3A4 hepatic Inhibitors
amiodarone, azole antifungals, cimetidine, clarithromycin, erythromycin, cylcosporine, diltiazem, verapamil, fluozetine, parozetine, grapefruit, isoniazid, metronidazole, protease inhibitors (ritonavir)
hepatic inducers
carbamazepine, phenobarbital, phenytoin, rifampin, st. Johns wort
how fast can inhibition occur?
less than 24 hours, can occure almost immediately
how fast does induction occur?
takes up to a week
- need enzymes to be produced by the liver
- enzyme turnover dependent on age and liver dysfunction
when is the peak effect of drug interaction?
once drug is at steady state
Warfarin
has 2 enatiomers, S and R
s (think snake: bad): 5x more potent substrate of cyp2C9
R (rabbit) substrate of cyp3a4
warfarin inhibitors of 2c9 (S)
amiodarone, azole antifungals, cimetidine, metronidazole
* note: warfarin interaction with 3A4 is still significant, but 2C9 is more.
what happens with warfarin inhibition
decrease in warfarin metabolism
increase in warfarin half life
increase in INR
increase risk of bleeding
what is the problem with warfarin and abx?
antiobiotics kill normal flora, which decrease vitamin K production
vitamin K antagonizes effects of warfarin... less vit K = higher INR = increased bleeding risk
Non-INR bleeding risks with Warfarin
heparin, LMWH, oral anticoagulants, ASA, NSAIDS, P2Y12 inhibitors (clopidogrel)
- bleeding risk even tho warfarin effect unchanged
AED DI
cyp induction/inhibition
- most AED are CYP substrates
Lamatorgine dosing when drugs that have DI
(cyp inhibitor)valproic acid: 25 mg every other day
monotherapy: 25 mg every day
(cyp inducers) carbamazepine, phenytoin, or phenobarbital: 50 mg/day
what happens if you give lamatrogine too fast?
get rash
slow and steady wins the race
Phenytoin and valproic acid interact via?
protein binding competition, this increases the percent of unbound drug that is active
Statins DI
- common drugs, cyp substrates
- cyp inhibition = increased statin concentration
- increases risk of myopathy and hepatotox
stats that have relevant 3A4 DI
simvistatin
atorovastatin
lovastatin
Statins and grapefruit DI
grapefruit inhibits p-glycoprotein efflux pumps
- also inhibits cyp3A4... increasing statin conc
Birth control DI
estrogens are cyp3A4 substrates
- BC might not work with 3A4 inducers
increased estrogen metab= dec estrogen half life= dec FSH suppression.
Why do Abx interact with BC?
- abx inhibit GI flora that hydrozlye BC conjugate back to active drug, thus less active drug in the body, so BC is not effective
Ritonavir
- use CYP inhibition to our advantage!
- used to boost HIV regimens
- protease inhibit for HIV, but used for its CYP inhibition
- boost results in greater AUC, half life, and cmax of HIV drugs.
Codeine and 2D6
Codeine needs cpy2d6 to be converted to morphine in the body.
2D6 inhibitors (also inhibit 3A4)
amiodarone
cimetidine
fluoxetine, paroxetine
what effect would you expect to see in a pt taking codeine and amiodarone?
codeine will not be converted to morphine as well
what would you recommend for monitoring and management of a pt taking amiodarone and codeine?
- stop codeine, counsel pt and doctor that DI could make codeine ineffective
Lithium
mood stabalizer used for bioplar disorder
- drug interaction involes similarity with Sodium.
how is Li eliminated?
renal (no cyp interactions)
how is Li reabosrbed?
in the PROXIMAL tubule (possible in loop of henle) using similar mechanisms as sodium
thiazides work on what part of nephron?
distal tibule
loop diuretics work on what part of nephron?
ascending loop of henle
How do thiazides effect Li clearance?
- they block distal sodium reabsorption (no effect on Li)
- this increases proximal Na reabsorption (increases Li reabsorption)
- that results in an increased Li halflife
How do loop diuretics effect Li clearance?
- minimal effect, still should monitor closely
Lithium interaction with NSAIDS and RAAS agents
NSAIDS, ACE, ARBs, DRIs
- dec renal blood flow, GFR = dec clearance of Li
Li concentrations can increase 200-300%!
DI with combined Serotonergic Agents
- excess serotonin can produce serotonin syndrome
- 90% of cases occur with therapeutic doses
- you cant predict the risk of serotonin syndrome
What happens during serotonin snydrome?
confusion, disorientation
hyperthermia, diaphoresis
myoclonus, hyperreflexia, rigidity
What are the big players in serotonin DI?
MAOIs, SSRIs, SNRIs, TCAs
what are other agents that effect serotonin DI?
CNS stimulants, LI, buspirone, meeridine, dextromethorphane, Linezolid, Tramadol, triptans,
QTC prolongation due to DI
- some meds increase QT interval= arrhythmias
- risk of prolongation inc with dose and number of qt prolonging drugs
Big players in QT prolongation
antiarrythmics
macrolides, quinolones, azole antifungals
haloperiodl
citalopram, escitalopram
methadone
ondansteron
CNS depression
- risk inc with dose and number of agents
- ethanol, opiods, AED, barbituates, Benzodiazepines, Anticholinergics, muscle relaxants
hyperkalemia
ACE, ARB, aliskiren, spironolactone, KCl, withdrawal of loop diuretics
what is the most common cause for hyperkalemia?
withdrawal of loop diuretics
polyvalent chelation
tetracyclines and quinolones chelate divalent and trivalent cations (Fe, Al, Ca, Mg)
- chelation product is INSOLUBLE and interfers with oral absorption
- seperate by atleast 2 hrs
Erection cycle
sexual stimulation releases NO via PDE5
that stimulates production of cGMP
relaxes smooth muslce increasing blood flow, causing erection
Sildenafil
pde5 is inhibited by sildenafil, thus you have more cGMP, so pathway will go faster.
PDE5 inhibitors and Nitrates
PDE5 and nitrates use reults in significatn hypOtension.
- combo CI within 24 hrs of sildenafil or vardenafil and 48 hrs for tadalafil
All PDE5s are cyp3A4 inhibitors
- erythromycin increases 24 hr sildenafil concentration 3-8x
Why does cyp interaction matter with respect to nitrates?
- if we give a drug that makes half life longer, then we are at higher risk for more ADR of sildenafil
- if we want to use nitro for heart attack, we need to know if they have sildenafil in body or not.
Metronidazole and ethanol
alcohol shouldnt be consumed during metro therapy and 3 days after bc of abd crams, N,V, HA, and flushing
Drug interactions info
- interactions are dose dependent (scale doesn't reflect)
- DI's are graded, grade is good but not great (based on in vitro testing)
why is in vitro testing of DI problematic?
enzyme induction/inhibition is dependent on concentration of unbound drug
many drugs show in vitro activity, but are not clinically relevant bc low unbound con in vivo