Drugs Affecting GI Motility

Drugs Affecting GI Motility A. Drugs Stimulating GI Motility “Prokinetic Agents” B. Laxative Agents. C. Antidiarrheal Agents. Peristaltic movement is due to reflex activation of proximal contraction and distal relaxation Drugs Stimulating GI Motility ” Prokinetic Agents” Potential Uses: •Lower esophageal sphincter: GERD. •Stomach: gastroparesis and postsurgical gastric emptying delay. •Small intestine: Postoperative ileus. •Colon: constipation. ” Prokinetic Agents” Cholinomimetic Agents: Bethanecol: Stimulates M3 receptors on muscle cells and myenteric plexus synapses. Was used in GERD and gastroparesis. Neostigmine: AChase inhibitor. ”Acute Colonic Pseudo-obstruction”: IV can result in rapid evacuation of flatus and feces. Can cause cholinergic effects. ” Prokinetic Agents” Dopamine Receptor Antagonists: Metoclopramide Domperidone. D2 antagonists. Dopamine inhibits cholinergic action on smooth muscle. Have actions on esophagus and stomach, but not the small or large intestine. Also inhibit the chemorecptor trigger zone( Area Postrema). ” Prokinetic Agents” Uses of Dopamine Receptor Antagonists: 1.GERD: Not effective with erosive esophagitis. Not superior to antisecretory agents. Used in combination with antisecretory drugs. 2. Gastroparesis: Postsurgical: vagotomy and antrectomy. Diabetic. Advancement of feeding nasoenteric tubes. ” Prokinetic Agents” Other Uses of Dopamine Receptor Antagonists: 3. Nonulcer dyspepsia. 4. Antiemetic agents. 5. Postpartum lactation stimulation. ” Prokinetic Agents” Adverse Effects of Dopamine Receptor Antagonists: Metoclopramide crosses BBB so can cause: Restlessness, drowsiness, insomnia, anxiety, agitation, extrapyramidal symptoms (dystonia, akathisia, parkinsonian features) and tardive dyskinesia. Domperidone does not cross the BBB, so does not cause CNS effects Both drugs can elevate serum prolactin levels causing galactorrhea, gynecomastia, impotence and menstrual disorders. ” Prokinetic Agents” Macrolide Antibiotics: Directly stimulate motilin receptors in the GIT. Gastroparesis: given IV, but tolerance develops rapidly. Acute upper GIT bleeding: to promote emptying of blood before endoscopy. ” Prokinetic Agents” Chloride Channel Activator: Lubiprostone: PG analog. Can be used in chronic constipation. Stimulates chloride channel opening in GIT. This increases liquid secretion in the intestine. Delays gastric emptying leading to nausea. Antiemetic Agents • Afferent Inputs to the Vomiting Center: – Chemoreceptor trigger zone: DA2, 5-HT3, NK1, and opioid receptors. – Vestibular system involved with motion sickness through cranial nerve VIII. Rich in M and H1 receptors. – Pharyngeal irritation through the vagus. – GIT afferents through the vagus and spinal afferent nerves, rich in 5-HT3 receptors. – Central mechanisms due to psychiatric disorders, stress, and anticipatory vomiting of cancer chemotherapy (5-HT3). Antiemetic Agents • Serotonin 5-HT3- Receptor Antagonists: – Ondansetron. – Granisetron. – Dolasetron. – Palonosetron. • 5-HT3 receptors are involved in three out of the five inputs involved with vomiting. • Activity restricted to vomiting due to vagal stimulation and chemotherapy. • Motion sickness is poorly controlled. Antiemetic Agents • Serotonin 5-HT3- Receptor Antagonists: • Used before chemotherapy, activity enhanced by dexamethasone and NK1 antagonist. • Can also be used in postoperative and post radiation vomiting. • Safe drugs but can cause headache, dizziness and constipation. • Also prolong QT interval( i.e. proarrhythmic). Antiemetic Agents • Neurokinin Receptor(NK1) Antagonists: – Apripetant: • Central blockade in the area postrema. • Used in combination with 5-HT3 antagonists. • Can cause fatigue, dizziness and diarrhea. Antiemetic Agents • Antipsychotic drugs: – Prochlorperazine. – Promethazine. – Droperidol. • Inhibit dopamine and muscarinic receptors. • Can cause extrapyramidal effects, hypotension