI irritation, alopecianitrosurea (-mustines)alkylating agentsrequire bioactivation, cross BBBbrain tumors (including glioblastoma multiforme)CNS toxicity; all alkylating agents: teratogen (missing digits), aplastic anemia cyclophosphamidecovalently cross-link DNA at guanine N7, require activation by liverNHL, breast, ovarian; also good immunosuppressantsmyelosuppression, hemorrhagic cystitis (lessened by mesna, better control w/ ifosfamide); SIADH for cyclophosphamideifosfamideprocarbazinealkylates DNAHodgkin's, brain tumorsdisulfiram-like effect w/ EtOHbusulfanalkylates DNACML, pre-marrow-transplant marrow ablationpulmonary fibrosis, hyperpigmentationvincristinemicrotubule inhibitor (M-phase)bind tubulin, block polymerization, inhibit mitotic spindle formationHodgkins, Wilm's, choriocaneurotoxic (areflexia, peripheral neuritis), paralytic ileusvinblastinebone marrow suppressionpaclitaxelhyperstabilize polymerized microtubules, inhibit mitotic spindle degradationovarian and breastmyelosuppression, hypersensitivity -TAXOLs(cis/carbo)-PLATINcross-link DNAtesticular, bladder, ovary, lungnephrotoxic, ototoxicamifostinecytoprotective free radical scavengerprevent nephrotoxicity and xerostomia, given with platinum and alkylating agentshydroxyurea(S-phase)ribonucleotide reductase inhibitormelanoma, CML; sickle-cell (increase HbF)nonmegaloblastic macrocytic anemia, GI upsettrastuzumab (herceptin)therapeutic abAb against HER-2 (erb-B2); possibly kills through Ab-dependent cytotoxicityHER-2-overexpressing breast cancercardiotoxicimatinib (Gleevec)NOT AN Abbcr-abl tyrosine kinase inhibitorCML (Philadelphia chr., main target), GISTfluid retentionrituximabtherapeutic abAb against CD-20 (on most BC neoplasms)BC non-Hodgkin's lymphoma, RA (+ MTX)MusculoskeletalDrugClassMechanismUseSFX/otheraspirin (ASA)NSAIDsirreversibly acetylates COX (1 and 2), prevents conversion of AA to TXA2, PGE2, PGI2low dose (>2), hyperpyrexia; tx OD w/ NaHCO3 (alkalinize urine)notriptylinedesipramineimipramine + bedwetting (decreases stage 4 sleep)clomipramine + OCD(par/flu)-oxetineSSRIusually takes 2-4 weeks for antidepressant effectsOCD, social phobia, specific phobia, panic disorder, PTSD, GAD, anorexia/bulimia, anxiety, depression (typical or atypical)less than TCAs: GI distress, sexual dysfunction, "Seratonin sz" (drug interactions, too much 5-HT causes HyperThermia, HyperTonism, CV collapse, flushing, diarrhea, seizures; tx=cyprohepadine [5HT2 ant])sertralinecitalopramvenlafaxineSNRI5-HT>NE reuptake inhibitordepression, GADstimulant effects (htn most common), sedation, nauseaduloxetine5-HT2*ALT; acute EtOH=P450 down; chronic EtOH=P450 up, gynecomastia; assn w/ periventricular hemorrhage/necrosis of mammillary bodieschronic EtOHStimulantscrash, depression, lethargy, wt gain, headachemood elevation, psychomotor agitation, insomnia, arrhythmias, tachycardia, anxietycaffeinerestlessness, diuresis, muscle twitchingnicotineirritability, anxiety, cravingrestlessnessteratogen (preterm labor, placental problems, IUGR, ADHD)HallucinogensPCPdepression, anxiety, irritability, restlessness, anergia, thought/sleep disturbanceshomocidality, delerium, belligerence, fever, nystagmus, tachycardia, psychomotor agitation, impulsivenessLSDflashbacks, pupillary dilation, marked anxiety/depression, delusions, visual hallucinationsmarijuanairritability, depression, insomnia, N, anorexia; peak in 48h, last up to 7days; can be detected in urine for up to 1 monthparanoid delusions, slowed time perception, social withdrawal, dry mouth, hallucinationsRenalDrugClassMechanismUseSFX/othermannitolosmotic diureticshock, drug OD, increased ICP/IOPpulmonary edema, dehydration, contraindicated in anuria and CHFacetazolamidecarbonic anhydrase inhibitor urinary alk (TCA/bartbiturate/salicylate OD, cystinuria), MAlk, altitude sickness, glaucomahyperchloremic (nAG) MAc, neuropathy, NH3 toxicity, sulfaethacrynic acidloop diureticphenoxyacetate derivative, same as Lasixdiuresis in sulfa-allergies or gout ptsototoxicity, hypokalemia, dehydration, interstitial nephritisfurosemideinhibit cotransport of NaK2Cl; lose hyper-tonicity of medulla, increase Ca excretionedema (CHF, cirrhosis, nephrotic sz, pulmonary edema), htn, hypercalcemia + sulfa allergy and gouthydrochlorothiazidethiazideinhibit NaCl reabs in distal tubule, low Ca excretionhtn, CHF, idiopathic hypercalciuria, nephrogenic DIhypokalemic MAlk, hyponatremia (low big 3), hyperglycemia, hyperlipidemia, hyperuricemia (gout), hypercalcemia, sulfa allergyeplerenoneK-sparing diureticscompetitive aldoR anthyperaldo, K-depletion, CHF, hirsutism (spironolactone)hyperkalemia, MAc spironolactone + mild testosterone R antendocrine SFx (antiandrogen, gynecomastia, amenorrhea)triamterineblock ENaC in DCThyperkalemia, MAc amiloride + nephrogenic DIcaptoprilACEIinhibit inactivation of bradykinin (vasodilator); causes renin release by loss of feedback inhibitionhtn, CHF, diabetic renal dzcough (not ARBs), angioedema (lip/larynx edema), teratogen (renal damage), proteinuria, taste change, hypotn, hyperK; NOT in bilateral renal a stenosis (decrease GFR by preventing efferent constriction)lisinoprilenalaprilReproDrugClassMechanismUseSFX/otherleuprolideGnRH agpulsatile=agonist, continuous=antagonistinfertility, prostate ca (+ flutamide), fibroidsantiandrogen, N/VmethyltestosteroneT agonist at androgen receptorshypogonadism, develop 2 sex characteristics, burn pts (promotes anabolism)masculinization in females, reduces intratesticular testosterone in males (inhibits LH) causing gonadal atrophy, premature closure of epiphyseal plates, raise LDL, lower HDLfinasteride5-reductase inhibitor, lower DHTBPH, male pattern baldnessgynecomastiaflutamidenonsteroidal competitive T-receptor antprostate cancer (+ leuprolide)ethinyl estradiolestrogenEstrogen receptor antagonisthypogonadism, POF, menstrual abnormailities, postmenopausal HRT, androgen-dependent prostate cancerendometrial cancer, postmenopausal bleeding, VTE; contraindications: ER-positive breast cancer, hx of DVTsmestranoldiethylstilbestrolteratogen (vaginal clear cell adenoC)clomipheneSERMinhibits negative feedback on hypthalamusovulation inductionhot flashes, ovarian enlargement, multiple pregnancies, visual disturbancestamoxifenag: bone, endometrium; antag: breastbreast cancer (ER-positive), prevent osteoporosisendometrial carcinoma, hot flashesraloxifeneag: bone; antag: endometrium, breastHRTmenopausal sx (hot flashes, vaginal atrophy, osteoporosis [E2 decreases osteoclast activity])unopposed estrogen RT increases the risk of endometrial cancer (P added), possible increased CV riskexemestanearomatase inhibitorER-positive breast cancer in postmenopausal womenmasculinization, premature epiphysial plate closureanastrozoleprogestinreduce growth and vascularization of endometriumoral contraceptives, endometrial cancer, abnormal uterine bleedingmifepristone (RU-486)competitive progesterone inhibitorpregnancy termination (+ misoprostol)heavy bleeding, N/V, anorexia, abdominal paindinoprostonePGE2 analog (dilation, uterine contraction)labor inducerterbutalineSymp ag2reduce premature uterine contractionsritodrinetamsulosin1A,DR ant (on prostate, 1BR on vessels)BPH (inhibits only prostatic smooth m)sildenafilinhibit cGMP PDE5IEDheadache, flushing, dyspepsia, impaired blue-green color vision, life-threatening hypotn in pts taking nitratesvardenafilRespiratoryDrugClassMechanismUseSFX/otherdiphenhydramine1G H1 blockersreversible inhibitors of H1 histamine Rallergy, motion sickness, sleep aidsedation, antimuscarinic, anti--adrenergicchlorpheniramineloratadine2G H1 blockersallergyless entry to CNS than 1G, so far less sedationfexofenadinedesloratadinecertirizinemethacholinedirect ACh aginhaled, causes bronchoconstrictionchallenge test for dx of asthmaanti-DUMBBELSSipratropiumACh antcompetitive block of MACh-Rasthma, COPDisoproterenolSymp aglowers BP (not used), asthmatachycardiametaproterenolSymp agselective 2 ag (2>>1)acute asthmaalbuterolacute asthmasalmeterollong term asthma (attack prophylaxis)tremor, arrhythmiatheophyllinemethylxanthinePDEI (decreases cAMP hydrolysis)asthma, adenosine toxicitynarrow TI (OD=-blocker), cardio-/neuro-toxic, metabolized by P450cromolynstabilizes mast cell granulesonly for asthma/allergy prophylaxis, not txzileutonantiLT5-lipoxygenase inhibitor (AA to LTs)asthma(zafir)-lukastLT receptor antagonistasthma (especially aspirin-induced)guaifenesinexpectorantdoes not suppress cough reflexN-acetylcysteinemucolytic, glutathione precursorloosen plugs (CF), acetaminophen ODbosentanendothelin-1 receptor antagonist (lower PVR)pulmonary htnBiochemNameVitaminFunctionDeficiencyExcessretinolAantioxidant, used in vision pigment, cell differentiation (tx AML M3), also used to treat measlesnyctalopia (night blindness), dry skinacute: N/V/dizziness, blurred vision; chronic: hepatotoxicity, increased ICP, papilledema, arthralgias, fatigue, headaches, skin changes, sore throat, alopecia; teratogenic (cardiac abnormalities, cleft palate)calcitriol (D3)Dincrease intestinal absorption of Ca and PO4rickets (kids), osteomalacia, hypocalcemic tetany, breast milk is low in vitamin Dhypercalcemia (delerium, stupor, stones), loss of appetite; seen in sarcoid: activated macrophages pump out vit Dvitamin EEantioxidant (RBCs and cell membranes)hemolytic anemia, mm weakness, posterior column and spinocerebellar demyelinationvitamin KK catalyzes -carboxylation of glutamate on clotting factors (II, VII, IX, X, protein C, S)neonatal hemorrhage w/ increased PT and PTT, normal bleeding time; warfarin, cephalosporinthimineB1cofactor for PDH, -KGDH, transketolase (HMP shunt), branched chain AA DHWernicke-Korsakoff or Beriberi (wet=dry + high output cardiac failure; dry=polyneuritis, symmetrical mm wasting); glucose can worsenriboflavinB2cofactor in redox (FADH2)cheilosis (inflammation of lips), corneal vascularizationniacinB3made from tryptophan and B6glossitis; severe=pellagra (diarrhea, dermatitis [Casal's collar], dementia)facial flushing (tx of hyperlipidemia), acanthosis nigricans, hyperuricemiapantothenateB5CoA (acyl transfers and FA synth)dermatitis, enteritis, alopecia, adrenal insuffpyridoxal PB6used in a ton of rxns (make niacin from trp); deficiency caused by INH, OCPsconvulsions, hyperirritability, peripheral neuropathy, sideroblastic anemia, pellagracobalaminB12homocysteine methyltransferase (regeneration of methionine after SAM) and methylmalonyl-CoA mutase (generation of succinyl CoA from catabolism) cofactormegaloblastic anemia, hypersegmented PMNs, neuro sx; from malabsorption in terminal ileum (Crohn's, sprue, enteritis, D. latum) or lack of intrinsic factor (PA, gastric bypass)folatenucleic acid synth, methyl transfers (SAM); most common deficiency in US (alcoholics and pregnancy)megaloblastic anemia, no neuro sx, but teratogenic (neural tube defects); can be from drugs (phenytoin, MTX, sulfonamides)biotin(B7)cofactor for carboxylations (pyruvate, acetyl-CoA, propionyl CoA)dermatitis, alopecia, enteritis; rare: excessive ingestion of raw eggs (avidin) or abx useascorbic acidCantioxidant, facilitates Fe absorption, collagen synthesis, DA to NE scurvy: swollen gums, bruising, hemarthrosis, anemia, poor wound healing, weak immuneZnessential for 100+ enzymes, transcription factors (Zn fingers)poor wound healing, hypogonadism, decreased adult hair, dysgeysia, anosmia, risk of cirrhosisToxins/AntidotesdrugclassantidoteSFX/otherMechanismsalicylateNaHCO3 (alkalinize urine), dialysisnot for gout (need too high of a dose)iron (hemochromatosis)deferoxamineacute: gastric bleeding; chronic: MAc, GI scarringperoxidation of membrane lipidslead1st line: CaEDTA and dimercaprol, 2nd: penicillamine; succimer for kidsmercurydimercaprol (BAL), succimerarsenicdimercaprol (BAL), succimer, penicillaminevomiting, rice water stool, garlic breath; SqCCinhibits lipoic acid (pyruvate and -KG DH complexes)goldcopper (Wilson's)penicillaminecyanidenitrite, hydroxocobalamin, thiosulfatecan be from nitroprusside (tx for malignant htn)electron transport inhibitormethemoglobinmethylene blue, vitamin Ccreated by nitrite bc it binds CN stronglyCO100% O2, hyperbaric O2electron transport inhibitormethanolethanol, fomepizole, dialysisinhibit alcohol dehydrogenaseethylene glycolbenzeneaplastic anemiaouabaininhibits Na/K ATPase (bind K site)Amanita phalloides (poison mushroom)hepatotoxicity/necrosis-amantin inhibits RNA Pol IIantimycin Aelectron transport inhibitorrotenoneelectron transport inhibitoroligomycinmitochondrial ATPase inhibitor2,4-DNPuncoupling agentorganophosphatesatropineirreversible AChEI (AChE regenerated by atropine)

