1 - Toxicokinetics Flashcards
What to consider in regards to absorption?
- Rate and extent
- Route of administration
- Transport mechanism (depends on characteristics of drug – MW, solubility, polarity, ionization, lipid solubility)
Define xenobiotic
External to the body
Xenobiotic characteristics that affect GI absorption
- Physicochemical properties of drug, dosage forms, dissolution profiles
- Pre-systemic elimination
Pt characteristics that affect GI absorption
- GI motility (gastric emptying time, GI transit time)
- GI disease (achlorhydria, gastric ulcer, duodenal ulcer, Crohn’s disease)
- Malnutrition (GI transit time, mucosal atrophy, altered flora)
- Pregnancy
How does GI motility affect GI absorption?
- If drug stays in stomach for longer time, absorption is delayed and decreased (most often) b/c most drugs absorbed in intestines
- If GI transit time increased (drug bases through intestine faster), absorption is increased b/c it reaches the intestines faster where it is absorbed
Describe absorption changes in pregnancy
- Increased gastric emptying time (30-50%)
- Decreased intestinal motility
- Increased intestinal blood flow
- Increased gastric pH and buffer capacity
- *Tendency towards increased absorption, therefore pregnant women may be at increased risk for xenobiotic toxicity; however, factors such as increased cardiac output can increase renal perfusion and thus clearance of some xenobiotics
Can we effectively alter GI absorption?
- Can decrease bioavailability
- Gastric emptying (emesis, gastric lavage, increase in intestinal motility)
- Administration of active charcoal (direct intervention on absorption process)
What is distribution?
Reversible transfer from systemic circulation to peripheral tissue compartments
Vd formula
Vd = F*dose / Co
What does a large Vd mean?
- A large Vd indicates that the xenobiotic resides outside the plasma compartment; in overdose, it can be used to estimate a max plasma concentration when dose is known
- Drugs w/ large Vd would not be adequately removed by dialysis
Which protein primarily binds acidic compounds?
Albumin
Which protein primarily binds basic compounds?
Alpha 1-acid-glycoprotein
Factors affecting distribution
- Membrane diffusion principles
- Affinity for plasma and tissue proteins
- Acid-base status of pt
- Physiological barriers
- Pt characteristics (obesity, age, pregnancy, disease)
Effect of obesity on Vd and serum concentration for lipophilic and hydrophilic xenobiotics
- Lipophilic xenobiotics -> increased Vd, decreased serum levels, and may have decreased toxicity
- Hydrophilic xenobiotics -> decreased Vd, increased serum levels, and may have increased toxicity
Significance of increase in body fat for Vd
Increase in Vd for lipophilic xenobiotics (ex: diazepam)
Significance of decrease in total body water for Vd
Decrease in Vd for hydrophilic xenobiotics (ex: aminoglycosides)
Significance of decrease in plasma albumin for Vd
Decrease in binding = increase in Fu = increase in toxicity (ex: phenytoin)
How does hypoalbuminemia affect distribution in pregnancy?
Decrease binding of acidic drug (salicylic acid, sulfonamides, phenytoin)
How does increased plasma volume affect distribution in pregnancy?
Increased Vd for many drugs (ex: increase dose for aminoglycosides)
How does increased cardiac output affect distribution in pregnancy?
Increased renal perfusion and output = increased Cl for some drugs
What remains unchanged during pregnancy w/ regards to distribution?
Hepatic blood flow
Effect of renal disease on distribution
- Hypoalbuminemia w/ accumulation of endogenous substances that may compete for binding sites
- Decreased binding of acidic drugs
- Ex: naproxen => increased Vd and t1/2
- Ex: phenytoin fraction unbound increases 2-3-fold partly due to decreased binding sites (so doses must be adjusted)
Can we effectively alter distribution?
- Manipulation of pH (salicylates)
- If alter pH of urine to make more alkaline, can trap salicylates in urine to prevent re-absorption
- If you can alter the pH of blood, can alter the distribution of salicylates in tissues
- Chelators (deferoxamine)
- Use of antibody fragments (digoxin)
What is clearance and what is the formula?
- Clearance = unit of volume per unit of time
- Cl = Q * ER
- ER = (Cin - Cout) / Cin
Factors affecting elimination
- Environmental/ social (smoking, alcohol, diet)
- Age
- Gender
- Disease
- Pregnancy
- Genetics
Smoking effect on elimination
- Induction of CYP P450 isoenzymes
- Ex: theophylline -> Cl increases and t1/2 decreases causing serum levels to fall => therapeutic failure
- Second-hand smoke is sufficient to induce enzymes
- NABQI formed from acetaminophen may exceed glutathione stores
- Smoking + malnutrition + alcohol = increased acetaminophen toxicity
Alcohol effect on elimination
- Acute effects = inhibition of oxidative metabolism immediately after ingestion
- Chronic effects = enzyme induction = “metabolic tolerance” (clearance of drugs such as warfarin, meprobamate, and phenytoin increases)
- Cirrhosis -> may decrease clearance; however, b/c of enzyme induction no changes may be seen until shunting occurs
- Shunting: hepatic damage leads to obstruction of normal blood flow
Age effect on elimination
- Influences hepatic function
- Hepatic blood flow decreases 0.5-1.5% per year after age 25
- Effect on drug metabolism is unclear; however, metabolism of high extraction drugs has been shown to decrease (ex: propranolol) => increased risk for poisoning
- Renal blood flow and function also decrease w/ age, as does CrCl, and dose/dosing interval of renally cleared drugs must be adjusted
Describe the effect of pregnancy on elimination
- Increased estrogen/ progesterone levels may exaggerate sex differences
- Estrogen -> inhibits oxidative metabolism and has cholestatic effects (risk for cholecystitis in pregnancy => impaired hepatic elimination of biliary excreted drugs)
- Progesterone -> induces microsomal enzymes and may increase clearance of some drugs
- Renal blood flow increased => increased renal clearance
- Caffeine, diazepam, and metoprolol metabolism may be decreased
- Metoprolol may have an increase in half-life
- Note: adjustments made on an individual basis
Can we effectively alter metabolism?
- Induction of metabolism
- Increase metabolic elimination of a poison (ex: rifampin = inducer of P450)
- Inhibition of metabolism
- Decrease production of a toxic metabolite (ex: cimetidine = inhibitor of P450)
Describe the steps of renal excretion
- Glomerular filtration (non-saturable process)
- Tubular secretion (saturable)
- Passive tubular reabsorption (non-charged, lipid soluble compounds)
Can we effectively alter excretion?
- Manipulation of pH (ion trapping; ex: salicylates)
- Chelators (deferoxamine)
- Multiple-dose activated charcoal
- In the gut, activated charcoal almost works like dialysis b/c it causes the drug to be reabsorbed into the gut & then eliminated
- Extracorporeal devices
Describe excretion in breast milk
- Toxic material may be passed from mother to infant
- Excretion occurs by simple diffusion
- pH 6.5, ion trap for basic compounds
- Differences in affinity to serum proteins vs. milk proteins affect excretion
- Drugs w/ longer t1/2 will have greater opportunity to be excreted in milk (ex: diazepam)
- *In general, not many drugs accumulate in breast milk & amount that transfers to breast milk is small
What are toxidromes?
- Group of signs and sx associated w/ a particular agent or toxin
- Frequent repeated assessment needed
- Individual patient’s response (clinical manifestation) more variable
- “Classic” case doesn’t always occur
- Monitoring of vital signs important to identify patterns of changes after intervention
