Lecture 8 Flashcards
what is a prodrug?
an inactive precursor of a drug, converted into its active form in the body by metabolic processes.
designed to maximise effectiveness of a drug
prodrugs are used to tackle what?
-problems with solubility
- poor membrane permeability
- drug toxicity
- bad taste
- short duration of action
prodrugs oral administration
- enters through GI tract (mouth, throat, stomach, intestines) (acid liable drugs; early penicillin and insulin cannot be given orally)
- if the drug survives the stomach, it enters the upper intestine in which it must penetrate the gut wall to be absorbed into the blood stream.
- the drug is then transported to the liver where it can be metabolised (1st pass effect)
or it may move to its target site
what is not mandatory for successful oral administration?
- acid liability
- good lipophilic balance
- resistance to stomach and liver enzymes
why are prodrugs useful for drugs given intravenously (through veins)
high concentrations and low volumes can be given
prodrugs to increase water soluability
the drug chloramphenicol, used as a potent broad-spectrum
antibiotic, exhibits poor water solubility. Conversion to its succinate ester
increases the solubility due to the extra carboxylic acid.
what is released when the ester is hydrolysed in vivo
- chloramphenicol
- succinic acid (naturally present in body)
what effect does increasing water solubility of prodrugs have?
proved useful in reducing the pain associated with some injectables.
what have polar prodrugs been used to improve?
the absorption of non-polar drugs from the gut
why do drugs have to have some water solubility if they are to be absorbed?
because they will dissolve is adipose tissue and fail to interact effectively with the gut wall.
what can polar groups such as carboxylic acids do in drug binding?
they can prevent a drug from crossing the cell membrane
how is the problem of polar groups preventing drugs from crossing the cell membrane overcame?
the group is masked in the form of an ester,
which is cleaved upon entry to the cell by enzymes, to yield the active drug
what is an example of an antibiotic prodrug?
pivampicillin (ampicillin)
an extended ester, that contains a second ester group further away from the penicillin molecular framework.
why are conventional monoesters, prepared from methanol (or ethanol) unsuitable as prodrug?
they become “hidden” from the esterase enzymes by the penicillin molecular framework (steric effect).
are all esters hydrolysed with equal efficiency?
no
how are esters made more susceptible to hydrolysis?
by adding electron withdrawing groups to the alcohol component of the ester
This makes the alcohol a better leaving group by stabilising the negative charge on the oxygen atom.
what is dipivefrin?
a prodrug of the antiglaucoma drug epinephrine
dipivaloyl esters allow for greater corneal permeability and are subsequently hydrolysed by corneal and aqueous humor esterases to release epinephrine
another method used to transport drugs across the cell membrane
taking advantage of carrier proteins in the cell membrane
what are certain carrier proteins responsible for?
transporting amino acids in and out of the cell
prodrug of dopamine?
L-dopa (levodopa) used to treat Parkinson’s disease.
why can’t dopamine itself be used?
it is too polar to cross the blood brain barrier
Conversion of dopamine, to the amino acid L-Dopa (although still polar), results in its transport across the blood-brain barrier by carrier proteins.
what is D-Alkylation?
The open ring analogs of alprazolam (anxiolytic) and triazolam (sedative),
which are members of the benzodiazepine family, undergo N-dealkyation
catalysed by Cytochrome P450 followed by spontaneous cyclisation.
what is epoxidation?
Carbamazepine, used in the treatment of epilepsy, is metabolically
transformed to the active epoxide derivative.
