Prokinetics

 

Prokinetics

Agents that increase motility of a segment of the GITand so augment transit of ingesta through that area.

-    Used in gastric or gastrodunodenal motility disorders viz. Vomition, anorexia, indigestion, belching, post prandial discomfort.

-    Stimulate contractions in gastropyloroduodenal area and accelerates gastric emptying.

-    Some agents may stimulate colonic motility and used in the treatment of constipation.

Classification

1.           D₂-dopamine receptor antagonists: Metoclopramide, domperidone.

2.           5-HT₄-receptor agonists: Cisapride, tegaserod, prucalopride.

3.           Motilin like drugs e.g. erythromycin.

4.           Histamine (H₂) receptor antagonist: Ranitidine, nizatidine.

5.           Prostanoids – Misoprostol.

6.           Lidocaine

7.           Miscellaneous agents – Mosapride, alvimopan, methylnaltrexone.

1.     D₂-dopamine receptor antagonists:

i) Metoclopramide: substituted benzamide compound, photosensitive. Prokinetic action is local action and antiemetic action is central action.

MOA: Blocks inhibitory D₂-dopaminepresynaptic receptors present on cholinergic myentric plexus and results in release of ACh which augment peristalsis. It is also 5-HT₄agonist and 5-HT₃ antagonist

Also block central D₂-dopaminergic receptors and produce antiemetic action.

Actions

GIT  -Increase tone of lower oesophageal sphincter.

-Increases force and frequency of gastric contractions, stimulates                  motility of the duodenum.

-No effect on gastric, pancreatic and biliary secretions.

-No effect on distal part of GIT.

These actions collectively produce antiemetic and prokinetic action, reduce hiccups and post operative ileus in horses.

CNS -Produce central antidopaminergic actions, viz. Antiemetic, sedatives, extrapyramidal and prolactin secretion stimulating effect:

Uses: Indigestion, belching and GI reflex.

Doses

Dogs and cats @ 0.01-0.02 mg kg^-1, continuous i.v. infusion

0.2-0.5 mg kg-1, P.O., S.C./I.V/ 3 x daily

Horse:               0.02-0.1 mg kg^-1i.m. or i.v. 3-4 x daily

Cattle:               0.5-1.0 mg kg^-1, i.v. followed by i.m. imj.

ii) Domperidone

Antiemetic and prokinetic effects lesser than metoclopramide. No Central action as it cannot cross BBB. But may produce antiemetic action by antagonizing dopamine receptors at CRTZ as area prostema of CRTZ does not have BBB.

Dose        

Dogs:        0.1-0.5 mg/kg, i.m.

                0.5-1.0 mg/kg, p.o.

2.     5-HT₄Receptor agonists: Cisapride, tegaserod.

i)      Cisapride – substituted benzamide

MOA: 5-HT₄-receptor against: 5-HT₄-receptors are present on myenteric neurons and facilitate the releases of ACh from neurons in myentric plexus.

Action

        Prokinetic action

        No central action

Indications: GI reflex, delayed gastric emptying, chronic constipation, gastroparesis occurring after surgery.

Dose

        Dogs:        0.1-0.5 mg/kg, p.o. 2-3 x daily

        Cats:         1-1.5 mg/kg, p.o. 2-3 x daily

        Horses:     0.5-0.8 mg/kg, p.o. 3 x daily.

ii)     Tegaserod

Partial agonist of 5-HT₄ receptor. It increases gastric emptying and small bowel transit. It is used to irritable bowel syndrome.

3.     Motilin like drugs: erythromycin.

It causes stimulation of motilin receptors via release of endogenous motilin or via cholinergic mechanism of upper GIT. Accelerates gastric emptying.

Dose: Dogs and cats – 0.5 – 1.0 mg/kg p.o. 3x daily.

4.     H₂-histamine receptor antagonist: e.g. Ranitidine and nizatidine

Gastric antisecretory effect, prokinetic agent

5.     Prostanoids: Misoprostol

-       PGE analogue

-       Cytoprotective, antiulcer agent

-       Colonic prokinetic agent, used in constipation in dogs/cats.

Dogs:        0.002-0.005 mg/kg, p.o. 3-4 x daily.

6.     Lidocaine. i.v. infusion in horses is used to improve intestinal motility and has been used postsurgically to reduce post-operative ileus. Exact mechanism is not known.

7.      Newer agents.

i) Mosapride – 5-HT₄ agonist, increases motility of small intestine and caecum.

ii) alvimopan and methylnaltrexone – peripheral opioid antagonists, donot cross BBB. Under investigation to use them as therapeutic agents to treat gastrointestinal motility problems associated with opioid analgesics, as well as other stress and pain syndrome.//