NTA Level 5 • Semester 1 • PST05104

Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer Disease

Pharmacology and Therapeutics • Source Session/Topic 10

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Session 10: Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer Disease.

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

Describe mechanism of action of Antiemetics and Drugs for Peptic Ulcer

Describe drug interactions associated with Antiemetics and Drugs for Peptic Ulcer Disease

Describe side effects of Antiemetics and Drugs for Peptic Ulcer Disease

Describe contraindications of Antiemetics and Drugs for Peptic Ulcer Disease

Resources Needed:

Flip charts, marker pens, and masking tape

Black/white board and chalk/whiteboard markers

Computer and LCD projector

SESSION OVERVIEW

Step

Time

Activity/

Content

Step

Time

Activity/

Content

Step

Time

Method

Content

Method

05 minutes

Presentation

Introduction, Learning Tasks

40 minutes

Presentation/

Mechanism of Action of Antiemetics and

40 minutes

Buzzing

Drugs for Peptic Ulcer Disease

Buzzing

Drugs for Peptic Ulcer Disease

Presentation/

Drug Interactions Associated With

20 minutes

Presentation/

Antiemetics and Drugs for Peptic Ulcer

20 minutes

brainstorming

Antiemetics and Drugs for Peptic Ulcer

brainstorming

Disease

20 minutes

Presentation

Side Effects of Antiemetics and Drugs for

20 minutes

Presentation

Peptic Ulcer Disease

20 minutes

Presentation/

Contraindications of Antiemetics and Drugs

PST 05104 Pharmacology & Therapeutics

NTA Level 5 Semester 1 Facilitator Guide

Brainstorming

for Peptic Ulcer Disease

05 minutes

Presentation

Key Points

05 minutes

Presentation

Evaluation

05 minutes

Presentation

Take Home Assignment

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Mechanism of Action of Antiemetics and Drugs for Peptic Ulcer Disease (40 minutes)

Activity: Buzzing (5 minutes)

ASK students to pair up and buzz on the following question for 2 minutes

What are the mechanisms of action of antiemetic and drugs for peptic ulcers?

ALLOW few pairs to respond and let other pairs add on points not mentioned

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below

The following are the mechanism of action for drugs for treating Peptic Ulceration;

Antiacids

o Antacids have a number of actions which include neutralizing gastric acid and thus relieving associated pain and nausea, reducing delivery of acid into the duodenum following a meal, and inactivation of the proteolytic enzyme pepsin by raising the gastric pH above 4–5.

o In addition, it is thought that antacid may increase lower oesophageal sphincter tone and reduce oesophageal pressure.

H2-Receptor antagonists

o H2-receptors stimulate gastric acid secretion and are also present in human heart, blood vessels and uterus (and probably brain).

PST 05104 Pharmacology & Therapeutics 80 NTA Level 5 Semester 1 Facilitator Guide

Competitive H2-receptor antagonists when used in clinical use block/inhibit gastric acid secretion.

Prostaglandin Analogues

Misoprostol is a synthetic analogue of prostaglandin E1 which inhibits gastric acid secretion, causes vasodilatation in the submucosa and stimulates the production of protective mucus.

Proton Pump Inhibitors

The proton-pump inhibitors inhibit gastric acid by blocking the H+/K+-adenosine triphosphatase enzyme system (the proton pump) of the gastric parietal cell. Examples are omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.

Bismuth chelate (a mucosal protective agent)

Colloidal tripotassium dicitratobismuthate precipitates at acid pH to form a layer over the mucosal surface and ulcer base, where it combines with the proteins of the ulcer

exudate. This coat is protective against acid and pepsin digestion.

It also stimulates mucus production and may chelate with pepsin, thus speeding ulcer healing.

It has a direct toxic effect on H. pylori and may be used as part of triple therapy.

Sucralfate (a mucosal protective agent)

Sucralfate is used in the management of benign gastric and duodenal ulceration and chronic gastritis. Its action is entirely local, with minimal if any systemic absorption.

It is a basic aluminium salt of sucrose octasulphate which, in the presence of acid, becomes a sticky adherent paste that retains antacid efficacy.

This material coats the floor of ulcer craters, exerting its acid-neutralizing properties locally, unlike conventional antacid gels which form a diffusely distributed antacid

dispersion.

In addition it binds to pepsin and bile salts and prevents their contact with the ulcer base.

Mechanism of action of Antiemetics

REFER Students to Handout 10.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function

STEP 3: Drug Interactions Associated with Drugs for Peptic Ulcer Disease (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are drug interactions associated with antiemetics and drugs for peptic ulcer disease?

