6GI MOTILITYProper movement of nutrients, wastes, electrolytes and water thru the intestine depends on a balance of absorption and secretion of water and electrolytes by the intestinal epithelium.And appropriate antegrade motility along the GI tract
7GI MOTILITYNormally, there is net absorption of water in the intestine in response to osmotic gradients from the uptake and secretion of ions and the absorption of nutrients.
8GI MOTILITYNeurohumoral mechanisms, pathogens and drugs can alter uptake and secretory processes and the osmotic gradients for water flux such that excessive absorption or net secretion of water occurs, contributing to constipation or diarrhea.
9GI MOTILITYNeurohumoral mechanisms, pathogens and drugs can alter uptake and secretory processes.
10GI MOTILITYAltered GI motility contributes to diarrhea or constipation.Drugs can stimulate or reduce intestinal motility.And thereby alter the transit time of cpds. Throud the intestine.
11GI MOTILITY GI motility is also an important component of vomiting. During nausea and vomiting there is inhibition of gastric motilityEnhanced gastric emptying is a significant aspect of the actions of some antiemetics.
13PATHOBIOLOGY Excessive fecal loss of fluid and electrolytes. Due to a combination of increased motility, decreased fluid absorption and increased fluid secretion.Dehydration and electrolyte imbalances occur.
14CAUSES Infections. Malabsorption-e.g. lactose, sorbitol, olestra. Allergy/inflammation.Intoxication and drug reactions (preformed enterotoxins, alcohol, some antibiotics, antacids and laxatives).Hormone secreting tumors.
15TREATMENT OF DIARRHEAThe aim is to enhance intestinal absorption of water by reducing the luminal contents of electrolytes (by increasing active Na absorption or decreasing secretion of anions) or decreasing intestinal motility.Treatment is generally nonspecific and is usually aimed at reducing the discomfort and inconvenience of frequent bowel movements.
16TREATMENT OF DIARRHEAThe aim is to enhance intestinal absorption of water or decreasing intestinal motility.Treatment is generally nonspecific.
17NONDRUG APPROACHESPatience-Although acute onset diarrhea is most often of infectious origin, it is usually self-limited and specific chemotherapy is seldom warranted or effective unless there is evidence of GI erosion or systemic disease.
19TREATMENT OF DIARRHEASupportive :A big risk in acute diarrhea is dehydration and electrolyte imbalances. Thus therapy is aimed at reducing fecal water loss and replacing lost fluid and electrolytes.
20TREATMENT OF DIARRHEASupportive therapy and oral rehydration therapy.
21PHARMACOTHERAPYReserved for patients with significant or persistent symptoms.
22TREATMENT OF DIARRHEARehydration fluids and proper diet- Sometimes oral or parenteral replenishment of fluid and electrolytes may be necessary and even lifesaving.Oral rehydration therapy begun soon after the onset of diarrhea is an effective component of therapy regardless of the origin of the diarrhea.
23DRUG-CAUSED DIARRHEASeveral drugs are among the common causes of acute, chronic or recurrent diarrhea.Adjustment of dosage or change in medication is preferred to the use of an antidiarrheal agent especially on a long term basis.Several drugs are among the common causes of acute, chronic or recurrent diarrhea.
24TREATMENT OF DRUG CAUSED DIARRHEA Adjustment of dosage or change in medication is preferred to the use of an antidiarrheal agent especially on a long term basis.Several drugs are among the common causes of acute, chronic or recurrent diarrhea.
25ANTIBIOTICS Usually not required. Infectious agent must be matched with the appropriate antibiotic.Improper use encourages resistance.
26OPIOIDS Mainstay of nonspecific drug therapy. Agonists for myenteric opiate receptors.Anti-secretory and anti-motility properties.Effective vs. moderate to severe diarrhea.
27OPIOIDSCodeine and paregoric are effective but have a high abuse potential.Synthetic opioids are preferred because they penetrate poorly into the CNS and produce antidiarrheal effects at doses that produce few central effects.
28OPIOIDSDiphenoxylate has some abuse potential (atropine added)(Lomotil) .Loperamide (Immodium) is highly specific for intestinal opiate receptors.
30TRAVELERS DIARRHEAThe combination of loperamide and an antimicrobial drug is probably the best treatment for most patients with travelers diarrhea (effective alone also).Ciprofloxacin (or another quinolone) is usually the DOC.
