Inflammation II Flashcards
Asthma, COPD, RA, OA, Gout, IBD (179 cards)
1
Q
What are the characterised symptoms of asthma?
A
Bronchial hyper-responsiveness
Airway remodelling -> reduced function
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
3
Q
What does it mean by bronchial hyper-responsiveness?
A
Lower concentration of bronchoconstrictors can cause bronchial response
4
Q
Give some examples of bronchoconstrictors.
A
Histamine
Methacholine - cholinergic analogue
Allergen - specific for asthmatic patients
Adenosine - specific for asthmatic patients
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
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.
7
Q
Symptoms of asthma.
A
Wheeze
Dyspnoea
Tightness of chest
Cough
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)
9
Q
Signs of asthma.
A
Wheeze
No signs between episodes
Hyperinflation (possible)
Reduced lung function
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
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
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
13
Q
What is the aim of asthma treatment?
A
Control symptoms
Prevent exacerbations
Achieve optimal lung function
Minimal side effects
14
Q
What are the two guidelines used for treating asthma?
A
Step-wise approach of BTS/SIGN
Step-wise approach of NICE guidelines
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
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
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
18
Q
Name the bronchodilators used in the management of asthma
A
Anticholinergics (muscarinic ACh receptors antagonist)
Beta-2 receptor agonists
Theophylline
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
20
Q
Name examples for long-acting and short-acting anticholinergics
A
Short-acting: ipratropium, oxitropium
Long-acting: tiotropium
21
Q
Explain how beta-2 receptor agonists can be effective in asthma management
A
Mimic effects of circulating adrenaline
Raise cAMP -> relaxation
22
Q
Name some short-acting and long-acting beta-2 receptor agonists.
A
Short-acting: salbutamol, bambuterol, terbutaline
Long-acting: salmeterol, formoterol
23
Q
What is the main issue with high-dose beta-2 receptor agonist?
A
Hypokalaemia -> cardiac arrhythmic
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
25
What is the main issue with the use of theophylline?
Hypokalaemia
Narrow therapeutic index
26
What is a non-bronchodilator that can be effective in asthma management?
Montelukast
CysLT1 receptor (Gq) antagonist -> prevent LT-induced bronchoconstriction
27
Name some cromones drugs and explain why it is used for asthma?
Sodium cromoglicate, nedocromil sodium
Stabilise afferent sensory nerve -> reduce hyperresponsiveness and twitchiness of airways to stimulus
28
What are the potent leukotrienes associated with asthma development?
LTC4, LTD4 and LTE4
From mast cells + activated eosinophils
Recruit + activate more eosinophils
Target CysLT1 receptors
29
Describe the target of some leukotriene inhibitors used for asthma
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.
30
Name some inhaled glucorcoticoids used in asthma.
Beclomethasone, budesonide, fluticasone, mometasone, ciclesonide
31
When are systemic glucocorticoids used for asthma management?
Severe asthma
Uncontrolled asthma
Exacerbations of well-controlled asthma
32
Explain how glucorticoids can tackle asthma efficiently
Inhibit cytokine production, inflammatory cell recruitment and PAF + LTs synthesis
Upregulate Beta-receptors with prolonged use
MAY downregulate muscarinic receptors through canine pathways
33
What are the local side effects with the use of inhaled corticosteroids?
Candidiasis
Dysphonia - change in voice quality
Pharyngitis
34
Name biologic drugs used for asthma and their indications
Anti-IgE - omalizumab - severe ashtma with allergic basis
Anti-IL5 - reslizumab, mepolizumab, benralizumab - severe eosinophillic asthma
Anti-IL13/IL4 - dupilumab, lebrikizumab, trealokinumab
35
Explain why helminth infection is a concern when targeting cytokines associated with eosinophil function
Eosinophil role = parasite management.
36
What are the clinical features of COPD that are different from asthma?
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
37
Why are COPD and asthma difficult to distinguish at first?
Both are obstructive airway disease
Marked with reduced FEV1 and reduced FEV1/PVC ratio
38
What inflammatory cells drive the pathogensis of COPD?
Neutrophils
39
Why does COPD not have bronchial hyperresponsiveness like asthma?
