GI DRUGS

1
GI DRUGS

• ANTIDIARRHEALS
• LAXATIVES
• ANTIEMETICS
• DRUGS FOR INFLAMMATORY BOWEL DISEASE.
• TREATMENT OF IRRITABLE BOWEL SYNDROME

2
GI MOTILITY AND SECRETION

• Colonic function is subject to complex sets of
  regulatory influences.

3
NEURAL PATHWAYS

• CNS -both sympathetic and parasympathetic
  innervation.
• Myenteric nervous system.

4
(No Transcript)
5
OTHER PATHWAYS

• Hormonal somatostatin, opioids, ADH,
  prostaglandins, VIP.
• Immunological.

6
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.

7
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.

8
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.

9
GI MOTILITY

• Neurohumoral mechanisms, pathogens and drugs can
  alter uptake and secretory processes.

10
GI MOTILITY

• Altered GI motility contributes to diarrhea or
  constipation.
• Drugs can stimulate or reduce intestinal
  motility.

11
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.

12
TREATMENT OF DIARRHEA
13
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.

14
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.

15
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.

16
TREATMENT OF DIARRHEA

• The aim is to enhance intestinal absorption of
  water or decreasing intestinal motility.
• Treatment is generally nonspecific.

17
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.

18
NONDRUG APPROACHES

• Patience

19
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.

20
TREATMENT OF DIARRHEA

• Supportive therapy and oral rehydration therapy.

21
PHARMACOTHERAPY

• Reserved for patients with significant or
  persistent symptoms.

22
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.

23
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.

24
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.

25
ANTIBIOTICS

• Usually not required.
• Infectious agent must be matched with the
  appropriate antibiotic.
• Improper use encourages resistance.

26
OPIOIDS

• Mainstay of nonspecific drug therapy.
• Agonists for myenteric opiate receptors.
• Anti-secretory and anti-motility properties.
• Effective vs. moderate to severe diarrhea.

27
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.

28
OPIOIDS

• Diphenoxylate has some abuse potential (atropine
  added)(Lomotil) .
• Loperamide (Immodium) is highly specific for
  intestinal opiate receptors.

29
(No Transcript)
30
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.

31
OPIOIDS-ADVERSE EFFECTS

• With excessive use or overdose.
• CNS depression, constipation, inflammatory
  conditions of the colon and megacolon.

32
(No Transcript)
33
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.

34
ADVERSE REACTIONS

• Staining of oral and anal tissues.
• Tinnitus.

35
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.

36
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.

37
BULK-FORMING AND HYGROSCOPIC AGENTS

• For mild diarrhea.
• Hydrophilic colloids (psyllium, polycarbophil and
  CMC).
• Kaolin and other clays.

38
BILE ACID SEQUESTRANTS

• Used in bile salt-induced diarrhea, as in
  patients with resection of the distal ileum.

39
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.

40
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.

41
AIM OF THERAPY

• To increase the water content of the feces and to
  increase intestinal motility.

42
TYPES OF THERAPY

• NonDrug Approaches
• Laxatives
• Enemas

43
NONDRUG APPROACHES

• Increasing water and fiber content of the diet,
  appropriate bowel habits and by exercise and
  bowel training.

44
LAXATIVES

• Promote passage of the stools.
• Overused by the public due to misconception of
  what is normal.

45
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.

46
CONTRAINDICATIONS

• Obstruction
• Megacolon and megarectum

47
ENEMAS AND SUPPOSITORIES

• Adjuncts to bowel preparation regimens.
• Glycerin suppositories (acts as hygroscopic agent
  and lubricant)

48
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.

49
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.

50
BULK FORMING LAXATIVES

• Increase fecal mass and stimulate colonic stretch
  receptors.
• Promote fluid retention in feces.
• Natural or semisynthetic polysaccharides and
  cellulose derivatives.

51
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

52
Dietary fiber, psyllium and methylcellulose

• Poorly digested fibers or digested by colonic
  bacteria.

