Inflammation and GI Diseases Flashcards
(278 cards)
1
Q
What is a tolerogen?
A
Antigens that induce tolerance rather than immune reactivity
2
Q
What is an immunogen?
A
A substance capable of eliciting an immune response
3
Q
What is autoimmunity?
A
An immune response against self antigens.
4
Q
What is central tolerance?
A
The limitation of the development of autoreactive B and T cells, essentially stopping new B and T cells from attacking our own cells.
5
Q
What is peripheral tolerance?
A
The regulation of autoreactive cells already in circulation. This stops mature cells from attacking own cells.
6
Q
Where do T-cells undergo development/maturation?
A
In the Thymus
7
Q
Where do B-cells undergo development/maturation?
A
In the Bone Marrow
8
Q
What are the different reactions of T-cell to a self antigen, and the consequent actions?
A
Strong reaction - Negative selection/Apoptosis
Intermediate reaction - Becomes T-regulatory cell
Weak reaction - Positive selection
No reaction - Apoptosis
9
Q
What are the different reactions of B-cell to a self antigen, and the consequent actions?
A
High avidity - receptor editing to make new light chain of antibodies that are no longer reactive to self antigen. If editing fails, apoptosis occurs.
Low avidity - antigen receptor expression is reduced and cells become anergic (functionally unresponsive).
10
Q
What occurs to a mature T-cell that responds to a self-antigen?
A
Anergy - functional unresponsiveness, without necessary co-stimulatory signals
Suppression - block in activation by T regulatory cells
Deletion - apoptosis
11
Q
What occurs to a mature B-cell that responds to a self antigen?
A
If a B-cell responds to a self antigen without T-cell help, it can either become functionally unresponsive (anergic), undergo apoptosis, or can become regulated by inhibitory receptors.
12
Q
What do T-cells do?
A
They recognise all different kinds of antigens.
13
Q
What do B-cells do?
A
They create antibodies to antigens that are recognised by T-cells.
14
Q
Where will peripheral anergy occur?
A
In the Secondary Lymphoid Tissue
15
Q
What are the secondary lymphoid tissues?
A
Lymph nodes, Spleen, Tonsils, and other mucous membranes in the body i.e. the bowels
16
Q
List types of self tolerance in different locations around the body
A
Central tolerance, antigen segregation, peripheral anergy, regulatory cells, cytokine deviation, clonal deletion
17
Q
How do autoimmune diseases arise in the body?
A
Develops when multiple layers of self tolerance are dysfunctional and fail. A response to endogenous self antigens lead to tissue damage and since the antigen cannot be eliminated, the response is sustained. Results from a combination of genetic susceptibility, breakdown of natural tolerance mechanisms and environmental triggers.
18
Q
List some common Autoimmune Diseases
A
Rheumatoid Arthritis, Myasthenia Gravis, Grave’s Disease, Autoimmune Diabetes
19
Q
Describe how a fever occurs in the body
A
- A macrophage will ingest a bacterium (gram negative)
- The bacterium is degraded, which releases endotoxins which induce IL-1 production inside the macrophage.
- IL-1 will travel through the bloodstream to the hypothalamus.
- IL-1 causes the hypothalamus to produce prostaglandins which ‘reset’ the body to a higher temperature causing a fever.
20
Q
Describe the sequence of the inflammatory response.
A
- Insult by trauma or pathogen causes acute phase reaction.
- Platelets adhere and due to histamine release there is a rapid, short term vasoconstriction of nearby vessels.
- Then, there is a cytokine-induced vasodilation of nearby vessels (increased heat & blood flow)
- Activation of complement, coagulation, fibrinolytic and kinin systems.
- Phagocytes marginate, and perform diapedesis, forcing their way into the tissue through gaps in the endothelium
- Increased vascular permeability and extravasation of serum proteins (exudate) with resultant tissue swelling
- Phagocytosis of foreign material with pus formation
- Wound healing and tissue remodelling
21
Q
What are some pro-inflammatory mediators?
A
Acute phase proteins, complement system (C3a, C5a), kinins, cytokines (TNF, IL-6, IL-1),
chemokines (CXCL8, CCL2, CCL5), growth factors (M-CSF, GM-CSF), adhesion molecules (VCAM-1, ICAM-1), MMPs (3&9), clotting factors, prostaglandins
22
Q
What are some acute phase proteins?
A
C-reactive protein, fibrinogen, serum amyloid A, complement factors, haptoglobin and ferritin
23
Q
What do the acute phase proteins do?
A
C-reactive protein - acts as an opsonin
Fibrinogen - coagulation
Serum Amyloid A - cell recruitment and MMP inducer
Complement factors - act as opsonins, lysis, clumping, chemotaxis
Haptoglobin and ferritin - bind haemoglobin and Fe
24
Q
Describe some of the major pro-inflammatory cytokines and their functions
A
IL-1 - induces inflammation, acts on hypothalamus, induces APPs from liver
TNFalpha - induces inflammation, induces APPs from liver, induces cell death, neutrophil activation
IL-12 - induces NK cells, promotes Th1
IL-6 - induces APPs, influences adaptive immunity
IFNalpha/beta - induces antiviral state, activates NK cells
25
Describe adhesion molecules and the different types
Transmembrane receptors that bind to other cells or to the ECM. Made up of four families: Ig superfamily (VCAM-1, ICAM-1), cadherins (E,P,N), selectins (E,P,L), integrins
26
Describe the metalloproteinases involved in inflammation and what they do
Matrix metalloproteinases - degrade and remodel ECM
ADAMs - cleave cytokine and adhesion molecules from cell surface
ADAMTs - cleaves the same as ADAMS and degrades proteoglycans
27
What is NFkB?
A family of transcription factors that regulate hundreds of pro-inflammatory mediators. It is activated by the phosphorylation of IkB and moves into the nucleus to begin transcription.
28
What mediators of inflammation does NFkB induce?
Cytokines (TNF, IL-6, IL-1), chemokines and their receptors, adhesion molecules, MMPs, growth factors, APPs
29
Name some anti-inflammatory mediators and their role
Anti-inflammatory cytokines (TGFbeta, IL-4, IL-10)
Soluble adhesion molecules - removes adhesion molecules
Tissue inhibitors of MMPs (TIMPs) - inhibit MMPs
Plasmin system - breaks down clot
Opioid peptides - counteract pain
Resolvins/protectins - anti-inflammatory lipid mediators
30
Describe the different types of inflammation.
Acute - necessary part of immune response, has a resolution phase
Chronic - sustained acute inflammatory response, no resolution phase, tissue destruction, can lead to disease.
31
Describe the process whereby prostaglandins are synthesised.
1. Phospholipids are transformed by Phospholipase A2 in response to a stimulus.
2. Arachidonic acid is made. This will then enter the COX enzyme and become PGG2 and then be rapidly changed into PGH2.
3. PGH2 is the precursor to all other prostaglandins. These can be synthesised by other pathways from PGH2.
32
Describe the process whereby leukotrienes and thromboxanes can be synthesised.
