Emetics, Antiemetics and Prokinetics Dr. Soe Aung Myint 30-11-2012

EMETICS AND ANTIEMETICS

Emetics drugs which induce vomiting Therapeutic emesis is rarely required except in cases of poisoning

drugs which suppress the vomiting Antiemetics drugs which suppress the vomiting If the cause of vomiting can’t be removed it may be desirable to attempt to prevent or suppress it by drugs ↓ the consequences of vomiting

Vomiting(Emesis) A protective function which serve to remove unsuitable material that have been swallowed A symptom of some systemic diseases

Mechanism of vomiting a complex series of movements controlled by vomiting centre (VC) & Chemoreceptor Trigger Zone (CTZ) Some peripheral signals bypass the trigger zone, reaching the emetic center via the solitary tract nucleus (eg, from pharynx, stomach, & small intestine)

Consequences of vomiting are ***- electrolyte imbalance exhaustion → collapse aspiration → pneumonitis ↑ intra-abdominal pressure → hernia & burst PU ↑ ICP

Receptors for vomiting* CTZ - high concentration of 5HT3, D2, opioid receptors, Neurokinin-1 receptors VC - contains histamine, cholinergic receptors

Local Emetics mustard & water, warm hypertonic solution of salt, salts of heavy metals, 1% Cupric sulphate, 1% Zinc sulphate, ipecac (alkaloid) syrup MOA: irritate sensory nerve endings in the pyloric half of the stomach

Apomorphine - selective action on CTZ Central Emetics* Apomorphine - selective action on CTZ Ipecacuanha - locally irritates the gut & centrally acts on CTZ

APOMORPHINE a semisynthetic morphine like alkaloid with pronounced emetic action (> morphine) Mechanism of action: Structurally related to dopamine & a powerful stimulant of dopamine receptors in the CTZ Onset of action: within 15-20 min after 1mg SC injection No second dose due to CNS depression

Ipecacuanha Dose-15-30ml oral Onset-15-20 min Can give second dose

Indications for Emetics* Acute poisoning by non-corrosive substances Acute indigestion due to excessive intake of food

Contraindications * for Emetics Poisoning by corrosives - cause scarring eg, strong acids & alkalis – gastric perforation & damage to esophagus petroleum distillates - chemical pneumonitis due to inhalation Comatose, stuporous or delirious patients - because of asphyxiation & aspiration pneumonia due to lack of coughing reflex Pregnancy,hernias,advanced PU,GI erosions Cardiac decompensate and hypertension patients Young children,debilitated patient

ANTIEMETICS

Classification of Antiemetics*** DRUGS Anticholinergics: - Hyoscine Anti-histamines: --Cinnarizine - Cyclizine Meclizine Diphenhydramine (Benedryl) Dimenhydrinate (Dramamine) Promethazine (Phenergan) SITE OF ACTION Vomiting centre and gut

Classification of Antiemetics*** DRUGS D2 receptor antagonists- Phenothiazines: Chlorpromazine (Buromazine) Prochlorperazine (Stemetil) Perphenazine Butyrophenone : Haloperidol Metoclopramide Domperidone (Motilium) SITE OF ACTION CTZ CTZ and gut

Classification of Antiemetics*** DRUGS 5HT3 receptor antagonists Ondansetron, tropisetron, granisetron Cannabinoids: nabilone, pronabilol, dronabinol Miscellaneous Pyridoxine (Vitamin B6) Steroids (dexamethasone) Benzodiazepines (lorazepam) Neurokinin-1 antagonists (aprepetant) SITE OF ACTION CTZ and gut CTZ Vomiting d/t cytotoxics Cannabis sativa

Mechanism of action of anti-emetics They may act either on VC or on CTZ Anti-emetic effect on VC - anticholinergic action, antihistaminic action on the CTZ - antidopaminergic or 5HT3 antagonist action

1. ANTICHOLINERGICS - HYOSCINE (Scopolamine) Mechanism of action: block central muscarinic receptor on VC & gut (relaxation of GIT) Use: motion sickness (given 1 hr before journey, lasts for 4 - 6 hrs) Hyoscine: 0.65 - 0.75 mg IM

2. ANTIHISTAMINES MOA: inhibition of histamine receptor & cholinergic receptor in VC CYCLIZINE - shortest duration of action, 50 mg TDS MECLIZINE - longest duration of action, 24 hrs or more, single dose 50 mg