53
CALCIUM POLYCARBOPHIL

• Synthetic resin that absorbs large amounts of
  water.

54
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.

55
SALINE LAXATIVES

• (MgSo4, Mg(OH)2, MgCitrate, Na Phosphate).
• Poorly absorbed ions that favor osmotic movement
  of water into the lumen.

56
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.

57
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.

58
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.

59
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.

60
POLYETHYLENE GLYCOL (PEG)-ELECTROLYTE

• Long-chain PEGs 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.

61
STIMULANT LAXATIVES

• Promote accumulation of water and electrolytes
  in the colonic lumen.
• Stimulate peristalsis.

62
STIMULANT LAXATIVES

• Direct effects on enterocytes, enteric neurons
  and muscle.
• Produce a low grade inflammation to promote water
  and electrolyte accumuln.
• Work by complex mechanisms (may make tight
  junctions leaky, may inhibit intestinal Na/K
  ATPase, may activate PG/cAMP and nitric
  oxide/cGMP pathways).

63
STIMULANT LAXATIVES

• Direct effects on enterocytes, enteric neurons
  and muscle.
• Produce a low grade inflammation to promote water
  and electrolyte accumuln.
• Work by complex mechanisms and via several
  different mediators (NO,PGs etc).

64
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.

65
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.

66
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.

67
STIMULANT LAXATIVES

• Diphenylmethane derivatives (phenolphthalein and
  bisacodyl).
• Phenolpthalein-potential carcinogen.

68
BISACODYL

• Enteric coated tablets and suppositories.
• Requires hydrolysis for activation so takes at
  least 6 hrs.
• Suppositories work more rapidly
• Dont use for more than 10 days.
• Overdosage can lead to catharsis and fluid and
  electrolyte disturbances.

69
STIMULANT LAXATIVES

• Anthraquinone laxatives (1,8-dihydroxyanthraquinon
  e and its glycoside derivatives that are
  contained in senna, cascara, rheum (rhubarb) and
  aloe.

70
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).

71
CASTOR OIL

• Unpleasant taste and potential toxicity on
  intestinal epithelium and enteric neurons.

72
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.

73
ADVERSE EFFECTS-STOOL SOFTENERS

• Mild side effects.
• Potential to increase intestinal absorption and
  toxicity of other drugs given concurrently.

74
DOCUSATES

• Prototype for this group.
• Although they produce only mild side effects
  (occasional cramping, rashes, nausea) they have
  potential serious effects.
• Docusate sodium (Colace)

75
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.

76
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.

77
MINERAL OIL

• Elicitation of foreign body reactions in the
  intestinal mucosa.
• Leakage of oil.
• Possibility of lipid pneumonitis.

78
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).

79
LUBIPROSTONE (Amitiza)

• Acts on chloride channels.
• Increases secretion of intestinal fluids.

80
ANTIEMETIC AGENTS
81
DRUG LIST

• Ondansetron
• Metoclopramide
• Aprepitant

82
NAUSEA AND VOMITING

• Follows administration of many drugs.
• Accompany infectious and noninfectious GI
  disorders.
• Early pregnancy.
• Motion sickness.
• Emergence from general anesthesia.

83
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.

84
EMETIC RESPONSE

• Following stimulation of the vomiting center,
  emesis is mediated by various efferent pathways.

85
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).

86
Higher Centers
Memory, fear, dread, and anticipation
Emetic Center
cerebellum
5-HT3
D2
M H1
Solitary tract nucleus
CNS
CTZ
BLOOD BRAIN BARRIER
D2
5-HT3
Periphery
M1
Inner ear
Vagal and sympathetic afferents
Stomach and small int
5-HT3
Sensory Input
Blood born emetics
Glossoph., trigeminal affs.
Local Irritants
Pharynx (gagging)
87
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.

