Pharm Intro, Distribution, Toxicity (1/2)

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  1. PHARM 1
  2. Drug development for most drugs includes the following steps:
    • 1. Drug discovery
    • 2. Pre-clinical testing
    • - IND (Investigative Application) -
    • 3. Clinical trials
    • - NDA (New Drug Application) -
    • 4. FDA submission
    • 5. FDA approval (& possibly Phase 4)
  3. Drug Discovery
    a process whereby hundreds -> thousands of compounds are screened & tested for efficacy
  4. Pre-clinical Testing
    • done to evaluate the potential risks/benefits of advancing drug candidates into clinical testing
    • scientists look for 2 features in this stage of testing:
    • 1. safety of the drug
    • 2. pharmacokinetics of the drug (mechanism by which it works)
  5. IND (Investigative Application)
    • the FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk
    • administrators can weigh in on the studies being proposed/done; an opportunity to intervene & suggest variables for testing
    • If the application is cleared, the candidate drug may enter a Phase 1 clinical trial
  6. Clinical Trials
    • which are most often further divided into 3 distinct phases
    • phase 3 (the last) involves large randomized controlled studies conducted in human subjects; these studies are usually the final proof that a drug has a favorable enough safety & efficacy profile to meet the needs of society
  7. Phase 1 Clinical Trial
    • first stage of testing in human subjects
    • usually done in a small group of 20-100 healthy volunteers
    • phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, & pharmacodynamics of a drug
  8. Phase 2 Clinical Trial
    • once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect
    • Phase II trials are performed on larger groups (100-500) & are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients
    • if a drug is going to fail, usually does so in phase II
  9. Phase 3 Clinical Trial
    • assess the effectiveness of the new intervention and its value in clinical practice
    • phase III studies are randomized controlled trials on large patient groups (1000–5000)
    • are the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment (usually compared against a placebo, very rarely an an active comparison)
    • because of their size and long duration, Phase III trials are the most expensive, time-consuming, & difficult trials to design and run
  10. NDA (New Drug Application)
    • how drug sponsors formally propose that the FDA approve a new pharmaceutical for sale & marketing
    • fee of ~$1 million payed for NDA as a result of Prescription drug User Fee Act (pays FDA to evaluate a drug)
  11. After the patent on a name-brand drug has run out, how are generic drugs approved by the FDA?
    • through Phase 1 studies must be done to approve generic version of drug
    • if the pharmacokinetics are comparable, a generic generic version can be produced - takes much less money & time
  12. FDA submission
    • an application is submitted to the FDA & all the data that previous testing has generated is reviewed
    • decisions are made as to whether or not the candidate drug is suitable for entry into the U.S. market (sometimes with the aid of an Advisory Committee)
  13. FDA approval & Phase 4
    • any further study of safety or efficacy of a drug that is conducted after it is approved is considered to have come from phase 4 “testing”
    • rare, unexpected side effects & off-label uses of medications are usually discovered during this time
  14. Risk Evaluation and Mitigation Strategy (REMS)
    • required from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks
    • the Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a REMS
  15. Off-Label Prescribing
    • when a drug meant for one treatment is discovered to assist in another unrelated condition (eg. Gabapentin originally developed to treat epilepsy, is mostly used to relieve neuropathic pain)
    • in order to MARKET it for its off-label use, manufacturer needs to do an abbreviated NDA + additional Phase III-like studies
  16. Pure Food and Drug Act (1906)
    • the first of a series of significant consumer protection laws enacted by the Federal Government
    • led to the creation of the FDA
    • banned foreign & interstate traffic in adulterated or mislabeled food/drug products
    • directed inspection of products & required active ingredients be placed on the label of a drug’s packaging
    • precipitated by Sinclair's The Jungle
  17. Federal Food, Drug, and Cosmetic Act (1938)
    • precipitated by the mixing of sulfanilamide w/ diethylene glycol
    • required drugs to be tested for safety & efficacy, specifically by putting them through the 3 phases of clinical trials
    • passed by FDR giving authority to the FDA to oversee the safety of food, drugs, & cosmetics
  18. Kefauver-Harris Amendment (1962)
    • precipitated by thalidomide birth defects
    • ammeded the Federal Food, Drug, and Cosmetic Act
    • requiremed drug manufacturers to provide PROOF of the effectiveness & safety of their drugs before approval
    • required drug adverts to disclose accurate information about side effects
    • stopped cheap generic drugs being marketed as expensive drugs under new trade names as new "breakthrough" medications
  19. Prescription Drug User Fee Act (PDUFA) 1992
    • potentiated by LONG wait times for drug approval
    • allowed FDA to collect fees from drug manufacturers to fund the new drug approval process
    • mean drug review time decreased from 3 years in 1990 to 1.2 years around 2010
  20. Dietary Supplement Health & Education Act (DSHEA)
    amendment to (1938) Food, Drug, & Cosmetic Act that established dietary supplement standards
  21. Prescription Drug vs. Dietary Supplement
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  22. What are the 3 categories of drug information?
