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Lecture 1
Intro to Pharmacology, Drug Development
| Question | Answer |
|---|---|
| Pharmacology | study of substances and their interactions with living systems |
| Medical Pharmacology/Therapeutics | science of substances designed to prevent, diagnose, and treat diseases |
| Toxicology | deals with the unwanted effects of chemicals on living systems |
| Drug | substance causing a change in biologic function through chemical processes |
| Hormones | found naturally in body |
| Xenobiotic | a foreign substance not found naturally in body |
| Pharmacogenomics | individual genetic makeup and response to specific drugs |
| Pharmacognosy | origins of drugs |
| Natural Drugs | oldest and most abundant; plants, animals, minerals, microorganisms |
| Plant Sources (alkaloids) | nitrogen, carbon, hydrogen, oxygen, amine-like structure, bases; insoluble in water, react with acids to form salts, names end with -ine = morphine, nicotine, quinine, atropine |
| Plant Sources (glycosides) | carbohydrate portion, consisting of one or more sugars combined with a hydroxy compound; cardiac glycosides = foxglove plant --> digoxin |
| Animal Sources | Insulin = anti-diabetic = cow/pigs = pancreas Protamine sulfate = heparin antidote = fish = sperms heparin = anticoagulant = pig = intestine Premarin = estrogen replacement = horse = urine |
| Natural Drugs Advantages | natural affinity; specific binding to targets |
| Natural Drugs Disadvantages | costly; less sustainable; may work differently than expected |
| Agonist | binds to and activates the receptor |
| Antagonist | blocks the receptor so it can't be activated |
| Receptor | biologic substrate target molecule of the agonist/antagonist |
| Drug and Receptor | "lock and key" |
| Drug properties | appropriate size, bonds, electrical charge, shape, anatomic position, may be solid or liquid at room temp --> vital in route of administration |
| size and molecular weight | MW 100-1000; at least 100 for selective binding; unique shape, charge prevents binding to other receptors; upper limit based primarily on need for movement throughout body; drugs with >1000 have poor absorption and distribution in body |
| Drug-Receptor Bonds | Types: covalent, electrostatic, hydrophobic; drugs binding through weak bonds are generally more selective than those bound by strong bonds --> weak bonds require very precise fit for interaction to occur |
| Covalent | very strong, usually not reversible, ex. dan-alkylating agents |
| Electrostatic | more common than covalent, vary in strength |
| Hydrophobic | usually very weak, vital in interactions of highly lipid-soluble drugs with lipids of cell membranes |
| Drug Shape | chirality "handedness" = not superimposable on its mirror image --> exist as enantiomeric molecules --> 2 non-identical mirror images - pair of enantiomers; the lower the kd value, the stronger the attraction |
| Drug Body Interactions (pharmacodynamics) | actions of drugs on the body; involved in drug group classifications determine whether a drug group is appropriate treatment for a certain disease or symptom |
| Drug Body Interactions (pharmacokinetics) | what the body does to the drug; involves four basic concepts --> absorption, distribution, metabolism, elimination |
| Drug Development (4) | discovery of new drug target, discoveries usually made in public sectors; development in industrial laboratories; in vitro studies and animal testing before human testing |
| 1) Drug Discovery | screening for biologic activity, modification of an active molecule, identification of new drug target, design of new molecule, translational research (moving from lab to clinic) |
| Drug Screening | pharmacologic profile: effects, receptor interaction, selectivity; pharmacokinetics; desired outcome is a lead compound; composition of matter potent = filed for effective novel compound; use patent = filed for new and nonobvious therapeutic use |
| FD&C Act of 1938 | federal food, drug & cosmetic act; replaced pure food and drug act of 1906; TN drug company marketed new sulfa wonder drug targeted at pediatric patients, elixir sulfanilamide |
| FD&C Act of 1938 | required new drugs to be safe and pure; labels shoved contain directions for safe use; mandated premarket approval of drugs by FDA; did not require proof of efficacy |
| Kefauver-Harris Amendment to FD&C Act | signed by president Kennedy in 1962; thalidomide tragedy; pregnant women --> birth defects; required proof of efficacy and safety; guidelines for reporting adverse reactions; guidelines clinical testing |
| FDA safety & innovation act of 2012 | renewed FDA authority to accelerate approval of urgently needed drugs; established new accelerated process; "fast track" procedures |
| Preclinical safety & toxicity testing | all chemicals toxic in some individuals at some dose; no drug completely risk free; goal is to estimate risk; animal testing |
| Preclinical safety & toxicity testing: no-effect dose | max dose at which specified toxicity is not seen |
| Preclinical safety & toxicity testing: maximum lethal dose | smallest dose observed to kill any experimental animal |
| Preclinical safety & toxicity testing: median lethal dose LD50 | dose that kills 50% of animals in test groups |
| Preclinical safety & toxicity testing | these doses used to calculate initial dose to be tested in humans (usually 1/100 to 1/10 of no-effect dose) |
| Investigational New Drug (IND) | filed once a new drug is ready to be studied in humans; includes: info on composition and source of drug, chemical and manufacturing info; animal studies data, clinical trial plans, names/credentials of prescribers, relevant preclinical data |
| Phase 1 | smallest # of subjects, healthy volunteers or patients with disease, blind or non-blind, predictable toxicities detected; performed in research centers by specially trained clinical pharmacologists |
| Phase 1 purpose | determine safety and clinical dose range |
| Phase 1 pharmacokinetics parameters | absorption, half-life, metabolism |
| Phase 2 | # subjects increases, subjects with target disease, single blind design, broader range of toxicities detected; highest rate of drug failures; approximately 25% of investigating drugs move onto phase 3 |
| Phase 2 Purpose | determine efficacy and doses to be used |
| Phase 3 | larger # subjects (thousands); further establishes safety and efficacy; designed to minimize errors caused by placebo effects, variable disease course; double blind and cross over used; performed in setting similar to those expected for drug use |
| Phase 3 | drug is formulated as intended for market use; investigators are specialist in disease state being treated; certain toxic effects may first appear |
| Phase 4 | occurs once a drug has been approved to market, large # patients, monitoring safety under actual conditions, no fixed duration |
| Clinical Trials for Drug Development Steps | Pre clinical trial -->IND --> Phase 1 --> Phase 2 --> Phase 3 --> NDA, BLA, PMA --> Phase 4 |
| Patents | time from filing to approval 5 years or longer; lifetime of patent is 20 years in USA |
| Patents | once expired, companies can file an abbreviated new drug application (ANDA) and demonstrate required equivalencies = generic drug; trademark = drug's proprietary trade name |
| Therapeutic Classification | based on usefulness in treating certain diseases; antihypertensives, antidepressants, antihypolipidemics |
| Pharmacologic Classification | based upon mechanism of action; ACE inhibitors, ARBs, beta-blockers |
| Drug Schedules | classified based upon medical use and potential for abuse/dependency; 5 distinct schedules; as drug schedule changes, so does abuse potential |
| Schedule 1 = ? | illicit drugs (LSD, marijuana) = highest for abuse and dependency |
| Risk Classifications for FDA pregnancy categories | A = safest B = no evidence C = cannot be ruled out D = positive evidence X = contradictions, WORST |
Created by:
bluedolphin7
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