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PHAY00011 > Inflammation II > Flashcards

Inflammation II Flashcards

Asthma, COPD, RA, OA, Gout, IBD

1
Q

What are the characterised symptoms of asthma?

A

Bronchial hyper-responsiveness

Airway remodelling -> reduced function

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2
Q

Describe how the airway has changed in asthmatic patients.

A

Basement membrane - inflammed

Goblet cells - hypertrophy and hyperplasia -> increased mucus production

Smooth muscle hyperplasia - thickened airway

Epithelial cells shedding - loss of mucus cilliary escalator -> less efficient mucus removal

Mucus build-up

Sensory nerve exposure - more prone to stimulus -> bronchial hyperresponsiveness

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3
Q

What does it mean by bronchial hyper-responsiveness?

A

Lower concentration of bronchoconstrictors can cause bronchial response

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4
Q

Give some examples of bronchoconstrictors.

A

Histamine

Methacholine - cholinergic analogue

Allergen - specific for asthmatic patients

Adenosine - specific for asthmatic patients

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5
Q

What is the main cause behind the decline in lung function when exposing to bronchoconstrictor?

A

Act on G-coupled receptors on bronchus

-> airway resistance

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6
Q

Explain the main differences between the decline in lung function in healthy patient, patients with mild/moderate asthma and severe asthma.

A

The more severe the asthma, the more left-shifting the trend -> much more prone to lower concentration

Maximal response is higher compared to normal people

Severe asthma - no plateau -> lung function get worse when concentration of stimulus increases.

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7
Q

Symptoms of asthma.

A

Wheeze

Dyspnoea

Tightness of chest

Cough

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8
Q

What are the hallmarks of asthma symptoms?

A

Symptoms variable

Intermittent

Worse at night and early morning

Provoked by triggers (allergens, drugs like NSAIDs or beta-blockers)

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9
Q

Signs of asthma.

A

Wheeze

No signs between episodes

Hyperinflation (possible)

Reduced lung function

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10
Q

How are the reduced lung function of asthmatic patient different from other restrictive airway diseases?

A

PEFR reduced

FEV1 redued

FEV1/FVC reduced

Other: FEV1/FVC ratio is generally normal as both equally reduced

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11
Q

What factor can also be considered to diagnose a patient with asthma?

A

Family history of asthma or atopy

Personal history of atopy

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12
Q

Explain the inflammatory basis of asthma

A

Allergens + inflammatory mediators -> activate mast cells.

Release of histamines + synthesis of acute mediators (PAF, PGs and LTs)

Histamine - interact with H1 receptors (Gq) - bronchoconstriction

Histamine - vascular leakage -> swelling

Acute mediators - enhance bronchoconstriction and vascular leakage

Acute mediators - activate eosinophils, T cells, alveolar macrophages

Eosinophils - cytotoxic release (major basic protein, cationic protein, peroxidase) -> damage

Eosinophils - release PAF, PGs, LTs -> recruit more (amplifcation) + 2nd wave bronchoconstriction (late-phase asthma response)

T cells and macrophage - cytokines release -> more recruiment, activation and production from bone marrow

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13
Q

What is the aim of asthma treatment?

A

Control symptoms

Prevent exacerbations

Achieve optimal lung function

Minimal side effects

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14
Q

What are the two guidelines used for treating asthma?

A

Step-wise approach of BTS/SIGN

Step-wise approach of NICE guidelines

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15
Q

How is the airway smooth muscle tone controlled?

A

basal tones - under parasympathetic system - ACh on M3 receptors (Gq) -> contraction

circulating adrenaline - beta 2 receptors (Gs) -> relaxation

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16
Q

How does the binding of adrenaline to beta-2 receptors induce the relaxation of airway smooth muscle?

A

2 mechanism

Activation of calcium-dependent potassium channels (Maxi K+ channels) -> hyperpolarisation of membrane -> relaxation

Activate AC -> ATP to cAMP -> activate PKA -> activate MLCP dephosphorylate rMLC -> relaxation

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17
Q

How does the normal parasympathetic tones of airway smooth muscle reset?

