HP98 /NK/1 06/10/2015. HP98 /NK/2 06/10/2015 Management of PU The aims of modern management are to:...

HP98 /NK/1 04/19/23

HP98 /NK/2 04/19/23

Management of PU

The aims of modern management are to:The aims of modern management are to:

Relieve the symptomsRelieve the symptoms

Induce ulcer healing not only on the short Induce ulcer healing not only on the short term but also on the long termterm but also on the long term

H. pylori eradicationH. pylori eradication

Prevent recurrencePrevent recurrence

Prevent complicationsPrevent complications

HP98 /NK/3 04/19/23

Drug Management of PUCytoprotective drugs:Cytoprotective drugs:

Colloidal BismuthColloidal Bismuth

– Has both antibacterial & cytoprotective activitiesHas both antibacterial & cytoprotective activities– Less potent antibacterial activity on Less potent antibacterial activity on H. pyloriH. pylori compared to PPI compared to PPI– Forms adherent coat over an active ulcer painForms adherent coat over an active ulcer pain– Enhances secretion of mucous & bicarbonateEnhances secretion of mucous & bicarbonate– Inhibits pepsin activityInhibits pepsin activity– Not readily absorbed after short term therapy (i.e. needs long term Not readily absorbed after short term therapy (i.e. needs long term

administration)administration)– Common side effects:Common side effects: Indigestion, constipation and dry mouth, renal Indigestion, constipation and dry mouth, renal

tubular injury, and rarely upon chronic use encephalopathy may occurtubular injury, and rarely upon chronic use encephalopathy may occur– Used nowadays as an adjuvant therapy with triple therapyUsed nowadays as an adjuvant therapy with triple therapy

HP98 /NK/4 04/19/23

Management of PUDiet & Lifestyle

It is now recognized that diet does not affect the course of peptic ulcer disease and it seems unfair to impose such "additional hardships and restrictions on patients.

Modify the patient's reaction to stress

Stopping smoking undoubtedly allows ulcers to heal more quickly

Evidence concerning the effect of coffee on ulcers is less conclusive but since it stimulates acid secretion it is probably best only taken on a full stomach

HP98 /NK/5 04/19/23

Drug Management of PU

Cytoprotective drugs:Cytoprotective drugs:

Synthetic ProstaglandinSynthetic Prostaglandin

– Approved for use in prevention of NSAIDs ulceration in Approved for use in prevention of NSAIDs ulceration in patients who must take aspirin-like drugspatients who must take aspirin-like drugs

– Main side effects:Main side effects: Abdominal pain, diarrhea and abortion Abdominal pain, diarrhea and abortion– Pregnancy category X: causes miscarriagePregnancy category X: causes miscarriage– Used nowadays in medical practice to induce labour and Used nowadays in medical practice to induce labour and

control post-partum bleedingcontrol post-partum bleeding– Misoprostol: Misoprostol: Cytotec®Cytotec®

HP98 /NK/6 04/19/23

Drug Management of PUCytoprotective drugs:Cytoprotective drugs:AlginateAlginate

Alginate-containing antacids form a ‘raft’ that floats on the surface of Alginate-containing antacids form a ‘raft’ that floats on the surface of the stomach contents to reduce reflux and protect the esophageal the stomach contents to reduce reflux and protect the esophageal mucosamucosa

they are used in the management of mild symptoms of gastro-they are used in the management of mild symptoms of gastro-esophageal reflux diseaseesophageal reflux disease

SucralfateSucralfate

It is aluminum hydroxide sulfated sucroseIt is aluminum hydroxide sulfated sucrose

Has minimal GI absorptionHas minimal GI absorption

When exposed to gastric pH it becomes negatively charged and forms When exposed to gastric pH it becomes negatively charged and forms viscous ulcer adherent complex that inhibits back diffusion of H+viscous ulcer adherent complex that inhibits back diffusion of H+

Side effects:Side effects: constipation, secondary hypophosphataemia (as its Al constipation, secondary hypophosphataemia (as its Al binds to phosphorous), Drug interactionsbinds to phosphorous), Drug interactions

HP98 /NK/7 04/19/23

Drug Management of PUAntacids:Antacids:

Alkaline compounds that yield an acid-base reaction and cause Alkaline compounds that yield an acid-base reaction and cause only acid neutralizationonly acid neutralization

Have the fastest onset of action and the shortest duration of Have the fastest onset of action and the shortest duration of actionaction