PST 05104 Pharmacology & Therapeutics 81 NTA Level 5 Semester 1 Facilitator Guide

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

Drugs for treating Peptic Ulceration

Antiacids

o Magnesium and aluminium salts can bind other drugs in the stomach, reducing the rate and extent of absorption of antibacterial agents such as erythromycin, ciprofloxacin, isoniazid, norfloxacin, ofloxacin, pivampicillin, rifampicin and most tetracyclines, as well as other drugs such as phenytoin, itraconazole, ketoconazole, chloroquine, hydroxychloroquine, phenothiazines, iron and penicillamine.

o They increase the excretion of aspirin (in alkaline urine).

H2-Receptor antagonists

o Absorption of ketoconazole (which requires a low pH) and itraconazole is reduced by cimetidine.

o Metabolism of several drugs is reduced by cimetidine due to inhibition of cytochrome P450, resulting in raised plasma drug concentrations.

o Interactions of potential clinical importance include those with warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine (cimetidine-induced reduction of hepatic blood flow is also a factor in this interaction), terfenadine, amiodarone, flecainide, quinidine and fluorouracil.

o Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased plasma concentrations of these drugs.

o Ranitidine has a lower affinity for cytochrome P450 than cimetidine and does not inhibit the metabolism of warfarin, phenytoin and theophylline to a clinically significant degree.

Proton Pump Inhibitors

o Pantoprazole does not appear to have any clinically significant drug interactions, whereas omeprazole inhibits cytochrome P450 thus affecting phenytoin and lansoprazole is a weak inducer of cytochrome P450.

o Some drugs require an acidic environment for their proper dissolution and absorption. By increasing gastric pH, the PPIs may therefore interfere with the absorption of vitamin B12, ampicillin, and ketoconazole, among others.

STEP 4: Side Effects of Drugs acting on Gastrointestinal System (20 minutes)

The following are the side effects of drugs for treating Peptic Ulceration

PST 05104 Pharmacology & Therapeutics 82 NTA Level 5 Semester 1 Facilitator Guide

Antacids

o Mg2+Containing Buffers cause diarrhoea: Mg2+ salt exerts an osmotic effect on the gut.

o Ca2+ Containing Buffers cause hypercalcemia (at high doses)

o These agents may lead to formation of calculi (milk alkali syndrome).

o Calculi are solid formations, typically consisting of minerals, which precipitate in organs such as the kidney and obstruct ducts.

o Bloating, flatulence, belching, and nausea are also common: These effects are caused

by the liberation of CO2 from carbonate-containing antacids. Constipation

o Al3+ Containing Buffers cause Hypophosphatemia: Al3+ can bind phosphate in the gut, inhibiting its absorption. Constipation is also observed.

o Milk alkali syndrome is a rare disorder caused by ingestion of large amounts of calcium, resulting in hypercalcemia and alkalosis.

o Sodium bicarbonate may cause systemic alkalosis

H2-Receptor antagonists

o Generally well tolerated

o Common: Diarrhoea, headache, drowsiness, fatigue, muscle pain, and constipation may occur.

o Central nervous system (CNS) side effects (rare): Confusion, delirium, hallucinations, slurred speech, and headache can occur and are thought to be caused by antagonism of H2 receptors in the CNS.

o Thrombocytopenia (rare): The mechanism has not been established, but theories include bone marrow suppression due to inhibition of DNA synthesis, and the development of platelet antibodies against H2 antagonists.

o Cimetidine Only: Gynecomastia (breast development in men) and galactorrhoea (lactation not associated with childbirth

Prostaglandin Analogues

o Pregnancy (or desired pregnancy) is an absolute contraindication to the use of misoprostol, as the drug causes abortion through its effects on PG receptors.

Proton Pump Inhibitors

o Generally well tolerated

o Hypergastrinemia, less common: Gastrin levels become elevated because of the body‘s response to chronic gastric acid suppression. This may lead to rebound hypersecretion of gastric acid if the PPI is stopped. There is also concern over the chronic effects of hypergastrinemia, including development of gastric tumours.

STEP 5: Contraindications of Drugs acting on Gastrointestinal System (10 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

PST 05104 Pharmacology & Therapeutics 83 NTA Level 5 Semester 1 Facilitator Guide

What are the contraindications of Antiemetics and Drugs for Peptic Ulcer Disease.? ALLOW few students to respond?

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

The contraindications of Drugs used for treating Peptic Ulceration includes;

Antiacids

o None of major significance

H2-Receptor antagonists

o None of major significance

Prostaglandin Analogues

o Pregnancy (or desired pregnancy) is an absolute contraindication to the use of misoprostol, as the drug causes abortion through its effects on PG receptors.

Proton Pump inhibitors

o None of major significance

STEP 6: Key Points (5 minutes)

The choice of antiemetics depends on the aetiology.

