Antiemetic and Prokinetic drugs Professor Salim M Hassan

Anti-emetic and Prokinetic drugs Professor Salim M Hassan Mutah Faculty of Medicine

Anti-emetic & Prokinetic Drugs v Anti-emetic drugs: ØPrevent or treat nausea and vomiting v Prokinetic drugs: ØEnhance coordinated motility and transit of materials in the GIT 9: 50 12/17/2021 PM 2

Anti-emetics; General remarks v Choice of the anti-emetic depends on aetiology v Identify the cause v Treat the cause 9: 50 12/17/2021 PM 3

Aetiology of nausea & vomiting v Pregnancy v Motion sickness v Acute and chronic diseases: ØHepatitis, renal failure, AMI, GIT diseases v Vestibular diseases of ear (Meniere’s disease) v Drug-induced: ØOpioids, digoxin, anti-epileptics, cytotoxics 9: 50 12/17/2021 PM 4

Mechanisms of nausea and vomiting q. Two sites involved in the vomiting reflex: v. Vomiting centre: Ø In the reticular formation in the medulla v. Chemoreceptor trigger zone (CTZ): Ø In the 4 th ventricle 9: 50 12/17/2021 PM 5

The vomiting centre v Coordinates motor activity of vomiting reflex v Receives stimuli from: ØCTZ ØVestibular system of the ear ØPeripheral systems (GIT, CVS, GUS) ØCerebral cortex (e. g. odour, colour) v Its neurotransmitters are: ØAch (M 1) & Histamine (H 1) 9: 50 12/17/2021 PM 6

Chemoreceptor Trigger Zone (CTZ) v In the area postrema on floor of 4 th ØOutside BBB ventricle: v Stimulated by drugs and chemicals in: ØBlood or CSF v Responds through activation of: ØDopamine receptors: (D 2 ) ØSerotonin receptors: (5 HT 3) 9: 50 12/17/2021 PM 7

Neurotransmitters and Receptors q. Vomiting centre: v Acetylcholine: v Histamine: M 1 receptors H 1 receptors q CTZ: v Dopamine: v Serotonin: 9: 50 12/17/2021 PM D 2 receptors 5 HT 3 receptors 8

Drug-induced vomiting v Central stimuli at cerebral cortex by: ØOdour, colour of a drug v Peripheral stimuli through: ØRelease of 5 HT from enterochromaffin cells of small intestine mucosa and ØStimulation of 5 HT 3 receptors 9: 50 12/17/2021 PM 9

Anti-emetic drugs v Anti-emetics acting on vomiting centre: ØAnti-muscarinics: ØAntihistamines: ØAlleviate vomiting from any cause v Drugs acting on CTZ: ØDopamine and serotonin antagonists ØFor disease or drug-induced vomiting producing stimulation of chemoreceptors 9: 50 12/17/2021 PM 10

Anti-emetic Drugs Anti-muscarinics v Antihistamines v Dopamine antagonists: v ØPhenothiazines ØMetoclopramide ØDomperidone v Serotonin antagonists: v Others: ØOndansetron ØNabilone, Benzodiazepines, Dexamethasone 9: 50 12/17/2021 PM 11

Anti-muscarinc agents q Hyoscine (Buscopan ) v Uses: motion sickness and as premedication v Actions: ØCentral: M 1 blockade in VC ØPeripheral: M 3 blockade in GIT: ØAnti-spasmodic ØAnti-sercetory ØAnti-diarrhoeal 9: 50 12/17/2021 PM 12

Antihistamines v Are 1 st Generation antihistamines: ØDiphenhydramine, cyclizine, chlorpheniramine v For motion sickness: mechanisms: ØH 1 Blockade in VC ØM 1 Blockade in VC ØSedative effect v In other types of emesis: ØNot drugs of first choice 9: 50 12/17/2021 PM 13

Dopamine antagonists: Phenothiazines (anti-psychotics) v Block D 2 – receptors in CTZ v For disease-induced vomiting (as CRF) v For drug-induced vomiting v Extrapyramidal effects may occur: ØDue to blockade of D 2 in basal ganglia v Have also anti-muscarinic effects 9: 50 12/17/2021 PM 14

Phenothiazines v Prochlorperazine (stemetil) v Promethazine (phenergan) v Others: ØChlorpromazine (largactil) ØLimited uses 9: 50 12/17/2021 PM 15

Adverse effects v High doses: dystonia reactions: ØTorticollis, facial spasm, trismus, oculogyric crisis v In children and very old v Subside within 24 hours v Treatment: either ØBenzatropine IV or ØProcyclidine, diphenhydramine 9: 50 12/17/2021 PM 16

Metoclopramide (Plasil) v Good anti-emetic v Superior to phenothiazines in emesis of GIT disorders (gastric, duodenal, liver, biliary) v Has central and peripheral actions: ØCentral: D 2 Blockade in CTZ ØPeripheral: enhances action of Ach at M 3 receptors in the gut 9: 50 12/17/2021 PM 17

