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Gastro-intestinal Pharmacology
1.
2. ďDrugs for Peptic Ulcer and Gastroesophageal Reflux Disease
ďAntiemetic, Prokinetic and Digestant Drugs
ďDrugs for Constipation and Diarrhoea
3.
4. ď Too frequent, often too precipitate passage of poorly formed stools
ďś WHO defined:- 3 or more loose or watery stools in a 24 hrs. period
ďś âfrequency of stool + consistency (watery stool)
ďś Occurs due to passage of excess water & Electrolytes in faces
ďś Dehydration-most common cause of death in diarrhea
Cause:-
ď â electrolyte and water absorption
ď â secretion by intestinal mucosa
ď â luminal osmotic load
ď Inflammation of mucosa and exudation into lumen
9. ď Absorption:-
ď Inhibition of Na+K+ ATPase and structural damage to mucosal cell by Rota virus
causes diarrhoea by reducing absorption
ď Secretion:-
ď Excess of bile acids also cause diarrhoea by activating adenylyl cyclase
ď Prostaglandins, Intracellular Ca++ also stimulate secretory process
ď Cholera toxin, Enterotoxigenic E. coli(ETEC) , Staph aureus, Salmonella
stimulate adenylyl cyclase- increasing secretion
ď GI motility:-âsegmentation + âperistalsis
-:Pathophysiology:-
10.
11. Treatment should always be directed according to underlying cause.
-most diarrhea-self limiting
Rehydration therapy
Drug therapy
I.V. Oral
# severe
fluid loss >10% BW
Oral rehydration therapy
12. ď The recommended composition of i.v. fluid
Composition:-
Nacl-5gm (85mM)
Kcl-1gm (13mM) in 1L of water or 5%
NaHCO3-4gm (48mM) glucose solution.
ď Volume equivalent to 10% BW should be infused over 2-4 hours
Dhaka Fluid:-
13. ď ORS therapy is the core of management of acute diarrhoea(mild-5-7%
BW/moderate-7.5-10% BW)
ď A mixture of salts and water
ď Purpose:-
ď To correct water electrolyte deficient
ď To prevent dehydration
ď Reduce mortality
ď Advantages:-
ďSimplest, safest, least expensive life saving method
ORS-Therapy
14. ď Improved form of ORS with addition of certain actively transported amino
acids like alanine, glycine
ď Glucose is replace with boiled rice powder
ď Advantages:-
ďś enhanced absorption
ďś decrease frequency of diarrhoea
ďś less chance of osmotic diarrhoea in high dose also
# it has been found to reduce stool volume compared to WHO-ORS in cholera
15. ď Mainly in children below 5 yr. age
ď Zn+ORS-âseverity of acute diarrhoea
ď Zn supplement cont. for 10-14days
ď Mechanism:-
1. âfluid secretion in intestine by inhibiting cAMP dependent Cl-
transport
2. improve immune response
and help regeneration
of intestinal epithelium
Roll of Zinc in diarrhoea
16. Diarrhoea patients
ď Watery Stool Without mucus or blood
ď Frequent vomiting,
ď Periumbilical cramps,
ď No fever
Causative organism:- (non-invasive enterotoxigenic bacteria)
include
ď Cholera,
ď ETEC,
ď Salmonella enteritidis,
ď Staph. aureus,
ď Bacillus cereus
ď Rota virus
ORS and not Antimicrobials
ď Watery Stool + mucus / blood
ď No vomiting,
ď Abdominal cramps
ď Mild dehydration with fever
Causative organism:- (entero-invasive
organisms) include
ď Shigella,
ď Enteropathogenic E. coli (EPEC),
ď Campy jejuni,
ď Salmonella typhimurium,
ď Yersinia enterocolitica,
ď E. histolytica,
ď Clostridium difficile
Antimicrobials
Non-invasive diarrhoea Invasive diarrhoea
Infective gastroenteritis
19. WHO:- âLive micro-organisms which when administered in adequate amounts
confer a health benefit on the hostâ
ď Microbial cell preparations, Live cultures or lyophillised powder
ďE.g.-Lactobacillus sp, Bifidobacterium bifidum, Strep.faecalis, Enterococcus sp.,
Saccharomyces b
ď Advantages:-
1. Restore and maintain healthy gut flora
2. Recolonization of the gut by non-pathogenic mostly lactic acid forming
bacteria
ďś Use:-Acute infectious diarrhoea, Antibiotic-associated diarrhoea,Travellers
diarrhoea, ulcerative colitis, relief in bloating and flatulence
#curd/yogurt is an abundant source of lactic acid producing organisms, which can
serve as probiotics.
