PROKINETIC DRUGS
By Abishek kumar K
Prokinetics are the type of drugs which enhances gastrointestinal
motility/transit by increasing the frequency or strength of contractions.
They speed up gastric emptying by enhancing coordinated propulsive
motility.
They treat the Gastrointestinal symptoms such as Abdominal discomfort,
Bloating, constipation,Heart burn, nausea and vomiting.
They also treat few gastrointestinal disorders: irritable bowel Syndrome,
gastritis, gastroparesis and functional dyspepsia
1. . Increases gastric emptying
2. Relief of gastric stasis
3. Decreases reflux esophagitis / heart burn
4. Decreases regurgitation of gastric contents & emesis
Types of Prokinetic drugs
Muscarinic agonist: Bethanechol (increases GI motility)
Anticholinesterases: Neostigmine
Dopamine D2 blockers: Metaclopramide, Domperidone, Levosulpiride,
Cinitapride.
5HT4 Agonist: Cisapride, Metaclopramide, Mosapride, Itopride, Cinitapride.
Metaclopramide
Substituted Benzamide (Procainamide)
Commonly used Antiemetic.
It acts in the GIT as well as in CNS.
Mechanism of action: D2 Antagonism, 5 HT4 Agonism, 5 HT3 Antagonism.
GIT : More prominent effect on upper g.i.t, ↑ gastric peristalsis while
relaxing the pylorus and first part of the duodenum. This speeds up
gastric emptying. Lower esophageal sphincter tone is increased and
gastro esophageal reflux is opposed. Increases intestinal peristalsis to
some extent. No significant action on colonic motility and on gastric
secretion.
CNS : acts on CTZ which blocks apomorphine induced vomiting. Gastrokinetic
action contribute to antiemetic affect.
D2 Antagonism
Dopamine (D2 Receptor) an inhibitory transmitter in g.i.t.
Delay gastric emptying when food is present in the stomach.
It causes gastric dilation and LES relaxation attending nausea and vomiting.
Metaclopramide blocks D2 receptor- hastens gastric emptying, enhances LES
tone by augmenting Ach release.
Secondary action, 5HT4 Being primary mechanism.Central antidopaminergic
action on CTZ is responsible for antiemetic property.D2 blockade:
Antagonism of Apomorphine induced vomiting, CPZ like extrapyramidal
Effects and Hyperprolactinaemia.
5HT4 Agonism
5HT4 Receptor activation on Primary afferent neurons of Enteric nervous
system which activates excitatory interneurons which enhances Ach
release from myenteric motor neurons.Gastric hurrying and LES tonic
effects of metaclopramide are mainly due to this action. Synergised by
Bethanechol and attenuated by atropine.
5HT3 Antagonism
5HT3 receptors present on inhibitory myenteric interneurons and in NTS and
CTZ.
Metaclopramide at high concentrations blocks 5HT3 receptors, This
augments Ach release in the gut which is very minor.
Its central action is significant only when large doses are used to control
Chemotherapy induced nausea and vomiting.
Pharmacokinetics
• Rapidly absorbed orally.
• Enters brain, crosses Placenta and is secreted in milk.
• Partly conjugated in liver, excreted in urine within 24 hours.
• Half life: 3-6 hours, action lasts for 4-6 hours.
• Oral, IM, IV.
Interactions: aspirin, diazepam, digoxin rate of
absorption alters due to gastric hurrying action.
Adverse effects: well tolerated.Sedation, dizziness, loose stools,
muscle dystonias.Long term: parkinsonism, galactorrhoea and
gynacecomastia.
Uses
Antiemetic: postoperative, drug induced, disease associated, radiation
sickness and less effective in motion sickness.
Prophylaxis and treatment of vomiting induced by emetogenic anticancer
drugs (cisplatin)
Gastrokinetic: accelerate gastric emptying, in emergency anaesthesia
conditions.
Relieve postvagotomy or diabetic gastroparesis associated gastric stasis.
Dyspepsia and other gi functional disorders.
Gastro esophageal reflux disease: milder cases.
Domperidone
D2 receptor antagonist.Chemically haloperidol relative.
Pharmacologically Metaclopramide relative.
Less efficacious (antiemetic and prokinetic action)
Blocks D2 receptors in upper g.i.t: prokinetic action
Antiemetic action: CTZ.
Crosses BBB poorly, side effects are rare.
Absorbed orally, 15% BA; First pass metabolism.
Completely biotransformed, excreted in urine. Half life is 7.5 hours.
Side effects: Dry mouth, loose stools, head ache, rashes and galactorrhoea. Rapid IV
injCardiac Arrhythmias.
Uses: antiemetic for mild to moderate cases of postopertative, drug and disease induced
nausea and vomiting. Not effective in severe cases, not useful In motion sickness and
morning sickness. Efficacy in CINV is low.
Cisapride vs mosapride
Cisapride Mosapride
Prokinetic with little antiemetic property (Lacks Gastrokinetic and LES tonic action due 5HT4
D2 receptor antagonsim) Agonistic (major) and 5HT3 Antagonistic
Accelerates gastric emptying, LES tone is (minor) action
improved, esophageal peristalsis is No clinically useful antiemetic action, does not
augmented. produce extrapyramidal or hyperprolactinaemic
Restores and facilitates motility throughout the side effects (Absence of D2 blocking property)
g.i.t including colon. Side effects: loose stools, abdominal pain, head
Prokinetic action 5HT4 Agonism, aided by weak ache, dizziness and insomnia.Q-T interval
5HT3 Antagonism which suppresses inhibitory prolongation; arrhythmias, torsades de
transmission in myenteric plexus. pointes.
Serious ventricular arrhythmias and death. The The plasma conc is elevated by erythromycin and
plasma conc is elevated by CYP3A4 inhibitors, CYP3A4 inhibitors.
Prolongs Q-T interval: Torsades de Earlier indications: non ulcer dyspepsia,
pointes/ventricular fibrillation. diabeticgastroparesis, GERD (as adjuvant to
Banned and suspended from market. PPIs) chronic constipation.
