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Recent advances in diabetic gastroparesis

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recent advances in diabetic gastroparesis

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Recent advances in diabetic gastroparesis

  1. 1. “ ” CURRENT AND EMERGING MEDICAL THERAPIES FOR GASTROPARESIS Short Topic Dr Shinde Viraj Ashok Junior Resident – 3 Department of Pharmacology Current and emerging medical therapies for gastroparesis 1 Guided by Dr Sonali Pimpalkhute Associate Professor Department of Pharmacology
  2. 2. OVERVIEW Introduction Correcting underlying conditions in diabetic gastroparesis treatment Current medical treatments Upcoming promotilides for gastroparesis Current and emerging medical therapies for gastroparesis 2
  3. 3. INTRODUCTION  Gastroparesis - Constellation of disorders of varying aetiology & pathophysiology  Gastroparesis –  Defined by objective evidence of delayed gastric emptying in absence of obstruction  Symptoms commonly include early satiety, post- prandial fullness, bloating, nausea, vomiting & abdominal pain Current and emerging medical therapies for gastroparesis 3
  4. 4. INTRODUCTION CONT’D  Mainstay of medical treatments includes  Modifying lifestyle & diet  Improving glucose control in diabetics  Prokinetic, anti-emetic & analgesic drugs  Non-medical modalities  Acupuncture  Hypnotherapy  Gastric electric stimulation & surgical procedures - Reserved for rare & severely refractory patients Current and emerging medical therapies for gastroparesis 4
  5. 5. CORRECTING UNDERLYING CONDITIONS IN DIABETIC GASTROPARESIS Current and emerging medical therapies for gastroparesis 5
  6. 6. TIGHTER GLUCOSE CONTROL IN DIABETICS  Chronically elevated blood glucose level in diabetes results in damage to vagus nerve & blood vessels of stomach  In a Multicenter Safety, Feasibility & Potential Efficacy of Continuous Glucose Monitoring & Insulin Pump Therapy in Diabetic Gastroparesis (GLUMIT- DG) study  Preliminary results – Continuous glucose monitoring (CGM) & combined with insulin pump  Improves glycemic control  Associated with improved symptoms & gastric emptying Current and emerging medical therapies for gastroparesis 6
  7. 7. REVIEWING MEDICATIONS  Various drugs  Analgesic, Muscle relaxant, Antihistamines & Neuropsychiatric medications like antidepressants - may delay gastric emptying  ↓ or withdrawn when possible  Diabetes medications - mimic or modify incretins can further slow gastric emptying  Amylin & exenatide - inhibits gastric emptying & should be avoided in gastroparesis  Inhibitors of enzyme dipeptidyl peptidase 4 (DPP-4) - do not delay gastric emptying nor reduce food intake & should be considered as replacements Current and emerging medical therapies for gastroparesis 7
  8. 8. DIETARY CHANGES  Small frequent meal, low-fat, low-residue & ↑ liquid content meals are best tolerated in patients with symptomatic gastroparesis  Chewing food well, drinking non-carbonated liquids with meals & avoiding lying down for 2 h after a meal may assist with gastric emptying Current and emerging medical therapies for gastroparesis 8
  9. 9. DIETARY CHANGES CONT’D  Ginger, peppermint & lavender, taken on their own, appear helpful in ↓ discomfort & symptoms of gastroparesis  Ginger (1.2 g) - accelerate gastric emptying & enhance antral contractions over placebo but does not alter plasma levels of gut peptide GLP-1, motilin or ghrelin  Peppermint tea  For some symptoms of gastroparesis - abdominal pain, bloating & gas  Anti-spasmodic, anti-inflammatory, serotonergic & anti- bacterial properties Current and emerging medical therapies for gastroparesis 9
  10. 10. CURRENT MEDICAL TREATMENTS  Medications used commonly for gastroparesis include prokinetics, analgesics & anti-emetics. Current and emerging medical therapies for gastroparesis 10
