Antiemetics

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Chapter: Essential pharmacology : Drugs For Emesis, Reflux And Digestive Disorders

These are drugs used to prevent or suppress vomiting.


ANTIEMETICS

 

These are drugs used to prevent or suppress vomiting.

 

Classification

 

1. Anticholinergics

 

Hyoscine, Dicyclomine

 

2. H1 Antihistaminics

 

Promethazine, Diphenhydramine, Dimenhydrinate, Doxylamine, Cyclizine, Meclozine, Cinnarizine.

 

3. Neuroleptics (D2 blockers)

 

Chlorpromazine, Prochlorperazine, Haloperidol, etc.

 

4. Prokinetic drugs

 

Metoclopramide, Domperidone, Cisapride, Mosapride Tegaserod

 

5. 5-HT3 antagonists

 

Ondansetron, Granisetron

 

6. Adjuvant

 

Dexamethasone, antiemetics Benzodiazepines, Cannabinoids.

 

ANTICHOLINERGICS

 

Hyoscine (0.2–0.4 mg oral, i.m.) is the most effective drug for motion sickness. However, it has a brief duration of action; produces sedation and other anticholinergic side effects; suitable only for short brisk journies. It acts probably by blocking conduction of nerve impulses across a cholinergic link in the pathway leading from the vestibular apparatus to the vomiting centre and is not effective in vomiting of other etiologies.

 

A transdermal patch containing 1.5 mg of hyoscine, to be delivered over 3 days has been developed. Applied behind the pinna, it suppresses motion sickness while producing only mild side effects.

 

Dicyclomine (10–20 mg oral) has been used for prophylaxis of motion sickness and for morning sickness. It has been cleared of teratogenic potential.

 

H1 ANTIHISTAMINICS

 

Some anti-histaminics are antiemetic. They are useful mainly in motion sickness and to a lesser extent in morning sickness, postoperative and some other forms of vomiting. Their antiemetic effect appears to be based on anticholinergic, antihistaminic and sedative properties.

 

Promethazine, Diphenhydramine, Dimenhydrinate These drugs afford protection of motion sickness for 4–6 hours, but produce sedation and dryness of mouth. By their central anticholinergic action they block the extrapyramidal side effects of metoclopramide while supplementing its antiemetic action. Their combination is used in chemotherapy induced vomiting.

 

Promethazine Theoclate (AVOMINE 25 mg tab.) It has been specially promoted as an antiemetic, but the action does not appear to be significantly different from promethazine HCl.

 

Doxylamine It is a sedative H1 antihistaminic with prominent anticholinergic activity. Marketed in combination with pyridoxine, it is specifically promoted in India for ‘morning sickness’ (vomiting of early pregnancy) although such use is not made in the USA, UK and many other countries.

 

After over 2 decades of worldwide use of a combination product of doxylamine for morning sickness, some reports of foetal malformation appeared and the product was withdrawn in 1981. Subsequent studies have both supported and refuted its teratogenic potential. Though the USFDA and CSM in UK found no credible evidence of increase in birth defects, they did not rule out the possibility. The product remains suspended in these countries, probably to avoid litigation, but not due to safety or efficacy concerns. In USA and UK doxylamine is available for treatment of allergic reaction, cough and cold.

Oral absorption of doxylamine is slow, and its t½ is 10 hr. The side effects are drowsiness, dry mouth, vertigo and abdominal upset.

 

Dose: 10– 20 mg at bed time; if needed additional doses may be given in morning and afternoon.

 

DOXINATE, GRAVIDOX, VOMNEX, NOSIC: 10 mg with pyridoxine 10 mg tab.

 

Cyclizine, Meclizine These are less sedative and less anticholinergic. Meclizine is long-acting, protects against sea sickness for nearly 24 hours.

 

MAREZINE: Cyclizine 50 mg tab; DILIGAN: Meclizine 12.5 mg + nicotinic acid 50 mg tab; PREGNIDOXIN: Meclizine 25 mg + Caffeine 20 mg tab.

 

Cinnarizine It is an antivertigo drug, and is also protective for motion sickness. It probably acts by inhibiting influx of Ca2+ from endolymph into the vestibular sensory cells which mediates labyrinthine reflexes.

 

Anticholinergic-antihistaminic antiemetics are the first choice drugs for motion sickness. Antidopaminergic and antiHT3 drugs are less effective. All antimotion sickness drugs act better when taken ½–1 hour before commencing journey. Once sickness has started, it is more difficult to control; higher doses/parenteral administration may be needed.

