W24 Steroids and Prodrugs (MM) Flashcards
What are prodrugs?
- Compounds that are pharmacologically inert but can be converted by an enzyme or chemical action to an active form of the drug, at or near their target site
- Inactive compounds that yield an active compound in the body – usually converted by enzymes
How does Levodopa work as a prodrug?
Levodopa – Used to treat Parkinson’s syndrome, is a prodrug for the neurotransmitter dopamine. Dopamine is too polar to cross the BBB but there is a transport system for amino acids, such as levodopa. Once it enters the brain it is decarboxylated to dopamine
What are some uses of prodrugs? (7)
- Increase solubility (lipid or water)
- Improve taste
- Increase stability (biological and chemical)
- Reduce toxicity
- Modify the time of duration of action
- Deliver drugs to specific site in the body
- Alleviate pain when administered by injection
What are the 2 main classes of prodrugs?
Bioprecursor and Carrier
What are bioprecursor prodrugs?
- Molecules that already contain the embryo of the active species within their structure
- Rely on metabolic or chemical modification
- Can involve one step, or a series of steps (oxidation or reduction)
What are carrier prodrugs?
- Combination of active drug and carrier species
- Example: lipophilic carrier transport drug across membranes
- The link between the carrier and active species must be a group that is easily metabolised e.g. ester or amide
To convert a bioprecursor prodrug to the active compound may involve a single step or a series of steps. What are the most common steps? (3)
Oxidation
Reduction
Phosphorylation
Note: There are fewer reductive enzymes in the body than oxidative enzymes
What is the criteria to be met by carrier prodrugs? (6)
- The prodrug should be less toxic than the drug
- The prodrug should be significantly less active (or inactive) than the parent drug
- The rate of formation of the active form from the prodrug should be rapid enough to maintain the drug’s concentration within the therapeutic window
- The metabolites from the prodrug should be non-toxic
- The prodrug should improve bioavailability if administered orally
- The prodrug should be site specific
What are the specific uses of carrier prodrugs?
- Improving absorption and transport through membranes
- Slow release e.g. slow hydrolysis of ester- and amide-linked fatty acid carriers
- Site-specificity e.g. hydrophilic drugs with lipophilic carriers to cross the blood-brain barrier (dihydropyridine is a particularly useful carrier)
- Minimising side effects e.g. aspirin is a prodrug for salicylic acid to minimise bleeding in the GI tract
- Improving drug stability e.g. adding metabolically labile groups so stable to undergo first-pass metabolism
- Antibody-directed enzyme prodrug therapy (ADEPT) – used to target cancer cells
What is protide technology?
A prodrug method devised to deliver nucleoside monophosphate intracellularly
Applications include:
* Antiviral medications such as carbocyclic adenosine derivatives
* Carbocyclic nucleosides such as
Abacavir (Anti-HIV medication)
* Stampidine – a nucleoside reverse
transcriptase inhibitor
* Remdesivir - Covid
* Advances in cancer treatments
* Parkinson’s disease treatments
What are steroids?
Important endogenous hormones found in many life forms:
* They all share a common tetracyclic structure but
have different functional groups and substituents
* The stereochemistry of the three 6-membered
rings in fully saturated steroids is identical in all
mammalian steroids (chair conformation)
* Only 1 stereoisomer occurs naturally for any
particular steroids despite having multiple
stereocentres
Which one of the following is not a common use of prodrugs?
a. Increase lipid solubility
b. Increase water solubility
c. Alleviate pain when administered by injection
d. Decrease biological stability
=D
Which one of the following statements about prodrugs is true?
. Carrier prodrugs are a combination of active drug and carrier species
b. Bioprecursor prodrugs are independent of metabolic modifications
c. Bioprecursor prodrugs always involve only one step (oxidation or reduction)
d. Not all prodrugs need to be modified in order for the active species to be release
=A
Methoxsalen is a photoactivated drug for the treatment of vitiligo and psoriasis. Which of the following is not a
possible transition from the triple excited energy state of a photoactivated drug?
a. Reaction with substrate
b. Decay with fluorescence
c. Formation of singlet oxygen which reacts with the substrate
d. Decay with phosphorescence
=B
What is the history behind Psoralen? (for info)
- Psoralen and derivatives have been
used since ancient times –documented use from over 3500 years ago by Egyptian and Indian
healers - Folk healers applied poultices of psoralen-containing plants to their patients’ skin and exposed these areas to sunlight (treatment of
vitiligo) - In 1950’s, El-Motfy identified psoralens as the natural products responsible for these therapeutic effects
