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Year 4 - Toxicology > 1 - Toxicokinetics > Flashcards

1 - Toxicokinetics Flashcards

1
Q

What to consider in regards to absorption?

A
  • Rate and extent
  • Route of administration
  • Transport mechanism (depends on characteristics of drug – MW, solubility, polarity, ionization, lipid solubility)
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2
Q

Define xenobiotic

A

External to the body

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3
Q

Xenobiotic characteristics that affect GI absorption

A
  • Physicochemical properties of drug, dosage forms, dissolution profiles
  • Pre-systemic elimination
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4
Q

Pt characteristics that affect GI absorption

A
  • 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
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5
Q

How does GI motility affect GI absorption?

A
  • 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
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6
Q

Describe absorption changes in pregnancy

A
  • 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
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7
Q

Can we effectively alter GI absorption?

A
  • Can decrease bioavailability
    • Gastric emptying (emesis, gastric lavage, increase in intestinal motility)
    • Administration of active charcoal (direct intervention on absorption process)
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8
Q

What is distribution?

A

Reversible transfer from systemic circulation to peripheral tissue compartments

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9
Q

Vd formula

A

Vd = F*dose / Co

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10
Q

What does a large Vd mean?

A
  • 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
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11
Q

Which protein primarily binds acidic compounds?

A

Albumin

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12
Q

Which protein primarily binds basic compounds?

A

Alpha 1-acid-glycoprotein

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13
Q

Factors affecting distribution

A
  • Membrane diffusion principles
  • Affinity for plasma and tissue proteins
  • Acid-base status of pt
  • Physiological barriers
  • Pt characteristics (obesity, age, pregnancy, disease)
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14
Q

Effect of obesity on Vd and serum concentration for lipophilic and hydrophilic xenobiotics

A
  • Lipophilic xenobiotics -> increased Vd, decreased serum levels, and may have decreased toxicity
  • Hydrophilic xenobiotics -> decreased Vd, increased serum levels, and may have increased toxicity
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15
Q

Significance of increase in body fat for Vd

A

Increase in Vd for lipophilic xenobiotics (ex: diazepam)

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16
Q

Significance of decrease in total body water for Vd

A

Decrease in Vd for hydrophilic xenobiotics (ex: aminoglycosides)

17
Q

Significance of decrease in plasma albumin for Vd

A

Decrease in binding = increase in Fu = increase in toxicity (ex: phenytoin)

18
Q

How does hypoalbuminemia affect distribution in pregnancy?

A

Decrease binding of acidic drug (salicylic acid, sulfonamides, phenytoin)

19
Q

How does increased plasma volume affect distribution in pregnancy?

A

Increased Vd for many drugs (ex: increase dose for aminoglycosides)

20
Q

How does increased cardiac output affect distribution in pregnancy?

A

Increased renal perfusion and output = increased Cl for some drugs

21
Q

What remains unchanged during pregnancy w/ regards to distribution?

A

Hepatic blood flow

22
Q

Effect of renal disease on distribution

A
  • 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)
23
Q

Can we effectively alter distribution?

A
  • 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)
24
Q

What is clearance and what is the formula?

A
  • Clearance = unit of volume per unit of time
  • Cl = Q * ER
  • ER = (Cin - Cout) / Cin
25
Q

Factors affecting elimination

A
  • Environmental/ social (smoking, alcohol, diet)
  • Age
  • Gender
  • Disease
  • Pregnancy
  • Genetics
26
Q

Smoking effect on elimination

A
  • 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
27
Q

Alcohol effect on elimination

A
  • 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
28
Q

Age effect on elimination

A
  • 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
29
Q

Describe the effect of pregnancy on elimination

A
  • 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
30
Q

Can we effectively alter metabolism?

A
  • 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)
31
Q

Describe the steps of renal excretion

A
  • Glomerular filtration (non-saturable process)
  • Tubular secretion (saturable)
  • Passive tubular reabsorption (non-charged, lipid soluble compounds)
32
Q

Can we effectively alter excretion?

A
  • 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
33
Q

Describe excretion in breast milk

A
  • 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
34
Q

What are toxidromes?

A
  • 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

Year 4 - Toxicology (22 decks)

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