Prodrugs Concept & Applications
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Prodrugs Concept & Applications

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What is the role of the phosphorylated derivative of a prodrug in site-specific chemical delivery?

  • To enhance the ability to penetrate the virus
  • To increase the polarity and retain the active species inside the virus (correct)
  • To increase human toxicity
  • To allow easier diffusion across the blood-brain barrier

    • Why is 2-PAM considered an important antidote?

  • It reverses the effects of lipophilic drugs
  • It provides direct delivery to the brain
  • It prevents the oxidation of dihydropyridine
  • It acts against phosphate and carbamate acetylcholinesterase inhibitors (correct)

    • How do lipophilic esters of epinephrine like dipivefrin improve drug delivery to the eye?

  • They are readily hydrolyzed by available esterases in the eye (correct)
  • They penetrate through skin layers more efficiently
  • They act as a prodrug for polar drugs only
  • They have lower affinity for corneal tissues

    • What key characteristic allows drugs to cross the blood-brain barrier effectively?

    <p>Lipophilicity</p> Signup and view all the answers

    What triggers the release of the drug from the quaternary pyridine cation in the brain?

    <p>A second metabolic or chemical event</p> Signup and view all the answers

    What unique enzymatic process in colon bacteria aids in drug delivery to the lower GI tract?

    <p>Metabolism specific to bacterial enzymes</p> Signup and view all the answers

    What structural change characterizes hetacillin as a prodrug of ampicillin?

    <p>Formation of an imidazolidinone ring system</p> Signup and view all the answers

    Which property of the dihydropyridine derivative aids in drug delivery to the central nervous system?

    <p>Facile oxidation to a quaternary ammonium</p> Signup and view all the answers

    What is the primary advantage of using a prodrug like dihydropyridine for dopamine delivery?

    <p>It allows for easier transport across the blood-brain barrier.</p> Signup and view all the answers

    How does rolitetracycline enhance the solubility of tetracycline?

    <p>By introducing an ionizable pyrrolidine nitrogen</p> Signup and view all the answers

    Why is progabide considered an effective prodrug for γ-aminobutyric acid (GABA)?

    <p>It can easily cross the blood-brain barrier.</p> Signup and view all the answers

    What transformation do amidines undergo to form orally active prodrugs?

    <p>Acylation</p> Signup and view all the answers

    What is a notable property of sulfonamide prodrugs compared to amines?

    <p>They generate an acidic proton upon acylation.</p> Signup and view all the answers

    Idoxuridine serves as a substrate for which type of enzymes to exert its antiviral effect?

    <p>Viral phosphorylating enzymes</p> Signup and view all the answers

    Which statement correctly describes the hydrolysis of rolitetracycline?

    <p>It completely and rapidly generates active tetracycline.</p> Signup and view all the answers

    What is the function of the basic nitrogen in rolitetracycline?

    <p>To introduce additional ionizable functionality</p> Signup and view all the answers

    What is the primary purpose of a prodrug?

    <p>To convert inactive compounds into active pharmacological agents.</p> Signup and view all the answers

    Which of the following characteristics is NOT associated with hard drugs?

    <p>Are susceptible to enzymatic transformation.</p> Signup and view all the answers

    What type of prodrug involves the synthesis with either an alcohol or carboxylic acid functionality?

    <p>Ester prodrugs</p> Signup and view all the answers

    What is a significant disadvantage of hard drugs?

    <p>They are less readily eliminated due to lack of metabolism.</p> Signup and view all the answers

    Which prodrug type is known to be rapidly cleaved by plasma enzymes?

    <p>Phenyl carbamates</p> Signup and view all the answers

    How do N-Mannich bases impact the pKa of amines?

    <p>Lower the pKa by approximately three units.</p> Signup and view all the answers

    What is one benefit of using prodrugs in drug formulation?

    <p>They can increase water solubility and reduce pain at administration sites.</p> Signup and view all the answers

    Which of the following statements about soft drugs is accurate?

    <p>Their design allows them to be converted into less active compounds.</p> Signup and view all the answers

    What is the primary benefit of glycosidase activity in bacteria within the colon regarding drug administration?

    <p>It allows hydrolysis of glycoside derivatives of drugs.</p> Signup and view all the answers

    Which of the following statements is true about capecitabine as an antitumor agent?

