Lecture 9 Flashcards
Pharmacodynamics: therapeutic index (25 cards)
What is the response to medication influenced by?
- genetics
- disease state
- environment
What must we do first to determine interpatient variability in response to medications?
must first set an endpoint (ex. endpoint for analgesic would be pain relief)
What can we use phase II clinical trial data?
- can evaluate the number of patients that experience the endpoint from each dose of the drug, plot this data on a frequency distribution curve
What is the average effective dose?
peak of the frequency distribution curve
- dose required to produce a response in 50% of the population
- often used as the initial dose for therapy
When is it okay to use the ED 50 as a starting dose?
- when the drug has a wide therapeutic range bc there will be a decreased risk of adverse events
How do we dose drugs with a narrow therapeutic range?
-should have dose titrated (start low and increase slowly until the desired response is achieved)
What are two negative responses to drugs?
- toxicity and death
How are these kind of responses tested?
- acute (short term) and chronic (6mo-2yr) animal testing used to determine the doses that produce toxicity or death
What is the TD50?
- dose in which 50% of animals experience drug toxicity
- expressed in mg drug/kg
What is the LD50?
- 50% of animals die
- expressed in mg drug/kg
What is the therapeutic index?
-indicator of a drugs safety
- ration of the TD/LD50 to the ED50
TI=TD50 (or LD50)/ED50
What does a high therapeutic index indicate?
- drug considered safe
- have large space between the dose that produces a therapeutic response vs the dose that produces a toxic/lethal response
What does a low therapeutic index indicate?
- drug considered unsafe
What factors affecting interpatient variation in response?
- body weight and composition
- genetics
- gender
- race
- kidney disease
- liver disease
- environment
How does body weight and composition cause interpatient variability?
- drug dose adjusted for the body weight of the patient (mg drug/kg body) to compensate for size differences
- % body fat can change distribution of the drug so obese patients may respond different
- clinicians use body surface area (BSA) bc it accounts for body composition
What is the normal BSA for an adult?
- 1.73m2
- so drugs doses as mg/1.73m2
What is pharmacogenetics?
- study of the effect of DNA sequence variation to the clinical response of drugs
How can genetics influence interpatient variability?
- SNPs (change in DNA sequence involving a single nucleotide like A, T, C, or G)
- exist in genes that regulate drug metabolism, transport, and receptors
- dose of some drugs adjusted based on patients phenotype
Examples of differences in drug response with gender
- alcohol metabolism is slower in females
- some opioids more effective in women so require lower doses
- certain drugs used to treat irregular heartbeat cause prolongation of the QT interval on the electrocardiogram of women (at risk for fatal cardiac dysrhythmia)
How can race influence interpatient variability?
- race is difficult to define so hard to relate the two
- people can be mixed race which also makes it hard
Example of race causing reaction variability
- rosuvastatin (cholesterol lowering drug) concentrates 2-3 times more in Asians which can lead to drastic side effects or death so dose should be decreased
How can kidney disease influence interpatient variability?
- kidney is primary organ responsible for drug elimination and disease leads to significantly decreased excretion
- decreased drug excretion = increase in half life for drugs renally excretion
- hepatic and intestinal drug metabolism also decreased in renal failure
- also leads to increased oral bioavailability
- dosage must be decreased
How can liver disease influence interpatient variability?
- primary organ responsible for metabolism
- liver disease = decreased hepatic drug metabolism
- half live may be significantly increased in patients with liver disease
How can the environment influence interpatient variability?
- can change the way patients respond to drugs
- exposure can be voluntary (smoking, alcohol etc) or involuntary (pesticides etc)