The Finer PointsBiochem (pathology)collagen one=90%, bONE, skin, tendon, dentin, fascia, cornea, late wound repair; II=cartilage, vitreus, nucleus pulposis; III (reticulin)=skin, vessels, uterus, fetal tissue, granulation tissue (think Ehlers-Danlos); IV=BMXLR diseases (XLD=hypophosphatemic rickets)2 blood dzsG6PDDHemophilia (A and B)Kwashiorkor: protein malnutrition (lesions, belly); marasmus: energy malnutrition (wasting)2 binomial dzsLesch-NyhanWiskott-Aldrichessential fructosuria: AR fructokinase def, fructose doesn't enter cells, asxatic except for fructosuria2 B'sBecker's MD (+DMD)Bruton's agammaglobulinemiafructose intolerance: AR aldolase B deficiency, F1P accumulation, depletion of P, inhibition of glycogenolysis, gluconeogenesis; sx: hypoglycemia, jaundice, cirrhosis, V; tx: no fructose/sucrose intake2 O'sOcular albinismOTC deficiency2 LSDsFabry'sHunter'sgalactokinase deficiency: AR, relatively mild, accumulation of galactitol (infantile cataracts), galactosuriaclassic galactosemia: AR gal-1-P UT def; sx: infantile cataracts, FTT, jaundice, HM, retardation; tx: no lactoseAmino acids (GluM HArV, PITT)alkaptonuria (ochronosis): AR homogentisic acid oxidase def, degrades Tyr to fumarate; sx: mostly benign, urine turns black on standing, dark connective tissue/sclera, older get arthralgias (HGA toxic to cartilige)EssentialKetogenicLeucine, LysineGlucogenicMethionine, Valine, Arginine, HistidineMSUD: -ketoacid DH def, no degradation of branched AAs (Ile, Val, Leu); organic acidemia, sweet odorBothPhenylalanine, Isoleucine, Threonine, Tryptophanhomocystinuria (HCU): excess HC, C becomes essential, 3 forms (cystathione synthase deficiency [tx=high B12/folate/diet=hi cys low met], low affinity of cystathione synthase for B6 [tx=high B6], HC methyltransferase deficiency); sx: HCU, mental retardation, osteoporosis, kyphosis, marfanoid habitus, inferonasal sublux of lens, atherosclerosis (stroke, MI);; cystinuria: defect of renal tubular positive-AA transporter (cysteine, ornithine, lysine, arginine); sx: cystine kidney stones (staghorn); tx: acetazolamide (alkalinize urine)AcidicGlutamate, AspartateBasicLysine, Arginine (most basic), Histidine (no charge at body pH)

