Drugs Acting on GastroIntestinal System.ppt

Drugs Acting on Gastro-Intestinal System
Pharmacotherapy PUD and GERD
Antiemetic Drugs
Agents for constipation
Antidiarrheal agents
Pharmacotherapy OF IBD

1. Drugs Acting on Gastro-
Intestinal System
1

2. Drugs Acting on GIT
•Pharmacotherapy PUD and GERD
•Antiemetic Drugs
•Agents for constipation
•Antidiarrheal agents
•Pharmacotherapy OF IBD
2

3. Drugs used for Peptic Ulcer Disease
(PUD) &
Gastroesophageal reflex disease
(GERD)
3

4. Introduction
•Acid-peptic diseases: gastric acid and pepsin
•Acid and pepsin: inherently caustic→ in the stomach normally do not produce
damage or symptoms because of intrinsic defense mechanisms.
•Barriers to the reflux of gastric contentsinto the esophagus comprise the primary
esophageal defense.
•Stomach: protected by “mucosal defense,” many of which are stimulated by the
local generation of prostaglandins and NO.
4

5. Introduction…
•If these defenses are disrupted, a gastric or duodenal ulcer
may form.
•Rx and prevention of these acid-related disorders are directed at
decreasing gastric acidity, enhancing mucosal defense, enhancing the
lower esophageal sphincter, or stimulating esophageal motility.
•Eradication of Helicobacter pylori needs a different approach
5

6. Physiology of gastric secretion
•Gastric acid secretion is a complex, continuous process in which multiple central
and peripheral factors contribute to a common end point: the secretion of H
+
by
parietal cells.
•Factors that regulate acid secretioninclude:
–Neuronal (acetylcholine, ACh): M
3
–paracrine (histamine):H
2and
–endocrine (gastrin): CCK
2
6

7. Physiology of gastric secretion….
•H
2receptor is a GPCR that activates the Gsadenylylcyclase–cyclic AMP–PKA
pathway.
•AChand gastrin signal through GPCRs that couple to the Gq–PLCIP3–Ca2+pathway in
parietal cells.
•In parietal cells, the cyclic AMP and the Ca2+ -dependent pathways activate H+, K+-
ATPase (the proton pump), which exchanges hydrogen and potassium ions across
the parietal cell membrane.
•This pump generates the largest ion gradient known in vertebrates, with an
intracellular pH of ~7.3 and an intracanalicularpH of ~0.8.
7

8. Fig: Physiological and pharmacological regulation of gastric secretion
8

9. Activators of proton pump
Acetylcholine
•Stimulates M
3 receptors resulting in increase in cytosolic Ca
++
in parietal cells
Gastrin
•Activates gastrin receptros, resulting in increase in cytosolic Ca
++
in parietal cells
Achand Gastrinactivate release of Histamine from Enterochromaffin-like
cells(ECL) which stimulates H
2 Receptors on parietal cells (the main
pathway of proton pump activation)
10

10. Inhibitors of proton pump
Somatostatinthrough somatostatinreceptors
Prostaglandins(Prostaglandins of the E and I type inhibit gastric acid
secretion, stimulate increased mucus and bicarbonate secretion by
gastric mucosa)
Epidermal growth factor
11

11. Mucosal protection
Mechanisms that protect the gastric mucosa from autodigestionof gastric acidity
and peptic enzymes
Mucus secretion
Bicarbonate secretion (surface epithelial cells)
Epithelial barrier
Mucosal blood flow
Prostaglandin synthesis
Favour production of mucus and bicarbonate
Inhibit acid secretion by parietal cells
PGE and PGI improve mucosal blood flow 12

12. Peptic ulcer disease (PUD)
Peptic ulcers are chronic lesions that occur in any portion of the GIT
exposed to the aggressive action of acid-peptic juices.
Causes: three major causes
H. pyloriinfection
NSAID use
Pathologic gastric acid secretion
Rare causes include herpes simplex infection, major physiologic stress (eg,
critical illness, severe burns)
13

13. 14

14. Pathogenesis
Imbalance between gastroduodenalmucosal defence mechanisms and
the damaging forces
Manyfactorscandisruptthebalance
Activationofaggressivefactors
Suppressionofprotectivefactors
H.pyloriisseenasanorganismcapableofdisruptingthisbalance
15

15. Drug groups used in PUD
Proton pump inhibitors
H
2-receptor antagonists
Antacids
Gastric protectants
16

16. Proton pump inhibitors (PPI)
•The most potent suppressors of gastric acid secretion
•In typical doses, PPIs diminish the daily production of acid (basal and
stimulated) by 80-95%.
•Six PPIs are available for clinical use: omeprazoleand its S-isomer,
esomeprazole, lansoprazoleand its R-enantiomer, dexlansoprazole,
rabeprazole, and pantoprazole.
17

