Module 9 - Therapeutic Index

Question 1

Phases of determining interpatient variability

Answer 1

Phase 1 - evaluation of pharmacokinetics/dynamics and animal testing (20-100 health volunteers)

Phase 2 - short term trial to determine efficacy and side effects; dose-response is determined (300-500 with the disorder)

Phase 3 - efficacy is verified and long-term side effects are evaluated (500-500 with target disorder)

Phase 4 - post-marketing surveillance

Question 2

how do you determine interpatient variability in response to medications

Answer 2

set an endpoint
ex: analgesic drug, the endpoint would be pain relief

Question 3

ED50

Answer 3

is the dose required to produce a response in 50% of the population
- is often used as the initial dose for therapy
- the average effective dose (ED50) is at the PEAK of the frequency distribution curve

Question 4

where is the ED50 on a frequency distribution curve

Answer 4

the peak

Question 5

When is it okay to use the ED50 as a starting dose?

Answer 5

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.

Question 6

How do we dose drugs that have a narrow therapeutic range?

Answer 6

Drugs with a narrow therapeutic range should have their dose titrated (start low and increase slowly until the desired response is achieved).

Question 7

what happens if all patients are given the ED50 as a starting dose

Answer 7

some patients will have more drug than they need and other will not have enough

Question 8

Average Toxic dose (TD50)

Answer 8

is the dose in which 50% of animals experience drug toxicity

Question 9

Average lethal dose (LD50)

Answer 9

is the dose in which 50% of animals die

Question 10

How are TD50 and LD50 expressed

Answer 10

in mg drug/kg body weight

Question 11

therapeutic index

Answer 11

The therapeutic index is an indicator of a drug’s safety.
* The therapeutic index is calculated by determining the ratio of the TD50 or LD50 to the ED50.

Question 12

Therapeutic Index (TI) equations

Answer 12

TI = TD50/ED50
or
TI= LD50/ED50

Question 13

Drugs with a high therapeutic index

Answer 13

Drugs with a high therapeutic index are SAFE (low is unsafe)

• 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

Question 14

what are the factors affecting interpatient variation in response

Answer 14

1. Body Weight and Composition
2. Genetics
3. Sex
4. Race
5. Kidney Disease
6. Liver Disease
7. Environment

Question 15

Body weight and composition

Answer 15

• response to medications is largely determined by the concentration of the drug in the body, with the higher concentrations giving a greater response.

Question 16

what happens when two people have the same body weight but different body composition?

Answer 16

Percentage of 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 1.73m2 so some drugs are dosed as mg/1.73m2

Question 17

Genetics

Answer 17

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).

Question 18

Single Nucleotide Polymorphism (SNP)

Answer 18

is a change in DNA sequence that involves a single nucleotide (A,T,C or G).

Question 19

Sex

Answer 19

• 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.

Question 20

why are the effects of drugs in different sexes unknown?

Answer 20

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.

Question 21

Race

Answer 21

• 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.

Question 22

Cholesterol-lowering drug

Answer 22

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

Question 23

Kidney Disease

Answer 23

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.
- 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.

Question 24

Liver disease

Answer 24

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, the half-life may be significantly increased in patients with liver disease

Question 25

Environment

Answer 25

• Environmental exposures can significantly change the way patients respond to drugs.
• Environmental exposure can be voluntary (smoking, alcohol, diet, exercise) or involuntary (environmental pesticides).

1. Cigarette smoke induces some drug-metabolizing enzymes and can make some drugs less effective.
2. Alcohol can exacerbate the toxicity of some other drugs.
3. Exercise improves the actions of insulin.
4. Some commonly used pesticides can induce CYPs and therefore decrease the response to drugs that are metabolized by CYP enzymes.