Tx of Vertigo, Hearing Loss, and N/V Flashcards
What are the major D2 antagonists?
prochloraperazine and chlorpromazine
What are the major 5HT3 antagonists?
dolasteron, granisetron
ondansetron, palonosteron
What are the major NK1 antagonists?
Aprepitant
fosaprepitant
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
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
How are aminoglycosides toxic to the ear?
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
How does cisplatin cause inner ear toxicity?
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
How do loop diuretics work?
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))
How is vertigo tx?
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.
What causes N/V?
Protective reflexes to rid the body of toxic substances and prevent further ingestion.
How is vomiting achieved?
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
Where is the process of vomiting coordinated?
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
Where else does the emesis center receive input from?
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
Where does the emesis center send efferents?
to the nuclei responsible for respiratory, salivary, and vasomotor activity, as well as to striated and smooth muscle involved in vomiting
The CTZ has high conc of receptors for what NTMs?
serotonin (5-HT3), dopamine (D2), and opiods
The STN has high conc of receptors for what NTMs?
enkephalin, histamine, and Ach, and some 5-HT3 receptors $
What antiemetic drugs are used for moderate to severe N/V?
serotonin (5-HT3) antagonists such as dolasetron, granisetron, ondansteron, and palonosetron
Where do serotonin (5-HT3) antagonists principally act?
the CTZ and STN
More on serotonin (5-HT3) antagonist metabolism
-hepatic metabolism (dose adjustment in dysfunction with ondansteron only)
What are the main AEs of serotonin (5-HT3) antagonists?
-hypersensitivity rxns
QT prolongation (ECG monitoring recommended when taking dolasetron or ondansteron)
-HA, constipation, and diarrhea
Describe D2 receptor Antagonists (prochlorperazine and chlorpromazine)
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)
What are the AEs of D2 receptor Antagonists?
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)
Describe the NK1 receptor antagonists (aprepitant and fosaprepitant)
These act in the ST, and possibly also in the GI tract (with hepatic metabolism)
How does dronabinol/THC work?
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
How are dronabinol/THC metabolized?
hepatic
What antineoplastics induce the highest rates of N/V?
cisplatin
mechlorethamine
streptozotocin
cyclophosphamide
carmustine
dacarbazine
Serotonin receptor blocker + corticosteroid and a NK-1 antagonist is the tx of choice for prophylaxis against acute emesis