  11. 11. PROKINETICS Dompamine D2-R antagonists  Metoclopramide & domperidone - equally effective in ↓ symptoms of diabetic gastroparesis Metoclopramide  D2 receptor antagonist & 5-hydroxytryptamine receptor 4 (5-HT4) agonist  Prokinetic action & anti-emetic properties  Provides prolonged symptomatic relief in gastroparesis  US-FDA - approved for gastroparesis Current and emerging medical therapies for gastroparesis 11
  12. 12. PROKINETICS CONT’D Metoclopramide cont’d  Overall adverse central nervous system (CNS) effects of metoclopramide, e.g., somnolence, dystonia & reduction in mental acuity, can be severe  Tardive dyskinesia can be irreversible & disfiguring - FDA black box warning in 2009  Treatment beyond 3 months should be avoided in most cases. Current and emerging medical therapies for gastroparesis 12
  13. 13. PROKINETICS CONT’D Domperidone  Anti-emetic & prokinetic effects  Unlike metoclopramide, CNS reactions are uncommon because of less penetration of blood–brain barrier  Rationally suitable for use in gastroparetic patients such as with Parkinson’s disease  Treatment - doses of 80–120 mg per day for up to 3 months is tried before considering as treatment failure  US - FDA issued warning about cardiac safety - regarding QT prolongation  Intravenous dosage form - withdrawn due to cardiotoxicity Current and emerging medical therapies for gastroparesis 13
  14. 14. PROKINETICS CONT’D Itopride  Antiemetic & prokinetic properties  Has D2 antidopaminergic & anti-ChE (ACh potentiating) activity, but very low affinity for 5-HT4 receptor  Very similar to domperidone & seems to be devoid of any cardiac toxicity or CNS side effects Levosulpiride  Dopamine D2 receptor antagonist  Reported to improve gastric emptying & symptoms (nausea, vomiting & early satiety) in diabetic gastroparesis during 6 months of treatment Current and emerging medical therapies for gastroparesis 14
  15. 15. SEROTONERGIC 5-HT4 AGONISTS Cisapride  Mixed 5-HT4 agonist/5-HT3 antagonist  ↑ acetylcholine release from enteric nervous system & directly ↑ smooth muscle contractions – ↓ gastric emptying time  Withdrawn in 2000 - side effect of causing long QT syndrome Mosapride  Improves gastric emptying & symptoms of gastroparesis & improves glycemic control Current and emerging medical therapies for gastroparesis 15
  16. 16. SEROTONERGIC 5-HT4 AGONISTS CONT’D Prucalopride  Dose selectivity for 5-HT4 receptors over cardiac human ether-a-go-go-related gene (hERG) channel & other receptors & has low adverse effects  Accelerates gastric emptying in animal models  Currently being studied for use in gastroparesis & dyspepsia Current and emerging medical therapies for gastroparesis 16
  17. 17. MOTILIN RECEPTOR AGONISTS Erythromycin  Effect on gastroparesis - two pathways activating motilin receptors on cholinergic neurons & muscle  Most effective intravenous prokinetic agent in acute setting - initial management of hospitalized patients with diabetic gastroparesis  Rapid development of tolerance is seen - By 4 weeks of oral treatment  Drawbacks - Potential to induce abdominal cramps, nausea & vomiting & to slow small intestinal transit Current and emerging medical therapies for gastroparesis 17
  18. 18. MOTILIN RECEPTOR AGONISTS CONT’D Clarithromycin & azithromycin  Promotilides & ↑ antral contractions  Effect on motilin receptor requires metabolism by acid & this should be kept in mind while prescribing to patients with dyspepsia , there by potentially making drug less effective as a promotilide  Fewer drug interactions than erythromycin, less incidence of QTc interval prolongation, a longer half-life & fewer untoward GI effects Current and emerging medical therapies for gastroparesis 18
  19. 19. MUSCARINIC RECEPTOR AGONIST/CHOLINESTERASE INHIBITORS  Pyridostigmine - ↓ symptoms due to gastroparesis that may be secondary to an underlying autoimmune disease Current and emerging medical therapies for gastroparesis 19