1. Phospholipids are transformed by Phospholipase A2 in response to a stimulus.
2. Arachidonic acid is made. This will then enter a different pathway involving lipooxygenases which act on arachidonic acid.
3. These lipooxygenases will turn arachidonic acid into different leukotrienes which can mediate allergy responses.
4. With respect to thromboxane, arachidonic can again enter the COX enzyme, be transformed to PGG2 then PGH2.
5. After this, thromboxane synthase can act on PGH2 and change it to thromboxane A2.
33
Describe COX-1
A constitutive enzyme present in most cells. It produces prostanoids which act as homeostatic regulators.
34
Describe COX-2
This enzyme is not normally present in the body (except for CNS and renal tissue), but it is induced by inflammatory stimuli.
35
Describe the pathophysiology of Rheumatoid Arthritis (PHASES).
1. Initiator phase - beginning of autoimmunity as joint. APCs and citrullination of proteins now seen as non-self.
2. Inflammation phase - self antigens presented. Increased numbers of T and B cells, uncontrolled by T-reg cells
3. Self perpetuating phase - inflammatory damage in synovium causes self antigens previously not recognised by immune system become visible. Immune response against cartilage and infiltration of immune cells.
4. Destruction phase - synovial fibroblasts and osteoclasts activated by cytokines (TNF, IL-6), destroy bone and cartilage.
36
Describe what T-cells do in Rheumatoid Arthritis.
Potentially activate monocytes, macrophages and synovial fibroblasts --> production of TNFalpha, IL-6 and IL-1, which induce the production of MMPs which degrade cartilage.
37
Describe what B cells do in Rheumatoid Arthritis.
Produce autoantibodies which can activate complement system and also bind to macrophages in synovium which can perpetuate inflammation.
38
Describe what autoantibodies do in Rheumatoid Arthritis
Rheumatoid factor (RF) and anti-citrullinated peptides (anti-CCP) are directed against self antigens on cells outside of joint.
39
Describe the mechanism of action of Methotrexate.
It is a competitive, reversible inhibitor of dihydrofolate reductase. It reduces the formation of dihydrofolate, tetrahydrofolate and N5,N10-methylenetetrahydrofolate. In turn, this will affect the synthesis of purines used for DNA synthesis.
40
Describe the mechanism of action of Azathioprine.
It is a pro-drug of 6-mercaptopurine. In the body, it is activated by glutathione to mercaptopurine. It then enters the purine salvage pathway where it undergoes metabolism in the body by hypoxanthine-guaninephosphoribosyltransferase which changes the molecule to a nucleoside derivative (TIMP) which can then undergo more enzymatic transformations into TGMP and TdGTP which act as substrates for DNA polymerase and becomes incorporated into DNA/RNA, inhibiting DNA synthesis.
41
Describe the mechanism of action of Allopurinol
Allopurinol works to inhibit xanthine oxidase which is responsible for the synthesis of uric acid. It does this by inhibiting xanthine synthesis and uric acid synthesis. In the body, some of the Allopurinol is metabolised into Oxypurinol in the liver.
42
Describe the mechanism of action of Febuxostat.
It blocks the active site of xanthine oxidase, stopping entry of substrate.
43
Describe the mechanism of action of Leflunomide.
It inhibits dihydroorotate dehydrogenase which is responsible for the synthesis of de novo pyrimidines. This affect the synthesis of new DNA/RNA.
44
Describe the differences and similarities of COX-1 and COX-2.
- Both enzymes have: a hydrophobic binding channel, a catalytic binding site, an acylation site (Serine 529), an arginine residue for ionic interactions.
- However, COX-1 has an Isoleucine residue at 523, where as COX-2 has a smaller Valine residue which allows for an extra hydrophilic binding pocket - this means there is more selectivity available for COX-2.
45
Describe the mechanism of action of Aspirin.
Aspirin is unique. It is the only non-selective NSAID that can irreversibly inhibit the COX enzyme. Aspirin forms a covalent bond with Serine 523 residue in both isoforms of COX, which blocks arachidonic acid access to binding site.
46
Describe the mechansim of action of non-selective NSAIDs.
The bulky molecule will block the COX channel, restricting the access of arachidonic acid to the active site. As well as this, the acid group in most non-selective NSAIDs mimics the acid group in arachidonic acid, allowing the drug to anchor itself in place at Arginine 120.
47
Describe the mechanism of action of COX-2 selective NSAIDs.
The sulfur containing group in COX-2 selective drugs (Sulfonamide, Sulfone) allows for a specific interaction in the hydrophilic binding pocket that is unique to COX-2 (Valine). This group must be able to hydrogen bond too. This allows for a stronger blockage of the enzyme's active site from arachidonic acid, and prevents arachidonic acid from ionically binding with Arginine 120.
48
What is Infliximab?
Chimeric (mouse/human) anti-TNF mAb
49
What is Adalimumab?
Anti-TNF, fully human recombinant mAb
50
What is Etanercept?
Recombinant soluble human TNF p75 fusion protein (two p75 receptors) linked to Fc portion of human IgG
51
What are the signs and symptoms of Myasthenia Gravis?
- Patients USUALLY present with ocular symptoms (diplopia, drooping eyelids, restricted eye movement.
- Dysphagia, slurred speech, weakness in arms, legs, neck, chewing difficulties, lack of facial expression, shortness of breath (Myasthenic crisis)
52
Describe how Acetylcholine helps induce a muscle contraction.
1. Action potential travels down motor neuron.
2. Action potential opens voltage-gated Ca2+ channel.
3. Calcium enters synaptic terminal.
4. This causes Acetylcholine to be exocytosed, and diffuses across synaptic cleft.
5. Once diffused, Acetylcholine interacts with nicotinic acetylcholine receptor.
6. Once bound, a ligand-gated ion channel opens allowing Na+ into the muscle cell.
7. With Na+ inside the muscle cell, the end plate action potential contracts the muscle fibers
8. Once the contraction is completed, acetylcholinesterase removes acetylcholine, and the muscle relaxes.
53
Describe the pathophysiology of Myasthenia Gravis.
In Myasthenia Gravis, there is a loss of nicotinic acetylcholine receptors. This results in impaired transmission of the action potential. The loss of receptors is caused by autoantibodies.
54
What are the effects of acetylcholinesterase inhibitors?
Acetylcholinesterase inhibitors are parasympathomimetic drugs, so they mimic the body's parasympathetic nervous system ("rest and digest").
Actions on:
- Cardiovascular system - bradycardia, decreased cardiac output, vasodilation (decrease blood pressure).