31OPIOIDS-ADVERSE EFFECTS With excessive use or overdose.CNS depression, constipation, inflammatory conditions of the colon and megacolon.
33BISMUTH SUBSALICYLATE AND SUBCITRATE Some anti-secretory and anti-inflammatory properties but also antibacterial activity.Nausea and abdominal cramps also are relieved.Prophylaxis and treatment of travelers diarrhea.
34ADVERSE REACTIONSStaining of oral and anal tissues.Tinnitus.
35SOMATOSTATIN ON THE GI TRACT Multiple actions.Inhibition of gastric acid and pepsin secretion.Inhibition of endocrine secretions.Inhibition of intestinal fluid and bicarbonate secretion.Decrease of smooth muscle contractility.Half-life is too short to be useful as a drug.
36OCTREOTIDE Peptide analog of somatostatin. Effective for the diarrhea associated with some hypersecretory tumors and AIDS - related diarrhea.Short-term therapy may produce nausea and GI upset.
37BULK-FORMING AND HYGROSCOPIC AGENTS For mild diarrhea.Hydrophilic colloids (psyllium, polycarbophil and CMC).Kaolin and other clays.
38BILE ACID SEQUESTRANTS Used in bile salt-induced diarrhea, as in patients with resection of the distal ileum.
39CONSTIPATION-PATHOPHYSIOLOGY Decreased intestinal and colonic motility and excessive fluid uptake.It is not a disease but a symptom that may result from a broad variety of underlying causes.
40CAUSES Congenital. Inadequate dietary fiber and fluid ingestion. Ignoring defecatory urge.Drugs and toxins.Neurogenic, metabolic and endocrine conditions.Structural abnormalities in the GI tract.
41AIM OF THERAPYTo increase the water content of the feces and to increase intestinal motility.Increasing water content, softens the feces.
42TYPES OF THERAPYNonDrug ApproachesLaxativesEnemas
43NONDRUG APPROACHESIncreasing water and fiber content of the diet, appropriate bowel habits and by exercise and bowel training.
44LAXATIVES Promote passage of the stools. Overused by the public due to misconception of what is normal.
45LAXATIVES Constipation. Used prior to surgical, radiological and endoscopic procedures where an empty colon is desirable.To help maintain soft stools in patients with anorectal disorders such as hemorrhoids and in patients with irritable bowel syndrome and diverticulitis.
46CONTRAINDICATIONSObstructionMegacolon and megarectum
47ENEMAS AND SUPPOSITORIES Adjuncts to bowel preparation regimens.Glycerin suppositories (acts as hygroscopic agent and lubricant)Primary purpose is to empty the distal colon or rectum or solid material
48LAXATIVESPrecise mechanism of action of many laxatives remains unknown.Three or four common groups can be described.Bulk forming laxatives, saline and osmotic laxatives, stimulant laxatives and stool softeners.
49LAXATIVESLaxatives work through complex actions such as the interaction of osmotic effects with epithelial transport, changes in the enteric nervous system and the release of extracellular regulators (e.g. PGs).Some increase activity of NO synthase and increase PAF in the gut.
50BULK FORMING LAXATIVES Increase fecal mass and stimulate colonic stretch receptors.Promote fluid retention in feces.Natural or semisynthetic polysaccharides and cellulose derivatives.
51ADVERSE EFFECTS Relatively safe and rarely abused. Allergic reactions. Flatulence occurs occasionally (as well as bloating and abdominal pain).Intestinal obstruction and impaction may occur.Some preps may release Ca++
52Dietary fiber, psyllium and methylcellulose Poorly digested fibers or digested by colonic bacteria.
53CALCIUM POLYCARBOPHIL Synthetic resin that absorbs large amounts of water.
54SALINE AND OSMOTIC LAXATIVES Poorly and slowly absorbed, act by their osmotic properties in the luminal fluid.Increase fluid retention in stools or increase luminal fluid contents. This stimulates peristalsis.May produce inflammatory mediators.
55SALINE LAXATIVES (MgSo4, Mg(OH)2, MgCitrate, Na Phosphate). Poorly absorbed ions that favor osmotic movement of water into the lumen.
