Drug metabolism Flashcards
what is the role of drug metabolism?
reduces/eliminates pharmacological activity
converts lipophilic chemicals to polar derivatives that can be readily excreted
what is the main site of drug metabolism?
the liver (hepatic first pass)
if all is metabolised at this point, no biological effect in the kidney
what is phase 1 of metabolism?
what reactions does it include?
introduction of a function group the drug
this is the point of attachment for phase 2 reactions
oxidation, reduction, hydrolysis
what do the phase 1 reactions do?
oxidation and reduction add function groups
hydrolysis unmasks the functional group
they produce metabolites that are inert or active (for prolonged effect e.g. cannabis) they can be toxic
they change the polarity of the drug a little
what do the phase 1 reactions produce?
oxidation produces electrophiles
reduction and hydrolysis produce nucleophiles
what does phase 2 do?
adds a larger polar group (water soluble conjugate) to the reactive group for excretion
which phase 1 reaction is most common?
oxidation (after the hydroxylation reaction has occurred via P450 system)
example of drug activation by metabolism
codeine is inert and metabolised to produce morphine (prodrug) which is the active ingredient
what enzymes are involved in phase 1?
cytochrome p450 enzymes
57 subtypes/isoenzymes , predominantly found in the liver
what happens to the phase 1 products i.e. the electrophiles and nucleophiles?
electrophiles undergo glutathione conjugation (occurs only with electrophiles)
nucleophiles undergo glucuronidation, acetylation and sulphation
these reactions require conjugation agents that target the reactive group added in phase 1
what is the most common phase 2 reaction?
glucuronidation- low affinity/high capacity reaction
only a small proportion of the large concentration of reactant becomes the final product
how efficient is sulphation in terms of affinity and capacity?
high affinity/low capacity
a small amount of reactant is converted to the final product as the reaction is very effective
e.g low amount of paracetamol can be completely sulphated but as conc of paracetamol is higher, glucuronidation is favoured
what are the less common phase 2 reactions?
acetylation
methylation
amino acid conjugation (of either the carboxyl group or the amino group)
Paracetamol overdose
creates reactive intermediate NAPQI which then is conjugated with glutathione
an overdose overwhelms the glutathione stores and leaves lot of reactive NAPQI intermediate
overall effects of metabolism
decreases the half life of the drug
altered the biological activity of a drug
toxicology, potency, pharmacology, duration is altered
accumulation is prevented
