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2012 BRC BW Day One Cover Page 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.
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