American College of Medical Toxicology 2012 www.acmt.net ACMT Medical Toxicology Board Review Course ARE YOU PREPARED? Astor Crowne Plaza Hotel New Orleans, LA September 8-10, 2012 SYLLABUS Day One - 3 slides per page Sponsored by the University of Alabama School of Medicine Division of Continuing Medical Education American College of Medical Toxicology Medical Toxicology Board Review Course September 8-10, 2012 - New Orleans, LA Day 1 - Saturday, September 8, 2012 7:00-7:50am Breakfast & Stimulus Room 7:50-8:20am Welcome & Introductions 8:20-9:10am Pharmacokinetics/Toxicokinetics Howard A. Greller, MD, FACMT 9:10-10:00am Molecular Mechanisms William P. “Russ” Kerns II, MD, FACMT 10:00-10:20am Break 10:20-11:10am Analytical/Forensics Evan S. Schwarz, MD 11:10-12:00pm Autonomics/Neurotransmitters G. Patrick Daubert, MD 12:00-1:30pm Lunch –n-Learn: Mushrooms & Fish-borne Howard A. Greller, MD, FACMT 1:30-2:20pm Psychotropics G. Patrick Daubert, MD 2:30-3:20pm Cardiovascular Toxins Trevonne M. Thompson, MD 3:20-3:40pm Break 3:40-4:05pm Hydrocarbons Trevonne M. Thompson, MD 4:05-4:30pm Pharmaceutical Additives G. Patrick Daubert, MD 4:30-4:55pm Endocrine Trevonne M. Thompson, MD 6:00-7:30pm Welcome Reception - Napoleon House, 500 Chartres Street in the French Quarter Day 2 - Sunday, September 9, 2012 7:00-8:00AM Breakfast & Stimulus Room 8:00-8:50am Pesticides J. Dave Barry, MD, FACMT 8:50-9:15am Terrorism Hazmat J. Dave Barry, MD, FACMT 9:15-9:40am Antimicrobials Michael Policastro, MD 9:40-10:00am Break 10:00-10:50am GI/Heme Michael Policastro, MD 10:50-11:15am Chemotherapeutics Michael Policastro, MD 11:15-12:05pm Plants Thomas C. Arnold, MD, FACMT 12:05-1:30pm Lunch-n-Learn: Historical Outbreaks Stephen W. Munday, MD, MPH FACMT 1:30-2:20pm Envenomations Thomas C. Arnold, MD, FACMT 2:20-3:10pm Carcinogens Stephen W. Munday, MD, MPH, FACMT 3:10-3:30pm Break 3:30-4:20pm Misc Toxins 1 Brandon K. Wills, DO, FACMT 4:20-4:45pm Misc Toxins 2 Brandon K. Wills, DO, FACMT Day 3 - Monday, September 10, 2012 7:00-8:00am Breakfast & Stimulus Room 8:00-8:50am Anesthetics; Drugs of Abuse & Withdrawal Kurt C. Kleinschmidt, MD, FACMT 8:50-9:15am Herbal/Supplemental Tox Kurt C. Kleinschmidt, MD, FACMT 9:15-10:05am Industrial Poisons Jefrey Brent, MD, PhD, FACMT 10:05-10:25am Break 10:25-11:15am Assessment/Population Health/Risk Jefrey Brent, MD, PhD, FACMT 11:15-12:05pm Metals/Metalloids 1 Cyrus Rangan, MD 12:05-12:30pm Metals/Metalloids 2 Cyrus Rangan, MD John G. Benitez, MD, MPH, FACMT 12:30-3:00pm Stimulus Room Russ Kerns, MD, FACMT Pharmacokinetics and Toxicokinetics Pharmacokinetics and Toxicokinetics Howard A. Greller, MD FACEP FACMT North Shore University Department of Emergency Medicine Division of Medical Toxicology 1 WHAT WE’LL COVER TODAY • Pharmacokinetics/Toxicokinetics • Absorption • Distribution • Metabolism • Elimination • Pharmacodynamics/Toxicodynamics • Xenobiotic interactions • Pharmacogenomics/Toxicogenomics 2 OVERVIEW Tissue Therapy Toxicity Absorption Elimination Dose Drug Excretion Liberation Metabolite Protein Biotransformation 3 1 Pharmacokinetics and Toxicokinetics ABSORPTION •Process by which a xenobiotic enters body •Rate of absorption (ka) determined by: •Route of administration •Dosing form •Bioavailability 4 ROUTE OF ABSORPTION •Affects rate and extent •IV, inhalation > IM, SQ, IN, PO> SQ, PR •Onset dependent on route 5 ROUTE OF ABSORPTION Oral, onset approximately 20 minutes 6 2 Pharmacokinetics and Toxicokinetics ROUTE OF ABSORPTION Smoking ~10 seconds, IV ~30 seconds 7 DISSOLUTION 8 DIFFUSION 9 3 Pharmacokinetics and Toxicokinetics DISINTEGRATION 10 EROSION 11 OSMOTIC PUMPS 12 4 Pharmacokinetics and Toxicokinetics ION EXCHANGE RESINS 13 BIOAVAILABILITY •Amount reaches systemic circulation, unchanged •Extent of absorption •Predicts intensity of effect •First pass effects modify bioavailability 14 FIRST PASS EFFECTS • Prevention of absorption • Decon / chelation (+/-) • P-glycoprotein • Bezoars, mod preps • Pre-systemic metabolism • Hepatic, gastric mucosa, intestinal BB • Bacterial • Saturable in overdose 15 5 Pharmacokinetics and Toxicokinetics FIRST PASS EXAMPLES • Gastric emptying time • Food, medications • Gastric ADH • Age, sex, H2 • “worst case” • High FP (“low bioavailability”) • Propranolol, cyclosporine, morphine, TCAs 16 IONIZATION • Uncharged, non-polar cross membranes • pH + pKa (dissociation constant) determine ionization (HH) - • Log (HA/A ) = pKa - pH • HA/A- = 10pKa-pH - • pH < pKa ➡ HA/A > 1 • Favors non-ionized - • pH > pKa ➡ HA/A < 1 • Favors ionized 17 SALICYLATE • Weak acid (pKa 3.5) Brain Blood Urine pH ~ 6.8 pH ~ 7.4 pH variable SH SH SH H+ + S- H+ + S- H+ + S- What is HA/A- in urine for pH=3.5? 7.5? 18 6 Pharmacokinetics and Toxicokinetics ION TRAPPING •HA/A- = 10pKa-pH •pH 3.5 = (103.5-3.5) = 100 = 1 = 1:1 •pH 7.5 = (103.5-7.5) = 10-4 = 1/10,000 •With alkalinization, ionized, “trapped” 19 LIPID SOLUBILITY • Partition coefficients (oil/water) • Higher lipid solubility, higher absorption • Even with similar pKa • Thiopental >> secobarbital >> barbital • All with pKa of ~7.8 20 SURFACE AREA •Affected by blood flow •Hypotension •Vasoconstriction 21 7 Pharmacokinetics and Toxicokinetics SPECIALIZED TRANSPORT • Active (energy dependent) • Transport against a concentration gradient • Facilitated (energy independent) • Xenobiotics utilize native systems • 5-FU resembles pyrimidine • Thallium/Pb resemble K+ and Ca2+ 22 P-GLYCOPROTEIN (PGP) • Active efflux transporter (inside out) - “ABC” family • BBB, BTB, brush border Digoxin, protease inhibitors, vinca alkaloids, S paclitaxel Amiodarone, ketoconazole, quinidine, verapamil St. John’s wort 23 24 8 Pharmacokinetics and Toxicokinetics DISTRIBUTION 25 VOLUME OF DISTRIBUTION • Where the drug goes • Vd (L/kg) = amount/Cp = SxFxdose/C0 [C]=(S x F x dose)/(Vd x kg) • Apparent proportionality constant • Not a real volume (i.e. chloroquine ~185 L/kg) 26 SOME EXAMPLES Large Vd (>1 L/kg) Small Vd (<1 L/kg) • Antidepressants • Alcohols • Camphor • Lithium • Digoxin • Phenobarbital • Opioids • Phenytoin • Phencyclidine • Salicylate • Phenothiazines • Valproic acid 27 9 Pharmacokinetics and Toxicokinetics ONE COMPARTMENT MODEL Change in [plasma] = change [tissue] Ka Vd Ke 28 TWO COMPARTMENT MODEL • Measure #1 • Effects in #2 • Examples K a • Digoxin k 12 #2 • Lithium k21 • There can be multiple, multiple #1 compartments . Ke 29 MODIFIERS •Lavage, AC and WBI ⬇Ka •MDAC, ion-trapping, chelation ⬆Ke •Decrease Cmax, tmax and AUC •Extracorporeal techniques ⬆Ke 30 10 Pharmacokinetics and Toxicokinetics DISTRIBUTION ≠ SITE OF TOXICITY / ACTION •Lead ➡ bone •CO ➡ Hgb