Lipid transportParticleChylomicronVLDLIDLLDLHDLfraGile X: 2nd most common cause of M retardation; (CGG) repeat, methylation and underexpression of FMR1, macroochidism, long face, large jaw, big ears, MVP; karyotype in folate def medium=discontinuous stainingProteinsB-48, C-2, EB-100, C-2, EB-100, EB-100A-1, A-2LCAT: lecithin-chlsl acyltransferase, in HDL and LDL, esterifies 2/3 of plasma chlsl ionizing radiation causes dsDNA breaks, end-joining enzyme repair (no sequence homology necessary)CETP: chlslester transfer protein, takes chlsl from HDL to LDL/VLDL, TG back to HDLdeamination causes abnormal bases, glycosylation makes AP site, AP endonuclease, DNA Pol, and ligase fixhyperchylomicronemia (I): LPL def or altered apoC-II (cofactor) causes high TG and chlsl; pancreatitis, HSM, eruptive xanthomas, no increased risk for atherosclerosisUV makes T-T, UV-specific endonucleases cause site specific strand break, exonuclease removal, Pol/ligase fix (def=XP); DNA Pol III has 3'-5' exonuclease proofreading activity for mismatch repair (def=HNPCC)familial hyperchlslemia (IIa): AD, absent LDL-R causes increased LDL, chlsl, tendon (Achilles) xanthomas, accelerated atherosclerosis (MI10mmHg during inspiration; 1. increased pulmonary capacity/low LV filling (all); 2. increased RV filling causes septal deviation and reduced LV filling (pericarditis, tamponade); 3. highly negative intrathoracic P decreases transmural P, increasing afterload (asthma, COPD, croup, apnea)EvolutionAgeMicroscopic ChangesGrossRiskday 14h: early coagulative necrosis; 12-24h: contraction bands, early PMN infiltratedark, mottled, pale w tetrazolium dyearrhythmiaRF: Ab to M protein of S. pyogenes; subQ nodules, polyarthritis (migratory), erythema marginatum, carditis, chorea; Anitschkow's cells (activated histiocytes) coalesce to form Aschoff bodies (giant cells w/i granuloma) day 2-4extensive coagulative necrosis, acute inflammation in tissue surrounding infarct, dilated vessels, PMN infiltratehyperemicarrhythmiabenign vascular tumors hemangiomas: strawberry (infancy, spontaneously regress), cherry (elderly, does not regress), pyogenic (polypoid capillary hemangioma, can ulcerate and bleed, assn w/ trauma and pregnancy); others: cystic hygroma (cavernous lymphangioma of neck, assn w/ Turner's sz), glomus tumor (painful, red-blue under fingernail, from smooth mm), bacillary angiomatosis (Bartonella henselae, PMNs)or rupture (day 4)

day 5-10ingrowth of granulation tissue as macro-phages degrade old structure and induce scar formationhyperemic border, centrally yellow-brownrupture (wall, chordae)

malignant vascular tumors angiosarcoma (liver, highly lethal, assn w/ vinyl chloride, As, Thorotrast [ThO2]), lymphangiosarcoma (caused by persistent lymphedema, post-radical mastectomy, eg), Kaposi's (lymphocytes)wk 7scargrey whiteaneurysmCABG LAD only=L internal mammary (thoracic); multiple=great saphenous (medial foot to inf. pubic tubercle)

Endocrineneurophysins=carrier proteins from hypothalamus to posterior pit; -subunit identical for TSH, FSH, LH, -hCGSignalling pathways of hormonespancreas: more endocrine cells in tail, s peripherally, s centrally, s interspersed; TRH -[+]> TSH and PRLcAMPCa (PTH, calcitonin), ADH (V2R)/-subunits (FSH, LH, TSH, -hCG), melanotropic (ACTH, MSH), pancreatic (glucagon), GHRHinsulin inhibits glucagon release, increases glucose transport (GLUT-4=insulin-responsive, in adipose and skeletal mm; GLUT-1=RBC and brain; GLUT-2=liver, small intestine, cornea, kidney, -cells), increases Na retention, increases cellular K uptake; enters -cell via GLUT-2, aerobic respiration (RLS=glucokinase), ATP binds to K channel and closes, causing depolarization and Ca channel opening, causing exocytosis of insulincGMPNO, ANPIP3-subunitRH (GnRH, TRH), posterior pit (oxytocin, ADH)nuclearT3/T4cytosolicall steroids but T3/4: DHT, P, E2, D3, cortisol, aldointrinsic TK (MAP kinase) -GF: FGF, PDGF, IGF-1, insulin (with IGF-1);; TK P-ationDM type 1: assn w HLA-D3/4, anti-glutamate decarboxylase Abs; acute sx: DKA (higher insulin requirement not met causes ketosis; Kussmaul breathing, N/V, abd pain, psychosis/delerium, dehydration, fruity breath odor, AGMAc, hyperkalemia [depleted intracellular]); chronic sx: small vessels (BM thickening causing retinopathy, neovascular glaucoma, nephropathy [nodular sclerosis, proteinuria, CRF, htn, Kimmelstiel-Wilson nodules]), large vessels (CAD, PVD, gangrene), osmotic damage (neuropathy, sorbitol cataracts)(inhibited by TNF-) recruits SOS protein, Ras hydrolyzes GTP and becomes activatedreceptor TK (JAK/STAT)GH, PRL, IL's, CSF

