OTHER PATHWAYS Hormonal –somatostatin, opioids, ADH, prostaglandins, VIP. Immunological.
GI MOTILITY Proper 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.
GI MOTILITY Normally, 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.
GI MOTILITY Neurohumoral 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.
GI MOTILITY Neurohumoral mechanisms, pathogens and drugs can alter uptake and secretory processes.
GI MOTILITY Altered GI motility contributes to diarrhea or constipation. Drugs can stimulate or reduce intestinal motility.
GI MOTILITY GI motility is also an important component of vomiting. During nausea and vomiting there is inhibition of gastric motility Enhanced gastric emptying is a significant aspect of the actions of some antiemetics.
PATHOBIOLOGY 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.
CAUSES Infections. Malabsorption-e.g. lactose, sorbitol, olestra. Allergy/inflammation. Intoxication and drug reactions (preformed enterotoxins, alcohol, some antibiotics, antacids and laxatives). Hormone secreting tumors.
TREATMENT OF DIARRHEA The 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.
TREATMENT OF DIARRHEA The aim is to enhance intestinal absorption of water or decreasing intestinal motility. Treatment is generally nonspecific.
NONDRUG APPROACHES Patience-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.
TREATMENT OF DIARRHEA Supportive :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.
TREATMENT OF DIARRHEA Supportive therapy and oral rehydration therapy.
PHARMACOTHERAPY Reserved for patients with significant or persistent symptoms.
TREATMENT OF DIARRHEA Rehydration 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.
DRUG-CAUSED DIARRHEA Several 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.
TREATMENT 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.
ANTIBIOTICS Usually not required. Infectious agent must be matched with the appropriate antibiotic. Improper use encourages resistance.
OPIOIDS Mainstay of nonspecific drug therapy. Agonists for myenteric opiate receptors. Anti-secretory and anti-motility properties. Effective vs. moderate to severe diarrhea.
OPIOIDS Codeine 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.
OPIOIDS Diphenoxylate has some abuse potential (atropine added)(Lomotil). Loperamide (Immodium) is highly specific for intestinal opiate receptors.
TRAVELERS DIARRHEA The 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.
OPIOIDS-ADVERSE EFFECTS With excessive use or overdose. CNS depression, constipation, inflammatory conditions of the colon and megacolon.
BISMUTH 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.
ADVERSE REACTIONS Staining of oral and anal tissues. Tinnitus.
SOMATOSTATIN 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.
OCTREOTIDE 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.
BULK-FORMING AND HYGROSCOPIC AGENTS For mild diarrhea. Hydrophilic colloids (psyllium, polycarbophil and CMC). Kaolin and other clays.
BILE ACID SEQUESTRANTS Used in bile salt-induced diarrhea, as in patients with resection of the distal ileum.
CONSTIPATION- 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.
CAUSES Congenital. Inadequate dietary fiber and fluid ingestion. Ignoring defecatory urge. Drugs and toxins. Neurogenic, metabolic and endocrine conditions. Structural abnormalities in the GI tract.
AIM OF THERAPY To increase the water content of the feces and to increase intestinal motility.
TYPES OF THERAPY NonDrug Approaches Laxatives Enemas
NONDRUG APPROACHES Increasing water and fiber content of the diet, appropriate bowel habits and by exercise and bowel training.
LAXATIVES Promote passage of the stools. Overused by the public due to misconception of what is normal.
LAXATIVES 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.
CONTRAINDICATIONS Obstruction Megacolon and megarectum
ENEMAS AND SUPPOSITORIES Adjuncts to bowel preparation regimens. Glycerin suppositories (acts as hygroscopic agent and lubricant)
LAXATIVES Precise 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.
LAXATIVES Laxatives 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.
BULK FORMING LAXATIVES Increase fecal mass and stimulate colonic stretch receptors. Promote fluid retention in feces. Natural or semisynthetic polysaccharides and cellulose derivatives.
ADVERSE 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 ++
Dietary fiber, psyllium and methylcellulose Poorly digested fibers or digested by colonic bacteria.
CALCIUM POLYCARBOPHIL Synthetic resin that absorbs large amounts of water.
SALINE 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.
SALINE LAXATIVES (MgSo 4, Mg(OH) 2, MgCitrate, Na Phosphate). Poorly absorbed ions that favor osmotic movement of water into the lumen.
SALINE LAXATIVES Use 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.
NONDIGESTABLE 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.
LACTULOSE, 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.
LACTULOSE 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 NH 3.
POLYETHYLENE 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.
STIMULANT LAXATIVES Promote accumulation of water and electrolytes in the colonic lumen. Stimulate peristalsis.