A

Phosphodiesterase 3 enzyme degrade cAMP (from AC activation) to AMP

No more cascade reaction

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18
Q

Name the bronchodilators used in the management of asthma

A

Anticholinergics (muscarinic ACh receptors antagonist)

Beta-2 receptor agonists

Theophylline

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19
Q

Explain how anticholinergics are effective in asthma management

A

Block ACh binding to M3 receptors -> reduce baseline parasympathetic tones -> relaxation

Reduce mucus secretion

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20
Q

Name examples for long-acting and short-acting anticholinergics

A

Short-acting: ipratropium, oxitropium

Long-acting: tiotropium

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21
Q

Explain how beta-2 receptor agonists can be effective in asthma management

A

Mimic effects of circulating adrenaline

Raise cAMP -> relaxation

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22
Q

Name some short-acting and long-acting beta-2 receptor agonists.

A

Short-acting: salbutamol, bambuterol, terbutaline

Long-acting: salmeterol, formoterol

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23
Q

What is the main issue with high-dose beta-2 receptor agonist?

A

Hypokalaemia -> cardiac arrhythmic

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24
Q

Explain how theophylline can be effective in asthma management.

A

Phosphodiesterase inhibitor -> prevent cAMP degradation

Adenosine receptor antagonist -> bronchodilator effect + anti-inflammatory effects

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25
Q

What is the main issue with the use of theophylline?

A

Hypokalaemia

Narrow therapeutic index

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26
Q

What is a non-bronchodilator that can be effective in asthma management?

A

Montelukast

CysLT1 receptor (Gq) antagonist -> prevent LT-induced bronchoconstriction

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27
Q

Name some cromones drugs and explain why it is used for asthma?

A

Sodium cromoglicate, nedocromil sodium

Stabilise afferent sensory nerve -> reduce hyperresponsiveness and twitchiness of airways to stimulus

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28
Q

What are the potent leukotrienes associated with asthma development?

A

LTC4, LTD4 and LTE4

From mast cells + activated eosinophils

Recruit + activate more eosinophils

Target CysLT1 receptors

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29
Q

Describe the target of some leukotriene inhibitors used for asthma

A

Montelukast and zafirlukast = CysLT1 recepto antagnoist -> not intefere with LTB4, important for neutrophils action -> not affect immune response

Zileuton = LOX antagonist -> not suitable as not selective for LTC4, D4 and E4 synthesis and activity.

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30
Q

Name some inhaled glucorcoticoids used in asthma.

A

Beclomethasone, budesonide, fluticasone, mometasone, ciclesonide

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31
Q

When are systemic glucocorticoids used for asthma management?

A

Severe asthma

Uncontrolled asthma

Exacerbations of well-controlled asthma

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32
Q

Explain how glucorticoids can tackle asthma efficiently

A

Inhibit cytokine production, inflammatory cell recruitment and PAF + LTs synthesis

Upregulate Beta-receptors with prolonged use

MAY downregulate muscarinic receptors through canine pathways

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33
Q

What are the local side effects with the use of inhaled corticosteroids?

A

Candidiasis

Dysphonia - change in voice quality

Pharyngitis

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34
Q

Name biologic drugs used for asthma and their indications

A

Anti-IgE - omalizumab - severe ashtma with allergic basis

Anti-IL5 - reslizumab, mepolizumab, benralizumab - severe eosinophillic asthma

Anti-IL13/IL4 - dupilumab, lebrikizumab, trealokinumab

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35
Q

Explain why helminth infection is a concern when targeting cytokines associated with eosinophil function

A

Eosinophil role = parasite management.

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36
Q

What are the clinical features of COPD that are different from asthma?

A

Smoking is present in nearly all patients with COPD

Symptoms - rarely for <35 years old

Chronic productive cough is common (dryg and irritating in asthma)

Persistent breathlessness (variable in asthma)

Night time dyspnoea and wheezing is uncommon in COPD

Significant diurnal variation is uncommon

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37
Q

Why are COPD and asthma difficult to distinguish at first?

A

Both are obstructive airway disease

Marked with reduced FEV1 and reduced FEV1/PVC ratio

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38
Q

What inflammatory cells drive the pathogensis of COPD?