56SALINE LAXATIVESUse caution or avoid in patients with congestive heart failure and renal impairment and in the elderly.Some have bitter taste.Excessive evacuation of intestinal contents is possible.
57NONDIGESTABLE SUGARS AND ALCOHOLS Glycerin,lactulose, sorbitol, mannitol.Poorly absorbed carbohydrates that favor osmotic movement of water into the intestinal lumen.Resistant to digestion.Relatively safe.
58LACTULOSE, SORBITOL AND MANNITOL Nonabsorbable sugars that are hydrolyzed in the intestine to organic acids which acidify the luminal contents and osmotically draw water into the lumen, stimulating motility.
59LACTULOSE Used also to treat hepatic encephalopathy. Drop in luminal pH that accompanies hydrolysis to short chain fatty acids in the colon results in trapping of NH3.
60POLYETHYLENE GLYCOL (PEG)-ELECTROLYTE Long-chain PEG’s are poorly absorbed and retain added water by virtue of their high osmotic nature.Prepared with an isotonic mixture of Na sulfate, bicarbonate, chloride and KCL (avoids transfer of ions).Used prior to colonoscopy and other bowel procedures.Used to treat constipation in difficult cases.
61STIMULANT LAXATIVESPromote accumulation of water and electrolytes in the colonic lumen.Stimulate peristalsis.
62STIMULANT LAXATIVESDirect effects on enterocytes, enteric neurons and muscle.Produce a low grade inflammation to promote water and electrolyte accumul’n.Work by complex mechanisms (may make tight junctions leaky, may inhibit intestinal Na/K ATPase, may activate PG/cAMP and nitric oxide/cGMP pathways).
63STIMULANT LAXATIVESDirect effects on enterocytes, enteric neurons and muscle.Produce a low grade inflammation to promote water and electrolyte accumul’n.Work by complex mechanisms and via several different mediators (NO,PG’s etc).
64ADVERSE EFFECTS Excessive laxation is common. Acute cramping and vomiting.Long-term-electrolyte disturbances, fat malabsorption, fat-soluble vitamin deficiency and laxative dependence.Allergic reactions.Carcinogenicity.Laxative abuse.
65LAXATIVE ABUSERepeated use of laxatives to force daily defecation can lead to laxative-dependent constipation, chronic diarrhea and electrolyte disturbances.Most common in the elderly especially in a nursing home environment.Stimulant laxatives are among the most commonly abused.
66TREATMENTEducate patients regarding the variability of normal bowel habits.Emphasize dietary fiber, adequate fluid intake, and regular physical activity in the maintenance of good bowel habits.All laxatives should be discontinued and the patient should be informed not to expect a bowel movement for several days.
67STIMULANT LAXATIVESDiphenylmethane derivatives (phenolphthalein and bisacodyl).Phenolpthalein-potential carcinogen.
68BISACODYL Enteric coated tablets and suppositories. Requires hydrolysis for activation so takes at least 6 hrs.Suppositories work more rapidlyDon’t use for more than 10 days.Overdosage can lead to catharsis and fluid and electrolyte disturbances.
69STIMULANT LAXATIVESAnthraquinone laxatives (1,8- dihydroxyanthraquinone and its glycoside derivatives that are contained in senna, cascara, rheum (rhubarb) and aloe.
70ANTHRAQUINONESProduce giant migrating colonic contractions and induce water and electrolyte secretion.Laxative effects are not seen for 6-12 hrs.Adverse effects have limited their use (melanotic pigmentation and cathartic colon).
71CASTOR OILUnpleasant taste and potential toxicity on intestinal epithelium and enteric neurons.
72SURFACTANT LAXATIVES (STOOL SOFTENERS) Anionic surfactants.Act primarily as stool-wetting and stool- softening agents, allowing the mixing of water, lipids and other fecal material.Alter intestinal permeabilityMarginal efficacy in most cases.By altering permeability they increase net water and electrolyte secretions in the intestine.
73ADVERSE EFFECTS-STOOL SOFTENERS Mild side effects.Potential to increase intestinal absorption and toxicity of other drugs given concurrently.
74DOCUSATES Prototype for this group. Although they produce only mild side effects (occasional cramping, rashes, nausea) they have potential serious effects.Docusate sodium (Colace)
75DOCUSATESThey increase the intestinal absorption and toxicity of other drugs administered concurrently.Overall their efficacy is slight and their potential for toxicity is significant.