 

The antihistaminics are suspected to have teratogenic potential, but there is no conclusive proof. Nevertheless, it is better to avoid them for morning sickness. Most cases of morning sickness can be managed by reassurance and dietary adjustment. If an antiemetic has to be used, dicyclomine, promethazine, prochlorperazine or metoclopramide may be prescribed in low doses.

 

 

NEUROLEPTICS

 

These are potent antiemetics; act by blocking D2 receptors in the CTZ; antagonize apomorphine induced vomiting and have additional antimuscarinic as well as H1 antihistaminic property. They have broad spectrum antiemetic action effective in:

 

·          Drug induced and post-anaesthetic nausea and vomiting.

·          Disease induced vomiting: gastroenteritis, uraemia, liver disease, migraine, etc.

·     Malignancy associated and cancer chemotherapy (mildly emetogenic) induced vomiting.

·          Radiation sickness vomiting (less effective).

·          Morning sickness: should not be used except in hyperemesis gravidarum.

 

They are less effective in motion sickness: the vestibular pathway does not involve dopaminergic link.

 

Most of these drugs produce significant degree of sedation. Acute muscle dystonia may occur after a single dose, especially in children and girls. The antiemetic dose is generally much lower than antipsychotic doses. These agents should not be administered until the cause of vomiting has been diagnosed; otherwise specific treatment of conditions like intestinal obstruction, appendicitis may be delayed due to symptom relief.

 

Prochlorperazine This D2 blocking phenothiazine is a labyrinthine suppressant, has selective antivertigo and antiemetic actions. It is highly effective when given by injection in vertigo associated with vomiting and to some extent in cancer chemotherapy associated vomiting. Prochlorperazine is used as an antiemetic rather than as antipsychotic. Muscle dystonia and other extrapyramidal side effects are the most important limiting features.

 

STEMETIL 5, 25 mg tabs., 12.5 mg/ml inj, 1 ml amp, 10 ml vial.

 

PROKINETIC DRUGS

 

These are drugs which promote gastrointestinal transit and speed gastric emptying by enhancing coordinated propulsive motility.

 

Metoclopramide

 

Metoclopramide is chemically related to procainamide, but has no pharmacological similarity with it. Introduced in early 1970s as a ‘gastric hurrying’ agent, it is now a widely used antiemetic.

 

Actions

 

GIT: It has more prominent effect on upper g.i.t.; increases gastric peristalsis while relaxing the pylorus and the first part of duodenum → speeds gastric emptying, especially if it was slow. This action is independent of vagal innervation, but is more prominent when vagus is intact. Lower esophageal sphincter (LES) tone is increased and gastroesophageal reflux is opposed. It also increases intestinal peristalsis to some extent, but has no significant action on colonic motility and gastric secretion.

 

CNS:  Metoclopramide is an effective antiemetic; acting on the CTZ, blocks apomorphine induced vomiting. The gastro-kinetic action may contribute to the antiemetic effect. However, it has no chlorpromazine (CPZ) like neuroleptic action, though it does share the extrapyramidal and prolactin secretion augmenting action of CPZ.

 

Mechanism Of Action: Metoclopramide acts through both dopaminergic and serotonergic receptors (see Fig. 47.2)

 


 

D2 Antagonism 

 

Dopamine (acting through D2 receptors) is an inhibitory transmitter in the g.i.t.— normally acts to delay gastric emptying when food is present in stomach. It also appears to cause gastric dilatation and LES relaxation attending nausea and vomiting. Metoclopramide blocks D2 receptors and has an opposite effect— hastening gastric emptying and enhancing LES tone by augmenting ACh release. However, clinically this action is secondary to that exerted through 5HT4 receptors.

 

The central antidopaminergic (D2) action of metoclopramide on CTZ is clearly responsible for its antiemetic property. Other manifestations of D2 blockade are antagonism of apomorphine induced vomiting, CPZ like extrapyramidal effects and hyper-prolactinaemia.

 

5HT4 Agonism

 

Metoclopramide acts in the g.i.t. to enhance ACh release from myenteric motor neurones. This results from 5HT4 receptor activation on primary afferent neurones (PAN) of the ENS via excitatory inter-neurones (Fig. 47.2). The gastric hurrying and LES tonic effects are mainly due to this action which is synergised by bethanechol and attenuated by atropine.

 

5HT3 Antagonism

 

At high concentrations metoclopramide can block 5HT3 receptors present on inhibitory myenteric inter-neurones and in NTS/CTZ. The peripheral action can augment ACh release in the gut, but appears to be minor. The central anti 5HT3 action appears to be significant only when large doses are used to control chemotherapy induced vomiting.