A

Neutrophils

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39
Q

Why does COPD not have bronchial hyperresponsiveness like asthma?

A

Persistent degree of bronchoconstriction

Ongoing inflammation and production of sputum

Permanent structural changes of airway -> not expose sensory nerves like in asthma

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40
Q

Why does COPD have limited response to bronchodilators?

A

Permanent structural changes

Only small function can be reversed by the use of bronchodilators

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41
Q

Asthma and COPD, which condition has a better response to corticosteroids?

A

Asthma

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42
Q

Explain how cor pulmonale arise from COPD.

A

COPD -> ventilation/perfusion mismatch

Hypoxic pulmonary vasoconstriction -blood move -> good ventilated areas -> for efficient gas exchange

Widespread vasoconstriction if large portions are under-ventilated

Increase pulmonary arterial pressure

Increase ventricular afterload

Right-sided heart failure (cor pulmonale)

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43
Q

Describe the pathogenesis of COPD

A

Smoking content - activate alveolar macrophages

Release of chemokines (IL-8), cytokines, LTB4.

IL-8 + LTB4 -> activate neutrophils -> main inflam cells

Macrophages + neutrophils - release MMPs (matrix metalloproteinases) - damage extracellular matrix -> damage structure

Neutrophils - release elastase - breakdown elastin - change in elasticity of lungs - stiffening

Neutrophils - release cathepsins - generalised activity - damage lungs over time

CD8+ cells - release perforins -> damage epithelium

Smoking - reduced production of protease inhibitors (alpha-1-antitrypsin, TIMPs) - over-activity of proteases

Outcome: emphysema + mucus hypersecretion

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44
Q

What enzymes do neutrophils released in COPD that contribute to permanent damage to the airway structure?

A

MMPs = destroy extracellular matrix

Elastase = stiffen the lung, break down elastin

Capthesins = cause damage over time

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45
Q

Emphysema meaning

A

Gradual destruction of the air sacs (alveoli) in the lungs

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46
Q

What are the pharmacological management of COPD?

A

Bronchodilators:
- Anticholinergics
- Beta-2 receptor agonist
- Theophylline

Steroids along with antibiotics where appropriate

Oxygen (care with concentration)

Smoking cessation

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47
Q

Why should patients with COPD not be managed with an excessive concentration of oxygen?

A

Removal of hypoxic drive in breathing of hypercapnia patients (COPD)

Vasodilation of capillaries but low ventilation to removal CO2 -> worse hypercapnia -> resp acidosis

Lower CO2 carrying capacity of Hb -> reduce CO2 removal -> worse hypercapnia

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48
Q

What drive the breathing in patients with COPD?

A

Hypoxic drive

Breathing based on reduction in O2 concentration (normal depend on increase in pCO2)

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49
Q

What are the benefits of smoking cessation?

A

Slow down the rate of decline in lung function

If stop early, the rate can level out with person who not smoke

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50
Q

How are anticholinergics effective in COPD management?

A

Reduce baseline parasympathetic tone of the airway

Reduce mucus secretion - break down the bonds in mucus -> less viscous -> easily cleared

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51
Q

Explain why salbutamol might not be effective in severe COPD cases?

A

Airways are so structurally damaged

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52
Q

Give example of PDE inhibitors that can be used in COPD.

A

Theophylline - non-selective phosphodiesterase inhibitor

Roflumilast - selective PDE4 inhibitor

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53
Q

How can rheumatoid arthritis reduce life expectancy?

A

General strain of chronic inflammation -> affect the cardiovascular system

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54
Q

Symptoms of rheumatoid arthritis.

A

Peripheral, symmetrical arthritis > 6 weeks duration

Sparing DIP, affecting PIP and MCP joints

Subcutaneous rheumatoid nodules on tip of elbow (pathognomic - characterised for RA)

Carpal tunnel syndrome might develop.

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55
Q

How does rheumatoid arthritis result in carpal tunnel syndrome?

A

Pressure on nerve caused by inflammatory process in joints

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56
Q

Laboratory signs of rheumatoid arthritis.