Persistent degree of bronchoconstriction
Ongoing inflammation and production of sputum
Permanent structural changes of airway -> not expose sensory nerves like in asthma
40
Why does COPD have limited response to bronchodilators?
Permanent structural changes
Only small function can be reversed by the use of bronchodilators
41
Asthma and COPD, which condition has a better response to corticosteroids?
Asthma
42
Explain how cor pulmonale arise from COPD.
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)
43
Describe the pathogenesis of COPD
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
44
What enzymes do neutrophils released in COPD that contribute to permanent damage to the airway structure?
MMPs = destroy extracellular matrix
Elastase = stiffen the lung, break down elastin
Capthesins = cause damage over time
45
Emphysema meaning
Gradual destruction of the air sacs (alveoli) in the lungs
46
What are the pharmacological management of COPD?
Bronchodilators:
- Anticholinergics
- Beta-2 receptor agonist
- Theophylline
Steroids along with antibiotics where appropriate
Oxygen (care with concentration)
Smoking cessation
47
Why should patients with COPD not be managed with an excessive concentration of oxygen?
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
48
What drive the breathing in patients with COPD?
Hypoxic drive
Breathing based on reduction in O2 concentration (normal depend on increase in pCO2)
49
What are the benefits of smoking cessation?
Slow down the rate of decline in lung function
If stop early, the rate can level out with person who not smoke
50
How are anticholinergics effective in COPD management?
Reduce baseline parasympathetic tone of the airway
Reduce mucus secretion - break down the bonds in mucus -> less viscous -> easily cleared
51
Explain why salbutamol might not be effective in severe COPD cases?
Airways are so structurally damaged
52
Give example of PDE inhibitors that can be used in COPD.
Theophylline - non-selective phosphodiesterase inhibitor
Roflumilast - selective PDE4 inhibitor
53
How can rheumatoid arthritis reduce life expectancy?
General strain of chronic inflammation -> affect the cardiovascular system
54
Symptoms of rheumatoid arthritis.
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.
55
How does rheumatoid arthritis result in carpal tunnel syndrome?
Pressure on nerve caused by inflammatory process in joints
56
Laboratory signs of rheumatoid arthritis.
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
57
Why is ACPA a specific test for RA?
Chronic inflammation -> arginine residue within protein coverted to citrulline
Change structure of protein -> produce Ig against
Can detect early
58
What factor play a more crucical role in the development of RA? Genetic or Environment?
Genetics
59
How do the produced autoantigens damage the joint?
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.
60
Describe the events happening in the rheumatoid joint.
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
61
What are the inflammatory cells recruited into the rheumatoid joint?
Macrophage - type A synoviocyte
Fibroblast-like - type B synoviocyte
Lymphocyte T and B
Plasma cells
Dendritic cells
62
What do inflammatory cells once recruited in the rheumatoid joints?
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
63
What are the classes of drugs that can be used for pharmacological treatment of RA?
NSAIDs
Steroids
DMARDs
Anti-cytokine
64
Why is NSAIDs suitable for RA?
Anti-inflammatory effect - suppress the response
Analgesic - reduce pain
65
Why is steroids suitable for RA?
Anti-inflammatory effect
Slow down disease progression
Bridge-therapy - needed when switching between DMARD agent
66
General mode of action of DMARDs?
Reduce activation of inflammatory cells
Reduce generation of pro-inflammatory cytokines like TNF-alpha, IL-6, IL-1
67
What are the common concerns about the use of DMARDs?
Side effects
Patients tolerance
Slow onset of action
68
Name the conventional DMARDs used for RA.
Methotrexate
Sulfasalazine
Penicillamine
Gold
Azathioprine
Ciclosporine
Hydroxychloroquine
Leflunomide
69
What anti-cytokine class is the first-line?
Anti-TNF alpha - infliximab, adalimumab, etanercept
70
What are the advantages of methotrexate?
Reasonably well tolerated
Effective in majority
Slow disease progression
Weekly dose
Side effects can be managed by folate -> N+V
71
What are the disadvantages of methotrexate?
Bone marrow suppression -> require blood monitoring
Require regular LFTs and urine tests
Increased susceptibility to infections - pneumonitis
Mucositis
Interaction with NSAIDs - kidney problems
72
What are the advantages of sulfasalazine?
