Toxicokinetics

1
Toxicokinetics

• Harold J. Manley, Pharm.D., BCPS
• Assistant Professor

2
Objectives

• Definition
• Understand differences between PK and TK
• Be familiar with general management of ODs
• Be familiar with management of specific ODs
• Understand the role of Pharmacist in ODs

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Toxicokinetics (TK)

• Definition
• the absorption, distribution, metabolism, and
  excretion of drugs at doses associated with
  clinical toxicity

4
Absorption

• most important TK parameter
• (gt70 poisonings are PO)
• still occurring in patients when they present
• After initial assessment/stabilization, 1st
  therapeutic attempt is to prevent further
  absorption

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Absorption (continued)

• In general, Absorption is slowed
• decreased rate of tablet dissolution
• decreased gastric emptying time
• anticholinergic effects
• sustained released formulations
• bezoar formation
• not all drugs are rapid and completely absorbed
• PHT 6-39 hrs, maprotaline up to 24 hrs

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Distribution

• VD and PPB
• Saturation of PPB sites allowing for more free
  drug
• More free drug allowing for other tissues to take
  up, thereby increasing VD
• Example
• ASA VD increases up to 50 in ODs
• reason for CNS effects

7
Metabolism

• Rate important because
• determines duration of intoxication
• formation of less (more) toxic metabolites to
  more water soluble substances
• Enzymes
• may become saturated
• remember we only have so much
• saturation or excessive utilization may prolong
  elimination/toxicity
• Example
• APAP

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Elimination

• Generally slower
• secondary to decreased metabolism
• secondary to toxic substance
• Example ASA
• decreases pH of urine due to metabolic acidosis
• low urine pH inhibits excretion of ASA
• Toxic effects on Kidney or Liver secondary to OD
• Approach to patient
• try to determine rate of elimination
• try to increase rate of elimination (HD, PD,
  Hemoperfusion, alkalinize urine, GI
  decontamination)

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Comparison of PK and TK
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Pathophysiologic Effects

• Gastrointestinal Motility
• a decrease will allow for greater dissolution and
  more absorption
• Cardiovascular/Pulmonary
• low cardiac output may decrease distribution,
  higher blood conc.
• Acid/Base Disturbances
• acidosis increases VD of salicylates, base admin.
  may aid in TCA overdoses

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Pathophysiologic Effects

• Renal Function
• May be compromised due to direct or indirect
  toxicity
• Hepatic function
• liver damage alters metabolism
• Inhibition/Stimulation of enzymes
• Decreases in blood flow
• Hypothermia
• may alter disposition of toxins

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General Management

• ABCs
• airway
• breathing
• circulation
• Apply TK principles to
• History of Exposure (ingestion)
• Clinical presentation
• Laboratory Data

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General Management (continued)

• Gastrointestinal decontamination
• activated charcoal
• syrup of ipecac
• gastric lavage
• whole bowel irrigation
• Extracorporeal elimination
• Hemodialysis
• Hemoperfusion
• Combined HD and HP
• Peritoneal dialysis
• Urinary Alkalinization

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Criteria for HD or HP

• Toxin causes severe M M
• Quantity of drug will cause severe M M
• Patients ability to remove toxins is impaired
• Available for treatment within window of
  opportunity
• No immed. irreversible damage
• Drug removed efficiently by HD or HP

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Salicylate overdose

• Absorption
• delayed gastric emptying and dissolution
• Distribution
• increases with acidosis, protein binding sites
  become saturated
• Elimination
• varies with dose and urine pH
• urine pH 5 yields 2-3 elimination
• urine pH 8 yield up to 80 elimination
• half-life increases with dose

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Salicylate overdose (continued)

• ASA
• weak acid, pKa 3.5
• hydrolyzed in stomach
• metabolized in liver
• Peak absorption 30-120 minutes
• half-life in therapeutic doses up to 19 hrs
• VD 0.12-0.17 L/kg therapeutic doses
• Levy and Yaffe found that VD increases up to 0.35
  L/kg in children
• VD increased because of low plasma pH, resulting
  in increased amount of nonionized salicylate
  available to cross membranes
• PPB 80-90 (decreases in overdose)

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Salicylate overdose (continued)

• Must differentiate between acute or chronic
  ingestion
• Done nomogram more closely correlates signs of
  toxicity with serum levels with acute toxicity
• Clinical presentation and serum levels must both
  be taken into consideration when determining
  therapy
• respiratory alkalosis (due to direct stimulation
  of resp center and subsequent hyperventilation)
• metabolic acidosis
• tinnitus
• pulmonary edema
• seizures, coma

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Salicylate effects

• PG inhibition
• PLT dysfunction, Renal failure, Gastric erosion
• CNS respiratory stimulation
• Hyperventilation, Resp. Alkalosis, Incr.
  insensible loss
• Smooth muscle stimulation
• Incr. O2 demands
• Fever, Metabolic acidosis, Respiratory alkalosis,
  Alterate cellular organ function
• Stimulate insulin secretion
• hypoglycemia