A

Increased ESR - not specific but useful for treatment monitoring

Increased CRP - not specific but useful for treatment monitoring

Rheumatoid factor - semi-specific

ACPAs = anti-citrullinated protein antibodies - specific

Leukocytosis = high WBC count - not specific

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57
Q

Why is ACPA a specific test for RA?

A

Chronic inflammation -> arginine residue within protein coverted to citrulline

Change structure of protein -> produce Ig against

Can detect early

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58
Q

What factor play a more crucical role in the development of RA? Genetic or Environment?

A

Genetics

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59
Q

How do the produced autoantigens damage the joint?

A

Immune complex deposition

Activation of inflammatory cells -> cytokines released

Development of chronic and self-perpentuating processs -> damage

Induce further inflammatory response -> further damage = cartilage destruction, bone destruction.

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60
Q

Describe the events happening in the rheumatoid joint.

A

Recruitment of inflammatory cells

Formation of inflammatory cell mass called pannus

Pannus invade joints space

Release enzymes like MMP -> degrade structure of tissue

Inflamed thickened synovial membrane

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61
Q

What are the inflammatory cells recruited into the rheumatoid joint?

A

Macrophage - type A synoviocyte

Fibroblast-like - type B synoviocyte

Lymphocyte T and B

Plasma cells

Dendritic cells

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62
Q

What do inflammatory cells once recruited in the rheumatoid joints?

A

Blocked emigration -> accummulation

Activated -> release destructive enzymes + mediators to recruit and activate more cells

Release pro-inflammatory cytokines -> prevent apoptosis

Induce angiogenesis -> supply oxygen to pannus

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63
Q

What are the classes of drugs that can be used for pharmacological treatment of RA?

A

NSAIDs

Steroids

DMARDs

Anti-cytokine

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64
Q

Why is NSAIDs suitable for RA?

A

Anti-inflammatory effect - suppress the response

Analgesic - reduce pain

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65
Q

Why is steroids suitable for RA?

A

Anti-inflammatory effect

Slow down disease progression

Bridge-therapy - needed when switching between DMARD agent

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66
Q

General mode of action of DMARDs?

A

Reduce activation of inflammatory cells

Reduce generation of pro-inflammatory cytokines like TNF-alpha, IL-6, IL-1

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67
Q

What are the common concerns about the use of DMARDs?

A

Side effects

Patients tolerance

Slow onset of action

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68
Q

Name the conventional DMARDs used for RA.

A

Methotrexate

Sulfasalazine

Penicillamine

Gold

Azathioprine

Ciclosporine

Hydroxychloroquine

Leflunomide

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69
Q

What anti-cytokine class is the first-line?

A

Anti-TNF alpha - infliximab, adalimumab, etanercept

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70
Q

What are the advantages of methotrexate?

A

Reasonably well tolerated

Effective in majority

Slow disease progression

Weekly dose

Side effects can be managed by folate -> N+V

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71
Q

What are the disadvantages of methotrexate?

A

Bone marrow suppression -> require blood monitoring

Require regular LFTs and urine tests

Increased susceptibility to infections - pneumonitis

Mucositis

Interaction with NSAIDs - kidney problems

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72
Q

What are the advantages of sulfasalazine?

A

Reasonably well tolerated

Slow disease progression

Similar efficacy to methotrexate

73
Q

What are the disadvantages of sulfasalazine?

A

Blood dyscrasisas -> require blood monitoring

Require LFT

Rashes and severe GI side effects

Reversible infertility (oligospermia)

74
Q

What DMARD is associated with severe GI side effects and rash?

A

Sulfasalazine

Ciclosporine

75
Q

What DMARD is associated with infertility issues?

A

Sulfasalazine

76
Q

Which DMARD is associated with susceptibility to infection?

A

Methotrexate

Azathioprine

Leflunomide

Ciclosporine

77
Q

What composition of the aminosalicylate (sulfasalazine) is responsible for the side effects

A

Sulfapyridine

78
Q

What components of the aminosalicylates (sulfasalazine) is responsible for the anti-inflammatory effects?

