Pharmacology in
Gastrointestinal Medicine
SJARIF ISMAIL
Lab. Farmakologi FK-UNMUL
Pharmacology in Gastrointestinal Medicine
Drug for acid-
acid-peptic disease Antiemetik Laxatives
Motility promoter Antidiarrheals
Metoklopamide,
Metoklopamide, Central acting Bulk-
Bulk-forming laxatives.
domperidon,
domperidon, dopamine antagonists Stool surfactant agents
cisapride.
cisapride. H1 blockers Osmotic laxatives
Cholinomimetic.
Cholinomimetic. Muscarinic antagonist Stimulant laxatives.
Macrolide 5-HT3 antagonists Prokinetic drugs
motilin Cannabinoid,
Cannabinoid, CS
Antacids. H2 blockers Opioid antagonists.
Antisecretory agents PPIs Kaolin & pectin.
Mucosal protectants Muscarinic Antimuscarinic
Antisecretory agents that antagonist Bile salt binding resin
enhance mucosal defenses Colloid bimuth compounds
antibiotics Octreotid
1
PATHOGENESA PEPTIC ULCER
H. PYLORI
ZES NSAIDs
ALTERED
MUCOSAL
DEFENCE
ACID &
PEPSIN
MUCOSAL DAMAGE
ULCER
Pathogensis of peptic ulcer
2
Defensive factors:
Mucus: forms barriers and protect underlying
cells from attack of acid and pepsin
Bicarbonate: secreted by epithelial cells of
stomach and duodenum; neutralize any
hydrogen ions that penetrate the mucus
Blood flow: sufficient blood flow to cells
maintain mucosal integrity
Prostaglandins: stimulate secretion of mucus
and bicarbonate, promote vasodilation which
help submucosal blood flow, suppress
secretion of gastric acid.
5
Aggressive factors:
H. pylori- bacteria that colonize in the
stomach and duodenum
NSAIDs- inhibit biosynthesis of PG;
- decrease submucosal blood flow;
- promote gastric acid secretion.
Gastric acid: form peptic ulcer by :
1) injuring cells of GI mucosa, and
2) activating pepsin (a proteolytic enzyme)
Pepsin: injure unprotected cells.
Smoking: delays ulcer healing. 6
3
HP contributes
to gastric mucosal
injury by:
1. Direct mechanism.
2. Alteration in the
immune /
inflammatory
response.
3. Hypergastremia
leading to increased
acid secretion.
NORMAL
Hypergastremia
leading to
increased acid
secretion
4
Membrane phospholipids
PLA2
Arachidonic acid
COX-1 COX-2
Constitutively expressed Induced at inflam.
inflam. site
NSAIDs
•Produced Pg for: •Produced Pg for:
GI mucosal Pain & inflammation
Mitosis & growth
integrity Bone formation
Platelet agregation Regulation of female
Renal function reproduction
Synthesis PG from arachidonic acid
Causes of damage to the GIT
mucosal barier & treatment
Cause of damage Treatment
H. pylori infection Antibiotik + PPIs or H2 Antagonis
Increased acid Reduced by PPIs or H2 Antago or PG
Reduced thickness of Prostaglandin & sucralfate stimulate
mucus layer mucus secretion
Reduced bicarbonate Prostaglandin & sucralfate stimulate
Increase in type Increase stomach pH, Al2+ salt or
pepsin sucralfate
Decrease mucosal Increase prostaglandins, sucralfate,
sucralfate,
blood flow increase blood flow
NSAIDs-
NSAIDs-induced NSAIDs withdrawal or COX-
COX-2 selective
ulcer erosion or substitute with an NSAIDs with a
potential low erosion potential + PG analog
5
Drug therapy: Goals
1. To alleviate symptoms
2. To promote healing
3. To prevent complications
4. To prevent recurrences
Classes of Antiulcer Drugs
Antisecretory agents
Mucosal protectants
Antisecretory agents that
enhance mucosal defenses
Antacids
Antibiotics
6
Food
13
Classes of Antiulcer Drugs
