Eleven

Question 1

Where are enteric neuroreceptors located? What information do they provide? What are the two types of nociceptor nerve fibers? What tissue do they innervate and what kind of pain do they produce? What does stimulation of nociceptors in the GI system lead to? Describe the pathway through which pain sensation is transmitted to the CNS? How are these signals modified?

Answer 1

• Enteric neuroreceptors are located within the mucosa and muscularis on hollow viscera, on serosa (e.g. peritoneum) and within the mesentery.

• Provide information on food and bacteria and regulation of secretion, motility and blood flow (intrinsic, enteric nervous system or ENS)
• Provide information on noxious stimuli (nociception, via ANS)

• Nociceptors

• Myelinated fibers –>skin and muscle (somatoparietal pain- sharp, sudden, well-localized following an acute injury)
• Unmyelinated fibers–>muscle, periosteum, mesentery, peritoneum, viscera
  (visceral pain- dull, burning, poorly localized)

• Stimulation leads to…

 local regulatory reflexes (ENS)
 pain transmission to CNS via ANS, SNS
 - autonomic signs
 - skeletal muscle activation
- brain perception of pain

• CNS transmission

• Largely via ANS
• Cell bodies located in dorsal root ganglia
• Afferent neurons enter dorsal horn, then the spinothalamic tract
• Neurons ultimately enter the limbic system and
  frontal cortex, and pain is perceived
• Modified by inhibitory mechanisms in the spinal cord and brain. In stress analgesia, these are decreased by counter stimulation.

Question 2

List 5 mechanical pain stimulants and what might cause them? List various things that will cause chemical mediators to be released that result in pain? What are some of these mediators? How might the accumulation of these substances affect the microenvironment?

Answer 2

• Mechanical (stretch; not cutting, tearing or crushing)

• Rapid distension (obstruction)
• Forceful muscular contractions (stone–>colic)
• Serosa or capsule stretching of solid organ (e.g. liver)
• Torsion/volvulus
• Traction tension (e.g. tumor)

• Chemical
- Mediators are released in response to local mechanical injury, inflammation, ischemia or necrosis, noxious thermal or radiation injury
- H+, K+, histamine, serotonin, bradykinin, substance P,
prostaglandins, leukotrienes
- Accumulation of these substances alter the microenvironment and may decrease the pain threshold (hyperalgesia) and cause allodynia (innocuous stimuli become painful).

Question 3

Describe visceral pain. Where do the impulses travel? What is the pain like? What are some secondary autonomic effects? What can help with the pain?

Answer 3

• Visceral pain (slow pain): viscera stimulated by noxious stimuli

• Impulses travel with autonomic nerves; T6-L2, S2-4
• Fewer nerve endings
• Dull and poorly localized in the midline but roughly correlate to the dermatomes corresponding with the diseased organ’s innervations
• Sensory afferents transfer information to both sides of the spinal cord at multiple levels, and any level may receive input from several organs
• Cramping, burning, gnawing pain
• Secondary autonomic effects: sweating, restlessness, nausea, vomiting, perspiration, pallor
• Movement may relieve discomfort–>patient may be restless

Question 4

Describe somatoparietal pain. Where do the impulses travel? What is the pain like? What makes the pain better? What can cause the pain?

Answer 4

• Somatoparietal pain (fast pain): parietal peritoneum stimulated by noxious stimuli

• Impulses travel with somatic nerves; T5-L2, C3-5 (diaphragm)
• More nerve endings
• Intense; more acute or sudden
• More precisely localized (nerves correspond to cutaneous dermatomes with only one side of spinal cord innervated)
• Aggravated by movement or coughing–>patients lie immobile
• Perforated ulcer, bacterial contents, ischemia,
  mesenteric embolus, ruptured aneurysm

Question 5

Describe referred pain. What branch of the nervous system is involved? What is the pain like?

