GI DRUGS ANTIDIARRHEALS

LAXATIVES

ANTIEMETICS

DRUGS FOR INFLAMMATORY BOWEL DISEASE.

TREATMENT OF IRRITABLE BOWEL SYNDROME

GI MOTILITY AND SECRETION

Colonic function is subject to complex sets of regulatory influences.

NEURAL PATHWAYS

CNS -both sympathetic and parasympathetic innervation.

Myenteric nervous system.

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

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.

TREATMENT OF DIARRHEA

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 or decreasing intestinal motility.

Treatment is generally nonspecific.

NONDRUG APPROACHES

Patience

TREATMENT OF DIARRHEA

Supportive therapy and oral rehydration therapy.

PHARMACOTHERAPY

Reserved for patients with significant or persistent symptoms.

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.

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

(MgSo4, 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 NH3.

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 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.

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 rapidlyDon’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.

ANTIEMETIC AGENTS

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

PeripheryBLOOD BRAIN BARRIER

5-HT3

CTZ5-HT3 D2

M1

Solitary tract nucleus

5-HT3 D2 M H1

Vagal and sympathetic afferents

Glossoph.,trigeminal affs.

NEUROTRANSMITTER 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.

NEUROTRANSMITTER PATHWAYS OF EMESIS

Dopamine acting at D2 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 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.

EMESIS

Sensory stimuli such as pain and sight can contribute to vomiting as can the anticipation of an unpleasant experience.

ANTIEMETIC AGENTS

5-HT3 antagonists

D2 antagonists

NK1 receptor antagonists CorticosteroidsCannabinoidsAntihistaminesMuscarinic antagonistsBenzodiazepines

ANTIEMETIC AGENTS

A number of useful antiemetics such as corticosteroids and cannabinoids do not yet fit into the scheme.

COMBINATIONS

Provide a major improvement in the ability to reduce nausea and vomiting.

Decrease toxicity associated with some antiemetics.

5-HT3 ANTAGONISTS

Selective serotonin receptor antagonists

5-HT3 ANTAGONISTS

Ondansetron (Zofran)

Granisetron (Kytril)

Dolasetron (Anzemet)

Palanosetron (Aloxi)

MECHANISM 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.

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.

D2 ANTAGONISTS

Antagonists 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).

METOCLOPRAMIDE (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.

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.

D2 ANTAGONISTS

Phenothiazines

Domperidone

APREPITANT (Emend)

NK1 receptor antagonist.

Very useful vs delayed nausea.

Synergistic with 5-HT3 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.

INFLAMMATORY BOWEL DISEASE (IBD)

Sulfasalazine (Azulfidine)

Non-sulfonamide containing formulations of mesalamine including Olsalazine and Balasalazide

Infliximab

INFLAMMATORY BOWEL DISEASE (IBD)

Inflammation of the colonic and/or intestinal linings.

Chronic with temporary remissions.

Familial and infectious components.

IBD

Probably results from a cascade of events and processes initiated by an antigen or antigens in genetically susceptible individuals.

SYMPTOMS

Diarrhea

Pain

Bleeding and related deficiencies.

Malabsorption

PATHOLOGY

Immune activation is followed by an inflammatory response that is mediated and amplified by several factors including cytokines, oxygen radicals and metabolites of arachidonic acid.

TYPES OF DISEASE

Ulcerative colitis- colon/rectum.

Crohn’s disease- extends to small intestine and deeper into intestinal walls, fistulas.

TREATMENT OF IBS IS COMPLEX

Unknown nature of the causative agent.

Chronic and variable nature of the inflammation.

Variability in goals of therapy.

5-AMINOSALICYLATES

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.

ADVERSE EFFECTS

Headache, nausea, and upper respiratory infections.

Allergic reactions

Immunosuppression.

IMMUNOSUPPRESSIVE AGENTS

Inhibit lymphocyte proliferation.

Mercaptopurine and azathioprine.

Cyclosporine and methotrexate are also used.

ANTIBIOTICS

Mainly adjunctive therapy

Mild to moderate Crohn’s disease.

Metronidazole and/or ciprofloxacin.

IRRITABLE BOWEL SYNDROME

Tegaserod (Zelnorm)

IRRITABLE BOWEL SYNDROME

A common disorder in which bowel habits are altered in association with abdominal pain or discomfort (prevalence of about 12%).

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.

TREATMENT OF CONSTIPATION

Fiber supplements

Magnesium salts

Phosphate salts

PEG-based laxatives

Non-absorbed carbohydrates.

ANTIDIARRHEAL AGENTS

Opiate and opioid analogs

Specific Therapies

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 HT3 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 HT4 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-HT3 receptor antagonists as well as 5-HT4

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 phenothiazinesBethanecholProkinetic agents-metoclopramide,

cisapride and domperidone

Prokinetic Agents

Cholinergic agentsDopamine 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

HyperprolactinemiaSignificant extrapyramidal symptomsAnxiety,depressionDrowsiness, 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.

ADVERSE EFFECTS

Extrapyramidal effects.

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.