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02-Pharma- Prokinetics-Dr Zunera Hakim Dr Haseeba Talat.pdf
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- 2. 2 SCHEME OF LECTURE 3rdYear Pharmacology LGIS Core Subject – 60% Pharmacology Horizontal Integration – 10% Same Year Subjects • Pathology (10%) Vertical Integration – 10% Clinical Subjects • Medicine (10%) Spiral Integration – 15% Different Year Basic Sciences Subjects • Physiology (10%) • Biochemistry (5%) Vertical Integration – 05% Research & Bioethics
- 3. 3 02 03 04 LEARNING OBJECTIVES At theend of the lecture, students of 3rd Year MBBS will be able to ; 01 Recall the physiology of gut motility Define pro-kinetics / pro-motility agents Classify pro-kinetics / pro-motility agents Discuss the mechanism of action of different pro- kinetics Describe the main therapeutic indications and adverse effects of different pro-kinetics 05
- 4. 4 CONTROL OF GASTROINTESTINALMOTILITY Spiral integration with Physiology
- 5. 5 CONTROL OF GASTROINTESTINALMOTILITY
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- 7. 7 PROKINETICS • Prokinetics area heterogeneous class of compound that act through different receptors to exert a stimulatory effect on gastrointestinal motility • They amplify and coordinate gastrointestinal muscular contractions among different segments of the gut thereby enhancing propulsion of intraluminal content • Some prokinetics are active in selective areas of the gastrointestinal tract, whereas the activity of other prokinetics is more generalized and reflects the location of receptor targets of the pharmacological agents. • Esophagus • Stomach • Small intestine • Colon
- 8. 8 PROKINETICS ❖ Upper Gastrointestinaltract • Gastroparesis • Diabetic • Idiopathic • Post operative • Gastrointestinal reflux disease • Functional dyspepsia • Intestinal manifestations of systemic disease (scleroderma, amyloidosis) ❖ Lower Gastrointestinal tract • Chronic pseudo –obstruction • Post operative ileus • Irritable bowel syndrome • Constipation ❖ Diagnostic uses THERAPEUTIC USES VERTICAL INTEGRATION WITH MEDICINE
- 9. 9 CLASSIFICATION OF PROKINETIC ❖ Dopamine receptorantagonist • Metoclopramide • Domperidone • Itopride • Levosulpride • Clebopride & bromopride ❖ Serotonin (5HT4) receptor agonists • Cisapride (benzamide) • Tegaserod (aminoguanidine indole) • Prucalopride • Naronapride • Velusetrag ❖ Motilin Receptor agonists • Erythromycin • Azithromycin • Clarithromycin • Camicinal • Mitmecinal ❖ Cholinomimetics • Bethanacol • Neostigmine • Pyridostigmine ❖ Ghrelin Agonist • Relamorelin • Ulimorelin ❖ Cholecystokinin 1 (CCK-1) receptor antagonist • Sinaclide • Loxiglumide • Devazepide ❖ Others • Opioid antagonist • NK1 antagonist • Leuprolide CORE -PHARMACOLOGY
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- 13. 13 DOPAMINE RECEPTOR ANTAGONIST METOCLOPRAMIDE •Metoclopramide is a dopamine D2 antagonist but also acts as an agonist on serotonin 5-HT4 receptors and causes weak inhibition of 5-HT3 receptors Metoclopramide promotes gut motility (proximal gut) by three mechanisms: i. inhibition of presynaptic (increase release of AcH from cholinergic enteric nervous system) and postsynaptic D2 receptors (direct inhibition of muscular D2 receptor on lower esophageal sphincter and stomach (antrum and fundus) ii. stimulation of presynaptic excitatory 5-HT4 receptors (increase release of AcH) iii. antagonism of presynaptic inhibition of muscarinic receptors (increase sensitivity of smooth muscle of esophagus, stomach and small intestine)
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- 15. 15 DOPAMINE RECEPTOR ANTAGONIST METOCLOPRAMIDE ❖PHARMACOKINETICS • Administered by oral and parenteral routes (intravenous and intramuscular). • Metabolized in liver (sulfation and glucuronide conjugation). • Crosses the blood–brain barrier • Excreted in urine. ❖ THERAPEUTIC USES Prokinetic effect is mostly utilized in conditions with diminished and impaired GIT motility • Gastroparesis (5–10 mg orally, 30 min before meals and at bedtime. The dose can be increased up to 20 mg four-times daily) • Post vagotomy • Dyspepsia • Gastro intestinal reflux disease • Facilitate duodenal intubation • Emergency surgery ❖ ADVERSE EFFECTS • CNS : Extrapyramidal effects • Endocrine : Galactorrhea • Reproductive system: Gynecomastia, menstrual abnormailities
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- 17. 17 SEROTONIN (5HT4)RECEPTOR AGONIST •95% of the body’s 5- HT is synthesized in the enterochromaffin, mast and smooth muscle cells of the GI tract. • 5-HT1p (expressed on intrinsic primary afferent neurons in the submucosa), 5-HT3 ( central and peripheral NS) and 5-HT4 (GIT, heart, CNS )receptors are the most clinically relevant in GI tract functioning. • Activation of these receptors evokes the release of excitatory (5HT4) & inhibitory neurotransmitters(5HT3), with the net result of increasing motility and orthograde peristalsis in the GI tract(distal esophagus, stomach, jejunum and colon)