Probiotics
20. ďAbsorbed Water & â stool bulk
ďModify consistency & frequency of stool
ďNo action on water electrolytes loss
Eg.- Ispaghula , Psyllium, methylcellulose
USE:-
ďśIrritable bowel syndrome
ďśDuring ileostomy
ďśColostomy diarrhea
ďśBile salt induced diarrhea-Cholestyramine
22. ďś Use:- Acute secretary diarrhoeas
ďś Use In children
ďś SE:- Nausea, Vomiting, flatulence, Drowsiness
Bismuth Subsalicylate
ďśAnti-secretory
ďśAnti-inflammatory
ďśAnti microbial effects(H. pylori)
Action:- â PG synthesis in intestinal mucosa
âCl- secretion
use:- Travellerâs diarrhoea (prophylaxis)
23. ď Antispasmodic actions
ď â bowel motility and secretion
ď Used in drug induced diarrhoea
ď Provide some symptomatic relief in dysenteries
ď They may beneficial in drug induced diarrhoeas
ď Atropine- used in nervous(stress induced) & drug induced diarrhoea
Anti- cholinergics
24. ď Synthetic octapeptide analogue of Somatostatin
ď Longer acting-t1/2-90min
ď Action-
ď Potent anti- secretory & antimotility action on the gut.
ď It Suppresses hormone (gastrin, cck, glucagon secretin, pancreatic polypeptide, vasoactive
intestinal peptide, and 5-HT) which enhance intestinal mucosal secretion
Use:-
ďś control diarrhoea in carcinoid
ďś Refractory diarrhoea in AIDS pt.(S.C.)
ďś higher doses diarrhoea due to vagotomy or dumping syndrome
ďś pancreatic fistula
SE:-nausea, abdominal pain, flatulence
Octreotide
25. Anti-motility drugs
ďThese are opioid drugs acting through Îź-receptor(enteric neuronal network)
ďOnly symptomatic relief in diarrhoea
ďź Opioid receptor Action:-
ď δ receptor action- secretion
ď Îź receptor action- propulsive movement
Advantages:-
ďâ tone & segmenting activity of the bowel
ďâpropulsive movement & intestinal secretion
ďNo tolerance develops to constipating action
ďśAnti- motility drugs not to be given in infective diarrheas
26. ď Codeine-Prominent constipating action at 60 mg TDS
ď MOA:-Îź-receptor agonist-âPeristalsis
ď Central effect
ď Side effects: nausea, vomiting, dizziness
ď Not been used due to abuse potential
Codeine
27. ď synthetic opioid, chemically related to pethidine
ď Most prominent antidiarrheal agent
ď Produced opioid dependence
ď Atropine is added in sub pharmacological dose to discourage abuse (dryness of
mouth-unpleasant which masks the euphoria produce by Diphenoxylate)
ď (2.5 mg diphenoxylate + 0.025 mg atropine)-FDC
ď The anticholinergic properties of atropine may contribute to the antidiarrheal
action
ď Contraindication:-
ď below 6 year of age- respiratory depression, paralytic ileus and toxic megacolon
in children
Diphenoxylate
28. ď Semisynthetic opioid analogue
ď Major peripheral Îź-opioid action+ Weak anti- cholinergic property
ď Most effective, suitable antimotility antidiarrheal agents
ď Acts on Îź-opioid receptor on circular+ longitudinal muscle fibers-inhibit
propulsive movement
ď Advantage:-
1) As antimotility agent-40 time more potent than morphine
2) Poor CNS penetration-no abuse liability
3) Longer duration of action (12hr)
4) âanal sphincter tone, antisecretory property
5) interaction with calmodulin receptor-inhibition
Loperamide
29. ď USE:-traveler diarrhoea
ď Adverse effects:- abdominal cramps and rashes
ď Contraindicated:-
ď Children age < 4 yrs.:- paralytic ileus occur
ď Infective diarrhea- delays clearance of pathogen by producing constipation
may also produced disastrous symptoms
30. ď US-FDA approve minimally absorbed oral rifamycin
ď Active against-E. coli
ď It is as effective as ciprofloxacin
ď Less side effect due to poor absorption
ď Used-
1.empiric treatment of âtravellers diarrhoeaâ
2.hepatic encephalopathy
3.IBS, before & after gut surgery
Side effect:- flatulence, abdominal pain, defecation urgency and headache
Rifaximin
31. Inflammatory bowel disease
ďGroup of Auto-immune disease in which intestine becomes inflamed
ďOccurs due to imbalance b/w pro-inflammatory & anti-inflammatory cytokines
ďmajor 2 types 1. Crohnâs disease 2.Ulcerative colitis
Drugs
5-amino salicylic acid
compound
Sulfasalazine
Mesalazine
Balsalazide
Olsalazine
Glucocorticoids
Prednisolone
Hydrocortisone
(enema)
Immunosuppressants
Azathioprine
Methotrexate
Cyclosporine
TNF inhibitor
infliximab
33. ďśToo infrequent passage of stool that may be due to decrease motility of
colon or due to difficulty in evacuation
ď low stool frequency alone is not the sole criterion for the diagnosis of
constipation.