- Smooth muscle - contraction of smooth muscle, increased peristaltic activity, bladder contraction, constriction of bronchioles
- Eye - pupil constriction, constriction of ciliary muscle (decreased intraocular pressure)
- Glands - increased secretion (saliva, tears, bronchial secretion, digestive enzymes, sweating)
55
What can exacerbate Myasthenia Gravis?
Infection (flu jabs!!!), stress/trauma, thyroid dysfunction, withdrawal of acetylcholinesterase inhibitors, rapid introduction or increase of steroids, anaemia, electrolyte disturbances, some drugs
56
What drugs can interfere with neuromuscular transmission?
- Phenytoin, Carbamazepine
- Clindamycin, Aminoglycosides (Gentamycin, Amikacin), Fluoroquinolones, Macrolides
- Lithium, Chlorpromazine
- Hydroxychloroquine
57
What drugs can increase muscle weakness?
- Magnesium causing hypermagnesemia
- Benzodiazepines
- Beta-blockers
- Diuretics
- Verapamil
- Statins
58
Dose for Pyridostigmine
15mg QDS initially, can step up to 60mg 4-6 times a day (WITH FOOD)
59
What side effects can present with acetylcholinesterase inhibitor treatment?
Nicotinic effects - muscle and abdominal cramps
Muscarinic effects - gut hypermobility (cramps/diarrhoea), increased sweat/salivation/crying, hypotension, bradycardia, miosis (small pupils), urinary incontinence, increased bronchial secretions, and tachypnoea (rapid breathing).
60
How do you manage side effects in Myasthenia Gravis treatment with Acetylcholinesterase inhibitors?
- Take with food, will reduce GI side effects
- Co-prescribing with anti-muscarinic will help prevent unwanted muscarinic effects (Glycopyrrolate, Propantheline)
- Diarrhoea can be managed with Loperamide
61
What can happen with excessive acetylcholinesterase inhibitor treatment?
Patients can experience as cholinergic crisis (muscle weakness that is not worsening MG)
62
Describe the mechanism of action of Pyridostigmine.
Pyridostigmine is a reversible inhibitor of Acetylcholinesterase. It inactivates the enzyme by carbamylating the hydroxyl group of the Serine residue. The enzyme's regeneration by water is very slow, hence the inhibition is reversible.
63
What are the special patient groups for Paracetamol?
Children, patients with body weight <50kg, patients with liver impairment
64
What groups of patients would you resort to Paracetamol instead of an NSAID for pain relief?
Elderly, patients with hypertension, CVD, renal impairment, GI issues and patients who take medicines interacting with NSAIDs (Warfarin).
65
What are the special patient groups for Aspirin?
Contraindicated in patients: <16y/o, previous/active peptic ulcer, bleeding disorders, severe cardiac failure, previous allergic reaction to Aspirin or NSAID, patients with Asthma
66
What interactions does Aspirin have with other drugs?
- Drugs that increase risk of GI irritation and bleeding (Steroids, NSAIDS, SSRIs, anticoagulants)
- Drugs that increase the risk of renal side effects (Bisphosphonates)
- Drugs where Aspirin can increase the toxicity of other drugs (Methotrexate)
67
When will analgesic effects be experienced by patients with NSAID usage?
Within a week
68
When will anti-inflammatory effects be experienced by patients with NSAID usage?
Around 3 weeks
69
What KEY side effects can be experienced with NSAID usage?
GI mucosa, renal, cardiovascular system
70
What GI side effects are caused by NSAID usage?
1. Suppression of homeostatic prostanoids (COX-1 inhibition) - reduced mucus protection, reduced bicarbonate production, reduced mucosal perfusion
2. Topical irritation and direct damage of mucosa
71
What are the highest and lowest risk NSAIDS for GI side effects
Highest risk: Piroxicam, Ketoprofen, Ketorolac
Intermediate risk: Indometacin, Diclofenac, Naproxen
Lower risk: Ibuprofen (low dose, max. 1.2g/day)
Lowest risk: 'coxib' drugs - selective COX-2 inhibitors
72
Why are selective COX-2 inhibitors preferred over non-selective NSAIDs?
They are designed to inhibit the prostanoids from the COX-2 isoform, which are more heavily involved with inflammatory responses and play less of a role in GI homeostasis.
73
What key points are there for reducing risk of GI side effects with NSAID usage?
- Co-prescribe with PPI
- Take with food to reduce contact irritation
- Lowest effective dose for shortest time
74
What are the highest and lowest risk NSAIDS for cardiovascular events?
Highest thrombotic risk: COX-2 inhibitors, Diclofenac (150mg/day), Ibuprofen (2.4g or more/day)
Lower thrombotic risk: Naproxen (1g/day)
No evidence of risk: Ibuprofen (low dose, 1.2g or less/day)
75
What key points are there for reducing the risk of cardiovascular events with NSAID usage?
- Careful selection of NSAID
- Lowest effective dose for shortest time
- COX-2 inhibitors, Diclofenac and high dose Ibuprofen are contraindicated in ischaemic heart disease, cerebrovascular disease and some stages of heart failure
76
What interactions can occur with NSAID use with respect to the cardiovascular system?
- NSAIDs can block the effect of anti-hypertensives, which can increase blood pressure
- Anti-platelet dose of Aspirin
77
How can NSAIDs effect the renal system?
NSAIDs can:
- decrease renal blood flow and increase the risk of AKI
- increase sodium and water retention - oedema and hypertension
78
What risk factors are there for experiencing renal side effects with NSAID usage?
Advanced age, renal impairment, heart failure, volume depletion, liver cirrhosis
79
What interactions can occur with NSAIDs use with respect to the renal system?
- Co-prescribed nephrotoxic drugs (ACEi, diuretics)
- NSAIDs can block the effect of anti-hypertensives, which can increase blood pressure
- Lithium and Methotrexate - decreased renal elimination causing toxicity
80
How often is Methotrexate taken?
ONCE a week, on the same day each week.
81
What strength of Methotrexate should be used?
Increments of 2.5mg tablets, to avoid incorrect administration (NOT 10MG TABS)
82
What tests should be done before commencing Methotrexate therapy?
Full blood count, LFTs, U&Es, renal function (eGFR/CrCL), chest X-ray
83
What tests need to be done during Methotrexate therapy?
LFTs, renal function (eGFR/CrCL), full blood count - every 1/2 weeks until stabilised then every 2/3 months
84
What red flag symptoms should patients be made aware of with Methotrexate?
- signs of severe immunosuppression (sore throat, bruising, bleeding)
- signs of liver toxicity (nausea, vomiting, abdominal discomfort, dark urine)
- signs of respiratory effects (shortness of breath)
85
What are the key side effects of Methotrexate?
Bone marrow suppression, GI toxicity, liver toxicity, pulmonary toxicity, skin reactions
86
What should be co-prescribed alongside Methotrexate?
Folic acid 5mg once daily, taken on non-MTX day(s).