DM dxHbA1CFasting glucose2h glucose toleranceadrenals vertical: chlsl -[desmolase]-> /(17-OH)/pregnenolone -[3-OHsteroid DH]-> /(17-OH)/progesterone -[21-OHase]-> 11-deoxycorti-/(sol)/costerone -[11--OHase]-> corti-/(sol)/costerone -[aldo synthase]-> aldo; DHEA to androstenedione (can be converted peripherally to estrone and estradiol) to testosterone (converted by 5-reductase to DHT or aromatase to estradiol); desmolase activated by ACTH, inhibited by ketoconazoleNormal200or sx of hyperglycemia and a casual (random) plasma glucose >200cortisol: increases gluconeogenesis, lipolysis, proteolysis, and -1 on arterioles (maintains BP), decrease bone formation and immune function, anti-inflammatory; excess tested by dexamethasone suppression testCAH (all have enlarged adrenal glands due to low cortisol and thus high ACTH)hyperaldo primary=Conn's: aldo-secreting tumor, htn, hypokalemia, MAlk, may be bilateral; secondary: all cause kidney to perceive low V (renal artery stenosis, CHF, CRF, cirrhosis, nephrotic sz), so secretes high reninDeficiencyEpidemSex HrmnsAldoBPOther21-OHase95%highlowlowhypovolemic shock in newbornadrenal insufficiency 1: (acute=Waterhouse-Friderichsen Sz: hemorrhage from N. meningitidis sepsis, DIC, shock), usually chronic=Addison's dz: can be from atrophy or destruction, def of aldo and cortisol, sx=hypotn, hyperK, acidosis, skin hyperpigmentation (from high ACTH binding to MSHRs); 2: low CRH or ACTH production: no skin hyperpigmentation, no hyperK; corticosteroid withdrawal can cause acute or chronic insufficiency11OHase5%highlowhighmasculinization, as w 21-OHase17OHaserarelowhighhighM=pseudoherm, F=sexual infant

Multiple endocrine neoplasias (MEN)neuroblastoma: kids, can be anywhere along sympathetic chain, elevated HVA in urine, less likely to have htn, n-myc=worse prognosis; pheo: adults, high urine VMA, episodic htn, headache, perspiration, palpitations, tachycardia, pallor, assn w/ NFM, MEN 2A/B, 10%: malignant, bilateral, extra-adrenal, calcify, kids, familialMEN 1 (Wermer's)parathyroid (kidney stones), pituitary (usually PRL or GH), and pancreas tumors (Zollinger-Ellison, so stomach ulcers)

MEN 2A (Sipple's)medullary thyroid cancer, pheo, parathyroid (kidney stones)PTH chief cells of paraT, PTH inhibited by low Mg (diarrhea, rxs [AG, EtOH, diuretics]); renal PO4 resorption down, ups renal Ca resorption (DCT), stimulates osteoblasts (secrete RANK-L [stimulates osteoclasts, ups bone resorption, raising blood Ca and PO4] and M-CSF), stimulates kidney 1-OHase (inhibited by calcitriol)MEN 2Bmedullary thyroid cancer, pheo, oral or intestinal ganglioneuromatosis (marfanoid habitus)

MEN 2A and MEN 2B associated w/ ret gene (oncogene, tyrosine kinase)vit D D2=ergocalciferol, from plants; D3=cholecalciferol, from sun, 24,25-(OH)2 vit D=inactive; 1,25-(OH)2 (calcitriol) increases intestinal Ca and PO4 absorption and stimulates osteoblasts in the same way as PTHT3/T4: synthesized by peroxidase from I + tyrosine (inhibited by anions and PTU or methimazole); bone growth, CNS maturation, increased 1 in heart, increased metabolic rate; TBG increases in OCP-use and pregnancyhyperPTH 1: usually adenoma, hypercalcemia, stones, hypoPO4, high alk phos, high cAMP in urine, can cause osteitis fibrosa cystica (cystic bone spaces filled w brown fibrous tissue); 2: decreased gut Ca absorption, high plasma PO4 (usually from chronic kidney failure) causes hyperplasia, sx=hypocalcemia, hyperPO4, high alk phos; 3: refractory hyperPTH from chronic renal dz, hypercalcemia; 2/3 can cause renal osteodystrophy

hyperT3 pretibial myxedema; toxic multinodular goiter: hot nodule, mutated TSH-R, rarely malignant; Grave's: presents during stress, type II hypersensitivity; thyrotoxicosis: complication of hyperT3, stress-induced catecholamine surge, death by arrhythmia; Jod-Basedow: thyrotoxicosis if a pt w/ I-def goiter is made I-replete

hypoPTH usually from accidental excision, autoimmune, or DiGeorge; hypocalcemia, tetany, Chvostek's sign (tapping facial n causes mm contraction), Trousseau's sign (occlusion of brachial a w/ BP cuff causes carpal spasm); pseudohypoPTH=Albright's hereditary osteodystrophy: AD kidney unresponsiveness to PTH

hypoT3 myxedema (facial/periorbital), severe=myxedema coma (hypothermia and altered mental status), can be a side effect of lithium or amiodarone; Hashimoto's: thyroiditis, so may be hyperT3 early, autoimmune (antimicrosomal antithyroglobulin Ab, HLA-DR5), Hurthle cells, lymphocytic infiltrate w/ germinal centers; cretinism: severe fetal hypoT3, co-endemic with goiter, pot-bellied, pale, puffy faced, protruding umbilicus, protuberant tongue; subacute thyroiditis (de Quervain's): self-limited, following flu-like illness, jaw pain, early inflammation (granulomatous), tender; Riedel's thyroiditis: replaced by fibrous tissue, rock-hardcalcitonin: parafollicular (C-) cells of thyroid, decrease bone resorption of Ca, not important physiologicallyDI no ADH response, USG290mOsM; central (from supraoptic nuc): pit tumor, trauma, surgery, or histiocytosis X, responds to desmopressin; nephrogenic: hereditary, 2 to hypercalcemia, demeclocycline, Li, doesn't respond to desmopressin; ADH responds to Osm before V, acts in medullary collecting duct

SIADH: excessive water retention, hypoNa, urine Osm>serum Osm, low aldo; can be from ectopic production, head trauma, pulmonary dz, or rxs (carbamazepine, cyclophosphamide); tx=demeclocycline, water restriction

pit adenoma usually PRL (amenorrhea, galactorrhea), then GH (insulin resistance, dx=glucose suppression)NET: most common tumor of appendix, secrete 5-HT, high 5-HIAA in urine, 1/3 (met, multiple, present w/ 2nd malignancy); carcinoid sz: recurrent diarrhea, cutaneous flushing, asthmatic wheezing, R-sided valvular dz, especially metastatic NETs from small bowel, not seen if tumor vessels go to liver (5-HT eliminated first pass)thyroid cancer papillary: most common, excellent prognosis, "Orphan Annie" nuclei (ground glass), nuclear grooves, psammoma bodies; follicular: uniform follicles, good prognosis; medullary: from C cells, sheets in amyloid stroma, assn w/ MEN2A/B; undifferentiated/anaplastic: very poor; lymphoma: assn w/ Hashimoto's

Zollinger-Ellison Sz: gastrin-secreting tumor of pancreas or duodenum, acid hypersecretion, thickened rugae, recurrent ulcers, assn w/ MEN 1; VIPoma: panc tumor, copious diarrhea (sphincter relaxation, H2O excretion)low T4 to T3: PTU, glucocorticoids, amiodarone, iopanoate, non-selective -blockers

