Introduction to Pharmacology Flashcards
High-throughput screening
Often, many chemicals are tested simultaneously, via high-throughout screening to find a lead compound through in vitro testing during pre-clinical testing.
Animal testing
- Tests for toxicity in mice or other mammals.
- If possible, tests effectiveness against the disease.
- Patent application usually filed during (or before) this time.
Ames test for carcinogenicity [Tests for toxicity]
Uses a special bacterial variant to detect DNA mutations from a chemical.
- Mutations cause cancer.
Testing for kidney or liver damage cannot be done in bacteria.
- Use mice, other mammals.
- May still be different in people.
Carcinogenicity
The ability or tendency of a chemical to induce tumors (benign or malignant), increase their incidence or malignancy, or shorten the time of tumor occurrence when it is inhaled, ingested, dermally applied, or injected.
FDA clinical trials in humans: Phase I
Show safety/toxicity, in <100 healthy people.
FDA clinical trials in humans: Phase II
Test effectiveness/dosing, in ~200 affected patients.
FDA clinical trials in humans: Phase III
Confirm effectiveness, in >1000 affected patients.
FDA approval: Phase IV
Trials are often required after approval, to follow-up on long-term safety and effectiveness.
FDA approval
Allows prescriptions by doctors, made/sold by pharmaceutical company that holds the patent.
- Patent expires 20 years after patent application.
- Allows sale of cheaper “generic” drug by other companies.
- Often only 10 years after FDA approval.
“evergreening”
Drug companies use various tactics to extend their patent protection and make more money.
- Developing & marketing minor variations of an older drug.
- Developing & marketing combination drugs.
- Filing additions patents.
- … hiring legions of lawyers.
Idiosyncratic or paradoxical effect
• Sometimes, a drug may cause a totally unexpected and often opposite effect in a few patients.
- Eg. Benadryl (diphenhydramine) is an antihistamine that commonly causes drowsiness, but occasionally acts as a stimulant.
- benzodiazapines (eg Valium) are prescribed as tranquilizers, but in a few individuals result in anxiety, aggressive tendencies, even convulsions.
Off-label uses
• drugs may legally be prescribed by physicians fo purposes other than those approved by the FDA.
• Pharmaceutical companies may not legally mark drugs for off-label use.
• >90% of gabapentin (Neurontin, an anti-seizure med) prescriptions are for off-label uses such as schizophrenia & neuropathic pain.
- Pfizer fined $430M in 2004, vs $2.7B sales that year.
Teratogens
• Some drugs are harmless to patients, but can harm fetal development.
- We don’t usually test drugs on pregnant women.
• Thalidomide (approved
1957 in Germany for morning sickness, not approved in US) caused children born with flipper-like hands/feet.
Teratogenicity: Category A
Extensive data on pregnant women shows it to be harmless to fetuses.
- Synthroid (synthetic thyroid hormone)
- Few other egs.
Teratogenicity: Category B
Available data in humans shows no evidence for birth defects, but the data is insufficient to be conclusive, OR there is little or no data on humans, but animal studies show no evidence for birth defects.
- Example: amoxicillin
Teratogenicity: Category C (Majority of Drugs)
• [FDA requires a lot of data for Category A or B]
• Adverse effects have been demonstrated in animal studies, but there is insufficient data on humans to reach any firm conclusion.
- May be prescribed when the physician feels the potential benefits outweigh the risks.
• Examples: Ibuprofen and naproxen (Aleve) Category C in first two trimesters/D in the third trimester.
- High ibuprofen taken by a pregnant woman can cause closing of the ductus arteriosus in the fetus.
