College of Pharmacy Pharmacology of GIT Anti-emetic drugs by Dr College of Pharmacy Pharmacology of GIT Anti-emetic drugs by Dr. sherzad kh RASHID

GI Agents Vomiting – Anti-emetics Vomiting : is the ejection a part or all of the contents of the stomach through the mouth, usually in a series of involuntary spastic movements Causes are many: Motion sickness, viral & bacterial infection, food intolerance, surgery, PG, pain, shock, effects of some drugs, radiation, & disturbances of the middle ear affection equilibrium.

Mechanisms that trigger vomiting Two brainstem sites have key roles in the vomiting reflex pathway. 1-The chemoreceptor trigger zone (CTZ), which lies near the medulla, & 2- the vomiting center, in the medulla – both cause vomiting when stimulated

Pathophysiology of Emesis Cerebral cortex Cancer chemotherapy Opioids Smell Sight Thought Anticipatory emesis Chemoreceptor Trigger Zone (CTZ) Vestibular nuclei Emetic Centre Motion sickness (Outside BBB) Muscarinic, 5 HT3 ,NK & Histaminic H1 Muscarinic Histaminic H1 Dopamine D2,NK 5 HT3,,Opioid Receptors Chemo & radio therapy Gastroenteritis Pharynx & GIT 5 HT3 receptors

Anti-emetic drugs

Antiemetic drugs I- Anti-dopamenergics drug 1- Phenothiazines: The first group of drugs shown to be effective antiemetic agents such as prochlorperazine , acts by blocking dopamine receptors. It is effective against low or moderately emetogenic chemotherapeutic agents (for example, fluorouracil and doxorubicin).

Phenothiazines Adverse effects 1-Extrapyramidal side effects EPS : EPS are movement disorders resulting from effects of antipsychotic drugs on the extrapyramidal motor system. Although the exact cause of EPS is unclear, blockade of D2 receptor is strongly suspected. Four types of EPS occur. Three of these reactions- acute and the fourth reactions occurs late in therapy and has no satisfactory treatment.

Extrapyramidal side effects EPS include 1.Acute Dystonia: (sustained contraction of muscles leading to twisting distorted postures). The reaction develops within the first few days of therapy. 2.Parkinson -like symptoms. Characterized by bradykinesia , tremor , rigidity , shuffling gait. Symptoms develop within first month of therapy. 3. Akathisia: (motor restlessness , this profound sense of restlessness can be very disturbing). This syndrome usually develops within the first 2 months of treatment.

4.Tardive dyskinesia TD : (involuntary movements of the tongue, lips, neck, trunk, and limbs) occur with chronic treatment. The risk is related to duration of treatment and dosage size. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted movement symptoms. .

2- Prokinetic agents: metoclopramide (plasil) Actions: metoclopramide has two beneficial actions: 1- it suppress emesis by blocking receptor for dopamine and serotonin in the CTZ 2- it increase upper GI motility by enhancing the action of acetylcholine.

Metoclopramide adverse effects Anti-dopaminergic side effects, including sedation, diarrhea, and extrapyramidal symptoms (EPE). These reactions can often be controlled by injection of diphenhydramine

3-Butyrophenones: Droperidol and haloperidol act by blocking dopamine receptors. The butyrophenones are moderately effective antiemetics. High-dose haloperidol was found to be nearly as effective as high-dose metoclopramide in preventing Cisplatin-induced emesis.

II)- 5-HT3 receptor blockers: This class of agents commands an important place in treating emesis linked with chemotherapy. They have the advantage of a long duration of action. The specific antagonists of the 5-HT3 receptor Ondansetron , granisetron , palonosetron and dolasetron , selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (chemoreceptor trigger zone).

III-Benzodiazepines: (lorazepam and alprazolam ) The antiemetic potency of lorazepam and alprazolam is low. Their beneficial effects may be due to their sedative, anxiolytic, and amnesic properties. These same properties make benzodiazepines useful in treating anticipatory vomiting.

IV-Corticosteroids: Dexamethasone and methylprednisolone , used alone, are effective against mildly to moderately emetogenic chemotherapy. Their antiemetic mechanism is not known, but it may involve blockade of prostaglandins.