GIfetal umbilical vein becomes ligamentum teres (in falciform), hepatoduodenal lig contains portal triadGI hormones/secretionssubmucosal plexus=Meissner's; myenteric plexus=Auerbach's (inner circular, outer longitudinal mm fibers)HormoneSourceRegulationActionOtherduodenum: Brunner's (submucosal) glands, crypts of Lieberkuhn (continue into ileum); [goblet cells] highest in jejunum; aorta: T12=celiac; L1=SMA, renal aa (L=lower); L2=gonadal aa (L=higher); L3=IMA; L4=bifurcationgastrinG cells (antrum)up: AAs, peptides, stomach distention/ alkalinizat'n, vagal stimulation (GRP)up: (ECL) gastric H+ secretion, mucosal growth, motility, & ectopic production= Zollinger-Ellison Sz; AAs: Phe and Try are potent stimulators

short gastric aa: from splenic a, supply fundus, poor anastamoses; block of abdominal aorta can use these anastamoses: S epigastric (internal thoracic) to inf epigastric (external iliac), S pancreaticoduodenal (celiac) to inf. PD (SMA), middle colic (SMA) to left colic (IMA), superior rectal (IMA) to middle rectal (internal iliac)parietal hyperplasiasecretinS cells (D)up: acid/FAs in duodenumup: bile and panc bicarb secretion; down: H+ secretionfemoral lateral to medial to find NAVEL; triangle (made of SAIL) has all, but sheath doesn't contain the nervehernias diaphragmatic: (congenital=pleuroperitoneal membrane defect), usually hiatal (stomach; sliding [GE jctn displaced] or paraesophageal [cardia into thorax]); direct: through inguinal (Hesselbach's) triangle (medial to inferior epigastric a), goes through external inguinal ring; indirect: M>F, congenital, through deep inguinal ring, failure of processus vaginalis to close, can form hydrocele; femoral: F>M, thru femoral canalGIPK cells (D/J)up: FA, AAs, oral glucoseup: insulin secret'n; down: H+ secretionincretin

CCKI cells (D/J)up: FA, AAsup: panc secretion, GB contract'n, tone of pyloric sphincteracts on neural muscarinic pathways to stimulate the pancsaliva parotid (serous), sublingual (mucinous); stimulated by parasympathetic (VII, IX) and superior cervical ganglia (T1-3); -amylase/ptyalin (-1,4 hydrolysis get disaccharides [maltose & -limit dextrins], inactivated by low pH), bicarb, mucins (lubrication), antibacterial, epithelial GFs; low flow rate=hypotonic (reabsorb NaCl)

somato-statin cells (panc/GI)up: acid; down: vagal stimulationdown: everythinganti-GH effectssalivary gland tumors usually in parotid; pleomorphic adenoma: most common, painless, movable, high rate of recurrance; Warthin's tumor: benign, heterotopic salivary tissue in LN; mucoepidermoid carcinomaVIPparaS gangliaup: distention, vagal stimulationup: sphincter relax-VIPoma: panc tumor, copious diarrheagastric acid secretion: H/K ATPase, H produced by carbonic anhydrase, bicarb exchanged for Cl basolaterallyation, water excret'npancreas -amylase & lipase secreted in active form, colipase (activated by trypsin) necessary for lipase to be effective; entero-kinase/-peptidase (duodenal excretion) activates trypsinogen, which activates all proteasesMotilinSm bowelup: fasting statemakes MMCsagonists usefulintrinsic factorparietal cellsB12 binding protein (uptake in ileum)autoimmune attack= chronic gastritis/PAoligosaccharides: hydrolases at brush border of intestine, RLS in carb digestion, makes monosaccharides; absorption: glucose and galactose by SGLT1 (Na dependent), fructose by GLUT-5; all basolaterally use GLUT-2gastric acidparietal cellsup: M3R (ACh), H2R, gastrin; down: SS, GIP, PG, secretindecreases stomach pHPeyer's patches: unencapsulated, specialized M cells take up Ag, BCs differentiate to IgA-secreting; bile: bile salts (acids conjugated to glycine or taurine), phospholipids, chlsl (only method of excretion), bilirubin, water

esophagus varices: painless bleeding of submucosal veis; achalasia: loss of myenteric plexus, NO implicated, Chagas', CREST; Mallory-Weiss Sz: mucosal lacerations at GE jctn from severe vomiting (alcoholics, bulemics), hematemesis; Boerhaave Sz: transmural esophageal rupture from violent retching; Plummer-Vinson: webs (dysphagia), glossitis, Fe def anemia; Barrett's: intestinal metaplasia; esophagitis: from bisphosphonatespepsinchief cellsup: local H+, vagal stimulationprotein digestionpepsinogen to pepsin by H+

bicarbmucosa, Brunner's glandsup: secretin (acts on pancreatic and biliary secretions)neutralize acidbicarb is trapped in mucous that covers gastric epithelium

esophageal cancer risk factors: achalasia, Barrett's, cigarettes, diverticuli, EtOH/esophageal web/esophagitis; SqCC (most common worldwide) mostly upper-middle 1/3, adenoca (most common US) mostly lower 1/3

malabsorption abetalipoproteinemia; pancreatic insufficiency: CF, obstruction, chronic panc; disaccharidase def: osmotic diarrhea, can be self-limited after insult; Whipple's dz; tropical sprue: similar to celiac sprue, but responds to abx and affects whole small bowel; celiac sprue: auto-Abs to gluten (gliadin, prolamin) and TTG (tissue transglutaminase), causes blunting of vili, crypt hyperplasia, and lymphocyte infiltrate (lamina propria) in proximal bowel, associated with dermatitis herpetiformis and increased risk of TC lymphomaIBDCrohn's (disordered response to flora)UC (autoimmune)Locationusually terminal ileum, skip lesions, rectal sparingcontinuous, always involves rectum

Grosscobblestone mucosa, creeping fat, bowel wall thickening, linear ulcers/fistulasfriable mucosal pseudopolyps, loss of haustragastritis acute/erosive: NSAIDs (RA), EtOH, uremia, burns (Curling's), brain injury (Cushing's); chronic: type A (body/fundus: Abs to parietal cells) and type B (antrum: most common, H. pylori infxn, increased risk of MALT)Micro-scopictransmural inflammation, noncaseating granulomas, lymphoid aggregatessub-/mucosal inflammation only, crypt abscesses/ulcersPUD clean margins; gastric: decreased mucosal protection, greater pain w/ meals, H. pylori in 70%; duodenal: increased gastric secretion and decreased mucosal protection, pain decreased with meals, H. pylori in 100%Complic-ationsmalabsorption, strictures, fistulas, colo-rectal cancer (minorly increased risk)malnutrition, toxic megacolon, colorectal carcinoma (hi risk)stomach cancer: 95% adenoca, early spread locally and mets to LNs/liver (Virchow's node=L supraclavicular; Krukenberg's tumor=bilateral mets to ovaries; Sister Mary Joseph's nodule=subQ periumbilical met); assn w/ nitrosamines, achlorhydria, chronic gastritis; signet ring cells, acanthosis nigricans; linitis plastica=diffuseSxdiarrhea blood, erythema nodosum, migratory polyarthritis, immunologic disordersbloody diarrhea, PSC, pyoderma gangrenosum, ankylosing spondylitis, uveitis

