Toxicokinetics Flashcards
What effect does pregnancy have on absorption?
- increased gastric emptying time (30-50%)
- decreased intestinal motility
- increased intestinal blood flow
- increased gastric pH and buffer capacity
(tendency towards increased absorption)
What things can decrease the bioavailability of a drug?
- gastric emptying (emesis, gastric lavage and increase in intestinal motility)
- administration of activated charcoal (direct intervention on absorption process)
Free drug is important for what?
the therapeutic (or toxic) effects of the drug
Albumin primarily binds what?
acidic compounds
alpha1-acid-glycoprotein primarily binds what?
basic compounds
What are some factors that affect distribution of a drug?
- membrane diffusion principles
- affinity for plasma and tissue proteins
- acid-base status of the patient
- physiological barriers
- patient characteristics (obesity, age, pregnancy, disease)
What effect does lipophilic xenobiotics have on the Vd?
- increases the Vd
- decreases serum levels
- decrease toxicity
What effect does hydrophilic xenobiotics have on the Vd?
- decreases the Vd
- serum levels increased
- increased toxicity
What are age related changes that affect the Vd?
- increase in body fat
- decrease in total body water
- decrease in plasma albumin
What are the pregnancy related changes that affect the Vd?
- hypoalbuminemia (decreases binding of acidic drugs- salicylic acid, sulfonamides, phenytoin)
- increases plasma volume (increase doses of aminoglycosides)
- increased cardiac output (increased clearance)
What affect does renal disease have on distribution?
- hypoalbuminemia with accumulation of endogenous substances that may compete for binding sites
- decreased binding of acid drugs (phenytoin and naproxen is affected)
How can we effectively alter distribution?
- manipulation of pH (salicylate)
- chelators (deferoxamine)
- use of antibody fragments (digoxin)
What 2 things are involved in elimination?
- biotransformation AND excretion
What are the main clearance organs?
- liver, kidney and lungs
What factors affect elimination?
- environmental/social (smoking, alcohol, diet)
- age
- gender
- disease
- pregnancy
- genetics
What affect does smoking have on elimination?
- induction of cytochrome P450 isoenzymes
- – theophylline: Cl increased, decreased t1/2, serum levels fall leading to therapeutic failure
- – NABQI formed from acetaminophen may exceed glutathione stores
What affect does alcohol have on elimination?
- acute effects: inhibition of oxidative metabolism immediately after ingestion
- chronic effects: enzyme induction - metabolic tolerance (clearance of drugs like warfarin/phenytoin increases)
- cirrhosis: decreases clearance
- shunting: hepatic damage leads to obstruction of normal blood flow
What affect does age have on elimination?
- influences hepatic function - hepatic blood flow decreases – increased risk for poisoning
- renal function also decreases with age - as does CrCl, and dose or dosing internal of renally cleared drugs
What effect does pregnancy have on elimination?
- estrogen: inhibits oxidative metabolism
- estrogen: cholestatic effects- impaired hepatic elimination
- progesterone induces microsomal enzymes, and thus may increase clearance of some drugs
- renal blood flow increased, thus increases renal clearance
- caffeine metabolism decreased
- diazepam met. decreased
- metoprolol metabolism decreased
What are some drugs that are metabolized by CYP2D6?
- codeine
- antiarrythmics
What drugs are metabolized by CYP2C9?
- warfarin
- phenytoin
- NSAIDs
What drugs are metabolized by CYP2C19?
- antidepressants
- clopridogrel
- diazepam
What drugs are metabolized by CYP2B6?
- cyclophosphamide
- effavirenz
What increases the metabolic elimination of a poison?
- rifampin- is an inducer of p450
What inhibitors the metabolism of a toxic metabolite?
- cimetidine - inhibitor of P450
What are ways to treat acetaminophen OD?
- give SH group (N-acetyl-cysteine)
- slow the rate of NABQI formation (eg. cimetidine)
At what pH are you ion trapping basic compounds?
6.5
