Vertigo Pharmacology

Question 1

Drugs with the most prominent effects in producing vertigo impact what?

Answer 1

the structure and funciton of the vestibular apparatus (ex. hair cells of the inner ear)

Question 2

What are the three major drug types that can lead to irreversible changes in the inner ear?

Answer 2

Aminoglycosides
Loop diuretics
Cytostatic drugs

Question 3

What can improve aminoglycoside-induced inner ear toxicity (through not completely reverse it)?

Answer 3

N-acetylcysteine

Question 4

Via what mechanism do aminoglycosides cause outer hair cell death?

Answer 4

either caspase-dependent or caspase-independent mechanisms

Question 5

Via what mechanism does cisplatin cause outer hair cell death?

Answer 5

praimrily caspase-dependent

Question 6

How do both aminoglycosides and cisplatin gain entry into outer hair cells?

Answer 6

mechano-transducer channels

Question 7

What is the significance in the fact that aminoglycosides form complexes with iron when they gain entry into outer hair cells?

Answer 7

complex can react with electron donors (ex. arachidonic acid) to form ROS (ex. superoxide, hydroxyl radical, and hydrogen peroxide)

Question 8

What do AG-iron complex induced ROS do in the outer hair cell?

Answer 8

activates JNK so that it can translocate to the nucleus and activate genes in the cell death pathway

Question 9

Activation of genes in the cell death pathway leads to waht?

Answer 9

release of cytochrome C from the mitochondria (triggers apoptosis via caspases)

Question 10

What happens to cisplatin after entering outer hair cells?

Answer 10

can be aquated to form the cisplatin- monohydrate complex (which is more reactive)

Question 11

What is the role of cisplatin-monohydrate complex?

Answer 11

can activate NOX3 (resulting in ROS production)

Question 12

Where to loop diuretics work in the inner ear?

Answer 12

stria vascularis

Question 13

What channels do loop diuretics block in the inner ear?

Answer 13

Na+/K+/2Cl- co-transporter

Question 14

What is the significance of blocking the Na+/K+/2Cl- co-transporter in the inner ear?

Answer 14

diuretics upset the fluid balance and this results in edema of stria vascularis and loss of function→ decrease in endocochlear potential.

Question 15

What is different about loop diuretic ototoxicity compared to cisplatin and aminoglycoside induced toxicity?

Answer 15

it is dose-rate dependent (and only temporary, though worsened by comorbidities)

Question 16

What part of the brain controls emesis? Where is it?

Answer 16

central emesis center in the lateral reticular formation of the mid-brainstem

Question 17

What receptors are present in the CTZ?

Answer 17

high in 5-HT3, D2 and opiod receptors

Question 18

What two structures is the central emesis center close to?

Answer 18

chemoreceptor trigger zone

solitary tract nucleus

Question 19

What receptors are present in the STN?

Answer 19

Enkephalin, Histamine, Ach and 5-HT3

Question 20

Where is the CTZ?

Answer 20

in the area postrema at the bottom of the fourth ventricle

Question 21

List the Antihistamine/ Anticholinergics used to treat vertigo-induced emesis.

Answer 21

Meclizine HCl
Diphenhydramine
Promethazine HCl
Scopolamine

Question 22

Which of the Antihistamine/ Anticholinergics has the longest half life?

Answer 22

scopolamine patches (72 hour)

Question 23

MOA: M1 receptor blocker

Answer 23

Scopolamine

Question 24

MOA: Cerebellum H1 and M1 receptor blockers

Answer 24

Meclizine HCl
Diphenhydramine
Promethazine HCl

Question 25

Which Antihistamine/ Anticholinergic is a CYP2D6 substrate and inhibitor?

Answer 25

Diphenhydramine | Promethazine HCl

Question 26

Which Antihistamine/ Anticholinergic is a CYP2D6 substrate and should be used with caution with CYP inhibitors?

Answer 26

Meclizine HCl

Question 27

What are the major DDIs for antihistamine/anticholinergics?

Answer 27

caution with anti-muscarinics and sedatives

Question 28

Which group of people should NOT take Antihistamine/ Anticholinergics?