Need highly repeat dosage regimen (may require taking Need highly repeat dosage regimen (may require taking medication up to once an hourmedication up to once an hour

No suppression of acid secretionNo suppression of acid secretion

Have many drug-drug & food-drug interactions as they have Have many drug-drug & food-drug interactions as they have divalent & trivalent cationsdivalent & trivalent cations

Used mainly as OTC drugs to relive dyspeptic & heartburn Used mainly as OTC drugs to relive dyspeptic & heartburn symptomssymptoms

HP98 /NK/8 04/19/23


Antacids:Antacids:

Include: Include: Aluminium & Mg hydroxideAluminium & Mg hydroxide, Na , Na bicarbonate and Ca carbonatebicarbonate and Ca carbonate

Side Effects:Side Effects:

– Al is known to cause constipation & Mg cause diarrhea Al is known to cause constipation & Mg cause diarrhea – Excessive absorption of Mg in patients with renal failure Excessive absorption of Mg in patients with renal failure

lead to CNS toxicitylead to CNS toxicity– Aluminum causes a decrease in phosphate levels due to Aluminum causes a decrease in phosphate levels due to

phosphate binding to the gutphosphate binding to the gut

HP98 /NK/9 04/19/23

Drug Management of PUAntacids:Antacids:

Include: Aluminium & Mg hydroxide, Include: Aluminium & Mg hydroxide, Na bicarbonateNa bicarbonate and and Ca carbonateCa carbonate


– The produced COThe produced CO22 causes abdominal distension that leads to causes abdominal distension that leads to

increased intra-abdominal pressure and discomfort or increased increased intra-abdominal pressure and discomfort or increased GERD or ulcer painGERD or ulcer pain

– Absorbed sodium causes blood pressure elevation especially in Absorbed sodium causes blood pressure elevation especially in hypertensive patients (may also worsen CHF cases)hypertensive patients (may also worsen CHF cases)

– Absorbed HCOAbsorbed HCO33 may cause systemic alkalosis may cause systemic alkalosis

HP98 /NK/10 04/19/23


Antacids:Antacids:

Include: Aluminium & Mg hydroxide, Na bicarbonate and Include: Aluminium & Mg hydroxide, Na bicarbonate and Ca Ca carbonatecarbonate


– The produced COThe produced CO22 cause abdominal distension cause abdominal distension

– Ca can cause rebound acidity (when absorbed to the blood taken by Ca can cause rebound acidity (when absorbed to the blood taken by parietal cell stimulate Ca dependent pathways activate proton parietal cell stimulate Ca dependent pathways activate proton pump & stimulate acid secretion again.pump & stimulate acid secretion again.

N.B. N.B. Early data implicated calcium carbonate as the only agent that caused Early data implicated calcium carbonate as the only agent that caused “acid rebound effect”; however, it is now clear that most antacids may “acid rebound effect”; however, it is now clear that most antacids may result in this effectresult in this effect

HP98 /NK/11 04/19/23

Acid-Suppression Therapy Acid-Suppression Therapy (Antisecretory Therapy)(Antisecretory Therapy)

Anticholinergics (Atropine/Pirenzepine)Anticholinergics (Atropine/Pirenzepine)Muscarinic cholinergic antagonists can reduce basal secretion of gas Muscarinic cholinergic antagonists can reduce basal secretion of gas tric acid by 40% to 50%; stimulated secretion is inhibited to a lesser tric acid by 40% to 50%; stimulated secretion is inhibited to a lesser extentextent

Selective antagonists of M1 receptors (e.g. Pirenzipine, telenzepine) Selective antagonists of M1 receptors (e.g. Pirenzipine, telenzepine) are as effective as atropine or other nonselective muscarinic are as effective as atropine or other nonselective muscarinic antagonists but are less likely to produce the adverse effects that are antagonists but are less likely to produce the adverse effects that are characteristic of cholinergic blockade characteristic of cholinergic blockade (e.g., (e.g., dry mouth, tachycardia)dry mouth, tachycardia)

M1 antagonists also may inhibit the secretion of gastrin, mucus, and M1 antagonists also may inhibit the secretion of gastrin, mucus, and HC0HC033

