MSOP1016 Lecture 3: Prodrugs and Optimising Access to the Target
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Questions and Answers

What is the main purpose of a carrier prodrug?

  • Decrease bioavailability of the drug
  • Increase toxicity of the drug
  • Enhance chemical and biological characteristics of the drug (correct)
  • Extend the duration of action of the drug

    • In prodrug design, why are simple aliphatic or aromatic esters not preferred?

  • Due to higher toxicity in vivo
  • Because they lead to extremely rapid drug metabolism
  • As they are not labile enough in vivo, resulting in poor conversion of the pro-drug (correct)
  • Because they enhance the drug's solubility

    • What issues can a prodrug help resolve?

  • Increasing drug toxicity
  • Enhancing drug resistance
  • Reducing bioavailability
  • Improving patient compliance (correct)

    • What is the classification based on in broad classification of prodrugs?

    <p>Based on acid sensitivity</p> Signup and view all the answers

    Why are carrier prodrugs formed by combining an active drug with a carrier?

    <p>To form a compound with desired chemical and biological characteristics</p> Signup and view all the answers

    What is the key advantage of a bioprecursor prodrug?

    <p>The active drug is already present within its structure</p> Signup and view all the answers

    What is the purpose of using drug carbidopa in conjunction with levodopa for Parkinson's treatment?

    <p>To prevent the degradation of levodopa by dopa decarboxylase before it reaches the brain</p> Signup and view all the answers

    Why is it challenging to use peptides and proteins directly as drugs?

    <p>They are too large and highly charged to easily cross into cells</p> Signup and view all the answers

    Why are antibodies important in drug therapy?

    <p>They can be used to target specific cells or parts of the body for drug delivery</p> Signup and view all the answers

    Which strategy is NOT used to optimize access to a drug target?

    <p>Using endogenous compounds directly as drugs</p> Signup and view all the answers

    What is a key concern regarding the use of natural hormones as drugs?

    <p>They are susceptible to adverse immune reactions when administered orally</p> Signup and view all the answers

    How are oligonucleotides stabilized for drug development?

    <p>By modifying their sugar-phosphate backbone to avoid enzymatic recognition</p> Signup and view all the answers

    What is the main advantage of designing prodrugs for drug delivery to the brain?

    <p>Crossing the blood-brain barrier</p> Signup and view all the answers

    Why are prodrugs linked to a polymer for colon delivery?

    <p>To prevent absorption and enable colonic release</p> Signup and view all the answers

    Which characteristic is NOT an ideal property of an effective prodrug?

    <p>High toxicity compared to the drug</p> Signup and view all the answers

    Why are carrier prodrugs designed for site specificity?

    <p>To transfer the drug to the specific site of action</p> Signup and view all the answers

    What is a key reason for designing prodrugs for improved solubility?

    <p>Essential for parenteral dosage forms</p> Signup and view all the answers

    How does a prodrug linked to a lipophilic carrier aid in brain drug delivery?

    <p>By crossing the blood-brain barrier efficiently</p> Signup and view all the answers

    What is the purpose of designing prodrugs for colon delivery?

    <p>To release the drug in the colon by bacterial enzymes</p> Signup and view all the answers

    Why does a prodrug have higher affinity for a specific site?

    <p>To enhance drug delivery to the target site</p> Signup and view all the answers

    What does a prodrug linked to a polymer achieve in colon delivery?

    <p>It prevents absorption and allows colonic release.</p> Signup and view all the answers

    Which is a common reason for designing prodrugs with a lipophilic carrier for brain delivery?

    <p>To facilitate crossing the blood-brain barrier and targeted release in the brain.</p> Signup and view all the answers

    Which approach is commonly used for esters/amides to block the approach of nucleophile or enzyme?

    <p>Steric shields</p> Signup and view all the answers

    What modification can be used to make drugs less resistant to metabolism?

    <p>Introducing metabolically susceptible groups</p> Signup and view all the answers

    Which modification can reduce the metabolic susceptibility of drugs?

    <p>Ortho phenol of noradrenaline</p> Signup and view all the answers

    For what purpose are prodrugs typically used?

    <p>To increase drug absorption</p> Signup and view all the answers

    Which type of drug is given alongside analgesics for migraine to increase absorption?

    <p>'Sentry' drug</p> Signup and view all the answers

    What is the major goal of modifying drugs to target exact locations?

    <p>Reduce side effects and toxicity</p> Signup and view all the answers

    Which approach involves attaching drugs to important building blocks needed by rapidly dividing tumor cells?

    <p>'Targeting' drugs</p> Signup and view all the answers

    'Chlorpropamide (X = Cl, n = 2)' was modified from which anti-diabetic drug?

    <p>'Tolbutamide (X = Me, n = 3)'</p> Signup and view all the answers

    'Levodopa' is a prodrug for which neurotransmitter?

    <p>'Dopamine'</p> Signup and view all the answers

    'A group that can't be important for binding can be masked temporarily in which type of modification?'

    <p>'Group shifts'</p> Signup and view all the answers

    What is the key factor that influences a drug's solubility and ADME?

    <p>Optimizing hydrophilic/hydrophobic properties</p> Signup and view all the answers

    Which type of drugs are preferentially distributed to hydrophobic compartments like the lipid bilayers of cells?