appy: kids=lymphoid hyperplasia after viral infxn, adults=fecalith; ddx: ectopic, Y. enterocolitis, diverticulitis (LLQ pain, fever, leukocytosis, BRBPR, can cause colovesical fistula [pneumaturia, cystitis], peritonitis; tx=abx)txcorticosteriods, infliximabASA, 6-MP, infliximab, colectomyMeckel's diverticulum: most common congenital GI anomaly, yolk stalk persistence, 2" long, 2' from ileocecal jctn, 2% of pop, commonly presents in first 2y, may contain 2 mucosae (gastric/panc); dx=pertechnetate studydrugs causing GI path: macrolides=acute cholestatic hepatitis; INH=hepatitis; hepatic necrosis: halothane, valproate, acetaminophen, Amanita mushroom poisoningintussusception: usually kids (adenovirus), in adults=intraluminal tumor; volvulus: usually elderlyHirschsprung dz: failure of neural crest cells to migrate, causes congenital megacolon, always involves rectumGI pathologyangiodysplasia: tortuous dilation of vessels, bleed; usually ileum/R-sided, older ptsMarkerUsepolyps 90% are non-neoplastic; neoplastic: adenomatous, villous, juvenile polyposis sz, Peutz-Jeghers Sz (AD, hamartomas throughout GI, hyperpigmented mouth, lips, hands, genitals, increased risk of CRC), FAP (AD APC mutation, pancolonic, always involves rectum; Gardner's, Turcot's), HNPCC (aka Lynch Sz, AD DNA mismatch repair defect, always involves proximal colon); distal=obstruction, hematochezia; proximal=dull pain, anemiaAminotransferaseshepatocyte damage (virus: ALT>AST; alcohol: AST>ALT), MI (AST)GGT (glut transpep-tidase)cholestasis, >2x ULN w/ heavy EtOH consumption

CRC: higher risk with IBD, S. bovis sepsis, use CEA tumor marker; 1. microsatellite instability (by mismatch repair gene mutations); 2. APC mutation (decreased cellular adhesion, increased prolif via -catenin), KRAS mutation (unregulated intercellular signal transduction) causes adenoma, loss of p53 marks carcinomaalk phosbone dz, cholestasis (biliary dz/obstruc-tion, macrolides)

micronodular cirrhosis: 3mm nodules, significant liver injury causing hepatic necrosis (infxn, halothane, acetaminophen, valproate), HCCamylaseacute panc, mumpslipaseacute panc (specific)EtOH hepatic steatosis: moderate intake causes short term, macrovescicular change, reversible; hepatitis: long-term EtOH, swollen/necrotic hepatocytes, PMN infiltrates, Mallory bodies (intracytoplasmic eosinophilic inclusions, "twisted-rope"); cirrhosis: micronodular "hobnail", sclerosis around central vein (zone III)Jaundicepre-HC (hemolysis)hepatocellularpost-HC (obstructive)conj blood bilirubinlow (all unconj)some (some unconj)highurine bilirubinlow (not soluble)high (some conj)highestHCC: jaundice, tender HSM, ascites, hypoglycemia, polycythemia, Budd-Chiari; spreads hematogenously, AFPurine bilinogenhighnl/lowlow1-AT def: misfolded gene product, decreased elasticity of lungs (panacinar emphysema) and PAS-positive globules in the liver (cirrhosis and liver failure); codominant traitheme to unconjugated bilirubin in macrophage, albumin carries (complex=indirect bilirubin) to liver, conjugated by UDP glucuronyl transferase to direct bilirubin, into biliary lumen by glucuronyl transferase, and broken down in gut to urobilinogen

hemochromatosis=dz caused by hemosiderosis (Fe deposition)=micronodular cirrhosis, "bronze diabetes" (DM, skin pigmentation), CHF, HCC; may be 1 (AR HFE mutation, transferrin R on basolateral enterocyte, binds plasma transferrin to sense blood Fe concentrations, adjust abs) or 2 (chronic transfusions); assn w/ HLA-A3

pancreatitis acute: autodigestion; obstruction (gallstones, ERCP), overworked (EtOH, hypercalcemia, hyperTGemia), mumps, trauma, autoimmune, drugs (sulfa, steroids); sx: epigastric abd pain radiating to back, anorexia, N, elevated lipase (more specific) and amylase; can cause DIC, ARDS, diffuse fat necrosis, hypoCa, pseudocyst, infxn, hemorrhage, multiorgan failure; chronic: can cause pancreatic insufficiency (ADEK deficiency, steatorrhea, DM), calcified assoc'd w/ EtOH, smoking, pancreatic cancerbiliary tract dz sx=pruritis, jaundice, dark urine, light stools, HSM; labs=high direct bilirubin, chlsl, GGTP, alk phos; PSC: idiopathic concentric "onion skinning" fibrosis causes "beads on a string" of any bile ducts, assn w/ hyperIgM, ulcerative colitis; PBC: anti-mitochondrial Abs causes PMN infiltrate, granulomas; SBC: high intraductal pressure from obstruction causes fibrosis and stasis, complication=ascending cholangitis

cholelithiasis 4Fs, high chlsl/bilirubin, low bile salts, stasis; chlsl: 80% of stones, radiolucent (but 15% are calcified); pigment: radiopaque, assd w/ chronic hemolysis, alcoholic cirrhosis, biliary infxn (Clonorchis, Salmonella); can cause cholecystitis (Murphy's sign), ascending cholangitis (Charcot's triad: jaundice, fever, RUQ pain), pancreatitis, biliary colic (can be painless in DM), fistulas, gallstone ileus (usually ileocecal jctn)pancreatic adenoca: CEA and CA-19-9 markers, NOT assoc'd w/ EtOH; sx: abd pain radiates to back, weight loss, Trousseau's, jaundice, palpable GB (Courvoisier's sign)

acute calculus cholecystitis: obstruction, chemical irritation, mucous disruption, bile acid attack on mucosa, PG release, hypomotility, distension, ischemia, bacteria

Heme/Onceosinophils: major basic protein (anti-helminth), histaminase and arylsulfatase (limit reaction after mast cell degranulation); eosinophilia=NAACP: neoplasm, allergy, asthma, collagen vascular dz, parasites (Loffler's)Hemolytic anemia (high LDH)Intravascular: low haptoglobin, Hb in urine, not usually jaundicedbasophil: granules of heparin, histamine, and vasoactive amines (LT); mast cell: + eosinophil chemokinesG6PDDtrigger: fava beans, infxn, INH, sulfa, anti-malarial, aspirin, ibuprofen, nitrofurantoin; back pain, Heinz bodies, and bite cellsagranulocytosis=granulocytopenia: PTU/methimazole, colchicine, carbamazepine, clozapine, dapsoneplatelet plug formation vWF binds subendothelial collagen, platelets bind vWF (GpIb), release dense granules (Ca [necessary for coagulation cascade], ADP [helps platelets adhere to endothelium and induces GpIIb/IIIa to platelet surface]), fibrinogen binds GpIIb/IIIa, links platelets; aggregation: pro=TXA2 (platelets), anti=PGI2PNHglycophosphatidyl inositol links decay accelerating factor onto RBC membrane, prevents complement cascade; high urine hemosiderin

