toxicokinetics and biotransformation Flashcards
difference between toxicokinetics and pharmacokinetics
pharmacodynamic effect is toxic
dosing info lacking or inaccurate
doses in excess of those ever studied
PK and PD often not know
drugs may be illegal unlicensed or untested
may be used in never studied before ocmbinations
xenobiotic characteristics affecting GI absorption
physiological properties
dosage forms
dissolution profiles
presystemic elimination
patient characteristics affecting gi absorption
GI motility
GI disease - ulcer, chrons
malnutrition
pregnancy -altered flora
diffference between gastric emptying time and GI transit time
gastric emptying is time stomach takes to empty since absorption takes place in SI the longer the agent is in the stomach the less absorption
transit time is the time to go through the GI tract so if increased the drug is eliminated more quickly
how cna pregnancy effect absorption
increased gastric emptying time
decreased intestinal motility
increased intestinal blood flow
increased hgastric ph and buffer capacity
tendency towards ___ absorption in pregnant women
increased absorption so increased risk for toxicity but increased cardiac output and renal perfusion can increase clearance of some xenobiotics
how can we alter gi absorption
gastric emptying - emesis, gastric lavage, increase in intestinal motility
administer activated charcoal
large Vd drug will be
xenobiotic residues outside the plasma compartment ( in the tissues)
____ binds acidic compounds
albumin
____ binds basic compounds
alpha 1 acid glycoprotein
factors affecting distribution
membrane diffusion principles affinit for plasma and tissue proteins acid base status physiological barriers patient characteristics
lipophilic xenobiotics effect on vd and serum concentration
higher affinity for fat gives a higher vd so lower serum levels and a decrease in toxicity
hydrophilic xenobiotics effect on vd and serum levels
decreased vd increases level in serum and may increase toxicity
increase in body fat will increase vd for
lipophilic xenobiotics
decrease in total body water will decrease vd for
hydrophilic
decrease in plasma albumin will cause
increased free fraction and increased toxicity
pregnancy causes hypoalbuminemia so _____ binding of acidic drugs
decreases
pregnancy increases plasma volume so ____ vd
increases
pregnancy has no effect on
hepatic blood flow
renal disease can cause hypoalbumiemia and accumulation of endogenous substances that may compete for binding sites will decrease binding of acidic drugs, examples of drugs afected
naproxen vd and half life increased
phenytoin fraction unbound increases
3 ways to alter distribution
mainpulation of pH - salicylates
chelators - deferoxamine, have a higher affinity for the drug than tissues so can trap it
antibody fragments ex. digoxin fragments have higher affinity and take dig away from myocardium
factors affecting elimination
environmental/social - drinking, smoking age gender disease pregnancy genetics
how does smoking affect elimination
induction of cytochrome P450 enzymes, even second hand smoke
smokings affect on theophyllin
increases clearance causing serum levels to fall = therapeutic failure
amoking affect on acetaminophen
NAPQI formed from acetaminophen due to the increased P450 enzyme activity may exceed glutathione stores
acute effects of alcohol on elimination of acetaminophen
inhibition of oxidative metabolism immediately after ingestion
chronic effects of alcohol on elimination
enzyme induction - metabolic tolerance
clearance of some drugs increases
what is shunting
hepatic damageleading to obstruction of normal blood flow… another way alohol can affect elimination
how can cirrhosis affect elimination
may decrease clearance but bc enzyme induction no changes may be seen until shunting occurs
how does increasing age affect elimination
hepatic blood flow decreases so metabolism of high extraction drugs has decreased so increased risk of poisoning
renal function decreases therfore creatinine clearance so renally cleared drugs need to be adjusted
pregnancy hormone changes affecting elimination
estrogen: inhibits oxidative metabolism, impaired hepatic elimination of biliary excreted drugs
progesterone induces enzymes thus may increase clearnace of some drugs
example of inhibition of metabolism
acetaminophin od
give SH groups with N acetyl cystein
**slow the rate of NABQI formation with a P450 inhibitor
types of renal excretion
glomerular filtration - non saturable
tubular secretion - saturable
passive tubular reabsorption - non charged, lipid soluble
normal crcl
> 90ml/min
how can we alter excretion
manipulate pH
chelators
multiple dose activated charcoal
extracorporeal devices (kind of like dialysis)
how are drugs excreted in breast milk
simple diffusion into breast milk
pH 6.5 more acidic than plasma making an ion trap for basic compounds
things affecting excretion into breast milk
basicity of compound
differences in affinity to serum proteins vs milk proteins
drugs with longer half life greater opportunity to be excreted
