Anti emetics

Emesis Vomiting is complex reflex action controlled by the vomiting center. Peripheral areas like gastric mucosa and other parts of GIT sent stimuli to the vomiting center. Stimuli also arise within the nervous system and impulses are sent to the vomiting center. CTZ is under the blood brain barrier that is why it gets stimulated by blood borne toxic substances and certain drugs. Nausea and vomiting is associated with pregnancy, infections, drugs , radiations, metabolic and painful stimuli. The neurotransmitters involved in the control of vomiting are acetylcholine, dopamine , serotonin and histamine.

Anti-emetics Classification : Anti-cholinergic: scopolamine Anti-histamines (H1 blockers): Dimenhydrinate, Diphenhydramine, cyclizine, meclizine, promethazine, hydroxazine. 5-HT3 -Receptor inhibitors: Ondansetron, Granisetron, Dolasetron Prokinetic drugs: metaclopromide, domperidone, cisapride, mosapride. Neuroleptics: cholpromazine,fluphenazine, prochlorperazinem haloperidol. Cannabinoids : dronabinol. Adjuvant anti-emetics: Glucocorticoids: betamethasone, dexamethasone, methylprednisolone. Benzodiazepines: lorazepam, alprazolam.

Scopolamine: it is an anti-cholinergic drug, It inhibits afferent impulses to the CNS. (anti-cholineregic side effects) Used for the treatment of motion sickness. Its sedative effect also contributes to its anti-emetic effect. (H1 -Blockers): their anti-emetic effect is due to sedative and central anti- cholinergic properties. Used for the treatment of motion sickness, morning sickness, Meniere’s disease, drug induced, chemotherapy induced vomiting. (sedation and dryness of mouth are the side effects) 5-HT3 receptor blockers: (ondansetrone is the prototype drug) They block the 5HT3-receptors in the afferent nerve fibers of the vagal nerve in the gut, they also block the 5HT3-receptors in CTZ and solitary tract neucleus . This group is useful in cancer chemotherapy ,radiotherapy innduced and post operative vomiting.

stimulation of afferent fibers of Emetogenic impulses to Ondansetron Chemo- tissue damage Serotonin from ECF stimulation of afferent fibers of Vagal nerve 5-HT3 Antagonists block Emetogenic impulses to CTZ & STN INDUCE VOMITING

Pro-kinetic drugs Metaclopromide: Metaclopromide and domperidone belong to this group. Metaclopromide: It is a D2receotor blocker. It has two main actions Central & Peripheral. Central: it blocks D2-receptors in CTZ. At higher conentration also blocks 5HT3 receptors. Peripheral effects: peripherally it has prokinetic effect due to release of Ach from the myenteric neurons. It enhances the rate of gastric and duodenal emptying . These effects are due to cholinergic, serotonergic( 5-HT4) & anti-dopaminergic effects. It also has direct effect on the smooth muscles of the of upper GIT. It also blocks 5-HT3-receptors on the afferent vagal nerve thus inhibiting the impulses to CTZ.

Metaclopromide Uses Metaclpromide increases gastric emptying by Incraesing the tone of lower oesophageal sphincter (LES) Increasing tone & amplitude of antral contractions. Relaxing the pyloric sphincters and duodenal bulb. Increasing the peristalsis of small intestine. Uses As an anti-emetic : For vomiting due to GI disorders Drug induced vomiting Post operative vomiting Vomiting of migrane Cancer chemo-induced vomitng Radiotherapy induced vomiting Motion sickness due to labyrinthine disorders

Uses As an anti-emetic : For vomiting due to GI disorders Drug induced vomiting Post operative vomiting Vomiting of migrane Cancer chemo-induced vomitng Radiotherapy induced vomiting Motion sickness due to labyrinthine disorders b) GERD c) Gastric stasis d).To promote gastric emptying before emergency surgery and also during GI radiological e) It is also used to treat intractable hiccups .

Adverse effects of Metaclopramide drowsiness, dizziness, diarhea. Due blockade of D2receptors in the basal ganglia there are EPS like tremors &rigidity . Due to long term blolckade of D2 receptors there is loss of inhibitory effect on the prolactin leading to gyneacomastia, gallactorea and menstrual irregularities. Drug interactions it accelerates the absorption of daizepam It slows the absorption of digoxin.

Domperidone It is a butyrophenone derivative and its actions are similar to metaclopromide. Its anti-emetic effects are due to its prokinetic and D2 receptor blockade. It is less potent than metaclopramide. It does not cross the blood brain barrier, due to which it is no tassociated with extra pyramidal effects, it also does not increase the serum prolactin level. It is very effective for the control of vomiting in children as it is not associated with EPS. It is also very effective for the control of vomiting induced by the dopiminergic drugs used for the control of parkinsonism. Without effecting the parkinsonial symptoms.

