HTHSCI 2H03 - 12.2 Drugs for Disorders of the GI System (N & V)

why is N&V a very important side effect to address

can affect drug absorption

what is the first priority for nausea & vomiting

preventing dehydration and fluid loss leads to an imbalance of electrolytes

vomiting

forceful expulsion of stomach contents and the contents of the proximal small intestine

a SYMPTOM and NOT a disease

consequences of vomiting

potassium deficincy

sodium depletion

alkalosis (loss of gastric acid)

malnutrition

esophageal and gastric injury (hemorrhage)

dental injury (erosions and caries)

purpura (pin prick red spots)

aspiration pneumonia

the act of vomiting (3 stages)

nausea

retching (dry heaves)

vomiting (projectile vomiting)

projectile vomiting

comes up an out

occurs more in kids due to them having a smaller stomach

what is not defined as vomiting

regurgitation (liquid burp and previously swallowed food or secretions coming up)

rumination (purposeful that is aligned with attention seeking)

nausea

unpleasant and difficult "psychic" experience

sensation of unease and discomfort

what is nausea physiologically associated with

decreased gastric motility

increased small intestine tone

reverse proximal small intestinal peristalsis

explain the process of vomiting

1 deep breath

2 glottis close and larynx raise upwards, opening epohageal sphincter

3 soft palate elevated to close off posterior nares

4 diaphragm contracted downwards

5 abdominal wall muscles contract

6 food moves up and out

what part of body coordinates vomitng?

brainstem

what areas in the brainstem control vomiting?

vomiting centre (VC)

nucleus tractus solitarius (NTS)

chemoreceptor trigger zones (CTZ)

process of vomiting activation in brainstem

NTS & CTZ synapses in and sends signals to the VC that will then initiate vomiting when stimulus triggered

vomiting centres (location + purpose + mechanism of action)

we have one in each hemisphere as we dont want to lose our ability to vomit

found in the reticular formation of the medulla

chemical(emetic drugs) & electrical stimulation cause vomiting

VC Afferents

CTZ & NTS

visceral afferents from GI tract, kidney, heart, bile ducts

extramedullary centres in the brain

- psychic stimuli (odours, fear)

- vestibular disturbances (motion sickness)

- cerebral trauma

chemoreceptor trigger zones (location + action)

bilateral centres in the brainstem (one in each hemisphere)

located in the fourth ventricle where the BBB is the most thinnest meaning the brain is able to detect any chemicals in bloodstream that we ingested that can be harmful to us

acts as emetic chemoreceptor for the VC (detects chemical abnormalities and sends excitatory signals to vomiting centres)

what type of stimulation does the CTZ receive / respond to?

chemical stimulation (emetic drugs)

electrical stimulation does not have an impact

why is nausea associated w/ feeling hot + salivation + deep breaths?

bc VC has direct effects on salivary/respiratory/vasomotor symptoms

how do chemotherapy drugs induce N & V

circulates in the blood and directly stimulates CTZ

stimulates enterochromaffin cells in GI tract to release serotonin = activates 5HT receptors in vagus nerve (stimulates VC due to signals from visceral afferent from GI + NTS + CTZ)

what causes most of the activation of vomiting from chemo therapy?

enterochromaffin cells

damage to these cells due to chemo causes a MASSIVE release of serotonin

what are the three Chemotherapy and Radiation Therapy Induced Nausea?

anticipatory N&V

acute N&V

delayed (late onset) N&V

anticipatory N&V

Occurs before or during therapy in individuals who have had severe symptoms with previous therapy

triggered by specific odours, tastes, or objects that a patient associates with treatment

acute N & V

Occurs within 24 hours after cancer treatment

Chemo directly affects the CTZ

what is treatment approach for N & V?

assess likely cause (GI)

assess consequences (dehydration)

treat consequences (IV)

confirm the case

treat the case

antiemetic drug classes

anticholinergic

antihistamines

cannabinoids

dopamine antagonists

serotonin antagonists

glucocorticoids

neurokinin receptor antagonists

antihistamines (use, mechanism)

antagonist at H1 receptors in the NTS and CTZ for motion sickness

can cause sedation

muscarinic antagonist/anticholinergic as antiemetic (action, AE)

acts on muscarinic receptors in CTZ & NTS for motion sickness & vestibular diseases

(muscarinic receptors highly implicated in those two)

AE: dry mouth, constipation, urinary retention, memory loss (AE associated w/ blocking parasympathetic)

what are the types of dopamine antagonists used as anti-emetics? (+mechanism, which one is used FIRST?)

1) atypical antipsychotics

2) gastric prokinetics

3) typical antipsychotics

binds to D2 receptors in CTZ & NTS

atypical used FIRST

cannabinoids (use, mechanism)

Agonists at CB1 receptor in the cortex and VC

dont do alot for N&V

use: increases appetite (chemo can make pts loose appetite & lack nutrients

atypical antipsychotics (mechanism, use, AE)

antagonist at D2(dopamine) receptors in CTZ & NTS

use: nausea & vomiting

AE: sedation, blurred visiondry mouth, constipation, urinary retention

gastric prokinetics (mechanism, use, AE)

antagonist at D2 AND 5HT receptors (dopamine & serotonin) at CTZ & NTS

use: stops reversal of gut that causes nausea

AE: sedationdiarrhea, galactorrhea(fluid from breast tissue), extrapyramidal signs(involuntary movements)

serotonin antagonists (mechanism, use)(which one should be used for CV pts, which one shouldn't be used?)

antagonist at 5HT receptors at CTZ & NTS to block binding of serotonin made by enterochromaffin cells (stimulated by chemo drugs)

use: prevents nausea & vomiting caused by chemo drugs

ondansetron: can induce cardiac arrhythmias if given by IV to CV pts(use palonosetron for CV pts instead)

typical antipsychotics (mechanism, use, AE)

antagonist at D2 receptors in CTZ & NTS

use: nausea and vomiting

AE: sedation, hypotension, extrapyramidal signs

NK1 receptor antagonists (mechanism, use, AE, drugs it's combined with)

blocks binding of substance P at NK1 receptors in CTZ & NTS

use: analgesia

combined w: glucocorticoids, 5HT antagonists

AE: inhibits CYP34A = ↓metabolism of other drugs (∴ glucocorticoid dose should be reduced if co-administered as an antiemetic drug)

Glucocorticoids (mechanism, use, what other drugs is it commonly combined with?)

decreases 5HT tone (↓receptors & ↓5HT produced); acts on NTS to dampen signals to VC

use: analgesic & anti-inflammatory effects + reverses hypofunctioning of HPA axis induced by chemo

combined with: serotonin antagonist & NK1 antagonist

ondansetron vs palonosetron

odansteron can cause cardiac arrhytmia's in CV pts if given by IV

Palonosetron should be used instead for CV pts

what is the gold standard for treating nausea/vomiting induced by chemotherapy?

1. NK1 receptor antagonist

2. serotonin antagonist

3. glucocorticoid (dexamethasone)

4. atypical antipsychotic (Olanzoapine)

which drugs should be used for psychogenic causes of nausea/vomting?

benzodiazepines

which drugs should be used for vestibular changes (motion sickness)?

anticholinergic

histamine antagonist

what are the opioids & anesthetics for chemotherapy affecting CTZ

anticholinergics, histamine antagonists, dopamine antagonists, cannabiboids

which drugs should be used for surgery & chemo induced GI changes causing nausea?

gastric prokinetics, serotonin antagonists

delayed (late onset) N&V

Occurs more than 24 hours after cancer treatment and may continue for several days

Due to the trauma of the gut → serotonergic tone + vagus efferents