Antisecretory agents
Drugs:
1. H2 (histamin-2) receptor antagonists
Cimetidine
Ranitidine
Famotidine
Nizatidine (axid®),
Mechanism of action:
Suppress acid secretion by blocking
H2 receptors on parietal cells
7
H2-RECEPTOR ANTAGONISTS
The most prominent effects:
basal acid secretion and less
(but still significant) on
stimulated
Cimetidine, ranitidine,
famotidine, nizatidine
Pharmacokinetics, price & doses
Cimetidin Ranitidin Famotidin Nizatidine
Bioavailability (%) 80 50 40 >95
Half-life (hours) 1-3 2-3 3-4 1.5
Duration of action 6 8 12 8
Potency (x) 1 5-10 32 5-10
Inhibits P-450 enzyms Yes Less No No
Elimination Renal Renal/liver R /biliary Renal
Antiandrogenic effects Yes No No No
Effects on serum alcohol Increase Increase No Increase
Interferes with renal tubular Yes No No No
secretion of creatinine
Usual dose for acute 800 mg hs or 300 mg hs or 40 mg hs or 300 mg hs or
duodenal or gastric ulcer 400 mg bid 150 mg bid 20 mg bid 150 mg bid
Usual dose for gastro- 800 mg bid 150 mg bid 20 mg bid 150 mg bid
esophageal reflux disease
Maintenance of duodenal or 400-800 mg hs 150-300 mg hs 20-40 mg hs 150-300 mg hs
gastric ulcer
Price (MIMS vol 6, Rp.100,-/200mg tab. Rp.450,-/150mg tab. Rp.140,-/20mg tab. Rp.4.800,-/150mg
Rp. 1.600 /amp Rp.1.000,-/300mg tab. Rp.220,-/40mg tab. cps
2005) Rp. 3.300 /amp
Rp. 16.300,- /amp
8
H2-RECEPTOR ANTAGONISTS
IN PEPTIC ULCER
A single dose of H2 blocker is
seldom adequate.
In the treatment of duodenal
ulcer, it is the suppression of
overnight gastric acidity that
is most closely correlated
with the therapeutic effect of
H2 blockers.
Side effects H2-RECEPTOR ANTAGONISTS:
Most of these interactions are of purely
pharmacokinetic interest.
Ranitidine might also bind to hepatic
cytochrome-P450, but the affinity for this is
much lower than it is for cimetidine , aman
untuk wanita hamil.
Famotidine, which has the highest affinity for
the H2 receptor, does not bind to
cytochrome-P450 and no important drug
interactions have been described, aman
untuk wanita hamil.
Nizatidine binds weakly to the right hepatic
microsome, but no significant drug
interaction has been reported.
9
Cimetidine exerts a weakly
antiandrogen effect and has rarely
been associated with
gynecomastia and diminished
libido in male patients. Reduction
in sperm counts and reversible
impotence (in long term use of
cimetidine)
Aman untuk wanita hamil
Classes of Antiulcer Drugs
Antisecretory agents
Drugs:
2. Proton pump inhibitors (PPI)
Lansoprazole, Esomeprazole (Nexium®)
Omeprazole , Rabeprazole (Pariet®)
Pantoprazole belum beredar
Mechanism of action:
Suppress acid secretion by inhibiting
noncompetitif & irreversible proton
pump H+, K+- ATPase
10
Proton Pump Inhibitors
These medications are similar agents
which are a reversible inhibitor of the
H+K+-ATPase which is found in the
secretory canaliculi of the parietal
cells.
Unlike the H2 blocker, the proton
pump inhibitor effectively inhibits
meal-stimulated acid secretion during
the day as well as basal secretion
overnight.
The proton pump inhibitors have been
shown to have higher overall healing rates in
many trials, where they have been shown to
be better than H2 blockers; for instance,
Omeprazole 20 mg has been shown to heal
about 73% of gastric ulcers after four weeks
and 89% after eight weeks of treatment.