ď Many constipated patients have a normal frequency of defecation but complain of
excessive straining
ď hard stools,
ď lower abdominal fullness, or a sense of incomplete evacuation
Introduction
34. ďśGeneral measures:-
ďźAdequate fluid intake
ďźHigh fiber contents in diet
ďźRegular exercise
ďźRegulation of bowel habit
ďźAvoid drug causing constipation are best to avoid constipation
According to intensity of action:-
Laxatives Purgatives
ďMilder action
ďSoft stool formation
ďStronger Action
ďMore fluid evacuation
37. Mechanism:-
â Bulk of intestinal content by water absorption
â Mechanical pressure on the wall of intestine
(mechanical distension)
Stimulate of stretch receptors
âperistalsis
(Promote defecation)
38. Caution:- large amount of water to be taken along with bulk purgatives
to avoid intestinal obstruction
USES:-
ďIrritable bowel syndrome-
ďź Functional bowel disorder associated by characteristic clusters of symptoms in
the absence of detectable structural abnormalities in GIT motility
Contraindication:-
Megacolon ,
Megarectum ,
gut ulceration
Side effect:-
Abdominal discomfort ,flatulance
39. Dietary fibers
ď Consists of âunabsorbable cell wall +(cellulose, gums, pectin's)
ď Residual product of flour industry
ď Facilitates colonic transit-absorbs water & âH20 content of stool in intestine
ď Support bacterial growth âcontribute to faecal mass
ď Certain DF (gums,pectins,lignins )-binds bile acid & promote there excretion in
faeces
ď USES-
ď Functional constipation
ď Constipation-(irrespective of improving straining of stools)
40. -:Ispaghula:-
ďObtain from seed of Plantago ovata
MOA:-
ďśThey contain natural colloidal mucilage which forms a gelatinous mass
by absorbing water
ďśLargey fermented in colon â increase bacterial mass & softens the
faeces
Dose:- Ispaghula hask(3-8g)+ water (OD/BID)
Should not swallowed dry- cause esophageal impaction
42. ďDrugs â water content in large intestine
ďMost powerful & rapidly acting purgative
-:Types:-
ďOrganic purgatives:-
Lactulose:-
ďsemi-synthetic disaccharide of fructose & lactose
ďNeither digested nor absorbed in small intestine-retains water
Osmotic purgative
Organic purgatives
(sugars)
Non-Organic purgatives /
Saline purgatives
43. MOA:-
Lactulose
â
After fermentation by colonic bacteria convert to Lactic acid & acetic
acid
â
Reduces luminal pH in the colon
â
NH3 NH4
+ (unabsorbed)
â
Blood ammonia level decrease
44. USES:-
ďLiver cirrhosis/Hepatic coma:- â NH3 Absorption by converting into
NH4
+(Ammonium ion)
ďHepatic encephalopathy
ďConstipation in children & pregnancy
Non-Organic purgatives /Saline purgatives
ďSalts of Mg,Na,K
ďE.g.-MgS04-epsonâs salts
ďMgO-(milk of magnesia)
ďSodium phosphate
45. Mechanism:-
Osmotic purgatives are given orally, early morning on empty stomach with plenty of water
â
Acts on the small & large intestines(within 1-3 hr)
â
Not absorbed in the gut
â
Draw fluid into the lumen by osmotic activity
â
Distend the bowel
â
Stimulate peristalsis
â
Evacuation of watery stools in 1-3 hrs
46. ⢠They should be avoided in young children & pt with renal failure-as
they may cause CNS & cardiac depressant
⢠Sodium phosphate- commonly used in colonoscopy
⢠Can also be used as enema
⢠Should be avoided in cardiac pt.
Polyethylene glycol-
Used to evacuate the bowel prior to surgical, Radiological and endoscopic
procedure
47. Stimulant or Irritant purgatives
ď Acts via direct stimulation of enteric nervous system
ď Leading to peristalsis & purgation
ď Also âPG and cAMP levels but Na+,K+-ATPase activity in the intestinal mucosa
ď Site of action-colon
ď They cause evacuation âsemi fluid stools
ď SE:- upon chronic use-atonic colon
ď Large doses may cause loss of fluid & electrolytes
ď contraindicated- pregnancy(reflex stimulation of uterus)
E.g.-Bisacodyl, anthraquinone derivatives, castor oil
48. Bisacodyl Anthraquinone derivatives
ďAvailable- rectal n tab form
ďOral absorption-poor
ďPreferred-at bed time(Effect seen
after-6-8hrs of admist.)
