Comprehensive Pharmacology: Drug Discovery, Development, and Safety

MAYA Pharm Set 2 -> Exam

What is the definition of a drug?

A chemical substance used for the diagnosis, prevention, or treatment of disease, and for the prevention of pregnancy.

What were the two historical paths of drug discovery?

Path 1 (older): isolation and use of natural substances from botanical, mineral, and animal sources.
Path 2 (later): chemical synthesis of compounds having biological activity.

What was the Doctrine of Signatures (1500s)?

The belief that plant parts resembling human body parts, animals, or objects had healing relevance to those parts (e.g., walnuts for the head). It was discredited by ~1650.

Who wrote the oldest known prescriptions, and when?

Sumerian physicians, on clay tablets, ~3000 BC (Southern Mesopotamia / modern-day Iraq).

What key idea did Hippocrates (5th century BC) promote?

That disease results from natural causes rather than evil spirits, and that the body has the ability to recuperate.

What drug came from Peruvian (Cinchona) bark in 1630, and why is it significant?

Quinine — used to treat malaria. It was the first specific drug used to treat an infectious disease, and is still a drug of choice against malaria.

Who introduced digitalis, from what plant, and for what condition?

"William Withering (1783) used purple foxglove (Digitalis purpurea) as a tea to treat cardiac ""dropsy"" (congestive heart failure). Digitalis is still the drug of choice for CHF and is still isolated from plants (Digitalis lanata leaves)."

Who isolated morphine, from what, and when?

Friedrich Serturner (German chemist) isolated the alkaloid morphine from opium in 1805. Opium comes from the poppy plant (Papaver somniferum).

By 1820, isolation of morphine led to techniques for isolating which other compounds?

Caffeine, atropine, and strychnine.

What is atropine's source and main medicinal use, and what discovery did it lead to?

Source: Atropa belladonna. Use: dilates the pupils (mydriasis; e.g., eye exams). Discovered in the 1830s, it led to the discovery of the neurotransmitter acetylcholine.

How does belladonna (atropine) act, and how is this used in dentistry?

It blocks acetylcholine binding to muscarinic receptors, reducing smooth muscle activity (gut, bronchi, uterus) and decreasing pancreatic/gastric secretions. In dentistry it can be used to dry up salivary secretions.

What is scopolamine, and what is it used for?

An alkaloid from Japanese belladonna, used for motion sickness (Transderm Scōp patch), as a sedative, and for mydriasis.

Trace the discovery of aspirin.

Willow bark reduced fever (Edward Stone, 1763) → salicin isolated (Buchner, 1828) → converted to salicylic acid → 1897 Felix Hoffman at Bayer synthesized acetylsalicylic acid (ASA/aspirin). Called the single most important drug discovery in medicine.

What are aspirin's main effects?

Reduces pain and fever, and prevents clotting (used to help prevent strokes).

Who discovered sulfanilamide (sulfa), how, and why is it significant?

Gerhard Domagk (1932) modified the dye Prontosil, yielding sulfanilamide — one of the first antibiotics. It was the first effective treatment for pneumonia and meningitis and predated penicillin.

What was the Elixir Sulfanilamide disaster, and what did it cause?

"In 1937, the Massengill Co. dissolved sulfanilamide in diethylene glycol (""antifreeze""), tested only for flavor/appearance (not toxicity) → 100+ deaths across 15 states → prompted the 1938 Food, Drug, and Cosmetic Act."

Who discovered penicillin, and who developed it into a medicine?

Alexander Fleming (1928) noticed mold on a contaminated staphylococcus plate inhibited bacterial growth. Howard Florey and Ernst Chain (Oxford) later developed it for medical use; it was used as a pharmaceutical in WWII.

How did battlefield antibiotic use change over WWII?

Early on, sulfa powder was sprinkled on wounds (but excess sulfa damaged the kidneys). By the end of WWII, penicillin had taken its place.

On average, how long does it take to develop a new drug?

About 12 years (some estimates 12-15 years).

On average, how much does it cost to bring a drug from concept to market?

Approximately $1.6 billion.

What fraction of potential drugs reaches human trials, and what is the failure rate in human testing?

About 1 in 1000 potential drugs reaches human trials, and about 9 out of 10 of those fail in human testing.

How long is a drug patent?

20 years (includes testing time and time getting to market).

In the development funnel, roughly how many compounds move from discovery to an approved drug?

~5,000-20,000 compounds in drug discovery → ~250 preclinical → ~5 in clinical research → 1 approved drug.

