DLA4, DLA5- Drug Development and Adverse Effects Flashcards
define the 4 types of ADRs
(ADR- adverse drug reaction) Type A- explainable/predictable ADR Type B- unexplainable/idiosyncratic ADR Type C- chronic ADR Type D- delayed ADR
Most ADR are type (1), accounting for (2)%. It includes the following examples: (3).
1- type A, explainable / predictable
2- 80%
3- toxicity of overdose, side effects, secondary effects, drug interaction
Type A ADR is dose (in-/dependent)
Type B ADR is dose (in-/dependent)
A- dose dependent
B- dose independent
list some examples of Type B ADRs
- intolerance
- hypersensitivity
- pseudoallergic (first exposure, unlike in type I hypersensitivity)
- idiosyncratic (unpredictable reactions)
describe Type C ADR
- only occurs with long-term drug use
- ex. dependence / withdrawal associated
- ex. some effects only appear after long-term use (steroids)
describe Type D ADR
- delayed ADR
- usually carcinogenic / teratogenic
- rare, commonly associated with chemotherapeutic agents
list the 5 mechanisms of drug toxicity
- on-target adverse effects
- off-target adverse effects
- toxic metabolite production
- harmful immune response production
- idiosyncratic responses
compare on-target and off-target drug toxicities
ON- either too much stimulation of receptor (i.e. hypoglycemia from insulin) or activating same receptor in non-target tissue (i.e. His receptors in CNS) [same receptor]
OFF- drug binds additional receptor(s) in target and or non-target tissue [different receptor]; Note this can include enantiomer of drug with different effects
95% of acetominophen is metabolized by (1). The remaining 5% is oxidized by (2) forming (3), a reactive intermediate. (3) is conjugated with (4) in non-toxic doses, but in toxic doses (4) stores are depleted and (5) occurs.
1- glucuronidation, sulfation 2- cytochrome P450 3- NAPQI (N-acetyl-benzoquinineimine) 4- glutathione 5- cell death
describe the two types of harmful immune responses to drugs
1) hypersensitivity / allergic response
2) autoimmune reactions
list the inducers of cytochrome P450
chronic EtOH use, rifampin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort
(mostly seizure drugs)
list the inhibitors of cytochrome P450
cimetidine, ketoconazole, clarithromycin, quinidine, sulfonamides, ciprofloxacin, grapefruit juice
(mostly antibiotics)
gingko biloba has a _____ effect
inhibits platelet aggregation
St. John’s wort has a _____ effect
antidepressant
list the results of cellular toxicity
- apoptosis
- fibrosis
- carcinogenesis
- teratogenesis
list the categories for classifying drug use in pregnancy (hint- 5)
A- adequate, no risk to fetus
B- animal studies show adverse effects, no evidence seen in with studies in pregnant women
C- animals studies shoe adverse effects or have not been conducted, no studies with pregnant women conducted
D- studies show risk to fetus, however benefits can outweigh potential risks
X- studies show risk to fetus, do not give to pregnant women
list the 5 approaches to discovering or developing a new drug
- identification of new drug target
- rational design of new molecule based on understanding biological mechanisms and drug receptor structure
- chemical modification of known molecule
- screening for biologic activity via large number of natural products (previously discovered chemical entities)
- combination of known drugs
FDA determines safety and efficacy of a drug through (1) studies, then (2) studies, and finally (3) studies
1- in vitro
2- in vivo
3- RCTs
list the three quantitative estimated in preclinical testing
- no-effect dose: max dose where specific toxic effect is not seen
- minimum lethal dose: smallest dose that killsexperimental animal
- LD50: dose at which 50% of experimental animals die
describe the approach and goal of Acute Toxicity preclinical testing
- determine no-effect dose
- determine maximum tolerated dose
describe the approach and goal of Subacute or Subchronic Toxicity preclinical testing
- 2 wks to 3 mos
- determines biochemical and physiological effects
describe the approach and goal of Chronic Toxicity preclinical testing
- used if drug will need to be used in humans for long periods
- runs concurrently with RCTs
- determines biochemical and physiological effects
describe the approach and goal of Effect on Reproductive Performance preclinical testing
test effects of animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development
describe the approach and goal of Carcinogenic Potential preclinical testing
- used if drug will need to be used in humans for long periods
- determines gross and histological pathology
describe the approach and goal of Mutagenic Potential preclinical testing
test effects on genetic stability and mutations in bacteria or mammalian cells in culture
describe the approach and goal of Investigative Toxicology preclinical testing
-determines sequence & mechanism of toxic action
-discover genes, proteins, pathways involved
(-develop new methods for assessing toxicity, like computer assisted modeling)
what are the limitations of preclinical testing
- time-consuming, expensive
- large number of animals required
- extrapolation of animals results to humans aren’t always accurate
- rare adverse effects are unlikely to be detected
list the number of subjects, length of phase, and purpose of Prephase I clinical trials
- Number: small
- Length: short, hr-days
- Purpose: facilitate efficient drug development
list the number of subjects, length of phase, and purpose of Phase I clinical trials
- Number: 20-100
- Length: months
- Purpose: safety
list the number of subjects, length of phase, and purpose of Phase II clinical trials
- Number: hundreds
- Length: months - 2 yrs
- Purpose: effectiveness, short-term safety
list the number of subjects, length of phase, and purpose of Phase III clinical trials
- Number: hundreds - thousands
- Length: 1-4 yrs
- Purpose: safety, dosage, effectiveness
list the number of subjects, length of phase, and purpose of Phase IV clinical trials
- Number: unlimited
- Length: unlimited
- Purpose: observe adverse effects
define Black Box Warning
-FDA assigns it to a drug if studies show it carries significant risk of serious or life-threatening adverse effects
define Orphan drugs
-drugs that are being research for rare diseases, which provides many obstacles
Defined as:
-affects <200,000 people in US
-affects >200,000 people in US, no expectation cost of drug will be recovered by its sales
drugs can receive ‘fast-track’ status if…
they are for serious. life-threatening diseases
- don’t need to meet all regular drug requirements
- can be ‘fast-tracked’ off the market too
define the Schedule classes of drugs
1- high potential for abuse, all non-research use is illegal under federal law
2- high potential for abuse, no telephone Rxs, no refills
3- abuse potential less than 1/2, Rx rewritten after 6 mos or 5 refills
4- abuse potential less than 3, Rx rewritten after 6 mos or 5 refills (illegal possession has different penalties)
5- abuse potential less than 4, no Rx required (depends on state)
New Drug Application occurs after Phase (1) trials and can (2) amount of time
1- phase 3
2- mos-yrs