    • primary, secondary, & tertiary
    • what defines secondary & tertiary sources and examples of each are debatable and vary depending on the authority -> group secondary and tertiary together
  23. Primary Literature on Drug Information
    • the full text of original research about a drug or drug class
    • such research is often published in biomedical journals & is commonly used for clinical decision making
    • risk for biases & confounders are least in this category
  24. Secondary/Tertiary Literature on Drug Information
    • refers to a summary of original work about a drug, not the actual original work
    • eg. information found in abstracts, text books, review articles, or quick reference guides
  25. Physicians' Desk Reference (PDR)
    • commercially published compilation of manufacturers' prescribing information (package insert) on prescription drugs, updated annually
    • provides physicians with the full legally mandated information relevant to writing prescriptions
    • is a photocopy of how the FDA has approved the use of a medication
    • includes dose adjustments, warnings, but would be MISSING off label uses
  26. What happens with drugs with predicted potential for abuse?
    • they're assigned a controlled substances schedule by the Drug Enforcement Administration (DEA)
    • the higher the potential for abuse, the more tightly regulated the drug is
    • drugs that are not felt to have potential for abuse are not scheduled (eg. lisinopril, penicillin, simvastatin)
    • in MA such drugs are categorized as Schedule VI
  27. Federal Schedules for Drugs w/ Predicted Potential for Abuse
    • Schedule I: HIGH potential for abuse; no accepted medical use (eg. heroin)
    • Schedule II: high potential for abuse, currently accepted medical use (eg. morphine)
    • Schedule III, IV, V: LESSER potential for abuse
    • Schedule VI: all other prescription (Rx) drugs
  28. Category A Drugs
    • adequate + well controlled studies in women have DO NOT demonstrate risk to the fetus in the 1st trimester of pregnancy
    • there is no evidence of risk in later trimesters
  29. Category B Drugs
    • animal reproductive studies DO NOT indicate risk & no controlled human studies exist
    • OR animal studies DO show harm, but well controlled studies in women DO NOT
  30. Category C Drugs
    studies have shown teratogenic or embryocidal effects in animals, but no controlled studies in women EXIST or no studies are AVAILABLE in animals or women
  31. Category D Drugs
    • positive evidence of human fetal risk exists
    • benefits may outweigh risks in certain situations
  32. Category X Drugs
    • studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk
    • the risk CLEARLY outweighs benefit
  33. PHARM 2
  34. Therapeutic Window
    • the range of drug concentrations in the blood that result in a therapeutic response but no overwhelming toxicity
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  35. Agonist
    a ligand that binds to receptors, altering the proportion of then that are in their active form --> resulting in a biological response
  36. Receptor
    • a collection of cellular macromolecules that are directly involved in signaling between & within cells
    • the combination of a hormone, NT, drug, or intracellular messenger w/ its specific receptor initiates a CHANGE in cell function
  37. EC50
    • the MOLAR CONCENTRATION of an agonist that produces 50% of the maximal possible effect of that agonist (may be stimulatory OR inhibitory)
    • x-axis: concentration
    • y-axis: amount of drug bound
  38. ED50
    • the DOSE of a drug that produces, on average, a specified all-or-none response in 50% of a test population
    • OR if the response is graded the dose that produces 50% of the maximal response to that drug
    • x-axis: dose
    • y-axis: biological effect (response/maximum response)
  39. Efficacy
    • the ability for a drug to cause/reach a maximum response
    • the degree to which different agonists produce varying responses even when occupying the same proportion of receptors
  40. Affinity
    • a measure of the avidity of binding of a drug to its receptor
    • the lower the concentration needed to produce half saturation (EC50) or half maximal response (ED50) the greater the affinity
    • affinity is independent of efficacy
    • potency may be used as an indication of affinity (potency = amount you need to reach max response)
  41. examples of differing potencies & efficacies
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    • Drug A: has a greater potency; it can achieve the same effect with a SMALLER dose (dA v. dB)
    • Drug B: has a greater efficacy; it has a greater maximum effect
  42. What can be assumed if curves referring to two different drugs are PARALLEL to each other?
    • it can be assumed they're acting on the same receptor
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  43. Partial Agonist
    • a drug that even when given in high concentrations cannot elicit as large an effect as that of a full agonist acting on the same receptors
    • a partial agonist has lower EFFICACY than a full agonist, but may have a higher AFFINITY
  44. What can happen to a partial agonist in the presence of a full agonist?
    it can become/turn into a complete ANTAGONIST, turning the complete agonist into an intermediate agonist (thereby working as an antagonist/competitive inhibitor)
  45. Antagonist
    a drug that reduces the action of an agonist (often by acting/occupying the same receptor)
  46. Competitive Inhibitors
    • reversibly compete with a substrate for an enzyme's active site
    • usually resemble the substrate in structure
    • they are able to fit into the active site but cannot be acted upon by the enzyme
    • the more used, the more COMPETITION there is with substrate
  47. Competitive Antagonism
    • the binding of agonist & antagonist is mutually exclusive
    • antagonism is surmountable, i.e. can be reversed by INCREASING the concentration of agonist
    • adding both ag & antagonist results is a decrease in affinity but no change in maximal response
