Pharmacological Pharmacological aspect of upper aspect of upper gastrointestinal gastrointestinal

diseases diseases

Nico L Lumbuun, dr., SpFKNico L Lumbuun, dr., SpFK

Faculty of MedicineFaculty of Medicine

UPHUPH

CaseCase

A 22 yo medical student, noted A 22 yo medical student, noted a burning pain a burning pain in his in his upper abdomen upper abdomen since 2 weeks ago. This sensation since 2 weeks ago. This sensation occurs 1 to occurs 1 to 2 hrs after eating2 hrs after eating. He is actually in a good . He is actually in a good health before, although he health before, although he smokessmokes approximately 2 approximately 2 packs of cigs & drink 5 cups of packs of cigs & drink 5 cups of coffee a daycoffee a day. He is . He is currently currently under stress under stress because of his bachelor exam. because of his bachelor exam. He also been taking 1-2 tabs He also been taking 1-2 tabs aspirin daily aspirin daily for the past for the past 2 months because of headache.2 months because of headache.

The pain frequently awakens him at midnight. His The pain frequently awakens him at midnight. His pain usually relieved by eating and by taking antacid.pain usually relieved by eating and by taking antacid.

What is the most likely problem?What is the most likely problem?

What is the most appropriate treatment?What is the most appropriate treatment?

Meaning of numbers1. Body of stomach 2. Fundus 3. Anterior wall 4. Greater curvature 5. Lesser curvature 6. Cardia 9. Pyloric sphincter 10. Pyloric antrum 11. Pyloric canal 12. Angular notch 13. Gastric Canal 14. Rugal folds

Anatomy

ProglumideACh

PGE2

Histamine Gastrin

Adenyl cyclase

_+

ATP cAMP

Protein Kinase (Activated)

Ca++

+

Ca++

Proton pump

KK+ H+

Gastric acid

Parietal cell

Lumen of stomach

AntacidOmeprazole

Ranitidine

H2M3

Misoprostol

_

__

_

+

PGE receptor

+

+

Gastrin receptor+

+

+

Antacids

Weak bases that react with gastric hydrochloric acid to form a salt and water.

Principal mechanism of action is :

reduction of intragastric acidity.

Acid-neutralization capacity among different proprietary formulations highly variable, depend on:

rate of dissolution (tablet versus liquid)

water solubility

rate of reaction with acid

rate of gastric emptying.

► Sodium bicarbonate (NaHCO3) reacts rapidly with HCl. NaHCO3 + HCl CO2 + NaCl + H2O pH gastric .

► Formation of CO2 results in gastric distention & belching. ► NaCl absorption may exacerbate fluid retention in patients with

heart failure, hypertension, and renal insufficiency. ► Unreacted alkali (NaHCO3) is readily absorbed potentially causing metabolic alkalosis when given in high

doses or to patients with renal insufficiency.

► Calcium carbonate (CaCOOH) less soluble, reacts slowly.

CaCOOH + HCL CO2 + CaCl2 + H2O► Also may cause belching or metabolic alkalosis. ► Other indications : bone mineralization.► Excessive doses + calcium-containing dairy products can lead

to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome)

Antacids – cont…

► Present day antacids : Aluminium Hydroxide Magnesium Hydroxide

React slowly with HCl magnesium chloride or aluminum chloride and water.

No gas is generated, belching does not occur.Metabolic alkalosis is also uncommon

because of the efficiency of the neutralization reaction.

OTC drug for symptomatic rapid relief of dyspepsia

Antacids – cont…

Antacids – cont…

Duration of action : 30 min when taken in empty stomach 2 hrs when taken after a meal

Side effects :

Al3+ antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying)

Mg2+ antacids – Osmotic diarrhoea . Both magnesium and aluminum are absorbed and

excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term.

