Lecture 6: Factors affecting ADME Flashcards
What age groups are more sensitive to certain drugs
Very young and very old
Why do very young individuals react differently to certain drugs
- BBB is not fully developed (opioids)
- Liver function is not fully developed (opioids, chlroamphenicol)
- Renal excretion is less
Why do elderly animals react differently to certain drug
- Slower gastric emptying
- Decreased gastric secretion
3, increase in total body fat - Decrease in muscle mass
- Decrease in renal excretion but no increase in serum creatinine
- Decrease in hepatic metabolism but no decrease in conjugations
- Decrease in renal functions precedes the decline of liver functions
How do fevers, infections and inflammation impact drug metabolism
Pro-inflammatory cytokines increase capillary permeability, resulting in increased extravascular distribution of drugs, increased Vd or decreased Vd by binding to inflammatory exudates
How does liver disease modify drug metabolism
Active and inactive cirrhosis, viral and drug induced hepatitis, and chronic and active hepatitis
Overall: drug is higher in concentration and longer lasting
How does renal impairment impact drug metabolism
Decrease GFR—> can be measured by measuring creatinine clearance
What can be measured to indicate renal impairment
Creatinine- decrease creatinine clearance= renal impairment
How does meningitis, encephalitis impact drug metabolism
Increased penetration into the CNS
What route of administration leads to the greatest species variation in absorption
PO
Herbivores tend to maintain a ___ gastric pH than non-herbivores
Higher
How does a greater gastric pH in herbivores impact absorption of both weak acids and weak bases
Increased pH, more basic environment, therefore weak acids are poorly absorbed because become ionized whereas weak bases are less ionizable and are more readily absorbed
What is the primary cause of differences in drug distribution
Fat content
Fat soluble drugs will exist in higher concentrations in target tissues from animals with ___body fat
Lower- because drugs that migrate into fatty tissues will become inactive
Distribution example: would you expect a mixed breed (more fat content) or greyhound (leaner) to have a greater L/kg dose
Mixed breed because greater fat content would cause more of the drug to enter fatty tissue and less to act on CNS
Which part of pharmacokinetics has the greatest species variability
Metabolism
Variability in metabolism is a result from differences in what
Liver enzyme function
Metabolism toxicity example: what drug do greyhounds struggle to metabolism at high doses
Thiobartbituates due to deficits in oxidative enzymes
Thiobarbituates are very lipid soluble and they lack enzyme so at great risk of toxicity
What are thiobarbituates used in
Euthanasia
Thiopental can be used in anesthesia what implications does this have in greyhounds. What is the solubility
Prolonged recovery time, is lipid soluble so very readily absorbed and therefore remains in body at high concentrations
Metabolism toxicity example: What enzyme are cats deficient in that is necessary for phase II metabolism
Glucuronidation
What does a deficit in Glucuronidation in cats lead to
- Glutathione depletion
- Increased cellular oxidative stress
- Hepatoxicity
- Increased Fe3+ to Fe2+ in heme
- Leads to decreased O2 supply by RBC’s and hemolysis
Why is acetaminophen/tylenol toxic to cats
Requires Glucuronidation, which then causes reduced O2 to be carried to cell and increase in free radial that causes oxidative stress, hepatotoxicity
Metabolism toxicity example 3: Neuromuscular agents are metabolized by plasma pseudocholinesterase (succinylocholine and atracurium). Which species have greater amounts of pseudocholinesterase and which don’t and what is the implication
Horses and pigs have greater levels of pseudocholinesterase therefore require greater doses of NMJ inhibitory agents because pseudocholinesterase metabolizes drug rapidly
Dogs and cows have less pseudocholinesterase and therefore require very lose doses of NMJ blocking drugs
What do excretion rates depend on
Proximal and distal convoluted tubule of the kidney
Why are loop diuretics like furosemide ineffective in snakes
Lack LOH
What gene do collies lack and therefore have reduced excretion of what drug
Lack MDR1 for P-gp which causes reduced excretion of avermectins from CNS
What is the result of acute avermectin toxicity in collies
CNS depression, ataxia, death
What receptors do xylazine act through
Alpha2-adrenergic
In sheep what does xylazine do
Causes hypoxemia, marked pulmonary edema and death due to acute inflammatory damage to pulmonary endothelium and type I alveolar cells
What genetic variation causes sheep to suffer hypoxemia, pulmonary edema and death from xylazine
Variant alpha2-adrenergic receptor in brainstem of sheep called alpha2D
What does dexmedetomidine do to sheep and goats
Causes hypoxemia, marked pulmonary edema and death
In what species do very low doses of morphine cause excitation and dysphoria
Horses
What are some postulated mechanisms that cause excitation and dysphoria in horses when exposed to high levels of morphine
Release of ACh, release of histamine and levels of opioid receptors in the brain
Is GFR related to BW or BSA
BSA
BSA~ ____
(BW)^b
In BSA equation what does b=
0.67
**for dogs >10kg
Example drug conversion for chemotherapy: 100mg of chemo drug A should be used for 24kg dog, how much should be used for 12kg dog. Drug dose is 120mg/m2
Dose= (BSA for Animal of interest)/ (BSA of known dog dose)^b
(12/24)^0.67= 0.63mg
**NOT 1/2 OF 100MG CUZ THAT WOULD BE 50MG
Calculate the dose based upon absolute surface area:
BW=12kg (given)
Constant=0.1
B=0.67
Dose=120mg/m2
Surface (dose)= (BW)^b (0.1)
=(12)^0.67 (0.1)= 0.528
Dose(12kg)= 0.528m^2 (120mg/m^2)= 63mg