ďUses:-
Constipation & empty the bowel before
endoscopy,surgery,radiological
investigation
SE:-local irritation,
Inflammation
ďSenna & cascara
ďPreferred-at bed time(Effect seen
after-6-8hrs of admist.)
ďActs locally & induce purgation
ďContraindicated in-lactating mother
as they secret by milk
ďSE:- skin rashes, black pigmentation
of colonic mucosa, discoloration of urine
49. Fecal softeners (lubricants)
Or Stool wetting agents
ďNon-absorbed drugs that soften the feces-promoting defecation
1. Surfactants- â surface tension of faces
ďCommonly prescribed-hospitalized pt to minimized straining
ďe.g.-Docudate-sodium dioctyl sulfosuccinate/Enema
2.Glycerin(suppository)- given twice after surgey to avoid any damage to
the surgery.
Preferred- children
ďMineral oil-(liquid paraffin) good for radiology preparation
50. CHOICE & USES OF PURGATIVES
1.Functional constipation-
a. Spastic Constipation(Irritable bowel)- dietary fibers
b. Atonic constipation âBulk purgatives
2. Bedridden pt-bulk purgatives
3.To avoid straining at stools-bulk purgatives ,luctolose
4.Preparation of bowel for surgery, colonoscopy-bisacodyl
51. Emetics & Anti emetics
⢠Vomiting:- it is a complex series of protective reflex that help to remove toxic
substances from the gastrointestinal tract (GIT)
⢠It is the forceful expulsion of the contents of the stomach and upper intestinal
tract through the mouth
⢠Nausea:- the feeling of vomiting (âgastric tone & peristalsis)
⢠Vomiting center-Reticular formation in medulla
⢠Stimulation of this center occur from cerebellum, cerebral cortex, CTZ, Nucleus
tractus solitarius(NTS)
⢠CTZ-unprotected by BBB
⢠Neurotransmitter:-involve in control of vomiting are acetylcholine (ACh),
histamine,5-hydroxytryptamine (5-HT) and dopamine
53. Emetics:-
⢠Drugs that cause vomiting-emetics
⢠Uses:-
ďź Acute case of poisoning
ďźAlcohol intoxication
ďźRemoval of foreign bodies from oesophagus
⢠Contraindication of emetics:-
ďźIn poisoning of any corrosive (danger of perforation)
ďźCNS stimulant (precipitation of convulsion)
ďźKerosene poisoning (Aspiration pneumonia due to low viscosity)
ďźMorphine or phenothiazine overdose (emetics are ineffective)
ďźIn unconscious pt.(laryngeal reflex impaired.)
54. ⢠Apomorphine:-
⢠Semisynthetic derivatives of morphine
⢠Acts as dopaminergic agonist on CTZ
⢠Induce vomiting (within 5-10min) after administered I.M./S.C.
⢠Ipecacuanha:-
⢠Obtained from root of plant Ipecacuanha
⢠Contains emetine which is used as syrup
⢠Produce CTZ stimulation & gastric mucosal irritation
⢠Household remedy:- Mustard oil, strong salt solution can be use in emergency
⢠They act through stimulation of receptor in stomach
ďDrug induced vomiting:-
ďAnti-cancer drug, Apomorphine, chloroquine, quinine, Diltizem, ergot
derivatives, tetracycline, metronidazole
56. Anti-cholinergic
⢠Drugs:- Hyoscine (Scopolamine),dicyclomine
⢠Used as transdermal patch in motion sickness
⢠Not effective-chemotherapy induced vomiting
⢠SE:-tachycardia, blurred vision, constipation, urinary retention
⢠Dicyclomine-effective in morning sickness + motion sickness
⢠Safe to use in pregnancy
⢠Anti-spasmodic action-use for colicky pain
⢠MOA:- Central anti-cholinergic, peripheral antimuscarinic & sedative properties
⢠USES:- effective against morning sickness, postoperative vomiting, motion
sickness, morning sickness, Meniere's disease
H1-Antihistaminics
57. ⢠They are less effectiveâ substance induce vomiting by acting directly on CTZ
⢠Cyclizine, Meclizineâ (long acting) use for sea sickness
⢠Cinnarizine â Anti-vertigo drug. Additional action. i.e. inhibit influx of Ca++
from endolymph into the vestibular sensory cells which mediate labyrinthine
reflex.
⢠Morning sickness in pregnancy-(Doxylamine+VitB6) safe drug
⢠In motion sicknessâ should be given half to one hour before journey
⢠These should be avoided in first trimester of pregnancy to avoid any foetal
damage
5-HT3 Receptor Antagonists
ďDrugs:- Ondansetron, granisetron, dolasetron and palonosetron.