Answer 28

the elderly

Question 29

Which drug has a BBW: for use by injection → fatal respiratory depression in <2 yo?

Answer 29

Promethazine HCl

Question 30

What drug has xerostomia and ocular effects if you get it in your eye?

Answer 30

scopolamine (patch form worse)

Question 31

Which drug has WORSE drowsiness in WOMEN?

Answer 31

Meclizine HCl

Question 32

What drug is used to treat psychosomantic emesis?

Answer 32

Diazepam

Question 33

What are the serotonin antagonists used prophylacticly to treat emesis?

Answer 33

Dolasetron Granisetron Ondansetron Palonsetron

Question 34

What is the MOA of the "setrons"?

Answer 34

Block 5-HT3 Receptors in the CTZ and STN

Question 35

How are the "setrons" usually given?

Answer 35

with corticosteroids for IV or PO prophylaxis of emesis

Question 36

Which "setron" needs to be dose adjusted in hepatic failure?

Answer 36

ondansetron

Question 37

What are the DDIs of concern with "setrons"?

Answer 37

CYP inhibitors or cardiac drugs

Question 38

TOXICITY: Chronic use→ blood marrow suppression/blood dyscrasias; risk of QT prolongation and torsade de pointes

Answer 38

Prochlorperazine | Chlorpromazine

Question 39

TOXICITY: Hypersensitivty reactions; QT prolongation; HA, constipation, diarrhea

Answer 39

Setrons

Question 40

Which "setrons" require EEG monitoring?

Answer 40

dolasetron and ondansetron

Question 41

List the D2 receptor antagonists.

Answer 41

Prochlorperazine | Chlorpromazine

Question 42

What is the major DDI with the D2 receptor antagonists?

Answer 42

antipsychotics (increase CNS adverse effects)

Question 43

What is the MOA of D2 receptor antagonists?

Answer 43

Block D2 receptors in CTZ and have anticholinergic and antihistaminic effects

Question 44

D2 receptor antagonists are useful in what type of vertigo?

Answer 44

motion sickness

Question 45

List the NK1/SP receptor antagonists used to treat emesis.

Answer 45

Aprepitant | Fosaprepitant

Question 46

What is the MOA of NK1/SP receptor antagonists?

Answer 46

Block receptors in the STN and GI

Question 47

Which of the NK1/SP receptor antagonists is a prodrug? How is it activated

Answer 47

Fosaprepitant is pro-drug activated by extra-hepatic metab.

Question 48

Do NK1/SP receptor antagonists have CYP interactions?

Answer 48

yes- CYP metabolized and inhibitor of CYP3A4

Question 49

List the cannabinoid receptor agonists.

Answer 49

Dronabinol | THC

Question 50

What is the MOA of cannabinoid receptor agonists?

Answer 50

GPCR coupled decrease in neuronal activity in medullary vomiting center and ST. Opposes 5-HT3 mediated stimulation from vagal afferents

Question 51

TOXICITY: Schedule III drug (produces high with elation and heightened awareness)

Answer 51

Dronabinol | THC

Question 52

In what patients should you avoid use of cannabinoid receptor agonists?

Answer 52

patients with h/o substance abuse

Question 53

How do cannabinoid receptor agonists stimulate appetite?

Answer 53

CB receptors in lateral hypothalamus

Question 54

What is commonly done for patients receiving highly emetogenic chemotherapy cocktails (ex. with cisplatin, carmustine, cyclophosphamide, etc)?

Answer 54

prophylactic drugs for emesis

Question 55

What are the main drugs used in prophylaxis of chemotherapy nausea/vomiting?

Answer 55

serotonin antagonist, an NK-1 antagonist, and a corticosteroid

Question 56

What drugs are just as effective as the normal anti-emesis cocktail for emesis prophylaxis but re ALWAYS used in combination?

Answer 56

corticosteroids (ex. methylprednisolone and dexamethasone)

Question 57

How do methylprednisolone and dexamethasone work to treat emesis?

Answer 57

antiemetic mechanism remains unclear, but possibly via steroid receptors in the STN or reduction in serotonin release