Tidak aman untuk wanita hamil, kecuali
lansoprasol
11
Pharmacokinetics:
Unstable at a low pH enteric coated
granule/tablet
Prodrug, requiring activation in an acid
environment (parietal cell) with or
before meal
Side effects:
Cyt P450 inhibitor
Hypergastrimenia: promote tumor
rebound hypersecretion
of gastric acid
Omeprazole Lansoprazole Esomeprazole Rabeprazole
Bioavailability (%) 40-65 80-90 50-89 52
Half-life (hours) 0.5-1 1.5 1.2 0.7-2.0
T max (hours) 1-3.5 1-1.7 1.5 2.0-5.0
Area Under Curve 0.2-1.2 1.7-5 4.2 (20mg 0.8
dose)
12.6 (40mg
dose)
Elimination Hepatic Hepatic Hepatic Hepatic
metabolism metabolism metabolism metabolism
Inhibits P-450 Yes Less Less Less
enzyms
Usual dosage for 20 mg qd 30 mg qd 20-40 mg qd 20 mg qd
peptic ulcer or GER
Maintenance 20 mg qd 30 mg qd 20 mg qd 20 mg qd
therapy
Price (MIMS vol 6, Rp.2.100,- Rp.2.200,- Rp.10.600,- Rp.7.200,-
2005) /20mg cps /30mg cps /20mg tab /10mg tab
12
Classes of Antiulcer Drugs
Antisecretory agents
Drugs:
3. Muscarinic antagonists
Pirenzepine (gastrozepine®)
Price Rp. 4.000/25mg tab
Mechanism of action:
Suppress acid secretion by blocking
muscarinic cholinergic receptors
Other Antiulcer Drugs
Antisecretory agents that
enhance mucosal defense
Drugs:
Misoprostol (cytotec®, Price: Rp.8.000
/200mcg tab & Gastrul® Rp.7.000/200mcg)
Mechanism of action:
Protects against NSAID-induced ulcers by:
Stimulating secretion of mucus and
bicarbonate,
Maintaining submucosal blood flow, and
Suppressing secretion of gastric acid.
13
Misoprostol
is the only synthetic prostaglandin derivative to
have been introduced into clinical practice for
management of acid-related disorders.
The structure comes from a prostaglandin–E1
The synthetic prostaglandin-E derivative has
been shown to be inferior to ranitidine in
maintenance treatment of patients with healed
duodenal ulcers.
SE : It is associated with a high incidence of
diarrhea. The diarrhea is usually mild.
Contraindicated during pregnancy
Pharmacokinetics Misoprostol
Onset of action : 30 minutes.
Food and antacids decrease the
absorbtion of misosprostol
14
Other Antiulcer Drugs
Mucosal protectants
Drugs:
Sucralfate (Musin®
Musin® Price: Rp.900/500mg tab,
tab,
Syrup: Rp.26.500/120ml 500mg/5ml;
Ulsanic®
Ulsanic® Rp.
Rp. 1.700/500mg tab, Rp.3.000/1g tab;
Ulsidex®
Ulsidex® Rp.1.000/500mg tab, Rp. 1.500/1g tab;
Ulsicral®
Ulsicral® syrup Rp.
Rp. 27.500/ 100ml, 500mg/5ml)
Mechanism of action:
Forms a barrier over the ulcer crater that
protects against acid and pepsin
Sucralfate
Complex synthetic salt of sucrose and aluminum
octasulfate.
In the presence of acid, sucralfate forms an insoluble
amorphous complex that has the ability, in animal
studies, to adhere to ulcerated tissue.
Stimulation of local prostglandin production
Inhibit the hydrolisis of mucosal protein by pepsin
It forms a protective coating of the ulcer that might
prevent further acid peptic digestion, and this might
persist for 12-
12-16 hours after administration.
Common side effect is constipation
Aman untuk wanita hamil
15
Other Antiulcer Drugs
Antacids
Drugs:
Aluminum hydroxide, Calcium
carbonate, Magnesium hydroxide
Mechanism of action:
React with gastric acid to form neutral
salts.
Taking antacids : 2 hours before or after
ingestion of other drugs
Antacids
Composition :
CaCO3 neutralize HCL rapidly ,
unpredictable effects on gastrointestinal
motility, hypercalcemia
AL(OH)3 Sustained neutralizing capacity,
relax gastric smooth muscle (delayed gastric
emptying and constipation), osteoporosis,
encephalopathy. Tidak aman untuk wanita
hamil
Mg(OH)2 sustained neutralizing capacity
but opposed delayed gastric emptying and
constipation)
16
33
Classes of Antiulcer Drugs
Antibiotics
Drugs:
One-Drug regimens eradikasi <40%
Two-Drug Regimens eradikasi <60%
Three-Drug Regimens eradikasi <85%
Four-Drug Regimens eradikasi >90%
Mechanism of action:
Eradication of H. pylori infection
17
The recommendation of the
consensus of the National
Institute of Health was that:
Ulcer patients with H. pylori
infection reguire treatment with
antimicrobial agents in addition
to antisecretory drugs wheter
on first presentation of the
ilness or on recurrence
Eradication therapy for
H.pyroli:
TRIPLE THERAPY:
PPI1 + Amoxicillin4 + Clarithromycin5
PPI1 + Amoxicillin4 + Metronidazole6
PPI1 +Metronidazole6+Clarithromycin5
Bismuth2+Metronidazole6+Tetracyclin7
PPI1 +Metronidazole6+Clarithromycin5
18
QUADRIPLE THERAPY:
PPI1 + Bismuth2 + Metronidazole6 +
Tetracycline7
PPI1: omeprazole 40 mg or 20 mg bid,
lansoprazole 30mg, pantoprazole 20mg,
rabeprazole 20 mg qd.