88
NEUROTRANSMITTER PATHWAYS OF EMESIS

• Dopamine acting at D2 receptors is implicated in
  emetic signaling thru the trigger zone and the
  solitary tract nucleus.

89
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.

90
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.

91
EMESIS

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

92
ANTIEMETIC AGENTS

• 5-HT3 antagonists
• D2 antagonists
• NK1 receptor antagonists
• Corticosteroids
• Cannabinoids
• Antihistamines
• Muscarinic antagonists
• Benzodiazepines

93
ANTIEMETIC AGENTS

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

94
COMBINATIONS

• Provide a major improvement in the ability to
  reduce nausea and vomiting.
• Decrease toxicity associated with some
  antiemetics.

95
5-HT3 ANTAGONISTS

• Selective serotonin receptor antagonists

96
5-HT3 ANTAGONISTS

• Ondansetron (Zofran)
• Granisetron (Kytril)
• Dolasetron (Anzemet)
• Palanosetron (Aloxi)

97
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.

98
PHARMACOKINETICS

• Orally, IV or IM.
• Effective upon once daily administration.
• Undergo CYT P450 metabolism.

99
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).

100
ADVERSE EFFECTS

• Transient, mild adverse effects including
  headache, sedation, light-headedness, dizziness
  and constipation.
• Lack extrapyramidal side effects associated with
  metoclopramide.
• Minor EKG changes.

101
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).

102
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.

103
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.

104
D2 ANTAGONISTS

• Phenothiazines
• Domperidone

105
APREPITANT (Emend)

• NK1 receptor antagonist.
• Very useful vs delayed nausea.
• Synergistic with 5-HT3 antagonists.

106
THERAPEUTIC USES

• Used with corticosteroids and serotonin receptor
  antagonists to prevent nausea and vomiting caused
  by highly emetogenic anticancer drugs.

107
ADVERSE EFFECTS

• Fatigue and asthenia
• Hiccups
• Diarrhea and dizziness.

108
CORTICOSTEROIDS

• Mechanism of antiemetic action is not known.
• Possible mechanisms include prostaglandin
  blockage and changes in cell permeability.

109
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.

110
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.

111
CANNABINOIDS (Dronabinol and Nabilone)

• Therapeutic Uses- reduce emesis due to moderate
  emetogenic chemotherapy.

112
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.

113
(No Transcript)
114
(No Transcript)
115
INFLAMMATORY BOWEL DISEASE (IBD)

• Sulfasalazine (Azulfidine)
• Non-sulfonamide containing formulations of
  mesalamine including Olsalazine and Balasalazide
• Infliximab

116
INFLAMMATORY BOWEL DISEASE (IBD)

• Inflammation of the colonic and/or intestinal
  linings.
• Chronic with temporary remissions.
• Familial and infectious components.

117
IBD

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

118
SYMPTOMS

• Diarrhea
• Pain
• Bleeding and related deficiencies.
• Malabsorption

119
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.

120
(No Transcript)
121
TYPES OF DISEASE

• Ulcerative colitis- colon/rectum.
• Crohns disease- extends to small intestine and
  deeper into intestinal walls, fistulas.

122
(No Transcript)
123
TREATMENT OF IBS IS COMPLEX

• Unknown nature of the causative agent.
• Chronic and variable nature of the inflammation.
• Variability in goals of therapy.

124
5-AMINOSALICYLATES
125
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 concns
  in the colon.

126
MECHANISM OF ACTION

• Inhibits prostaglandin and leukotriene synthesis.
• Reactive oxygen scavengers.
• Antiinflammatory effects-inhibits cytokine
  production and immunoglobulin secretion.

127
THERAPEUTIC USES

• Oral use for mild or moderate ulcerative colitis.
• Less certain value for severe colitis (often
  given with steroids).
• Crohns disease is less responsive.

128
ADVERSE EFFECTS

• Fever and malaise.
• Nausea, vomiting,headaches, epigastric discomfort
  and diarrhea.
• Megaloblastic anemia and low sperm counts.
• Allergic reactions.