17. Proton pump inhibitors (PPI)…
•Omeprazole is a racemic mixture of R-and S-isomers; the S-isomer,
esomeprazole (S-omeprazole), is eliminated less rapidly than R-
omeprazole, which theoretically provides a therapeutic advantage
because of the increased t
1/2.
•Despite claims to the contrary, all PPIs have equivalent efficacyat
comparable doses.
18

18. PPI….
MOA
Prodrugs that require activation in an acidic environment? where?
Absorbed into the systemic circulation and then accumulated in parietal
cell acidic secretory channel
Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide,
trapping the drug so that it cannot diffuse back across the canalicularmembrane
19

19. PPI….
MOA…
Covalent binding with sulfhydryl groups (-SH) of cysteine in the H
+
/K
+
-
ATPase
Irreversibleinactivation of the pump molecule
•Acid secretion resumes only after new pump molecules are synthesized
Have long duration of action (24-48h) despite short t
1/2 of the parent
compound (0.5-2h)
20

20. Fig: Proton pump inhibitors. A. Inhibitors of gastric H +, K+ -ATPase B. Conversion of omeprazole to a sulfenamide in the
acidic secretory canaliculi of the parietal cell….. The other three proton pump inhibitors undergo analogous conversions.
21

21. PPI...
Pharmacokinetics: oral and IV
The prodrugsare unstable in the presence of acid and therefore must be
administered as
Enteric-coated drugs
Powdered drug combined with sodium bicarbonate (e.g., omeprazole)
These drugs ideally should be given about 30 minutes before meals.
Rate of absorption may be reduced by food.
22

22. Table: Pharmacokinetics of proton pump inhibitors.
23

23. PPI...
Pharmacokinetics: oral and IV
The prodrugsare unstable in the presence of acid and therefore must
be administered as
Enteric-coated drugs
Powdered drug combined with sodium bicarbonate (e.g., omeprazole)
These drugs ideally should be given about 30 minutes before meals.
Rate of absorption may be reduced by food.
24

24. PPI...
Once in the small bowel, they are rapidly absorbed, highly protein
bound, and extensively metabolized by hepatic CYPs, particularly
CYP
2C
19and CYP
3A
4
–severe hepatic disease: dose reduction is recommended for
esomeprazole and lansoprazole.
25

25. PPI...
Adverse Effects
Most common: nausea, abdominal pain, diarrhea, flatulence, and constipation.
Sub acute myopathy, headaches, and skin rashes have also been reported.
Frequent, more severe Hypergastrinemia(risk of rebound hypersecretionupon
discontinuation and gastrointestinal tumors)
26

26. PPI...
Drug interactions
Among the PPIs, only omeprazole inhibits CYP
2C
19(thereby decreasing the
clearance of disulfiram, phenytoin, and other drugs) and induces the
expression of CYP1A2 (thereby increasing the clearance of imipramine,
several antipsychotic drugs, and theophylline).
Omeprazole and esomeprazole may decrease the effectiveness of
clopidogrelbecause they inhibit CYP2C19 and prevent the conversion of
clopidogrelto its active metabolite.
27

27. PPI...
Drug interactions…
Prolonged acid suppression with PPIs (and H2antagonists) may result in
low vitamin B
12.
Loss of gastric acidity also may affect the bioavailability of such drugs as
ketoconazole, ampicillin esters, and iron salts.
28

28. PPI...
Therapeutic Uses
To promote healing of gastric and duodenal ulcers and to treat gastroesophageal
reflux disease (GERD)
Treatment of hypersecretoryconditions e.g., Zollinger-Ellison syndrome
Treatment and prevention of recurrence of NSAID-associated gastric ulcers in
patients who continue NSAID use
Reduce the risk of duodenal ulcer recurrence associated with H. pyloriinfections.
In children, omeprazole is safe and effective for treatment of erosive esophagitis
and GERD.
29

29. H
2-Receptor antagonists
Drugs:Cimetidine,Famotidine,Ranitidine,Nizatidine
MOA
ReversibleantagonistsofH
2-histaminereceptorsonparietalcellsblock
histamineinducedstimulationofacidsecretion.
Predominantlyinhibitbasalacidsecretion
efficaciousinsuppressingnocturnalacidsecretion
Prolongeduse,down-regulationofreceptoroccurstolerancetotheseagents
30

30. Fig: Histamine and H
2receptor antagonists
31

31. H
2-Receptor antagonists…
Pharmacokinetics
Rapidlyabsorbedafteroraladministration,whichmaybeenhancedby
foodordecreasedbyantacids.
IVandIMpreparationsofcimetidine,ranitidine,andfamotidinealsoare
available.
Onlysmall%ageofthedrugsareprotein-bound.
32

32. H
2-Receptor antagonists…
Pharmacokinetics
Excretion:renalfiltrationandtubularsecretionoftheparentand
metabolites,metabolisminliver(<10%to35%).
•Doseadjustmentmayberequiredinpatientswithdecreased
creatinineclearance.
•Neitherhemodialysisnorperitonealdialysisclearssignificant
amountsofthedrugs
33