Answer 5

• Referred pain
- ANS + SNS
- Felt in areas remote from diseased organ
Biliary colic: right shoulder blade
- Cutaneous or deep, usually well-localized
- Visceral afferents and somatic afferents from a different region converge on second-order neurons in the spinal cord at the same segment

Question 6

Describe chronic abdominal pain. What causes it? Describe the pathophys

Answer 6

• Abnormal functioning of brain-gut axis
• No increased afferent visceral stimuli or motility abnormality
• CNS amplification (lack of down-regulation of afferent signals) and potential subsequent hyperalgesia from repeated peripheral stimulation
• Enhanced pain perception due to activation of silent nociceptors (visceral hypersensitivity); long-term sensitization of visceral pathways transmitting pain
• Altered or enhanced central pain modulation due to cognitive, emotional or psychosocial factors

Question 7

Define nausea, retching, vomiting, regurgitation, rumination. What triggers these things?

Answer 7

• Nausea: a conscious awareness of and subjective sense of the impending urge to vomit
• Retching: forceful somatic and gastrointestinal contractions against a closed glottis (no

discharge of gastric contents)

• Vomiting: just like retching except the UES opens and out come gastric contents
• Regurgitation: gentle return of esophageal contents into the hypopharynx
• Rumination: regurgitation of gastric contents into the hypopharynx
• Triggers can be central or peripheral

Question 8

Describe 4 different neuropathways that lead to vomiting.

Answer 8

The action of vomiting is coordinated in the brain through the emetic (or vomit) center.

All roads (neural pathways) that carry nausea

signals lead to this structure, which then makes

you vomit. The list of etiologies that cause nausea

and vomiting is huge. Triggers that cause nausea

and potentially vomiting can come from

peripheral or central sources. First, triggers from

the GI tract itself travel along afferent fibers

along the digestive tract, such as from the

pharynx, stomach and small intestine. Afferent signals from these organs travel to the solitary nucleus and are then relayed to the emetic

center (see below). Secondly, nausea can also arise from non-digestive organs (such as

the heart and testes). These signals travel along afferent pathways to the solitary nucleus

then emetic center as well. Third, circulating endogenous or exogenous chemicals can

stimulate vomiting. A specialized area in the brain called the chemoreceptor trigger

zone (CTZ), which is located on the area postrema on the floor of the fourth ventricle,

sits partially just outside of the blood-brain barrier. This sensory apparatus detects

molecules in the blood stream that can cause emesis. Finally, many triggers at the level of

the central nervous system (CNS) can cause nausea and vomiting. These include the

vestibular system, cerebral cortex and brainstem. The brief outline below summarizes

many triggers of nausea and vomiting.

Question 9

Give specific triggers of the 4 emetic pathways. Via which nerves do they send their signals?

Answer 9

A. The GI Tract- via vagus and splanchnic nerves

a. Gastric outlet obstruction
b. Volvulus
c. Peptic ulcer disease
d. Appendicitis
e. Pancreatitis
f. Pharyngeal stimulation

B. Non-GI tract peripheral triggers - via vagus and splanchnic nerves

a. Cardiac abnormalities
i. Congestive heart failure
ii. Myocardial infarction
b. Acute testicular injury

C. CTZ-mediated triggers – accessible to blood and CSF, ideal location for sampling

a. Medications/Toxins (i.e., anti-microbials, digoxin, opioids, chemotherapeutic agents, alcohol, blood-borne infectious toxins/enterotoxins)
b. Metabolic disturbances (e.g. uremia, hypoxemia, diabetic ketoacidosis, hypercalcemia

D. CNS Triggers

a. Vestibular system
i. Otitis media
ii. Ménieré’s disease
iii. Motion sickness

iv. Skull base tumors
b. Cerebral cortex
i. Emotions- fear, sadness, pain

ii. Increased intracranial pressure

Question 10

Describe the steps of emesis.

Answer 10

 A deep breath is taken, the glottis is closed and the larynx is raised to open the upper esophageal sphincter

 The soft palate is elevated to seal off the nasal pharynx

 The diaphragm is contracted sharply downward to create negative pressure in the thorax, which facilitates opening of the lower esophageal sphincter

 The muscles of the abdominal walls contract vigorously, squeezing the stomach and thus elevating intragastric pressure

 Retrograde peristaltic contraction of the jejunum to seal off down stream

 Vomiting occurs

Question 11

Which receptors are involved at the various points in the emetic neuropathways?