129
ADVERSE EFFECTS

• Necrolysis, Stevens Johnson syndrome,
  pancreatitis, eosinophilic pneumonia.

130
(No Transcript)
131
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).

132
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.

133
INFLIXIMAB (Remicade)

• Chimeric monoclonal antibody that binds tumor
  necrosis factor (TNF).
• Given by i.v. injection.

134
THERAPEUTIC USES

• Produces and maintains remissions in CD and helps
  promote healing.

135
ADVERSE EFFECTS

• Headache, nausea, and upper respiratory
  infections.
• Allergic reactions
• Immunosuppression.

136
IMMUNOSUPPRESSIVE AGENTS

• Inhibit lymphocyte proliferation.
• Mercaptopurine and azathioprine.
• Cyclosporine and methotrexate are also used.

137
ANTIBIOTICS

• Mainly adjunctive therapy
• Mild to moderate Crohns disease.
• Metronidazole and/or ciprofloxacin.

138
IRRITABLE BOWEL SYNDROME

• Tegaserod (Zelnorm)

139
IRRITABLE BOWEL SYNDROME

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

140
(No Transcript)
141
PATHOPHYSIOLOGY

• Unknown cause.
• Altered GI motility and increased gut
  sensitivity.
• Heightened sensitivity to visceral distention.
• Interplay between motor and sensory dysfunction
  explains many symptoms.

142
SYMPTOMS

• Abdominal pain, bloating and disturbed bowel
  function (diarrhea or constipation or both
  alternating)

143
NONPHARMACOLOGICAL THERAPIES

• Fiber supplements
• Elimination diets followed by sequential
  reintroduction of specific foods.
• Avoidance of dietary excesses, caffeine and
  dietary triggers.
• Psychotherapy.

144
NONSPECIFIC BOWEL-DIRECTED THERAPY

• Measures to reduce specific symptoms related to
  constipation and diarrhea.

145
TREATMENT OF CONSTIPATION

• Fiber supplements
• Magnesium salts
• Phosphate salts
• PEG-based laxatives
• Non-absorbed carbohydrates.

146
ANTIDIARRHEAL AGENTS

• Opiate and opioid analogs

147
Specific Therapies
148
ANTISPASMODICS

• Anticholinergics
• Combined sedatives and antispasmodics

149
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.

150
SSRIs

• Have similar efficacy but lack many of the side
  effects of the TCAs

151
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.

152
ALOSETRON (Lotronex)

• Beneficial in women with IBS who did not have
  constipation.
• Reduces diarrhea and urgency, improved quality of
  life.

153
ADVERSE EFFECTS

• Constipation (25-30).
• Ischemic colitis was diagnosed in 1/700
  patients and the drug was withdrawn. Then
  reintroduced for select patients.

154
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.

155
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.

156
(No Transcript)
157
PROKINETIC AGENTS

• Medications that enhance coordinated GI motility
  and transit in the GI tract.
• Pharmacologically and chemically diverse.

158
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.

159
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.

160
TREATMENT

• Antiemetic phenothiazines
• Bethanechol
• Prokinetic agents-metoclopramide, cisapride and
  domperidone

161
Prokinetic Agents

• Cholinergic agents
• Dopamine receptor antagonists-domperidone and
  metoclopramide.
• Serotonin receptor modulators-cisapride and
  metoclopramide.

162
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

163
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.

164
THERAPEUTIC USES

• Diabetic gastroparesis.
• Esophageal reflux.
• Prevention of nausea and vomiting from a variety
  of causes including pregnancy.

165
ADVERSE EFFECTS

• Extrapyramidal effects.

166
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.

167
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.

168
ADVERSE EFFECTS

• Transient abdominal cramping and diarrhea.
• May increase absorption of diazepam and alcohol.

169
(No Transcript)
170
(No Transcript)