ďMOA:- block the depolarizing action of 5-HT3 receptors or vagal afferents in
GIT as well as in CTZ & NTC
ďIt blocks emetogenic impulses both of central & peripheral origin
58. ⢠Advantage:- highly effective(DOC) for anti-cancer drug induced vomiting such
as cisplatin
⢠Disadvantage:- not effective for motion sickness
⢠Ondansetron:- prototype drug with short duration of action
⢠5HT3 receptor Antagonist
⢠Pharmacokinetics:-
⢠Absorption-orally with BA of 70% (due to First pass metabolism)
⢠Distribution- through out the body
⢠Metabolism-(hepatic metabolism + glucuronide conjugation)
⢠Excretion-urine
ďUses:-
ďźChemotherapy(cisplatin) induce vomiting-I.V. infusion
ďźPost operative vomiting
59. ⢠SE:- constipation, headache, rashes, hypotension
⢠Neuroleptics (D2-receptor Antagonist):-
⢠Antiemetic effect â blockade of D2-receptors in the CTZ
⢠D2 blocked in gut ââgut motility
⢠Drugs:-phenothiazines, haloperidol
⢠Advantages:- antipsychotic action+ potent Anti-emetic action
⢠Disadvantages:-
ďźNot effective â Motion sickness (Muscarinic & Histaminic receptors involve)
ďźCause Extra pyramidal side effect (EPS)
ďźProchlorperazine:-D2 blocking phenothiazine
ďźAntivertigo and antiemetic actions- labyrinthine suppressant
ďźEffective-Orally + i.v. preparation
60. Prokinetic Agents:-
⢠Agents which âpropulsive gastric motility in coordinated manner to promote
gastric emptying
⢠Metoclopramide:-
⢠Prokinetic action due to 5-HT4 Agonist activity in GIT (Peripheral action)
⢠Central actionâD2 blocked in CTZ
⢠Cumulative effect result in-ââgastric and duodenal emptying
⢠The effects of metoclopramide on the upper GI tract are:
1.âtone of lower oesophageal sphincter (LES).
2. âtone and amplitude of antral contractions.
3. Relaxation of pyloric sphincter.
4. âperistalsis of small intestine.
Thus, it promotes forward movement of contents in the upper GIT.
61. Metoclopramide
5-HT4 agonism D2-antagonism 5-HT3 antagonism
ââACh secretion from the myenteric motor neurons
Peristalsis
ď Pharmacokinetics:-
ď Absorption:-well absorbed orally
ď Distribution- cross âBBBâ-produce EPS (not seen with domperidone)
ď Plasma t1/2-4-6hr.
ď Metabolism-sulfation & glucuronide conjugation in liver
ď Excretion-urine
62. ⢠USES:-
ďąVomiting due to
ďźdrug induced, Radiation induced,
ďźPost operative, Toxins induced
ďąPost operative paralytic ileus, diabetic gastroparesis
ďąGERD- but less effective than PPI or H2 blockers
ďąEmergency surgery-as pt. May not be empty stomach (before GA)
ďSE:- sedation, drowsiness, dizziness and diarrhoea, EPS
ďLong-term use âgynaecomastia, galactorrhoea and menstrual irregularity
ďInteraction:-
ďMetoclopramide ĂDiazepam- âabsorption of diazepam(Toxicity)
ďMetoclopramide ĂDigoxin-âabsorption of Digoxin (therapeutic failure)
ďMetoclopramide Ălevodopa- interfering anti-parkinsonian effect(due to D2 blocked action )
63. Domperidone:-
⢠Similar anti-emetic action of metoclopramide
⢠Donât cross âBBBâ-No EPS âpreferred in children
⢠Prokinetic actionâdue to blocked of D2 receptor
⢠less potent and less efficacious than metoclopramide
⢠Pharmacokinetics:-
⢠Absorption-orally effective but low BA (High first-pass metabolism)
⢠Distribution- Cant cross BBB
⢠Plasma t1/2-7-8hr
⢠Metabolism-liver
⢠Excretion- urine
⢠USES:-
⢠Vomiting in children
⢠levodopa induced vomiting in Parkinson pt.
⢠Drug induce vomiting-mild-moderate case
64. ⢠Not effectiveâ sever vomiting, Morning sickness
⢠SE:-
⢠Hyperprolactinaemia-D2 blocked action (Pituitary devoid of BBB)
⢠Dryness of mouth,
⢠diarrhoea, headache,
⢠skin rashes, galactorrhoea and menstrual irregularities
⢠Dose-adult-10-40mg children-0.3-0.6mg/kg(TDS)
ďMosapride:-5-HT4 agonist
ďNeurokinin-1 receptor blockers:- Aprepitant
ďThese are substance-P antagonist that acts by blocking neurokinin-1 receptor
ďDOC-delayed chemotherapy induce nausea & vomiting
ďUse for PO nausea & vomiting
65. Adjuvant Antiemetics
⢠Glucocorticoids:-
⢠Dexamethasone, betamethasone and methylprednisolone are used as adjuvant
antiemetics.
