Toxicokinetics

Question 1

Absorption Drug Variables (6)

Answer 1

1. Dose: sheer bulk extends absorption with delayed/wide [peak]
2. Formulation
3. Water Solubility
4. Slowed gut motility
5. Increased gut motility
6. First pass effect

Question 2

Formulation Effects

Answer 2

• Liquids may have enhanced absorption due to volume stimulating gastric emptying
• EC and SR are designed to prolong absorption
• Excipients form concretions (phenytoin)

Question 3

Water Solubility

Answer 3

• 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

Question 4

Gut Motility

Answer 4

• TCA, phenothiazines, antihistamines**, anticholinergics, CCB, opioids
• Total drug absorbed increases due to prolonged contact
• Increased gut motility: salicylates, theophylline
• Emesis decreased total amount absorbed

Question 5

First Pass Effect

Answer 5

• 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.

Question 6

Absorption Pathophysiology Effects

Answer 6

• Hypothermia or hypotension decreases mesenteric perfusion and decreases/delays absorption
• CCB, B-blockers, procainamide

Question 7

High First Pass Effect Drugs

Answer 7

• Propranolol
• Cyclosporine
• Morphine
• Desipramine and other TCAs
• Implications: first pass effect can saturate in overdose, greater proportion of drug will reach systemic circulation

Question 8

Large Vd Drugs

Answer 8

• Camphor
• Antidepressants
• Digoxin
• Opioids
• Phenothiazines

Question 9

Small Vd Drugs

Answer 9

• Alcohol
• Lithium
• Phenobarbital
• Phenytoin
• Salicylate
• Valproic Acid

Question 10

Vd + [Peak]

Answer 10

• Vd can use to predict max [peak] or body burden in overdose
• Cp = Dose/Vd

Question 11

Compartments

Answer 11

• 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

Question 12

Protein Binding

Answer 12

• 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)

Question 13

Increased Vd

Answer 13

• 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

Question 14

Drug Metabolism + Overdose

Answer 14

• Altered rate of biotransformation
• Prominence of enterohepatic recirculation
• Relative utilization of elimination routes
• Relative utilization of elimination routes
• Impact of toxic or active metabolites

Question 15

Phase I Metabolism

Answer 15

• 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

Question 16

Liver Toxic Metabolites

Answer 16

• APAP: NAPQI
• Valproic Acid: 4-ene, 2/4-dienes, inhibit fatty acid metabolism, alkylate 3-ketoacyl-CoA thiolase
• Halothane: trifluoroacetyl chloride, hapten, immune hepatitis

Question 17

Skin Toxic Metabolites

Answer 17

• Aromatic anticonvulsants: pheytoin, CBZ, PB, lamotrigine, epoxide metabolites, deficient in epoxide
• Sulfonamides: hydroxylamine
• Procainamide: defective N acetylation, oxidative metabolite, form DNA adducts, SLE syndrome

Question 18

Blood Toxic Metabolites

Answer 18

• 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

Question 19

Methemoglobinemia Toxic Metabolites

Answer 19

-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

Question 20

Neurologically Toxic Metabolites

Answer 20

• Meperidine: normeperidone, seizures

- Bromethalin: demethyl, inhibits oxidative phosphorylation

Question 21

Phase II Metabolism

Answer 21

• 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

Question 22

Enterohepatic Recirculated Toxins

Answer 22

• Amatoxin (mushroom)
• Carbamazepine
• Dapsone
• Meperidine

Question 23

First vs Zero Order Kinetics

Answer 23

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

Question 24

Zero Order Drugs

Answer 24

• Theophylline
• Salicylates
• Phenytoin
• Ethanol
• Toxic alcohols (methanol, ethylene glycol)

Question 25

Interventions for Altered Absorption

Answer 25

- 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)

Question 26

Interventions for Altered Distribution

Answer 26

-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%

Question 27

Interventions for Altered Metabolism

Answer 27

- Multiple dose activated charcoal | - Enterohepatic circulation, prevent reabsorption in distal ileum

Question 28

Interventions for Altered Elimination

Answer 28

- 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