What are the five stages of drug development?

1) Synthesis/discovery of a new chemical
2) Safety evaluation in animals and humans
3) Effectiveness evaluation in humans
4) Review of the New Drug Application
5) Post-marketing surveillance for adverse effects.

What is LD50?

The dose of a drug that kills 50% of the test animals that received it (measure of lethality/toxicity).

What is ED50?

The dose of a drug that causes the desired effect in 50% of the test animals that received it (measure of effectiveness).

What is the formula for the margin of safety?

\[ \text{Margin of Safety} = \frac{LD_{50}}{ED_{50}} \]

If LD50 = 10 mg and ED50 = 2 mg, what is the margin of safety, and what does it indicate?

Margin of safety = 5, meaning the lethal dose is only 5× the effective dose — a low margin, possibly predictive of a low margin of safety in humans.

What is considered an acceptable margin of safety?

2000 or more.

What is long-term (chronic) toxicity testing?

Daily dosing of rats and dogs for 3 months to 2 years, observing for toxicities and blood chemistries; animals are then sacrificed for histopathology. Many toxic effects appear only after repeated dosing.

What specialized animal safety studies are done before human testing?

Reproduction studies (ovulation, fertilization, embryo expulsion, teratogenicity/birth defects) and carcinogenicity studies — any sign of cancer is enough to stop testing.

What is an IND, and when is it submitted?

Investigational New Drug application — submitted to the FDA when a drug shows an impressive margin of safety in mice, lacks long-term toxicities, and does not cause cancer, reproductive effects, or birth defects. Usually a 30-day approval.

What is Phase 0 of clinical studies?

"An ""exploratory,"" first-in-human trial using a microdose (

Describe Phase 1 clinical studies.

"Begins after IND approval; 20-80 healthy volunteers. Studies safety, pharmacokinetics, pharmacodynamics, and dosing. Single then ascending doses; dosing stops at unacceptable adverse events to set the ""tolerable"" dose."

Describe Phase 2 clinical studies.

~100-300 patients who have the condition the drug is intended to treat. Studies short-term effectiveness, therapeutic efficacy, dose-response, and therapeutic dose range; often compared to a placebo.

Describe Phase 3 clinical studies.

~1000-3000 subjects; confirm drug safety and long-term efficacy and detect adverse effects missed earlier. Design is always a randomized, double-blind, placebo-controlled trial.

"What does ""double-blind"" mean, and why is it used?"

Neither the subject nor the investigator knows whether the subject is receiving the drug or placebo. It is the most effective design for avoiding bias and distributing unknown variables between groups.

What is a key limitation of Phase 3 trials?

Toxicities occurring at less than 1 in 1000 exposures may not be revealed, because too few subjects take the drug long term. These appear only after marketing, when millions take the drug (post-marketing surveillance).

What is an NDA?

New Drug Application — submitted after ~8 years of animal and human testing. If FDA-approved, the manufacturer can sell the drug as an exclusive proprietary product and holds the patent for 20 years.

What is Phase 4 (post-marketing surveillance)?

Occurs after FDA approval; the drug is used by far greater numbers, and additional data on side effects is collected. New toxicities can cause the drug to be pulled from the market or relabeled with new warnings/precautions.

"What is ""compassionate use"" (treatment use of investigational drugs)?"

"During NDA review, a drug may be used before approval for desperately ill patients with no comparable alternative, where side effects are not the main concern (""compassionate use protocols"")."

What is a drug's chemical name?

The name based on its chemical structure (e.g., acetylsalicylic acid). Used during investigation before marketing.

What is a drug's generic name, and what are its rules?

The single official name approved by the USAN Council and listed in the official pharmacopeia. Each drug has only one generic name (but many possible brand names), and generic names are not capitalized (e.g., warfarin, ibuprofen).

What is a drug's trade (brand/proprietary) name?

The name given by the manufacturing company; registered as a trademark and owned by that company. It is capitalized, and one drug can have many trade names (e.g., Coumadin, Advil).

Generic vs. trade name: warfarin and Coumadin — which is which?

warfarin = generic name; Coumadin = trade (brand) name.

How does capitalization distinguish generic from brand names?

Generic names are lowercase; brand/trade names are capitalized.

What did the 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) do?

Allowed generic drugs to receive expedited approval, provided the generic's active ingredient enters the bloodstream at the same rate as the brand-name product.

What is an ANDA?

Abbreviated New Drug Application — for approval of a generic version of an already-approved drug. It does not require new preclinical/clinical trial data; the applicant must instead demonstrate bioequivalence.