Answer 11

The major players are dopamine (D2), histamine (H1), 5-hydroxytrypatmine3-serotonin (5HT3), acetylcholine (muscarinic, M1), neurokinin (NK-1) and cannabinoid (CB1) receptors.

A. GI tract- serotonin (5HT3) (additionally, the pharynx has multiple receptor classes)

B. Peripheral organs- non-GI tract- acetylcholine (M1)

C. Chemoreceptor-Trigger Zone- 5HT3, D2, M1, CB1

D. CNS

a. Vestibular- H1, M1
b. Cerebral cortex (mostly via the vagal system, mechanism not well understood)

E. Solitary tract nucleus- has all receptors- 5HT3, D2, M1, H1, CB1, NK-1

Question 12

List the major stimuli of nausea and vomiting.

Answer 12

 Acute intestinal obstruction

 Gastric outlet obstruction

 Intestinal infarction

 Non-intestinal causes (myocardial infarction, renal or biliary colic)

 Toxins and drugs

 Metabolic disturbances (diabetic ketoacidosis, hyponatremia)

 Infection

 Neurologic causes (vestibular, cerebellar disorders, migraine headaches)

 Post-operative (PONV)

 Gastrointestinal motility disorders

 Pregnancy

 Functional nausea and vomiting

Question 13

List 8 categories of drugs use for nausea and vomiting.

Answer 13

Drugs used for symptomatic relief of nausea and vomiting:

• Muscarinic receptor antagonists.
• Histamine H1 receptor antagonists.
• Dopamine receptor antagonists.
• 5-HT, receptor antagonists.
• Steroids.
• Sedatives and hypnotics.
• Neurokinin receptor antagonists.
• Cannabinoids

Question 14

What is the most effective muscarinic receptor antagonist drug for vomiting? When is it used? Where does it work? What are its side effects?

Answer 14

• Scopalamine is the most effective remedy for motion sickness. (Think of passengers on a cruise ship wearing a scopolamine patch.)

• Blockade of muscarinic cholinergic receptors in the area
postrema or associated nuclei of the dorsal vagal complex.

• Many side effects (see images at right).
Blurred vision
confusion
mydriasis
constipation
urinary urgency

Question 15

List various Histamine H1 receptor antagonists. What conditions are they used to treat? Where do they exert their effect/mechanism?

Answer 15

• Antihistamines used for motion sickness include buclizine, dimenhydrinate, meclizine, promethazine.
• Central blockade of H1 receptors in the area postrema.
• Most are also potent muscarinic receptor antagonists.
• A sedative capability may also contribute to the effect.
• May play some role in the treatment of PONV and pregnancy sickness.

Question 16

Where are dopamine receptors found? Where do the antagonists exert their effect? List 3 categories. What are the side effects?

Answer 16

• Dopamine receptors found in high concentrations in the area postrema, dorsal motor nucleus of the vagus nerve, and nucleus tractus solitarius.
• Dopamine receptor antagonists block CTZ receptors.

Butyrophenones
Metoclopramide and Domperidone:
Phenothiazines:

• Motor impairment, severe akinesia and muscle rigidity and dystonias caused by striatal dopamine receptor blockade, particularly in young people.

Question 17

What are 3 examples of butyrophenones? For what conditions are they used?

Answer 17

• Haloperidol, fluphenazine, droperiol

* Can be used for emesis induced by chemotherapy

Question 18

What is another mechanism of metoclopramide and domperidone? Explain. How do they differ? For which conditions are they used?

Answer 18

• Have peripheral prokinetic actions leading to increased gastric and intestinal activity which may contribute directly to its anti-nauseant/antiemetic actions
– Such actions probably reflect an agonist action at the 5-HT4 receptor

• Contrary to metoclopramide, domperidone does not cross the blood brain barrier (CTZ is on the blood side of the barrier) thus does not have CNS side effects.
• Used as an anti-nauseant/antiemetic for GI disorders and migraine and, in much higher doses for cancer chemotherapy- and radiation-induced sickness.