⢠USES:-
ďźAnticancer drug-induced vomiting:- in combination with ondansetron or
metoclopramide due to anti-inflammatory action by blocking PG synthesis
ďBenzodiazepines:- (sedative, amnesic and antianxiety effects)
ďLorazepam and alprazolam are used to control psychogenic and anticipatory
vomiting.
66. Question paper:-
Q1. Write short notes on:- (2.5M)
ď Metoclopramide (2.5M)
ď Prokinetic Agents(3M/2.5M)
ď Antiemetics-(3M)
ď Ondansetron (3M)
Q2.Discuss the pharmacological basis of :-
ďOndansetron in vomiting (3M)
ďMetoclopramide as prokinetic agent(3M)
ďDomperidone as antiemetic(3M)
Q3.Discuss treatment of:- Vomiting (3M)
68. ⢠Acid peptic disease â includes
ďźPeptic ulcer
ďźGERD-gastroesophageal reflex disease
ďźZollinger-Ellison syndrome (ZE-syndrome)-pathological hypersecretory states
induced by gastrin secreting tumour
ďUlcerâ occur in any part of GIT due to imbalance between aggressive(acid,
pepsin, and H.pylori infection) & defensive mucosal factor (gastric mucosa,
bicarbonates, prostaglandins)
ďPeptic ulcer- stomach & duodenum expose to acid(HCl) & pepsin
Factors affecting HCL secretion
Factor âAcid secretion
ďź Acetylcholine
ďź Histamine
ďź Gastrin
Factor âAcid secretion
ďź PGE2
ďź somatostatin
69. ⢠Mucosal barrier:-
⢠Consist of âmucous & bicarbonate (HCO3-) secreted by neck cells of gastric
gland & surface of mucosal cells
⢠Function:-
ďźProtection of GI-tract from infective, chemical, physical agents
ďźIt encloses the gastric juice in stomach (impermeable porcelain vase)
ďźHCO3- is trapped in mucous gel together help in maintaining the pH gradient
of
ďśLuminal side-pH (1-2)
ďśSurface of epithelial cells-pH(6-7)
⢠PGsâ stimulate mucous+HCO3 secretion & also âmucosal BF
⢠Epithelial protection also involve though tight junction that serve as a physical
barrier
⢠HCL(gastric acid)âsecreted from gastric parietal cells due to stimulation of
proton pump (H+/K+ ATPase pump)
70. ⢠Physiology of Gastric secretion:-
⢠The stomach secretes -2â3 L of gastric juice/day.
⢠The chief or peptic cells secrete pepsinogen,
⢠Pepsinogen pepsin
⢠Parietal or oxyntic cells secrete acid and intrinsic factor (IF).
⢠Regulation of gastric acid secretion:-
⢠Receptor mediated binding of Ach(M3), histamine(H2), gastrin(CCK2) in the
activation of protein kinaseâ stimulate proton pump to secrete H+ ions in
exchange for K+ into the lumen of stomach
⢠A Cl- channel couple chloride efflux to the release of H+
⢠In contrast receptor binding of PG E2 & somatostatin diminish gastric acid
production
Gastric acid
73. ⢠Gastric Anti-secretory Drugs:-
⢠H2 Receptor Blocker(Anti-Histaminics):-
⢠Drugs:-Cimetidine, Ranitidine, Famotidine, Roxatidine
ďCimetidine is the prototype drug and was the first H2-blocker to be used in clinical
practice
ďMOA:-Competitively block H2 receptor on parietal cellsââAcid production
ďâNocturnal acid secretion (histamine mediated) more effectively than acid
secretion stimulated by gastrin,Ach-most effective for duodenal ulcer
ďFamotidine-higher dose-blocks Non-Competitively
ďPPI Preferred over H2 blockers due to Side effect & potency
ďPharmacokinetics:-
ďźAll absorbed orally-food doesnât interfere with absorption
ďźLowest BA-Famotidine(40%) & highest BA-Nizatidine(>90%)
ďźCimetidine-Cross BBB produces CNS side effects especially in elderly patients
74. ďźT1/2-1.5-4hr. Duration of Acting-6-12hr.
