DLA4, DLA5- Drug Development and Adverse Effects

Question 1

define the 4 types of ADRs

Answer 1

(ADR- adverse drug reaction)
Type A- explainable/predictable ADR
Type B- unexplainable/idiosyncratic ADR
Type C- chronic ADR
Type D- delayed ADR

Question 2

Most ADR are type (1), accounting for (2)%. It includes the following examples: (3).

Answer 2

1- type A, explainable / predictable
2- 80%
3- toxicity of overdose, side effects, secondary effects, drug interaction

Question 3

Type A ADR is dose (in-/dependent)

Type B ADR is dose (in-/dependent)

Answer 3

A- dose dependent

B- dose independent

Question 4

list some examples of Type B ADRs

Answer 4

• intolerance
• hypersensitivity
• pseudoallergic (first exposure, unlike in type I hypersensitivity)
• idiosyncratic (unpredictable reactions)

Question 5

describe Type C ADR

Answer 5

• only occurs with long-term drug use
• ex. dependence / withdrawal associated
• ex. some effects only appear after long-term use (steroids)

Question 6

describe Type D ADR

Answer 6

• delayed ADR
• usually carcinogenic / teratogenic
• rare, commonly associated with chemotherapeutic agents

Question 7

list the 5 mechanisms of drug toxicity

Answer 7

• on-target adverse effects
• off-target adverse effects
• toxic metabolite production
• harmful immune response production
• idiosyncratic responses

Question 8

compare on-target and off-target drug toxicities

Answer 8

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

Question 9

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.

Answer 9

1- glucuronidation, sulfation
2- cytochrome P450
3- NAPQI (N-acetyl-benzoquinineimine)
4- glutathione
5- cell death

Question 10

describe the two types of harmful immune responses to drugs

Answer 10

1) hypersensitivity / allergic response

2) autoimmune reactions

Question 11

list the inducers of cytochrome P450

Answer 11

chronic EtOH use, rifampin, phenytoin, phenobarbital, carbamazepine, St. John’s Wort
(mostly seizure drugs)

Question 12

list the inhibitors of cytochrome P450

Answer 12

cimetidine, ketoconazole, clarithromycin, quinidine, sulfonamides, ciprofloxacin, grapefruit juice
(mostly antibiotics)

Question 13

gingko biloba has a _____ effect

Answer 13

inhibits platelet aggregation

Question 14

St. John’s wort has a _____ effect

Answer 14

antidepressant

Question 15

list the results of cellular toxicity

Answer 15

• apoptosis
• fibrosis
• carcinogenesis
• teratogenesis

Question 16

list the categories for classifying drug use in pregnancy (hint- 5)

Answer 16

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

Question 17

list the 5 approaches to discovering or developing a new drug

Answer 17

• 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

Question 18

FDA determines safety and efficacy of a drug through (1) studies, then (2) studies, and finally (3) studies

Answer 18

1- in vitro
2- in vivo
3- RCTs

Question 19

list the three quantitative estimated in preclinical testing

Answer 19

• 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

Question 20

describe the approach and goal of Acute Toxicity preclinical testing

Answer 20

• determine no-effect dose

- determine maximum tolerated dose

Question 21

describe the approach and goal of Subacute or Subchronic Toxicity preclinical testing

Answer 21

• 2 wks to 3 mos

- determines biochemical and physiological effects

Question 22

describe the approach and goal of Chronic Toxicity preclinical testing

Answer 22

• used if drug will need to be used in humans for long periods
• runs concurrently with RCTs
• determines biochemical and physiological effects

Question 23

describe the approach and goal of Effect on Reproductive Performance preclinical testing

Answer 23

test effects of animal mating behavior, reproduction, parturition, progeny, birth defects, postnatal development

Question 24

describe the approach and goal of Carcinogenic Potential preclinical testing

Answer 24

• used if drug will need to be used in humans for long periods
• determines gross and histological pathology

Question 25

describe the approach and goal of Mutagenic Potential preclinical testing

Answer 25

test effects on genetic stability and mutations in bacteria or mammalian cells in culture

Question 26

describe the approach and goal of Investigative Toxicology preclinical testing

Answer 26

-determines sequence & mechanism of toxic action -discover genes, proteins, pathways involved (-develop new methods for assessing toxicity, like computer assisted modeling)

Question 27

what are the limitations of preclinical testing

Answer 27

- 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

Question 28

list the number of subjects, length of phase, and purpose of Prephase I clinical trials

Answer 28

- Number: small - Length: short, hr-days - Purpose: facilitate efficient drug development

Question 29

list the number of subjects, length of phase, and purpose of Phase I clinical trials

Answer 29

- Number: 20-100 - Length: months - Purpose: safety

Question 30

list the number of subjects, length of phase, and purpose of Phase II clinical trials

Answer 30

- Number: hundreds - Length: months - 2 yrs - Purpose: effectiveness, short-term safety

Question 31

list the number of subjects, length of phase, and purpose of Phase III clinical trials

Answer 31

- Number: hundreds - thousands - Length: 1-4 yrs - Purpose: safety, dosage, effectiveness

Question 32

list the number of subjects, length of phase, and purpose of Phase IV clinical trials

Answer 32

- Number: unlimited - Length: unlimited - Purpose: observe adverse effects

Question 33

define Black Box Warning

Answer 33

-FDA assigns it to a drug if studies show it carries significant risk of serious or life-threatening adverse effects

Question 34

define Orphan drugs

Answer 34

-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

Question 35

drugs can receive 'fast-track' status if...

Answer 35

they are for serious. life-threatening diseases - don't need to meet all regular drug requirements - can be 'fast-tracked' off the market too

Question 36

define the Schedule classes of drugs

Answer 36

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)

Question 37

New Drug Application occurs after Phase (1) trials and can (2) amount of time

Answer 37

1- phase 3 | 2- mos-yrs