  20. 20. ANTIEMETICS Prochlorperazine  D2 antagonist - one of most commonly used medicines for treatment of nausea in patients with gastroparesis  Major side effects are sedation, extrapyramidal side effects Granisetron transdermal form - effective for refractory nausea & vomiting in gastroparesis Aprepitant  Substance P antagonist & works by blocking neurokinin 1 (NK1) receptor  Effective for refractory nausea in severe gastroparesis & is currently under investigation Current and emerging medical therapies for gastroparesis 20
  21. 21. PAIN MANAGEMENT  Anti-convulsant/anti-epileptic drugs have much less adverse effect on GI motility & could be very valuable options for treating pain associated with gastroparesis  Of alternative medical treatments, acupuncture & acupressure (shiatsu) treatment may lead to symptomatic improvement in patients with gastroparesis Current and emerging medical therapies for gastroparesis 21
  22. 22. GASTRIC ACID SUPPRESSION  Stomach acid suppression plays important role for overall symptom management in gastroparesis  Careful choice of acid-suppressing drugs can optimize gastroparesis symptom management  Nizatidine - Histamine H2 receptor antagonist - demonstrated to hasten stomach emptying in patients with Parkinson’s disease Current and emerging medical therapies for gastroparesis 22
  23. 23. GASTRIC ACID SUPPRESSION CONT’D  Misoprostol synthetic prostaglandin E1 analogue  Particularly at higher doses - Profound effect on intestinal post-prandial motility & results in accelerated transit time, particularly expediting orocecal transit Current and emerging medical therapies for gastroparesis 23
  24. 24. TARGETING ACCOMMODATION  Impaired accommodation - may contribute to symptoms of post-prandial fullness & early satiety  Clonidine acts - alpha 2 sympathetic receptor agonist & also blocks other sympathetic receptors  Evidence for acutely improving symptoms in patients with dyspeptic symptoms & diabetic gastroparesis - might be due to changes in accommodation  Recent study indicates that clonidine causes hyperglycemia & also interacts with glibenclamide to ↓ hypoglycemic activity in rats  Role in improving gastric emptying remains controversial Current and emerging medical therapies for gastroparesis 24
  25. 25. TARGETING ACCOMMODATION CONT’D  Other medications implicated in gastric accommodation include acotiamide (Z-338, YM 443) - muscarinic M1/M2 receptor antagonist & possibly an M5-like receptor approved in Japan that enhances acetylcholine release & appears to enhance gastric accommodation  Associated with improved dyspeptic symptoms Current and emerging medical therapies for gastroparesis 25
  26. 26. TARGETING ACCOMMODATION CONT’D Buspirone -5HT1A agonist  Positive effect on gastroparesis symptomatic relief, even without evidence showing of gastric emptying in healthy volunteers  In addition to ↓ in transient lower esophageal sphincter relaxation, which is major mechanism underlying gastroesophageal reflux disorder, this symptomatic relief might be due to fundic relaxation & ↑ gastric accommodation Sumatriptan - 5-HT1D/1B agonist,  Relaxes fundus & effective in functional dyspepsia Both buspirone & sumatriptan have potential disadvantage of slowing gastric emptying Current and emerging medical therapies for gastroparesis 26
  27. 27. TARGETING PYLORIC FUNCTION  Conceptually, gastric retention could be due to impaired relaxation of pyloric sphincter, which might be caused by a lack of normal inhibitory innervation through nitric-oxide-producing intrinsic neurons  Nitric oxide exerts its effect through cyclic GMP as a mediator & sildenafil which protects second messenger from breakdown should mimic effects of nitric oxide release & relieve gastric retention  Sildenafil did not improve emptying in pilot study of patients with diabetic gastroparesis, possibly because of its concurrent relaxatory action on fundus Current and emerging medical therapies for gastroparesis 27