ďźExcretion âurine
ďźCimetidineânot use due to First pass metabolism & antiandrogenic effect
ďźAnti-androgenic effect-
ďźreversible gynecomastia in maleââprolactin release (higher dose)
ďźMenstrual irregularities and galactorrhoea in women
ďźCimetidineĂ Phenytoin, digoxin, theophylline, warfarin, propranolol
(Cimetidine -enzyme inhibitor of Cytochrome-P450-may cause toxicity)
ďźFamotidine-Most potent + longest Acting drug
ďźless Side effect(Anti-androgenic effect) & less drug interaction
USES:-
ďDuodenal ulcer, gastric ulcer, stress induce ulcer, ZE syndrome, GERD
75. Proton pump inhibitors:-
ďDrugs:-Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole
ďIrreversible inhibit H+K+ATPase pump(proton pump) plays an important role in
the final step of gastric acid secretion
ďOmeprazole is the prototype drug
ďMOA:- PPI(Prodrug)
â
Activated in Acidic medium in canaliculi of parietal cells into sulfenamide
â
Active form react with sulfhydryl group(-SH) in H+K+ATPase
ââ
Irreversible inhibit proton pump
(Inhibit gastric acid secretion)
76. ⢠Pharmacokinetics:-
⢠Absorption:-PPIâ degraded in Acidic pH of stomach (except-Pantoprazole)
⢠âBA-when taken with food (should be taken empty stomach/Enteric coated
gelatine capsule)
⢠Omeprazole+NaHCo3âcombination therapy (âpH of stomachâ prevent
degradation)
⢠Distribution-Highly bound to plasma protein
⢠They hv shorter t1/2-1-2hr but action last for more than 24hr.due to irreversible
inhibition (hit & run drug)
⢠Metabolism-sulfation by liver cytochrome-P-450(CYP3A4,CYP2C19)
⢠Excretion-urine
⢠Lansoprazoleâ most potent, safe in pregnancy
⢠Pantoprazole, esomeprazole, lansoprazoleâ can be given I.V. route
⢠Rabeprazoleâ fastest onset of Action
77. ď USES:-
1. Peptic ulcer:-
ďPPI âPreferred over H2-blockers due to rapid onset of action & ulcer healing.
ďomeprazole is 20 mg and lansoprazole is 30 mg once daily.
ďDuodenal ulcers- require 4-weeks therapy and gastric ulcers require 6â8-weeks
therapy for healing.
ďIn acute bleeding ulcers-I.V. PPIs are preferred. (Pantoprazole)
ďH. pylori-associated ulcers:- triple & quadruple therapy (Lansoprazole)
ďStress ulcers (Curling ulcer):- Prophylactic use of oral omeprazole /i.v.PPI
ďNSAID-induced ulcers:- PPIs are more effective
ď2. GERD-DOC-PPI(Esomeprazole most effective)
ď3. ZollingerâEllison syndrome (ZâE syndrome):- PPI âDOC for Higher doses
of PPIs are needed for healing of ulcers. Surgery is the definitive treatment.
78. ⢠SE:-
ďUncommon-safe drug in short term use
ďLong term therapy-
ďźSever hypocholorhydria
ďźHypergastrinemia-include gastric hyperplasia
ďźâabsorption of Vit-B12
ďźRisk of hip fracture-âCa++ absorption
Interaction:-
⢠Omeprazole Ă Diazepam, phenytoin, warfarinâ
⢠PPI inhibit metabolism (CYP2C19) leading to âplasma levels (interaction rare
with pantoprazole, rabeprazole)
79. Anti-cholinergic:-
⢠Drugs:- Pirenzepine,Telenzepine
⢠MOA:- Inhibit M1 receptor in intramural ganglia, histamine secreting cells,
gastric parietal cells
⢠âacid secretion at doseâthat have minimal effect on heart, eye, bladder
⢠Oral efficacy equal to anti-histaminic(cimetidine) action in healing gastric &
duodenal ulcer
⢠SE:-dry mouth, blurring of vision
⢠Low efficacy
⢠side effects
Not commonly use
ď Prostaglandin analogues:- Drug-Misoprostol-PGE1 Analogue orally effective
ď Action-
ďź Inhibit Acid secretion
ďź Promote âHCO3 secretion
80. ďźCytoprotective action-
ďReinforce mucus layer by âphospholipid content of surface epithelium &
âmucosal BF
⢠USES-
⢠NSAID-induced gastric and duodenal ulcersâ Producing cytoprotective
⢠SE:-Nausea, diarrhea, abdominal cramp, dysmenorrhea
⢠Contraindication-
⢠Pregnancy-promote abortion (Abortifacients)
⢠Weak bases that neutralize GA (They donât â Acid production )
⢠âpH of gastric contents (optimum peptic activity between pH 2-4)
⢠Major roleâ to provide prompt relief from ulcer pain
Neutralization of Gastric acid (Antacids)
81. ďAn ideal antacid:-
ďź should be insoluble and capable of neutralizing acid.