Bismuth subcitrat2 120 mg qid.
Amoxicillin4 1000 mg bid or 500 mg tid.
Clarithromycin 150 mg bid.
Metronidazole 500 mg qid.
Tetracycline 500 mg qid
Comparison drug regimens use to eradicate H. pylori
19
39
Pharmacology in Gastrointestinal Medicine
Drug for acid-
acid-peptic disease Antiemetik Laxatives
Motility promoter Antidiarrheals
Metoklopamide,
Metoklopamide, Central acting Bulk-
Bulk-forming laxatives.
domperidon,
domperidon, dopamine antagonists Stool surfactant agents
cisapride.
cisapride. H1 blockers Osmotic laxatives
Cholinomimetic.
Cholinomimetic. Muscarinic antagonist Stimulant laxatives.
Macrolide 5-HT3 antagonists Prokinetic drugs
motilin Cannabinoid,
Cannabinoid, CS
Antacids. H2 blockers Opioid antagonists.
Antisecretory agents PPIs Kaolin & pectin.
Mucosal protectants Muscarinic Antimuscarinic
Antisecretory agents that antagonist Bile salt binding resin
enhance mucosal defenses Colloid bimuth compounds
antibiotics Octreotid 40
20
41
Conceptual model of
prokinetic agents
42
21
Classification of prokinetic agents
General
Example of Used
pharm. Mech. Of action
drug medications
class
Dopamine Domperidone
Metoclopramide
D2 antagonism GERD
receptor
5HT4 rec. activation . &
Serotonin Cisapride 5HT3 rec. antagonism
receptor 5HT4 rec. activation . & Gastroparesis
modulation metoclopamid D2 rec. antagonism
PROKINETIC DRUG
(MOTILITY-PROMOTING DRUG)
In GERD, prokinetic drug that increase lower
esophageal sphincter pressure and increase gastric
motility and thus empties the stomach more quickly
may ameliorate the symptoms.
Metoclopamide,
Metoclopamide, domperidone & ondansentron are D2
type receptor antagonist in GIT dopamine
receptor antagonist may potentiate cholinergic
smooth muscle stimulation
Metoclopamide has anticholinergic and CNS, effects
as a result of blocking dopamine receptor and cross
the BBB. Domperidon hasn’
hasn’t anticholinergic
effects not cross the BBB.
22
Cisapride exhibits agonist
activity at 5-HT4 receptors but
hasn’t activity at dopamine
receptors.
Metoklopamid dan ondansentron
aman untuk wanita hamil,
domperiodon tidak ada data untuk
wanita hamil
Pharmacology in Gastrointestinal Medicine
Drug for acid-
acid-peptic disease Antiemetik Laxatives
Motility promoter Antidiarrheals
Metoklopamide,
Metoklopamide, Central acting Bulk-
Bulk-forming laxatives.
domperidon,
domperidon, dopamine antagonists Stool surfactant agents
cisapride.
cisapride. H1 blockers Osmotic laxatives
Cholinomimetic.
Cholinomimetic.
Muscarinic antagonist Stimulant laxatives.
Macrolide
5-HT3 antagonists Prokinetic drugs
motilin
Cannabinoid,
Cannabinoid, CS
Antacids. H2 blockers Opioid antagonists.
Antisecretory agents PPIs Kaolin & pectin.
Mucosal protectants Muscarinic Antimuscarinic
Antisecretory agents that antagonist Bile salt binding resin
enhance mucosal defenses Colloid bimuth compounds
antibiotics Octreotid 46
23
Mayor stimuli of nausea & vomiting:
GIT irritation.
Motion sickness.
Hormon disturbance.