angio-pathicschistocytes; micro-: from DIC, HUS (Shiga toxin), SLE, malignant htn; macro: prosthetic valves, aortic stenosiscoagulation cascade XIIa activates XI and prokallikrein; kallikrein=serine protease, breaks down HMWK ([XII activator] to bradykinin [vasodilation, pain]) and plasminogen (to plasmin, which activates C3a and degrades fibrin); Ca and phospholipid needed for all factor activation but XII, VIII, V, and I; IIa=thrombin, Ia=fibrin; protein S activates protein C, which inactivates Va, VIIIa; tPA + vWF from endothelial cells, vWF protects VIIIinfxnmalaria, BabesiaExtravascular: cleared in spleen; high unconjugated bilirubin, jaundice; (Wilsons)sickle cell (HbS)glu to val on gene; marrow expansion, aplastic crisis (B19), bone crises, renal papillary necrosis/microhematuria, splenic sequestration crisis, autosplenectomy (Howell-Jolly bodies, Salmonella osteomyelitis)coagulopathy hemophilia: A=VIII, B=IX; vit K def/warfarin=loss of cofactor for -carboxyglutamation rxn, inactive II, VII, IX, X, C, S; Bernard-Soulier: GpIb def; Glanzmann thrombasthenia: def GpIIb/IIIa; ITP: anti-GpIIb/IIIa Abs, increased megakaryocytes; TTP: ADAMTS 13 def (vWF metalloprotease), vWF multimers, clots, schistocytes, pentad=neuro/renal sx, fever, thrombocytopenia, microangiopathic hemolytic anemia; vW dz: mild, AD; factor V Leiden: Va resistant to APC; C/S def: risk of thrombotic skin necrosis/hemorrhage w warfarin

HbC defglu to lys, compound heterozygotes w/ HbSC have milder dz than HbSSsphero-cytosishereditary def in cytoskeletal elements (ankyrin, band 3.1, spectrin); high MCHC, high RDW, SM, aplastic crises; tx=splenectomy (Howell-Jolly body)

DIC causes: sepsis (GN), trauma, OB complications, acute pancreatitis, malignancy, nephrotic sz, transfusionPK defAR, pyruvate kinase def, low ATP, rigid RBC membrane; HA in newbornmicrocytic hypochromic anemia MCV -aminolevulinic acid (aka -ALA) -[-ALA dehydratase (Pb poisoning)]-> porphobilinogen -[porphobilinogen deaminase (acute intermittent porphyria)]->hydroxymethylbilane->uroporphyrinogen III-[uroporphyrinogen decarboxylase (porphyria cutanea tarda)]-> coproporphyrinogen III -> protoporphyrin -[+ Fe, ferrochelatase (Pb poisoning)]-> heme (feeds back onto -ALA synthase); porphobilinogen & uroporphyrinogen are converted to uroporphyrinLab values in anemia: primary cause in redSerum FeTransferrin or TIBC ("tissue need")Ferritin (storage)% transferrin sat (serum Fe/TIBC)

Fe deficiencylowhighlowlowP. cutanea tarda: most common, tea-colored urine, blistering cutaneous photosensitivity; acute intermittent P.: red-wine colored urine, abd pain, polyneuropathy, psych disturbances, ppted by rxs, tx=glucose and hemechronic dzlowlowhighnlhemochromatosishighlowhighhighHodgkin's: contiguous spread through nodes, constitutional B sxs, mediastinal LAD, M>F, good prognosis=high lymphs, few Reed-Sternberg cells (binucleate, "owl eye", CD30+, CD15+); nodular sclerosing (most common, RSC=lacunar, collagen banding surrounding nodules), mixed cellularity (more RSCs), lymphocyte predominant (rare), lymphocyte depleted (very rare, high RS to lymphocyte ratio, older men, poor prognosis)pregnancy/OCPsnlhighnllowlead poisoninghighlownlhighPb poisoning: microcytic/sideroblastic anemia, basophilic stippling of RBCs, renal, GI dz; kids: neuro deterioration, wrist/foot drop, Pb lines on gums/long bones (XR), abd pain; adults (usually work-related): headache, memory loss, demyelination

lymphoma diffuse large cell lymphoma: most common NHL, usually in elderly (20% kids), mostly BC (20% TC); BC: Burkitt's: young, starry sky appearance (sheets of lymphs, interspersed macrophages); mantle cell: older, poor prognosis, CD5+; follicular: bcl-2, indolent; TC: adult TC: HTLV1, aggressive, cutaneous lesions; Sezary sz

Translocationsmultiple myeloma: commonest 1 bone tumor, monoclonal plasma cell (fried egg), IgG>IgA, infxn-prone, lytic bone lesions (hypercalcemia), M-spike, anemia, renal failure (Bence Jones proteins, AL [1 amyloid]), rouleauxLeukemia/lymphomaAML M3CMLBurkitt'sFollicularMantleEwing'sTranslocationt(15;17)t(9;22)t(8;14)t(14;18)t(11;14)t(11;22)Waldenstrom's macroglobulinemia: hyperIgM, hyperviscosity sx; MGUS: monoclonal expansion, no sxActivated product-bcr-ablc-mycbcl-2--ALL: kids, marrow involvement/mediastinal mass, lymphoblasts, TdT+ (pre-T/-BC), CALLA+, therapy responsive (esp if t(12;21)); hairy cell: middle aged; CLL: >60yo, asxatic, smudge cells in smear; Small LL: no lymphocytosisPolycythemia primary cause in redAML: Auer rods (fused granules), myeloblasts; AML M3: responds to all-trans vit A (induces differentiation); CML: Philadelphia chromosome=t(9;22), bcr-abl, granulocytosis, metamyelocytes, SM, can have blast crisis (AML or ALL), low alk phos (differentiate from leukemoid rxn), responds to imatinib (TK inhibitor)plasma VRBC massO2 satEPOassociated dzsrelativelownlnlnlappropriate absolutenlhighlowhighlung dz, CHD, altitudeLangerhans cell histiocytosis: S-100+, CD1a+, Birbeck granules (tennis rackets) on EM; can cause DIinappropriate abs.nlhighnlhighectopic erythropoietinchronic myeloproliferative disorders (other than CML) all have JAK2 mutations in stem cell; polycythemia vera: mutation in early cell, pancytosis; essential thrombocytosis: specific for megakaryocytosis; myelofibrosis: fibrotic obliteration of marrow, teardrop RBCs, anemia, platelets/WBCs variable, megakaryocytes implicatedpolycythemia verahighhighnllow

Musculoskeletalzona occludens: claudins & occludins; zona adherens (intermediate jctn): below occludens, cadherins bind actin (Ca-dependent); macula adherens (desmosome): cadherens bind intermediate filaments; integrins to BMUpper extremity nerve lesionsNerveRootMotor DeficitSensory DeficitInjuryrotator cuff: supraspinatus (abduction before deltoid, most common cuff injury), subscapularis (adduction and medial rotation), infraspinatus and teres minor (adduction and lateral rotation)AxillaryC5-6shoulder abduction (deltoid)over shoulderhumerus dislocation, surgical neck break

other nerve lesions Erb's palsy (waiter's tip): upper trunk (C5-6), paralysis of abductors, lateral rotators, and biceps (so pronated); posterior cord; deltoid paralysis + wrist drop; long thoracic n: winged scapula; thoracic outlet sz (cervical rib): Klumpke's palsy and disappearance of radial pulse on moving head ipsilaterallyMusCutanC5-7elbow flexionlateral forearmupper trunkRadialC5-8extensors, brachio-radialis, supinatorposterior arm, dorsal hand/thumbhum. midshaft break, Saturday night palsy

skeletal/cardiac mm contraction nAChR causes depol, travels down T-tubule, activates DHPR, lets in Ca, Ca activates ryanodine R on SR, more Ca release, Ca binds troponin C, moves tropomyosin from myosin-binding sites on actin; H-/I-bands shrink, A doesn't; type 1=slow, red; type 2=fast, white (hypertrophy, don't switch)Median (distal)C5-T1thumb opposition, lateral MCP flex'ndorsal + palmar lateral 3 1/2 fingerscarpal tunnel, lunate dislocation

