W8.4_Prodrugs Flashcards
State the different equations explaining the equilibria in drug absorption (3). What are the factors affecting each of them?
- Drug(s) ⇌ Drug(aq)
- LogP, lattice interactions
- Drug(aq) ⇌ Ionised drug(aq)
- pKa, pH
- Drug(aq) in GI tract ⇌ Drug(aq) in blood
- LogD, molecular weight, hydrogen bonds
Explain why drugs acting on the CNS and gram-negative bacteria have more stringent permeability rules. State the usual range of pKa in drugs and the consequence of being out of range. Explain why most drugs are charged despite its drawback.
- Drugs acting on CNS/gram-negative bacteria: high expression of efflux pumps and tight junctions between cells in blood-brain barrier/bacterial cell membrane -> permeability rules are more stringent
- Usual range of pKa of drugs: 4-11
- Concentration of passively permeable drugs would be too low if outside of range
- Most drugs are charged
- Improved dissolution and aqueous solubility could compensate the potential reduction in permeability (ionisation equilibrium is much faster than dissolution/precipitation equilibria)
State the usual range of logP in drugs and the consequence of being out of range. What are the exemptions of logP restrictions in some of the drugs? Describe the permeability of zwitterionic drugs.
- Usual range of logP of drugs: 1-4
- Out of range indicates poor solubility and limited absorption
- Exemptions/different criteria:
- Parenteral administration requires high solubility
- CNS penetrant drugs require very high permeability/active uptake
- Zwitterions: able to permeate membrane due to neutrality but typically very low passive permeability due to highly charged nature
Explain how some drug compounds can be taken by active transport. State the ways to increase chemical stability in esters (2).
- Drug compounds structurally related to substrates of transporters (ex. nucleotides, amino acids, carbohydrates) can be taken by active transport (ex. vidarabine, gabapentin, miglitol)
- Ways to increase chemical stability in esters (unfavourable in long-lasting drugs)
- Convert to a more stable group (ex. procaine into lidocaine with amide)
- Increase steric hindrance around carbonyl to block nucleophilic attack
Define prodrug. State the uses of prodrugs (5).
- Definition of prodrug: chemically altered in body before exhibiting its desired pharmacological effects
- Uses of prodrugs:
- Improve membrane permeability
- Prolong activity
- Mask toxicity and side effects
- Increase water solubility
- Target drugs to specific tissues
Describe the mechanism of phosphate prodrugs by giving an example. Explain the rise of resistance to nucleoside therapeutics and the way to overcome it.
- ex. acyclovir
- Enter cell by passive diffusion/active transport -> phosphorylated by kinases -> bind to nucleosides to cause drug action
- Phosphate forms are too polar and highly charged, thus are not recognised by nucleoside transporters and enter the cell by passive diffusion
- When enzyme that conducts first phosphorylation mutates -> often causes resistance to nucleoside therapeutics
- To overcome: create a new prodrug that masks the phosphate groups, increase logP, and be neutral -> convert back to phosphate form by intracellular enzymes
Explain the mechanisms and purposes of ester prodrugs (3).
- Mask polar and ionisable carboxylic acids that are used for target binding to increase permeability-> hydrolysed by esterases in blood/cells (leaving alcohol group should be non-toxic) (ex. enalapril -> enalaprilat)
- Change administration route from oral to intramuscular injection and allow long-lasting action by increasing lipophilicity (ex. fluphenazine decanoate -> fluphenazine)
- Mask phenol group that may cause stomach ulcers (ex. aspirin -> salicylic acid)
Explain the downside of thiol group in drug compounds.
- Thiol group (-SH) can form chelates with zinc and cause toxicity and taste masking (thus new drug compound has to be discovered)