and prolong QT interval. Antiemetic Agents • Antihistamines and anticholinergic Drugs: – Diphenhydramine – Meclizine. – Hyoscine (scoplamine). • Particularly useful in motion sickness. • Can cause dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. • Hyoscine can be used as a transdermal patch. Antiemetic Agents • Benzodiazepines: – Lorazepam. – Diazepam. • Antianxiety-hypnotic drugs • Reduce anticipatory vomiting caused by anxiety. Antiemetic Agents • Cannabinoids: • Dronabinol. • Nabilone. – Delta-9- tetrahydrocannabinol from marijuana is useful for chemotherapy-induced vomiting. – Mechanism not understood. – Can cause euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite(the munchies). – Also, hypotension, tachycardia, and conjunctival injection. Emetic Agents • • • • Many drugs. Hypertonic saline. Apomorphine. Ipecac syrup. Drugs used in Irritable Bowel Syndrome • Idiopathic, chronic, relapsing disorder characterized by abdominal discomfort (pain, bloating, distension, or cramps) in association with alterations in bowel habits( diarrhea, constipation, or both). Drugs used in Irritable Bowel Syndrome • Antispasmodic or Anticholinergic Agents: – Dicyclomine – Hyoscyamine. • Spasm is not an important symptom in IBS. • They inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. • At usual low doses, have minimal side effects. Drugs used in Irritable Bowel Syndrome • Serotonin 5-HT 4- Receptor Agonists: • Tagaserod: – Approved for short term treatment of women with IBS who predominantly have constipation. – Reduces pain, bloating and hardness of stool. – Expensive. Drugs used in Inflammatory Bowel Disease • Ulcerative Colitis. • Crohn’s Disease. – Unknown etiology. – Drugs have different nonspecific antiinflammatory actions. Drugs used in Inflammatory owel Disease • Aminosalicylates: • • • • Used for decades. All contain 5-aminosalicylic acid(5-ASA). Believed to work topically. But, actually, 80% of 5-ASA is absorbed from the small intestine and does not reach the lesions. Drugs used in Inflammatory Bowel Disease • Aminosalicylates: • Azo Compounds: – Sulfasalazine. – Balsazide. – Olsalazine. • All contain 5-ASA bound by an azo bond (N=N). • In the intestine, bacteria cleave the bond to release the active 5-ASA. • Mesalamine Compounds: – – – – Pentasa: time release 5-ASA formulation. Asacol: enteric coated in a pH sensitive resin. Rowasa: enema. Canasa: suppository. Drugs used in Inflammatory Bowel Disease • Aminosalicylates: • Pharmacodynamics: – Modulate inflammatory mediators derived from both COX and lipooxygenase pathways. – Interfere with the production of inflammatory cytokines: • Inhibit nuclear factor ҚB (NF- ҚB). – Inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages and may scavenge reactive oxygen metabolites. Drugs used in Inflammatory Bowel Disease • Aminosalicylates: • Clinical Uses: – First line drugs for the treatment of mild to moderate active ulcerative colitis. – Can induce and maintain remission in ulcerative colitis. Drugs used in Inflammatory Bowel Disease • Aminosalicylates: • Adverse Effects: – Attributable to systemic absorption: especially in slow acetylators: Nausea, headache, arthralgia, myalgia, bone marrow suppression, and malaise. – Also, allergic reactions, oligospermia, and folate deficiency. Drugs used in Inflammatory Bowel Disease • Glucocorticoids: • Prednisolone and Prednisone: – Oral • Hydrocortisone: – Enemas, foam or suppositories. • Budesonide: – Controlled release oral formulation. Inhibit production of cytokines(TNF-α, IL-1) and chymokines(IL-8), inflammatory cell adhesion molecules, nitric oxide synthase, phospholipase A2, Cyclooxygenase-2 and NF-КB. Drugs used in Inflammatory Bowel Disease • Glucocorticoids: • Clinical Uses: – Moderate to severe active IBD. • Prednisolone orally or IV. • Hydrocortisone, rectally, preferred for rectal and sigmoid involvement. • Budesonide for ileal and proximal colon involvement. • Not