Flashcards in Carlson Learning Objectives Exam 1 Deck (50):
What is the purpose of drug metabolism?
To eliminate the drug from the body. Does this by polarizing the active lipoidal drug.
What would happen if drug metabolism did not occur?
Uncontrolled, prolonged activity of the given drug
Other drugs may never be activated
Where does drug metabolism occur?
Hepatic microsomes located in the Smooth ER
Explain what causes renal elimination vs renal absorption
Renal elimination can only occur when the drug has been polarized and made water soluble.
If not, the drug will be re-absorbed.
How can renal absorption be avoided by some polar drugs?
Penicillin fits into the same transporter for uric acid; this means that Pe can be actively transported out of the renal system
Name the predominating biochemical reaction for phase II drug metabolism. Phase I?
Name the 4 outcomes of biotransformation
Active drug > inactive metabolite
Active dug >active metabolite >inactive metabolite
Prodrug >active matabolite>inactive metabolite
Active drug>toxic metabolite
What are two examples of drugs that can become toxic metabolites?
Acetaminophen in cats
Dscribe the first pass effect and what steps can be taken to avoid it
This is when a drug becomes metabolized before reaching the systemic circulation. Orally administered and IP administered drugs can have this fate. Give more orally or give via an alternate route.
What is the evolutionary basis for drug metabolism?
Animals just needed a generic way to eliminate non-nutritive compounds absorbed from the diet.
What animals are the best at metabolizing drugs? The worst?
Herbivores are the best. Been exposed to more xenobiotics.
Cats are the worst, poor glucouronidation.
What are some factors that affect biotransformation?
Plasma protein binding, hepatopathy, adipose sequestration, age and gender, hypothermia, lactation, etc.
What could decrease decrease an animals drug metabolism? What are ways to overcome that?
Animal could be on medication that inhibits microsomal enzymes or have a porto-systemic shunt
Give less of the drug or try a transdermal patch
What could increase an animals drug metabolism and what are ways to overcome that?
Taking medication that activates microsomal enzymes or the animal just genetically has an abundance of them.
You could give more of the drug or give via an alternate route.
What is the definition of pharmacogenomics?
Relationship between genetic elements and responses to drugs with emphasis placed on differences.
What are the three main mechanisms for pharmacogenetic differences?
Alterations in drug metabolism
Alterations in the target of the drug
Altered drug transport issues
Name three types of undesirable effects of altered drug metabolism:
Prolonged effect: Viagra (priapism)
Toxic effect: Acetaminophen in cats and isoniazid
Side effect: Opioids can act as stimulats in cats and horses as they inhibit the removal of dopamine from synapses.
Describe the mechanism and potential evolutionary basis for acetaminophen toxicity in cats
Cats are very poor at glucouronidation, because they lack the genes necessary.
Acetaminophen is also a phytoalexin, which is a plant derivative. Carnivores have no use for this
Name two types of alterations in drug metabolism that can lead to treatment failures:
Atropine in bovine: plasma esterases plus hepatic activity rapidly inactivate this
Lack enzyme needed for drug activation. Cats cannot convert primidone to phenobarbital
Describe two outcomes related to alterations of a drug target:
No activity of the drug: Fluoroquinolone antibiotics are inactive vs bacteria with an altered enzyme
Drug side effect: erythromycin can sporadically cause GI distress. Esp. motilinR subtype A
Describe the double edged sword of drug transportation:
Selective tissue distribution is good.
Toxic accumulation is bad.
What are the 5 overall outcomes of pharmacogenomic differences?
Unwanted side effect
Exploitable feature: some drugs that accumulate in CNS can be used to treat meningitis
Describe the pharmacologic basis for ivermectin toxicity in collies
Deletion mutation of mdr1 gene. Dogs that are homozygous for this mutation are affected. With this mutation the transporter does not work and ivermectin accumulates in the brain.
How do auto-active receptors present a pharmacologic problem?
Receptor mutation where the receptor is insensitive to the antagonist or inhibitor.
The reaction is always going, so the drug or inhibitor have no effect.
NEXT STUFF IS DAY'S STUFF
The % of receptors bound by a drug increases as the concentration of that drug increases
This is once all the receptors are bound by a drug, increasing conc of drug will have no effect
What is the dissociation constant?
KD = (DxR)/DR; it is the relationship between drug, receptor, and drug-receptor complex
Why is the dissociation contstant important?
It describes the drug concentration that is required to produce half the max occupancy of the receptor population
This is chemical attraction
What is the equation for affinity?
What does a high affinity mean?
This means the drug has a high affinity for the receptor, which means the DR will be high and will be a low dissociation constant
What is specificity?
This refers to the selectivity of the drug for a particular receptor
What are the three types of modulation of drug binding to receptors and what affect do they have?
1. Competitive inhibition of binding; Will increase the Kd
2. Non-competitive inhibition of binding; number of receptors available to be bound are reduced, but the Kd is unaffected
3. Allosteric modulation of binding; affinity for the first drug is changed
What is an agonist?
Produces the maximum response that can be elicited by those receptors
What is a partial agonist?
Produces a response, but is less than max that can be elicited by other agonists at the same receptors
What is an antagonist?
Binds to the receptor but does not activate the system. Competitively BLOCKS the activation.
The concentration required of a drug to produce 50% of that drug's max response
What is the main measure of a drug's potency? Is a high or low number more potent?
EC50; a low number indicates higher potency
What is the difference between Kd and EC50?
Kd: measures affinity
EC50: measures potency
What is the dose-response relationship?
% of patients that reach a clinically defined response at or below that dose
Dose required to elicit a response in 50% of population
Define therapeutic index. Is it better to be high or low?
LD50/ED50; Want a high therapeutic index
What is the standard safety margain?
This is the % by which the dose effective in 99% of the population must be increased to cause death in 1% of the population. ((LD1/ED99)-1)x100
What are the four ways a drug can cross a membrane?
Passive diffusion, facilitated diffusion, active transport, and pinocytosis
What are the three ways a drug can passively diffuse across a membrane?
1. Non-polar molecules diffuse across the lipid bilayer
2. Oil-water partition coefficient
3. pH and polarity
What does Ka stand for?
This is the association constant. It describes the constant relationship between the concentrations of H+, A, and HA
What is the definition of pKa?
This is the pH at which 50% of the molecule is protonated
What environment would be favorable for diffusion with a weak acid drug?
A low pH environment; has a lot of H that can cause HA formation.