Neuroleptic drugs are effective anti-emetics. They act by blocking D2 receptor in CTZ . They also have anti-cholnergic and anti-histaminic effects. Prochlorperazine is an important anti-emetic . It is used in drug induced and cancer chemo and radiotherapy induced vomiting, it is also effective for the control of vomiting due to uremia and systemic infections. Side effects are sedation, EPS, dryness of mouth and hypotension.

Cannabinoids Dronabinol : this is a important psychoactive component of marijuan. This anti-emetic is only used when a person is refractory to all the other remmedies. It is associated with serious side effects like sedation, hallucinations, dizzziness, disorientation, increased appitite and drug dependence. it is always kept as the last option.

Adjuvant drugs Glucocorticoids Dexamethasone, betamethasone & methylprednisolone are used as adjucnt anti-emetics. they are specifically used in the control of vomiting due to cancer chemotherapy and radiotherapy. The beneficial effect of steroids is due to their anti- inflammatory property and and inhibition of PGs synthsis. Benzodizepines: Lorazepam and alprazolam is used to control anticipatory vomiting.

Chemotherapy induced vomiting .Nearly 70 to 80 percent of all patients who undergo chemotherapy experience nausea or vomiting. Several factors influence the severity of chemotherapy-induced emesis like the specific chemotherapeutic drug, dose, route, schedule of administration, also the young patients and women are more susceptible than older patients and men, 10 to 40 percent of patients experience nausea or vomiting in anticipation of their chemotherapy (anticipatory vomiting). Emesis not only affects the quality of life but can lead to rejection of potentially curative antineoplastic treatment.

. Emetic actions of chemotherapeutic agents Chemotherapeutic agents can directly activate the medullary chemoreceptor trigger zone or vomiting center; several neuroreceptors, including dopamine receptor Type 2 and serotonin Type 3 (5-HT3), play critical roles. Often, the color or smell of chemotherapeutic drugs and even stimuli associated with chemotherapy, can activate higher brain centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing cell damage in the gastrointestinal tract and releasing serotonin from the enterochromaffin cells of the small intestinal mucosa. The released serotonin activates 5-HT3 receptors on vagal and splanchnic afferent fibers, which then carry sensory signals to the medulla, leading to the emetic response.

The major categories of drugs used to control chemotherapy-induced nausea and vomiting Phenothiazines :phenothiazines, such as prochlorperazine , acts by blocking dopamine receptors. It is effective against low or moderately emetogenic chemotherapeutic agents (for example, fluorouracil and doxorubicin) Hypotension and restlessness are dose limiting factors. Extrapyramidal effects and sedation may also occur.

5-HT3 receptor blockers: they are the most important class of antiemetic for chemotherapy induced vomiting. ondansetron , granisetron , palonosetron , dolasetron selectively block 5-HT3 receptors in the periphery (visceral vagal afferent fibers) and in the brain (chemoreceptor trigger zone). These drugs can be administered as a single dose prior to chemotherapy (intravenously or orally) and are efficacious against all grades of emetogenic therapy. Ondansetron and granisetron can prevent emesis in 50 to 60% of cisplatin- treated patients. Electrocardiographic changes, such as prolongation of the QT interval, can occur with dolasetron; therefore, patients who may be at risk should receive this medication with caution.

Benzamides: out of several benzamides, Metachlopromide is the one that is useful as an anti-emetic. It is used to prevent emesis induced by cisplastin (chemotherapeutic drug with strong emetic potential) in 30— 40% of the patients. They are pro-kinetic drugs. Butyrophenones : Droperidol and Haloperidol are the two drugs that are moderately effective anti-emetics. Droperidol has found to prolong QT interval therefor e should be used with great caution. Haloperidol in high doses is as effective as metachlopromide in cisplastin induced vomiting. Benzodaizepines: lorazepam and alprazolam due to their sedative, anxiolytic and amnesic activity is used as antiemetics in chemottherapy in combination with other drugs.

Corticosteroids: Dexamethasone and methylprednisolone are effective against mild to moderately ememtogenic chemotherapy. They are given in combination with other drugs. They probably inhibit the prostaglandins Cannabinoids: dronabinol and nabilone , are effective against moderately emetogenic chemotherapy. Due to their psychological adverse effects their use is limited and rarely used as first line anti-emetics. Substance P/neurokinin-1 receptor blocker: Aprepitant ,belongs to a new family of antiemetic agents. It acts on the neurikinins receptors in the brain and inhibits the action of the naturally occurring substance P on these receptors. Aprepitant is usually administered orally with dexamethasone and palonosetron.

Combination regimes: Corticosteroids, most commonly dexamethasone, increase antiemetic activity when given with high-dose metoclopramide, a 5-HT3 antagonist, phenothiazine, butyrophenone, a cannabinoid, or abenzodiazepine. Diphenhydramine, are often administered in combination with high-dose metoclopramide to reduce extrapyramidal reactions or with corticosteroids to counter metoclopramide-induced diarrhea.