Question 19

What are 4 examples of phenothiazines? What is their mechanism? When is it used?

Answer 19

• Agents such as chlorpromazine, promethazine, prochlorperazine, and trimeprazine have a mixed pharmacology as antagonists at muscarinic, histaminergic,
dopaminergic, adrenergic, and serotonergic receptors.

• Symptoms that fail to respond to specific receptor blockade may sometimes respond to this multi-receptor blockade (e.g. pregnancy sickness, PONV).
• In presence of many contributory stimuli, the use of a ‘mixed’ pharmacologic approach is logical.

Question 20

List 3 examples of 5-HT3 receptor antagonists? Where are these receptors located? Describe their mechanism. For what conditions are they used? Not used? Which drug has additional uses? What are they? What are the major advantages of this class of drugs?

Answer 20

• Ondansetron, granisetron, and tropisetron.

• 5-HT3 receptors are located in high density in
– the area postrema and nucleus tractus solitarius
– on vagal afferent nerve endings in the gut

• Hypothesis: severely emetogenic chemicals cause GI tissue disruption, which initiates the release of 5-HT from the enterochromaffin cells within the mucosa.

– The release of 5-HT stimulates 5-HT3 receptors located on vagal afferent nerve endings and trigger vagus nerve firing to initiate the emetic reflex.

• Control nausea, retching, and vomiting in patients with cancer receiving emetogenic treatments, especially during the acute phase
• No effect on motion sickness.
• Ondansetron has also been shown to antagonize:

– The nausea induced by morphine.
– The nausea and GI adverse effects of SSRIs.
– Effective against post operative nausea and vomiting

• Major advantages:

– No sedation
– No interaction with other drugs
– No generalized autonomic adverse effects, endocrine changes, or motor impairments
– Remarkable safety profile, small incidence of headache, constipation, and a sensation of warmth or flushing.

Question 21

How do steroids work to produce an anti-emetic effect? How are they used?

Answer 21

• In high doses have antiemetic activity.
• Mechanism is not clear but it may involve inhibition of prostaglandin synthesis.
• Frequently used in combination with 5-HT3 receptor antagonists to secure optimal control of chemotherapy-induced nausea and vomiting.

Question 22

What are some examples of sedatives/hypnotics used for anti-emesis? Which is the most contemporary? What is its advantage? Explain a possible catastrophic side effects of these drugs.

Answer 22

• Barbiturates and chloral hydrate have been used
• Benzodiazepines are more contemporary and have the advantage of causing amnesia to prevent recall of a highly distressing event.
• The presence of reduced consciousness with a reduction or loss of reflex closure of the trachea, can be catastrophic.

Question 23

Where are the NK-1 receptors located? Which neuropeptide activates it? What are some NK1 receptor antagonists and what are they used to treat? When are they contraindicated?

Answer 23

• Substance P is a mammalian neuropeptide found in neurons that innervate the brainstem nucleus tractus solitarius and the area postrema.
• The emetogenic effects of substance P are mediated through the neurokinin-1 (NK1) receptor.
• NK1 receptor antagonists (eg, aprepitant, Emend®) are a relatively new class for the prevention of chemotherapy-induced emesis.
• Prevent not only acute but also delayed emesis in patients treated with highly emetogenic chemotherapy drugs (ie, cisplatin).
• Contraindicated in patients receiving concurrent drugs that are primarily metabolized through CYP3A4.

Question 24

Which pathway do the synth cannabinoids affect? What are some examples? What is a possible mechanism? What are some side effects?

Answer 24

• The potential antiemetic utility of cannabinoids was first observed in patients using marijuana during chemotherapy.
• Synthetic cannabinoids derivatives such as nabilone and dronabinol decrease emesis induced by agents that stimulate the CTZ.
• Antiemetic effects are antagonized by naloxone which suggests that opioid receptors may be important in the action.
• The modest antiemetic activity of this class of agents combined with their relatively unfavorable side effect profile (vertigo, xerostomia, hypotension, dysphoria) in older patients limited their utility.