SALICYLATES. Anthony F. Pizon, M.D. Associate Professor Division Medical Toxicology University of Pittsburgh School of Medicine

Transcription

1 SALICYLATES Anthony F. Pizon, M.D. Associate Professor Division Medical Toxicology University of Pittsburgh School of Medicine

2 Overview: Salicylates Found in Willow bark (Salix alba vulgaris) Widely used analgesic/anti-inflammatory agent Multitude of preparations Prescription (percodan) Over-the-counter (pepto-bismol, aspirin) Topical preparation (wart removal) Combinations (excedrin, fiorinal) Other (oil of wintergreen)

3 Overview: Salicylate Formulations Aspirin (acetylsalicylic acid) mg/tab BASA 81 mg/pill Suppository mg Fiorinal/Soma or Darvon Compounds 325 mg of ASA Oil of Wintergreen (methyl salicylate) 5 g/5 cc

4 Overview: Salicylate Pharmacokinetics Absorption With therapeutic use: Rapidly absorbed In overdose: SAL impairs gastric emptying Enteric coating produces delayed absorption Toxic [SAL] may be delayed for > 6 hrs Topical application have been assoc with deaths

5 Salicylate Ion pka = 3.5

6 Overview: Salicylate Pharmacokinetics Distribution Decrease ph favors un-ionized state: At ph 7.4, 98% of SAL is ionized Un-ionized [SAL] doubles At ph 7.2, 96% of SAL is ionized Unionized SAL distributes into tissues

7 Overview: Salicylate Pharmacokinetics Distribution Salicylate-albumin binding is saturable: Serum Concentration: 8 mg/dl 92 mg/dl Protein Binding: 83% 40% From: Br J Clin Pharmac 1981; 11:

8 Overview: Salicylate Pharmacokinetics Distribution Salicylate exists in plasma in equilibrium between: + SAL SALH ALBUMIN-SAL ALBUMIN + SAL The unbound unionized salicylate diffuses into tissues

9 Overview: Distribution Un-ionized & Non-protein bound Sal Favors distribution into tissue

10 Salicylate Neurotoxicity

11 Overview: Salicylate Pharmacokinetics Elimination T 1/2 = 3 hrs (36 hrs in overdose) Bio-elimination via first-order (at very low body burden) and then zero-order kinetics (in overdose) Glucuronide and Glycine Conjugation Microsomal Oxidation Renal Excretion

12 outer membrane citric acid cycle intermembrane space matrix DNA inner membrane; cristae

13 intermembrane space CytC I Q III IV II Electron Transport Chain matrix

14 mv citric acid cycle ph ~.5 matrix DNA

15 P intermembrane space CytC I II Q III IV -200 mv 4 2 ADP + Pi + succinate NAD 4 O 2 H 2 O 3 ATP + H 2 O N matrix

16 P ph Generic Acid Uncoupler intermembrane space R-COO - R-COOH matrix ph N

17 P ph Generic Acid Uncoupler intermembrane space R-COO - R-COOH R-COOH matrix ph N R-COOH

18 P ph intermembrane space Generic Acid Uncoupler R-COO - R-COOH R-COOH matrix ph N R-COO - R-COOH

19 P ph Generic Acid Uncoupler intermembrane space R-COO - R-COOH R-COO - R-COOH matrix ph N R-COO - R-COOH

20 P intermembrane space R-0 - R-0H CytC I II Q III IV R-0H 4 NAD N succinate 4 O 2 H 2 O Generic Acid Uncoupler 2 heat R ADP + Pi + ATP + H 2 O matrix

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22 Salicylate: Mechanisms of Toxicity Major (recurrent) toxic effects: Metabolic Acidosis Hypoglycemia Decreased energy production

23 Salicylate: Mechanisms of Toxicity MECHANISMS Uncouples Ox-Phosphorylation Inhibition of Krebs Cycle (TCA) Inhibition of Amino Acid Metabolism Stimulates Respiratory Center Stimulation of Glycogenolysis Inhibit Vitamin K 1 2,3-epoxide Stimulation of Lipid Metabolism GI Corrosive Increased Capillary Permeability MANIFESTATIONS Metabolic Acidosis, Decrease ATP Increased Heat, Hypoglycemia Hypoglycemia/Metabolic acidosis Hypoglycemia/Metabolic Acidosis Tachypnea, Respiratory Alkalosis Renal Excretion of HCO 3- /Fluids Hyperglycemia (Early,Transient) Prolonged PT Metabolic acidosis Nausea / Vomiting Third Spacing/Pulmonary Edema