Median (proxim.)C5-T1 + lateral DIP/PIP flexion, wrist flex'ndorsal + palmar lateral 3 1/2 fingerssupracondylar humerus fracturesmooth mm contraction membrane depol, Cav (DHP, L-type) open, Ca binds calmodulin, activates myosin light chain kinase (MLCK), P-ation, cross bridge formation; cGMP inhibits MLCK, MCLPhosphorylase inactivatesUlnar (distal)C8-T1interossei, thumb adduction, lumbricals 4 and 5; sensory: medial 1 1/2 fingersfracture of the hook of the hamateachondroplasia: constitutive FGFR3 inhibits chondrocyte prolif, failure of long bone growth (endochondral ossification, short limbs), membranous ossification fine (big head); AD, but 85% sporadic (hi paternal age)Ulnar (proxim.)C8-T1 + wrist flexionmedial 1 1/2 fingersmedial epicondyle of humerus, funny bonenl bone labs osteoporosis: reduction of spongy bone mass despite normal bone mineralization; I=menopause; II=age; vertebral crush fracture, femoral neck, distal radius (Colle's); corticosteroids, heparin, homocystinuriaKlumpkeC8-T1 +all lumbricals; sensory: medial forearmlower trunk (birth)nl bone labs (cont'd) osteopetrosis: carbonic anhydrase II def, no osteoclast fctn, failure of nl resorption, too dense (prone to breaks), pancytopenia (low marrow space, extramedullary hematopoiesis), CN impingementLower extremity nerve lesionsNerveRootMotor DeficitSensory DeficitInjuryhigh alk phos Paget's dz (osteitis deformans): increased osteo-clast, then -blast activity causes "mosaic" bone architecture, possibly viral origin (paramyxo-), chalk-stick fractures, AV shunts (high-output cardiac failure), osteogenic (increased hat size, CN impingement, 2 osteosarcoma/fibrosarcoma); also think 1 hyperPTHObtruatorL2-4thigh adductionmedial thighant. hip dislocationFemoralL2-4flex thigh, extend legant./medial thighpelvic fractureCommon peronealL4-S2foot eversion/dorsi-flexion, toe extens'nanterolateral leg, dorsal footfibular neck fracture, lateral leg traumaosteomalacia/Rickets: defective mineralization, from vitamin D def, usually high PTH, alk phos, low Ca and PO4polyostotic fibrous dysplasia: fibroblasts, collagen, and irregular trabeculae replace bone; McCune-AlbrightTibialL4-S2foot inversion/plan-tarflexion, toe flex'nsole of footknee traumaOA: mechanical destruction of articular cartilage, ; sx: pain after use, medial before lateral, no systemic sx (non-inflammatory); can get subchondral cysts, osteophytes, Heberden's nodes (DIP), Bouchard's nodes (PIP)In. glutealL5-S2hip extension (stairs) - post. hip dislocationRA: synovial joints, MCP/PIP pannus formation, subQ nodules (fibrinoid necrosis surrounded by palisading histiocytes), NO DIP INVOLVEMENT, ulnar deviation, subluxation, Baker's cyst; type III hypersensitivity, 80% rheumatoid factor [+] (anti-IgG; anti-CCP=less sensitive, more specific), HLA-DR4; improves w/ use, systemic sx S. glutealL4-S1Trendelenburg - + polio

Bone tumorsseronegative spondyloarthropathies no RF, assn w/ HLA-B27, M>F; psoriatic arthritis: pencil-in-cup, dactylitis (sausage fingers), minority of psoriatic pts; ankylosing spondylitis: spine and sacroiliac inflammation, bamboo spine, uveitis, aortic regurg; IBD; Reactive arthritis: conjunctivitis/uveitis, urethritis, arthritisBenignEpidem.Descriptionosteochondroma (exostosis)M, >F, tx=sumatriptan or hyperbaric O2vertigo peripheral: more common, positional testing=delayed horizontal nystagmus; central: brain stem/cerebellum, testing=immediate nystagmus, any direction

Psych (dzd=disorder)diseases/NTs anxiety=SONIGO; depression=SODONO; Parkinson's: ODISIA; Schizophrenia: ID; Alzheimer's: OAEgo defenseshospitalism/anaclitic depression: infant depression from to separation, withdrawn/unresponsive babyPathologicconversionmanifestation as physical sx (grief causes "blindness", hysteria)childhood dzs ADHD: normal intelligence, commonly continue into adulthood, low frontal lobe V; conduct dzd: antisocial personality disorder 2w of stable mood w psychotic sx + a major depressive, manic, or mixed episodeParanoidpervasive distrust, projectiondissociative identity dzd: multiple personalities, ass'd w/ sexual abuse; depersonalization dzd: persistent feeling of detachment/estrangement; dissociative fugue: abrupt change in geographic location w/ amnesiaSchizoidvoluntary social withdrawal, limited emotional expressionSchizotypal + eccentric beliefs/appearance, magical thinking, awkwardbipolar 1 manic (bipolar I) or hypomanic (II) episode, depression always occurs eventually; high suicide riskCluster B: dramatic, emotional; associated w/ mood disorders and substance abusedysthymia: mild depression, >2yr; cyclothymic dzd: + hypomania, mild bipolar>2yrAntisocialdisregard for rights of others, criminal, M>F >18, (conduct dzd)manic >1wk, pick 3: distractable, irresponsible (hedonism), grandiose, flight of ideas, agitation (high activity level), sleeplessness (no need), talkativeness (pressured speech); hypomanic: no impairment or psychosesBorderlineunstable, impulsive, self-mutilating, emptiness, F>M; splittingHistrionicexcessively emotional, attention seeking, overly sexualdepression self-limited, episode lasts 6-12mo, lifetime prevalence: F=20%, M=10%; 2+ wk of pick 5: sleep disturbance (early morning awakening most important), loss of interest (anhedonia, necessary), worthless/ guilt, low energy, low concentration, change in appetite, psychomotor sx, suicidal ideation, depressed mood; MDD: 2 episodes w/ 2mo sx-free; atypical depression: hypersomnia, overeating, mood reactivity; postpartum depression: 15% incidence, depressed affect, anxiety, poor concentration, lasts 2w-2mo; refractory=ECT txNarcissisticgrandiose, sense of entitlement, lacks empathyCluster C: anxious, fearful; associated w/ anxiety dzdsAvoidanthypersensitivity to rejection, inhibited, desires relationshipsOCPDperfectionist, ego syntonic (OCD=dystonic, ass'd w Tourette's)Dependentsubmissive, clingy, low self confidencesuicide sex (M), age (teen/elderly), depression, previous attempt, EtOH/drugs, rational thinking, sickness (3+ rxs or medical illness), organized plan, no spouse/lack of social support; F try more, M succeed morePsych txspanic dzd recurrent, intense fear, peaks in 10m, pick 4: palpitations, parasthesias, abd distress, N, fear of dying/losing control, light-headed, chest pain, chills, choking, sweating, shaking, SOB, disconnectednessEtOH withdrawal/cocaine ODBDZADHDmethylphenidate, amphetamines (dexedrine)GAD: >6mo, uncontrolled anxiety, sleep disturbance, fatigue, GI sx, difficulty concentrating; adjustment dzd: GAD with specific stressor, usually