A

5-ASA = 5 - amino salicyclic acid

79
Q

Issues associated with the use of hydroxychloroquine

A

Retinopathy

Overdose extreme toxicity

CI in hepatic and renal impairment

Blood dyscrasis

Hair loss and depigmentation

80
Q

Which DMARDs is associated with visual issues?

A

Hydroxychloroquine

81
Q

Which DMARDs is associated blood dyscransias?

A

Sulfasalazine

Hydroxychloroquine

Gold

Penicillamine

82
Q

Which DMARDs are associated with bone marrow suppression?

A

Methotrexate

Azathioprine

83
Q

Name of gold given IM.

A

Aurothiomalate - discontinue if not effective within 2 months

84
Q

Name of gold given PO

A

Auranofin

85
Q

Which DMARDs is associated with alopecia?

A

Gold

86
Q

Which DMARDs is associated with nephrotoxicity?

A

Gold

Penicillamine

Ciclosporine

87
Q

Which DMARDs is associated with rash?

A

Sulfasalazine

Penicillamine

Ciclosporine

88
Q

Which DMARDs is associated with hepatoxicity?

A

Leflunomide

89
Q

Which DMARDs is severely tetratogenic?

A

Leflunomide

90
Q

Which DMARD is associated with loss of taste?

A

Penicillamine

91
Q

Which DMARD is associated with hair loss?

A

Hydroxychloroquine

92
Q

Which DMARD is licensed for severe active RA?

A

Ciclosporine

93
Q

Why is ciclosporine the last option for RA?

A

Side effects profile:
- severe nephrotoxicity
- severe immunosuppression
- severe GI side effects

94
Q

When should anti-cytokine be used for RA?

A

when cDMARDs failed

95
Q

What classes of biological DMARDs are preserved for last choices?

A

CTLA4 fusion protein - abatacept

JAK inhibitors - tofacitinib, baricitinib

96
Q

Classes of biological DMARDs

A

anti-TNF-alpha antibodies - infliximab, adalimumab

TNF-alpha fusion protein - etanercept

IL-1-beta receptor antagonist - anakinra

anti-IL-6 receptor antibodies - tocilizumab, sarilumab

anti-CD20 antibody - rituximab

CTLA4 fusion protein - abatacept

JAK inhibitors - tofacitinib, baricitinib

97
Q

Roles of tendon in the knee.

A

Stabilise bones

Connect bones - muscles

98
Q

Roles of ligament in the knee.

A

Stabilise bone

Connect bones - bones

99
Q

Roles of lubricant cartilage in the knee

A

Cover the end of the bones

Allow the joint to move freely

Prevent damage to the end of bones

100
Q

What is synovium?

A

a membrane in the joint capsule

contain synovial fluid - rich in glucosaminoglycan -> lubricant

101
Q

Describe what happened in the joint structure in osteoarthritis.

A

Cartilage rough and thinning

Joint capsule thickened and stretched

Synovium thickended + inflammed - secondary to the damage to cartilage

Joint space narrowed

Osteophyte formation from imbalance in the joint

102
Q

What is osteophyte?

A

Bony projections

Response from the body to stabilise the joint

Worsen the situation instead

103
Q

Describe what happened in the joint in advanced OA case.

A

Little cartilage remained

Angulation of the bone

Exposure of subchondral bone -> polishing the bone structure as two bones rubbing on each

104
Q

In terms of inflammation, what is the main differences between RA and OA?

A

OA - inflammation is the response to joint damage

RA - inflammation drives the damage of joint + disease propagation

105
Q

What causes pseudogout?

A

Calcification

deposition of calcium pyrophosphate in synovium

106
Q

What are the possible causes of OA?

A

Joint overuse -> abnormal wear and tear

Muscle weakness - loss of muscle mass -> more strain on joints

Obesity -> weight bearing joints

Genetic

107
Q

Symptoms of OA?

A

Stiffness - start of the day

Pain

Creaking or crackling of affected joint

Visible remodelling of joint (angulation or deformation-late stages)

Symptoms gradually worsen or plateau

108
Q

Treatment of OA?