How is bioequivalence of a generic demonstrated?

By measuring the time for the drug to reach the bloodstream in 24-36 healthy volunteers (rate of absorption/bioavailability). The generic must deliver the same active ingredient amount in the same time (≥90% bioavailability of the innovator).

How do patents and exclusivity differ?

Patents are granted by the patent/trademark office anytime during a drug's development. Exclusivity is exclusive marketing rights granted by the FDA upon approval; it may or may not run concurrently with a patent.

What did the 1906 Pure Food and Drug Act do?

Created the FDA; required drugs to meet standards of purity and quality and manufacturers to provide truthful labeling; prohibited interstate/foreign commerce of adulterated or misbranded food and drugs. (It did not yet require proof of safety or efficacy.)

What did the 1938 Food, Drug, and Cosmetic Act require?

Pre-market approval from the FDA contingent on demonstrated safety and purity, and regulation of labeling/packaging. (Triggered by the Elixir Sulfanilamide deaths.)

What did the Durham-Humphrey Act of 1952 establish?

Gave the FDA authority to determine which drugs may be sold without a prescription (the prescription vs. OTC distinction), based on toxicity and ability to self-diagnose.

What did the 1962 Kefauver-Harris Amendments require?

Proof of efficacy as well as safety for new drugs (and drugs approved since 1938), plus guidelines for adverse-event reporting, clinical testing, and advertising. (Prompted by thalidomide.)

What did the Dietary Supplement Health and Education Act of 1994 (DSHEA) establish?

The FDA oversees the safety, manufacturing, and health claims of dietary supplements but does NOT evaluate efficacy. The FDA must demonstrate a supplement is unsafe before taking action against it.

What did the Orphan Drug Amendments of 1983 do?

Provided incentives to manufacturers who develop drugs for orphan diseases (those affecting

What did the Expedited Drug Approval Act of 1992 do?

Allowed accelerated FDA approval for drugs of significant medical need, but required detailed post-marketing surveillance.

What did the FDA Modernization Act of 1997 do?

"Allowed manufacturers to discuss unapproved/""off-label"" indications with practitioners; provided accelerated approvals for life-threatening disorders; made provisions for pediatric drug research."

What did the FDA Amendments Act (FDAAA) of 2007 do, and why?

In response to COX-2 inhibitor cardiac events and strokes, it gave the FDA enhanced authority over approved-drug safety and introduced REMS (Risk Evaluation and Mitigation Strategies).

"What is ""Right-to-Try"" legislation (2018)?"

Allows gravely ill patients to bypass the FDA to access experimental drugs that have passed only Phase 1. It does not guarantee the manufacturer will provide the drug or that insurance will cover it. Colorado enacted the first such law (2014).

What did the Harrison Narcotic Act of 1914 regulate?

The use of opium, opiates, and cocaine (marijuana was added in 1937). Before it, mixtures containing opium and cocaine were sold OTC.

What is the Controlled Substances Act (1970), and who administers it?

Administered by the DEA, it regulates the manufacture and distribution of substances with abuse potential, including opioids (narcotics), stimulants, and sedatives.

When did the FDA require boxed warnings on opioids?

2013 for long-acting opioids (e.g., OxyContin); March 22, 2016 for short-acting opioids — warning of serious risks of misuse, abuse, addiction, overdose, and death.

What authority does the FDA have over OTC drugs?

It reviews OTC drugs for misbranding and adulteration, sets guidelines for their safety and effectiveness, and can prevent their sale or withdraw them from the market.

"What does the FDA require of OTC drugs regarding ""GRAS/GRAE/GRAHL""?"

Since 1962, OTC drugs must be Generally Recognized As Safe (GRAS), Effective (GRAE), and Honestly Labeled (GRAHL).

How are OTC drugs approved?

They must follow the NDA process or, more commonly, conform to existing drug monographs.

What claims can and cannot dietary supplements make?

"They cannot make therapeutic claims (treat/cure conditions) but can make structure-function claims (e.g., ""promotes sleep""). They must carry the disclaimer: ""This product is not intended to diagnose, treat, cure, or prevent any disease."""

Does the FDA evaluate the efficacy of dietary supplements?

No — the FDA oversees supplement safety, manufacturing, and claims but does not evaluate efficacy.

What is a package insert, and why is it a limited information source?

An agreement between the FDA and the manufacturer presenting the drug in a marketable way. Because it is written by the manufacturer, it carries significant bias and is not the best source of drug information.