PMP201 GI

Inflammatory Bowel Disease (IBD) - What is it?

IBD is a collective term for 2 conditions that cause inflammation of the GI tract:

• Ulcerative Colitis (UC) - Mostly effects colon and rectum

• Crohn’s Disease (CD) - Can effect anywhere in GI tract

Inflammatory Bowel Disease - Symptoms

• Pain, swelling, cramping of the abdomen

• Recurring Diarrhoea

• Bloody Diarrhoea

• Weight Loss

• Tiredness

• Also - Joint pain, red eyes

Ulcerative Colitis - What is it?

Chronic relapsing-remitting, non-infectious inflammatory disease of the gastrointestinal tract

Diffuse, continuous inflammation of intestinal mucosa in the colon and rectum

Gut-Brain Axis - 6 Components

1. Gut microbiome

2. Nervous System

3. Immune System

4. Endocrine

5. Neurotransmitters

Enteric NS - Definition

The “second brain“ of digestion, managing digestion independently

Autonomic NS - Definition

Heartbeat, breathing

Short Reflexes - 3 Steps

1. Stimulus Detection - Sensory neurons in the GI tract detect changes (e.g stretch, chemical composition, osmolarity)

2. Signal Integration - The sensory neurons relay the information to interneurons within the ENS

3. Effector response - Motor neurons in the ENS stimulate smooth muscle contraction, secretion of digestive enzymes, or change in the blood flow to the gut

Omeprazole - Function

PPI that inhibits gastric acid secretion by blocking hydrogen-potassium ATP enzyme system (The proton pump) of the gastric parietal cell

Why is omeprazole always prolonged release?

• The active drug is a weak base

  • Therefore would be destroyed in the stomach

• Enteric coating stops it from being dissolved in the stomach

• Drug remains basic as it enters the small intestine

• Gets absorbed into the blood stream and into parietal cells

• Forms disulphide bond with hydrogen-potassium-ATPase, therefore stopping ATPase moving H+ to stomach

• Reduces stomach acidity

H2 Receptor Antagonists (-idine) - Function & Uses

Function: Block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach

Used to treat acid-peptic disease (Duodenal/gastric ulcers)

Prodrug - Definition

A biologically inactive compound which can be metabolised in the body to produce a drug

Promotility Agents - Mechanism and Uses

• Enhancing the effect of acetylcholine (Smooth muscle contraction)

• Blocking the effect of an inhibitory neurotransmitter (e.g dopamine)

Used to treat conditions with slow movement of matter through the digestive system (Gastroparesis, constipation)

Laxatives - Mechanism and uses

• Increase fluid retention by hydrophilic or osmotic action

• Decrease absorption of fluid by manipulation of electrolyte transport

• Stimulation of propulsive contractions / inhibition of non-propulsive contractions

Used to treat constipation with limited movement through the DS

Activation of PPIs

1. Protonation of benzimidazole ring

2. Nitrogen of the pyridine ring then acts as a nucleophile - bonds with the 2-carbon of the benzimidazole ring

3. Spiro structure is formed - imidazole portion of ring is no longer aromatic

4. The ring wants to re-aromatise

5. Lone pair of e- from the nitrogen reform the double bond and cleave the S-C bond, forming sulfenic acid

6. Sulfenic acids are highly reactive

7. Cationic, tetracyclic, pyridinium sulfenamide is formed and is an irreversible enzyme inhbitor

8. It forms a covalent bond to an accessible cysteine residue on the proton pump

9. Cys-813, Cys-821, Cys-892 all can be attacked, depending on the drug (Omeprazole prefers 813 and 892)

What cysteine types does omeprazole target

Cys-813 and Cys-892

What cysteine type does pantoprazole only react with?

Cys-813