GI Pharmacology -4

Irritable Bowel Syndrome and

Antiemetics Dr. Alia Shatanawi

11-04-2018

Drugs used in Irritable Bowel

Syndrome

• Idiopathic, chronic, relapsing

disorder characterized by abdominal

discomfort (pain, bloating,

distension, or cramps) in

association with alterations in bowel

habits( diarrhea, constipation, or

both).

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For chronic abdominal pain, low doses of tricyclic

antidepressants (eg, amitriptyline or desipramine, 10–50

mg/d) appear to be helpful.

At these doses, these agents have no effect on mood but

may alter central processing of visceral afferent

information.

The anticholinergic properties of these agents also may

have effects on gastrointestinal motility and secretion,

reducing stool frequency and liquidity.

Tricyclic antidepressants may alter receptors for enteric

neurotransmitters such as serotonin, affecting visceral

afferent sensation.

Drugs used in Irritable Bowel

Syndrome

Drugs used in Irritable Bowel Syndrome

• Antispasmodic or Anticholinergic

Agents:

– Dicyclomine

– Hyoscyamine.

• Spasm is not an important symptom

in IBS.

• They inhibit muscarinic cholinergic

receptors in the enteric plexus and

on smooth muscle.

• At usual low doses, have minimal

side effects.

Drugs used in Irritable Bowel Syndrome

• Serotonin 5-HT3- Receptor Antagonists:

– Alosterone:

• 5-HT3 receptors are present in the

afferent pain fibers in the extrinsic

sensory neurons. Also present on

the terminals of the enteric

cholinergic neurons. Centrally, 5-HT3

is involved in the central response to

visceral afferent stimulation.

Drugs used in Irritable Bowel Syndrome

• Serotonin 5-HT3- Receptor Antagonists:

• Alosterone:

– Selective antagonist of 5-HT3 receptors.

– Has long duration of action.

– Approved for women with severe IBS in whom

diarrhea is the prominent symptom.

– Efficacy in men is not established.

– Can cause ischemic colitis, severe

constipation requiring hospitalization and

surgery.

Drugs used in Irritable Bowel Syndrome

• Serotonin 5-HT 4- Receptor Agonists:

• Tagaserod:

– Approved for short term treatment of women

with IBS who predominantly have constipation.

– Reduces pain, bloating and hardness of stool.

– Expensive.

9

Vomiting Centre

(medulla)

Cerebral cortex

Anticipatory emesis

Smell

Sight

Thought

Vestibular

nuclei Motion

sickness

Pharynx & GIT

Chemo & radio therapy

Gastroenteritis

Chemoreceptor

Trigger Zone

(CTZ)

(Outside BBB)

Cancer chemotherapy

Opioids

Muscarinic, 5 HT3 &

Histaminic H1

5 HT3 receptors

Dopamine D2

5 HT3,,Opioid Receptors

Muscarinic

Histaminic H1

Pathophysiology of Emesis

Which group of drugs can be used as antiemetics ?

Serotonin 5 HT3 Antagonists

Dopamine D2 Antagonist

Anticholinergics

H1 Antihistaminics

Cannabinoids

Antiemetic Agents

• Afferent Inputs to the Vomiting Center:

– Chemoreceptor trigger zone: DA2, 5-HT3, NK1,

and opioid receptors.

– Vestibular system involved with motion

sickness through cranial nerve VIII. Rich in M

and H1 receptors.

– Pharyngeal irritation through the vagus.

– GIT afferents through the vagus and spinal

afferent nerves, rich in 5-HT3 receptors.

– Central mechanisms due to psychiatric

disorders, stress, and anticipatory vomiting of

cancer chemotherapy (5-HT3).

Antiemetic Agents

• Serotonin 5-HT3- Receptor Antagonists:

– Ondansetron.

– Granisetron.

– Dolasetron.

– Palonosetron. • 5-HT3 receptors are involved in three out of the

five inputs involved with vomiting.

• Activity restricted to vomiting due to vagal stimulation and chemotherapy.

• Motion sickness is poorly controlled.

Antiemetic Agents

• Serotonin 5-HT3- Receptor Antagonists: – Ondansetron.

– Granisetron.

– Dolasetron.

– Palonosetron. • Used before chemotherapy, activity enhanced by

dexamethasone and NK1 antagonist.

• Can also be used in postoperative and post radiation vomiting.

• Safe drugs but can cause headache, dizziness and constipation.

• Also prolong QT interval.

Antiemetic Agents

• Neurokinin Receptor Antagonists:

– Apripetant:

• Central blockade in the area postrema.

• Used in combination with 5-HT3 antagonists.

• Can cause fatigue, dizziness and diarrhea.

Antiemetic Agents

• Antipsychotic drugs:

– Prochlorperazine.

– Promethazine.

– Droperidol.

• Inhibit dopamine and muscarinic

receptors.

• Can cause extrapyramidal effects,

hypotension and prolong QT interval.

Antiemetic Agents

• Antihistamines and anticholinergic

Drugs:

– Diphenhydramine

– Meclizine.

– Hyoscine (scoplamine).

• Particularly useful in motion sickness.

• Can cause dizziness, sedation, confusion,

dry mouth, cycloplegia, and urinary

retention.

• Hyoscine can be used as a transdermal

patch.

Antiemetic Agents

• Benzodiazepines:

– Lorazepam.

– Diazepam.

• Reduce anticipatory vomiting caused by anxiety.

Antiemetic Agents • Cannabinoids:

• Dronabinol.

• Nabilone.

– Delta-9- tetrahydrocannabinol from marijuana

useful for chemotherapy-induced vomiting.

– Mechanism not understood.

– Can cause euphoria, dysphoria, sedation,

hallucinations, dry mouth, and increased

appetite.

– Also, hypotension, tachycardia, and

conjunctival injection.

Emetic Agents

• Many drugs.

• Hypertonic saline.

• Apomorphine.

• Ipecac syrup.