Side effects including : V-Cannabinoids: Marijuana derivatives, including dronabinol and nabilone , are effective against moderately emetogenic chemotherapy. However, they are seldom first-line anti-emetics because of their serious side effects, and potential abuse Side effects including : Dysphoria, hallucinations, sedation, vertigo, and disorientation.

( Aprepitant and fosaprepitant ). VI- Substance P/neurokinin-1 receptor blocker: ( Aprepitant and fosaprepitant ). Mechanism of action Aprepitant belongs to a new family of antiemetic agents. It targets the neurokinin receptor NK1- in the brain and blocks the actions of the natural substance P. Pharmacokinetic Aprepitant is usually administered orally with dexamethasone and palonosetron. It undergoes extensive metabolism, primarily by CYP3A4. Thus, as would be expected, it can affect the metabolism of other drugs that are metabolized by this enzyme.

Aprepitant can also induce this enzyme and, thus, affect responses to other agents; for example, concomitant use with warfarin can shorten the half-life of the anticoagulant. Side Effects Constipation and fatigue appear to be the major side effects.

VII-Combination regimens: Antiemetic drugs are often combined to increase antiemetic activity or decrease toxicity . Corticosteroids, most commonly dexamethasone, increase antiemetic activity when given with high-dose metoclopramide, a 5-HT3 antagonist, phenothiazine, butyrophenone, a cannabinoid, or a benzodiazepine. Antihistamines, such as diphenhydramine, are often administered in combination with high-dose metoclopramide to reduce extrapyramidal reactions or with corticosteroids to counter metoclopramide-induced diarrhea.

Drugs for motion sickness Scopolamine: A muscarinic antagonist Antihistamine ( dimenhydrinate , meclizine and cyclizine), this drugs block the receptors for acetylcholine in addition to receptors for histamine in the neuronal pathway that leads from the inner ear to the vomiting center.

LAXATIVES Widely prescribed and more widely purchased without prescription, indicating a cultural preoccupation with “regularity.” Drugs are classified by simplified mechanism of action as irritants or stimulants, bulking agents, and stool softeners. Laxatives work through more complex actions such as the interaction of osmotic effects with epithelial transport, changes in the enteric nervous system, and the release of extracellular regulators such as prostaglandins.

Laxatives Laxatives are commonly used to accelerate the movement of food through the gastrointestinal tract. These drugs can be classified on the basis of their mechanism of action as: A. Irritants and stimulants B. Bulk laxatives C. Saline and osmotic laxatives D. Stool softeners (emollient laxatives or surfactants) E. Lubricant laxatives

A. Irritants and stimulants Senna is taken orally, it causes evacuation of the bowels within 8 to 10 hours. It also causes water and electrolyte secretion into the bowel. Bisacodyl , available as suppositories and enteric-coated tablets, is a potent stimulant of the colon. It acts directly on nerve fibers in the mucosa of the colon. Adverse effects include abdominal cramps and the potential for atonic colon with prolonged use.

B. Bulk laxatives The bulk laxatives include hydrophilic colloids (from indigestible parts of fruits and vegetables). They form gels in the large intestine, causing water retention and intestinal distension, thereby increasing peristaltic activity. Similar actions are produced by methylcellulose, psyllium seeds, and bran.

C. Saline and osmotic laxatives Saline cathartics , such as magnesium citrate, magnesium sulfate, sodium phosphate, and magnesium hydroxide, are non absorbable salts (anions and cations) that hold water in the intestine by osmosis and distend the bowel, increasing intestinal activity and producing defecation in a few hours. Electrolyte solutions containing polyethylene glycol (PEG) are used as colonic lavage solutions to prepare the gut for radiologic or endoscopic procedures.

D. Stool softeners (emollient laxatives or surfactants) Surface-active agents that become emulsified with the stool produce softer feces and ease passage. These include docusate sodium, docusate calcium, and docusate potassium. They may take days to become effective.

E. Lubricant laxatives Mineral oil and glycerin suppositories are considered to be lubricants. They facilitate the passage of hard stools. Mineral oil should be taken orally in an upright position to avoid its aspiration and potential for lipid or lipoid pneumonia.

Anti-diarrheal Drugs

ANTIDIARRHEAL DRUGS Include anti-motility agents, adsorbents, and drugs that modify fluid and electrolyte transport Anti-motility drugs: Diphenoxylate (lomotil) and Loperamide (vacontil) ; analogues of meperidine (opiate agonists)