Reasonably well tolerated
Slow disease progression
Similar efficacy to methotrexate
73
What are the disadvantages of sulfasalazine?
Blood dyscrasisas -> require blood monitoring
Require LFT
Rashes and severe GI side effects
Reversible infertility (oligospermia)
74
What DMARD is associated with severe GI side effects and rash?
Sulfasalazine
Ciclosporine
75
What DMARD is associated with infertility issues?
Sulfasalazine
76
Which DMARD is associated with susceptibility to infection?
Methotrexate
Azathioprine
Leflunomide
Ciclosporine
77
What composition of the aminosalicylate (sulfasalazine) is responsible for the side effects
Sulfapyridine
78
What components of the aminosalicylates (sulfasalazine) is responsible for the anti-inflammatory effects?
5-ASA = 5 - amino salicyclic acid
79
Issues associated with the use of hydroxychloroquine
Retinopathy
Overdose extreme toxicity
CI in hepatic and renal impairment
Blood dyscrasis
Hair loss and depigmentation
80
Which DMARDs is associated with visual issues?
Hydroxychloroquine
81
Which DMARDs is associated blood dyscransias?
Sulfasalazine
Hydroxychloroquine
Gold
Penicillamine
82
Which DMARDs are associated with bone marrow suppression?
Methotrexate
Azathioprine
83
Name of gold given IM.
Aurothiomalate - discontinue if not effective within 2 months
84
Name of gold given PO
Auranofin
85
Which DMARDs is associated with alopecia?
Gold
86
Which DMARDs is associated with nephrotoxicity?
Gold
Penicillamine
Ciclosporine
87
Which DMARDs is associated with rash?
Sulfasalazine
Penicillamine
Ciclosporine
88
Which DMARDs is associated with hepatoxicity?
Leflunomide
89
Which DMARDs is severely tetratogenic?
Leflunomide
90
Which DMARD is associated with loss of taste?
Penicillamine
91
Which DMARD is associated with hair loss?
Hydroxychloroquine
92
Which DMARD is licensed for severe active RA?
Ciclosporine
93
Why is ciclosporine the last option for RA?
Side effects profile:
- severe nephrotoxicity
- severe immunosuppression
- severe GI side effects
94
When should anti-cytokine be used for RA?
when cDMARDs failed
95
What classes of biological DMARDs are preserved for last choices?
CTLA4 fusion protein - abatacept
JAK inhibitors - tofacitinib, baricitinib
96
Classes of biological DMARDs
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
Roles of tendon in the knee.
Stabilise bones
Connect bones - muscles
98
Roles of ligament in the knee.
Stabilise bone
Connect bones - bones
99
Roles of lubricant cartilage in the knee
Cover the end of the bones
Allow the joint to move freely
Prevent damage to the end of bones
100
What is synovium?
a membrane in the joint capsule
contain synovial fluid - rich in glucosaminoglycan -> lubricant
101
Describe what happened in the joint structure in osteoarthritis.
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
What is osteophyte?
Bony projections
Response from the body to stabilise the joint
Worsen the situation instead
103
Describe what happened in the joint in advanced OA case.
Little cartilage remained
Angulation of the bone
Exposure of subchondral bone -> polishing the bone structure as two bones rubbing on each
104
In terms of inflammation, what is the main differences between RA and OA?
OA - inflammation is the response to joint damage
RA - inflammation drives the damage of joint + disease propagation
105
What causes pseudogout?
Calcification
deposition of calcium pyrophosphate in synovium
106
What are the possible causes of OA?
Joint overuse -> abnormal wear and tear
Muscle weakness - loss of muscle mass -> more strain on joints
Obesity -> weight bearing joints
Genetic
107
Symptoms of OA?
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
Treatment of OA?
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
Why is the use of opioid not ideal in patients with OA?
side effects not ideal for elderly
110
What is the main caution for the use of intra-articular steroids?
Must not inject pathogens immune-protected environment
Sepsis arthritis, avascular necrosis
111
What dietary supplementation can be given to OA patients?
Glycosaminoglycans
Might induce the production of hyaluronic acid -> synovial fluid and cartilage
112
Why do we need to consider shellfish allergy when giving glycosamineglycans supplement?
glycosaminoglycans supplement are derived from shell-fish
113
What is gout?