vs •DDT ➡ fat •Paraquat ➡ type II alveolar 31 PROTEIN BINDING • Phenytoin 90% bound with normal albumin • Albumin decreases, more free active drug • [phenytoin] = 14 mg/L (10-20 mg/L) • Sick (2 g/dL) vs. Healthy (4 g/dL) • [adjusted] = [measured] / ((0.25 x albumin) + 0.1) • 23.33 mg/L vs. 12.73 mg/L 32 PROTEIN BINDING - ASA •Overdose increases apparent Vd •⬆ free drug ➞ lower pH ⬆ HA ⬆ diffusion •More drug in tissues, more toxicity •Other drugs with high protein binding •Carbamazepine, valproate, warfarin, verapamil 33 11 Pharmacokinetics and Toxicokinetics 34 POOR LITTLE JOHNNY . • Johnny got dumped • He went home and took grandma’s digoxin • Grandma calls poison control • Do we have to be worried? • Johnny weighs 50 kg • Grandma’s pills are 250 mcg each • There were 25 of them left . 35 WORST CASE SCENARIO . • [C] = (S x F x dose) / (Vd x kg) = (1 x 0.7 x 25 x 0.25mg) / (6 L/kg x 50kg) = (4.38mg) / (300L) = 0.015mg/L • Units, units, units . = (0.015mg/L) x (106ng/mg) x (1L/1000mL) • [digoxin] = 15 ng/mL (worry) 36 12 Pharmacokinetics and Toxicokinetics HOW MUCH FAB? • TBL (total body load) = S x F x dose • 1 x 0.7 x (25 x 0.25 mg) = 4.375 mg • Each vial binds 0.5 mg digoxin • Therefore, need 9 vials based on dose • Worst case ([C] x kg)/100 = 8 vials (round up) 37 HIS LEVEL IS 4 NG/ML . • Dose = Vd x Cp; Vd = 6 L/kg; wt = 50 kg; 0.5mg digoxin bound / vial Dose = (6 L/kg) x (50 kg) x (4 ng/mL) = 1200 . 1200 what? (103 mL/1 L) x (6 L/kg) x (50 kg) x (4 ng/mL) x (1 mg/106 ng) = 1.2 mg • 0.5 mg/vial = 3 vials (round up) • Shorthand ([C] x kg)/100 = 2 vials 38 39 13 Pharmacokinetics and Toxicokinetics METABOLISM 40 METABOLISM • “Morally” neutral • Toxicate vs detoxify vs biotransform • LEO GER (CYP 450) • Oxidize substrate (lose e-) • Reduce electrophile (gain e-) • Cyclical oxidation co-factor • i.e. NADH / NAD+ • Links catabolism to synthesis 41 PHASE I (PREPARATORY) • Add/expose polar groups •HHydrolysis • Esterase, peptidase, epoxidase •OOxidation • P450, ADH, MAO, etc. •RReduction • Azo-, Nitro-, Carbonyl-, Quinone •DeDe-alkylation 42 14 (A1) Carboxylic acid ester (delapril) (A2) Carboxylic acid ester (procaine) O NH2 NH2 C OC2H5 O O H2O H2O N CH CH NH CH CNCH COOH C OH C H OH + 2 2 2 + 2 5 HO hCE1 hCE2 CH3 R N C O COOH O (B) Amide (procainamide) (C) Thioester (spironolactone) O Pharmacokinetics and ToxicokineticsO NH2 NH2 O O H2O H O + N 2 H N + CH3COOH N 2 C NH COOH OPHASE I EXAMPLES O SCOCH3 O SH (D) Phosphoric acid ester (paraoxon) + + (E) Acid anhydride (diisopropylfluorophosphate) CH3CH2OH + NADPH + H + O2 CH3CHO + NADP + 2H2O O CYP2E1 C2H5 O P O C2H5 O OH O O H O CH3 CH3 2 CH3 CH3 O CH OP OCH CH OP OCH + HF + + CH CH CH CH CH3CH2OH + NAD H 2O CH3CHO + NADH + H 3 3 3 3 C H C H F OH Alcohol Dehydrogenase + 2 5 OP O 2 5 hPON1 OH NO2 NO2 (F) Transesterification (cocaine) (G) Lactone (spironolactone) O methyl ester ethanol ethyl ester COOH O CH CH OH O 3 2 O OH H3C COCH H C 3 3 C OCH2CH3 N N H2O O hCE1 O hPON3 OC OO CH3OH methanol SCOCH O SCOCH3 O 3 Casarett & Doull’s 7th Edition 43 (H) Phosphate prodrugs (fosamprenavir) OH OH O P OH O H O 2 H H O N N NH2 + H PO O N N NH2 3 4 Alkaline Phosphatase O S O S O O O O O O Figure 6-4.PHASE Examples of reactions II catalyzed (SYNTHETIC) by carboxylesterases, cholinesterases, organophosphatases, and alkaline phosphatase.