A

Non-pharmacological - light exercise, non weight-bearing exercise

Paracetamol with/without opioids - not ideal - not routinely

NSAIDs - topical NSAIDs, capsaicin, supplements

Intra-articular steroids

Surgery

109
Q

Why is the use of opioid not ideal in patients with OA?

A

side effects not ideal for elderly

110
Q

What is the main caution for the use of intra-articular steroids?

A

Must not inject pathogens immune-protected environment

Sepsis arthritis, avascular necrosis

111
Q

What dietary supplementation can be given to OA patients?

A

Glycosaminoglycans

Might induce the production of hyaluronic acid -> synovial fluid and cartilage

112
Q

Why do we need to consider shellfish allergy when giving glycosamineglycans supplement?

A

glycosaminoglycans supplement are derived from shell-fish

113
Q

What is gout?

A

Disorder of purine metabolism -> increased uric acid level

sodium urate crystal deposits -> inflammation and pain

114
Q

The roles of urate in the plasma?

A

effective antioxidant

115
Q

Causes of increased plasma uric acid level.

A

increased intake or production

reduced excretion (majority of cases)

116
Q

Describe the cycle of uric acid in human body.

A

Purines - from diet or tissue turnover

Covert to uric acid by xanthine oxidase

Excreted by kidney and intestine (mainly kidney)

117
Q

Why is gout easy to develop?

A

uric acid level in plasma is close to saturation

small disturbance -> increase easily

118
Q

What are the signs of gout?

A

Swollen joint - mostly the metatarsal joint

Inflammed and painful - ‘most intense feel of pain’

Tophi - developed in chronic gout -> restrict movement + not painful

119
Q

Compare and constrast primary and secondary gout.

A

More common in male (primary), equal risk in secondary

primary common in middle age, secondary in elderly

primary: late tophi develop, secondary: early tophi develop

acute attacks common in primary

Different association risk factors

120
Q

Why is secondary gout more common in older age?

A

declined renal function

use of diuretics

OA

121
Q

Associated risk factors of primary gout?

A

obesity

hypertension

hyperlipidaemia

alcohol use

122
Q

Associated risk factors of secondary gout.

A

diuretics

renal impairment

OA

123
Q

What are the 4 phases of gout?

A

Asymptomatic - hyperuricaemia all life + no acute attack develop

Acute - attack on isolated, peripheral joint - peak 24 hours, resolve within 1 - 2 weeks - require NSAIDs and analgesic

Intercritical - symptom-free period - more attacks + more joints affected (if no management -> joint damage

Chronic - formation of large tophi -> loss of function

124
Q

What are the treatment plan for gout?

A

Lifestyle changes

Acute attack management

Maintenance drugs

125
Q

Why is it important to identify primary or secondary gout?

A

Modify lifestyles

Modify medications

126
Q

What are the lifestyle changes needed for patients with gout?

A

Weight loss

Reduce consumption of high purine food

Reduce intake of alcohol

127
Q

What medications are used to manage acute gout attack?

A

NSAIDs - NOT aspirin

Colchicine

Intra-articular steroids

128
Q

Why is aspirin not suitbale for acute gout attack management?

A

effects on renal excertion

worsen the condition

129
Q

Why is colchicine suitable for manage gout attack?

A

Interfere with microtubles formation in neutrophil -> reduce inflammatory response

130
Q

What is the main issues with colchicine use?

A

Intense GI side effects

131
Q

What drugs are used for maintenance of gout?

A

Xanthine oxidase inhibitors - allopurinol + febuxostat -> reduce generatio

Uricosuric drugs - sulfinpyrazone -> increase excretion rate

132
Q

Why should maintenance therapy not be initiated during an acute gout attack?

A

Induce movement of crystal in affected joints

Promote inflammatory response

Worsen the pain

133
Q

Name the compound that can be used prophylactically?

A

Rasburicase - recombinant urate oxidase

134
Q

Which case should rasburicase be used to prevent gout?

A

Certain cancer treatment

Rapid tissue destruction -> increased purine release

135
Q

How are urate excreted by the kidneys?

A

Urate - freely filtered at glomerulus

Active anion exchange in early proximal tubule -> reabsorption (majority), some secreted

Dependent on tubular fluid pH, tubular flow rate, renal blood flow.