Disorder of purine metabolism -> increased uric acid level
sodium urate crystal deposits -> inflammation and pain
114
The roles of urate in the plasma?
effective antioxidant
115
Causes of increased plasma uric acid level.
increased intake or production
reduced excretion (majority of cases)
116
Describe the cycle of uric acid in human body.
Purines - from diet or tissue turnover
Covert to uric acid by xanthine oxidase
Excreted by kidney and intestine (mainly kidney)
117
Why is gout easy to develop?
uric acid level in plasma is close to saturation
small disturbance -> increase easily
118
What are the signs of gout?
Swollen joint - mostly the metatarsal joint
Inflammed and painful - 'most intense feel of pain'
Tophi - developed in chronic gout -> restrict movement + not painful
119
Compare and constrast primary and secondary gout.
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
Why is secondary gout more common in older age?
declined renal function
use of diuretics
OA
121
Associated risk factors of primary gout?
obesity
hypertension
hyperlipidaemia
alcohol use
122
Associated risk factors of secondary gout.
diuretics
renal impairment
OA
123
What are the 4 phases of gout?
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
What are the treatment plan for gout?
Lifestyle changes
Acute attack management
Maintenance drugs
125
Why is it important to identify primary or secondary gout?
Modify lifestyles
Modify medications
126
What are the lifestyle changes needed for patients with gout?
Weight loss
Reduce consumption of high purine food
Reduce intake of alcohol
127
What medications are used to manage acute gout attack?
NSAIDs - NOT aspirin
Colchicine
Intra-articular steroids
128
Why is aspirin not suitbale for acute gout attack management?
effects on renal excertion
worsen the condition
129
Why is colchicine suitable for manage gout attack?
Interfere with microtubles formation in neutrophil -> reduce inflammatory response
130
What is the main issues with colchicine use?
Intense GI side effects
131
What drugs are used for maintenance of gout?
Xanthine oxidase inhibitors - allopurinol + febuxostat -> reduce generatio
Uricosuric drugs - sulfinpyrazone -> increase excretion rate
132
Why should maintenance therapy not be initiated during an acute gout attack?
Induce movement of crystal in affected joints
Promote inflammatory response
Worsen the pain
133
Name the compound that can be used prophylactically?
Rasburicase - recombinant urate oxidase
134
Which case should rasburicase be used to prevent gout?
Certain cancer treatment
Rapid tissue destruction -> increased purine release
135
How are urate excreted by the kidneys?
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
Describe how uricosurics are effective in treatment of gout.
Inhibit organic anion transport -> reducing urate reabsorption
Impact on tubular fluid pH, flow rate and renal blood flow -> reduce secretion of uric acid
137
What are the other drugs that have uricosuric effects?
Losartan - but no useful extent (active metabolite has NO effect)
HIgh dose aspirin - cannot be used in gout
138
Describe the metabolism of purine into uric acid.
Purine catabolism -> hypoxanthine and xanthine
hypoxanthine is converted to xanthine by xanthine oxidase
xanthine oxidase converts xanthine into uric acid
139
Describe the mechanism of allopurinol in gout management.
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
What is the main consideration for the use of allopurinol?
renal impaired patients
lower dose or use alternative
141
Pathogenesis of IBD?
Idiopathic
Some suggestions about underlying pathology.
142
What are the suggested underlying pathology of IBD?
Genetic susceptibility = NOD2 mutation
Linked with GI infection
Environmental factors - food poisoning, diet, smoking, stress
Underlying immunosuppression - linked with prolonged infection and autoimmune
143
Describe the inflammation of ulcerative colitis.
Continuous lesions - stretch
Inflammation limited to gut mucosa
Affected areas: rectum, left to whole colon
144
Describe the inflammation of Crohn's disease
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
Symptoms of IBD.
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
Describe how rashes can arise in IBD
Inflammation of subcutaneous fat -> painful nodules on shin
147
What is strictures and fistulaes?
Strictures - permanent narrowing of the gut section
Fistulaes - abnormal connection between lumen of gut on another section or another organs
148
How does short bowel syndrome arises from IBD?