  28. 28. TARGETING PYLORIC FUNCTION CONT’D  Botulinum toxin A injected into pyloric area during endoscopy initially reported symptomatic improvement & acceleration of gastric emptying  Two controlled trials did not demonstrate superiority over placebo Current and emerging medical therapies for gastroparesis 28
  29. 29. ANTIBIOTICS FOR TREATMENT OF BACTERIAL OVERGROWTH  Gastric stasis can lead to bacterial overgrowth in stomach & intestine  Patients with small intestinal bacterial overgrowth also present with symptoms similar to those of gastroparesis & various antibiotics used for bacterial overgrowth may also improve gastric motility  Rifaximin has gained more recent attention since it is poorly absorbed & therefore works primarily in intestine with fewer potential side effects Current and emerging medical therapies for gastroparesis 29
  30. 30. UPCOMING PROMOTILIDES FOR GASTROPARESIS Current and emerging medical therapies for gastroparesis 30
  31. 31. SEROTONERGIC RECEPTOR AGENTS  TD-5108 is a potent, highly selective & high- efficacy 5-HT4 agonist  Can significantly accelerate intestinal and colonic transit after single dosing & recent phase 2 blinded, placebo randomized control trial involving both diabetic & idiopathic gastroparesis patients demonstrated accelerated gastric emptying Current and emerging medical therapies for gastroparesis 31
  32. 32. SEROTONERGIC RECEPTOR AGENTS CONT’D  Prucalopride - undergoing phase 3 clinical trial in diabetic gastroparesis  Alosetron - Being considered for treatment of gastroparesis  Naronapride - investigational 5-HT4 receptor agonist that was designed to have similar activity as cisapride without QT prolongation Current and emerging medical therapies for gastroparesis 32
  33. 33. SEROTONERGIC RECEPTOR AGENTS CONT’D  In addition, naronapride is not metabolized by CYP450  ↑ spontaneous bowel movements in a phase 2 randomized, placebo-controlled study of patients with chronic idiopathic constipation  Study demonstrated that it can accelerate overall colonic transit & tends to accelerate gastric & ascending colon emptying & loosen stool consistency Current and emerging medical therapies for gastroparesis 33
  34. 34. SEROTONERGIC RECEPTOR AGENTS CONT’D  Renzapride - Gastroprokinetic agent & anti-emetic  Despite initial encouraging results, however, phase III trial in the USA in 2008 did not show sufficient efficacy over placebo to justify further development  TD-2749 - selective 5-HT4 agonists - currently being studied for use in gastroparesis Current and emerging medical therapies for gastroparesis 34
  35. 35. MOTILIN RECEPTOR AGONISTS  Several erythromycin derivatives are being studied as promotilides without antibiotic activity  EM574 has emerging evidence to improve delayed gastric emptying in dogs, but evidence in humans is still lacking  Various other coded molecules in pipeline are ABT81229, KC11458, GM611 , GSK962040 Current and emerging medical therapies for gastroparesis 35
  36. 36. OTHER CCK-A ANTAGONIST  Loxiglumide ↑ gastric & colonic motilities & reduces visceral perception  Appears effective for constipation & studies in healthy volunteers showed acceleration of both liquid & solid gastric emptying Current and emerging medical therapies for gastroparesis 36
  37. 37. GHRELIN AND GHRELIN RECEPTOR AGONISTS  Pharmacological doses of ghrelin accelerate gastric emptying & improve symptoms but contraction of proximal stomach may conceivably aggravate post- prandial symptoms  TZP-101 - small studies to ↓ overall post-meal symptom intensity & post-prandial fullness & improve symptoms in six patients with severe gastroparesis  Other coded compounds undergoing trials are TZP -102, RM -131 Current and emerging medical therapies for gastroparesis 37