87
What are the contraindications of Methotrexate?
Active infection, severe renal impairment, hepatic impairment, bone marrow suppression, immunodeficiency, pregnancy/breastfeeding
88
What interactions can occur with Methotrexate?
- Anti-folates - Co-trimoxazole, Trimethoprim
- NSAIDs
- Live vaccines (recommend pnuemococcal and influenzae)
- Ciclosporin
89
What is the dose for Leflunomide in Rheumatoid Arthritis?
100mg OD (loading dose) then reduce to 10-20mg OD
90
What risks are associated with a loading dose of Leflunomide?
It can increase the risk of adverse effects, and can be omitted if necessary.
91
What tests should be done before and during Leflunomide therapy?
LFTs, full blood count, blood pressure
92
What key side effects are associated with Leflunomide?
Hepatic impairment, bone marrow suppression, increased blood pressure
93
What common side effects can occur with Leflunomide?
GI disturbances, alopecia, skin reactions, dizziness
94
What are the contraindications of Leflunomide?
Hepatic impairment, severe immunodeficiency, severe infection, severe hypoproteinaemia, moderate to severe renal impairment, pregnancy/breastfeeding
95
What is the step-down/washout procedure of Leflunomide?
- Monitoring after discontinuation
- Washout procedure - stop treatment, give Cholestyramine 8g TDS or activated charcoal 50g QDS, treat for 11 DAYS
96
What is the mechanism of action of Ciclosporin?
* Ciclosporin binds to the intracellular receptor, cylocphilin-1, which creates a complex.
* The complex inhibits calcineurin, in turn preventing dephosphorylation of nuclear factor of activated T-cells (NF-AT).
* The inhibition of NF-AT prevents pro-inflammatory mediators from being transcripted.
97
What key side effects are associated with Ciclosporin therapy?
Headaches, tremor, hypertension, hirsutism, renal impairment, increased risk of infections, increased risk of malignancies
98
What are the contraindications of Ciclosporin?
Abnormal baselines renal function, malignancy, uncontrolled hypertension, uncontrolled infection
99
What tests should be done before and during Ciclosporin therapy?
Renal function, hepatic function, blood pressure, lipids, U&Es, uric acid
100
What are the clinical signs and symptoms of Rheumatoid Arthritis?
- Symmetrical articular inflammation
- Stiffness (can be intermittent - morning is common)
- Area is warm and tender
- Positive metacarpophalangeal squeeze test (tenderness on palpation of joint(s)
- Weight loss, fatigue, fever
- Extra-articular manifestations - lungs, heart, eyes, skin
101
What result in a blood test can indicate Rheumatoid Arthritis?
Elevated inflammatory markers (ESR, CRP)
Elevated immunological parameters (RF, ANA, anti-CCP)
102
What is DAS28?
A score of disease activity in Rheumatoid Arthritis. It is measured using number of swollen and tender joints, ESR/CRP levels and a global assessment of health.
103
What does a DAS28 score of >5.1 mean?
Active disease
104
What does a DAS28 score of <3.2 mean?
Low disease activity
105
What does a DAS28 score of <2.6 mean?
Remission
106
What are some general pharmaceutical considerations to take with patients beginning anti-TNF agents?
- Increased risk of infection (stopping therapy around surgery)
- Potential risk of malignancies
- Potential risk to patients in Class III or IV heart failure
- Use of alcohol (keep within normal limits)
107
What monitoring would be done before commencing anti-TNF/biologic treatment?
- Co-morbidities
- FBC, renal function, LFTs
- Tuberculosis and Hepatitis (B&C) screen
- Chest X-ray
108
What is the pathophysiology of osteoarthritis?
Osteoarthritis occurs when:
- rate of damage of joint > rate of repair
- the joint fails to dissipate 'load' efficiently
- cycle of degeneration occurs
- more load = more damage
- loss of cartilage and build up of bony masses (osteophytes)
- joint space narrows
- synovitis and effusion
109
What are the risk factors for osteoarthritis?
- Age 45+ y/o
- Gender = female
- Obesity (BMI >25)
- Physically demanding occupation
110
What signs and symptoms can be associated with osteoarthritis?
- activity related joint pain
- morning stiffness lasting no longer than 30 mins
- muscle wasting
- hands/fingers presenting as nodes
111
What pharmacological approaches are there to osteoarthritis?
Pain relief:
1st line - Topical NSAIDs or topical Capsaicin
2nd line (if ineffective or unsuitable) - Oral NSAIDs (+PPI), paracetamol, weak opioids
112
What is gout?
An over-production or under-excretion of uric acid (leading to hyperuricaemia).
113
What is the normal physiology of uric acid synthesis?
Uric acid is the end product of purine metabolism. Xanthine oxidase breaks down hypoxanthine into xanthine and then uric acid.
114
What is gout caused by?
- Increased rate of synthesis of purine precursors of uric acid (10%)
- Decreased elimination of uric acid by kidney (90%)
115
What can cause over-production of uric acid?
- Excessive cell-turnover
- Cell lysis caused by chemotherapy and radiotherapy
- Excessive synthesis of uric acid due to rare enzyme defects
116
What can cause under-excretion of uric acid?
- Over-consumption of purines in diet (oily fish, offal, seafood)
- Alcohol
- Drugs (diuretics, aspirin, ciclosporin, omeprazole)
- Renal failure
- Hyperuricaemia (large amounts of uric acid filtered through glomerulus, increased reabsorption to avoid dumping of crystals in urinary tract)
117
How does a build-up of uric acid crystals lead to inflammation?
- crystal build-up bursts into bursa (sacs of fluid around joint)
- inflammatory response triggered via humoral and cellular inflammatory mediators and complement system
- this causes: pro-inflammatory cascade of cytokines, chemotactic factors and TNF.
- then, build up of inflammatory cells
- IL-1beta has been shown to be critically related to inflammatory response in gout.
118
Describe the 5 stages of the clinical presentation of gout.
1) Asymptomatic hyperuricaemia
2) Acute gouty arthritis
3) Interval/intercritical gout
4) Chronic tophaceous gout
5) Gouty nephropathy
119
What is acute gouty arthritis?
Acute monoarticular attacks of pain in joints caused by deposition of uric acid crystals in joints. Attacks are characterised by hot, red, swollen and extremely painful joints and can last around 7 days if untreated.
120
What is interval/intercritical gout?
The time between an acute attack of gout, interval can vary.
121
What is chronic tophaceous gout?
The build-up of small tophi around the body due to deposition of uric acid in subcutaneous or periarticular areas.
122
What is gouty nephropathy?
Uric acid crystals deposited in/around renal tubules causing an inflammatory response inside the kidney known as interstitial nephritis. Can lead to proteinuria and renal impairment.
123
What is recommended for an acute attack of gout?
