Toxicokinetics Flashcards
Absorption Drug Variables (6)
- Dose: sheer bulk extends absorption with delayed/wide [peak]
- Formulation
- Water Solubility
- Slowed gut motility
- Increased gut motility
- First pass effect
Formulation Effects
- Liquids may have enhanced absorption due to volume stimulating gastric emptying
- EC and SR are designed to prolong absorption
- Excipients form concretions (phenytoin)
Water Solubility
- Poor water solubility has prolonged absorption
- Phenytoin Cmax increases significantly with dose increases
- Carbamazepine has a wider plateau
- Aspirin solubility increases in alkaline medium due to ionized form, net result is increased absorption
Gut Motility
- TCA, phenothiazines, antihistamines**, anticholinergics, CCB, opioids
- Total drug absorbed increases due to prolonged contact
- Increased gut motility: salicylates, theophylline
- Emesis decreased total amount absorbed
First Pass Effect
- Saturable in overdose, resulting in less presystemic clearance and higher blood levels
- Drugs: opioids, verapamil, lidocaine, propranolol, TCA
- Removal of drug after ingestion: gut enzymes, liver uptake, vomiting, AC, WBI, etc.
Absorption Pathophysiology Effects
- Hypothermia or hypotension decreases mesenteric perfusion and decreases/delays absorption
- CCB, B-blockers, procainamide
High First Pass Effect Drugs
- Propranolol
- Cyclosporine
- Morphine
- Desipramine and other TCAs
- Implications: first pass effect can saturate in overdose, greater proportion of drug will reach systemic circulation
Large Vd Drugs
- Camphor
- Antidepressants
- Digoxin
- Opioids
- Phenothiazines
Small Vd Drugs
- Alcohol
- Lithium
- Phenobarbital
- Phenytoin
- Salicylate
- Valproic Acid
Vd + [Peak]
- Vd can use to predict max [peak] or body burden in overdose
- Cp = Dose/Vd
Compartments
- Part of distribution
- Shallow peripheral: highly perfused organs, brain, liver, kidneys
- When rapidly equilibrated, one compartment model is evident
- Deep peripheral: slow distribution to muscle, adipose tissue, bone
Protein Binding
- Part of distribution
- Poly-drug overdose: competes for binding sites
- High dose: can saturate protein binding resulting in higher free levels
- Drugs not normally considered dialyzable may be so in overdose (valproic acid, salicylates)
Increased Vd
- Increased Vd in chronic vs acute overdose produce toxicity at levels considered mildly toxic or therapeutic in acute overdose
- Ex: theophylline, salicylate, lithium
- Cause a [gradient] created by chronically elevated serum levels, leading to increased tissue compartment stores
Drug Metabolism + Overdose
- Altered rate of biotransformation
- Prominence of enterohepatic recirculation
- Relative utilization of elimination routes
- Relative utilization of elimination routes
- Impact of toxic or active metabolites
Phase I Metabolism
- CYP P450s, hydroxylation, demethylation, epoxidation
- Metabolites excreted into bile, transported from central compartment for renal elimination, or further metabolized
- Drugs w/ active metabolites: TCA, diazepam, meperidine
Liver Toxic Metabolites
- APAP: NAPQI
- Valproic Acid: 4-ene, 2/4-dienes, inhibit fatty acid metabolism, alkylate 3-ketoacyl-CoA thiolase
- Halothane: trifluoroacetyl chloride, hapten, immune hepatitis
Skin Toxic Metabolites
- Aromatic anticonvulsants: pheytoin, CBZ, PB, lamotrigine, epoxide metabolites, deficient in epoxide
- Sulfonamides: hydroxylamine
- Procainamide: defective N acetylation, oxidative metabolite, form DNA adducts, SLE syndrome
Blood Toxic Metabolites
- Aromatic anticonvulsants: aplastic anemia
- Phenylbutazone: 4-hydroperoxyphenyl, butazone, aplastic anemia
- Chloramphenicol: hydroxylamines
- Zidovudine: 3’-amino-3’-deoxythymidine, bone marrow toxicity
- Clozapine: oxidized by myeloperoxidase to free radical
Methemoglobinemia Toxic Metabolites
-Dapsone: hydroxylamine, occurs in all, induced by cimetidine
-Sulfasalazine, hydroxylamine, not induced by cimetidine
Phenacetin: forms APAP by CYP2D6, alternate pathway forms phenetidine
-Naphthalene: epoxides, hemolysis
Neurologically Toxic Metabolites
- Meperidine: normeperidone, seizures
- Bromethalin: demethyl, inhibits oxidative phosphorylation
Phase II Metabolism
- Conjugation with water soluble moiety, sulfate, glutathione, glucuronide, enterohepatic circulation
- Clinical course prolonged in overdose
- Greater toxicity, linger half-life, conjugate depletion
- Hypotension can decrease metabolism
Enterohepatic Recirculated Toxins
- Amatoxin (mushroom)
- Carbamazepine
- Dapsone
- Meperidine
First vs Zero Order Kinetics
First Order
- Curve on linear paper, straight line on semi-log
- t1/2 = Kel/.693 on linear paper, time elapsed at [1/2] on semi-log
Zero Order
- Fixed elimination rate, common in overdose
- Straight line on linear paper, curve on semi-log
Zero Order Drugs
- Theophylline
- Salicylates
- Phenytoin
- Ethanol
- Toxic alcohols (methanol, ethylene glycol)
Interventions for Altered Absorption
- Late gastric evacuation
- Late gastrointestinal decontamination
- Multiple dose activated charcoal: anticholinergics (concretions, slowly absorbed), salicylates, meprobamate, phenytoin
- Whole bowel irrigation: delayed absorption, not bound to charcoal (lithium, iron)
Interventions for Altered Distribution
-Digoxin immune fab
-Multiple dose activated charcoal
-Gut dialysis: these patients drink charcoal quickly
(+aspirin)
-All have Vd < 1L/kg and/or protein binding <60%
Interventions for Altered Metabolism
- Multiple dose activated charcoal
- Enterohepatic circulation, prevent reabsorption in distal ileum
Interventions for Altered Elimination
- Urinary alkalinization: for drugs with pKa in urine normal range (5-8), normal GFR, low hepatic metabolism
- EX: salicylates, phenobarbital (not as effective) 2/4-D
- Urinary acidification isn’t appropriate