useful for long term maintenance therapy. Drugs used in Inflammatory Bowel Disease • Antimetabolites: • Azathioprim • 6-Mercaotopurine. – Are purine analogs; which produce thioguanine nucleotides. – Immunosuppressive. – Inhibit purine nucleotide metabolism and DNA synthesis and repair, resulting in inhibition of cell division and proliferation and may promote T-lymphocyte apoptosis. Drugs used in Inflammatory Bowel Disease • Antimetabolites: • Clinical Use: – Onset delayed for 17 weeks. – Used in induction and maintenance of remission. – Allow dose reduction or elimination of steroids. Drugs used in Inflammatory Bowel Disease • Antimetabolites: • Adverse Effects: – Nausea, vomiting, bone marrow suppression, hepatic toxicity and allergic reactions( fever, rash, pancreatitis, diarrhea and hepatitis). – Allopurinol increases levels of the drugs. Drugs used in Inflammatory Bowel Disease • Methotrexate: – Antimetabolite. – Can be given orally, subcutaneously and intramuscularly. – Works by inhibiting dihydrofolate reductase (DHFRase) enzyme which is important in the synthesis of thymidine and purines. – At high doses it inhibits cellular proliferation. – At low doses used in IBD, it interferes with the inflammatory actions of interleukin-1, stimulates adenosine release, apoptosis and death of activated T lymphocytes. Drugs used in Inflammatory Bowel Disease • Methotrexate: – Used in cancer chemotherapy, rheumatoid arthritis and psoriasis. • Used for induction and maintenance of remissions of Crohn’s Disease. • At high doses, can cause bone marrow depression, megaloblastic anemia, alopecia and mucositis. • Renal insufficiency may increase risk of hepatic accumulation and toxicity. • Side effects counteracted by folate supplementation. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: • TNF-α is a key proinflammatory cytokine in the TH1 response in IBD. • Infliximab “Remicade”: – Is a chimeric mouse-human monoclonal antibody to human TNF-α . – Given IV. • Adalimumab: – Fully humanized IgG antibody, given SC. • Certolizumab: – Polyethylene glycol Fab fragment of humanized anti- TNF-α, also given SC. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: • Half life 8-10 days with persistence of antibodies in plasma for 8-12 weeks. • Binds to cell surface as well as to membrane-bound TNF-α receptors, preventing the cytokine from binding to its receptors. • The Fc portion of human IgG1 region promotes complement activation and antibody-mediated apoptosis and cellular cytotoxicity of activated lymphocytes and macrophages. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: – Used in acute and chronic treatment of patients with moderate to severe IBD. – Given in repeated doses at 0, 2, and 6 weeks for induction. – If response is adequate, infusions are repeated every 8 weeks. – Response might be lost due to development of antibodies to infliximab. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: – Serious Adverse effects: • Infection due to immunosuppression, occur in 6% of patients on infliximab, e.g. reactivation of TB or dissemination, pneumonia, sepsis, pneumocystis, listeriosis, and reactivation of hepatitis B. • Antibody formation against the murine epitope of infliximab develops in 1/3rd of patients leading to loss of response or infusion reactions. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: • Acute Infusion Reactions: fever, headache, dizziness, urticaria, chest pain, and dyspnea, hypotension, shortness of breath, muscle spasm and chest discomfort. • Delayed Reactions or Serum Sickness-like Reactions: occur after retreatment with infliximab include myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema. Drugs used in Inflammatory Bowel Disease • Anti-Tumor Necrosis Factor: • Other Adverse Reactions: Positive antinuclear antibodies, anti-double stranded DNA, Lupus-like syndrome, severe hepatic reactions, lymphoma, multiple sclerosis and congestive heart failure.