Week 7: Workshop 1 – Prodrug strategies in drug development Flashcards
What is CYP450?
Major metabolisizing enzyme in the liver
What factors do you consider when selecting a route of administration?
- molecular properties of the drug
- physiological nature of the route
- patient compilance
- onset of action
- the condition being treated
- systemic or local effect (side effects)
- metabolism
What is a prodrug?
A prodrug is a molecule with little or no pharmacological activity that is converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two.
What are the requirements for a drug to be absorbed through the mucosal membranes that line the gut?
Must be in its lipophilic unionised from to partition out of the aqueous medium
What are the alternative administartion methods if oral administrtion and absorption is not appropriate?
- Rectal
- Vaginal
- Topical
- Buccal/ Sublingual
- Injection
- Respiratory
- Chemically modify the drug
What is resporatory administartion?
Local administration by aerosols to the lungs eg salbuatamol, nasal steroids
What is rectal administartion?
Local administration, and an alternative systemic route that avoids degrading pH and enzymes (pepsin, gastrin), although the absorbing surface is smaller.
How do you chemically modify a drug?
- Design out problemst of bioavailability
- Considre pharmacodynamic/ Pharmacokinetic balance eg steroids
- Pro drug design strategy
How do you chemically modify a drug?
- Design out problemst of bioavailability
- Considre pharmacodynamic/ Pharmacokinetic balance eg steroids
- Pro drug design strategy
Why are pro drugs designed?
To control the ADME of the drug
What determines how much of a drug is absorbed?
- LogP
- LogD
What is the absorption phase of a dose-respose curve influenced by?
pKa and log P of a drug.
What is topical administartion
Local administration with creams, ointments and drops. Systemic delivery of lipophilic drugs by transdermal patches (avoids spiking).
Describe buccal/ sublingual delivery
Fast onset of action that avoids first-pass metabolism – requires high Log P properties
Describe injections
- i.v. for rapid onset, requires water soluble forms. Cant have high logP because has to be soluble in water.
- i.m can be used for sustained-release depot injections, requires lipid-soluble forms.
How can drugs be chemically modified to improve absorption?
- Improve bioavaiablity problems by modifying lipophilicity/ hydrophilicity, enhance stability, block metabolic transformations
- always consider pharmacokinetic/ pharmacodynamic balance
- Design the drugs as pro drugs - temporary structural modification, labile functional groups mask problem being overcome, Parent drug released once absorbed
What is the active form of enalipril?
Enalaprilat
How is enalapril converted to enaliprilat?
By liver esterases
What is the logP of enalapril?
0.7 - lipophilic, so good absorption
What is the logP of enaliprilat?
-0.5 so poor absoprtion
What is the IC50 of enalipril
1.2
What is the IC50 of enaliprilat?
0.0012 - good pharmacodynamic activity
What is the ester carbonyl group?
A weak electrophile and relies on attack by a weakly nucleophilic water molecule
What is an esterase?
Enzymes used to catylyse the hydrolysis of ester groups.
What does the active site of an esterase contain?
Asp, His, Ser residue
What does asp in an esterase act as?
Base - Proton acceptor
What does His in an esterase act as?
Acid - Proton donor, donates proton to carbonyl group
What does Ser in an esterase act as?
strong nucleophile
When are IV injections required?
- Low bioavaibility of other routes
- Unable to dose by other routes
- Fast onset needed
What physicochemical properties must a drug have to be administered by intravenous injection?
- Good aqueous solubility
- Low logP, logD
- Low tendancy to precipitate in blood plasma
What is IV promethazine used to treat?
Anaphylaxis
What is IV doxapram used to treat?
Respiratory failure
What is IV diclofenac used to treat?
Inflammation
What is the target drug for promethazine?
α1-adrenergic receptor
(vasodilation)
What is the target drug for doxapram?
Potassium channel blocker
(respiratory stimulant)
What is the target drug for diclofenac?
COX enzymes (COX-2)
(reduced inflammatory response)
What is the pKa of promethazine?
9
What is the pKa of doxapram?
8
What is the pKa of diclofenac?
4
What state would promethazine need to be formulates as for an IV injection?
Promethazine HCl
What state would doxapram need to be formulates as for an IV injection?
Doxapram HCl
What state would diclofenac need to be formulates as for an IV injection?
Diclofenac sodium
What do acute hypersensitivity reactions require?
i.v. administration of hydrocortisone
What may be required for anaphylactic shock or angioeadema of the upper respiraory tract?
100-300mg of hydrocortisone
What is the salt form of hydrocortisone?
Hydrocortisone Sodium Succinate
