Drug Interactions - Metabolism Flashcards
What are the different phases of metabolism?
phase 1
- reactions involve oxidation, reduction and hydrolysis
phase 2
- reactions involve conjugation (e.g. glucuronidation) of a reactive group (often inserted during phase I reaction)
What is phase 1 of metabolism?
phase 1
- reactions involve oxidation, reduction and hydrolysis
- makes the compound more chemically reactive
has 3 possible results
- drug becomes completely inactive
= metabolites are pharmacologically inactive
- one of more of the metabolites are active but is less active than the drug
- original substance was not pharmacologically active but the metabolite is
= from pro-drug to active metabolite
products which can be pharmacologically active or toxic
What is phase 2 of metabolism?
phase 2
- reactions involve conjugation of a reactive group (often inserted during phase I reaction) and usually lead to inactive and polar products that are readily excreted (mainly by the kidney)
= conjugation means it is attached to an ionisable group which is excreted
some conjugated products are excreted via bile and some are reactivated in the intestine and then reabsorbed
What is the liver?
the liver serves as the main organ responsible for drug metabolism
What are the two mechanisms of drug interaction in metabolism?
drug interactions involving metabolism occur when the metabolism of Drug A is either inhibited or increased by Drug B
methods
- enzyme induction
- enzyme inhibition
What is enzyme induction? What is the effect?
drug A induces the enzymes that metabolise drug B
- induction is the result of increased synthesis and/or reduced breakdown of the microsomal enzyme responsible for metabolising drug B
the interaction reduces the effects and/or the duration of action of drug B
- could result in sub-therapeutic treatment by drug B = below therapeutic level
What are examples of enzyme inducers?
Rifampicin Phenobarbital Phenytoin Carbamazepine Topiramate Chronic alcohol St John’s Wort Cigarette smoking
What is a tricycling regimen in combine oral contraceptives usage?
3 packs of active pills
- 63 days/9 weeks of active pill
- no breakthrough bleeding = no period time of where there are no pills being taken
What should be taken along side COCs when also taking enzyme inducers? Why should they be taken?
enzyme inducers will initiate the metabolism of the contraceptive pill faster
- makes it less effective
must take ethinylestradiol daily
- must take greater amounts as the duration of COC and enzymes inducer taken together increases
What is enzyme inhibition? What are the different mechanisms for it?
drug A inhibits the action of the metabolising enzyme of drug B
- many interactions of this type involve liver microsomal enzymes
mechanisms include
- substrate competition
- forming a complex at the active site of the enzyme
- destruction of the enzyme
- reduced synthesis of the enzyme
- lack of co-factors
- allosteric effects
interaction increases the effect of drug B
- may result in and exaggerated or prolonged response of drug B with an increased toxicity of drug B
What are examples of enzyme inhibitors?
Cimetidine Macrolides = erythromycin Quinolones = ciprofloxacin Chloramphenicol Imidazole anti-fungals = ketoconazole Isoniazid Ethanol (short consumption) Omeprazole Grapefruit juice
How do protein binding displacement interactions affect distribution?
many drugs and drug metabolites are highly bound to plasma proteins (albumin)
displacement of one drug by another from its site of binding to plasma proteins will cause an increase in the circulating concentration of the unbound active drug with the potential of its increased effect
interaction only occurs if
- the object drug must be highly protein bound (>90%)
- must have a low apparent Vd
Why are protein binding displacement interactions typically not clinically important/relevant?
displacement of a drug from binding sites in plasma transiently increases the concentration of free (unbound drug)
but this is followed by increased elimination, so a new steady state is achieved where the [total drug] is decreased but the [unbound] is unchanged
When will protein binding displacement interactions result in toxicity?
toxicity can arise due
- transient increase in [unbound drug] until new steady state is reached (unbound conc is higher until that point)
- if displacing drug also decreases the elimination of the displaced drug (increased conc in circulation and reduced elimination)
How do tissue binding displacement interactions affect distribution?
can occur when one drug displaces another from tissue-binding sites with potential of adverse effects