In renal failure Al3+ antacid – Aluminium toxicity &

Encephalopathy

Antacids – Common additives

Simethicone – Decrease surface tension, reduce bubble formation Added to prevent reflux .Alginates is a viscous gum that is abundant in the cell walls of

brown algae. – Form a layer of foam/gel on

top of gastric contents &

reduce reflux

Oxethazaine – Surface anaesthetic (Strocain®)

Antacid - Interactions

Adsorb drugs (binding the drug) and form insoluble complexes that are not absorbed (ex.tetracycline, quinolone)

Increasing intragastric pH so that the drug's dissolution or solubility (especially weakly basic or acidic drugs) is altered.(ketocanazole, iron)

Clinical importance :

Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs .

Is it rational to combine aluminium hydroxide and magnesium hydroxide in antacid preparations ?

Combination provides a relatively fast and sustained neutralising capacity .

(Magnesium Hydroxide – Rapidly acting

Aluminium Hydroxide - Slowly acting )

Combination preserves normal bowel function.

(Aluminium Hydroxide – constipation

Magnesium hydroxide – diarrhoea )

Histamine H2 Receptor Antagonist

Reversible competitive inhibitors of H2 receptor

Highly selective, No action on H1 or H3 receptors

Very effective in inhibiting nocturnal acid secretion ( as it depends largely on Histamine )

Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)

Cimetidine Ranitidine Famotidine Nizatidine

Bioavailability 80 50 40 >90

Relative Potency 1 5 -10 32 5 -10

Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6

Duration of 6 8 12 8

action (hrs)

Inhibition of 1 0.1 0 0 CYP 450

Dose mg(bd) 400 150 20 150

H2 Blockers–Side effects & Interactions

Extremely safe drugs

Cimetidine causes gynecomastia, galactorrhea (as it is antiandrogenic & increases

prolactin level)

Cimetidine inhibits CYP450 (specifically CYP1A2,

CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) & increases conc. of Warfarin, Theophylline, Phenytoin, Ethanol.

Proton Pump Inhibitors

Most effective drugs in antiulcer therapy

Irreversible inhibitor of H+ K+ ATPase

Prodrugs requiring activation in acid environment

Lipophilic , weakly basic drugs & so accumulate in canaliculi of parietal cell

Activated in canaliculi & binds covalently to extracellular domain of H+ K+ ATPase

Acid secretion resumes only after synthesis of new molecules

Proton Pump Inhibitors

Omeprazole 20 mg o.d. (Once Daily)

Esomeprazole 20 - 40 mg o.d.

Lansoprazole 30 mg o.d.

Pantoprazole 40 mg o.d.

Rabeprazole 20 mg o.d.

Proton Pump Inhibitors – Kinetics

PPI are administered as inactive prodrugs.

To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated tablet or capsule formulations.

Esomeprazole, lansoprazole, and pantoprazole

also given intravenously

Half life – 1.5 hrs

Since it requires acid for activation - given 1 hr before meals

Other acid suppressing agents not coadministered

P.P.I. – Side effects & Interactions

Extremely safe drugs

Causes hypergastrinemia which leads to carcinod tumor (ECL cell hyperplasia) in rats, but no evidence of such tumors in man

Inhibit CYP 450 & hence metabolism of warfarin, phenytoin, etc

Pantoprazole & Rabeprazole have no significant interactions

A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose?

Answer :

Antacids

Explanation :

Antacids neutralise the already secreted acid in the stomach. All other drugs act by stopping acid secretion and so may not relieve symptoms at least for 45 min.

Mucosal Protective Agents

Sucralfate

Misoprostol

Colloidal Bismuth compounds

Sucralfate

Salt of sucrose complexed to sulfated aluminium hydroxide

In acidic pH polymerizes to viscous gel that adheres to ulcer crater & stimulates mucosal prostaglandin

Taken on empty stomach 1 hr. before meals

Concurrent antacids, H2 antagonist avoided

( as it needs acid for activation )

Misoprostol

PGE analogue

Modest acid inhibition Stimulate mucus & bicarbonate secretion

Enhance mucusal blood flow

Approved for prevention of NSAID induced ulcer

Side effect : Diarrhoea & cramping abd. pain – 20 %

Not so popular as P.P.I are more effective & better tolerated

Colloidal Bismuth Compounds

Coats ulcer, stimulates mucus & bicarbonate secretion

Direct antimicrobial activity against H.pylori

May cause blackening of stools & tongue

Not used for long periods – bismuth toxicity

Available compounds :

Bismuth subsalicylate – in USA (IndScantoma)

Bismuth subcitrate – in Europe

Bismuth dinitrate

A pregnant lady (first trimester) comes to you with peptic ulcer disease. Which drug will you prescribe for her ?