    <p>It undergoes multiple activation steps in the liver and tumors.</p> Signup and view all the answers

    What is the key characteristic of a tripartate prodrug?

    <p>The cleavage site is distant from the carrier.</p> Signup and view all the answers

    How does the action of thymidine phosphorylase specifically benefit tumor cells?

    <p>It catalyzes the transformation of 5-deoxy-5-fluorouridine selectively in tumor cells.</p> Signup and view all the answers

    What issue does macromolecular drug delivery systems aim to address?

    <p>Overcoming limitations associated with small molecule therapies.</p> Signup and view all the answers

    Why are glycoside drug derivatives often utilized in drug delivery to the lower GI tract?

    <p>They demonstrate enhanced effectiveness after transformation.</p> Signup and view all the answers

    In the context of drug activation, which enzyme initiates the transformation of capecitabine in the liver?

    <p>Carboxylesterase</p> Signup and view all the answers

    Which factor contributes to the selective activation of prodrugs like capecitabine in tumor cells?

    <p>Higher growth rates of tumor tissues resulting in higher enzyme activity.</p> Signup and view all the answers

    What is the main advantage of using macromolecular drug carriers over traditional drug delivery methods?

    <p>They improve targeting and minimize interactions with non-target tissues.</p> Signup and view all the answers

    Which of the following is considered a disadvantage of macromolecular drug delivery systems?

    <p>Potential for poor absorption.</p> Signup and view all the answers

    What role does the spacer arm play in macromolecular drug delivery systems?

    <p>It enhances water solubility and stability of the drug.</p> Signup and view all the answers

    Which of the following drugs was mentioned as being linked to poly(vinyl alcohol) to decrease toxicity?

    <p>Aspirin</p> Signup and view all the answers

    In the context of site-specific drug delivery systems, what does the term 'homing device' refer to?

    <p>A component that ensures the drug reaches its specific site of action.</p> Signup and view all the answers

    How long did the slow-release poly(L-glutamine) formulation of norethindrone last in rats?

    <p>9 months</p> Signup and view all the answers

    What was the outcome for the mice treated with the nitrogen mustard-linked antibody in the study?

    <p>All mice remained alive and tumor-free after 60 days.</p> Signup and view all the answers

    Which type of polymers is indicated as a carrier in macromolecular drug delivery systems?

    <p>Synthetic polymers</p> Signup and view all the answers

    What is a common concern regarding the immunogenicity of macromolecular carriers?

    <p>They may provoke an immune response.</p> Signup and view all the answers

    What characteristic determines the absorption and distribution of drugs linked to macromolecular carriers?

    <p>Physicochemical properties of the macromolecular carrier</p> Signup and view all the answers

    Study Notes

    Prodrugs Concept & Applications

    • Prodrugs are compounds designed for pharmacological activity but not susceptible to metabolic or chemical transformation until the body acts upon them.
    • Hard drugs are compounds with structural characteristics necessary for activity but do not require transformation to be active.
    • Prodrugs increase metabolic efficiency by avoiding metabolism initially, resulting in no toxic metabolites.
    • However, prodrugs are less readily eliminated because metabolism is avoided.
    • Two mechanisms for prodrug activation: enzymatic and chemical.
    • Enzymatic conversion is more common, and is chemically stable degradation within the body and is patient dependent.
    • Chemical conversion is less common, chemically unstable, occurs outside the body, and is not patient dependent.

    Types of Prodrugs

    • Prodrugs contain various compounds with different functional groups.
    • Prodrugs can include esters, amides, imides, amines, and compounds with carbonyl groups.
    • Ester prodrugs easily synthesized if molecule has an alcohol or carboxylic acid.
    • Examples of prodrug types include esters, amides, and imides.
    • Esters are compounds with an ester group.
    • Amides include primary, secondary, and tertiary amine groups.
    • Imides have nitrogen double bonds.

    Functional Groups in Prodrugs

    • Carboxylic acids and alcohols are most common.
    • Includes types of esterase enzymes such as ester hydrolase and related enzymes.
    • Wide variety of alcohol promoieties available.
    • Steric, electronic, and hydrophobicity properties control the rate and extent of hydrolysis.
    • Examples include Erythromycin, an antibiotic useful in treating respiratory infections, Legionnaires' disease, and skin infections.