  38. 38. GUANYL CYCLASE AGONIST  Linaclotide - peptide agonist of guanylate cyclase 2C - ↑ smooth muscle contraction and promotes bowel movement  Target receptor is less expressed in stomach, some have used this off-label for gastroparesis  IW-9179 - GC-C agonist - for potential treatment of functional dyspepsia and gastroparesis Current and emerging medical therapies for gastroparesis 38
  39. 39. OTHER PROMOTILITY MEDIATORS  Calcitonin gene-related peptide, or CGRP - potent smooth muscle relaxant shown to slow gastric emptying in healthy rodents  CGRP & transient receptor potential vanilloid subtype 1 (TRPV1) antagonists - potential in treatment of gastroparesis  Recent study TRPV1 blockade elicited marked, but reversible & generally plasma concentration dependent hyperthermia Current and emerging medical therapies for gastroparesis 39
  40. 40. OTHER PROMOTILITY MEDIATORS CONT’D Lubiprostone  selective type 2 chloride channel (ClC-2) activator - induces intestinal secretion & has been shown to relieve constipation in clinical trials  Some of its action may be mediated through prostaglandin E2 effects, raising possibility that this could also enhance gastric emptying  Accelerated small bowel & colonic transit & fasting ↑ gastric volume but retarded gastric emptying  ↓ fullness 30 min after fully satiating meal Current and emerging medical therapies for gastroparesis 40
  41. 41. CONCLUSION Current available medications are limited symptomatic control is aimed at improving gastric emptying , alleviating nausea and vomiting, and treating abdominal pain . Many drugs are in pipeline for treating gastroparesis. Various newer mechanism under study are 1. Serotonergic agents – prucalopride 2. Motilin receptor agonists – EM574 3. CCK – A Antagonist- loxiglumide 4. Ghrelin receptor antagonists – TZP101 5. Guanyl cyclase agonist – Linactolide 6. Calcitonin gene related peptides antagonists Current and emerging medical therapies for gastroparesis 41
  42. 42. REFERENCES  Current and Emerging Medical Therapies for Gastroparesis ,Xiaofeng Zhao, PhDHiroshi Mashimo, Drugs 2015  “ The pharmacological basis of therapeutics” Goodman and Gilman( 12th edition )  Basic and clinical pharmacology – Bertram Katzung (12th edition) Current and emerging medical therapies for gastroparesis 42
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  44. 44. REMOVE ???  A number of herbal preparations have emerged as dietary supplements for treatment of functional bowel and gastroparesis symptoms  STW5 (Iberogast, Steigerwald Arzneimittelwerk GmbH) is a herbal preparation of nine herbs (clown’s mustard, German chamomile, angelica, caraway, milk thistle, lemon balm, peppermint, celandine & licorice)  Initial studies of Iberogast - show promise in treatment of dyspeptic symptoms & for gastroparesis, although gastric emptying was not enhanced Current and emerging medical therapies for gastroparesis 44
  45. 45. CHOLECYSTOKININ (CCK) ANTAGONISTS  Cholecystokinin (CCK) natural hormone in body that influences gastric motor, gall bladder & pancreatic enzyme function Current and emerging medical therapies for gastroparesis 45
  46. 46. TZP-102 - oral counterpart of TZP-101  Did not accelerate gastric emptying  Initially ↓ composite symptom score of nausea, inability to finish meals, upper abdominal pain & bloating  Phase 2b trial with diabetic gastroparesis - no significant symptomatic benefit over placebo RM-131 - pentapeptide synthetic ghrelin receptor agonist  In animal models has nearly 100-fold greater potency than native ghrelin and a longer plasma half-life.  Two studies - accelerated gastric emptying & ↓ subjective vomiting severity but not other GI symptoms Current and emerging medical therapies for gastroparesis 46
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