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- 22. 22 SEROTONIN (5HT4)RECEPTOR AGONIST ❖ GASTROINTESTINAL EFECTS •Improves the tone of lower esophageal sphincter. • Increases esophageal peristalsis • Improve antroduodenal coordination • Accelerates gastric emptying. • Increases colonic motility and fluid secretion (unlike metoclopramide & domperidone). • Mild antiemetic activity except mosapride ❖ ADVERSE EFFECTS • Nausea, diarrhea ,abdominal pain • Headache • QT interval prolongation and cardiac arrhythmias (hERG receptor block) • Drug drug interactions
- 23. 23 CHOLINOMIMETICS • Cholinomimetics donot fulfill the true definition of prokinetics as they produce tonic and uncoordinated contractions Acotiamide (2013 ) produces gastro-kinetic effects by: • inhibiting acetylcholine-esterase in peripheral nerve endings and suppresses degradation of acetylcholine • Acting as M1/M2 antagonist on enteric nervous system
- 24. 24 MOTILIN RECEPTOR AGONISTS ❖Motilin is a 22 amino acid endogenous peptide produced by entero-chromaffin cells of the proximal small intestine (duodenum) ❖ The majority of motilin receptors (GPCR) are found on • Cholinergic nerves within the enteric nervous system • Gastrointestinal smooth muscle ❖ Motilinomimetics stand for any compound able to interact with motilin receptor • Motilides (macrolide derivatives) • Motilin analogues
- 25. 25 MOTILIN RECEPTOR AGONISTS ❖Erythromycin mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by binding to motilin receptors and acting as a motilin agonist ❖ The pharmacodynamics effects of erythromycin in humans are DOSE DEPENDENT mediated via different pathways: • At low dose (40 mg or 0.5-1mg/kg IV)-action on enteric nerves • At high dose (200-350mg)- action on smooth muscles ❖ ADVERSE EFFECTS • Nausea, vomiting and abdominal pain • QT interval prolongation • Tachyphylaxis (after 4 weeks of therapy) Rx: drug holiday • Drug Drug interactions
- 26. 26 GHRELIN RECEPTOR AGONISTS •Ghrelin is an appetite stimulating 28 amino acid which is released from endocrine cells in oxyntic glands of the fundus and corpus, and to a lesser extent from the antrum, duodenum, jejunum, ileum and colon • It binds to its receptors ( GHSR1a,GHSR1b and GRLN) present in gastrointestinal (stomach, intestine and pancreas) and non-gastrointestinal areas (brain) • Exogenous synthetic ghrelin initiate phase III MMC activity & increase gastric emptying of meals • Relamorelin, a synthetic pentapeptide is more stable with a longer plasma half life • When given S/C it activates GHSR1a receptor with approximately 6-fold greater potency than natural ghrelin. • A/E hyperhidrosis and dizziness; fatigue and abdominal pain/cramping; and decreased blood pressure, hunger, feeling cold, and muscular weakness
- 27. 27 CHOLECYSTOKININ RECEPTOR ANTAGONIST •Cholecystokinin(CCK) is a peptide GI hormones produced through out the gastrointestinal tract especially enteroendocrine cells of duodenum and jejunum • It produces its physiological effects via GPCR (Gq) CCK1R and CCK2R receptors present in upper GIT • CCK1 R selective antagonist block the effect of endogenously released CCK increasing gastric and colonic motility
- 28. 28 RESEARCH Camilleri, M. andAtieh, J., 2021. New developments in prokinetic therapy for gastric motility disorders. Frontiers in Pharmacology, 12, p.711500. Crone, V., Møller, M.H., Bækgaard, E.S., Perner, A., Bytzer, P., Alhazzani, W. and Krag, M., 2023. Use of prokinetic agents in hospitalised adult patients: a scoping review. Acta Anaesthesiologica Scandinavica.
- 29. 29 BIOETHICS Taking written consentfrom the patient and if he/she is minor from parents before publishing case report including images
- 30. 30 ARTIFICIAL INTELLIGENCE Pourbahman, F.,Zeeb, M., Monzavi, A. et al. Simultaneous trace monitoring of prokinetic drugs in human plasma using magnetic dispersive micro-solid phase extraction based on a new graphene oxide/metal–organic framework-74/Fe3O4/polytyramine nanoporous composite in combination with HPLC. Chem. Pap. 73, 3135–3150 (2019). https://doi.org/10.1007/s11696-019-00855-
- 31. 31 END OF LECTUREASSESSMENT 1. Which of the following prokinetic is associated with QT interval prolongation? a) Cisapride b) Metoclopromide c) Tegaserod d) Domperidone e) Itopride 2. The most common adverse effect of metoclopramide is ? a) Extrapyramidal syndrome b) Abdominal pain c) Vomiting d) Arrhythmia e) Nausea 3. Metoclopramide produces its prokinetic effect by mainly acting on which of the following receptor? a) D1 receptor b) 5HT4 receptor c) 5HT1 receptor d) Motilin receptor e) CCK- receptor
- 32. 32 END OF LECTUREASSESSMENT 4. Metoclopramide does not produce which of the following effect? a) Increases tone of lower esophageal sphincter b) Increases tone of pyloric sphincter c) Increases gastric peristalsis d) Increases antroduodenal contraction e) Increases intestinal peristalsis 5. Which of the following is not a neuropeptide/neurotransmitter involved in gastrointestinal motility? a) Motilin b) Ghrelin c) CCK d) Acetylcholine e) Glutamate