• Reduction of acidity is achieved by the use of antacids; H2-blockers; proton-pump inhibitors; and muscarinic blockers.

Eradication of H. Pylori is important in treatment of peptic ulceration.

STEP 7: Evaluation (5 minutes)

What are adverse effects of cimetidine?

What are contraindications of promethazine?

What is eradication regime?

STEP 8: Take HomeAssignment (5 minutes)

Activity: Take Home Assignment (5 minutes)

DIVIDE students in three groups and assign one assignment for each group

ASK the students to work on the following Assignment

Prepare a presentation on the mechanism of drugs used to treat the following conditions; (Give examples of drugs for this pharmacological group)

Antispasmodics

PST 05104 Pharmacology & Therapeutics 84 NTA Level 5 Semester 1 Facilitator Guide

Cathartics

Drugs used for diarrhoea

ALLOCATE time for students to do the assignments and submit

REFER students to recommended reference

PST 05104 Pharmacology & Therapeutics 85 NTA Level 5 Semester 1 Facilitator Guide

References

Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.

Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.

Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:

Jaypee Brothers Medical P.

Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.

Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill Education.

Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.

The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.

PST 05104 Pharmacology & Therapeutics 86 NTA Level 5 Semester 1 Facilitator Guide

Handout 10.1 Pharmacodynamics of Antiemetic Drugs

Mechanism of action of Antiemetics

Metoclopramide: Dopamine Receptor Antagonists

o It is a central dopamine antagonist and raises the threshold of the CTZ. It also decreases the sensitivity of the visceral nerves that carry impulses from the gut to the emetic centre.

o Metoclopramide also increases the amount of acetylcholine released at post-ganglionic terminals.

o It is relatively ineffective in motion sickness and other forms of centrally mediated vomiting.

o High doses of metoclopramide block 5HT3 receptors.

Domperidone : Dopamine Receptor Antagonists

o Domperidone is a dopamine-receptor antagonist similar to metoclopramide. It does not penetrate the blood–brain barrier, however, and therefore seldom causes sedation orextrapyramidal effects.

o However, the CTZ lies functionally outside the barrier and thus domperidone is an effective antiemetic which can logically be given with centrally acting dopamine agonists or levodopa or apomorphine to counter their emetogenic effect.

Phenothiazines : Dopamine Receptor Antagonists

o Phenothiazines act on the CTZ and larger doses depress the vomiting centre as well. Phenothiazines used as anti-emetics include prochlorperazine, trifluoperazine,

o perphenazine and chlorpromazine

PST 05104 Pharmacology & Therapeutics 87 NTA Level 5 Semester 1 Facilitator Guide

Muscarinic Receptor Antagonists

o These act partly by their antimuscarinic action on the gut, as well as by some central action.

o Hyoscine is effective in preventing motion sickness and is useful in single doses for short journeys, as the anticholinergic side effects make it unsuitable for chronic use.

o These are effective against opioid- and radiation-induced vomiting and are sometimes helpful in vestibular disturbances. They are least effective in the treatment of motion sickness.

Serotonin(5HT-3) Receptor Antagonists

o Block serotonin (5HT-3) receptors; however their exact site of action is uncertain.

o It may be peripheral at abdominal visceral afferent neurones, or central within the area postrema of the brain, or a combination of both.

o Examples include ondansetron, granisetron, dolasetron and tropisetron

Cannabinoids

o Cannabis and its major constituent, D-9-tetrahydrocannabinol (THC), have anti-emetic properties and have been used to prevent vomiting caused by cytotoxic therapy.

o In an attempt to reduce side effects and increase efficacy, a number of analogues, including nabilone, have been synthesized.

o The site of action of nabilone is not known, but an action on cortical centres affecting vomiting via descending pathways

seems probable.

Drug interactions

Metoclopramide: Dopamine Receptor Antagonists

Metoclopramide potentiates the extrapyramidal effects of phenothiazines and butyrophenones.

Its effects on intestinal motility result in numerous alterations in drug absorption, including increased rates of absorption of several drugs such as aspirin, tetracycline and paracetamol

Side effects

Side effects of antiemetic drugs are: o Headache

o Dizziness

o Constipation o Drowsiness o Sedation

o Dry mouth o Hypertension

PST 05104 Pharmacology & Therapeutics 88 NTA Level 5 Semester 1 Facilitator Guide

Hypotension

Nasal congestion o Diarrhea

Contraindications

Antiemetic drugs are contraindicated in patients with known hypersensitivity to these drugs

Prochlorperazine is contraindicated in patients with: o Narrow angle glaucoma

o Severe liver disease

o Cardiovascular disease

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