33. Table: Clinical comparisons of H
2–receptor blockers.
34

34. H
2-Receptor antagonists…
Adverse effects
Generally well tolerated (<3% of incidence)
Include diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation.
Less common: confusion, delirium, hallucinations, slurred speech (with IV
administration)
Long-term use of cimetidineat high doses decreases testosterone binding to the
androgen receptor and inhibits a CYP that hydroxylatesestradiol.
oClinically, these effects can cause galactorrheain women and gynecomastia,
reduced sperm count, and impotence in men.
35

35. H
2-Receptor antagonists…
Drug interaction
Cimetidine is a liver enzyme inhibitor (e.g., CYP
1A
2, CYP
2C
9, and CYP
2D
6)and
can increase the levels of a variety of drugs
It interfere with the metabolism warfarin, phenytoin, and clopidogrel
(prodrug).
Ranitidine interferes only minimally with hepatic metabolism of other drugs.
No significant drug interactions mediated by enzyme inhibition with Famotidine
and nizatidine.
36

36. H
2-Receptor antagonists…
Therapeutic Uses.
To promote healing of gastric and duodenal ulcers
To treat GERD
To prevent the occurrence of stress ulcers.
37

37. Tolerance and Rebound with Acid-Suppressing Drugs
Tolerance to the acid-suppressing effects of H
2-receptor antagonists.
Effect of the secondary hypergastrinemiato stimulate histamine release from ECL
cells.
Does not occur with PPI, even with higher hypergastrinemia
Rebound increases in gastric acidity can occur upon discontinuation of
PPI as well as H
2histamine receptor antagonists.
38

38. Anticholinergics
–Pirenzepin??
–Librax®:clidinium bromide + cholorodiazepoxide) (2.5 mg + 5 mg)
39

39. Antacids
The rationale lies in the assumption that buffering of H
+
in the
stomach permits healing.
NaHCO
3
Very water-soluble and rapidly absorbed from the stomach
Alkali and sodium loads may pose a risk for patients with cardiac or
renal failure
40

40. Antacids…
CaCO
3
Release of CO
2from HCO
3
-
-and CO
3
2-
-containing antacids can cause
belching, nausea, abdominal distension, and flatulence.
Calcium may induce rebound acid secretion, necessitating more
frequent administration.
41

41. Antacids…
Magnesium hydroxide
May produce osmotic diarrhea
Excessive absorption of Mg
++
in patients with renal failure may result in toxicity.
Aluminumhydroxide
Its use is associated with relaxation of gastric smooth muscle, producing delayed
gastric emptying and constipation
Serum phosphate levels also may become depressed because of phosphate
binding within the gut.
42

42. Antacids…
Combinations of Mg
2+
(rapidly reacting) and Al
3+
(slowly reacting)
hydroxides provide a relatively balanced and sustained neutralizing
capacity.
Combination of Mg(OH)
2and Al(OH)
3
Magnesium trisilicate alone
•Fixed combinations of magnesium and aluminum theoretically
counteract the adverse effects of each other on the bowel??
43

43. Antacids…
•By altering gastric and urinary pH, antacids may affect a number of
drugs (e.g., thyroid hormones, allopurinol, and imidazole antifungals, by
altering rates of dissolution and absorption, bioavailability, and renal
elimination).
•Al
3+
and Mg
2+
antacids also are notable for their propensity to chelate
other drugs present in the GI tract, forming insoluble complexes that
pass through the GI tract without absorption.
44

44. Antacids…
•Thus it generally is prudent to avoid concurrent administration of
antacids and drugs intended for systemic absorption.
•Most interactions can be avoided by taking antacids 2 hours before or
after ingestion of other drugs.
45

45. Antacids…
•Therapeutic uses:
–Symptomatic relief of peptic ulcer disease and GERD, and
–They may also promote healing of duodenal ulcers.
–They should be administered after meals for maximum effectiveness. WHY?
–Note: Calcium carbonate preparations are also used as calcium supplements for
the treatment of osteoporosis.
46

46. Antacids…
•Adverse effects:
–Aluminum hydroxide tends to cause constipation, whereas magnesium hydroxide
tends to produce diarrhea.
•Preparations that combine these agents aid in normalizing bowel function.
–Absorption of the cationsfrom antacids (Mg
2+
, Al
3+
, Ca
2+
) is usually not a problem
in patients with normal renal function; however, accumulation and adverse
effects may occur in patients with renal impairment.
47

47. Simethicone
•MOA: Changes surface tension of gas bubbles and causes collapse of foam
bubbles, thus allowing easier passage of gas and preventing gas pockets in
gastrointestinal tract
•Use: Gas Retention in Gastrointestinal Tract
•Elimination: Feces (as unchanged drug)
•Adverse Effects: Loose stools has been reported
•Contraindications: Hypersensitivity to simethicone
•Pregnancy:category C
48