1st line - NSAIDs and potentially a PPI (full dose for 24-48hrs then reduce)
2nd line - Colchicine (used when NSAIDs are C/I or ineffective - CVD, renal disease, GI toxicity)
3rd line - Corticosteroids (oral = Prednisolone, articular = Triamcinolone)
124
What would side effect would elicit an immediate stop in Colchicine treatment?
DIARRHOEA
125
What is the typical dosing regime for Colchicine?
0.5mg 2-4 times a day until relief of pain or development of GI side effects or a total of 6mg has been taken - DO NOT REPEAT COURSE WITHIN 3 DAYS
126
What is recommended for urate lowering therapy in patients with gout
1st line - Allopurinol (w/ Colchicine whilst target is being reached) - start at 100mg daily and increase up to 300mg daily (usual maintenance dose)
Alternate 1st line/2nd line - Febuxostat - start at 80mg OD and increase to 120mg OD if uric acid levels remain high (used if Allopurinol is C/I or ineffective)
127
What should be used in the first 6 months or during an up-titration of urate lowering therapy?
Colchicine 0.5-1mg daily. If C/I, use low dose NSAID or selective COX-2 inhibitor (+PPI)
128
What other drugs can be used in urate lowering therapy?
Uricosuric agents (Sulfinpyrazone), Canakinumab, Anakinra and Rilonacept
129
What important interaction should be considered with Allopurinol?
It interacts with Azathioprine. Due to the way Allopurinol works, it can cause an accumulation of Azathioprine, which can cause fatal bone marrow suppression. REDUCE DOSE OF AZATHIOPRINE BY 75%
130
What are the four main processes of the Digestive system?
- Motility
- Secretion
- Digestion
- Absorption
131
In what 2 ways can gut motility be categorised?
- Phasic motility - action potential induced bursts of contraction (propulsive and mixing movements)
- Tonic motility - constant low level of contraction (steady pressure on gut contents to prevent stretching of gut)
132
What 2 main things are secreted to help with digestion?
- Digestive juices (from exocrine glands)
- GI hormones which regulate motility and exocrine gland secretion (from endocrine glands)
133
What is digestion?
The biochemical breakdown of complex proteins, carbohydrates and fats by enzymes.
134
What does maltase do?
It breaks down the disaccharide maltose into glucose.
135
What does sucrase do?
It breaks down the disaccharide sucrose into glucose and fructose.
136
What does lactase do?
It breaks down the disaccharide lactose into glucose and galactose.
137
What three layers make up the mucosa in the digestive tract?
Mucous membrane, lamina propria and muscularis mucosa
138
What function does the submucosa have?
Connective tissue allowing GI tract to distend and be elastic. It also contains a nerve plexus.
139
What function does the muscularis externa have?
It is a major smooth muscle which is made up of circular and longitudinal layers. They are responsible for mixing and propulsive movements. The myenteric nerve plexus lies between the two layers.
140
What function does the serosa have?
It secretes serous fluid which lubricates and prevents friction between tract and other surrounding tissues and organs.
141
How does the digestive tract regulate its function?
- Autonomic smooth muscle function - self induced electrical activity along with interstitial cells of Cajal which provide a cyclic slow wave of activity
- Intrinsic nerve plexuses - submucosa and myenteric nerve plexuses regulate local activity
- Extrinsic nerve plexuses - sympathetic (slow) and parasympathetic (fast) nerves influence motility and secretion.
- GI receptors - chemo, mechano and osmoreceptors help with secretion of hormones and neural reflexes.
- GI hormones - hormones released by endocrine gland cells can help stimulate or inhibit exocrine glands or smooth muscle.
142
What three sections make up the stomach?
The fundus (top), the body (middle) and the antrum (bottom)
143
What can effect gastric emptying?
- Factors in the stomach:
Amount of chyme influences force of contraction
- Factors in the duodenum:
Fat - If there is fat in the duodenum, further gastric emptying is prevented.
Acid - un-neutralised acid contents in the duodenum prevents further gastric emptying.
Hypertonicity - If osmolarity of duodenum rises, gastric emptying is prevented
Distension - If the duodenum is full of chyme, gastric emptying is prevented.
144
What is the enterogastric reflex?
A reflex mediated by intrinsic nerve plexuses and autonomic nerves, which work to inhibit gastric emptying when the duodenum is distended.
145
What hormones are released in response to duodenum distension?
- Secretin from S cells which works to neutralise acid by stimulating release of bicarbonate from duct cells in the pancreas.
- Cholecystokinin from I cells which stimulates acinar cells in the pancreas to release digestive enzymes and also bile release from gallbladder.
146
What two areas in the stomach secrete juices?
The oxyntic mucosa and the pyloric gland area.
147
What secretory cells exist in the oxyntic mucosa?
Mucous, chief, paritetal and enterochromaffin cells
148
What secretory cells exist in the pyloric gland area?
G and D cells
149
What do mucous cells do?
They line gastric pits and the entrance of glands. They also secrete a thin, watery mucous.
150
What do chief cells do?
They secrete the enzyme precursor pepsinogen.
151
What do parietal cells do?
They secrete HCl and intrinsic factor.
152
What is the function of HCl in the stomach?
- Activates pepsinogen to pepsin and provides an acid medium for optimal pepsin activity
- Aids in the breakdown of muscle fibers and connective tissue
- Denatures proteins by uncoiling
- Kills microorganisms
153
What do G cells do?
They secrete gastrin which stimulates parietal, chief and enterochromaffin cells.
154
What do D cells do?
They secrete somatostatin which inhibits parietal, G and enterochromaffin cells.
155
What do enterochromaffin cells do?
They secrete histamine which stimulates parietal cells.
156
What does intrinsic factor do?
Helps with B12 absorption
157
Describe the phases of gastric secretion.
- Cephalic phase - increased HCl and pepsinogen secretion
- Gastric phase - increased gastric secretions
- Intestinal phase - inhibitory, helps shut off flow of gastric phases as chyme is emptied.
158
What enzymes is the pancreas able to secrete?
- Proteolytic enzymes - trypsinogen, chymotrypsinogen and procarboxypeptidase
- Pancreatic amylase
- Pancreatic lipase
159
How is trypsinogen activated?
It is changed from trypsinogen to trypsin by enterokinase.
160
How is chymotrypsinogen activated?
It is changed from chymotrypsinogen to chymotrypsin.
161
How is procarboxypeptidase activated?
It is changed from procarboxypeptidase to carboxypeptidase.
162
What three segments make up the small intestine?
Duodenum, Jejunum and Ileum.
163
What is segmentation (small intestine)?
It is the primary method of motility in the small intestine. It consists of ring-like contractions which mix and propel chyme through the small intestine. Pacemaker cells produce a basic electrical rhythm.
164
What is the migrating motility complex (small intestine)?
A secondary motility method where the small intestine is swept clean during meals.
165
What digestion is taking place in the small intestine?
