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Pharmacology > Lecture 6: Factors affecting ADME > Flashcards

Lecture 6: Factors affecting ADME Flashcards

1
Q

What age groups are more sensitive to certain drugs

A

Very young and very old

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2
Q

Why do very young individuals react differently to certain drugs

A
  1. BBB is not fully developed (opioids)
  2. Liver function is not fully developed (opioids, chlroamphenicol)
  3. Renal excretion is less
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3
Q

Why do elderly animals react differently to certain drug

A
  1. Slower gastric emptying
  2. Decreased gastric secretion
    3, increase in total body fat
  3. Decrease in muscle mass
  4. Decrease in renal excretion but no increase in serum creatinine
  5. Decrease in hepatic metabolism but no decrease in conjugations
  6. Decrease in renal functions precedes the decline of liver functions
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4
Q

How do fevers, infections and inflammation impact drug metabolism

A

Pro-inflammatory cytokines increase capillary permeability, resulting in increased extravascular distribution of drugs, increased Vd or decreased Vd by binding to inflammatory exudates

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5
Q

How does liver disease modify drug metabolism

A

Active and inactive cirrhosis, viral and drug induced hepatitis, and chronic and active hepatitis

Overall: drug is higher in concentration and longer lasting

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6
Q

How does renal impairment impact drug metabolism

A

Decrease GFR—> can be measured by measuring creatinine clearance

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7
Q

What can be measured to indicate renal impairment

A

Creatinine- decrease creatinine clearance= renal impairment

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8
Q

How does meningitis, encephalitis impact drug metabolism

A

Increased penetration into the CNS

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9
Q

What route of administration leads to the greatest species variation in absorption

A

PO

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10
Q

Herbivores tend to maintain a ___ gastric pH than non-herbivores

A

Higher

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11
Q

How does a greater gastric pH in herbivores impact absorption of both weak acids and weak bases

A

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

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12
Q

What is the primary cause of differences in drug distribution

A

Fat content

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13
Q

Fat soluble drugs will exist in higher concentrations in target tissues from animals with ___body fat

A

Lower- because drugs that migrate into fatty tissues will become inactive

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14
Q

Distribution example: would you expect a mixed breed (more fat content) or greyhound (leaner) to have a greater L/kg dose

A

Mixed breed because greater fat content would cause more of the drug to enter fatty tissue and less to act on CNS

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15
Q

Which part of pharmacokinetics has the greatest species variability

A

Metabolism

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16
Q

Variability in metabolism is a result from differences in what

A

Liver enzyme function

17
Q

Metabolism toxicity example: what drug do greyhounds struggle to metabolism at high doses

A

Thiobartbituates due to deficits in oxidative enzymes

Thiobarbituates are very lipid soluble and they lack enzyme so at great risk of toxicity

18
Q

What are thiobarbituates used in

A

Euthanasia

19
Q

Thiopental can be used in anesthesia what implications does this have in greyhounds. What is the solubility

A

Prolonged recovery time, is lipid soluble so very readily absorbed and therefore remains in body at high concentrations

20
Q

Metabolism toxicity example: What enzyme are cats deficient in that is necessary for phase II metabolism

A

Glucuronidation

21
Q

What does a deficit in Glucuronidation in cats lead to

A
  1. Glutathione depletion
  2. Increased cellular oxidative stress
  3. Hepatoxicity
  4. Increased Fe3+ to Fe2+ in heme
  5. Leads to decreased O2 supply by RBC’s and hemolysis
22
Q

Why is acetaminophen/tylenol toxic to cats

A

Requires Glucuronidation, which then causes reduced O2 to be carried to cell and increase in free radial that causes oxidative stress, hepatotoxicity

23
Q

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

A

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

24
Q

What do excretion rates depend on

A

Proximal and distal convoluted tubule of the kidney

25
Q

Why are loop diuretics like furosemide ineffective in snakes

A

Lack LOH

26
Q

What gene do collies lack and therefore have reduced excretion of what drug

A

Lack MDR1 for P-gp which causes reduced excretion of avermectins from CNS

27
Q

What is the result of acute avermectin toxicity in collies

A

CNS depression, ataxia, death

28
Q

What receptors do xylazine act through

A

Alpha2-adrenergic

29
Q

In sheep what does xylazine do

A

Causes hypoxemia, marked pulmonary edema and death due to acute inflammatory damage to pulmonary endothelium and type I alveolar cells

30
Q

What genetic variation causes sheep to suffer hypoxemia, pulmonary edema and death from xylazine

A

Variant alpha2-adrenergic receptor in brainstem of sheep called alpha2D

31
Q

What does dexmedetomidine do to sheep and goats

A

Causes hypoxemia, marked pulmonary edema and death

32
Q

In what species do very low doses of morphine cause excitation and dysphoria

A

Horses

33
Q

What are some postulated mechanisms that cause excitation and dysphoria in horses when exposed to high levels of morphine

A

Release of ACh, release of histamine and levels of opioid receptors in the brain

34
Q

Is GFR related to BW or BSA

A

BSA

35
Q

BSA~ ____

A

(BW)^b

36
Q

In BSA equation what does b=

A

0.67

**for dogs >10kg

37
Q

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

A

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

38
Q

Calculate the dose based upon absolute surface area:

BW=12kg (given)
Constant=0.1
B=0.67
Dose=120mg/m2

A

Surface (dose)= (BW)^b (0.1)

=(12)^0.67 (0.1)= 0.528

Dose(12kg)= 0.528m^2 (120mg/m^2)= 63mg

Pharmacology (14 decks)

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