pharmacodynamics - prodrugs Flashcards
(36 cards)
prodrug definition
inactive forms of drugs that are metabolised to the active form in vivo
give 3 reasons why prodrugs are used
- improves patient acceptability
- alters + improves absorption
- alters biodistribution/metabolism/elimination
promoiety definition
non toxic group that is attached to drug to improve characteristics and is enzymatically removed when required
give 2 examples of prodrugs
aspirin - has an ester group which is hydrolysed into salicylic acid + carboxylic acid, used because salicylic acid can cause mouth ulcers
L-dopa - inactive amino acid structure, is decarboxylated into dopamine, used so drug can pass blood brain barrier
how does plasma protein binding affect drug action?
drugs can bind to proteins in blood, this lowers [free drug] in systemic circulation
what 2 proteins are the main plasma proteins that drugs bind to?
HSA - human serum albumin
AGP - α-acid glycoprotein
give 4 effects of plasma protein binding
- level of distribution/where drug ends up
- onset of action, this is why loading doses are used before starting treatments, drug won’t have an effect initially as too much is bound to proteins/inactive
- duration of action, increased binding means drug is in circulation for longer, harder to metabolise/excrete
- drug/drug interactions, a second drug can affect plasma protein binding changing [free drug]
when does plasma protein binding have more extreme affects?
when considering drugs that bind to plasma proteins to a higher degree
why is consideration of plasma protein binding especially important for drugs with a low therapeutic index?
low therapeutic index means there is a narrow margin between therapeutic dose and toxic dose
if a particular dosage has been given that accounts for plasma protein binding, administration of a second drug could push out some of the first drug, making the dosage toxic
what is the BCS and how does it classify drugs?
biopharmaceutical classification system
used to describe drugs in terms of dissolution, water solubility and intestinal permeability, overall essentially described absorption
what are the 4 classes within the BCS?
class I = ideal, high solubility, high permeability
class II = low solubility, high permeability
class III = high solubility, low permeability
(most drugs are class II/III)
class IV = low solubility, low permeability
how does the BCS relate to prodrugs?
many prodrugs are derived from parent drugs in classes II/III, where the prodrug form enhances either solubility or permeability
what is the BDDCS and how does it classify drugs?
biopharmaceutics drug disposition classification system
used to describe drugs in terms of solubility and metabolism
what are the 4 classes within the BDDCS?
class I = ideal, high solubility, extensive metabolism
class II = low solubility, extensive metabolism
class III = high solubility, poor metabolism
class IV = low solubility, poor metabolism
(again most drugs are class II/III)
are drug classes consistent between BCS and BDDCS?
no, drugs can switch between classes between these 2 characterisations
give 8 issues that can be solved by prodrugs
- low oral bioavailability/non-linear exposure with dose
- pH dependent absorption
- high pill burden, formulation issues
- high intersubject pharmacokinetic variability
- high dosing frequency
- poor drug exposure at therapeutic site
- dose related toxicity
- chemical instability
how can prodrugs fix low oral bioavailability?
this is due to poor solubility/permeability, prodrug can enhance this by increasing polarity/lipophilicity
(enhancing polarity also reduces loading and crystallisation)
how can prodrugs fix pH dependent absorption?
this is due to pH dependent solubility, prodrug can enhance solubility as specific pHs
how can prodrugs fix high pill burdens/formulation issues?
this is due to low solubility, prodrug can enhance this
pharmacokinetic variation definition
when there is variability in the drug concentration at the effector site after administration of a standard dose - this means a dose can be ineffective in one patient but potentially toxic with unwanted side effects in another
how can prodrugs fix intersubject pharmacokinetic variability?
this is due to first pass metabolism, prodrugs can be used to slow or bypass this
how can prodrugs fix high dosing frequency?
this is due to a drugs short half life, prodrug can extent half life or allow sustained/slow release, some large lipophilic modifiers can be used to localise a drug in an inactive location e.g. as fatty tissue, from where the prodrug/active drug is slowly released form fat over time
how can prodrugs fix poor drug exposure at therapeutic site?
this is due to non-selective delivery, prodrug can help to target a specific site + deliver drug to it, some large lipophilic modifiers can be used to localise a drug in an inactive location e.g. as fatty tissue, from where the prodrug/active drug is slowly released form fat over time
how can prodrugs fix dose related toxicity?
this is due to non-selective action on tissues, prodrug can help to target a specific site + deliver drug to it, can also help to use a slow-release mechanism to minimise toxic effects