    Examples of Prodrugs

    • Chloramphenicol(antibiotic) is given parentrally by IM inj.
    • It is painful since it precipitates at the injection site due to low water solubility.
    • Enhancing water solubility using a polar functional group, like succinate, reduces pain.
    • Prodrugs' design often involves increasing lipid solubility or changing pH stability to improve absorption or resistance to degradation in the body or outside of the body.

    β-Lactam prodrug – Double Esters

    • Increased absorption and less acid decomposition are the goals for these prodrugs.
    • They are useful for treating upper and lower respiratory diseases, Legionnaire's disease, skin infections.

    Other Ester Prodrugs - Soluble

    • Sodium succinate prodrugs are unstable and should be used immediately.
    • They are more stable with less tendency towards hydrolysis.
    • Sulfate and phosphate prodrugs also exist.

    Example of increasing absorption by addition of a nonpolar carboxylic acid

    • Polar functional groups increase solubility and reduce pain with injection as in chloramphenicol.
    • This technique is applied to increase drug absorption and improve its clinical efficacy.
    • Pivalic acid has demonstrated effectiveness for increasing epinephrine absorption.

    Example (Double ester prodrug)

    • Cefpodoxime proxetil and cefuroxime axetil are double ester prodrugs, designed for increased water solubility for better absorption.
    • They are unstable forms of the parent active drug.

    Example (Mutual prodrug)

    • Estramustine is a prodrug combining normustard, an alkylating agent, with estradiol. This is intended for prostatic cancer treatment, using the synergistic effect of both compounds.
    • The drug is administered as an inactive form by a drug carrier, which must release the drug for it to act.

    Prodrugs for Stability (first-pass metabolism)

    • Prodrugs are used to improve drug stability and reduce metabolism or breakdown in the body.
    • They are especially important for drugs that are rapidly metabolized when first entering and are absorbed into the bloodstream.

    2-Amines

    • Amides are less commonly used as prodrugs because of high chemical stability.
    • Lack of amidase enzymes for hydrolysis is a challenge for amide prodrugs.
    • Activated amides that typically are low-basicity amines, or amides of amino acids, are more likely to be cleaved enzymatically.
    • N-Mannich bases are used to lower the pKa of amines.

    4. Human eye

    • Lipophilic esters show better corneal penetration.
    • The more polar form of the drug, epinephrine, is readily available and active in the eye, so it performs better as an antiglaucoma prodrug.

    4. Colon and lower GI tract

    • Colon bacteria demonstrate increased effectiveness when glycoside derivatives are administered.
    • Polar glycoside derivatives have poor absorption, allowing them to act as substrates for colon bacteria which are prevalent in the human colon.

    Antitumor agent

    • High growth rates in tumor tissue increase enzyme activities such as peptidases and proteases. These cells are better targets for anticancer prodrugs.
    • Capecitabine is a prodrug used to treat cancer. It is a carbamic acid that converts into 5-deoxy-5-fluorocytidine and then 5-deoxy-5-fluorouridine. The latter is a precursor to the active drug fluorouracil which acts more selectively on tumor cells.

    Chemical Delivery Systems

    • Many delivery systems use oxidative, reductive, or phosphorylation activation processes to release the drug.
    • Examples include drugs which involve bioprecursor prodrugs that are chemically activated in the body to produce the active drug form.
    • Pro-2-PAM is used to treat enzyme inhibitors in insecticides or nerve agents, since it easily crosses the blood-brain barrier (BBB).

    Tripartate Prodrugs

    • These prodrug systems use a carrier to help transport the drug to the target. They are often more effective in targeting specific sites.
    • The linkage between carrier and drug is more stable to prevent degradation during administration to the site of delivery.

    Macro-molecular Drug Carriers

    • These may be superior to short prodrugs in how well they target a particular receptor site.
    • These carriers increase the stability and bioavailability of drugs to help them reach their target.

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    Prodrugs Concept & Applications PDF

    Description

    Explore the fascinating world of prodrugs and their role in pharmacology. This quiz covers the mechanisms of prodrug activation, the differences between hard drugs and prodrugs, and the various types of prodrugs based on their chemical structure. Test your knowledge on how these compounds enhance metabolic efficiency and their implications in drug design.

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