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GI DRUGS

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Title: 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
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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
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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
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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
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114
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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
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121
TYPES OF DISEASE
  • Ulcerative colitis- colon/rectum.
  • Crohns disease- extends to small intestine and
    deeper into intestinal walls, fistulas.

122
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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
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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.

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IRRITABLE BOWEL SYNDROME
  • Tegaserod (Zelnorm)

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

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

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

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

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NONSPECIFIC BOWEL-DIRECTED THERAPY
  • Measures to reduce specific symptoms related to
    constipation and diarrhea.

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

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ANTIDIARRHEAL AGENTS
  • Opiate and opioid analogs

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Specific Therapies
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ANTISPASMODICS
  • Anticholinergics
  • Combined sedatives and antispasmodics

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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.

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

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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.

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

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

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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.

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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.

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

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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.

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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.

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

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

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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

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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.

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

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ADVERSE EFFECTS
  • Extrapyramidal effects.

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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.

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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.

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

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