Tx of Vertigo, Hearing Loss, and N/V

Question 1

Question 2

What are the major D2 antagonists?

Answer 2

prochloraperazine and chlorpromazine

Question 3

What are the major 5HT3 antagonists?

Answer 3

dolasteron, granisetron

ondansetron, palonosteron

Question 4

What are the major NK1 antagonists?

Answer 4

Aprepitant

fosaprepitant

Question 5

Note how most drugs with the most prominent vertigo producing effects do so by impacting the structure and function of the vestibular apparatus, for example, the hair cells of the inner ear

Question 6

These drugs are toxic to the inner ear. Note that the effects of many are reversible but for the aminoglycosides and cisplatin, they are irreversible, and for loopi-diuretics they may not be if chronic use

Question 7

How are aminoglycosides toxic to the ear?

Answer 7

AG entry into the outer hair cell results in cell death by either caspase-dependent or independent mechanisms and occur via the following steps:

1) entry into the outer hair cell through the mechanoelectrical transducer channels
2) formation of an AG-iron complex that can react with electron donors, such as arachidonic acid to form ROS like superoxide, hydroxyl radicals, and hydrogen peroxide
3) ROS can then activative JNK, when can then
4) translocate to the nucleus to activate genes in the cell death pathway. These genes can then translocate to the mitochondria, causing the release of cytochrome C which can trigger apoptosis via caspases

Question 8

How does cisplatin cause inner ear toxicity?

Answer 8

Cisplatin entry into outer hair cells result in cell death which appears to be primarily caspase dependent via the following steps:

1) Entry into the outer hair cell through mechano-transducer channels
2) CP within cells can be aquated to form the monohydrate complex (MHC), which is more reactive
3) CP and/or MHC can activate NOX-3, resulting in ROS production
4) ROS may inturn activate JNK
5) These molecules then translocate to the nucles to promote cell death via caspase dependent processes

Question 9

How do loop diuretics work?

Answer 9

they inhibit NaK2Cl transporter in the thick ascending loop of Henle. Note that similar ion transport exists in the inner ear where they maintain the production of endolymph and by interferring with this, diuretics upset the fluid balance, resulting in edema and loss of function (dose dependent and temporary))

Question 10

How is vertigo tx?

Answer 10

They act primarily on the H1 and M1 receptors

Note that diazepam is useful for nausea arising from higher brain centers mediating fear, emotion, anticipation, etc.

Question 11

Answer 11

Question 12

Answer 12

Question 13

What causes N/V?

Answer 13

Protective reflexes to rid the body of toxic substances and prevent further ingestion.

Question 14

How is vomiting achieved?

Answer 14

Consists of a pre-ejection phase (gastric relaxation and retroperistalasis), retching (rhythmic action of respiratory muscles preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphrag, against a closed glottis), and ejection

This is accommpanied by multiple autonomic phenomena including salivation, shivering, and vasomotor changes and lethargy, and withdrawal may occur with extended vomiting

Question 15

Where is the process of vomiting coordinated?

Answer 15

By a central emesis center in the lateral reticular formation of the mid-brainstem adjacent to both the chemoreceptor trigger zone (CTZ) in the area postrema (AP) at the bottom of the fourth ventricle

The lack of BBB here allows the CTZ to monitor blood and CSF constantly for toxic substances and to relay info to the emesis center to trigger N/V

Question 16

Where else does the emesis center receive input from?

Answer 16

the gut, principally by the vagus nerve (via the STN) but also by splanchnic affarents via the spinal cord

Also from the cerebral cortx (particularly in anticipatory nausea or vomiting) and the vestibular apparatus in motion sickness

Question 17

Where does the emesis center send efferents?

Answer 17

to the nuclei responsible for respiratory, salivary, and vasomotor activity, as well as to striated and smooth muscle involved in vomiting

Question 18

The CTZ has high conc of receptors for what NTMs?

Answer 18

serotonin (5-HT₃), dopamine (D2), and opiods

Question 19

The STN has high conc of receptors for what NTMs?

Answer 19

enkephalin, histamine, and Ach, and some 5-HT3 receptors $

Question 20

What antiemetic drugs are used for moderate to severe N/V?

Answer 20

serotonin (5-HT3) antagonists such as dolasetron, granisetron, ondansteron, and palonosetron

Question 21

Where do serotonin (5-HT3) antagonists principally act?

Answer 21

the CTZ and STN

Question 22

More on serotonin (5-HT3) antagonist metabolism

Answer 22

-hepatic metabolism (dose adjustment in dysfunction with ondansteron only)

Question 23

What are the main AEs of serotonin (5-HT3) antagonists?

Answer 23

-hypersensitivity rxns

QT prolongation (ECG monitoring recommended when taking dolasetron or ondansteron)

-HA, constipation, and diarrhea

Question 24

Describe D2 receptor Antagonists (prochlorperazine and chlorpromazine)

Answer 24

These are general-purpose anti-nauseants and anti-emetics (NOT used for CINV) that act in the CTZ (also possess antihistaminic and anticholinergic activity; useful in other forms of nausea, such as motion sickness)

Question 25

What are the AEs of D2 receptor Antagonists?

Answer 25

chronic use leading to bone marrow suppression

QT prolongation

co-admin with antipsychotics may increase CNS AEs (drowsiness, dizziness, orthostatic hypotension, seizures, neuroleptic malignant syndrome)

Question 26

Describe the NK1 receptor antagonists (aprepitant and fosaprepitant)

Answer 26

These act in the ST, and possibly also in the GI tract (with hepatic metabolism)

Question 27

How does dronabinol/THC work?

Answer 27

They reduce N/V by G-coupled protein mediated decrease in neuronal activity in the medullary vomiting center and STN (oppose 5-HT3 stimulation from vagal affarents). Also stimulated appetite at lower doses via CB receptors in the lateral hypothalamus

Question 28

How are dronabinol/THC metabolized?

Answer 28

hepatic

Question 29

Question 30

What antineoplastics induce the highest rates of N/V?

Answer 30

cisplatin

mechlorethamine

streptozotocin

cyclophosphamide

carmustine

dacarbazine

Question 31

Serotonin receptor blocker + corticosteroid and a NK-1 antagonist is the tx of choice for prophylaxis against acute emesis

Answer 31

Question 32