136
Q

Describe how uricosurics are effective in treatment of gout.

A

Inhibit organic anion transport -> reducing urate reabsorption

Impact on tubular fluid pH, flow rate and renal blood flow -> reduce secretion of uric acid

137
Q

What are the other drugs that have uricosuric effects?

A

Losartan - but no useful extent (active metabolite has NO effect)

HIgh dose aspirin - cannot be used in gout

138
Q

Describe the metabolism of purine into uric acid.

A

Purine catabolism -> hypoxanthine and xanthine

hypoxanthine is converted to xanthine by xanthine oxidase

xanthine oxidase converts xanthine into uric acid

139
Q

Describe the mechanism of allopurinol in gout management.

A

Inhibit the activity of xanthine oxidase

analog of hypoxanthine

being coverted into oxypurinol - oxypurinol can inhibit xanthine oxidase

De novo purine synthesis is inhibited by negative feedback if xanthine oxidase is inhibited

140
Q

What is the main consideration for the use of allopurinol?

A

renal impaired patients

lower dose or use alternative

141
Q

Pathogenesis of IBD?

A

Idiopathic

Some suggestions about underlying pathology.

142
Q

What are the suggested underlying pathology of IBD?

A

Genetic susceptibility = NOD2 mutation

Linked with GI infection

Environmental factors - food poisoning, diet, smoking, stress

Underlying immunosuppression - linked with prolonged infection and autoimmune

143
Q

Describe the inflammation of ulcerative colitis.

A

Continuous lesions - stretch

Inflammation limited to gut mucosa

Affected areas: rectum, left to whole colon

144
Q

Describe the inflammation of Crohn’s disease

A

Patchy lesions

Inflammation throughout the bowel wall

Affected areas: whole ileum, colon, other areas out of GI tract like mouths and eyes

Associated with strictures and fistulae

145
Q

Symptoms of IBD.

A

Abdominal pain

Recurrent diarrhoea

Rectal bleeding

Arthralgia - esp in Crohn’s

Rashes

Renal and hepatic effects

Inflammation of mouth or eyes - Crohns’

Strictures and fistulaes - Crohns

Short bowel syndrome - Crohn’s

146
Q

Describe how rashes can arise in IBD

A

Inflammation of subcutaneous fat -> painful nodules on shin

147
Q

What is strictures and fistulaes?

A

Strictures - permanent narrowing of the gut section

Fistulaes - abnormal connection between lumen of gut on another section or another organs

148
Q

How does short bowel syndrome arises from IBD?

A

In Crohn’s disease, surgery -> disect areas (patchy lesions) -> connect

Shorter GI tract -> reduced nutrients absorbed

149
Q

Complications of IBD

A

Affecting the absorption lead to:

Weight loss

Anaemia

Nutritional deficient

Growth suppression

Psychological effects

150
Q

Aims of pharmacological treatment of IBD

A

Induce remission - control symptoms

Maintain remission - prevent flares up

Minimal side effects

Step-wise approach

151
Q

What are the drugs used for pharmacological treatment of IBD?

A

Aminosalicylates

Glucocorticosteroids

Immunomodulators

Anti-TNF-alpha therapy

Codeine, loperamide -> symptomatic relief (require cautions)

Surgery

152
Q

When is surgery required for IBD management?

A

Conditions cannot be controlled with pharmacological

Correction needed for fistulae and strictures

153
Q

Describe the mechanism of action of aminosalicylates

A

Has 5-ASA group in the structure - anti-inflammatory effect

Diazo bond cleaved by bacteria in the GI -> release 5-ASA to exert effects

154
Q

Name some aminosalicylates that are used in IBD management

A

Sulfasalazine (not anymore)

Mesalazine

Olsalazine

Balsalazide

155
Q

Why is sulfasalazine withdrawn?

A

Contains the sulfapyridine moiety that toxic

Induce serious side effects:
Allergic reactions, rashes, GI disturbances, oligospermia, haemolytic anaemia, pancreatitis, lupus-like, Stevens-Johnson syndrome

156
Q

Efficacy of aminosalicylates in IBD management.

