Sweatman Drug-Drug interactions Flashcards
How the drug affects the body
pharmacodynamics
how the body acts on the drug
pharmacokinetics
(L-ADME)
*lending to means of D-D interactions
1+ 1= 2
additivity
1+1=3
synergism
change in serum blood level
pharmacokinetics
receptor/non-receptor interactions
pharmacodynamics
*lending to means of D-D interactions
many drug-drug interactions are susceptible to control by
dose adjustment
co-admin of cyclosporin with erythromycin has what effect
increases cyclosporin levels and decreases its cost
are all D-D interaction bad
no
some actually beneficial
why are elderly, women and very young at increased risk for ADR’s
decreased capacity to metabolize and excrete drug, normonal changes, immature metobolic mechs etc
*Pharmacokinetics are different than in adults/ men
relationship b/w polypharmacy and incidence
greater number of concurrent drugs being taken–> increases likelihood of ADR’s
*greater drug exposure=greater likelihood of drug-drug interactions
therapeutic window
MTC-MEC
lag period on a dose concentration-time curve indicated
rate of uptake/distribution following adminstration for orally administered drugs
lag time for IV
NONE
duratio of action
time for which the plasma concentration is above the MEC for maximal action upon the recptor
drugs with smaller therapeutic windows are more likely to
exhibit adverse effects
if the plasma concetration remains within the therapeutic window when interacting with a concurrent drug…will it be apparent
NO–> this is why most D-D interaction go unoticed
only when it goes above MTC (toxic) or below MEC (loss of clinical efficacy–>will drug-drug interactions become notiecd
High suspicion of drugs affecting which three categories should be monitored for D-D interactions
- anticoag (thrombosis or hemorrhage)
- Cardiovascular (arrhythmogenic events)
- CNS (ability to cross BBB can cause sedative or seizure activity)
Classifications of Chemical (D-D) interactions
- additive
- synergistic
- potentiation
- antagonism
outcome of physical changes that occur in all of the four chemical interactions
functional changes
chemical changes
dispositional changes
receptor changes
women need lower doses bc
they tend to not clear the drug as rapidly
most common CYP’s
3A4 and 2D6–> expression varies up to 40 fold for 3A4 and these two cyps have MANY different SNP’s
atorvastatin MOA regarding CYP
Enters cell–>binds to nuclear receptor (PXR) which dimerizes with RXR–> binds DNA00> recruits coactivator which binds to TBP at the TATA box–> activates RNA POl II–> upregulates CYP3A4 transcription–> metabolizes Atorvastatin
atorvastatin induces
its OWN metabolism
A concurrent drug can impact the metabolism of other agents via
semi-selective nuclear effects–> bc the enzyme produced via ligan-NR transcription upregulation can metabolism MANY DIFFERENT DRUGS NOT JUST THE ONE THAT CAUSES THE UPREGULATION
*EX–> ATORVASTATIN LEADS TO CYP3A4 UPREG–> WHICH WOULD DECREASE ALL OTHER DRUGS BEING TAKEN THAT ARE SUBSTRATES FOR CYP3A4
Semiselective nuclear effects can affect which phases of metabolism
phase I -cyp mediated
AND PHASE II–> GLUCORONOSYLTRANSFERASES
WARFARIN-RIFAMPIN INTERACTION
BOTH HANDLED BY CYP3A4:
taken together–> rifambin induces CYP and warfarin concentration declines–> PRO-THROMBOTIC STATE no longer sufficiently anticoagulated
ORAL CONTRACEPTIVES AND RIFAMPIN
RIFAMPIN INCUCES CYP3A4 AND NOW CONTRACEPTIVE LEVELS ARE LOW–> RESULTING IN PARENTHOOD
RIFAMPIN AND CYCLOSPORIN AND TAC
RIFAMPIN INDUCES CYP3A4–> cyclosporin and Tac are substrates–> lower plasma levels of tac and clycosporin via increased Cyp activity–> organ rejection
Herbal remedies can cause what problems
- can affect CYP activity–> indirect drug interactions
- some are anticoagulant which can have an ADDITIVE EFFECT
- Some possess CNS activity–> additive or antagonistic effects on CNS
three forms of CYP inhibition
reversible (most common)-
quasi irreversible
irreversible
most cyp inhibition is
