1. Prodrugs:
    1958 – refers to a
    pharmacologically inactive compound that is transformed by the mammalian system
    into an active substance by either chemical or metabolic means. Includes:
    • –Cmpds designed to undergo a
    • transformation to yield an active substance
    • –Cmpds that were discovered by
    • serendipity
  2. Drug Latentiation
    • 1959-
    • refers to drugs that were/are specifically designed to require bioactivation
  3. Advantages for prodrugs
    • Reduce pain associated with administration
    • Alter absorption (increased)
    • Alter distribution
    • Alter metabolism (decreased)
    • Alter elimination
    • Elimination of unpleasant taste associated with drug
    • Decreased toxicity
    • Increased chemical stability
    • Prolonged or shortened duration of action
  4. Hard Drugs
    • Compounds designed to contain the structural
    • characteristics necessary for pharmacological activity, but in a form that is not susceptible to
    • metabolic or chemical transformation
  5. Characteristics of Hard Drugs
    • Production of toxic metabolites is avoided
    • Increased efficiency of action
    • Less readily eliminated
  6. Soft Drugs
    Active compounds that after exerting their desired pharmacological effect are designed to undergo metabolic inactivation to give a nontoxic product
  7. Mechanisms of prodrugs:
    • Metabolizing enzymes (most often)
    • Chemical means [hydrolysis, decarboxylation)] (less common)
  8. Advantages and disadvantages of prodrugs by chemical means:
    • Chemical transformation does NOT depend on the presence or relative amounts of metabolizing enzymes; less interpatient variability
    • These compounds are generally chemically unstable – problems with storage or shelf-life
  9. Disadvantages of metabolizing enzymes for prodrugs:
    All of us have different metabolic profiles
  10. Carrier-linked prodrugs
    Drugs which have been attached through a metabolically labile linkage to another molecule (promoiety)
  11. What is a promoiety involved in carrier-linked
    • Kicked off; The promoiety is not necessary for activity but may impart some desirable property to the drug, such as increased lipid, water solubility, or site-directed delivery
    • Ex. chloramphenicol
  12. Bioprecursor prodrugs
    Drugs contain no promoiety, but rather rely on metabolism to introduce the functionality necessary to create an active species
  13. Example of Bioprecursor prodrugs
    NSAID sulindac is inactive as the sulfoxide and must be reduced metabolically to the active sulfide (Slide 12)
  14. Selection of the appropriate promoiety depends on which properties are sought for the agent:
    • If goal to increase water solubility, then a promoiety containing an ionizable function or numerous polar functional groups is used
    • If goal to increase lipid solubility or decrease water solubility, then add a nonpolar promoiety
  15. What does the ability to prepare prodrugs require?
    Either a hydroxyl group or carboxyl moiety present in the molecule
  16. What are some important characteristics of a promoiety?
    The promoiety should be easily and completely removed after it has served its function (able solubility and absorption) and should also be nontoxic
  17. Mutual Prodrugs
    A slight variation on the carrier-linked prodrug in which the carrier (promoiety) also has activity; both have to be therapeutic
  18. Example of Mutual Prodrug:
    • Estramustine (used in the treatment of prostate cancer)
    • Steroid portion directs drug to prostate, then hydrolysis occurs to give the normustard and CO2. The normustard then acts as an alkylating agent, exerting a cytotoxic effect. The estradiol also has an antiandrogenic effect on the prostate and slows cancer cell growth
  19. Bioprecursor example
    • Metabolism of Sulindac:
    • Sulindac is administered orally, absorbed in the small intestine and subsequently reduced to the active species
    • Administration of the inactive form reduces GI irritation
  20. Meaning of "Participation of alternate
    metabolic paths may inactivate the compound"
    If you administers 100 gm of that and 50 percent become inactive then the other 50 may go to the reduced form but since it has to be in equilibrium- but eventually it will all become active but is important to consider with dosage
  21. Major types of prodrugs (carrier-linked)
    • Carboxylic acids and alcohols
    • Amines
    • Azo linkage
    • Carbonyl compounds
  22. Other factors contributing to the popularity of ester prodrugs:
    • Ease of formation (synthesis) –if drug molecule already contains an alcohol or carboxylic acid, it’s an easy synthesis
    • Can introduce a wide range of lipophilic or hydrophilic properties to the drug
    • Manipulation of the steric and electronic properties of the promoiety allows control of the rate and extent of hydrolysis
  23. What should be done to decrease water solubility?
    Nonpolar alcohol or carboxylic acid choosen as promoiety
  24. What are the benefits of decreasing hydrophilicity of compound?
    • Increased absorption
    • Decreased dissolution in aqueous environment (stomach)
    • Longer duration of action
  25. Example of decreasing water solubilty:
    • Dipivefrin HCl (glaucoma)
    • Prodrug form of epinephrine in which the catechol hydroxyl groups used in the formation of an ester linkage with pivalic acid
    • Increased lipophilicity (relative to epinephrine) allows the agent to move across the eye easily and achieve higher intraocular concentrations
  26. Additional benefits of decreasing H20 solubility besides increasing absorption?
    • # of drugs have an unpleasant
    • taste when given orally, dissolves, and interacts with tast receptors
    • Problem with pediatric patients
    • A prodrug which reduces water solubility will not appreciably dissolve in the mouth
  27. Bioprecursor Prodrugs
    Do NOT contain a carrier or promoiety, but rather contain a latent functionality that is metabolically or chemically transformed to the active drug molecule
  28. Bioprecursor Prodrug activation:
    • Oxidation (most common)
    • Reduction
    • Phosphorylation (widely exploited in the development of antiviral agents)
    • In some cases, chemical activation
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