N/V and Anticholinergics- Khan

Which enzyme is responsible for ACh biosynthesis?

Choline acetyltransferase

Which enzyme is responsible for ACh metabolism?

Acetylcholinesterase

Which enzyme is used as a drug target?

acetylcholinesterase

What are the 2 receptors of cholinergic nervous system?

1. muscarinic

2. nicotinic

Where are the muscarinic receptors located? What location is the only place with sympathetic neurons?

• brain

• any organs with parasympathetic neurons

• sweat glands w/ SYMPATHETIC neurons that released ACh

List the steps associated transduction with M1-M3 receptors:

1. Ach binds to M receptor

2. M receptor activates Gq

3. Gq activates PLC

4. PLC cuts PIP2 into DAG and IP3

5. DAG and IP3 activate PKC

Which muscarinic receptors are present in the salivary gland and GI organs?

M3

What are the important muscarinic functions? Which function is mediated by sympathetic neurons?

• GI—> gastric acid secretion, increase tone and mobility of GI smooth muscle

• salivation

• Sweating—> sympathetic

• bladder contraction

• eye—> miosis, focusing, decrease eye pressure

• others: bradycardia, bronchial secretions, bronchoconstriction

What are the names of the muscarinic agonists? What are each used for?

• pilocarpine- glaucoma, miotic agent, dry mouth

• cevimeline- dry mouth (Xerostomia, Sjogrens)

What are the structural requirements for muscarinic agonists?

• NEED + charged N

• NEED alkyl groups on N should not exceed size of methyl

• Should have O

• Should have 2C bridge between N and O

List the names of the muscarinic antagonists? What are they used for in the GI system?

• atropine

  • hyoscyamine

• dicyclomine

Used for GI spasms

What isomer is responsible for the effect of atropine?

L-isomer aka hyoscyamine

What are the important biological effects of muscarinic antagonists?

• GI—> INHIBIT gastric acid secretion, DECREASE tone and mobility of GI smooth muscle, prolong gastric emptying

• INHIBIT salivation

• INHIBIT sweating—> sympathetic

• bladder relaxation

• eye—> mydriasis, distance focus, increase eye pressure

• others: tachycardia, reduce bronchial secretions, bronchodilation

Which muscarinic antagonist has a contraindication? What is it?

Atropine- glaucoma

What are some drugs with anticholinergic side effects?

What are the symptoms of nausea?

• unpleasant feeling

• tachycardia

• salivation

• increase respiration rate

• sweating

Which drugs are known to cause emesis?

• chemotherapy drugs

• opioids

• bromocriptine

• apomorphine

Where is the emetic center located in the brain? Where is the BBB located?

emetic center is located in the medulla.

BBB is located between periphery and CNS

What are the 2 broad categories of antiemetic drugs? What drugs classes belong to each?

• category: motion sickness

  • H1 antihistamines

  • antimuscarinic/ muscarinic receptor antagonist

• category: chemo-induced n/v

  • 5-HT3 receptor antagonists

  • substance P antagonists

  • corticosteroids

  • antipsychotic

  • dopamine antagonist

  • cannabinoids

  • benzodiazepine

Answer the following about Scopolamine:

• what is it used to prevent?

• site of action?

• MOA?

• used to prevent motion sickness

• acts in BBB between inner ear and cerebellum

• muscarinic receptor antagonist

Answer the following about antihistamines:

• list the generic names

• site of action

• Meclizine, Diphenhydramine, Dimenhydrinate

• acts on h1 receptors in STN and inner ear

All serotonin receptors are ___________ except for 5HT3.

GCPRs

How is the 5HT3 receptor different from other receptor subtypes?

It is a Na+/K+ Ion channel receptor

What is the enzyme involved in the rate limiting step of converting Tryptophan to Serotonin?

Tryptophan hydroxylase

Answer the following about 5HT3 antagonists:

• list the brand/generics

• MOA

• what peripheral and central cellular sites do they act on?

• What does the structure of serotonin look like?

• Ondansetron (Zofran), Granisetron (Kytril), Palonosetron (Aloxi)

• Block 5HT3 receptors

• Peripheral- Block small intestine 5HT3 to vagal and spinal afferent

• Central- CTZ and STN

What are the functions of substance P and NK receptor?

• pain transmission

• hypotension

• n/v

Answer the following about Substance P Antagonists (NK antagonists):

• list the agents generic ONLY

• brand name of aprepitant

• MOA

• Drug Interactions with dexamethasone

• Aprepitant, Fosaprepitant, Netupitant, Rolapitant

• EMEND

• NK1 receptor antagonists

• FOR ALL BUT ROLAPITANT—→ interacts with dexamethasone, must decrease dose of DEXA

Answer the following about Dexamethasone:

• MOA

• antiemetic effect in cancer

• activates Glucocorticoid receptor (nuclear receptor)

• in cancer, suppresses peritumoral inflammation and PG production

Answer the following about Olanzapine:

• class

• what is it used for?

• atypical antipsychotic

• used for chemotherapy induced n/v

Answer the following about Lorazepam:

• what component is decreased by Lorazepam?

• site of action

• side effect

• reduces anticipatory component of nausea and vomiting (like fear)

• cerebral cortex?

• sedative, anti-anxiety, amnesia

What brain structure receives the anticipatory component of n and v?

• higher centers of the brain/ medulla?

What is the main MOA of prochlorperazine and promethazine?

Block D2 receptors at the CTZ

What is the site of action of dopamine antagonists?

CTZ

Answer the following about Cannabinoids:

• list brand/generic

• MOA

• ADRs

• Dronabinol (Marinol), Nabilone (Cesamet)

• Stimulate CB1 receptors around the emetic center

• Euphoria, Dysphoria, Somnolence, Increased appetite