A

Effective in mild to moderate active disease

Very effective in maintain remission of ulcerative colitis

Less effective in Crohn’s disease

157
Q

The use of glucocorticosteroids in IBD management.

A

Only for active disease - Not for maintain remission

Use for all acute mild, moderate and severe diseases

158
Q

What drugs and formulations of glucocorticosteroids are used for IBD management for each severity.

A

Mild - topical steroids first like PR prednisolone and hydrocortisone or aminosalicylate

Moderate or mild refractory - 4-8 weeks PO steroid like prednisolone

Severe - IV hydrocortisone

159
Q

Why PO budesonide and beclomethasone is less effective in IBD management?

A

Systemic elements of inflamamtion -> vascular involved

Cause effects to absorption of these drugs

160
Q

Efficacy of glucocorticosteroids in IBD management

A

1/3 refractory

1/3 steroid-dependent disease -> additional care with withdrawal

Not useful in maintaining remission in long-term

161
Q

What is the main concern of glucocorticosteroids use?

A

Osteoporosis

162
Q

What is the option for patients with steroid refractory or dependent?

A

Use of immunomodulator

163
Q

Name the immunomodulators that can be used in IBD management.

A

Ciclosporin

Azathioprine

Methotrexate

Mercaptopurine

164
Q

Describe the mechanism of action of ciclosporin

A

bind to cyclophilin in cytoplasm of lymphocytes -> form complex

Complex inhibits calcineurin (a protein phosphatase)

Inhibit cytokine production esp IL-2

165
Q

Effectiveness of ciclosporin in IBD

A

Short course may be benefit for unresponsive and sever ulcerative colitis

166
Q

Main concerns for the use of ciclosporin

A

Significant nephrotoxic

167
Q

Effectiveness of azathioprine and mercaptopurine in IBD.

A

Useful for unresponsive or chronically active Crohn’s disease

168
Q

Metabolism of azathioprine and mercaptopurine.

A

Azathioprine cleaved -> mercaptopurine

Mercaptopurine is metabolised by thiopurine S-methyltransferase (TPMT)

169
Q

Main consideration for the used of azathioprine and mercaptopurine

A

TMPT deficiency

Accumulation -> toxicity

170
Q

What are the potential side effects of azathioprine and mercaptopurine?

A

Bone marrow suppression - bruising, blood counts

Hepatotoxicity -> require regular liver function tests

Hypersensitivity reactions -> renal failure

Immunosuppression

171
Q

Mechanism of action of azathioprine and mercaptopurine in IBD

A

Promote remission in steroid refractory patients

Allow faster reduction in steroid dose

Maintain remission

172
Q

How long does it take for azathioprine and mercaptopurine to exert its therapeutic effects?

A

3-6 months

173
Q

Requirements for the initiation of azathioprine and mercaptopurine

A

slow stepping-up to monitor adverse effects

require steroids at the start then withdrawn

174
Q

Methotrexate in IBD

(m.o.a, indications, dose, CI?)

A

Antimetabolite - dihydrofolate reductase inhibitor

Useful for refractory Crohn’s disease if azathioprine or mercaptopurine is not suitable

single weekly dose

CI in renal impairment

175
Q

Side effects of methotrexate in IBD.

A

Bone marrow suppression

Hepatoxicity

Pulmonary effects - interstitial pneumonitis

176
Q

What to monitor during the use of methotrexate in IBD?

A

Full blood count

LFTs

Signs of infection

177
Q

First-line biologic therapy for IBD

A

Anti-TNF-alpha antibodies - infliximab, adalimumab, golimumab

Effective in severe active Crohn’s disease wheer steroids and immunomodulators failed + surgery not suitbale

178
Q

Other biologic therapies for IBD

A

Vedolizumab - inhibit migration of lymphocytes to the mucosa of gut -> intestinal specific effects

Ustekinumab - second-line

179
Q

Main concerns about the use of anti-TNF-alpha therapy

A

Severe risk of infection - need to rule out latent TB

Infliximab esp - hypersenstivity reactions

PHAY00011 (9 decks)

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