Intracranial pathology.
Metabolic disorder.
Psychogenic factor.
Pain.
Drug & radiation.
Endogenous toxins.
Post operative nausea & vomiting
Schematic diagram of antiemetic drugs 48
24
49
General classification of antiemetic agents
Type vomiting
Antiemetic class Examples
most effective
5 HT3-
HT3-antagonist Ondansetron Cytotoxic drug
Metoclopramide
Centrally acting (5HT3)
Cytotoxic drug
dopamine antagonist Promethazine
(antimusc & antihist)
antihist)
Vestibular
H1-
H1- antagonist Cyclizine
(motionsickness)
motionsickness)
Muscarinic
Scopolamine Motion sickness
antagonist
Neurokinin rec Investigational Cytotoxic drug
Cannabinoid rec
Dromabinol Cytotoxic drug
antag
25
Others:
Glucorticoid (dexamethazone) by
supressing prostaglandin production
Benzodiazepines (lorazepam)
reducing the anticipatory of nausea
and vomiting
Subtance P receptor antagonist
26
53
27
55
28
Pharmacology in Gastrointestinal Medicine
Drug for acid-
acid-peptic disease Antiemetik Laxatives
Motility promoter Antidiarrheals
Metoklopamide,
Metoklopamide, Central acting Bulk-
Bulk-forming laxatives.
domperidon,
domperidon, dopamine antagonists Stool surfactant agents
cisapride.
cisapride. H1 blockers Osmotic laxatives
Cholinomimetic.
Cholinomimetic. Muscarinic antagonist Stimulant laxatives.
Macrolide 5-HT3 antagonists Prokinetic drugs
motilin Cannabinoid,
Cannabinoid, CS
Antacids. H2 blockers Opioid antagonists.
Antisecretory agents PPIs Kaolin & pectin.
Mucosal protectants Muscarinic Antimuscarinic
Antisecretory agents that antagonist Bile salt binding resin
enhance mucosal defenses Colloid bimuth compounds
antibiotics Octreotid 57
Prokinetic
agents
Mechanism of action laxatives
29
Agents used for constipation & diarrhea
Generally mechanism of action of laxatives:
1. Luminal active agents :
bran,physsilum) bulk forming
Hydriphillic colloids (bran,physsilum)
agents
Osmotic agent (MgSO4, Nafosfat, Lactulosa) non
Nafosfat, Lactulosa)
absorbalble in organic salts/sugar
Stool wetting agentas (stool surfactant agents) and
emollients Softeners. Eg:
Eg: glycerin supp, docusate po
2. Non specifec stimulants or irritants (with effects
on fluid secretion and motility)
Diphenylmethanes (bisacodyl)
bisacodyl)
Anthraquinones (senna and cascara)
Castor oil
3. Prokinetic agents (acting primarily on motility)
o 5 HT4 rec antagonist
o Opioid rec antagonist
30
Pharmacology in Gastrointestinal Medicine
Drug for acid-
acid-peptic disease Antiemetik Laxatives
Motility promoter Antidiarrheals
Metoklopamide,
Metoklopamide, Central acting Bulk-
Bulk-forming laxatives.
domperidon,
domperidon, dopamine antagonists Stool surfactant agents
cisapride.
cisapride. H1 blockers Osmotic laxatives
Cholinomimetic.
Cholinomimetic. Muscarinic antagonist Stimulant laxatives.
Macrolide 5-HT3 antagonists Prokinetic drugs
motilin Cannabinoid,
Cannabinoid, CS
Antacids. H2 blockers Opioid antagonists.
Antisecretory agents PPIs Kaolin & pectin.
Mucosal protectants Muscarinic Antimuscarinic
Antisecretory agents that antagonist Bile salt binding resin
enhance mucosal defenses Colloid bimuth compounds
antibiotics Octreotid 61
Diarrhea :
The mainstay therapy is rehydration.
Another therapy in these patients is :
Intraluminal agents :
Bulk forming and hydroscopic agents
Cholestyramine (binds bile acid & bact. toxin)
Bismuth (antiinflam., antimicrobial effects)
Antimotility and antisecretory agents:
opioids (loperamide, diphenoxylate)
receptor (intestinal motility )
atropin antimuscarinic
Octreotide (analog somastotin) inhibit the
severe secretory diarrhea, hormone,
chemotherapy, diabetic)
31
63
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