NJMS Kinetics -toxico and pharmaco.pdf

Kinetics Bruce Ruck, BS, Pharm.D., Managing Director, New Jersey Poison Information and Education System New Jersey Poison Information Education System Regionally certified Poison & Drug Information Center ~ 50,000calls/year (combination home and ho...

Kinetics Bruce Ruck, BS, Pharm.D., Managing Director, New Jersey Poison Information and Education System New Jersey Poison Information Education System Regionally certified Poison & Drug Information Center ~ 50,000calls/year (combination home and hospital) COVID hotline 800 962 1253 AIDS STD hotline 800 624 2377  NJPIES SPIs (specialists in poison information) MDs, PharmDs, and NPs Medical Toxicologists Attendings Fellows 24x7x365  Who we help? – Health professionals – First Responders – Health Departments – Public  Beyond Poisoning and Meds Flu on call Ebola hotline Zika hotline Lead hotline Vaccine Osteo-releif knee hotline  Epidemiologic surveillance and fascinating cases Biggest mass murder in NJ New Drugs of Abuse Puffer fish Sindoor Mushroom toxicity Fentanyl Botulism toxin Tiki torch oil Tejocote Root  New Jersey Poison Information & Education System Help is a phone call away 1-800-222-1222 Questions? NJ Poison Information and Education System Department of Emergency Medicine dosis sola facit venenum  dosis sola facit venenum Credited to Paracelsus who expressed the classic toxicology maxim "All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison." This is often condensed to: "The dose makes the poison" What is an antidote?  What is an antidote? A medicine or remedy to counteract the effects of a poison, toxin, etc. Anyone name an antidote and what it is used for? Pharmacokinetics vs Toxicokinetics  Pharmacokinetics The study of ADME at therapeutic doses Absorption Distribution Metabolism Elimination of drugs What the body does to the drug at therapeutic doses  Toxicokinetics Doses above the “therapeutic dose” may result in altered ADME Slowed absorption Altered distribution Decreased metabolism Decreased elimination rates  Pharmacokinetics vs Toxicokinetics Therapeutic dose Excessive dose Absorption Often well known Not well known Distribution Often well known Not well known Metabolism Often well known Not well known Excretion Often well known Not well known Absorption  Absorption What are some things that alter rate and extent of absorption? Formulation of product Bioavailability 1st pass effect Co-ingestants Route Change in permeability  Absorption What can slow or decrease GI absorption? Anticholinergic agents Opioids Large Ingestions Hypotension Concretions/pharmacobezoar/glob of pills Aggregation into a mass Decreases surface area Disintegrates slowly May have multiple “peaks”  Pharmaco/toxicokinetics What can this be used to predict? – Onset of efficacy/toxicity – Duration of efficacy/toxicity  Absorption Formulation alters rate of absorption Liquids faster vs solids vs IV vs SQ vs IM vs IN vs SL Sustained release slower vs non-sustained release Opening, crushing, breaking sustained release products alters the rate of absorption – How does this alter the pharmacodynamics? What do you think about Decontamination?  Bupropion XL Found in Small Intestines Found in Stomach Extracorporeal Removal Extracorporeal Removal Extracorporeal Removal  Bioavailability What is Bioavailability? % or fraction of an administered dose that reaches the systemic circulation IV = 100% bioavailable 1st pass effect 1st pass effect in OD 1st pass effect Antidote? Enterohepatic Recirculation After absorption comes ?  Distribution Reversible transfer of a medication/toxin to and from the site of measurement What are some things that alter distribution? – Protein binding – Molecular size – Lipid solubility – Ionization status at a given pH – time  Tissue Vasculature Brain heart Kidney Liver  Distribution Why is it important to know how long it takes for something to distribute? – Distribution is a major component in the time course to clinical toxicity Time to and from “toxic effect” compartment What are some medications that “demonstrate” this concept? – Digoxin – ASA – Lithium  MS 67 yo male Sent into the ED by his PMD after a lab test showed a digoxin level of 3.6 ng/ml at 8 AM Therapeutic range is 0.8-2 ng/ml He is AAOx4, normal vital signs and no medical complaints Why may he not have side effects despite the high serum level?  Distribution Digoxin – ~6-8 & 4-6 hrs after oral and IV administration – Post-distribution level that best corresponds to efficacy and toxicity  Distribution Lithium Distribution from plasma to interstitial fluids is faster than distribution into brain May not have symptoms of CNS toxicity with initially high levels after an acute OD  29 yo female Seen in the ED for a suspected digoxin OD N/V, HR 32 BPM, BP 100/60 Digoxin level of 4.8 ng/ml (Therapeutic range is 0.8-2 ng/ml) K level 5.5 mEq/L (N- 3.5-4.5 mEq/L) ECG Hr 32, 2-3rd degree heart block – Antidotal therapy with digoxin immune fab fragments were given Patient responded well to therapy Digoxin level rose to 8.2 ng/ml – Why?  Distribution 19 yo male presented to the ED after a suicide attempt n/v, rr 26 Salicylate level of 65 mg/dl (serum ph 7.55) Salicylate level of 55 mg/dl 3 hrs later (serum ph 7.35) Is this good, bad, indifferent? Why?  