Module 9: Therapeutic Index Flashcards
What is interpatient variability in response to a drug?
- Why is this important?
Response to medication is variable between patients
- Every patient’s response must be evaluated to ensure an adequate therapeutic response (i.e. toxic effect, intermediate effect, no effect)
What is the response to medication influence by? (3)
- Provide an example for each
Genetics
- Gender
Disease state
- Immune disease
Environment
- Smoking/alcohol
How is interpatient variability determined? (3)
1) Clinical trials
2) Dosing implications
3) Toxic and lethal doses
How do clinical trials determine interpatient variability?
Use of data from phase II clinical trials to establish dose-response relationships over a range of doses
1) Set an endpoint to measure (e.x. pain relief)
2) Evaluate number of patients experiencing pain relief
3) Plot data on frequency distribution curve
4) ED50 (avg. effective dose) is at the peak of this curve
- The dose required to produce a response in 50% of the population
What is ED50 often used for?
Initial dose for therapy
What are dosing implications we must consider?
ED50 as the starting dose, this may be too much for some patients and not enough for others
- Many patients will require dose adjustments to optimize efficacy and minimize adverse events
When is it okay to use ED50 as a starting dose? Why?
When the drug has a wide therapeutic range
- If the drug has a wide therapeutic range there will be a decreased risk of adverse events
How do we dose drugs that have a narrow therapeutic range?
Drugs with a narrow therapeutic range should have their dose titrated (start low and increase slowly until the desired response is achieved)
T/F
Responses to medication can be quite variable
- It is more important to adjust dosing based on the patient’s response rather than simply using a dosing reference
True
Why is it important to determine toxicity and lethal doses of drugs?
- How do we do this?
We need to know the effects to prevent adverse effects and death
- Acute and chronic testing on animals
What is TD50?
The average toxic dose in which 50% of experimental animals die
How is TD50 and LD50 expressed?
mg drug/kg body weight
What is the therapeutic index an indicator of?
The drugs safety
How is the therapeutic index calculated?
By determining the ratio of TD50 or LD50
TI = TD50/ED50
TI = LD50/ED50
T/F
Drugs with a high therapeutic index are considered unsafe whereas those with a low therapeutic index are considered safe.
False
- Drugs with a high therapeutic index are considered SAFE whereas those with a low therapeutic index are considered UNSAFE.
T/F
Drugs that are safe have a small space in between the dose that produces a therapeutic response and the dose that produces a toxic or lethal response
False
Drugs that are safe have a LARGE space in between the dose that produces a therapeutic response and the dose that produces a toxic or lethal response
What are factors that affect interpatient variation in response?
- Body Weight and Composition
- Genetics
- Sex
- Race
- Kidney Disease
- Liver Disease
- Environment
How does body weight & composition affect interpatient variation?
We know that the response to medications is largely determined by the concentration of the drug in the body, with the higher concentrations giving a greater response
- Let’s give the same dose of drug to these two guys. What would you expect in terms of plasma concentration?
For many drugs, the dose is adjusted for the body weight of the patient (i.e. mg drug/kg body weight) in order to compensate for differences in size
Although body weight helps to normalize dose, what happens when two people have the same body weight but different body composition?
Percentage body fat can change the distribution of the drug so obese patients may respond differently. Clinicians often adjust the dose of drugs by body surface area (BSA) because this partially accounts for body composition as well
- Normal BSA for an adult is 1.73m^2 so some drugs are dosed as mg/1.73m^2.
How does genetics affect interpatient variation?
Pharmacogenetics is the study of the effect of DNA sequence variation to the clinical response of drugs
- Single Nucleotide Polymorphism (SNP, pronounced “SNIP”) is a change in DNA sequence that involves a single nucleotide (A,T,C or G)
- SNPs can exist in genes that regulate drug metabolism, drug transport or drug receptors
- Genetic variation such as SNPs can explain some of the intersubject variation in drug response
Doses of some drugs are adjusted based on a patient’s genotype (genetic makeup).
How does sex affect interpatient variation?
For many drugs the effect of sex is unknown, why?
- Until relatively recently, the majority of drug research was conducted in men
- In 1997 drug regulatory bodies (Health Canada and the US FDA) put pressure on drug companies to include women in trials of new drugs
A few differences between women and men that we know of in terms of variation in drug response are:
- Alcohol metabolism is slower in females.
- Certain opioids are more effective in women, therefore they require lower doses
- Certain drugs used to treat irregular heart beat cause prolongation of the QT interval on the electrocardiogram of women - This means it is more likely for women to have a fatal cardiac dysrhythmia
How does race affect interpatient variation?
The effect of race or ethnicity is difficult to relate to variability of drug response - One reason is that race is difficult to define
- Many people in our society are from an ethnically heterogeneous background so they cannot simply be categorized by a single race
There are some instances where generalizations are made by race because of convincing data
- For example, concentrations of the cholesterol lowering drug rosuvastatin are 2-3 times higher in Asian compared to Caucasian patients; This can (and has) led to drastic side effects and even death - Therefore doses of rosuvastatin should be decreased in Asian patients.
How does kidney disease affect interpatient variation?
The kidney is the primary organ responsible for drug elimination
- In patients with kidney disease, drug excretion is significantly decreased.
- Decreased drug excretion causes an increase in the half life for drugs that are renally excreted
Recent evidence also suggests that hepatic and intestinal drug metabolism is also decreased in renal failure.
- The net effect of renal failure is increased oral bioavailability and decreased excretion
Therefore, the dosage of many drugs must be decreased in patients with kidney disease.
How does liver disease affect interpatient variation?
The liver is the primary organ responsible for drug metabolism.
- Patients with liver diseases such as cirrhosis or hepatitis exhibit decreased hepatic drug metabolism.
- For drugs that are extensively metabolized, half life may be significantly increased in patients with liver disease
How does the environment affect interpatient variation?
- Examples
Environmental exposures can significantly change the way patients respond to drugs.
- Environmental exposure can be voluntary (smoking, alcohol, diet, exercise) or involuntary (environmental pesticides)
Examples:
- Cigarette smoke induces some drug metabolizing enzymes and can make some drugs less effective.
- Alcohol can exacerbate the toxicity of some other drugs.
- Exercise improves the actions of insulin.
- Some commonly used pesticides can induce CYPs and therefore decrease the response to drugs that are metabolized by CYP enzymes.