- The continued digestion of carbohydrates and lipids by pancreatic enzymes.
- Brush border enzymes complete digestion of carbohydrates and proteins.
- Fat is digested entirely in the small intestine by pancreatic lipase.
166
How is the small intestine adapted to ensure maximum absorption?
- Inner surface has permanent circular folds for extra surface area
- Microscopic finger-like projections called villi have large surface area and blood supply to ensure absorption occurs
- Brush border (microvilli) arise from surface of epithelial cells for enzyme release and further absorption.
167
Describe how carbohydrates are absorbed.
1. Dietary polysaccharides, starch and glycogen, are converted into the disaccharide maltose by salivary and pancreatic amylase.
2. Maltose and dietary disaccharides, sucrose and lactose, are converted into their respective monosaccharides (maltase, sucrase, lactase) by disaccharidases in brush border epithelial cells.
3. Monosaccharides, glucose and galactose, are absorbed into epithelial cells by Na+ and energy dependant secondary active transport (via symporter SGLT) located at luminal membrane.
4. The monosaccharide, fructose, enters cells via passive facilitated diffusion via GLUT-5.
5. Glucose, galactose and fructose exit cells at basal membrane by passive facilitated diffusion at GLUT-2.
6. The monosaccharides enter the blood by simple diffusion.
168
Describe how fat is absorbed.
1. Dietary fat in the form of large fat globules composed of triglycerides is emulsified by bile salts into a suspension of smaller fat droplets. This emulsion prevents the fat droplets from coalescing and thereby increases surface area available for attack by pancreatic lipase.
2. Lipase hydrolyses triglycerides into monoglycerides and free fatty acids.
3. These water insoluble products are carried to the luminal surface of the small intestine epithelial cells within water soluble micelles, which are formed by bile salts and other bile substituents.
4. When a micelle approaches the absorptive epithelial surface, the monoglycerides and fatty acids leave the micelle and passively diffuse through the lipid bilayer of luminal membranes.
5. Monoglycerides and free fatty acids are re-synthesised into triglycerides inside epithelial cells.
6. The triglycerides aggregate and are coated with a layer of lipoprotein from the endoplasmic reticulum to form water soluble chylomicrons.
7. Chylomicrons are extruded at the basal membrane of cells by exocytosis.
8. Chylomicrons enter lymphatic vessels, the central lacteals.
169
Describe how protein is absorbed.
1. Dietary and endogenous proteins are hydrolysed into small peptide fragments by gastric pepsin, released as pepsinogen from chief cells.
2. Pancreatic proteolytic enzyme, trypsinogen is converted into trypsin by enterokinase, which breaks down other proteins into peptides.
3. Peptidases in the brush border epithelial cells break down the peptides into amino acids in the small intestine.
4. Amino acids are absorbed into epithelial cells by Na+ and energy dependant secondary active transport via a symporter. Various amino acids are transported by carriers specific to them.
5. Some small peptides are absorbed by a different type of symporter driven by H+, Na+ and energy dependant tertiary active transport.
6. Most absorbed small peptides are broken down into their amino acids by intracellular peptidases.
7. Amino acids exit the cell at the basal membrane via various passive carriers.
8. Amino acids enter the blood by simple diffusion.
170
Describe the motility of the large intestine.
- Mass movements - massive contractions, moves colonic contents to distal colon
- Gastrocolonic reflex
- Defecation reflex - initiated when stretch receptors in rectum are distended. Causes internal anal sphincter to relax and if external anal sphincter is also relaxed, defecation occurs.
171
What secretion occurs in the large intestine?
Alkaline mucus is produced to lubricate and protect membranes.
172
What digestion occurs in the large intestine?
NONE, except for cellulose breakdown by colonic microflora.
173
What absorption occurs in the large intestine?
Water, salt, and Vitamin K synthesised by colonic bacteria.
174
What excretion occurs in the large intestine?
Approximately 2/3 water, undigested cellulose, bilirubin and salt.
175
What is the function of Gastrin and why is it released?
Its release is stimulated by the presence of protein in the stomach. It works to primarily increase secretion of HCl (parietal) and pepsinogen (chief).
176
What is the function of Secretin and why is it released?
Its release is stimulated by the presence of acid in the duodenum. It works to inhibit gastric emptying and stimulate the pancreas to produce large amounts of bicarbonate solution.
177
What is the function of Cholecystokinin?
It works to inhibit gastric motility and emptying. It also stimulates the acinar cells in the pancreas to secrete pancreatic enzymes required for digestion and also forces the gall bladder to contract forcing bile into the duodenum.
178
What is Gastritis?
An inflammatory response of the GI mucosa in the stomach in response to Helicobacter Pylori.
179
How do Helicobacter Pylori initiate inflammation in the stomach?
The bacterium are capable of producing ammonia by hydrolysing urea which acts as a buffer to H+ ions. Their colonisation below the mucus layer in the stomach allows for chronic inflammation, reduced somatostatin from D cells, increased gastrin production from G cells leading to increased acid production.
180
How do you test for a Helicobacter Pylori infection?
Use of radio labelled urea causes CO2 to be detected on the breath when it comes into contact with Helicobacter Pylori.
181
What drugs can cause drug-induced Dyspepsia?
NSAIDs, Sulfasalazine, iron preparations, corticosteroids, MR Potassium, bisphosphonates, theophylline, calcium antagonists, nitrates
182
What is Dyspepsia?
It is impaired digestion where the stomach acid irritates the mucosa towards the top of the stomach (fundus) and the oesophagus. It can be described as functional dyspepsia when there is no underlying cause for the irritation (no organic disease).
183
What is the timeline of ulceration and damage to the stomach?
inflammatory response to H. Pylori --> gastritis --> chronic gastritis --> peptic ulcer disease (duodenal and gastric) --> gastric cancer
184
What are the signs and symptoms of a gastric (stomach) ulcer?
pain on eating and epigastric pain (indigestion/dyspepsia)
185
What are the signs and symptoms of a duodenal ulcer?
localised pain (towards the right side) occurring between meals and at night (indication of pain occurring as duodenum fills with chyme) and pain will be relieved by eating
186
What is GORD?
It is irritation of the lower oesophagus by the presence of gastric juices in the oesophagus. It is caused by decreased pressure of the lower oesophageal sphincter.
187
What is a hiatus hernia?
An asymptomatic condition where part of the stomach is pushed up through the diaphragm. It prevents the lower oesophageal from closing. It may present as GORD.
188
What factors can decrease the pressure of the lower oesophageal sphincter?
Dietary factors (fat, caffeine, chocolate, alcohol), smoking, endocrine factors (increased levels of oestrogen and progesterone), drugs
189
What drugs can decrease lower oesophageal sphincter pressure?
Anticholinergics, beta-2 agonists, CCBs, Diazepam, nitrates, alcohol, progesterones, oral contraceptives, theophylline
190
What drugs can cause oesophageal ulceration?
