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