48. Misoprostol
An analogue of prostaglandin E
1
Pharmacokinetics
Absorbed rapidly after oral administration and is hydrolyzedto the active
compound
Metabolized by the liver and excreted mainly in the urine.
Adverse effects
Include crampyabdominal pain, dose-related diarrhea, and uterine contractions
49

49. Misoprostol
Therapeutic use: prevention of NSAID–induced ulceration (Prophylactic
use)
oIn patients who are taking NSAIDs and are at moderate to high risk of NSAID-
induced ulcers, such as elderly patients and those with previous ulcers.
oPPIs are preferred agents for the prevention of NSAID-induced ulcers.
Misoprostol is contraindicated in pregnancy, since
oIt can stimulate uterine contractions and cause miscarriage.
50

50. Sucralfate
Is an aluminumhydroxide–sulphated sucrose complex that is only minimally
absorbed from the GIT.
After exposure to gastric acid, the compound becomes negatively charged, creating a
viscous adherent complex, which is believed to inhibit back-diffusion of H
+
.
Also causes direct reduction in pepsin activity and a slight rise in tissue prostaglandin
levels.
It has no acid-buffering capacity.
51

51. Sucralfate…
•Complex of aluminum hydroxide and sulfated sucrose binds to positively
charged groups in proteins of both normal and necrotic mucosa.
•By forming complex gels with epithelial cells, sucralfatecreates a physical
barrier that protects the ulcer from pepsin and acid, allowing the ulcer to
heal.
•It requires an acidic pH for activation
52

52. 53

53. Sucralfate…
Use: Although sucralfateis effective for the treatment of duodenal ulcers and
prevention of stress ulcers, its use is limited due to the need for multiple daily
dosing and drug–drug interactions.
Adverseeffects:
oConstipation, secondary hypophosphatemia (due to the aluminium). Binding to a
number of other coadministeredmedications may result in a significant
reduction in their bioavailability.
oSucralfatedoes not prevent NSAID-induced ulcers, and it does not heal gastric
ulcers.
54

54. Bismuth subsalicylate
•This agent is used as a component of quadruple therapy to heal peptic
ulcers.
•In addition to its antimicrobial actions, it inhibits the activity of pepsin,
increases secretion of mucus, and interacts with glycoproteins in
necrotic mucosal tissue to coat and protect the ulcer
55

55. Drugs against H. pylori
Initial treatment (triple therapy for 7 to 10 days)
Proton pump inhibitor (PPI), standard dose twice daily
Rabeprazole, lansoprazole, omeprazole, pantoprazole, and
esomeprazolein combination with
2 antimicrobials:
Clarithromycin, and
Amoxicillin (or metronidazolefor penicillin allergic patients)
56

56. Alternative treatment and retreatment for patients who failed
initial therapy (14 days)
PPI (twice/once daily), and
Metronidazole (4 times daily), and
Tetracycline (4 times daily), and
Bismuth subsalicylate (4 times daily)
57

57. Summary of Rx of GERD
58

58. Summary of Rx of GERD…
59

59. Summary of Rx of GERD…
60

60. Summary of Rx of GERD…
61
•Non-pharmacologic therapy
Potential lifestyle changes depending on the patient situation:
Elevate head of the bed by placing 6-to 8-in blocks under the headposts. Sleep
on a foam wedge
Weight reduction for overweight or obese patients.
Avoid foods that decrease LES pressure.
Include protein-rich meals to augment LES pressure.
Avoid foods with irritant effects on the esophageal mucosa.

61. Summary of Rx of GERD…
62
•Non-pharmacologic therapy…..
–Eat small meals and avoid eating immediately prior to sleeping (within 3 hours if
possible).
–Stop smoking.
–Avoid alcohol.
–Avoid tight-fitting clothes.
–For mandatorymedications that irritate theesophageal mucosa, take in the
upright Position with plenty of liquid or food (if appropriate).

62. Summary of Rx of GERD…
63

63. 64
Summary of Rx of GERD…

64. Summary of Rx of PUD
65

65. Summary of Rx of PUD….
66

66. Summary of Rx of PUD….
67
•Non-pharmacologic treatment
–Patients with PUD should eliminate or reduce psychological stress, cigarette smoking, anduse of
NSAIDs (including aspirin).
–If possible, alternative agents such as acetaminophen or a nonacetylatedsalicylate (eg, salsalate)
should be used for pain relief.
–Although there is no need for a special diet, patients should avoid foods and beverages that
cause dyspepsia or exacerbate ulcer symptoms (eg, spicy foods, caffeine, andalcohol).
–Elective surgery is rarely performed because of highly effective medical management.
–Emergency surgery may be required for bleeding, perforation, or obstruction