 

Pharmacokinetics

 

Metoclopramide is rapidly absorbed orally, enters brain, crosses placenta and is secreted in milk. It is partly conjugated in liver and excreted in urine within 24 hours; t½ is 3–6 hours. Orally it acts in ½–1 hr, but within 10 min after i.m. and 2 min after i.v. injection. Action lasts for 4–6 hours.

 

Interactions

 

It hastens the absorption of many drugs, e.g. aspirin, diazepam, etc. by facilitating gastric emptying. It reduces the extent of absorption of digoxin by allowing less time for it. Bioavailability of cimetidine is also reduced.

 

By blocking DA receptors in basal ganglia, it abolishes the therapeutic effect of levodopa.

 

Adverse Effects

 

Metoclopramide is generally well tolerated.

Sedation, dizziness, loose stools, muscle dystonias (especially in children) are the main side effects.

 

Long-term use can cause parkinsonism, galactorrhoea and gynaecomastia.

 

It should not be used to augment lactation. Though the amount secreted in milk is small, but suckling infant may develop loose motions, dystonia, myoclonus.

 

Dose: 10 mg (children 0.2–0.5 mg/kg) TDS oral or i.m. For chemotherapy induced vomiting 0.3–1.0 mg/kg slow i.v./i.m. PERINORM, MAXERON, REGLAN, SIGMET, 10 mg tab; 5 mg/5 ml syr; 10 mg/2 ml inj.; 50 mg/ 10 ml inj.

 

Uses

 

1. Antiemetic: Metoclopramide is an effective and popular drug for many types of vomiting— postoperative, drug induced, disease associated (especially migraine), radiation sickness, etc, but is less effective in motion sickness. Though ondansetron is preferred, metoclopramide continues to be used for prophylaxis and treatment of vomiting induced by highly emetic anticancer drugs (cisplatin, etc.). A higher dose (1 mg/kg i.v.) is often needed, but is effective when phenothiazines and antihistamines do not work. Promethazine, diphenhydramine, diazepam or lorazepam injected i.v. along with metoclopramide supplement its antiemetic action and reduce the attending dystonic reactions. Dexamethasone i.v. also augments the efficacy of metoclopramide.

 

Though no teratogenic effects have been reported, metoclopramide should be used for morning sickness only when not controlled by other measures.

 

2. Gastrokinetic: to accelerate gastric emptying:

 

·       When emergency general anaesthesia has to be given and the patient has taken food less than 4 hours before.

·          To relieve post-vagotomy or diabetes associated gastric stasis.

·          To facilitate duodenal intubation. Clinical efficacy is moderate.

 

3. Dyspepsia and other functional g.i. disorders. Metoclopramide may succede in stopping persistent hiccups.

 

4. Gastroesophageal Reflux Disease (GERD) Metoclopramide may afford symptomatic relief in milder cases of GERD, but is much less effective than PPIs/H2 blockers. It does not aid healing of esophagitis. It may be used as adjuvant to acid suppressive therapy, but additional benefit is uncertain.

 

Domperidone

 

It is a D2 antagonist, chemically related to haloperidol, but pharmacologically related to metoclopramide. It has lower ceiling antiemetic and prokinetic actions. Unlike metoclopramide, its prokinetic action is not blocked by atropine and is based only on D2 receptor blockade in upper g.i.t. Domperidone crosses blood-brain barrier poorly. Accordingly, extrapyramidal side effects are rare, but hyper-prolactinaemia can occur. However, it does act on CTZ which is not protected by blood-brain barrier. Antiemetic efficacy is lower than metoclopramide. Administered with levodopa or bromocriptine, it counteracts their dose limiting emetic action without affecting the therapeutic effect in parkinsonism.

 

Domperidone is absorbed orally, but bioavailability is only ~15% due to first pass metabolism. It is completely bio-transformed and metabolites are excreted in urine. Plasma t½ is 7.5 hr.

 

Side Effects

 

Are much less than with metoclopramide: dry mouth, loose stools, headache, rashes, galactorrhoea. Cardiac arrhythmias have developed on rapid i.v. injection.

 

Dose: 10–40 mg (Children 0.3–0.6 mg/kg) TDS. Its indications are similar to that of metoclopramide, but it is a less efficacious gastrokinetic and not useful against high emetogenic chemotherapy.

 

DOMSTAL, DOMPERON, NORMETIC 10 mg tab, 1 mg/ml susp, MOTINORM 10 mg tab, 10 mg/ml drops.