    <p>Hydrophobic drugs</p> Signup and view all the answers

    Why are too polar/hydrophilic drugs unable to cross cell membranes effectively?

    <p>They cannot cross cell membranes due to their properties</p> Signup and view all the answers

    What is the measure of a chemical substance's hydrophobic or hydrophilic nature?

    <p>Partition Coefficient (P)</p> Signup and view all the answers

    Which strategy can help in improving a drug's absorption by increasing molecular flexibility?

    <p>Implementing a rigidification strategy</p> Signup and view all the answers

    What type of modifications for polar groups can be used as bioisosteres?

    <p>-NH2 to -NHR or -NR2</p> Signup and view all the answers

    Which type of substituents can be varied to alter a drug's pKa value?

    <p>-N-alkyl substituents</p> Signup and view all the answers

    Why is it important to be cautious when changing substituents in drugs?

    <p>To ensure good binding properties are maintained</p> Signup and view all the answers

    Which type of modifications can help improve a drug's efficacy by making it more resistant to hydrolysis?

    <p>-SO3H to -SO2R</p> Signup and view all the answers

    What is the purpose of prodrugs like Lisdexamphetamine and Methyldopa?

    <p>To target specific areas within the body</p> Signup and view all the answers

    Why are dipeptide analogues of Methyldopa preferred over Methyldopa?

    <p>They have increased intestinal absorption due to PepT1 transporter</p> Signup and view all the answers

    What makes Lisdexamphetamine inactive prior to its absorption?

    <p>Essential amino acid L-lysine</p> Signup and view all the answers

    How does Methyldopa act as an antihypertensive?

    <p>By inhibiting DOPA decarboxylase in the brain</p> Signup and view all the answers

    How does Lisdexamphetamine become active after GI absorption?

    <p>By enzymatic cleavage by enzymes in red blood cells</p> Signup and view all the answers

    What is a common feature of prodrugs like Prodrug Parecoxib, Nalbumetone, and Lisdexamphetamine?

    <p>They are all designed to avoid GI irritation</p> Signup and view all the answers

    Which strategy is NOT mentioned for optimizing access to drug targets?

    <p>Eliminating drug toxicity by faster release</p> Signup and view all the answers

    What role does the PepT1 transporter play in enhancing drug properties?

    <p>It enhances intestinal absorption of dipeptide analogues</p> Signup and view all the answers

    Study Notes

    Prodrugs and Optimizing Access to the Target

    • A prodrug is a pharmacologically inactive compound that is metabolized to the active drug by chemical or enzymatic process.
    • Prodrugs can be used to resolve issues of acid sensitivity, poor membrane permeability, toxicity, bad taste, short duration of action, etc.
    • Bioprecursor prodrugs have the active drug already inside the structure, whereas carrier prodrugs are formed by combining an active drug with a carrier to form a compound with desired chemical and biological characteristics.

    Design Strategies for Prodrugs

    • Improve oral bioavailability
    • Improve patient compliance
    • Improve solubility
    • Improve site specificity
    • Improve resistance to chemical and enzymatic degradation
    • Decrease resistance to drug metabolism
    • Targeting drugs
    • Drug alliances
    • Endogenous compounds as drugs

    Prodrug Design for Better Patient Acceptance

    • Masking bitter taste or odor of the drug
    • Improve solubility for parenteral dosage forms
    • Use of palmitate ester in liquid formulations to mask bitter taste of chloramphenicol

    Prodrug Design for Improved Solubility

    • Use of disodium phosphate or hemi-succinate prodrugs to improve solubility
    • Example: dexamethasone disodium phosphate

    Prodrug Design for Site Specificity

    • Design prodrugs that have a higher affinity for the specific site of action
    • Use an enzyme that is mainly found at the target site to release the drug
    • Example: brain delivery using dihydropyridine system

    Prodrug Design for Brain Delivery

    • Use a lipophilic carrier that distributes quickly in the body but eliminates quickly from other organs except the brain
    • Use an enzyme that is mainly found in the brain to release the drug

    Prodrug Design for Colon Delivery

    • Link the active drug to a polymer to produce a prodrug that cannot be absorbed
    • The drug is released in the colon by bacterial reductive enzyme

    Resistance to Chemical and Enzymatic Degradation

    • Use bioisosteres to stabilize labile functional groups
    • Block susceptible positions
    • Remove or replace susceptible metabolic groups
    • Use fluoro substituent or H/D exchange
    • Group shifts to move vulnerable groups
    • Ring variation and ring substituents
    • Introduce metabolically susceptible groups to reduce toxicity

    Targeting Drugs

    • Use targeting strategies to deliver the drug to the specific site of action
    • Examples: tumor cells, gastrointestinal infections, peripheral regions, and nervous system

    Drug Alliances

    • Use a second drug to guard or assist the principal drug
    • Examples: metaclopromide with analgesics for migraine, adrenaline with procaine for localized anesthesia

    Endogenous Compounds as Drugs

    • Natural hormones as drugs
    • Peptides and proteins as drugs
    • Oligonucleotides as drugs
    • Antibodies as drugs

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    Description

    Join Dr. A. Edwards, Senior Lecturer in Pharmaceutical Chemistry at Medway School of Pharmacy, as he covers the topic of Prodrugs and Optimising Access to the Target in this lecture. Recommended reading includes 'An introduction to medicinal chemistry' by Graham Patrick.

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