67. Antiemetics
68

68. Nausea: inclination to vomit (feeling in the throat or epigastricregion
alerting that vomiting is imminent)
Vomiting is the ejection/expulsion of gastric content through the mouth.
Are protective reflexes that prevent further absorption from the GIT.
Etiology
GI, CV, Neurologic, metabolic, drug, pregnancy, irritant food/drug, noxious
odours
69

69. Vomiting is mediated by two separate brainstem centres:
•The chemoreceptor trigger zone and the vomiting centre.
•The CTZ may be activated endogenously or exogenously by toxins or drugs such as
opiates.
–It is rich in dopaminergic receptors.
–Activation of the trigger zone stimulates the vomiting center.
•The act of vomiting is controlled by the vomiting center, mainly through vagal action.
–The vomiting center has afferent input from the gut, higher cortical centers and the vestibular
apparatus.
–Muscarinic and histamine H
1-receptors are highly concentrated around the area of the vomiting
center.
72

70. Fig: Pharmacologist’s view of emetic stimuli.
73

71. Neural pathways controlling vomiting

72. Drugs used in treatment of vomiting
Anticholinergics
Antihistamines
Cannabinoids
Centrallyacting Dopamine antagonists
5-HT
3Receptor Antagonists
75

73. Anticholinergics
Drugs: scopolamine(hyoscine)
oHyoscine butylbromideVersus hyoscine hydrobromide?
Used in the prevention and treatment of motion sickness
Use of antihistamine and anticholinergic drugs is limited by sedation,
dizziness, confusion, dry mouth, cycloplegia, and urinary retention.
76

74. Antihistamines
Primarily useful for motion sickness and postoperative emesis
They act on vestibular afferents and within the brainstem.
Drugs: Cyclizine, meclizine, hydroxyzine, promethazine,and Diphenhydramine and
one of its salts, dimenhydrinate.
Meclizine has minimal anticholinergic properties that also causes less sedation.
oIt is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth
dysfunction.
Navidoxone®
77

75. 5-HT
3Receptor Antagonists
Drugs: Ondansetron, Granisetron, Dolasetron, tropisetronand Palonosetron(IV only)
Potent antagonists of 5-HT
3receptors, on peripheral vagal nerve terminals and centrally
in the CTZ.
During chemotherapy that induces vomiting, mucosal enterochromaffincells in the GIT
release serotonin, which stimulates 5-HT
3receptors. This causes vagal afferent
discharge, inducing vomiting.
78

76. 5-HT
3Receptor Antagonists ….
Are the most widely used drugs for chemotherapy-induced emesis.
Also used to prevent or treat post-operative/radiationnausea and
vomiting
Adverse effect: headache, dizziness, and constipation (most frequently
reported)
They also cause a small but statistically significant prolongation of the
QT interval, but this is most pronounced with dolasetron.
79

77. 5-HT
3Antagonists in Chemotherapy-Induced Nausea/Emesis
DRUG CHEMICAL NATURERECEPTOR INTERACTIONS T
1/2 DOSE (IV)
Ondansetron Carbazole derivative5-HT
3antagonist and weak 5-
HT
4antagonist
3.9 hours 0.15 mg/kg
Granisetron Indazole 5-HT
3antagonist 9-11.6 hours10 ug/kg
Dolasetron Indole moiety 5-HT
3antagonist 7-9 hours 0.6-3 mg/kg
Palonosetron Isoquinoline 5-HT
3antagonist; highest
affinity for 5-HT
3receptor in
this class
40 hours 0.25 mg
Ramosetron Benzidazolylderivative5-HT
3antagonist 5.8 hours 300 ug/kg
80

78. Centrally acting Dopamine antagonists
Phenothiazinessuchaspromethazine?,prochlorperazineandchlorpromazineare
amongthemostcommonlyused
Principalmechanismofaction:dopamineD
2-RantagonismattheCTZ.
oTheyalsodecreasevomitingcausedbygastricirritants,suggestingthatthey
inhibitstimulationofperipheralvagalandsympatheticafferents.
Alsopossessantihistaminicandanticholinergicactivities
Sedationfrequentlyoccurfollowingtheiradministration.
81

79. Dopamine antagonist…
Metoclopramide
MOA
It is a prokineticagent
Central dopamine receptor
antagonism (CTZ).
5-HT
4-receptor agonism,
Vagal and central 5-HT
3-antagonism
Sensitization of muscarinic receptors
on smooth muscle
Results in coordinated contractions
that enhance transit.
Increases lower esophagealsphincter
tone
Stimulates antraland small intestinal
contractions.
82

80. Metoclopramide….
Pharmacokinetics
Absorbed rapidly after oral ingestion,
Metabolism in the liver and excreted principally in the urine, with a half-life of 4 to 6
hours.
Therapeutic Use.
Metoclopramide is effective in most causes of vomiting, apart from motion sickness.
•The usual dose is 10 mg 8-hourly, orally or parenterally
Gastroesophagealreflux disease
In gastroparesis(improvements of gastric emptying)
83