No full acid inhibitionNo full acid inhibition

Side effects (dry mouth, blurred vision, constipation) may limit the Side effects (dry mouth, blurred vision, constipation) may limit the

utility of these drugsutility of these drugs

HP98 /NK/12 04/19/23


Anticholinergics Anticholinergics ((Clidinium + chlordiazopoxide: Clidinium + chlordiazopoxide:

Librax®Librax®))Librax combines in a single capsule formulation the Librax combines in a single capsule formulation the antianxiety action of Librium (chlordiazepoxide antianxiety action of Librium (chlordiazepoxide hydrochloride 5 mg) and the anticholinergic/spasmolytic hydrochloride 5 mg) and the anticholinergic/spasmolytic effects of Quarzan (clidinium bromide 2.5 mg)effects of Quarzan (clidinium bromide 2.5 mg)

FDA labeling: as adjunctive therapy in the treatment of FDA labeling: as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitisand acute enterocolitis

In practice this drug mainly is prescribed in cases of In practice this drug mainly is prescribed in cases of stress ulcers (psychologic not physiologic)stress ulcers (psychologic not physiologic)

Anticholinergic side effects & sedation may occurAnticholinergic side effects & sedation may occur

HP98 /NK/13 04/19/23


HH22-Antogonists or Blockers-Antogonists or Blockers

They provide reversible & competitive blockage for HThey provide reversible & competitive blockage for H2 2 receptors on the parietal cell surface thus inhibit acid secretion receptors on the parietal cell surface thus inhibit acid secretion that is caused by histaminethat is caused by histamine

Still there is acid secretion from the other pathways No Still there is acid secretion from the other pathways No full acid inhibition less potent than PPIfull acid inhibition less potent than PPI

They are selective, no anticholinergic effects appearThey are selective, no anticholinergic effects appear

Drug tolerance occurs: gradual loss of efficacy & thus there is Drug tolerance occurs: gradual loss of efficacy & thus there is a need to increase the dose to get the same effecta need to increase the dose to get the same effect

The drugs have similar adverse reaction profile The drugs have similar adverse reaction profile

Cimetidine appears to have the greatest degree of Cimetidine appears to have the greatest degree of antiandrogenic (e.g. sexual impotence, gynaecomastia) & CNS antiandrogenic (e.g. sexual impotence, gynaecomastia) & CNS effects(e.g. mental confusion), inhibition of cytochrome P450 effects(e.g. mental confusion), inhibition of cytochrome P450 (drug-drug interactions)(drug-drug interactions)

HP98 /NK/14 04/19/23


Proton Pump Inhibitors or PPIsProton Pump Inhibitors or PPIsAll PPIs are substituted benzimidazoles which are protonatable All PPIs are substituted benzimidazoles which are protonatable weak basesweak bases

PPIs concentrate in acidic environment (any space with a pH less PPIs concentrate in acidic environment (any space with a pH less than 4)than 4)

This accounts for their high selective targeting in the secretory This accounts for their high selective targeting in the secretory canaliculi of the parietal cells with a pH 0.8 - 3 as this region is the canaliculi of the parietal cells with a pH 0.8 - 3 as this region is the only physiological space with such low pHonly physiological space with such low pH

PPIs are unstable in acidic environment (they undergo conversion to PPIs are unstable in acidic environment (they undergo conversion to active sulfenamide form by protonation)active sulfenamide form by protonation)

HP98 /NK/15 04/19/23

Gastric Gland Secreting Gastric Acid and Pepsin

HCI and Pepsin

Mucus

Parietal Cells

ChiefCells

Lumen of Gland

Epithelium

Feldman M. In: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 7th ed. 2002:715-732.Guyton AC, Hall HE. Textbook of Medical Physiology. 1996;815-851. Keet JD. The Pyloric Sphincteric Cylinder in Health and Disease. Available at: http://med.plig.org. Accessed July 15, 2003.

HP98 /NK/16 04/19/23

HCI and Pepsin

Mucus

Parietal Cells

ChiefCells

Lumen of Gland

Epithelium

Parietal Cells in the Walls of the Gastric Gland

HP98 /NK/17 04/19/23

Structure of the Active Parietal Cell

Mitochondria

TubulovesiclesCanalicular Membrane

Basolateral Membrane

Canaliculus

HP98 /NK/18 04/19/23

The parietal Cells (Mechanism of HCl Secretion):

- The Parietal Cells of the human stomach can secrete 2L of acidic gastric juice a day.

- When maximally stimulated they can secrete HCl at concentrations that can produce pH of 0.8.