ďźshould not liberate CO2
ďźshould be nonabsorbable
ďźshould not disturb the acidâbase balance of the body
ďTypes:- Systemic(absorbed from GIT),Local (poorly absorbed)
ďSystemic antacids:-
ďSodium bicarbonate (NaHCO3):-
ďWater soluble short acting rapidly neutralizes gastric acid
Disadvantages :-
ďśHighly Water soluble & rapidly dissolve from gut
ďśpH raise above 7 cause alkalosis & CO2 accumulation in stomach
ďśRelease CO2 cause belching & gastric distension(perforation of ulcer can occur)
82. ďContraindicated in chronic cardiac failure pt.ââNa+ load cause water retention
ďSodium citrate:- Action similar to NaHCO3 but no CO2 production
ďUse to treat systemic acidosis
ďLocal Antacids:-
⢠Drugs:- Magnesium hydroxide, Magnesium trisilicate, Aluminum hydroxide, Calcium
carbonate
⢠Insoluble in water are poorly absorbed.
⢠formed chloride salt in stomach which react with bicarbonate
⢠HCO3¯ is not available for absorption, hence, there is no systemic alkalosis -no acid
base disturbance
⢠Combination of antacids produces various beneficial effects.
⢠1. Aluminum salts cause constipation and magnesium salts cause diarrhea; so
combination of these two can counteract the adverse effects of each other.
⢠2. Magnesium hydroxide has a rapid onset of action, but aluminum hydroxide acts
slowlyâthe combined product produces rapid and sustained effect.
⢠3. Dose of individual antacid is reduced; hence systemic toxicity is minimized.
83. ⢠SE of antacids:-
⢠1. NaHCO3-cause systemic alkalosis and sodium overload.
⢠2. Magnesium hydroxide- cause diarrhoea.
⢠3. Aluminium hydroxide may produce constipation and phosphate depletion.
⢠4. Calcium carbonate may produce hypercalcaemia and hypercalciuria.
⢠5. Acid rebound can occur
⢠Drug interactions:-
⢠Antacids à iron, tetracyclines, fluoroquinolones, ketoconazole
(Antacids â absorption of those drug by forming complex)
⢠These drugs forms a cover over ulcer surface
⢠Drugs- Sucralfate, Colloidal bismuth subcitrate (CBS)
Ulcer Protectives
84. ⢠Sucralfate:-
⢠It is a complex of aluminium hydroxide and sulphated sucrose.
⢠MOA:-
⢠In the acidic environment of the stomach (pH <4)
Sucralfate
undergoes polymerization to form a sticky gel
Which bind to protein & glycoprotein in the ulcer
Form a protective coating which acts as barrier to acid, pepsin & bile salt
(Ulcer protecting action)
ďCytoprotective effect byââPG release, âmucus & HCO3- secretion (âmucosal defence)
Acidic medium (pH-4)
Stomach
85. ⢠Sucralfate à Antacids-(for action acidic medium require)
⢠Sucralfate Ă digoxin, tetracyclines, ketoconazole, fluoroquinolonesâ
sucralfateâabsorption of these drugs (to be taken 2hr after the consumption of
these drugs )
⢠Minimal absorption-orally
⢠Should be given empty stomach & 1hr before meal
⢠Contraindication-Chronic renal insufficiency- Al toxicity occur
⢠SE:-constipation, Nausea
⢠Colloidal bismuth subcitrate (CBS):-
ďźMost commonly used oral bismuth preparations
ďźMOA:-
ďźReact with protein in the base of the ulcer and protect it from peptic digestion.
ďźStimulate the secretion of PGE2, mucus and bicarbonate.
ďźEffective against H. pylori along with tetracycline, metronidazole etc.
86. ⢠SE:-Nausea, vomiting, blackening of the tongue and stools
⢠H.Pylori infection:-
⢠Helicobacter pylori, a gram-negative, helical rod-shaped bacteria, is associated
with gastritis, duodenal ulcer, gastric ulcer and gastric carcinoma
⢠Bacteria Residing in deeper portion of mucus gel between mucus layer &
epithelium
⢠H.pylori produced urease which convert urea â NH3
⢠Developing countries-80% population infected
⢠Transmission occurâ contaminated water & food
⢠Diagnosis-biopsy urease test
⢠Single Antibiotic regimen â ineffective
⢠The objectives of combination therapy:-
⢠To prevent or delay the development of resistant organism.(relapse)
⢠Promote rapid ulcer healingâby eradicating H.pylori infection
88. Question paper
⢠Q1. Write Drug treatment of: - H. Pyroli infection
⢠Q2. Write short notes on:- (2.5M)
ď Omeprazole (2.5M)
ď Proton pump inhibitors (5M)
⢠Q3. Briefly describe drug treatment of any:- Peptic ulcer
⢠4.Discuss the following: -Therapeutic use of Clarithromycin in peptic ulcer (3M)
⢠5.Describe the following: - Proton pump inhibitors (2.5 M)
⢠6.Discuss the pharmacological basis of the use of: (5M)
ď Omeprazole in peptic ulcer
ď Sucralfate in peptic ulcer
ď Antacids in GERD
ď 7. Classify drugs used for treatment of peptic ulcer. Discuss mechanism of action, uses and
adverse effects of proton pump inhibitors