NSAIDs, bisphosphonates, clindamycin, co-trimoxazole, doxycycline, potassium, theophylline
191
# triple therapy
What is the pharmacological management of a gastric/duodenal ulcer?
* **Identify and eradicate H. Pylori** - PPI (Lansoprazole 30mg) + Triple antibiotic therapy (Amoxicillin 1g AND EITHER Clarithromycin 500mg OR Metronidazole 400mg
* **Reduce acid production to reduce gastritis and enable mucosal repair** - Block H2 or proton pump
192
What is the management options for GORD?
* Remove causative agent
* Use of a rafting product (Gaviscon)
* Reduce acid prodcution to enable oesophageal mucosal repair
* Non-pharmacologicval advice (smaller meals, avoid eating before bed, stop smoking and decrease alcohol, drugs affecting LOS pressure)
193
What treatments are available for upper GI conditions?
* Antacids - neutralise acid and increase LOS pressure
* Alginates & Dimethicone - form high pH raft over acid and protects LOS from gastric juices
* H2-receptor antagonists - block histamine from binding to H2 receptor on parietal cells
* Proton-pump inhibitor - blocks the H+/K+ ATPase pump on parietal cells
194
When would you refer to a doctor with respect to upper GI conditions?
* Patient is >45 y/o with new or changed symptom of heartburn or dyspepsia
* Continuous dyspepsia
* Increasing severity
* Weight loss, loss of appetite, signs of anaemia
* Pain on exercise - caridac origin??
* Dysphagia
* Blood in stools or vomit
195
Describe how parietal cells create acid.
* The parietal cell can be stimulated at various receptors on the surface (M3 receptors for acetylcholine, CCK2 receptors for gastrin and H2 receptors for histamine).
* Hydrogen ions are formed by the dissociation of water.
* Carbonic anhydrase works with water and carbon dioxide to produce bicarbonate ions
* The bicarbonate ions are exchanged with chloride ions on the basal side of the cell
* Potassium and chloride ions are pumped out of the cell into the canaliculi.
* Hydrogen ions are exchanged with potassium at the H+/K+ ATPase via ATP-mediated active transport.
* Hydrochloric acid is produced and flows out of the canaliculi into the gastric lumen.
196
What is the mechanism of action of H2-antagonists (Cimetidine)?
They competitively block the H2 receptor on parietal cells, preventing histamine, released from enterochromaffin-like cells, from binding to receptors.
197
What is the mechanism of action of proton-pump inhibitors (Omeprazole)?
* PPIs ingested orally and pass into systemic circulation
* Drug can access systemic circulation due to lipophilicity and they are neutral
* Drug reaches parietal cell and flows into canaliculus invagination
* Drug undergoes a metabolic conversion into charged species due to low pH environment
* Cascade reaction occurs in which PPI is transformed into an active species
* Active species forms disulfide bond with one or more of the three available cysteine residues on the proton pump. Inhibition is irreversible due to covalent bond.
* Acid production can be restored by new proton pump synthesis or regeneration through glutathione.
198
Why is the position of the methoxy group important in Omeprazole?
The methoxy group sits para to the pyridine-like nitrogen. This allows for sufficient electron donating (+M effect) across the ring which increases the nucleophilicity of the pyridine nitrogen opposite.
199
What different laxatives are available for use in Constipation?
* Bulking forming laxatives - Isphagulka Husk, Methylcellulose
* Stimulant laxatives - Senna, Bisacodyl
* Faecal softeners - Docusate, Glycerol
* Osmotic laxatives - Lactulose, macrogols
200
# lifestyle
What managements options are there for acute constipation?
1. Lifestyle advice and manage underlying cause
2. Bulk forming laxative
3. (+/-) osmotic laxative (macrogol)
4. Stimulant laxative
201
# lifestyle
What management options are there for chronic constipation?
1. Lifestyle advice and manage underlying cause
2. Bulk forming
3. (+/-) osmotic laxative (macrogol)
4. Stimulant
5. Prucalopride (specialist)
202
What pharmacological management options are available for faecal loading and or impaction with hard stools?
1. High dose oral osmotic laxative (macrogol)
2. Stimulant laxative
**If response is inadequate or slow:**
3. Glycerol alone or with Bisacodyl suppositories
203
What pharmacological management options are available for faecal loading and or impaction with soft stools?
1. Stimulant laxative
**If response is inadequate or slow:**
2. Faecal softeners (Docusate) or Sodium citrate enema
204
What pharmacological management options are available for opioid induced constipation?
**AVOID BULK FORMING (ISPHAGULA HUSK)**
1. Osmotic laxative or Docusate **AND** stimulant laxative
2. Naloxegol - PAMORA
3. Methylnaltrexone - PAMORA
4. Naldemedine - PAMORA
205
What pharmacological management options are available for patients who are pregnant?
1. Bulk forming laxative
2. Add or switch to osmotic laxative
3. Consider short course of Senna **(NEVER CLOSE TO TERM, CAN INDUCE PREMATURE LABOR)**
4. Glycerol suppository
206
What pharmacological management options are available for patients who are breastfeeding?
1. Bulk forming laxative
2. Add or switch to osmotic laxative
3. Consider short course of Senna or Bisacodyl
4. Glycerol suppository
207
What pharmacological management options are available for children?
1. Macrogols and non-punitive behavioural interventions suited to development
2. (If first line not tolerated) add stimulant laxative
3. Lactulose
208
What lifestyle advice should be offered to patients suffering with constipation?
* High fibre diet (30g) + fluids (2L/day)
* Increased physical activity
209
What is the mechanism of action of Prucalopride?
It is a selective serotonin 5HT-4-receptor agonist. The activation of 5HT-4 leads to increased Ach release, which pushes the parasympathetic drive (rest and digest).
210
What is the mechanism of action of bulk forming laxatives?
They mimic polysaccharides so increase osmolarity in the gut when broken down causing water retention, which expands and softens stool. This bulk stimulates stretch receptors and initiates peristalsis. Furthermore, this distension causes acetycholine to be released which increases the parasympathetic drive.
211
What is the mechanism of action of osmotic laxatives?
These agents are poorly absorbed so cause increased water retention in the gut. As they are hyperosmolar agents, they are absorbed into stool making it softer. Also some osmotic laxatives contain Mg2+ which stimulates CCK release, this increases secretions and colonic motility.
212
What is the mechanism of action of stimulant laxatives?
The drug stimulates local reflexes of myenteric nerve plexus in the gut. The nerve endings are 'irritated' which causes a motor effect on the gut wall, increasing propulsion. As well as this, water secretion is increased and transit time through the gut is decreased.
213
What is the mechanism of action of Senna?