2. ANTIHISTAMINES PROMETHAZINE is chemically a phenothiazine but functionally an antihistamine, used for morning sickness & space motion sickness, Dose- 25 mg BD DIPHENHYDRAMINE & DIMENHYDRINATE- motion sickness & Meniere’s disease, common side effect is drowsiness Dose- 50 - 100 mg TDS

3. D2 RECEPTOR ANTAGONISTS PHENOTHIAZINE, CHLORPROMAZINE central inhibition of dopamine receptor on CTZ (with low non sedative dose) PROCHLORPERAZINE, PERPHENAZINE with piperazine side chain are more powerful antiemetics Dose - 25 - 50 mg 8 hourly IM Untoward effects - drowsiness, hypotension, extrapyramidal effects

METOCLOPRAMIDE structurally related to procainamide (lacks LA & antiarrhythmic action) Pharmacological Actions antiemetic action prokinetic action- ↑ lower esophageal sphincter tone, ↑ gut peristalsis & emptying , relaxation of pyloric antrum & duodenal cap

Mechanism of Action Central - inhibits dopamine D2 r/c on CTZ Peripheral – may be due to 5HT4 r/c agonistic action, – 5HT3 r/c antagonist action, – D2 r/c blocking action on cholinergic enteric neurones – All these facilitate ACh release from enteric neurones

METOCLOPRAMIDE Therapeutic Uses Gastro esophageal reflux disease (together with antisecretory drugs) patients with delayed gastric emptying due to postgastrectomy, diabetes gastroparesis Non ulcer dyspepsia (symptomatic improvement in chronic dyspepsia) small bowel intubation to empty stomach before emergency anaesthesia & labour prevention and treatment of vomiting caused by gastrointestinal disorder, cytotoxic drugs, radiation & uraemia

METOCLOPRAMIDE Untoward Effects extrapyramidal dystonia, more common in children & young adults with high dose fatigue, motor restless, spasmodic torticollis (involuntary twisting of neck), occulogyric crisis (involuntary upward eye movement) gynaecomastia, galactorrhoea (due to ↑ prolactin secretion), menstrual disorder somnolence, drowsiness, dizziness, diarrhoea

METOCLOPRAMIDE Pharmacokinetic rapidly & completely absorbed, first pass metabolism present Bioavailability 75%, T1/2 – 4-6 hr Contraindication*** intestinal obstruction, perforation, haemorrhage Dose - 10 mg 8 hourly oral, IM, IV

4. 5HT3 RECEPTOR ANTAGONISTS: ONDANSETRON 5HT3 antagonist for cytotoxic drug induced & radiation induced vomiting , post-op vomiting dose – 8 mg TDS

5. Cannabinoids (nabilone) vomiting due to stimulation of CTZ, used when other drugs failed

6. Miscellaneous PYRIDOXINE (Vitamin B6) no specific action doubtful efficacy - advantage of being harmless - suitable placebo to support psychotherapy used alone & with antiemetics in hyperemesis gravidarum

6. Miscellaneous STEROIDS (Dexamethasone) mechanism unknown by inhibiting PG formation to control vomiting induced by cytotoxic drugs

6. Miscellaneous NEUROKININ-1 antagonist (Aprepitant) antagonise substance P which may cause vomiting adjunct to dexamethasone & 5HT3 receptor antagonist in preventing N & V caused by cytotoxics (eg, cisplatin)

CHOICE OF ANTIEMETICS

Motion Sickness Hyoscine - best for motion sickness, short lasting Other drugs- cinnarazine, cyclizine, dimemhydrinate, promethazine For prophylaxis, an antiemetic is best taken 1 hr before exposure to the motion Once motion sickness has started, IM, SC or rectal routes are required. Alternatively, hyoscine may be administered as a dermal patch.

Vomiting due to Cytotoxic Drugs 5HT3 receptor antagonist (ondansetron) is highly effective. For severe vomiting, ondansetron plus dexamethasone with or without lorazepam (all given IV) is most effective combination & well tolerated. Metoclopramide may be substituted for ondansetron.

Vomiting after General Anaesthesia Metoclopramide or 5HT3 receptor antagonist (ondansetron) or butyrophenone (haloperidol, droperidol)

Vomiting in Pregnancy Occurs at 10-11 weeks & usually resolves by 13-14 weeks of gestation. By reassurance that the problem is transient & discussion of diet. Rarely, decision is taken to take a drug & then H1 receptor antagonist or phenothiazine (eg, promethazine) is preferable. Pyridoxine deficiency may occur in hyperemesis gravidarum which requires IV fluids & multivitamin supplement.