81. Metoclopramide…
Adverse Effects
Extrapyramidal effects, parkinsonian-like symptoms, Like other dopamine
antagonists.
•They can be treated with an intravenous anticholinergic agent, such as benzotropine.
Metoclopramide also can cause galactorrheaby blocking the inhibitory effect of
dopamine on prolactin release.
84

82. Dopamine antagonists….
•Butyrophenones: Droperidoland haloperidolact by blocking dopamine receptors.
•They are moderately effective antiemetics.
•Droperidolhad been used most often for sedation in endoscopy and surgery, usually
in combination with opioids or benzodiazepines.
oHowever, it may prolong the QTcinterval and should be reserved for patients with inadequate
response to other agents.
•High-dose haloperidol was found to be nearly as effective as high-dose
metoclopramide in preventing cisplatin-induced emesis.
85

83. Canabinoids
Dronabinolis 
9
-tetrahydrocannabinol (THC), is the major psychoactive
chemical in marijuana.
The antiemetic site of action is unknown; appears to affect the central
cerebral cortex axis
Also has appetite stimulant effect
From the marijuana plant, Cannabis sativa
86

84. Dronabinol…
Pharmacokinetics
THC is a highly lipid-soluble absorbed readily PO
Extensive first-pass metabolism with limited systemic bioavailability (10% to 20%).
Therapeutic Use
Prophylactic agent in patients receiving cancer chemotherapy when other
antiemetic medications are not effective. (legislation ????)
Appetite stimulate in patients with acquired immunodeficiency syndrome (AIDS)
and anorexia.
87

85. Dronabinol…
Adverse Effects
Palpitations, tachycardia, vasodilation, hypotension
Euphoria, detachment, dizziness, anxiety, paranoid reactions and thinking
abnormalities.
Nabiloneis a closely related THC analog.
88

86. Others antiemetic drugs….
Corticosteroids
–Mechanism of action not clear
–May be related to blockage of PGs
•Dexamethasone
•Prednisone
Benzodiazepines
–Good for anticipatory nausea and vomiting before cancer therapy
•Diazepam-typical dose is 2-5mg, once or twice/day
•Lorazepam-typical dose is 0.5mg BID
89

87. Potency of anti-emetic drugs
•Active against highly emetogenic chemotherapy
–Ondansetron
–Metoclopramide
•Active against mildly or moderately emetogenic chemotherapy
–Phenothiazinesegchlorpromazine
–Corticosteroids eg. Dexamethasone
–Butyrophenoneseg. haloperidol
–Cannabinoidseg. Dronabinol
•Minimally active
–Antihistamines( eg. prometazine)
–Benzodiazepines(eg. lorazepam)

88. Combination regimens: Antiemetic drugs
91
Fig: Effectiveness of antiemetic activity of some drug combinations against emetic episodes
in the first 24 hours after cisplatin chemotherapy.

89. 92

90. Summary: Anti-emetic drugs
•Anti-cholinergic agents
•Dopamine antagonists
–substituted benzamides:
metoclopramide
–butyrophenones: haloperidol
–phenothiazines: chlorpromazine
•H1 antihistamines
•Corticosteroids: prednisolone
•Benzodiazepines: lorazepam
•5HT
3blockers: ondansetron
•Cannabinoids

91. Drugs Used in The
Treatment of
Constipation
94

92. Constipation
Fluid content is the principal determinant of stool volume and consistency;
Net stool fluid content reflects a balance between luminal input (ingestion and
secretion of water and electrolytes) and output (absorption) along the length of the
GI tract.
Neurohumoralmechanisms, pathogens, and drugs can alter the balance changes
in either secretion or absorption of fluid by the intestinal epithelium.
Decreased motility excess fluid removal constipation.
When the capacity of the colon to absorb fluid is exceeded, diarrheawill occur
95

93. Constipation…
Normal stool frequency on a Western diet is at least 3 times a week
Decreased frequency, difficulty in initiation or passage, passage of firm or small-
volume feces, or a feeling of incomplete evacuation.
Causes
Lack of dietary fiber, drugs, hormonal disturbances, neurogenic disorders, and systemic
illnesses.
In most cases no specific cause is found.
96

94. Laxativescause the evacuation of formed fecalmaterial from the rectum
while
Catharticscause evacuation of unformed, usually watery fecalmaterial
from the entire colon.
The evacuantaction of alaxativeis less pronounced, but large doses of
alaxativemay produce catharsisorpurgation.
–Cathartic,laxativeandpurgativedrugs will be referred to aslaxatives.
97

95. LAXATIVES
•Laxatives are commonly used for constipation to accelerate the movement of food
through the GI tract.
•These drugs can be classified on the basis of their mechanism of action though
many work through more than one mechanism.
•Laxatives increase the potential for loss of pharmacologic effect of poorly absorbed,
delayed-acting, and extended-release oral preparations by accelerating their transit
through the intestines. They may also cause electrolyte imbalances when used
chronically. Many of these drugs have a risk of dependency for the user
98

