Week 9: Inflammation and GIT disorders

The four characteristics of inflammation are:

Swelling

Redness

Pain

Heat

Innate (non adaptive) Immune Response

First line of defence:

- Mast cells (histamine), macrophages (phagocytotic), dendritic cells (activate T cells + phagocytotic), natural killer cells (kills shit without antigens)

- Release of chemicals like cytokines, chemokines (small molecules that attract cells to the site of damage), complement activation (cascade of proteases), vasodilators, histamine, prostaglandins and others

Diapedesis:

Movement of cells from blood to interstitial fluid

Adaptive (acquired/specific) Immune Response

- Highly specific

- Immunological memory

- Key cells: Lymphocytes (20-40% of WBC)

- Congregate in lymph nodes, spleen, thymus and travel

in blood

- React to antigens provided by APCs (antigen

presenting cells)

- APCs eg macrophages, dendritic cells

- Main lymphocytes: B cells (bone marrow), T cells (differentiate in thymus), NKs

Cyclo-oxygenase (COX) enzyme 1 & 2:

Catalyses formation of prostanoids from arachidonic acid

Isoforms COX-1 and COX-2-differences in distribution

COX-1: constitutive production in most tissues (NB gastric protection, platelet activation)

COX-2: induced in inflammatory cells (but constitutive in

kidney and CNS)

Aspirin, Diclofenac (Voltaren), Ibuprofen (Nurofen),

Celecoxib and meloxicam

D: Non-steroidal anti-inflammatory drugs (NSAIDs)

D: Cyclo-oxygenase Inhibitors

MOA: Anti inflammatory (including Reduced swelling): reduces inflammatory mediators and reduces vasodilation and vascular permeability

Antipyretic: reduces PGE2 production in hypothalamus (which elevates the temp set point)

Analgesic: Reduced production of PGs that sensitise nociceptors , Act centrally to reduce COX-2 action

AE: GIT Disturbances: mild dyspepsia through to ulceration.

Renal damage: resulting in oedema, salt retention and

hyperkalemia.

Cardiovascular effects: Seen with the -coxibs. Increased

risk of major cardiovascular events eg, stroke and

myocardial infarction

Therapeutic Uses For Cyclo-oxygenase: Inhibitors - NSAIDS

Antithrombotic: Aspirin

Analgesia Short-term: Aspirin, paracetamol, ibuprofen

Analgesia Long-term: Codeine

Anti-Inflammatory: Ibuprofen, naproxen for RA, Gout, etc

Antipyretic: Paracetamol

Disease-modifying anti-rheumatic drugs (DMARDS):

Conventional synthetic (csDMARDS). First line

Biological (bDMARDS)

Targeted synthetic (tsDMARDS)

Added if csDMARDs not adequately controlling RA

Corticosteroids

Corticosteroids used to achieve rapid symptom control at presentation, or during an exacerbation of disease,

Used only short-term in conjunction with csDMARDS

Eg. Prednisolone (oral), methylprednisolone (im, iv for flare-ups)

Methotrexate, leflunomide, sulfasalazine, hydroxychloroquine

D: Conventional synthetic (csDMARDS)

D: Rheumatoid Arthritis

MOA: First line treatment for RA, Folic acid antagonist-but not the MOA, this is unknown

AE: Bone marrow depression

G: Hence folic acid co-administered. Combination of two csDMARDS used if monotherapy not

adequate*

D: Biological (bDMARDS)

Adalimumab , Certolizumab, Etanercept, Golimumab:

- Anti-tumour necrosis factor (TNF):

Abatacept:

- Inhibit T cell activation

Tocilizumab:

- IL-6 inhibitor

Rituximab (specialist only use):

- CD20 inhibitor

- Binds to CD 20 and marks the B cells for attack by NK cells (other bDMARDs target other ILs and used for other forms of arthritis eg secukinumab inhibits IL-1. Used for psoriatic arthritis)

Targeted synthetics (tsDMARDS).

Tofacitinib (only tsDMARD approved for RA):

MOA: JAK inhibitor (inhibits the transduction pathway that influences gene transcription (IL synthesis)

(also used for inflammatory bowel disease)

GOUT

Excess uric acid. Forms crystals in joints

Immune response initiated

Involves kinins, prostaglandins, Leukotriene B4

Neutrophil migration into site and phagocytosis of crystals: Production of tissue damaging chemicals eg reactive oxygen species, production of IL-1 leading to immune responses

Gout is the most common form of inflammatory

arthritis in men

Acute Gout treatment

• Colchicine

- Evidence suggests that low doses (for example,0.5 mg three times daily) may be sufficient for some patients with acute gout

- MAO: inhibits microtubule function. Inhibits chemotaxis of Neutrophils; prevents pro-inflammatory cytokine generation (IL- 1beta)

• NSAIDs

- Use if no contraindications, ie renal and GI disease

• Prednisolone

- Use in patients with severe disease, ie not responding to colchicine and NSAIDs

Treatment of Chronic Gout

Lifestyle changes

Deplete urate stores

Allopurinol:

- (purine analogue)

- (competitive)