Answer :

Antacids or Sucralfate

Explanation ;

H2 antagonists cross placenta and are also secreted in breast milk. Safety of Proton pump inhibitors not established in pregnancy. Misoprostol causes abortion .

Eradication of H.pylori

Triple Therapy

The BEST among all the Triple therapy regimen is

Omeprazole / Lansoprazole - 20 / 30 mg bd

Clarithromycin - 500 mg bd

Amoxycillin / Metronidazole - 1gm / 500 mg bd

Given for 14 days followed by P.P.I for 4 – 6 weeks

Short regimens for 7 – 10 days not very effective??

Newest 7 days…

Triple Therapy – cont …

Bismuth subsalicylate – 2 tab qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Some other Triple Therapy Regimens are

Ranitidine /Bismuth citrate - 400 mg bd

Tetracycline - 500 mg bd

Clarithromycin / Metronidazole - 500 mg bd

Quadruple Therapy

Given when Triple Therapy fails

Omeprazole / Lansoprazole - 20 / 30 mg bd

Bismuth subsalycilate - 2 tabs qid

Metronidazole - 250 mg qid

Tetracycline - 500 mg qid

Drugs causing peptic ulcer

Non Steroidal Anti Inflammatory Drugs (NSAIDs)

Glucocorticoids

Cytotoxic agents

Stress induced ulceration after head trauma (ICP) = Cushing’s ulcer

Stress induced ulceration after severe burns

= Curling’s ulcer

AntiemeticsAntiemetics

Vomiting Centre (medulla)

Cerebral cortex

Anticipatory emesisSmellSight

Thought

Vestibular nucleiMotion

sickness

Pharynx & GIT

Chemo & radio therapy Gastroenteritis

Chemoreceptor Trigger Zone

(CTZ)

Cancer chemotherapyOpioids

Muscarinic, 5 HT3 & Histaminic H1

5 HT3 receptors

Dopamine D2,

5 HT3,Opioid Receptors

Muscarinic Histaminic H1

Pathophysiology of Emesis

Now answer this question

Which group of drugs can be used as antiemetics ?

Serotonin 5 HT3 Antagonists

Dopamine D2 Antagonist

Anticholinergics

H1 Antihistaminics

Cannabinoids

Serotonin 5 HT3 Antagonist

Potent antiemetics

Even though 5 HT3 receptors are present in vomiting centre & CTZ, the antiemetic action is restricted to emesis caused by vagal stimulation.

High first pass metabolism

Excreted by liver & kidney

No dose reduction in renal insufficiency but needed in hepatic insufficiency

Given once or twice daily – orally or intravenously.

Drugs Available

Ondansetron 32 mg / day

Granisetron 10 g / kg / day

Dolasetron 1.8 mg / kg / day

Indications

Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy.

Postoperative & postradiation nausea & vomiting

Adverse EffectsExcellent safety profile

Headache & constipation

All three drugs cause prolongation of QT interval, but more pronounced with dolasetron.

Dopamine D2 Antagonist

Antagonise D2 receptors in CTZ.

Drugs available

Metoclopramide 10 mg tid

Domperidone 10 mg tid

Both drugs are also prokinetic agents due to their 5 HT4 agonist activity.

Domperidone – oral ; Metoclopramide – oral & i.v

Metoclopramide crosses BBB but domperidone cannot.

Now answer this question

Which is a better antiemetic – Metoclopramide or Domperidone ?

As CTZ is outside BBB both have antiemetic effects.

But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects.

Domperidone is well tolerated.

Phenothiazines & Butyrophenones

Phenothiazines

Prochlorperazine

Promethazine

Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism.

Butyrophenone

Droperidol

Droperidol used for post-op. nausea & vomiting, but cause QT prolongation.

