Interactions Flashcards
what are pharmacokinetic interactions
interactions which can affect the process by which drugs are absorbed, distributed, metabolised or excreted
(ADME INTERACTIONS)
what are pharmacodynamic itneractions
interactions that occur when the effect of drug A is altered by the presence of drug B without affecting its pharmacokinetics
what are CYP450 enzymes and how do they work?
haemoprotein metabolising enzymes
they are major enzymes involved in drug metabolism
they are primarily involved in phase 1 monooxygenase reactions
the source of oxygen is the oxygen joined to the heme co-factor
please draw the mechanism of CYP oxidation
aliphatic hydroxylation
what will happen if drug A is a CYP substrate and drug B is a CYP inhibititor?
drug a concentration will increase
risk of toxicity
what will happen if drug A is a CYP substrate and drug B is a CYP inducer?
drug A concentration will decrease
reduced substrate A efficacy
risk of therapeutic failure
what is the rate of onset of effect for CYP inducers? and why?
gradual onset and offset
this is because the process is slow and involves increased DNA transcription and synthesis of new CYP enzymes
what affects the length of effect of the CYP inducer?
half life of the inducer
time to make new CYP proteins
rate of degeneration of new CYP proteins
what is the rate of onset of effect for CYP inhibitors? and why?
rapid onset of action
how long does the effect of CYP inhibiting enzymes last
may be a long lasting effect (depends on the exact MOA)
may be long lasting depending on how long it takes to make new enzymes
what are the two methods of inhibiting CYP enzymes
o
oxidative metabolism
n-oxidation
how does oxidative metabolism act to inhibit CYP enzymes?
capable of alkylating either the protein or the prosthetic heme group
blocks the enzyme action
prevents its return to function until a new CYP enzyme is produced
how does n-oxidation act to inhibit CYP enzymes?
if the inhibitor contains an amine functional group
can lead to formation of an irreversible metabolic intermediate between a nitrogen group and the heme iron (prevents complete function)
Inhibitor or inducer?
rifampicin
inducer
Inhibitor or inducer?
carbemazapine
inducer
Inhibitor or inducer?
phenobarbital
inducer
Inhibitor or inducer?
phenytoin?
inducer
Inhibitor or inducer?
nevirapine
inducer
Inhibitor or inducer?
pioglitazone
inducer
Inhibitor or inducer?
st. johns wort
inducer
Inhibitor or inducer?
sulfamethazazole
inhibitor
Inhibitor or inducer?
amioderone
inhibitor
(not the parent dug amioderone itself but its metabolites
it is the inhibitory metabolites of amioderone that are responsible for causing the drug drug interaction)
Inhibitor or inducer?
cimetadine
inihibtor
Inhibitor or inducer?
fluoxetine
inhibitor
Inhibitor or inducer?
fluxonazole
inhibitor
Inhibitor or inducer?
ritonavir
inhibitor
what is the role of ritonavir in highly active antiviral therapy?
used in combination with other retrovirals
ritonavir is rarely used for its own retroviral activity but remains widely used as a “booster” for other protease inhibitors
it has these abilities because of its off-target inhibitory action agains CYP3A4
ritonavir is sacrificed to the CYP enzymes
it is a potent CYP enzyme inhibitor
it reduces the metabolic action of the enzymes
therefore it prevents other protease inhibitors being metabolised by the CYP enzymes and so BOOSTS their therapeutic action of the other antiretrovirals !!
what is Pglycoprotein
it is a transmembrane molecular pump that acts to protect our cells from toxic molecules
it is the most characterised memeber of the ABC-transported subfamily of proteins
what is special about the PgP structure that makes it really good
cone shaped intracellular cavity allows it to accept a wide range of structurally diverse substrates
explain the process of PgP action
1) PgP sits in the cell membrane and searches for foreign hydrophobic molecules
2) when it finds a foreign hydrophobic molecule it grabs it deep within the protein and then it flips to a new conformation
(substrate binding initiates ATP recruitment)
3) the new conformation has an opening towards the outside of the cell and the molecule is ejected out of this opening
(the whole process if powered by ATP to ensure the process occurs in a timely manner)
what happens in the interaction between anioderone and digoxin
amioderone increases the serum concentration of digoxin but inhibiting the Pgp that facilitates the elimination of digoxin from the body
amioderone may also influence the serum concentrations of digoxin bu changing the tissue distribution of digoxin (Vd)
name 3 interactions that can occur between a drug molecule and PgP
hydrophobic interaction (weak electrostatic forces, Van Der Waals )
hydrogen bonding
aromatic cage formation (align electrons with the drug)
what are antacids made of
they are chemically week bases formulated as salts
hydroxides, tricilates, carbonates
how can antacids cause drug drug interactions
because of their effect on pH
they increase gastric pH (make it less acidic and more alkaline) therefore this impacts on pH dependent dissolution
as most drug molecules contain an ionisable functional group, changes in pH will have a knock on effect fo the dissolution profiles of any co-administered drugs
as dissolution is the rate limiting step of drug administration from a solid dosage form changes in drug dissolution due to changes in stomach pH can therefore lead to enhanced or reduced absorption
chelation
occurs between polyvalent metallic ions (magnesium or aluminium) and organic mocules
form an insoluble ring complex in solution that cannot be absorbed
what is the problem with using antacids with ketoconazole
ketoconazole is a weak base pH approx 3
it is therefore nearly insoluble at pH 4 but is soluble at acidic pH
if the gastric ph is raised >4 for a period longer than gastric emptying (10-20 mins)
then the drug may reach the small intestine before dissolution has taken place therefore absorption will be decreased as the drug will not be in solution when it reaches the small intestine therefore it cannot be absorbed
what is the problem with using mallow with tetracyclines
reduces the oral bioavailability of the tetracycline and its metabolites bu 80%
(the same effect doesnt occur when using omeprazole) this means that tetracycline chelates with the metal ions in the antacids and forms an insoluble complex
as the tetracycline has formed the insoluble complex it cannot be absorbed and therefore cannot exert its therapeutic effect.
where can pharmacodynamic reactions occur
at the receptor (where it binds)
or the effector (the therapeutic effect that it has)
please give an example of a negative interaction at the receptor
salbutamol (beta 2 agonist)
propranolol (non selective beta antagonist)
please give an example of a positive interaction at the effector
using a combination of ACE inhibitor and calcium channel blockers to treat hypertension
both have different MOA but exert the same final effect of reducing blood pressure
please give an example of a negative interaction at the effector
using carvedilol (beta blocker) and verapamil (CCB)
both have cardiac suppressant effects
can cause serious cardio depression e.g bradycardia, systole, sinus arrest :-(