Febuxostat:

- (non-purine)

- (Non-competitive)

- Inhibition of Xanthine oxidase

- Reduces uric acid production

Probenecid:

- Increase uric acid excretion

Characteristics of Asthma:

- Bronchoconstriction

- Airway oedema and inflammation

- Increased mucus secretion

- Airway hypersensitivity

Airway remodeling:

- Increased thickness or 'hypertrophy' of smooth muscle cell layer, resulting in a narrowing of the lumen

Major groups of drugs used in the treatment of asthma

1. Relieve

- (eg short acting beta-2 agonists eg salbutamol)

- Provide acute symptomatic relief

2. Symptom control

- Longer acting beta 2 agonists (LABAs eg salmeterol)

- Muscarinic receptor antagonists (eg tiotropium)

3. Prevent

- Anti-inflammatory agents eg (corticosteroids)

Fluticasone, beclomethasone, budesonide

D: Corticosteroids

D: Asthma

MOA: Inhibit COX enzyme and phospholipase enzyme preventing releases of Prostaglandins, thromboxanes and leukotrienes, Inhaled

AE:

G: Ineffective for acute asthma, Used for maintenance and prophylaxis, gargling is recommended to avoid oral thrush

Basic Roles of GIT

1. Secretion

- Digestive glands secrete enzymes and acids to help break down food.

2. Digestion

- Food is chemically and mechanically broken down into smaller molecules.

3. Absorption

- Nutrients from digested food are absorbed into the bloodstream or lymph.

4. Motility

- Muscular contractions move food through the digestive tract.

Peristaltic contractions:

- One direction, involves -longitudinal muscles

Segmental contractions:

- Both directions, involves circular muscles

5. Immune function

- The GIT defends against harmful microbes using gut-associated immune cells.

Loperamide

D - Opioid/Anti-diarrhoeal

D - Diarrhoea

MOA - Agonists at µ (mu) opioid receptors in GIT

reduce peristalsis (one direction, longitudinal muscles), increases water absorption due to increase transit time, acts peripherally

AE - Constipation, cramps, sedation

G - Not significantly absorbed in gut, poorly passes BBB

Hyoscine

D - Anti-cholinergic

D - Diarrhoea

MOA - Reduce intestinal movement and are effective against

both diarrhoea and accompanying cramping

AE - Dry mouth, dry eyes, reduced urine

or difficulty passing urine, constipation.

G -

Docusate

D - Faecal softener

D - Constipation

MOA - Wetting agent used to soften faecal matter

AE - Throat irritation in liquid form

G - 1-3 day action, dilute in milk/juice

Psyllium hydrophilic

D - Bulk forming (high-fibre) agent

D - Constipation

MOA - Absorbs water to increase bulk, distending bowel to initiate reflex bowel activity

AE - Contraindicated in dysphagia due to oesophageal obstruction occurrence, dehydration

G - 12hrs-3 days

Senna, Bisacodyl

D - Stimulants

D - Constipation

MOA - Increases peristalsis (one way, longitudinal muscles) via nerve stimulation in colon

AE - Discolouration of faeces and urine

G - 6-12hrs

Liquid paraffin

D - Lubricant/faecal softener

D - Constipation

MOA - Coats surface of faeces and eases passage of stool; softens mass

AE - Contraindicated in dysphagic and bedridden patients due to liquid pneumonitis (inflamed lungs due to inhaling foreign body)

G - 6-8hrs, can disrupt vitamin absorption if taken within 2hrs of a meal

Lactulose

D - Osmotic

D - Constipation

MOA - Increase volume of fluid in the lumen, resulting in distention, peristalsis, and evacuation

AE - Avoid use in colostomy and ileostomy, and in impaired renal functioning persons

G - 1-3hrs

Docusate + Senna combination

D - Stool softener + stimulant combination

D - Constipation

MOA - Increases peristalsis whilst using wetting agent

AE - ?

G - Laxatives, 6-12hrs

Crohn's disease

- Characterised by localised deep ulcers interspersed with areas of normal tissue

- Usually occurs in small intestine, but can appear in any other areas of the GIT

- Reoccurring condition: Alternating periods of active disease (flare-up) and relatively symptom-free intervals (remission)

- Symptoms: abdominal pain, diarrhoea, nausea, tiredness

Ulcerative Colitis

- Characterised by diffuse mucosal inflammation (i.e. inner lining of wall)

- Occurs in the rectum and lower colon

- Recurring condition

- Symptoms: include diarrhoea (often profuse and bloody), urgency and abdominal pain

Mesalazine, Balsalazide

D - 5-aminosalicylates (5-ASA's)

D - Inflammatory bowel disease

MOA - Exact mechanism unknown, Inhibits pro-inflammatory cytokines, Elicits an anti-inflammatory effect at the bowel wall, Used to induce and maintain remission

AE -

G -

Prednisolone, Budesonide

D - Corticosteroids

D - Inflammatory bowel disease

MOA - Potent anti-inflammatory agents, various routes of administration/formulations; Used to induce remission

AE - Adrenal suppression can occur.

