Vertigo Pharmacology Flashcards
Drugs with the most prominent effects in producing vertigo impact what?
the structure and funciton of the vestibular apparatus (ex. hair cells of the inner ear)
What are the three major drug types that can lead to irreversible changes in the inner ear?
Aminoglycosides
Loop diuretics
Cytostatic drugs
What can improve aminoglycoside-induced inner ear toxicity (through not completely reverse it)?
N-acetylcysteine
Via what mechanism do aminoglycosides cause outer hair cell death?
either caspase-dependent or caspase-independent mechanisms
Via what mechanism does cisplatin cause outer hair cell death?
praimrily caspase-dependent
How do both aminoglycosides and cisplatin gain entry into outer hair cells?
mechano-transducer channels
What is the significance in the fact that aminoglycosides form complexes with iron when they gain entry into outer hair cells?
complex can react with electron donors (ex. arachidonic acid) to form ROS (ex. superoxide, hydroxyl radical, and hydrogen peroxide)
What do AG-iron complex induced ROS do in the outer hair cell?
activates JNK so that it can translocate to the nucleus and activate genes in the cell death pathway
Activation of genes in the cell death pathway leads to waht?
release of cytochrome C from the mitochondria (triggers apoptosis via caspases)
What happens to cisplatin after entering outer hair cells?
can be aquated to form the cisplatin- monohydrate complex (which is more reactive)
What is the role of cisplatin-monohydrate complex?
can activate NOX3 (resulting in ROS production)
Where to loop diuretics work in the inner ear?
stria vascularis
What channels do loop diuretics block in the inner ear?
Na+/K+/2Cl- co-transporter
What is the significance of blocking the Na+/K+/2Cl- co-transporter in the inner ear?
diuretics upset the fluid balance and this results in edema of stria vascularis and loss of function→ decrease in endocochlear potential.
What is different about loop diuretic ototoxicity compared to cisplatin and aminoglycoside induced toxicity?
it is dose-rate dependent (and only temporary, though worsened by comorbidities)
What part of the brain controls emesis? Where is it?
central emesis center in the lateral reticular formation of the mid-brainstem
What receptors are present in the CTZ?
high in 5-HT3, D2 and opiod receptors
What two structures is the central emesis center close to?
chemoreceptor trigger zone
solitary tract nucleus
What receptors are present in the STN?
Enkephalin, Histamine, Ach and 5-HT3
Where is the CTZ?
in the area postrema at the bottom of the fourth ventricle
List the Antihistamine/ Anticholinergics used to treat vertigo-induced emesis.
Meclizine HCl
Diphenhydramine
Promethazine HCl
Scopolamine
Which of the Antihistamine/ Anticholinergics has the longest half life?
scopolamine patches (72 hour)
MOA: M1 receptor blocker
Scopolamine
MOA: Cerebellum H1 and M1 receptor blockers
Meclizine HCl
Diphenhydramine
Promethazine HCl
Which Antihistamine/ Anticholinergic is a CYP2D6 substrate and inhibitor?
Diphenhydramine
Promethazine HCl
Which Antihistamine/ Anticholinergic is a CYP2D6 substrate and should be used with caution with CYP inhibitors?
Meclizine HCl
What are the major DDIs for antihistamine/anticholinergics?
caution with anti-muscarinics and sedatives
Which group of people should NOT take Antihistamine/ Anticholinergics?
the elderly
Which drug has a BBW: for use by injection → fatal respiratory depression in <2 yo?
Promethazine HCl
What drug has xerostomia and ocular effects if you get it in your eye?
scopolamine (patch form worse)
Which drug has WORSE drowsiness in WOMEN?
Meclizine HCl
What drug is used to treat psychosomantic emesis?
Diazepam
What are the serotonin antagonists used prophylacticly to treat emesis?
Dolasetron
Granisetron
Ondansetron
Palonsetron
What is the MOA of the “setrons”?
Block 5-HT3 Receptors in the CTZ and STN
How are the “setrons” usually given?
with corticosteroids for IV or PO prophylaxis of emesis
Which “setron” needs to be dose adjusted in hepatic failure?
ondansetron
What are the DDIs of concern with “setrons”?
CYP inhibitors or cardiac drugs
TOXICITY: Chronic use→ blood marrow suppression/blood dyscrasias; risk of QT prolongation and torsade de pointes
Prochlorperazine
Chlorpromazine
TOXICITY: Hypersensitivty reactions; QT prolongation; HA, constipation, diarrhea
Setrons
Which “setrons” require EEG monitoring?
dolasetron and ondansetron
List the D2 receptor antagonists.
Prochlorperazine
Chlorpromazine
What is the major DDI with the D2 receptor antagonists?
antipsychotics (increase CNS adverse effects)
What is the MOA of D2 receptor antagonists?
Block D2 receptors in CTZ and have anticholinergic and antihistaminic effects
D2 receptor antagonists are useful in what type of vertigo?
motion sickness
List the NK1/SP receptor antagonists used to treat emesis.
Aprepitant
Fosaprepitant
What is the MOA of NK1/SP receptor antagonists?
Block receptors in the STN and GI
Which of the NK1/SP receptor antagonists is a prodrug? How is it activated
Fosaprepitant is pro-drug activated by extra-hepatic metab.
Do NK1/SP receptor antagonists have CYP interactions?
yes- CYP metabolized and inhibitor of CYP3A4
List the cannabinoid receptor agonists.
Dronabinol
THC
What is the MOA of cannabinoid receptor agonists?
GPCR coupled decrease in neuronal activity in medullary vomiting center and ST. Opposes 5-HT3 mediated stimulation from vagal afferents
TOXICITY: Schedule III drug (produces high with elation and heightened awareness)
Dronabinol
THC
In what patients should you avoid use of cannabinoid receptor agonists?
patients with h/o substance abuse
How do cannabinoid receptor agonists stimulate appetite?
CB receptors in lateral hypothalamus
What is commonly done for patients receiving highly emetogenic chemotherapy cocktails (ex. with cisplatin, carmustine, cyclophosphamide, etc)?
prophylactic drugs for emesis
What are the main drugs used in prophylaxis of chemotherapy nausea/vomiting?
serotonin antagonist, an NK-1 antagonist, and a corticosteroid
What drugs are just as effective as the normal anti-emesis cocktail for emesis prophylaxis but re ALWAYS used in combination?
corticosteroids (ex. methylprednisolone and dexamethasone)
How do methylprednisolone and dexamethasone work to treat emesis?
antiemetic mechanism remains unclear, but possibly via steroid receptors in the STN or reduction in serotonin release