• Krebs cycle inhib.
• Metab.Acid. Imp. glucose metab. ketone production
• Hypoprothrombinemia
• Incr. PT
• Capillary leak
• Pulmonary edema
• Impaired CNS glucose uptake
• Encephalopathy

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Salicylate overdose Management

• Hydration
• 0.25-0.5 N saline titrate to urine output of
  100-200 mL/h
• Activated Charcoal
• 50-60 grams will decrease absorption by 25-50
• Alkalinization of urine
• urine pH goal gt 7.5
• 1 mEq/kg sodium bicarb (mild)
• 50-100 mEq sodium bicarb bolus therapy in
  addition of above (moderate to severe cases)
• HD or HP may increase elimination
• reserved for severe patients (seizures)

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APAP overdose

• Absorption
• may be delayed with increasing dose
• F may increase as first-pass metabolism is
  saturated
• 500mg F 63
• 2000mg F 87
• Distribution
• dose-dependant
• Elimination
• conjugate stores deplete and increases amount
  metabolized to toxic metabolite (occurs once
  glutathione stores are lt30 of normal)
• toxic metabolite N-acetly-p-benzoquinonimine
  NAPBQ

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APAP Stages of Poisoning

• Stage I
• 6-14 hrs post ingestion
• anorexia, N/V, diaphoresis
• may be asymptomatic
• Stage II
• above symptoms improve
• LFTs and PT may be elevated
• Stage III
• 3-5 days post ingestion
• acute liver failure with increased bilirubin,
  uremia, metabolic acidosis
• Stage IV
• recovery 7-8 days

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APAP overdose management

• Rumack - Matthew Nomogram
• N-acetylcysteine
• acts as a substrate for toxic metabolite
• maximum protection against hepatotoxicity if
  administered 8-10 hrs post ingestion (up to 16
  hrs)
• PO 140mg/kg load then 70 mg/kg q 4 hrs x 17
  doses
• IV investigational in US
• 20 hr regimen 150mg/kg in 200 ml 5 dex over 15
  min50mg/kg in 500 ml 5 dextrose over 4 hrs 100
  mg/kg in 1L 5 dextrose over 16 hrs
• 48 hr regimen 140mg/kg in 5 dextrose over 1
  hr followed 4 hr after initiation of treatment
  by 12 maintenance doses (70 mg/kg) over 1 hr in
  5 dextrose each commencing 4 hr post initiation
  of preceding dose

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APAP overdose management (continued)

• Vit K (PT gt 1.5 x normal) or FFP (PT gt 3.0 x
  normal) if needed
• maintain normal hydration and electrolyte balance
• Problems with IV NAC
• not sterile
• must be prepared by pharmacy
• patient adverse reactions (presumed due to
  histamine release)

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Extended Release APAP

• 1994 introduced by McNeil
• Contains 325 mg APAP immediate release and 325mg
  APAP delayed release
• Overdoses produce a dilemma due to the altered
  absorption
• Interpretation of Rumack - Matthew Nomogram
  difficult

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Alcohols Methanol

• Absorption
• absorbed rapidly, small amount can be lethal
  peak in 30-60 min.
• Distribution
• small VD
• Metabolism/Elimination
• metabolized to toxic metabolites
• toxins resp for metabolic acidosis
• Half-life varies from 12-20 hours
• EtOH competes for Al.Dehydrog
• fomepizole alcohol dehydrogenase inhibitor

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Alcohol ethylene glycol

• colorless, odorless liquid which has a sweet
  taste and an inebriating effect
• accumulation of toxic metabolites assoc. M M
• Half-life of ethylene glycol approx. 3 hours
• Toxic metabolites include formaldehyde, formic
  acid, glycolic acid, oxalic acid

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Alcohol ethylene glycol

• Stage 1
• neurologic (0.5-30 hrs) inebriation, nausea and
  vomiting, hyporeflexia, seizures, coma, opth.
  manifest.
• Stage 2
• cardiopulm. (12-24hrs) tachycardia, htn, pulm.
  edema
• Stage 3
• renal (gt24 hrs) flank pain, oliguria to anuria,
  renal failure

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Alcohol ethylene glycol

• Absorption
• rapidly and completely absorbed peak within 1-4
  hours
• Distribution
• similar to MeOH, small VD
• Metabolism/Elimination
• metabolized to toxic metabolites
• half-life approx 3 hours
• EtOH competes for metabolism
• fomepizole alcohol dehydrogenase inhibitor

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Role of a Pharmacist

• Apply TK fundamentals to OD situations
• Suggest specific antidotes for certain overdoses
• Determine duration of treatment of OD by
  monitoring serum/plasma toxin levels