HP98 /NK/19 04/19/23

- Parietal cells are stimulated to secrete HCl by the binding of Parietal cells are stimulated to secrete HCl by the binding of either gastrin, acetylcholine or histamine (most significant either gastrin, acetylcholine or histamine (most significant role) to specific receptors on the surface of the parietal cellrole) to specific receptors on the surface of the parietal cell

- Stimulation of these receptors activates the H- Stimulation of these receptors activates the H++-K-K++ ATPase ATPase system (the proton pump) located on the apical membrane system (the proton pump) located on the apical membrane and tubulovesicles bordering the secretory canaliculi of the and tubulovesicles bordering the secretory canaliculi of the parietal cellsparietal cells

The parietal Cells (Mechanism of HCl Secretion):

HP98 /NK/20 04/19/23

Stimulation of the Proton Pump

ACh = acetylcholine; G = gastrin; H = histamine.

H+

ACh H G

HP98 /NK/21 04/19/23

1- Acetylcholine pathway: (stimulated by sight, smell and taste of food).

2- Gastrin pathway: stimulated when food enters the stomach

3- Histamine pathway: stimulated when food enters the stomach

Acid production by parietal cells

HP98 /NK/22 04/19/23

Structure of the Proton Pump

1 2 3 4 5 6 7 8 9 10

107

158

303

353

792 833853 945

963

1014

ATPα

β

ATP = adenosine triphosphate.

HP98 /NK/23 04/19/23

Proton Pump in the Canalicular Membrane

CanalicularMembrane

`CanalicularLumen HCI

Cl-H+

K+

Inside of Parietal Cell

HP98 /NK/24 04/19/23

K+

Canaliculus

Interstitial Fluid

HP98 /NK/25 04/19/23

PPIs Mechanism of Action

PPIs undergo activation to the active sulfenamide form by PPIs undergo activation to the active sulfenamide form by protonation depending upon some factorsprotonation depending upon some factors

This active form binds with cysteine (-SH) on the surface of HThis active form binds with cysteine (-SH) on the surface of H++, , KK++ ATPase molecule by a covalent bond blocking its activity ATPase molecule by a covalent bond blocking its activity

Thus the PPIs effect is largely Thus the PPIs effect is largely irreversibleirreversible

Reverse inhibition thus requires Reverse inhibition thus requires the synthesis of a new Hthe synthesis of a new H++, K, K++ ATPase moleculeATPase molecule

As the half-life of the proton pump is 50 hours, 96 hours are As the half-life of the proton pump is 50 hours, 96 hours are required for full restorationrequired for full restoration

HP98 /NK/26 04/19/23

PPIs Mechanism of Action

The plasma half-life of The plasma half-life of PPIsPPIs is 60 - 90 min is 60 - 90 min

Since only the stimulated cells are inhibited during Since only the stimulated cells are inhibited during presentation of the drug, the acid secretory capacity presentation of the drug, the acid secretory capacity of resting cells during that time is not inhibitedof resting cells during that time is not inhibited

Intragastric pH restores rapidly after the first dose Intragastric pH restores rapidly after the first dose due to subsequent stimulation of these resting cells due to subsequent stimulation of these resting cells and and 3 days are required for steady state inhibition3 days are required for steady state inhibition

HP98 /NK/27 04/19/23

Proton Pump Inhibition: Proton Pump Inhibition: The Final Common PathwayThe Final Common Pathway

ACh = acetylcholine; G = gastrin; H = histamine.ACh = acetylcholine; G = gastrin; H = histamine.

proton pump, blocking its actionproton pump, blocking its action

Receptors are Receptors are still active, still active, but cannot but cannot stimulate acid stimulate acid production, production, as the pump as the pump is blockedis blocked

AChACh HH GG

HP98 /NK/28 04/19/23

Management of PUSurgical Treatment

– vagotomy/gastric resection

– Not used nowadaysAntimicrobial Agents

– Used for eradication of H pylori

– High resistance to metronidazole

– Triple therapy: most commonly used (reserved for resistant or frequently relapsing duodenal ulcer)

– Old regime: colloidal bismuth for one month with simultaneous metronidazole (3 x 400 mg) & amoxicillin (4 x 250 mg) during the first week

– Current regimen: zantac + Amoxicillin + Klacid

– Long-term maintenance: Zantac

HP98 /NK/29 04/19/23

Management of H. pylori InfectionThrough Through H. pyloriH. pylori eradication eradication