 

Cisapride

 

It is a prokinetic drug with little antiemetic property, because it lacks D2 receptor antagonism. Effects of cisapride on gastric motility resemble metoclopramide—gastric emptying is accelerated, LES tone is improved and esophageal peristalsis is augmented. It restores and facilitates motility throughout the g.i.t., including colon (metoclopramide/domperidone do not accelerate colonic transit). Cisapride often produces loose stools. Its prokinetic action is exerted mainly through 5HT4 agonism which promotes ACh release from myenteric neurones, aided by weak 5HT3 antagonism which suppresses inhibitory transmission in myenteric plexus. Enteric neuronal activation via 5HT4 receptor also promotes cAMP-dependent Cl– secretion in the colon, increasing water content of stools. Cisapride is devoid of action on CTZ and does not produce extrapyramidal symptoms or hyper-prolactinaemia.

 

Oral bioavailability of cisapride is ~33%. It is primarily inactivated by hepatic metabolism by CYP3A4 with a t½ of ~10 hr. Dose needs to be reduced in liver disease.

 

Cisapride is a prokinetic drug without antidopaminergic side effects, but abdominal cramps and diarrhoea can occur. Other side effects are dizziness and occasional rise in serum transaminases.

 

Primary indication of cisapride has been GERD. Some patients derive symptomatic relief, but this is less complete compared to PPIs/H2 blockers. Healing of esophageal lesions is infrequent. Other indications of cisapride are nonulcer dyspepsia, impaired gastric emptying and chronic constipation, though usefulness in these conditions also is limited.

 

Safety of cisapride was challenged by reports of serious ventricular arrhythmias and death, mainly among patients who took CYP3A4 inhibitors like azole antifungals, macrolide antibiotics, antidepressants, HIV protease inhibitors, etc. concurrently. At high concentrations, cisapride blocks delayed rectifying K+ channels in heart—prolongs QTc interval and predisposes to torsades de pointes/ventricular fibrillation. It has been withdrawn in USA and some other countries, but is available in India.

 

Dose: 10–20 mg TDS; SYSPRIDE, UNIPRIDE, NUPRIDE 10 mg tab; MOTEN, PULSID 10 mg tab, 5 mg/5 ml susp.; CIZA also 20 mg tab

 

Mosapride

 

A newer congener of cisapride with similar gastrokinetic and LES tonic action due to 5HT4 agonistic (major) and 5HT3 antagonistic (minor) action in the myenteric plexus, but has not caused QTc prolongation or arrhythmias. Like cisapride, it has no clinically useful antiemetic action and does not produce extrapyramidal/hyper-prolactinaemic side effects due to absence of D2 blocking property. Indications and side effects are similar to cisapride.

 

Dose: 5 mg (elderly 2.5 mg) TDS.

 

MOZA, MOZASEF, NORMAGUT 2.5, mg, 5 mg tabs; MOZA MPS: 5 mg + methylpolysiloxane 125 mg tab.

 

Tegaserod

 

It is a recently introduced selective 5HT4 partial agonist, with no action on 5HT3 and other receptors, which mainly augments colonic motility along with promotion of gastric emptying and intestinal transit, and less effect on LES tone. The 5HT4 agonistic action also increases colonic Cl– (and water) secretion. The current indication of tegaserod is constipation predominant irritable bowel syndrome (described in Ch. No. 48). Its possible use as a gastro-kinetic is being explored.

 

5HT3 ANTAGONISTS

 

Ondansetron

 

It is the prototype of a new class of antiemetic drugs developed to control cancer chemotherapy/radiotherapy induced vomiting, and later found to be highly effective in postoperative nausea and vomiting as well. It blocks the depolarizing action of 5HT through 5HT3 receptors on vagal afferents in the g.i.t. as well as in NTS and CTZ. Cytotoxic drugs/ radiation produce nausea and vomiting by causing cellular damage release of mediators including 5HT from intestinal mucosa activation of vagal afferents in the gut emetogenic impulses to the NTS and CTZ. Ondansetron blocks emetogenic impulses both at their peripheral origin and their central relay. It does not block dopamine receptors and apomorphine or motion sickness induced vomiting. A weak gastrokinetic action due to 5HT3 blockade has been detected, but it is clinically insignificant. A minor 5HT4 antagonistic action has also been shown.

 

Pharmacokinetics:

 

Oral bioavailability of ondansetron is 60–70% due to first pass metabolism. It is hydroxylated by CYP 1A2, 2D6 and 3A, but no clinically significant drug interactions have been noted. It is eliminated in urine and faeces, mostly as metabolites; t½ being 3–5 hrs, and duration of action 4–12 hr.