  48. What does a the dose-response curve of competitive antagonism look like?
    • in comparison to the original, the S-shaped curve shifts to the right but achieves the same height (maximum effect) as that produced by the agonist alone
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    •     agonist/antagonist concentration
  49. What is the effect of Competitive Inhibitors on Km and Vmax?
    Competitive Inhibitors increase Km but DO NOT alter Vmax
  50. Non-competitive Inhibitors
    • bind to the enzyme in a location OTHER THAN the active site (whether or not a substrate is present) & affect the amino acid residues of the enzyme involved in the catalysis of the reaction
    • (catalytic machinery only)
  51. Non-competitive Antagonism
    • is insurmountable
    • the agonist may inactivate some receptors, leading to a decrease in maximal response but no change in the affinity of the remaining receptors
  52. What does a the dose-response curve of noncompetitive antagonism look like?
    • in comparison to the original, the S-shaped curve shifts to the right & fails to reach the same height (maximum effect) produced by the agonist alone
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  53. Pharmacokinetics
    • what happens to the drug in the body, specifically ADME
    • A: absorption
    • D: distribution
    • M: metabolism
    • E: excretion
  54. Pharmacodynamics
    what the drug DOES to the body --> what its effect is
  55. What provides the link between pharmacokinetics and pharmacodynamics?
    • drug Concentration
    • it's the focus of the target concentration approach to rational dosing
  56. LD50
    • the dose of a drug that produces DEATH in 50% of a population of test animals
    • a cumulative dose response curve can be constructed by giving different doses to separate groups of animals
    • the assumption is made that animals killed by a low dose would CERTAINLY be killed by a higher dose (permits use of smaller # of animals)
  57. Therapeutic Index
    • LD50/ED50
    • the distance between 2 curves
    • a larger number means a safer drug
    • this ratio's a relative indication of safety
    • however drugs w/ a high therapeutic index may still be unsafe if there is an appreciable overlap of the higher doses producing efficacy w/ the lowest doses causing toxicity
  58. most drugs are:
    • weak acids or bases that exist as a mixture of charged & uncharged forms
    • the proportion of each depends on BOTH the pH & the Ka (dissociation constant)
    • the ratio of uncharged to charged forms determines the rate of diffusion across lipid membranes
  59. Acidic Drug
    • AH <--> A- + H+
    • Ka = [H+][A-]
    •           [AH]
  60. pH =
    (for a weak acid)
    • pH = pKa - log [AH]                     
    •                      [A-]

    • [AH] = 10pKa - pH
    • [A-]
  61. Basic Drug
    • BH+ <--> B + H+
    • Ka = [H+][B]
    •         [BH+]
  62. pH =
    (for a weak base)
    • pH = pKa + log [B]    
    •                     [BH+]

    •   [B]   = 10pH - pKa
    • [BH+]
  63. Asprin
    • becomes more ionized in the plasma than in the stomach, therefore the concentration gradient always seems like it's higher in the stomach than in the plasma
    • caused by ION TRAPPING
  64. Ion Trapping
    • leads to accumulation of basic drugs in the stomach, even after intravenous injection
    • also causes the secretion of basic drugs in milk in concentrations higher than in the mother's plasma
  65. How does ingesting substances which lower the pH of the environment (eg. cola or coffee) affect the absorption of a basic drug (eg. nicotine) through mucus membranes of the mouth?
    • the absorption of basic dugs DECREASES in an acidic environment (aka in a low pH)
    • nicotine is a weak base; in an acid compartment it ionizes, and therefore isn't absorbed as readily through the mucus membrane
  66. What form of a drug is reabsorbed from the kidney and what form is excreted in the urine?
    • uncharged drugs: re-absorbed into kidney medulla --> blood stream
    • ionized drug: excreted into urine
  67. How can the urine be acidified & what effect does acidifying the urine have on drug excretion?
    • ammonium chloride acidifies the urine (pH = 5)
    • when acidified, the excretion of basic drugs is favored because they're ionized in an acidic environment
    • eg. amphetamine
    • (acidic drugs, like phenobarbital or salicylic acid, are in their nonionic/lipophilic form in an acidic environment --> reabsorbed)
  68. How can the urine be alkylated & what effect does alkylating the urine have on drug excretion?
    • sodium bicarbonate alkylates the urine (pH = 8)
    • when alkylated, the excretion of acidic drugs is favored because they're ionized in a basic environment
    • eg. phenobarbital or salicylic acid; ion form
    • (basic drugs, like amphetamine, are in their nonionic/lipophilic form --> reabsorbed)
  69. Normal pH of Blood (Serum)
  70. Normal pH of the Milk
  71. Normal pH of the Stomach
  72. Normal pH of Sweat
  73. Normal pH of the Urethra
  74. Normal pH of the Vagina
  75. Normal pH of the Colon
  76. Normal pH of the Conjunctival sac
  77. Normal pH of the Duodenum
  78. Normal pH of the Jejunum & Ileum
Card Set:
Pharm Intro, Distribution, Toxicity (1/2)
2013-11-20 03:07:38

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