76MINERAL OIL Penetrates and softens the stool. Adverse effect profile precludes regular use.May interfere with water absorption.Interferes with absorption of fat soluble vitamins.
77MINERAL OILElicitation of foreign body reactions in the intestinal mucosa.Leakage of oil.Possibility of lipid pneumonitis.
78GLYCERINTrihydroxy alcohol that is absorbed orally but acts as a hygroscopic agent and lubricant when given rectally.Water retention stimulates peristalsis.For rectal use only (may cause local discomfort, burning or hyperemia and bleeding).
79LUBIPROSTONE (Amitiza) Acts on chloride channels.Increases secretion of intestinal fluids.
82NAUSEA AND VOMITING Follows administration of many drugs. Accompany infectious and noninfectious GI disorders.Early pregnancy.Motion sickness.Emergence from general anesthesia.
83NEURAL PATHWAYS LEADING TO EMESIS Coordinated by the vomiting center.This center receives input from CTZ.From vestibular apparatus via the cerebellum.From higher brainstem and cortical structures.From visceral afferents in the periphery.From emetic substances in the circulation.
84EMETIC RESPONSEFollowing stimulation of the vomiting center, emesis is mediated by various efferent pathways.
85NAUSEA AND VOMITING Thought to be protective reflexes. Nausea occurs initially followed by reduced gastric tone, reduced peristalsis and increased tone in the duodenum and upper jejunum. Gastric reflux then occurs.Accompanied by multiple autonomic phenomena (salivation, shivering, vasomotor changes).
86Higher Centers Emetic Center cerebellum D2 M H1 CNS CTZ D2 Memory, fear, dread,and anticipationEmetic Centercerebellum5-HT3D2M H1Solitary tractnucleusCNSCTZ5-HT3D2BLOOD BRAIN BARRIERPeripheryM1InnerearVagal andsympatheticafferentsStomachand small int5-HT3SensoryInputBlood bornemeticsGlossoph.,trigeminal affs.LocalIrritantsPharynx(gagging)
87NEUROTRANSMITTER PATHWAYS OF EMESIS Serotonin acting at 5-HT3 receptors is an important emetic signal and transmitter in the afferent pathways from the stomach and small intestine, in the CTZ and in the solitary tract nucleus.
88NEUROTRANSMITTER PATHWAYS OF EMESIS Dopamine acting at D2 receptors is implicated in emetic signaling thru the trigger zone and the solitary tract nucleus.
89NEUROTRANSMITTER PATHWAYS OF EMESIS Substance P/neurokinin 1 receptor- substance P induces vomiting and binds to NK-1 receptors in the abdominal vagus, STN and the area postrema.
90NEUROTRANSMITTER PATHWAYS OF EMESIS Histamine and H1 receptors are concentrated in the solitary tract nucleus as well.Cholinergic and histaminergic synapses seem to be involved in transmission from the vestibular apparatus to the emetic center.Basis for use of H1 receptor antihistamines and muscarinic cholinergic antagonists in motion sickness.
91EMESISSensory stimuli such as pain and sight can contribute to vomiting as can the anticipation of an unpleasant experience.
97MECHANISM OF ACTION 5-HT3 antagonists in both the periphery and CNS. Act at several sites critical for emesis.No effects on dopamine receptors (lack toxicity of metoclopramide).Differences between the individual drugs mainly pharmacokinetics.
98PHARMACOKINETICS Orally, IV or IM. Effective upon once daily administration.Undergo CYT P450 metabolism.
99THERAPEUTIC USESPrevent or minimize emesis due from moderate-high doses of chemotherapy (e.g. cisplatin) and radiation.Effective vs. hyperemesis of pregnancy and to a lesser extent postoperative nausea (not motion sickness).
100ADVERSE EFFECTSTransient, mild adverse effects including headache, sedation, light-headedness, dizziness and constipation.Lack extrapyramidal side effects associated with metoclopramide.Minor EKG changes.No significant drug interactions.
101D2 ANTAGONISTSAntagonists at the D2 dopamine receptor (some may have 5-HT3 receptor antagonism also).Several drugs are in this class including substituted benzamides (metoclopramide, phenothiazines, benzimidazole derivatives (domperidone) and butyrophenones (haloperidol, droperidol).