Metoclopramide v Prokinetic v Enhances gastric emptying: ØIncreases lower oesophageal sphincter tone ØIncreases peristalsis & emptying of stomach and upper gut ØRelaxes pyloric antrum 9: 50 12/17/2021 PM 18

Indications of metoclopramide q Nausea and vomiting associated with: GIT diseases v Cytotoxic therapy v Radiotherapy v Migraine q As prokinetic: v ØIncreases GIT motility ØBefore emergency anaesthesia, labour 9: 50 12/17/2021 PM 19

Main adverse effects v Dystonia reactions v Diarrhoea v Long-term use: ØGynecomastia and galactorrhoea: ØDopamine blockade ØIncrease prolactin secretion 9: 50 12/17/2021 PM 20

Domperidone v Is a butyrophenone v Selective blockade of D 2 receptors in CTZ v Has no acetylcholine-like effects v Relief of nausea and vomiting of: ØGIT disorders ØCytotoxics ØDrug-induced vomiting as in Parkinson’s disease: ØLevodopa, Bromocriptine 9: 50 12/17/2021 PM 21

Domperidone v Poor crossing of BBB: ØLess dystonia reactions v May produce gynecomastia & galactorrhoea: ØDopamine blockade ØIncrease prolactin secretion 9: 50 12/17/2021 PM 22

Ondansetron: 5 HT 3 antagonist v Blocks 5 HT 3 -receptors: ØCentral in CTZ ØPeripheral in gut v For cytotoxic-induced nausea & vomiting v For radiotherapy-induced N & V 9: 50 12/17/2021 PM 23

Ondansetron v Before cytotoxic therapy v Then oral for 5 days v Adverse effects: ØConstipation ØHeadache ØFlushing 9: 50 12/17/2021 PM 24

Nabilone v Synthetic cannabinoid v Derivative of marijuana (cannabis) v Has anti-emetic effect (on CTZ) v Used to relieve N & V of cytotoxics v Adverse effects: ØMood changes ØHallucinations 9: 50 12/17/2021 PM 25

Other Anti-emetics v Benzodiazepines: Lorazepam ØControl anticipatory N&V before cytotoxics v Corticosteroids: Dexamethasone v. Anti-emetic effect by blocking PG synthesis 9: 50 12/17/2021 PM 26

Prokinetic drugs v Enhance coordinated motility and transit of materials in the GI tract: ØIncrease gastric motility and gastric emptying ØIncrease lower oesophageal sphincter pressure v Useful in some GI disorders as: ØIrritable bowel syndrome (IBS) ØGERD (Gastro-Esophageal Reflux Disease) ØNon-ulcer dyspepsia 9: 50 12/17/2021 PM 27

Prokinetic drugs v Prokinetics may increase peristalsis due to one or more of the following: ØIncrease Ach release ØIncrease sensitivity of M 3 receptors to Ach ØInhibition of Ach breakdown 9: 50 12/17/2021 PM 28

Prokinetic drugs v Cholinergic agents: ØBethanechol, Neostigmine v Dopamine antagonists: ØMetoclopramide, domperidone v Serotonin receptors modulators: ØMetoclopramide v Macrolide antibiotics: ØErythromycin, Clarithromycin 9: 50 12/17/2021 PM 29

Dopamine antagonists v Are effective prokinetics by: ØEnhance release of Ach from myenteric motor neurons ØAntiemetic effect v Examples: Metoclopramide, domperidone 9: 50 12/17/2021 PM 30

Metoclopramide v Increases Ach release from neurons v Increases muscarinic receptor sensitivity to Ach ØIncreases lower esophageal sphincter tone ØStimulates gastric emptying ØRelaxing pylorus and duodenum 9: 50 12/17/2021 PM 31

Therapeutic uses as prokineic v GERD v Postoperative ileus v Non-ulcer dyspepsia v Speed transit of barium: ØBarium follow through v Empty stomach before emergency anaesthesia and labour 9: 50 12/17/2021 PM 32

Domperidone v Regulates motility GIT v Antiemetic effect v Similar to metoclopramide v Less central adverse effects 9: 50 12/17/2021 PM 33

Erythromycin & clarithromycin v GIT side effects v Increase lower oesophageal pressure v Stimulate gastric and SI contractility v Useful in diabetic gastroparesis: ØWhen metoclopramide or domperidone are ineffective 9: 50 12/17/2021 PM 34

General remarks v Identify the cause v Treat the cause: ØKetacidosis, digoxin or antiepileptic toxicity v Drug combination is useful as: ØDexamethasone with metoclopramide ØDexamethasone with ondansetron v Lorazepam used as adjunct 9: 50 12/17/2021 PM 35