G - Administrated orally, rectally or injection

Azathioprine, Mercaptopurine

D - Immunosuppressant/antimetabolite

D - Inflammatory bowel disease

MOA - Full mechanism of action poorly understood, Impair purine biosynthesis and inhibit cell proliferation (esp. of lymphocytes). Anti-inflammatory effects via immune modulation

AE - ?

G -

Infliximab, Adalimumab

D - TNFα-inhibitor

D -

MOA - Monoclonal antibody that binds to and inhibits TNFα.

AE -

G - Used for IBD unresponsive to conventional treatment (second line therapy)

Acid secretion

1. Hydrogen ions (protons) are

produced inside parietal

cells

2. Protons are actively pumped

into the lumen by the proton

pump (H+/K+ ATPase - active transport)

3. Chloride is drawn out

passively through chloride

channels

Regulation of acid secretion - Gastrin

1. from G cells

2. activates the

cholecystokinin 2 (CCK2) receptors

(GPCRs) on parietal cells and

enterochromaffin-like (ECL) cells.

Regulation of acid secretion - Histamine

1. from ECL (enterochromamaffin-like cells) acts on H2 receptors

(GPCRs) on parietal cells

2. increases activity of the H+-K+-ATPase 'proton pump' in the luminal membrane.

Regulation of acid secretion - Acetylcholine

1. from nerves

2. Acts via M3 receptors (GPCRs) on the parietal and ECL (enterochromamaffin-like cells)

Regulation of acid secretion - PGE2

1. acts on prostanoid EP3 receptors

(GPCRs)

2. inhibits HCL (hydrochloric acid) secretion from

parietal cells

Gastritis

- An inflammation (swelling and irritation) of the lining of the stomach. Usually due to non-specific irritants eg alcohol, NSAIDs, acute.

- Symptoms: Dyspepsia - pain associated with fullness, bloating in the upper

Abdomen, ulcer formation

Gastro-oesophageal reflux disease (GORD)

- Common disorder characterised by regurgitation of stomach contents back into the oesophagus, lower oesophageal sphincter dysfunction

- Dyspepsia 2x + weekly or mucosal damage

(oesophagitis) produced by the abnormal reflux into the oesophagus

- Symptoms: Heartburn, Regurgitation, Hypersalivation, Dysphagia (difficulty swallowing), Dyspepsia

Peptic Ulcer Disease (PUD)

- An ulcer is a lesion in the lining of the GIT,

classified by location.

Most common in the duodenum (~75%), but

also occur in the stomach.

Ulcers can be superficial or penetrating.

Peptic ulcers are most commonly caused by:

1. Helicobacter pylori infection (main)

80% stomach; 90% duodenum

2. NSAID use

3. Higher risk with smoking and excessive

alcohol consumption

Omeprazole, Esomeprazole -

Nexium

D - Proton pump' inhibitors (PPIs)

D - GIT diseases

MOA - Irreversibly inhibit the H+/K+-ATPase pump. Inhibits basal and food-stimulated secretion of gastric acid, most powerful gastric acid inhibitor, heals environment

AE - Abdominal pain, flatulence, headaches, lost absorption, drug-drug interactions (CYPs)

G - Long action

Ranitidine, Zantac, Famotidine, Pepcid, Cimetidine

D - Histamine H2 receptor antagonists

D - GIT diseases

MOA - Competitively block H2 receptors on the parietal cell. Reduced cAMP production leading to inhibition of basal and food-stimulated secretion of gastric acid.

AE - Drug-drug: inhibits cytochromes P450 (including CYP2C9 (warfarin,

NSAIDs) and CYP2D6 (antidepressants, opioids)

G -

misoprostol (prodrug)

D - Prostaglandin analogue

D - GIT diseases

MOA - Stable synthetic analogue of PGE1 that acts

on prostanoid (EP) receptors. Inhibits basal and food-stimulated secretion of gastric acid and increases secretion of mucus and HCO3-, reduces gastric acid secretion

AE - Diarrhoea, abdominal cramping. Contraindicated in pregnancy (can induce premature labour)

G -

Sucralfate

D - Cytoprotective agent

D - GIT diseases

MOA - Reacts with acid to form a sticky gel

Provides an acid and pepsin-resistant

protective coating at the ulcer site

AE - Drug-drug: Decreased absorptions of digoxin, warfarin, tetracyclines

Aluminium hydroxide, Magnesium carbonate - Mylanta

D - Antacids

D - GIT diseases

MOA - Combine with HCl to neutralise upset stomach

AE - Constipation, diarrhoea

Esomeprazole,

Clarithromycin +

Amoxycillin or Metronidazole

D - Triple therapy

D - Peptic ulcer disease (PUD)

MOA - Proton Pump Inhibitor (e.g., esomeprazole) to reduce acid secrtion creating a health environment,

Two anti-bacterials (clarithromycin +

amoxycillin (or metronidazole if cannot

tolerate penicillin eg., allergy) to kill H. pylori

AE - Abdominal pain, flatulence, headaches, lost absorption, drug-drug interactions (CYPs)

G - 7 day minimum treatment