6. Drug Safety Flashcards
“Primum non nocere” (latin) means
Do no harm
Thalidomide
Was a drug used for morning sickness & causes birth defects in some children whose mothers took the drug during pregnancy
Frances Kelsey
a Canadian Pharmacologist working at the US FDA, considers toxicology evidence insufficient for US marketing
Kefauver-Harris Amendments to the Food, Drug and Cosmetics Act (1962)
- Drug manufacturers required to prove, scientifically, that the drug is: Safe
& Effective
FDA Regulations on Preclinical Safety Testing
1) Adequate information about pharmacological and toxicological studies
2) Duration and scope of in vitro animal testing and other tests required varies
3) Guidance documents are available
3 ways to test for Toxicity
1) Death of proportion of cells/ organisms
2) Pathology (microscope)
3) Surrogate measures of organ toxicity by measuring the blood or urine
Units of Toxicity
mg of drug per kg of organism
4 examples of ways Drug development is highly regulated by the FDA
1) Generally 2 species (one rodent, one non-rodent)
2) Drug may behave differently in different species (Not always clear which species is more predictive for human)
3) Regulatory requirements (exaggerate the dosing & exaggerate the duration of exposure)
4) Time involved (Chronic exposure studies in animal models- 6 months to 1 year)
In vivo
in living organism
In vitro
“in glass”. Can mean biochemistry (proteins + drug) experiment or cell culture experiment
Example of in vivo question
Safety concern – does the drug cause cancer in people?
Example of in vitro test
Indirect safety test – does the drug damage DNA of bacteria?
MAJOR MECHANISMS IN DRUGS
1) Reversible binding of drug to receptor
2) Activation of drug to metabolite that binds/damages protein, DNA (The activation can occur by drug metabolizing enzymes)
Pharmacokinetics
what the body does to the drug
Ames Assay
In vitro mutagenesis test
- A biological test for the carcinogenic potential of a compound
Ames assay for mutagenicity
Use a strain of bacteria that have been genetically modified to require histidine (an amino acid)
If bacterial DNA mutates (due to the drug added), then the bacteria can change to being able to grow in His-free media
What to put into plate to determine of a drug or its metabolite cases mutations
Add drug + enzymes + His-requiring bacteria
What are the 7 major target organs for Toxicity
1) Liver
2) Kidney
3) Heart
4) Lungs
5) Brain
6) Reproductive
7) Skin
the 6 human organ systems
1) Skeletal system
2) Muscular system
3) Digestive system
4) Respiratory system
5) Nervous system
6) Circulatory system
Cardiotoxicity
heart toxicity (a major concern for drug development)
We can test a drug for reproductive toxicity using…
sperm morphology and motility
Biomarkers
a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
(indirect marks of internal state) (urine & blood tests)
Toxicology considers a spectrum of undesired effects (4)
1) Allergic reactions
2) Abnormal reactivity to standard dose
3) Reversible vs. irreversible effects (Liver- ability to regenerate, CNS degeneration, cancer)
4) Local vs. systemic effects (site of first contact- skin, while organism & bloodstream )
Liver toxicity can be measured through urine because
liver cells burst and release liver specific enzymes
