Lecture 1 - Toxicology & Biotransformation Flashcards
ADME
Absorption
Distribution
Metabolism
Excretion
Metabolism and Excretion make up ________
Elimination
What are the 2 types of kinetics involved in elimination?
- Linear kinetics
- Capacity-limited kinetics
Bioavailability
The amount of drug that enters the circulation and is able to have an active effect
First-pass effect
- the concentration of the drug is greatly reduced before it enters the circulation
- drug heads to the liver first via the hepatic portal vein before entering circulation
Half-life
The time it takes for the drug to be reduced by 50%
AUC
area under the curve
Michaelis menten kinetics is an example of _____-____ kinetics
capacity-limited
Toxicokinetics vs. Pharmacokinetics:
The pharmacodynamic effect is _____
toxic
Toxicokinetics vs. Pharmacokinetics:
Dosing information is ?
lacking or inaccurate
**you don’t always know the dose, you just know it’s too much
Toxicokinetics vs. Pharmacokinetics:
PK and PD in these circumstances is usually ___ ____
not known
Toxicokinetics vs. Pharmacokinetics:
Drugs may be _______
illegal, unlicensed, untested compounds (street drugs)
Toxicokinetics vs. Pharmacokinetics:
Drugs may be used in ___ ___ ___ combinations
never studied before
It’s important to know ____ of admin for OD to think about absorption rates
ROUTE
What does absorption depend on?
- rate and extent
- route of admin
- transport mechanism (MW, solubility, polarity, ionization, lipid solubility)
What are xenobiotic characteristics that affect GI absorption?
- Physicochemical properties, dosage forms, dissolution profiles
- Presystemic elimination
Xenobiotic
means that it’s foreign to the system
What are patient 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 pregnancy affect absorption?
- Increased gastric emptying time (30-50%)
- Decreased intestinal motility
- Increased intestinal blood flow (increases absorption)
- Increased gastric pH and buffer capacity
Does pregnancy increase or decrease absorption?
Tendency towards increased absorption, therefore the pregnant woman 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
How can we decrease bioavailability?
- Gastric emptying (emesis, gastric lavage, increase in intestinal motility)
- Administration of activated charcoal (direct intervention on absorption process)
When is gastric emptying useful?
- only useful when we know for sure that the exposure is massive and the drug is still in the stomach
- airways have to be protected
When is activated charcoal good?
- used 1 hour after exposure
- very effective, but only studied in healthy volunteers who have not taken that high of doses
- relatively safe
What does a large Vd indicate?
that the xenobiotic resides outside the plasma compartment. in OD it can be used to estimate a max plasma concentration when the dose is known
Albumin primarily binds ____ compounds
acidic
Where is albumin
in plasma
alpha 1 acid glycoprotein primarily binds _____ compounds
basic
Anything that alters _____ will alter the free fraction available and can slow down or prevent absorption
binding
Normal range of albumin
35-50 g/L
Normal range of alpha-1 acid glycoprotein
0.4-1 g/L
What factors affect distribution?
- membrane diffusion principles
- affinity for plasma and tissue proteins
- acid-base status of the patient
- physiological barriers
- patient characteristics (obesity, age, pregnancy, disease)
How does obesity affect lipophilic drugs?
- increased Vd
- serum levels will decrease
- may decrease toxicity
How does obesity affect hydrophilic drugs?
- decreased Vd
- serum levels will increase
- may increase toxicity
How does increase in body fat affect Vd?
increases Vd for lipophilic drugs (ex. diazepam)
How does decrease in total body water affect Vd?
decreases Vd for hydrophilic drugs (ex. aminoglycosides)
How does a decrease in plasma albumin affect binding?
decrease in binding = increase in free fraction of drug = increase in toxicity
(ex. phenytoin)
Pregnancy:
How does hypoalbuminemia affect binding?
decreases binding of acidic drugs (salicylic acid, sulphonamides, phenytoin)
Pregnancy:
How does increase in plasma volume affect Vd?
increase in Vd for many drugs (ex. increase dose for aminoglycosides)
Pregnancy:
How does increased cardiac output affect clearance?
increase renal perfusion and output which increases clearance for some drugs
Does pregnancy affect hepatic blood flow?
nope
Hypoalbuminemia decreases binding of _____ drugs
acidic
ex. naproxen (hypoalbuminemia increases Vd and t1/2)
How does hypoalbuminemia affect phenytoin?
phenytoin fraction unbound increases 2-3 fold partly due to decreased binding sites (phenytoin doses must be adjusted)
Do phenytoin doses need to be adjusted for hypoalbuminemia?
Yes
How can we alter distribution of drugs??
- Manipulation of pH (salicylates)
- Chelators (deferoxamine)
- Use of antibody fragments (digoxin)
What are the clearance organs?
liver, kidney, lungs
Define clearance
unit of volume per unit of time (ex. mL/min)
What is the formula for clearance?