STIMULANT LAXATIVES Direct 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).
STIMULANT LAXATIVES Direct 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).
ADVERSE 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.
LAXATIVE ABUSE Repeated 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.
TREATMENT Educate 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.
STIMULANT LAXATIVES Diphenylmethane derivatives (phenolphthalein and bisacodyl). Phenolpthalein-potential carcinogen.
BISACODYL Enteric coated tablets and suppositories. Requires hydrolysis for activation so takes at least 6 hrs. Suppositories work more rapidly Don’t use for more than 10 days. Overdosage can lead to catharsis and fluid and electrolyte disturbances.
STIMULANT LAXATIVES Anthraquinone laxatives (1,8- dihydroxyanthraquinone and its glycoside derivatives that are contained in senna, cascara, rheum (rhubarb) and aloe.
ANTHRAQUINONES Produce 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).
CASTOR OIL Unpleasant taste and potential toxicity on intestinal epithelium and enteric neurons.
SURFACTANT 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 permeability Marginal efficacy in most cases.
ADVERSE EFFECTS-STOOL SOFTENERS Mild side effects. Potential to increase intestinal absorption and toxicity of other drugs given concurrently.
DOCUSATES Prototype for this group. Although they produce only mild side effects (occasional cramping, rashes, nausea) they have potential serious effects. Docusate sodium (Colace)
DOCUSATES They increase the intestinal absorption and toxicity of other drugs administered concurrently. Overall their efficacy is slight and their potential for toxicity is significant.
MINERAL OIL Penetrates and softens the stool. Adverse effect profile precludes regular use. May interfere with water absorption. Interferes with absorption of fat soluble vitamins.
MINERAL OIL Elicitation of foreign body reactions in the intestinal mucosa. Leakage of oil. Possibility of lipid pneumonitis.
GLYCERIN Trihydroxy 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).
LUBIPROSTONE (Amitiza) Acts on chloride channels. Increases secretion of intestinal fluids.
DRUG LIST Ondansetron Metoclopramide Aprepitant
NAUSEA AND VOMITING Follows administration of many drugs. Accompany infectious and noninfectious GI disorders. Early pregnancy. Motion sickness. Emergence from general anesthesia.
NEURAL 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.
EMETIC RESPONSE Following stimulation of the vomiting center, emesis is mediated by various efferent pathways.
NAUSEA 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).
Blood born emetics Local Irritants Emetic Center Higher Centers Sensory Input Memory, fear, dread, and anticipation Stomach and small int Pharynx (gagging) Inner ear cerebellum CNS Periphery BLOOD BRAIN BARRIER 5-HT 3 CTZ 5-HT 3 D2 M1 Solitary tract nucleus 5-HT 3 D2M H1 Vagal and sympathetic afferents Glossoph., trigeminal affs.
NEUROTRANSMITTER PATHWAYS OF EMESIS Serotonin acting at 5-HT 3 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.
NEUROTRANSMITTER PATHWAYS OF EMESIS Dopamine acting at D 2 receptors is implicated in emetic signaling thru the trigger zone and the solitary tract nucleus.
NEUROTRANSMITTER 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.
NEUROTRANSMITTER PATHWAYS OF EMESIS Histamine and H 1 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 H 1 receptor antihistamines and muscarinic cholinergic antagonists in motion sickness.
EMESIS Sensory stimuli such as pain and sight can contribute to vomiting as can the anticipation of an unpleasant experience.
MECHANISM OF ACTION 5-HT 3 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.
PHARMACOKINETICS Orally, IV or IM. Effective upon once daily administration. Undergo CYT P450 metabolism.
THERAPEUTIC USES Prevent 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).
ADVERSE EFFECTS Transient, mild adverse effects including headache, sedation, light-headedness, dizziness and constipation. Lack extrapyramidal side effects associated with metoclopramide. Minor EKG changes.
D 2 ANTAGONISTS Antagonists at the D 2 dopamine receptor (some may have 5-HT 3 receptor antagonism also). Several drugs are in this class including substituted benzamides (metoclopramide, phenothiazines, benzimidazole derivatives (domperidone) and butyrophenones (haloperidol, droperidol).
METOCLOPRAMIDE (Reglan) D 2 antagonist and potent antiemetic (at high doses). Prokinetic effects on the intestine (at standard doses). At higher concentrations it also blocks 5-HT 3 receptors.
THERAPEUTIC 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.
APREPITANT (Emend) NK1 receptor antagonist. Very useful vs delayed nausea. Synergistic with 5-HT 3 antagonists.
THERAPEUTIC USES Used with corticosteroids and serotonin receptor antagonists to prevent nausea and vomiting caused by highly emetogenic anticancer drugs.
