Drug Interactions
Addition of carbamazepine to a patient on stable doses of methadone might develop what symptoms? Over what time period do these symptoms develop?
opiate withdrawal symptoms--days to weeks
Name 2 secondary & 2 tertiary TCAs
Secondary: nortriptyline & desipramine
Tertiary: imipramine & amitriptyline
Audio Clip 1
Everybody Wants to Rule the World (Tears for Fears)
Describe signs of Depakote toxicity.
Nausea/vomiting (common), sedation, confusion, headache, ataxia, atrial tachyarrhythmias, miosis or nystagmus, tremor
List at least three antidepressants with minimal P450 inhibition.
citalopram, escitalopram, mirtazapine, venlafaxine
Name at least four antidepressant medications that have 2D6 inhibitory effects.
Prozac, Paxil, Zoloft (high doses), Bupropion, Duloxetine
Describe the receptor profile of secondary & tertiary TCAs (both therapeutic & side-effect profile).
Secondary have NE>5-HT
Both have blockade at
1) muscarinic cholinergic receptors
2) H1 histamine receptors
3) alpha-1-adrenergic receptors
Audio Clip 2
Never Gonna Give You UP (Rick Astley)
Which of the following pharmacokinetic properties is associated with Depakote:
P450 induction
P450 inhibition
High protein binding
P450 induction -- none
P450 inhibition -- 2C9 inhibition
High protein binding -- YES! (note how this may impact VA drug level monitoring when combining with other highly protein bound medications)
Name five categories of substances/medications that have pro-serotonergic activity (other than SSRIs, SNRIs, TCAs, MAO-Is, buspirone, Trazodone, Mirtazapine).
Antimigraine drugs; Lithium; Synthetic Opioids (remember Libby Zion case!); Stimulants/Illicit Drugs (amphetamines, cocaine, LSD, Ecstasy); herbal supplements (St. John's Wort, Ginseng); OTC cough & cold meds (dextromethorphan/Robitussin -- SRI's); Ritonavir; bromocriptine (D2 agonist + 5-HT receptor agonist); Linezolid
What is a possible adverse effect associated with combination of fluoxetine and propranolol?
bradycardia, hypotension, lightheadedness
List 2 potentially life-threatening adverse effects associated with TCA overdose.
seizures, cardiac dysrhythmias, apnea
Initial O/D tx: activated charcoal
Seizures: self-limited, consider benzos
Cardiac (tachycardia, QTc prolongation): sodium bicarb (may decrease binding to Na channels), consider phenytoin & magnesium
Apnea: ICU monitoring/airway support
Other issues: hypotension (IV fluids), metabolic acidosis. Note--hemodialysis unhelpful--TCAs highly protein bound, large volume of distribution
Audio Clip 3
What was the first auto-tune song in mainstream music, and who is the artist associated with that song?
Cher Believe (1998)
What is the essential amino acid that may be depleted by valproic acid requiring supplementation to avoid/counter symptoms of deficiency (hyperammonemia, delirium, hepatotoxicity)
carnitine
Name the precursor molecule to catecholamines.
Tyrosine
List at least five P450 inducers. List one UGT inducer.
Carbamazepine (3A4, 2C9, 1A2), Oxcarbazepine (3A4), Topiramate (3A4), Ritonavir (3A4), St. John's Wort (3A4), Phenobarbital (pan-inducer), Phenytoin (pan-inducer), cigarettes (1A2) UGT inducer-ethinylestradiol (affects blood level of lamotrigine)
Which of the TCAs is a virtually pure NE reuptake inhibitor?
Desipramine
Audio Clip 4
Britney Spears ...Baby One More Time
Name the three black box warnings associated with valproic acid.
1) teratogenicity (neural tube defects, rate 1-6%)
2) hepatotoxicity (especially if <2 years old)--special warning for those w/ hereditary neurometabolic syndromes caused by mitochondrial DNA polymerase gamma (POLG) gene mutations; highest risk 1st 6 months of treatment
3) pancreatitis
List three medications that are heavily protein bound.
benzodiazepines (e.g. diazepam bound 98%), warfarin (bound 99%), aspirin, valproic acid (plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 µg/mL to 18.5% at 130 µg/mL), phenytoin
What is the cigarette component responsible for metabolic induction?
Polyaromatic hydrocarbon in the cigarettes (NOT nicotine)--also present in marijuana smoke (thank you PGY-3 BH!)
Which heterocyclic antidepressant has heightened seizure risk even at therapeutic doses?
Maprotiline
Audio Clip 5
When You Wish Upon a Star
What does a valproic acid therapeutic drug level reflect?
Free (unbound) + protein bound VA
List at least four signs and symptoms of clozapine-related myocarditis.
symptoms: dyspnea, 'flu-like illness', chest pain, fatigue signs: fever, persistent tachycardia, elevated troponin, elevated eosinophil count Typically presents in first 4-8 weeks of treatment. Risk: 1/500, may have high mortality rate (10%), important to catch illness early for better outcome (note: viral myocarditis lower mortality rate)