competitive and reversible
most cyp inhibitors contain
Nitrogen–>simultaneously binds prosthetic heme iron and lipophillic region of protein
*inhibitor potency determined by lipophillicity and strength of bonds
Both reversible and quasi-irreversible inhibition is caused by
formation of reactive metabolites that covalently bind to the active site for ever (irreversible) or apprently/effectively forever (quasi)
*require at least 1 cycle of CYP catalytic processes
STATINS in too high concentrations can cause
Rhabdomyolysis–> breakdown of muscle tissue
muscle pain and acute renal failure
*monitor via CPK and aldolase
so Erythromycin and Statin doctor should–>
Erythromycin–> CYP3A4 inhibitor–> rhabdomyolysis
- ->consider another macrolide such as azithromycin which is not a CYP3A4 inhibitor
- ->reduce dose of either
- ->monitor for muscle enzymes
- ->change statin
only statins which are substrates CYP3A4
simvastatin
lovastatin
atorvastatin
ranitidine interaction MOA
affects absorption of other drugs
–> raises stomach pH which would caused increased absoprtion of basic drugs
ranitidine increases uptake of…
triazolam–> benzo sedative agent
*increases bioavailabiltiy
bile sequesterant agents will bind up and decrease absorption of
propanolol–> a beta blocker
*decreases bioavailability
heavily protein bound drugs should not be given with…
other protein bound drugs
*warfarin and valproic acid
Conditions leading to toxicity/overdose of heavily protien bound drugs
- -> when protein sites become saturated
- ->physiologic/pathologic states causing hypo-albuminemia
- -> when protein bound fraction is altered and more free drug enters the plasma
agents that bind up a toxin and promote safe renal elimination
chelating agens
–> for toxic agents such as iron, mercury etc
what is important about wafarin and chronic NSAID use
DUPLICATION OF OVERALL EFFECT
both produce anti-coag state–> but through different effects–> increased bleeding risk
MEASURABLE CHARACTERISTIC OF WARFARIN PLUS NSAIDS
INCREASD INR
SSRI’S SHOULD NOT BE GIVEN WITH
other drugs or herbal remedies that increase serotinin levels
- -> drugs than inhibit CYP metabolism
- ->TRYPTANS–RECEPTOR ANTAGONISTS WHICH MAKE SEROTONINE MORE POTENT
- CAN LEAD TO SEROTONIN SYNDROME AND HTN CRISIS WITH NON-SELECTIVE MAOI’S
DIFFERENT TARGETS, UNRELATED PATHWAYS
*beneficial
AMOXICILLIN + CLAVULANATE
DIFFERENT TARGETS, RELATED PATHWAYS
*beneficial
synergistic
salmeterol + fluticasone
salmeterol–> agonist on beta 2 receptors
fluticasone upregulates beta 2 receptors
*synergistic T-cell activation and apoptosis induction
Upstream-Downstream targets
*beneficial
synergistic
sulfamethexazole + trimethoprim
facilitated action
erythromycin + penicillin
*penicillin weakens cell wall (increases effectiveness of erythromycin) and erythromycin is able to penetrate better
indirect ineraction with caffeine
xanax and echinacea
indirect effect of signalling cytokine
lisinopril and aspirin–> removed PG’s
–>coupling effect is removed and Lisinopril effect not as large
penicillin ad plavix both have affects on
platelets
Enhanced distribution/localization
*potentiation effect
ergotamine and caffeine
caffiene increases water solubility of ergoteramine thus increasing its absorption
additive equivalent action
niacin (b3) + simvastatin
–> both drugs either decrease secretion or decrease synthesis–> lowering LDL
captopril leads to what
retension of potassium–> pro-arrhythmogenic
ACE inhbitor
Same target different binding site
cisplatin + cyclophosphamide
–> compliment each others actions
Same target: increases capalities
methotrexate + flourouracil
M binds to F when bound to thymydylate synthase–> increase activity
Same target: Pharmacologic antagonism
propanolol + salmterol
–> taking propanolon cannot respond to salmeterol bc the B2 adrenergic receptor is blocked by propanolon (non-specific beta blocker)
when a previously stable pt. starts a new drug and new symptoms start what is assumed to be responsible
the new drug!
