Protein Binding
Name three molecular/vascular level factors that can affect medication distribution.
protein binding, molecule size, lipophilicity, vascular permeability
Audio Clip 1
Rick Astley
Never Gonna Give You Up
Pharmacodynamic or pharmacokinetic drug interaction:
citalopram + imipramine --> blurry vision, dry mouth, constipation.
Pharmacodynamic (anticholinergic)
Which high mortality cardiac adverse effect is typically experienced during a patient's initial 4-8 weeks of treatment with clozapine? And which cardiac adverse effect is typically seen later in treatment (median 9 months)
1) myocarditis
2) dilated cardiomyopathy
What pharmacokinetic feature is characteristic of triazolobenzodiazepines?
triazolobenzodiazepines: alprazolam, triazolam, midazolam, estazolam are 3A4 substrates so may be affected by inducers at this site (e.g. carbamazepine, oxcarbazepine). Note that clonazepam, while not a triazolobenzodiazepine, is also metabolized at 3A4.
Name four patient clinical/medical factors that affect protein binding.
1) age 2) hepatic disease 3) chronic renal disease/uremia 4) presence of other protein-bound medications/substances (especially antiepileptics) 5) hypoalbuminemia 6) pregnancy 7) critical illness 8) acidity of the medication
Audio Clip 2
take on Me
Is fluvoxamine likely to increase or decrease serum benzodiazpine levels (e.g. clonazepam)?
Increase (pharmacokinetic inhibition)
A) Which benzodiazepines bypass oxidative metabolism and may are therefore safer in patients with liver disease? B) Which lack active metabolites?
A) LOT B) CLOT
Name the most common blood protein.
Albumin
Audio Clip 3
Tainted Love
Soft Cell
What are the four components of pharmacokinetics to consider for potential drug interactions?
Absorption, Metabolism, Distribution, Elimination
lamotrigine is a UGT 1A4 substrate
EE decreases the blood level of lamotrigine
Which mood stabilizer is associated with increased risk of calcium phosphate stone formation?
topiramate
List three psychotropic meds that are hydrophilic, not protein bound, and excreted essentially unchanged by the kidneys.
1) lithium 2) gabapentin 3) pregabalin/Lyrica (negligible metabolism by liver)
Audio Clip 4
Conga
Gloria Estefan and the Miami Sound Machine
List at least one pro-drug and its associated active metabolite.
hydrocodone-->hydromorphone, tramadol-->M1, codeine-->morphine The above pro-drugs all 2D6 substrates
List three medications that increase lithium levels.
NSAIDS, thiazides, ACE inhibitors, Ca channel blockers
What potential carbamazepine adverse effect may be more common in patients with the HLA-B 1502 allele?
TENS/SJS (frequency of allele highest in specific Chinese populations as well as those from other areas of Asia)
High risk patients should be screened for this allele and if positive carbamazepine contraindicated
List three highly protein bound medications (or medication classes).
Audio Clip 5
Everybody Wants to Rule The World
Tears for Fears
Describe the pharmacokinetic drug interaction components and potential clinical effects associated with the carbamazepine + valproic acid combination (list at least 3).
CBZ induction (UGT, P450): decreased VA level, increased VA metabolite 4-ene-VA (hepatotoxic)
VA inh 2C9 --> increased CBZ level
VA inh epoxide hydrolase --> increased CBZ-10-11 epoxide (neurotoxic)
Name at least 2 medications/substances that decrease lithium levels.
caffeine, acetazolamide (carbonic anhydrase inhibitor for glaucoma), theophylline
Which mood stabilizer may lead to depletion of carnitine levels?
Depakote