H1 Antihistaminics

Most effective drugs for motion sickness

Drugs available

Betahistine

Meclizine

Cyclizine

Dimenhydrinate

Diphenydramine

Promethazine – Used in pregnancy,

used by NASA for space motion sickness

AnticholinergicsScopolamine (hyoscine) – used as oral or

transdermal patch for motion sickness

Cannabinoids

Dronabinol – used as adjuvant in chemotherapy induced vomiting.It is a psychoactive substance

Nabilone

Now answer this question

A physician prescribed Tab.Ondansetron for prophylaxis of motion sickness. Even though ondansetron is a potent antiemetic it didn’t produce any effect in this patient. Can you explain why ?

Explanation :

Vestibular nuclei has only muscarinic and H1 histaminic receptors.

GERD GERD (Gastroesophageal Reflux (Gastroesophageal Reflux

Disease)Disease) ► Chronic symptoms or mucosal damage produced

by the abnormal reflux in the esophagus due to incompetence of the lower esophageal sphincter (LES), transient LES relaxation, impaired expulsion of gastric reflux from the esophagus, or a hiatal hernia

► Symptom :Symptom :Heartburn, cough, hoarseness, voice changes, chronic ear ache, burning chest pains, nausea & vommiting & vommiting

► Principle Management :Principle Management : lifestyle modifications lifestyle modifications weight loss and elevating the head of the bedweight loss and elevating the head of the bed avoiding eating two hours before bed avoiding eating two hours before bed

► Certain foods & lifestyle are considered to promote reflux:Certain foods & lifestyle are considered to promote reflux: Coffee, alcohol, and excessive amounts of Vitamin C supplements Coffee, alcohol, and excessive amounts of Vitamin C supplements

stimulate gastric acid secretion. Taking these before bedtime stimulate gastric acid secretion. Taking these before bedtime especially can cause evening refluxespecially can cause evening reflux

Foods high in fats and smoking reduce lower esophageal Foods high in fats and smoking reduce lower esophageal sphincter competence, so avoiding these tends to help. Fat also sphincter competence, so avoiding these tends to help. Fat also delays stomach emptyingdelays stomach emptying

Large meals Large meals Carbonated soft drinks (regular or diet). Carbonated soft drinks (regular or diet). Chocolate and peppermintChocolate and peppermint Acidic foods, such as oranges and tomatoes Acidic foods, such as oranges and tomatoes Cruciferous vegetables: onions, cabbage, cauliflower, broccoli, Cruciferous vegetables: onions, cabbage, cauliflower, broccoli,

spinach, brussels sprouts spinach, brussels sprouts Milk and milk-based products contain calcium and fat, and should Milk and milk-based products contain calcium and fat, and should

be avoided before bedtime. be avoided before bedtime.

GERD GERD (Gastroesophageal Reflux (Gastroesophageal Reflux

Disease)Disease)

► Drug treatmentDrug treatment Proton pump inhibitors Proton pump inhibitors are the most effective in reducing gastric are the most effective in reducing gastric

acid secretion. These drugs stop acid secretion at the source of acid secretion. These drugs stop acid secretion at the source of acid production.acid production.

Antacids before meals or symptomatically after symptoms begin Antacids before meals or symptomatically after symptoms begin can reduce gastric acidity (increase pH). can reduce gastric acidity (increase pH).

Alginic acid may coat the mucosa as well as increase pH and Alginic acid may coat the mucosa as well as increase pH and decrease reflux.decrease reflux.

Gastric H2 receptor blockers can reduce gastric secretion of acid. Gastric H2 receptor blockers can reduce gastric secretion of acid. They relieve complaints in about 50% of all GERD patients.They relieve complaints in about 50% of all GERD patients.

Prokinetics strengthen the LES and speed up gastric emptying. Prokinetics strengthen the LES and speed up gastric emptying. Sucralfate is also useful as an adjunct in helping to heal and Sucralfate is also useful as an adjunct in helping to heal and

prevent esophageal damage caused by GERD, however it must be prevent esophageal damage caused by GERD, however it must be taken several times daily and at least 1-2 hours apart from meals taken several times daily and at least 1-2 hours apart from meals and medications. and medications.

GERD GERD (Gastroesophageal Reflux (Gastroesophageal Reflux

Disease)Disease)