ADVERSE EFFECTS Fatigue and asthenia Hiccups Diarrhea and dizziness.
CORTICOSTEROIDS Mechanism of antiemetic action is not known. Possible mechanisms include prostaglandin blockage and changes in cell permeability.
THERAPEUTIC USES Useful 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.
THERAPEUTIC USES Use cautiously in certain patient groups such as diabetics and patients with a history of psychiatric disease. Dexamethasone, methylprednisolone and occasionally prednisone have been used.
CANNABINOIDS (Dronabinol and Nabilone) Therapeutic Uses- reduce emesis due to moderate emetogenic chemotherapy.
ADVERSE EFFECTS Hallucinations, 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.
SULFASALAZINE Conjugate 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.
MECHANISM OF ACTION Inhibits prostaglandin and leukotriene synthesis. Reactive oxygen scavengers. Antiinflammatory effects-inhibits cytokine production and immunoglobulin secretion.
THERAPEUTIC 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.
ADVERSE EFFECTS Fever and malaise. Nausea, vomiting,headaches, epigastric discomfort and diarrhea. Megaloblastic anemia and low sperm counts. Allergic reactions.
ADVERSE EFFECTS Necrolysis, Stevens Johnson syndrome, pancreatitis, eosinophilic pneumonia.
NONSULFONAMIDE 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).
CORTICOSTEROIDS Prednisone 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.
INFLIXIMAB (Remicade) Chimeric monoclonal antibody that binds tumor necrosis factor (TNF). Given by i.v. injection.
THERAPEUTIC USES Produces and maintains remissions in CD and helps promote healing.
PATHOPHYSIOLOGY Unknown cause. Altered GI motility and increased gut sensitivity. Heightened sensitivity to visceral distention. Interplay between motor and sensory dysfunction explains many symptoms.
SYMPTOMS Abdominal pain, bloating and disturbed bowel function (diarrhea or constipation or both alternating)
NONPHARMACOLOGICAL THERAPIES Fiber supplements Elimination diets followed by sequential reintroduction of specific foods. Avoidance of dietary excesses, caffeine and dietary triggers. Psychotherapy.
NONSPECIFIC BOWEL- DIRECTED THERAPY Measures to reduce specific symptoms related to constipation and diarrhea.
ANTISPASMODICS Anticholinergics Combined sedatives and antispasmodics
TRICYCLIC 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.
SSRIs Have similar efficacy but lack many of the side effects of the TCA’s
SEROTONIN-3-RECEPTOR ANTAGONISTS Activated HT 3 receptors stimulate intestinal motility, secretion and sensation. Antagonists reduce colonic transit, and gastrocolic reflex. They reduce sensitivity to distention.
ALOSETRON (Lotronex) Beneficial in women with IBS who did not have constipation. Reduces diarrhea and urgency, improved quality of life.
ADVERSE EFFECTS Constipation (25-30%). Ischemic colitis was diagnosed in 1/700 patients and the drug was withdrawn. Then reintroduced for select patients.
SEROTONIN-4 RECEPTOR AGONISTS-TEGASEROD Partial agonist at the HT 4 receptor. Accelerates gastric emptying and small- bowel transit. Improves symptoms of abdominal discomfort, bloating and constipation.
TEGASEROD (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.
PROKINETIC AGENTS Medications that enhance coordinated GI motility and transit in the GI tract. Pharmacologically and chemically diverse.
NEURAL 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- HT 3 receptor antagonists as well as 5- HT 4 agonists stimulate gastric motility.
ETIOLOGY 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.
TREATMENT Antiemetic phenothiazines Bethanechol Prokinetic agents-metoclopramide, cisapride and domperidone
Prokinetic Agents Cholinergic agents Dopamine receptor antagonists- domperidone and metoclopramide. Serotonin receptor modulators-cisapride and metoclopramide.
METOCLOPRAMIDE CNS effects characteristic of dopaminergic blockade. Antagonism of emesis induced by apomorphine and ergotamine Hyperprolactinemia Significant extrapyramidal symptoms Anxiety,depression Drowsiness, dizziness and anxiety
MECHANISM OF ACTION Dopaminergic antagonist, blocks G.I. Effects caused by local or systemic administration of dopaminergic agonists. May promote release of ACH from myenteric neurons.
THERAPEUTIC USES Diabetic gastroparesis. Esophageal reflux. Prevention of nausea and vomiting from a variety of causes including pregnancy.
CISAPRIDE Effects 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.
THERAPEUTIC USES Disorders 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.
ADVERSE EFFECTS Transient abdominal cramping and diarrhea. May increase absorption of diazepam and alcohol.