Cl = Q x ER
Q = blood flow ER = extraction ratio
Formula for extraction ratio
ER = (Cin-Cout)/Cin
What factors affect elimination?
1) Environmental/social (smoking, alcohol, diet)
2) Age (ex. renal fcn decreases w old age)
3) Gender (ex. metabolic capacity differences)
4) Disease
5) Pregnancy
6) Genetics
Smoking induces what isoenzymes?
cytochrome P450
How does smoking affect Theophylline?
- Clearance increases
- Half life decreases
- Serum levels fall leading to therapeutic failure
- *Smoking makes theophylline ineffective
Is second-hand smoke enough to induce enzymes?
Yes - common in children of smokers
How does smoking affect NABQI (formed from acetaminophen) ?
May exceed glutathione stores
What does Smoking + Malnutrition + Alcohol = ?
Increased acetaminophen toxicity
What are the acute effects of alcohol?
Inhibition of oxidative metabolism immediately after ingestion.
**In acute situations, the risk of toxicity is not that high chronic alcohol consumption is what leads to toxicity.
Describe chronic effects of alcohol
Enzyme induction - “metabolic tolerance” which means that the clearance of drugs such as warfarin, meprobamate and phenytoin increases
Describe cirrhosis and alcohol
may decrease clearance, however, because of enzyme induction no changes may be seen until shunting occurs
Describe shunting and alcohol
hepatic damage leads to obstruction of normal blood flow
How does age influence hepatic function?
- influences hepatic function - hepatic blood flow decreases 0.5 - 1.5% per year after age 25
- the effect on drug metabolism is unclear, however the metabolism of high extraction drugs has been shown to decrease (e.g. propranolol)
- if a drug decreases then you increase risk for poisoning
Renal blood flow and function ____ with age
decrease
Creatinine clearance decreases with ___
age
Pregnancy:
Increased _____ levels may exaggerate sex differences
estrogen/progesterone
Pregnancy:
What does estrogen do?
inhibits oxidative metabolism
Pregnancy:
Estrogen has _____ effects (a risk for cholecystitis in pregnancy - impaired hepatic elimination of biliary excreted drugs)
cholestatic
Pregnancy:
Progesterone induces microsomal enzymes, and thus may increase ______ of some drugs
clearance
Pregnancy:
Renal blood flow is ______
increased
*therefore renal clearance is increased
Pregnancy:
Caffeine metabolism may be ______
decreased
Pregnancy:
Diazepam metabolism may be _____
decreased
Pregnancy:
Metoprolol metabolism may be ______ with an increase in half-life
decreased
Describe the oxidative reaction of P450
SH + NADPH + H+ + O2 = SOH + NADP+ + H2O
What enzyme is involved in the following drug substrates:
- Analgesics (codeine)
- Antiarrhythmics
- Antipsychotics
- B-blockers
- SSRI’s
- TCAs
CYP 2D6
What enzyme is involved in the following drug substrates:
- Antidiabetic agents
- Warfarin
- Phenytoin
- NSAIDs, Celecoxib
CYP 2C9
What enzyme is involved in the following drug substrates:
- Antidepressants
- Clopidogrel
- Diazepam
CYP 2C19
What enzyme is involved in the following drug substrates:
- Cyclophosphamide
- Efavirenz
CYP 2B6
What enzyme is involved in the following drug substrates:
- Cisplatin
- Acetaminophen
Glutathione S-transferase
What enzyme is involved in the following drug substrates:
- Azathioprine
- Mercaptopurine
Thiopurine S-methyltransferase
What enzyme is involved in the following drug substrates:
- Isoniazid
- Sulfonamides
N-acetyltransferase
What enzyme is involved in the following drug substrates:
-Irinotecan
Glucuronosyltransferases
Give an example of inducing metabolism
increasing the metabolic elimination of a poison (ex. rifampin is an inducer of P450)
Give an example of inhibiting metabolism
decreasing the production of a toxic metabolite (ex. cimetidine is an inhibitor of P450)
Why is altering metabolism not a very effective intervention in an acute OD ?
because it takes some time to work
What is the treatment of acetaminophen OD ?
1) Give SH groups (i.e. N-Acetyl-Cysteine)
2) Slow the rate of NABQI formation: P450 inhibitor (ex. cimetidine)
Describe the parts of renal excretion
- Glomerular filtration (non-saturable process)
- Tubular secretion (saturable)
- Passive tubular reabsorption (non-charged, lipid soluble compounds)
What is a normal CrCl?
> 90 mL/min
How can we alter excretion?
- Manipulation of pH (ion trapping or salicylates)
- Chelators (deferoxamine)
- Multiple-dose activated charcoal
- Extracorporeal devices (ex. dialysis)
How does excretion into breast milk occur?
occurs by simple diffusion
Excretion in breast milk: pH of ____ ion trap for basic compounds
6.5
What affects excretion in breast milk?
differences in affinity to serum proteins vs. milk proteins
Drugs with _____ half-life will have greater opportunity to be excreted in milk
longer