Vertigo Antimuscarinics & phenothiazines are generally preferable. Cyclizine or prochlorperazine may be used to relieve an acute attack. Betahistine (a histamine analogue) is used to improve blood circulation to the inner ear in Meniere’s disease; also cinnarazine.

Prokinetics 1..Medication used to a.Enhance coordinated motility of GIT b.Enhance transit of foods in GIT 2.Therapeutic uses a.GERD b.Gastroperesis (delayed gastric emptying time) c.Pseudoobstruction ..1.False obstruction(if no intrinsic obstruction if bowel is dissected) 2.may be due to muscle abnormalities,nervous defect,constipation

Prokinetic Agents Rapidly Promote Gastric Emptying By Selectively Duodenal Motility Esophagus Gastroesophageal Sphincter Fundus pH 2.3 Stomach HCL Mucus Pyloric Sphincter H+ Duodenum H+ H+ H+ H+ Cholinomimetic will be unselective Proknetics modulate ACh release to promote opening of the Gastro-Duodenal Sphincter & Selectively  Duodenal Motility.

Categories of Prokinetics 1.Cholinergic agents a.Cholinergic derivatives ,Bethanechol b.Acetylcholinesterase inhibitor,Neostigmine 2.Dopamine receptor antagonists Domperidone,metoclopramide 3.5HT4(serotonin)receptor agonists*** Cisapride,Metaclopromide (maxalon) 4.Motilin- like agent Macrolide antibiotics..erythromycin 5.Chloride channel activator- lubiprostone

1. METOCLOPRAMIDE (Maxolon) See antiemetics

2. DOMPERIDONE (Motilium) Mechanism of Action blocks dopamine receptor in CTZ (D2) Pharmacological Actions ↑ tone in lower esophageal sphincter relax pyloric sphincter not peneterate well into blood brain barrier antagonise D2 in pituitary block α adrenoreceptor (→ ↑ motility by decreasing relaxation)

2. DOMPERIDONE (Motilium) Use Chronic dyspepsia of unknown cause to promote post partum lactation Untoward Effect hyperprolactinaemia, galactorrhoea, gynaecomastia Dose 10-20 mg 4-8 hourly

3. CISAPRIDE (Prepulsid) Now obsolete due to ventricular arrhythmias & sudden death (K+ channel blockade & long QT interval) Mosapride Tegaserod

directly stimulates motilin receptor on GI smooth muscle & 4. ERYTHROMYCIN directly stimulates motilin receptor on GI smooth muscle & Promotes onset of a migrating motor complex ↑ lower esophageal pressure & stimulation of gastric & small bowel contractility

4. ERYTHROMYCIN Use: diabetic gastroparesis, acute upper GI haemorrhage to promote gastric emptying of blood prior to endoscopy Limited practical use because of rapid development of tolerance due to down regulation of motilin receptor

5. LUBIPROSTONE(prostanoic acid derivative) MoA- stimulates Cl- channel opening in intestine → ↑ liquid secretion into the intestine → shortens intestinal transit time Use - chronic constipation

----- a. prochlorperazine ----- b. ondansetron ----- c. apomorphine Antiemetic drugs are: ----- a. prochlorperazine ----- b. ondansetron ----- c. apomorphine ----- d. lobelline ----- e. dimenhydrinate Y Y N N Y

D2 receptor antagonists used for vomiting: ----- a. nabilone ----- b. ondansetron ----- c. domperidone ----- d. promethazine ----- e. hyoscine N N Y N N

The followings are useful for motion sickness: ----- a. hyoscine ----- b. meclizine ----- c. diphenhydramine ----- d. domperidone ----- e. atropine Y Y Y N N

Antiemetics acting on CTZ: ----- a. chlorpromazine ----- b. atropine ----- c. metoclopramide ----- d. prochlorperazine ----- e. cyclizine Y N Y Y N

____a. is a prokinetic and antiemetic agent Metoclopramide ____a. is a prokinetic and antiemetic agent ____b. is potent antidoperminergic with cholinomimetic properties ____c. is used in vomiting and diarrhea ____d. is used in vomiting due to cytotoxic drugs ____e. is also used in motion sickness Y Y N Y N

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