Lecture 6 - Factors affecting ADME Flashcards
What is different about older animals in regards to their GI tract that makes them more susceptible to some drugs?
Slower gastric emptying
Decreased gastric secretion
What is different about older animals in regards to their body composition that makes them more susceptible to some drugs?
Increase in total body fat
Decrease in muscle mass
What is different about older animals in regards to their renal function that makes them more susceptible to some drugs? How does this differ from other types of renal disease?
Decrease in renal excretion - do not see an increase serum creatinine
What is different about older animals in regards to their hepatic function that makes them more susceptible to some drugs?
Decrease in metabolism - but no decrease in conjugations
What comes first in older animals, hepatic or renal issues?
Renal
What three components of disease effect drug metabolism greatly?
Fever + Infections + Inflammation
What mechanisms occur with disease that cause a change in drug metabolism?
Pro-inflammatory cytokines increase capillary leakage
Increased extravascular distribution of drugs
What happens to Vd with an increased extravascular distribution of drugs?
Increases
What causes a decrease in Vd in regards to illness?
Binding to inflammatory exudates
What changes to drug metabolism do you see with meningitis or encephalitis?
Increased penetration into the CNS
What is a major characteristic of renal impairment?
Decrease in creatinine clearance
Why do you see such a difference in absorption per os between species?
Due to the differences in pH’s of the GI tract
What happens to drugs that are weak acids within a herbivores stomach?
they have a higher gastric pH (more basic) therefore weak acid drugs are going to be ionized and trapped within the lumen of the GI tract = decreased absorption
What changes in the movement of fat soluble drugs in animals with lower body fat?
Exist at higher concentrations at target tissues (Vd will be lower)
What is a big factor that effects distribution of a drug?
Fat content of an animal
What is a big factor when it comes to variability in metabolism between species?
Liver enzyme function
What is different about greyhounds in regards to liver function?
Lacking enzymes needed for thiobarbituates, leading to prolonged recovery times
What are cats missing in their phase II pathways that effect drug metabolism?
Deficits in glucuronidation enzymes
What happens when a cat is deficient in glycyronidation enzymes?
Glutathione depletion Increased cellular oxidative stress Hepatotoxicity Increase Fe3+ to Fe2+ Decrease O2 supply
What part of kidney do excretion rates depend on the most?
Proximal + Distal convoluted tubules
What is the biggest culprit for difference between species when it comes to excretion?
Molecular differences
What occurs with ruminants and xylazine?
Sheep have a variant alpha2-adrenergic receptor in their brain stem, therefore the use of this drug can lead to
Hypoxemia + Pulmonary edema + Death
What animals, given in lecture, experience morphine mania?
Dogs + Cats + Horse
Which of the three animals discussed in lecture are most sensitive to morphine?
Horses
What side effects are seen in dogs when given morphine?
EEG patterns of excitation
What symptoms do cats experience when given morphine?
Clinical signs of excitation
What symptoms do horses experience when given morphine?
Clinical signs of excitation + dysphoria
What are the possible reasons for morphine mania?
Release of acetylcholine
Release of histamine
Levels of opioid receptors in the brain
What is allometry?
Correlation of physiological functions across body sizes
What is allometry used for clincally?
To determine drug conversions (especially for chemotherapy)
What is a very important application of dose converstion?
Gives you a starting point for clinical trails
Why are young animals more sensitive to certain drugs?
BBB not fully developed
Liver not fully functional
Renal excretion not as great