24 Salicylate Neurotoxicity Brain is most energy dependant organ Glucose quickly spent during SAL toxicity Severe hypoglycorrhachia = Death Mortality correlates best with [SAL] in brain

25 Salicylates: Toxic Dose* Therapeutic Range: mg/kg Mild Toxicity: Moderate Toxicity: Severe Toxicity: < 150 mg/kg mg/kg > 300 mg/kg * Approximate ranges

26 Serum Salicylate Levels

27 Acute Salicylate Toxicity Physical Exam Subjective General Cardiac Respiratory Gastric Neurologic Depressed, Abdominal pain, N/V, Tinnitus Ill-appearing, Diaphoretic, Febrile, ALOC Tachycardia, Hypotension (Dehydrated) Tachypnea, Kussmaul s, Rales Nausea and vomiting Agitation, Lethargy, Seizures or Coma

28 Acute Salicylate Toxicity Labs BMP UA ABG Hypokalemia, Ketones, Anion Gap ph, Ketones, Rhabdomyolysis Respiratory Alkalosis and Metabolic Acidosis Coags Elevated PT CXR CTH Pulmonary Edema, ARDS, Aspiration Cerebral Edema

29 Acute Salicylate Toxicity Must quantitate serum SAL level

30 Initial [Sal] don t correlate with severity. Done AK. Salicylate Toxicity. Pediatrics. Nov 1960

31 Treatment Strategies for Salicylate Poisoning Initial Stabilization Limit Absorption Limit Distribution Enhance Elimination

32 Treatment of Salicylate Poisoning Initial Stabilization Obtain detailed history Central Line, Arterial Line Aggressive IVFs (Usually 4-6 L volume depleted) Maintain Respiratory Drive

33 Treatment of Salicylate Poisoning Limit Absorption Activated Charcoal 1 gm/kg Best decontamination method No GI lavage No Ipecac

34 Treatment of Salicylate Poisoning Limit Distribution Salicylic acid has a pk a 3.5 (weak acid) At physiologic ph exists mostly in ionized form Treat with large doses of IV Bicarbonate: Keep blood ph ??Can protein binding be increased??

35 Acad Emerg Med 2007;14:

36 p=0.07

37 Treatment of Salicylate Poisoning Aggressive IV Hydration NSS or LR Maintain brisk urine output Enhanced Elimination Alkalinization of Blood ( ) and Urine (>8.0) Sodium Bicarb boluses (1 meq/kg until blood ph > 7.5)

38 Indications for Hemodialysis Signs of Neurotoxicity Severe Acid-Base/Electrolyte Abnormality (despite appropriate therapy) Acute Salicylate Level > 100 mg/dl Chronic Salicylate Level > 40 mg/dl

39 Indications for Hemodialysis Renal Failure Congestive Heart Failure Hepatic Dysfunction with Coagulopathy Noncardiogenic Pulmonary Edema

40 Chronic Salicylate Toxicity Risk Factors Daily Aspirin Use Nursing Home Patient Psychiatric Comorbidity Dehydration Renal Failure Diuretics (Carbonic Anhydrase Inhibitors)

41 Acute vs. Chronic Salicylate Toxicity ACUTE CHRONIC INCIDENCE 85% 15% AGE YOUNG OLD INTENTION OD OFTEN RARE COINGESTION OFTEN RARE PSYCH. HX COMMON UNCOMMON (UNRELATED) COMORBIDITY RARE COMMON TIME TO DX EARLY LATE ABNORMAL PROTIME NO YES RENAL FXN NORMAL OFTEN ABNORMAL HEPATIC FXN NORMAL OFTEN ABNORMAL NEUROLOGIC SYMPTOMS OCCASSIONALLY COMMON PULMONARY SYMPTOMS RARE COMMON (50%) GI SYMPTOMS VERY COMMON RARE MORBIDITY 16% 30% MORTALITY 2% 25%

42 Salicylate Therapy Pearls Failing to consider the diagnosis Underestimating toxicity and not treating aggressively A falling serum levels means pt is getting better Failing to follow and correct serum Potassium Sedating a pt with Salicylate toxicity and not hyperventilating

43 Questions? On Call Medical Toxicologist 24/7 or Med Call or Poison Center