In Crohn's disease, surgery -> disect areas (patchy lesions) -> connect
Shorter GI tract -> reduced nutrients absorbed
149
Complications of IBD
Affecting the absorption lead to:
Weight loss
Anaemia
Nutritional deficient
Growth suppression
Psychological effects
150
Aims of pharmacological treatment of IBD
Induce remission - control symptoms
Maintain remission - prevent flares up
Minimal side effects
Step-wise approach
151
What are the drugs used for pharmacological treatment of IBD?
Aminosalicylates
Glucocorticosteroids
Immunomodulators
Anti-TNF-alpha therapy
Codeine, loperamide -> symptomatic relief (require cautions)
Surgery
152
When is surgery required for IBD management?
Conditions cannot be controlled with pharmacological
Correction needed for fistulae and strictures
153
Describe the mechanism of action of aminosalicylates
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
Name some aminosalicylates that are used in IBD management
Sulfasalazine (not anymore)
Mesalazine
Olsalazine
Balsalazide
155
Why is sulfasalazine withdrawn?
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
Efficacy of aminosalicylates in IBD management.
Effective in mild to moderate active disease
Very effective in maintain remission of ulcerative colitis
Less effective in Crohn's disease
157
The use of glucocorticosteroids in IBD management.
Only for active disease - Not for maintain remission
Use for all acute mild, moderate and severe diseases
158
What drugs and formulations of glucocorticosteroids are used for IBD management for each severity.
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
Why PO budesonide and beclomethasone is less effective in IBD management?
Systemic elements of inflamamtion -> vascular involved
Cause effects to absorption of these drugs
160
Efficacy of glucocorticosteroids in IBD management
1/3 refractory
1/3 steroid-dependent disease -> additional care with withdrawal
Not useful in maintaining remission in long-term
161
What is the main concern of glucocorticosteroids use?
Osteoporosis
162
What is the option for patients with steroid refractory or dependent?
Use of immunomodulator
163
Name the immunomodulators that can be used in IBD management.
Ciclosporin
Azathioprine
Methotrexate
Mercaptopurine
164
Describe the mechanism of action of ciclosporin
bind to cyclophilin in cytoplasm of lymphocytes -> form complex
Complex inhibits calcineurin (a protein phosphatase)
Inhibit cytokine production esp IL-2
165
Effectiveness of ciclosporin in IBD
Short course may be benefit for unresponsive and sever ulcerative colitis
166
Main concerns for the use of ciclosporin
Significant nephrotoxic
167
Effectiveness of azathioprine and mercaptopurine in IBD.
Useful for unresponsive or chronically active Crohn's disease
168
Metabolism of azathioprine and mercaptopurine.
Azathioprine cleaved -> mercaptopurine
Mercaptopurine is metabolised by thiopurine S-methyltransferase (TPMT)
169
Main consideration for the used of azathioprine and mercaptopurine
TMPT deficiency
Accumulation -> toxicity
170
What are the potential side effects of azathioprine and mercaptopurine?
Bone marrow suppression - bruising, blood counts
Hepatotoxicity -> require regular liver function tests
Hypersensitivity reactions -> renal failure
Immunosuppression
171
Mechanism of action of azathioprine and mercaptopurine in IBD
Promote remission in steroid refractory patients
Allow faster reduction in steroid dose
Maintain remission
172
How long does it take for azathioprine and mercaptopurine to exert its therapeutic effects?
3-6 months
173
Requirements for the initiation of azathioprine and mercaptopurine
slow stepping-up to monitor adverse effects
require steroids at the start then withdrawn
174
Methotrexate in IBD
(m.o.a, indications, dose, CI?)
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
Side effects of methotrexate in IBD.
Bone marrow suppression
Hepatoxicity
Pulmonary effects - interstitial pneumonitis
176
What to monitor during the use of methotrexate in IBD?
Full blood count
LFTs
Signs of infection
177
First-line biologic therapy for IBD
Anti-TNF-alpha antibodies - infliximab, adalimumab, golimumab
Effective in severe active Crohn's disease wheer steroids and immunomodulators failed + surgery not suitbale
178
Other biologic therapies for IBD
Vedolizumab - inhibit migration of lymphocytes to the mucosa of gut -> intestinal specific effects
Ustekinumab - second-line
179
Main concerns about the use of anti-TNF-alpha therapy
Severe risk of infection - need to rule out latent TB
Infliximab esp - hypersenstivity reactions