102METOCLOPRAMIDE (Reglan) D2 antagonist and potent antiemetic (at high doses).Prokinetic effects on the intestine (at standard doses).At higher concentrations it also blocks 5-HT3 receptors.
103THERAPEUTIC USES AND TOXICITY Reduces cisplatin emesis in most patients and prevents it in 30-40%.The use of high dose metoclopramide is limited by its antidopaminergic side effects which include extrapyramidal reactions, anxiety and depression.These side effects are most prominent in younger patients especially when given orally.
105APREPITANT (Emend) NK1 receptor antagonist. Very useful vs delayed nausea.Synergistic with 5-HT3 antagonists.
106THERAPEUTIC USESUsed with corticosteroids and serotonin receptor antagonists to prevent nausea and vomiting caused by highly emetogenic anticancer drugs.
107ADVERSE EFFECTSFatigue and astheniaHiccupsDiarrhea and dizziness.
108CORTICOSTEROIDS Mechanism of antiemetic action is not known. Possible mechanisms include prostaglandin blockage and changes in cell permeability.
109THERAPEUTIC USESUseful in mild to moderate chemotherapy-induced emesis.Addition to other antiemetic therapies enhances the overall antiemetic effect achieved and can reduce the severity and incidence of some adverse effects.
110THERAPEUTIC USESUse cautiously in certain patient groups such as diabetics and patients with a history of psychiatric disease.Dexamethasone, methylprednisolone and occasionally prednisone have been used.
111CANNABINOIDS (Dronabinol and Nabilone) Therapeutic Uses- reduce emesis due to moderate emetogenic chemotherapy.
112ADVERSE EFFECTSHallucinations, disorientation, vertigo and others limits their use to patients refractory to or intolerant of other antiemetic agents.Concurrent use of prochlorperazine in low doses can reduce the incidence of dysphoria that accompanies cannabinoid administration.
125SULFASALAZINEConjugate of mesalamine(5-ASA) linked to sulfapyridine by a diazo bond.5-ASA is the main therapeutic moiety.Sulfapyridine accounts for most of the toxicity.The azo bond prevents early absorption of the ASA from the upper small bowel allowing high conc’ns in the colon.
126MECHANISM OF ACTION Inhibits prostaglandin and leukotriene synthesis. Reactive oxygen scavengers.Antiinflammatory effects-inhibits cytokine production and immunoglobulin secretion.
127THERAPEUTIC USES Oral use for mild or moderate ulcerative colitis. Less certain value for severe colitis (often given with steroids).Crohn’s disease is less responsive.
128ADVERSE EFFECTS Fever and malaise. Nausea, vomiting,headaches, epigastric discomfort and diarrhea.Megaloblastic anemia and low sperm counts.Allergic reactions.
129ADVERSE EFFECTSNecrolysis, Stevens Johnson syndrome, pancreatitis, eosinophilic pneumonia.
131NONSULFONAMIDE FORMULATIONS Mesalamine(aminosalicylic acid)-enteric coated, delayed release, microgranules, in a wax matrix.Olsalazine(2 mesalamines linked together).Balsalazide(mesalamine linked to an inert carrier).
132CORTICOSTEROIDSPrednisone administered orally, parenterally or rectally (Budesonide also).Antiinflammatory and immunosuppressive, inhibition of production and action of cytokines and inflammatory mediators.Adverse reactions are typical of systemic corticosteroids.
133INFLIXIMAB (Remicade) Chimeric monoclonal antibody that binds tumor necrosis factor (TNF).Given by i.v. injection.
134THERAPEUTIC USESProduces and maintains remissions in CD and helps promote healing.
135ADVERSE EFFECTS Headache, nausea, and upper respiratory infections. Allergic reactionsImmunosuppression.
136IMMUNOSUPPRESSIVE AGENTS Inhibit lymphocyte proliferation.Mercaptopurine and azathioprine.Cyclosporine and methotrexate are also used.
141PATHOPHYSIOLOGY Unknown cause. Altered GI motility and increased gut sensitivity.Heightened sensitivity to visceral distention.Interplay between motor and sensory dysfunction explains many symptoms.