Two-week triple-therapy regimens offer the possibility of higher eradication Two-week triple-therapy regimens offer the possibility of higher eradication rates compared to one-week regimens, but there is higher possibility for rates compared to one-week regimens, but there is higher possibility for adverse effects and less complianceadverse effects and less compliance

Resistance to clarithromycin or to metronidazole is much more common Resistance to clarithromycin or to metronidazole is much more common than to amoxicillin and can develop during treatmentthan to amoxicillin and can develop during treatment

A regimen containing amoxicillin and clarithromycin is therefore A regimen containing amoxicillin and clarithromycin is therefore recommended for initial therapy and one containing amoxicillin and recommended for initial therapy and one containing amoxicillin and metronidazole for eradication failuremetronidazole for eradication failure

Other regimens, including those combining clarithromycin and Other regimens, including those combining clarithromycin and metronidazole are best used in specialist settingsmetronidazole are best used in specialist settings

Treatment failure usually indicates antibacterial resistance or poor Treatment failure usually indicates antibacterial resistance or poor compliancecompliance

HP98 /NK/30 04/19/23

Management of H. pylori InfectionA two-week regimen using tripotassium dicitratobismuthate A two-week regimen using tripotassium dicitratobismuthate plusplus a a

proton pump inhibitor proton pump inhibitor plusplus two antibacterials may have a role in the two antibacterials may have a role in the treatment of resistant cases after confirmation of the presence of treatment of resistant cases after confirmation of the presence of H. H. pyloripylori

Metronidazole 400 mg can be substituted with Tinidazole 500 mgMetronidazole 400 mg can be substituted with Tinidazole 500 mg

Tetracycline 500 mg 4 times daily can be also used in combination with Tetracycline 500 mg 4 times daily can be also used in combination with metronidazole, PPI & bismuthmetronidazole, PPI & bismuth

Dual treatments combining a proton pump inhibitor with either Dual treatments combining a proton pump inhibitor with either amoxicillin or clarithromycin were popular a few years ago as they amoxicillin or clarithromycin were popular a few years ago as they were easy to explain and well tolerated. They have now been were easy to explain and well tolerated. They have now been abandoned because they were not very effective.abandoned because they were not very effective.

Note: Note:

– Clarithromycin should not be given for patients with renal failureClarithromycin should not be given for patients with renal failure– Metronidazole should not be given for patients taking alcoholMetronidazole should not be given for patients taking alcohol– Amoxicillin should not be given for patients who have penicillin hypersensitivityAmoxicillin should not be given for patients who have penicillin hypersensitivity

HP98 /NK/31 04/19/23

Recommended Regimens for Management of H. pylori

Infection Acid SuppressantAcid Suppressant Antibacterial AgentAntibacterial Agent

AmoxicillinAmoxicillin ClarithomycinClarithomycin MetronidazoleMetronidazole

OmeprazoleOmeprazole

20 mg20 mg

twice dailytwice daily

1 g twice daily1 g twice daily 500 mg twice 500 mg twice dailydaily

________

500 mg 3 times 500 mg 3 times dailydaily

______ 400 mg 3 times 400 mg 3 times dailydaily

______ 500 mg twice 500 mg twice dailydaily

400 mg twice 400 mg twice dailydaily

HP98 /NK/32 04/19/23




LansoprazoleLansoprazole

30 mg30 mg



________

1 g twice daily1 g twice daily ______ 400 mg twice 400 mg twice dailydaily



HP98 /NK/33 04/19/23




Ranitidine Ranitidine bismuthbismuth

citratecitrate

400 mg400 mg



________

1 g twice daily1 g twice daily ______ 400 mg twice 400 mg twice dailydaily



HP98 /NK/34 04/19/23




EsomeprazoleEsomeprazole

20 mg20 mg



________

________ 500 mg twice 500 mg twice dailydaily


HP98 /NK/35 04/19/23

Peptic ulcer is typically recurrent disease

80% of ulcer healed with medical relapse “major problem”

Reduced rate of relapse provides effective treatment of recurrence

Long term maintenance ( One year or more) for :

1- In whom recurrence is likely

2- In whom recurrence is potentially very serious

HP98 /NK/36 04/19/23

HP98 /NK/1 06/10/2015. HP98 /NK/2 06/10/2015 Management of PU The aims of modern management are to:...

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