96. 99

97. Laxatives
1. Stool-surfactant agents (Stool softeners)
–Docusatesalts
Anionic surfactants that lower the surface tension of the stool mixing of
aqueous and fatty substances, soft stool and easy defecation.
Also stimulate intestinal fluid and electrolyte secretion (possibly by increasing
mucosal cAMP) and alter intestinal mucosal permeability.
Docusate sodiumand docusate calcium
100

98. 2. Lubricant laxatives
Mineral oil and glycerine suppositories
Mineral oil: mixture of aliphatic hydrocarbons,
are indigestible.
On oral administration, the oil penetrates and softens the stool, retarding water
absorption from the stool.
Mineral oils should be taken orally in an upright position to avoid its aspiration
and potential for lipid or lipoid pneumonia.
Unwanted effects: interference with absorption of fat-soluble substances (such
as vitamins A,D,E,K), lipid pneumonitis due to aspiration.
101

99. 3. Osmotic laxatives
Saline Laxatives/NonabsorbableSalts
Laxatives containing magnesium cationsor phosphate anions:
Magnesium sulfate, magnesium hydroxide (milk of magnesia), magnesium
citrate, sodium phosphate.
Osmoticallymediated water retention stimulates peristalsis.
Other mechanisms
•Production of inflammatory mediators.
•Mg
++
containing laxatives stimulate release of cholecystokinin intraluminal fluid
and electrolyte accumulation and increased intestinal motility.
102

100. 3. Osmotic laxatives
Magnesium-and phosphate-containing preparations: generally
well tolerated.
Use with caution or avoided in patients with renal insufficiency,
cardiac disease, or pre-existing electrolyte abnormalities
When taking these agents, it is very important that patients
maintain adequate hydration
103

101. Non-digestible Sugars and Alcohols
Sorbitoland mannitolhydrolyzedto short-chain fatty acids 
osmoticallydraw water into the lumen stimulate colonic propulsive
motility.
In the treatment of constipation caused by opioids and vincristine,of
constipation in the elderly, and of idiopathic chronic constipation.
Abdominal discomfort or distention and flatulence.
104
Osmotic.. (cont’d)

102. Lactulose(synthetic disaccharide of galactose and fructose
that resists intestinal disaccharidaseactivity)
Lactulose is also used for the Rx of hepatic encephalopathy, due
to its ability to reduce ammonia levels.
105
Osmotic.. (cont’d)

103. Osmotic… (cont’d)
Polyethylene Glycol-Electrolyte Solutions
Long-chain polyethylene glycols(PEGs): poorly absorbed, and retained in the
lumen.
Used widely for colonic cleansing for radiological, surgical, and endoscopic
procedures
To avoid net transfer of ions, preparations contain isotonic mixture of sodium
sulfate, sodium bicarbonate, sodium chloride, and potassium chloride.
Is designed so that no significant intravascular fluid or electrolyte shifts occur.
Therefore, they are safe for all patients.
Should be ingested rapidly (2–4 L over 2–4 hours) to promote bowel cleansing.
106

104. 4. Stimulant (Irritant) Laxatives
Have direct effects on enterocytes, enteric neurons, and GI smooth
muscle.
Mechanisms: activation of prostaglandin-cAMPand NO-cyclicGMP
pathways
Drugs: diphenylmethanederivatives, ricinoleicacidand
anthraquinones
107

105. Stimulant Laxatives (cont’d)
DiphenylmethaneDerivatives
Phenolphthalein, Sodium picosulfate, Bisacodyl
Bisacodyl(tablet and suppository)
for acute and chronic constipation.
also used in conjunction with PEG solutions for colonic cleansing prior to
colonoscopy.
induces a bowel movement within 6–10 hours when given orally and 30–60
minutes when taken rectally.
It has minimal systemic absorption and appears to be safe for acute and
long-term use.
Phenolphthaleinwas removed from the market owing to concerns about
possible cardiac toxicity.
108

106. Stimulant Laxatives (cont’d)
AnthraquinoneLaxatives
Derivatives of plants aloe, cascara,and senna
Chronic use leads to a characteristic brown pigmentation of the colon known as
"melanosiscoli.“
These laxatives are poorly absorbed and after hydrolysis in the colon, produce a
bowel movement in 6–12 hours when given orally and within 2 hours when given
rectally.
109

107. Stimulant Laxatives (cont’d)
Castor Oil
Castor oilis derived from the bean of the castor plant, Ricinuscommunis
contains ricin(extremely toxic protein) and a triglyceride ricinoleicacid.
The triglyceride is hydrolyzedinto glycerol and ricinoleicacid stimulates
secretion of fluid and electrolytes and speed intestinal transit.
110