 

Dose and efficacy: For cisplatin and other highly emetogenic drugs—8 mg i.v. by slow injection over 15 min ½ hr before chemotherapeutic infusion, followed by 2 similar doses 4 hour apart. To prevent delayed emesis 8 mg oral is given twice a day for 3–5 days. For postoperative nausea/vomiting 4–8 mg i.v. given before induction is repeated 8 hourly. For less emetogenic drugs and for radiotherapy an oral dose of 8 mg is given 1–2 hr prior to the procedure and repeated twice 8 hrly. It is effective in 60–80% cases; similar to or better than high doses of metoclopramide, and does not cause dystonias or sedation like the latter.

 

EMESET, VOMIZ, OSETRON, EMSETRON 4,8 mg tabs, 2 mg/ml inj in 2 ml and 4 ml amps.

 

Patients who do not obtain optimum protection by ondansetron alone, addition of dexamethasone, promethazine/diazepam or both enhances antiemetic efficacy. Adjuvant drugs are more often required for delayed phase vomiting that occurs on the second to fourth day of cisplatin therapy, because 5HT3 antagonists alone are less effective.

 

Other Types Of Vomiting: Efficacy of 5HT3 antagonists in prevention and treatment of postoperative nausea and vomiting is now well established. Since this vomiting is multifactorial in origin, 5HT3 blockers are not as completely efficacious as in chemotherapy induced vomiting, and many other classes of antiemetic drugs are also protective. In comparative trials, superiority of ondansetron in terms of efficacy as well as lack of side effects and drug interactions has been demonstrated. Administered before surgery ondansetron (4–8 mg i.v.) repeated after 4 hours has become the first choice antiemetic at many centres.

 

Reports of efficacy in vomiting associated with drug overdosage, side effect of cotrimoxazole and fluvoxamine, uraemia and certain neurological injuries are also available.

 

Some 5HT3 antagonists have produced symptomatic relief in diarrhea-predominant irritable bowel syndrome.

 

Side Effects:

 

Ondansetron is generally well tolerated: the only common side effect is headache. Mild constipation or diarrhoea and abdominal discomfort occur in few patients. Rashes and allergic reactions are reported, especially after i.v. injection.

 

Granisetron

 

It is 10–15 times more potent than ondansetron and probably more effective during the repeat cycle of chemotherapy. The weak 5HT4 blockade seen in ondansetron has not been detected in granisetron. Its plasma t½ is longer (8–12 hrs) and it needs to be given only twice on the day of chemotherapy. Side effect profile is similar to ondansetron.

 

Dose: 10 μg/kg i.v. 30 min before chemotherapy, repeated after 12 hr. For less emetogenic regimen 2 mg oral 1 hr before chemotherapy or 1 mg before and 1 mg 12 hr after it.

 

GRANICIP, GRANISET 1 mg, 2 mg tabs; 1 mg/ml inj. (1, 3 ml amps).

 

Dolasetron, Tropisetron, and Palonasetron are the other selective 5HT3 antagonists.

 

ADJUVANT  ANTIEMETICS

 

Corticosteroids

 

(e.g. dexamethasone 8–20 mg i.v.) can alleviate nausea and vomiting due to moderately emetogenic chemotherapy, but are more often employed to augment the efficacy of other primary antiemetic drugs like metoclopramide and ondansetron for highly emetogenic regimens and for cisplatin induced delayed emesis. They also serve to reduce certain side effects of the primary antiemetic. However, because of their metabolic effects, they should be used only in selected and refractory cases.

 

Benzodiazepines

 

The weak antiemetic property of BZDs is primarily based on the sedative action. Used as adjuvant to metoclopramide/ondansetron, diazepam/ lorazepam (oral/i.v.) help by relieving anxiety, anticipatory vomiting and produce amnesia for the unpleasant procedure. They also suppress dystonic side effects of metoclopramide.

 

Cannabinoids

 

9 Tetrahydrocannabinol ( 9 THC) is the active principle of the hallucinogen Cannabis indica. It possesses antiemetic activity against moderately emetogenic chemotherapy. It probably acts at higher centres or at vomiting centre itself by activating CB1 subtype of cannabinoid receptors. The disorienting and other central effects of 9 THC limit its clinical utility.

Dronabinol, a synthetic  9 THC, is less hallucinogenic and more antiemetic than 9 THC. Dronabinol has been used for chemotherapy induced vomiting in patients who cannot tolerate other antiemetics or are unresponsive to them.

 

It has also been tried as an appetite stimulant in cachectic/AIDS patients. Nabilone is another cannabinoid with antiemetic property.

 

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