142SYMPTOMSAbdominal pain, bloating and disturbed bowel function (diarrhea or constipation or both alternating)
143NONPHARMACOLOGICAL THERAPIES Fiber supplementsElimination diets followed by sequential reintroduction of specific foods.Avoidance of dietary excesses, caffeine and dietary triggers.Psychotherapy.
144NONSPECIFIC BOWEL-DIRECTED THERAPY Measures to reduce specific symptoms related to constipation and diarrhea.
145TREATMENT OF CONSTIPATION Fiber supplementsMagnesium saltsPhosphate saltsPEG-based laxativesNon-absorbed carbohydrates.
148ANTISPASMODICSAnticholinergicsCombined sedatives and antispasmodics
149TRICYCLIC ANTIDEPRESSANTS Low doses.Underlying mechanism is unknown.For moderate to severe IBS in which pain is prominent or when other therapies have failed.Combined with antispasmodics.
150SSRIsHave similar efficacy but lack many of the side effects of the TCA’s
151SEROTONIN-3-RECEPTOR ANTAGONISTS Activated HT3 receptors stimulate intestinal motility, secretion and sensation.Antagonists reduce colonic transit, and gastrocolic reflex.They reduce sensitivity to distention.
152ALOSETRON (Lotronex)Beneficial in women with IBS who did not have constipation.Reduces diarrhea and urgency, improved quality of life.
153ADVERSE EFFECTS Constipation (25-30%). Ischemic colitis was diagnosed in 1/700 patients and the drug was withdrawn. Then reintroduced for select patients.
154SEROTONIN-4 RECEPTOR AGONISTS-TEGASEROD Partial agonist at the HT4 receptor.Accelerates gastric emptying and small- bowel transit.Improves symptoms of abdominal discomfort, bloating and constipation.
155TEGASEROD (Zelnorm)Approved by the FDA for use for up to 12 weeks in women with constipation predominant irritable bowel syndrome.Side effects are generally mild, with diarrhea, the most predominant.Flatulence and headache also are common.
157PROKINETIC AGENTSMedications that enhance coordinated GI motility and transit in the GI tract.Pharmacologically and chemically diverse.
158NEURAL REGULATION OF GASTRIC MOTILITY Stimulation by cholinergic neurons.Inhibition by adrenergic neurons.Modulatory influence of the enteric nervous system where dopamine and serotonin play a role. Thus D2 and 5-HT3 receptor antagonists as well as 5-HT4 agonists stimulate gastric motility.
159ETIOLOGY OF GASTRIC HYPOMOTILITY Symptoms may include nausea, vomiting, heartburn, postprandial discomfort, indigestion and gastroesophogeal reflux.Causes are unknown in many patients but often results from diabetic neuropathy a concomitant of anorexia nervosa and achlorhydria and a result of gastric surgery.Component of a number of G.I. disorders.
160TREATMENT Antiemetic phenothiazines Bethanechol Prokinetic agents-metoclopramide, cisapride and domperidone
161Prokinetic Agents Cholinergic agents Dopamine receptor antagonists-domperidone and metoclopramide.Serotonin receptor modulators-cisapride and metoclopramide.
162METOCLOPRAMIDE CNS effects characteristic of dopaminergic blockade. Antagonism of emesis induced by apomorphine and ergotamineHyperprolactinemiaSignificant extrapyramidal symptomsAnxiety,depressionDrowsiness, dizziness and anxiety
163MECHANISM OF ACTIONDopaminergic antagonist, blocks G.I. Effects caused by local or systemic administration of dopaminergic agonists.May promote release of ACH from myenteric neurons.
164THERAPEUTIC USES Diabetic gastroparesis. Esophageal reflux. Prevention of nausea and vomiting from a variety of causes including pregnancy.
166CISAPRIDEEffects on motility of the stomach and small bowel closely resemble those of metoclopramide.Increases colonic motility and can cause diarrhea.Devoid of dopamine antagonist activity. Thus it does not influence concentration of prolactin in plasma or cause extrapyramidal symptoms.
167THERAPEUTIC USESDisorders of gastric hypomotility. Efficacy equals that of metoclopramide and domperidone without the side effects that result from dopamine receptor blocakde.Gastroesophageal reflux disease.Gastroparetic conditions.Chronic idiopathic constipation and colonic hypomotility.
168ADVERSE EFFECTS Transient abdominal cramping and diarrhea. May increase absorption of diazepam and alcohol.