Distribution ASA – Weak acid – Low pH favors unionized form – As pH falls salicylate can move from plasma into the cells > effect in the cells > toxicity  Ionization Salicylic acid is a weak acid Exists primarily in the ionized state at physiologic pH Not permeable to cell membranes when ionized Becomes un-ionized as pH falls More permeable to cell membranes when un-ionized  Distribution CS is a 42 yo female that ingested Lithium in a suicidal attempt – Significant altered mental status – Li level 4.4 mEq/L (therapeutic free levels and > effects  Protein Binding How may protein binding differ after a therapeutic dose vs OD? OD – Binding capacity becomes saturated Free/bound ratio tends to increase More free= > effects  Protein Binding 32 yo with an OD of valproic acid Unconscious with serum level > 600 mcg/ml (5-100) – Medical student looks up info on valproic acid – Manufactures info says not dialyzable – Poison center is called and specialist suggests dialysis Why was dialysis suggested?  Protein Binding 17 yo comes into the ED – Ataxic and has been bumping into things – Hx- phenytoin for 10 years, rarely has a seizure, level is almost always 17 mcg/ml – Significant weight loss (? Anorexia) – Current level is 26 mcg/ml Why does she appear phenytoin toxic?  Phenytoin Why does she appear phenytoin toxic? What other labs may help you? Albumin level? 2.5 mg/dl (N ~ 4.5)  Phenytoin Albumin level 2.5 mg/dl Free phenytoin level is very high Corrected of 43mcg/ml Compared with 28mcg/ml (Albumin 4)  Metabolism Liver – Major organ involved Oxidation, reduction, hydrolysis, conjugation, (P-450 enzyme system) – Active medication to inactive metabolites – Active drug to active metabolites + inactive metabolites – Inactive medication to active medication  Metabolism Active drug to active/toxic metabolites Example – Citalopram/Escitalopram Desmethylcitalopram Metabolite is responsible for qt prolongation – Alters the length of time we follow an asymptomatic patient with a suspected OD  Metabolism Active drug to active/toxic metabolites – Methanol and Ethylene glycol Fomepizole (4mp) or Ethanol  Elimination Irreversible loss of substance from site of measurement Metabolism + excretion Total clearance= renal clearance + metabolic clearance + other  Renal Elimination Glomerular filtration + secretion (into tubule) – reabsorption (from tubule) ASA- weak acid Use of NaBicarb – Ion trapping – Raise plasma pH – Raise urine pH 7.5 – Increase fluids – Make sure K levels are adequate  Elimination Block Metabolism of the toxic alcohol and urinate it out, or for methanol breath it out Ethanol or Fomepizole  Half-life Time for the medication concentration to decrease by ½ – Substance specific – Patient specific Organ function Age Disease states Other medication How does this relate to the duration of toxicity?  Half-life Why would someone want to know what the t1/2 of a medication is? – To predict how long it will take to clear the medication – How long the “side effects/toxic effects/unwanted effects last”  Half-life Why may t1/2 be slower then expected? – Literature reflects therapeutic doses – Clearance may change in the OD situation 1st order to zero order kinetics – Still absorbing medication ASA Lithium  Toxin induced alteration in metabolism and elimination Consider effect of toxin on “organ” perfusion How may toxin induced hypotension alter metabolism/elimination? – Decrease renal blood flow Decreased clearance  Issues in - Metabolism Drug interactions involving the p450 system Decreased ability to metabolize based upon levels achieved with a dose  Pharmacodynamics vs toxicodynamics Parmacodynamics is what the drug does to the body Toxicodynamics is what the toxicant does to the body Most commonly, it is the dose/serum level that determines if we will be dealing with pharmacodynamics to toxicodynamics  Pharmacodynamics vs toxicodynamics Can you give some examples of meds where we commonly see a pharmacodynamic response change to a toxicodynamic response?  Pharmacodynamics vs toxicodynamics Insulin BB Water Opiod Benzodiazepines Alcohol Almost every med  Idiosyncratic side effects Rare after an OD Often risk of an idiosyncratic effect is no more common after an OD vs therapeutic dose  Antidotes EMS/Paramedics carry some Naloxone Glucose Oxygen Atropine Physostigmine Pralidoxime (2-Pam)  Antidotes Contd Hospitals carry some Cyanide antidote kits Snake antivenin (some hospitals some antivenins) Succimer Calcium Disodium Versonate Antibiotics (for anthrax)  Antidotes Contd Specialized resources Snake antivenin (some hospitals some antivenins) HBO Botulism immune globulin Strategic National Stockpile https://www.phe.gov/about/sns/Pages/default.aspx CDC CHEMPACK Program, https://chemm.nlm.nih.gov/chempack.htm)  Summary Questions 1. Why is duration of effect difficult to predict in OD? 2. Everyone on TV gets their stomach pumped Is this real? Is it commonly done? Why or why not? 3. Is HD beneficial for most ODs?  New Jersey Poison Information & Education System Help is a phone call away 1-800-222-1222 Questions? NJ Poison Information and Education System Department of Emergency Medicine