108. 5. Chloride Channel Activator
•Lubiprostone
–Prostanoicacid derivative
–labeled for use in chronic constipation and irritable bowel syndrome (IBS) with
predominant constipation
–acts by stimulating the type 2 chloride channel (ClC-2) in the small intestine.
oThis increases chloride-rich fluid secretion into the intestine, which stimulates intestinal
motility and shortens intestinal transit time
111

109. Opioid Receptor Antagonists
•Chronic therapy with opioids may cause constipation by decreasing intestinal
motility
•These effects are mainly mediated through intestinal mu (m)-opioid receptors
•Selective antagonists of mopioid receptor methylnaltrexoneand alvimopan
•Do not readily cross the blood-brain barrier, they inhibit peripheral -opioid receptors
without impacting analgesic effects within CNS
•Methylnaltrexoneis approved for the treatment of opioid-induced constipation
112

110. Serotonin 5-HT
4-Receptor Agonists
•Stimulation of 5-HT
4receptors on the presynaptic terminal of submucosalintrinsic
primary afferent nerves enhances the release of their neurotransmitters, including
calcitoningene-related peptide (CGRP), which stimulate second-order enteric
neurons to promote the peristaltic reflex.
•enteric neurons stimulate proximal bowel contraction (via acetylcholine and
substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal
peptide).
113

111. Serotonin 5-HT
4-Rec….
•Tegaserod
–serotonin5-HT
4partial agonist that has high affinity for 5-HT
4receptors but no
appreciable binding to 5-HT
3or dopamine receptors
–for the treatment of patients with chronic constipation and IBS with predominant
constipation
–Removed from the market (serious CVS events, b/c of inhibition of the 5-HT
1B
receptor)
•cisapride: Another partial 5-HT
4agonist, also associated with CVS events
•Prucaloprideis a high-affinity 5-HT
4agonist that is in clinical development.
114

112. Antidiarrheal Agents
115

113. Diarrhea
" too rapid evacuation of too fluid stools."
Since stool weight is largely determined by stool water, most cases of diarrhea
result from disorders of intestinal water and electrolyte transport.
Increased osmotic load within the intestine
Excessive secretion of electrolytes and water into the intestinal lumen
Exudation of protein and fluid from the mucosa
Altered intestinal motility resulting in rapid transit (and decreased fluid
absorption).
Severe diarrheadehydration and electrolyte imbalances 116

114. Oral rehydration therapytherefore is a cornerstone for patients with
acute illnesses resulting in significant diarrhea.
Pharmacotherapy of diarrheashould be reserved for patients with
significant or persistent symptoms.
These agents should not be used in patients with bloody diarrhea, high
fever, or systemic toxicity because of the risk of worsening the
underlying condition.
117

115. 1. Bulk-Forming and Hydroscopic Agents
Hydrophilic and poorly fermentable colloids or polymers such as
carboxymethylcelluloseand calcium polycarbophil
Absorb water and increase stool bulk
The mechanism is not clear, but they may work as gels to modify stool texture
and viscosity and to produce a perception of decreased stool fluidity.
Some of these agents also may bind bacterial toxins and bile salts.
118

116. Bulk-Forming....
Clays such as kaolinand other silicates such as hydrated magnesium
aluminum silicate (attapulgite)bind water avidly and also may bind
enterotoxins.
Pectinis an indigestible carbohydrate derived from apples.
Charcoal plays the same role as kaolin
119

117. 2. Bile Acid Sequestrants.
Cholestyramine, colestipol,and colesevalambind bile acids and some bacterial toxins.
In the treatment of bile salt-induced diarrhea
3. Bismuth.
Bismuth subsalicylate + HClBismuth oxychloride(unabsorbable) + Salicylic acid
Mechanism of action remains poorly understood.
Has antisecretory, antiinflammatory, and antimicrobial effects.
Nausea and abdominal cramps also are relieved by bismuth.
Use for the prevention and treatment of traveller'sdiarrhea
120

118. Antimotilityand AntisecretoryAgents
Opioids
Effects mediated through m-or -opioid receptors on enteric nerves,
epithelial cells, and muscle
Effects on intestinal motility (mreceptors), intestinal secretion (receptors),
or absorption (mandreceptors).
Commonly used: diphenoxylate, difenoxin,and loperamideact principally via
peripheral m-opioid receptors and are preferred over opioids that penetrate
the CNS.
121

119. Loperamide
Has m-receptor activity, is an orally active antidiarrheal agent.
40 to 50 times more potent than morphine as an antidiarrheal agent and
penetrates the CNS poorly.
It increases transit times, increases anal sphincter tone, has antisecretoryactivity
(against cholera toxin and some forms of E. colitoxin, ingcAMP)
Loperamide: as adjunct in almost all forms of chronic diarrheal disease.
It lacks significant abuse potential
Overdosagecan result in CNS depression (especially in children) and paralytic
ileus.
122

120. FIGURE 23–1. Recommendations for treating acute diarrhea.124

121. Fig: Recommendations for treating chronic diarrhea.
125

122. Thank you
127