Drug Interactions Flashcards
pharmacokinetic considerations
drug A may influence the effectiveness of drug B by altering its ‘availability’
pharmacodynamic considerations
drug A may influence the effectiveness of drug B by altering its interaction with its receptor
interactions
could lead to loss or enhancement of drug action
or enhanced drug toxicity/adverse effects
listed in product monographs by manufacturers → contraindicated conditions, potential drug interactions
therapeutic index
narrow TI = most susceptible to issues with drug interactions
→ small changes in responsiveness can lead to toxic outcomes
pharmacodynamic interactions
antagonistic interaction
synergism or additive interactions
indirect interactions
antagonistic interaction
drug A may act as an antagonist at receptor for drug B → reduce effectiveness of drug B
ex. Vitamin K and warfarin
vitamin K cycle
oxidized vitamin K (KO) is reduced to KH2 by vitamin K epoxide reductase → generate prothrombin
→ production of active clotting factors
balance of clotting factors is important (too much = clots; too little = unstoppable bleeding)
warfarin + vitamin K
anticoagulant for patients with blood clot issues
inhibitor of vitamin K epoxide reductase
= reduces level of clotting factors (no prothrombin)
foods rich in vitamin K will weaken effectiveness of warfarin (compete for occupancy of enzyme)
lower vitamin K (antibiotic that inhibits production) → stronger warfarin effectiveness
INR
international normalized ratio: ratio of clotting time compared to a ‘normal’ sample
measure prothrombin time
high INR → sample requires long time to form a clot
synergism or additive interactions
multiple agonists/modulators act on same receptor → excessive activation
effect is greater than individual effects (synergism) or roughly the sum of individual effects (additive)
ex. alcohol and GABA-A receptor modulators
GABA-A receptor drugs
act on GABA-A receptor (chloride channel) and enhance activity
benzodiazepines: PAM of GABA-A
barbituates: PAM or agonists of GABA-A
alcohol: PAM
zolpidem: PAM
combination of multiple drugs at low concentrations enhance GABA-mediated activation of receptors → sedation, unconsciousness
indirect interactions
effects of multiple drugs might influence the same signalling pathway, but not necessarily the same receptor
- acting on different components of same signalling pathway
ex. serotonin syndrome
serotonin syndrome
arises from combinations of drugs that lead to overabundance of 5-HT in CNS and overstimulation of 5-HT receptors (especially 5-HT2a and 1a)
characterized by high body temperature, agitation, sweating, dilated pupils, muscle twitching, elevated blood pressure
monoamine oxidase inhibitors
prevent breakdown of 5-HT by MAO-A → increased cellular levels of 5-HT
many act irreversibly = long lasting effects → increase susceptibility to serotonin syndrome when combined with other drugs
tricyclic antidepressants, SSRIs, SNRIs
prevent reuptake of 5-HT from synaptic cleft → prolonging lifetime of 5-HT in synapse
= increased stimulation on postsynaptic neuron
various opioids
metabolites may have direct serotonergic effects or interfere with serontonin reuptake
St. John’s wort
herbal remedy
acts as serotonin reupatke inhibitor
recreational drugs (MDMA, methamphetamine)
promote serotonin release by causing uptake transporters’pumps to operate in reverse
ex. ecstasy
precursors of serotonin
used as anti-depressants
body is making more 5-HT → releasing more
pharmacokinetic interactions
alter drug availability (absorption or distribution)
- drugs that alter gut motility, pH → alter absorption
- drugs that alter local blood flow → alter distribution
alter metabolism - CYP enzymes
lidocaine
co-administration of lidocaine with epinephrine for local vasoconstriction
lidocaine blocks sodium channels in nerve to block pain transmission
epinephrine constricts blood vessels to prevent diffusion away
= lidocaine lasts longer at site of injection
CYP enzymes
induction of CYP enzymes → increased metabolism of other drugs
CYP3A4 - common for biotransformation
expression is induced by rifampicin, anti-convulsants, glucocorticoids, etc.
CYP3A4 and warfarin
CYP3A4 metabolizes warfarin
= individuals taking a drug that induces CYP3A4 will be resistant to warfarin
enhancer of CYP3A4 = higher expression → faster breakdown of warfarin = reduced effectiveness
CYP3A4 and grapefruit juice
grapefruit juice inhibits CYP3A4 enzyme
high amounts of grapefruit juice→ heightened sensitivity to drugs metabolized by CYP3A4 (like warfarin)
with warfarin → high INR; prone to bleeding