Senna is an anthraquinone laxative. It combines with sugars to form glycosides. The glycoside bond is hydrolysed by colonic bacteria to release the irritant anthracene glycoside derivatives, specifically sennosides A & B. These are then absorbed and have direct action on the myenteric nerve plexus, increasing smooth muscle activity. Senna is also believed to increase secretion of PGE2, which can increase gut motility.
214
What is the mechanism of action of stool softeners (or emollient laxatives)?
These laxatives are surfactants so reduce the surface tension of the stool, allowing intestinal water/fat to enter and combine with the stool. This eases the passage of the stool through the intestine.
215
What is the mechanism of action of peripherally-acting mu-opioid receptor antagonists (PAMORAs)?
These drugs prevent the activation of mu-opioid receptors in the gut. By doing this, you can target the GI side effects associated with opioids, like: decreased GI motility, hypertonicity and increased fluid absorption.
215
What red flag symptoms are associated with constipation?
* pain on defecation - suppresses defecation reflex
* patient >40y/o with sudden change in bowel habits
* longer than 2 weeks
* associated fatigue
* presence of blood
* repeated failure of laxatives
* suspected laxative abuse
216
What is acute diarrhoea?
An abrupt onset of >3 loose stools, lasting NO LONGER than **14 DAYS**
216
What is chronic diarrhoea?
Diarrhoea that lasts LONGER than **14 DAYS**
217
What is the pathophysiology of diarrhoea?
* Osmotic force driving water into the gut lumen, e.g. after ingestion og non-absrobable sugars
* Enterocytes actively secreting fluid e.g. enterotoxin induced diarrhoea
218
Describe the mechanism of invasive bacteria-causing diarrhoea.
* Bacteriums directly attack mucosal cells causing diarrhoea
* Stools may contain blood or pus
* Fever
* Salmonella, Yersinia, Shigella, enteroinvasive E. coli
218
Describe the mechanism of non-invasive bacteria-causing diarrhoea.
* Bacteriums do not damage the gut
* Bacteria produce enterotoxins that disrupt secretion
* watery diarhhoea
* S. aureus, B, cereus, C. perfinigens, enterotoxigenic E. coli
219
What is the mechanism of action of Loperamide?
The drug is an opioid analogue that binds to mu-opioid receptors in the gut. This inhibits Ach and prostaglandin release (PGE2). This leads to reduced gastric motility, decreased peristalsis and increases intestinal transit time.
219
Should Loperarmide be given to pregnant women?
No, avoid. Or seek specialist.
219
Should Loperamide be given to children?
No, instead use oral rehydration therapy.
220
What red flag symptoms should be considered with diarrhoea?
* Recent travel abroad
* Blood or mucus in stools
* Associated w/ severe vomiting and fever
* Severe or persistent abdominal pain
* Pregnancy
* Signs of dehydration
220
What sick day guidance should be offered to patient unwell with diarrhoea, vomiting, fever etc?
* Stop taking: ACEis, ARBs, NSAIDs, diuretics, Metformin
* Retrun to normal after 24-48hrs w/ no symptoms
221
What treatment is reccommended for a C. diff infection?
Vancomycin 125-500mg every 6 hours for 10 days
221
What risk factors are there for a C. diff infection?
broad spectrum antiobiotics, >65y/o, prolonged stay in hospital/care home, immunocompromised
221
Describe the pathophysiology of Crohn's disease.
* Any region of the GI tract can be affected
* usually terminal ileum and ascending colon
* deep ulcers can appear
* mucous membranes between fissures have 'cobblestone-like' appearance
* can progress to deep fissuring ulcers, fibrosis, abscesses and gut perforations
* inflammation extends through all layers of the bowel (transmural)
* associated with **Th1**
221
Describe the pathophysiology of Ulcerative Colitis.
* only mucosa and submucosa are affected
* continuous and starts in rectum
* formation of crypt abcesses and mucosal ulceration
* psuedopolyps (scar tissue) can appear in severe inflammation
* mucosa appears red and inflammed, will bleed easily
* associated with **Th2**
221
What is PROCTITIS?
Ulcerative Colitis involving just the rectum
221
What is LEFT-SIDED COLITIS?
Ulcerative Colitis involving the sigmoid and descending colon
222
Describe the clinical features of both UC and CD.
* Diarrhoea
* Fever
* Abdominal pain
* Nausea and vomiting (more common in CD)
* Malaise
* Lethargy
* Weight loss (more common in CD)
* Malabsorption
* Growth stunting in children
223
Describe the clinical features that are unique to Crohn's disease.
* Pain in the LRQ
* Anaemia
* Palpable masses
* Small bowel obstructions
* Abcesses
* Fistulas
* Gut perforation
224
Describe the clinical features that are unique to Ulcerative Colitis.
* Diarrhoea (possibly with blood and mucus)
* 10-20 liquid stools a day
* Abdominal pain with fever
* Constipation
225
What are some of the extra-intestinal complications of IBDs?
* Joints and bones - arthropathies and osteopenia
* Skin - Erythema nodosum, pyoderma gangrenosum
* Ocular - episcleritis, uveitis
* Scleroising chlolangitis - inflammed biliary tree
226
What antibody result can help diagnose an IBD?
**p-ANCA**
* -ve in CD
* +ve in UC
227
What pro-inflammatory mediators are invovled with Crohn's disease?
* Th1 - IFNgamma, TNF, IL-6
* Th17 - IL-17A/F, IL-21, IL-22
228
What pro-inflammatory mediators are invovled with Ulcerative Colitis?
* Th2 - IL-5, IL-6, IL-13, TNF
* Th9 - IL-9
* Th17 - IL-17A/F, IL-21, IL-22
229
What mediators are involved with a healthy immune response in the gut?
* T-reg - IL-10, TGFbeta
230
Describe the mechanism of action of corticosteroids.
* Glucocorticoids passively diffuse into target cells and bind to intracellular glucocorticoid receptor.
* The glucocortcoid receptor is held in the cytoplasm due to it being bound to the heat-shock protein (hsp) complex.
* Once the glucocorticoid receptor is activated by a ligand, a homodimer made up of two acitvated glucocorticoid recptors, which is then transported into the cells nucleus.
* This can then inhibit promoter regions of genes like NF-kB and activator protein 1.
* Also, glucocortcoids induce IkB which can bind to and sequester NF-kB in the cytoplasm.
231
Describe the mechanism of action of 5-aminosalicylates.
* 5-ASAs have actions on both prostaglandin synthesis/cyclooxygenase pathway and suppression of pro-inflammatory cytokines
* Actions on prostaglandin synthesis comes via COX inhibition
* Actions on suppression of cytokines comes via inhibition of PPARgamma, NF-kB and other non-COX targets.
* 5-ASAs can also scavenge reactive oxygen metabolites from superoxide anion generation by neutrophils which can in turn prevent DNA and tissue damage.
232
Describe the two forms of TNF.
* membrane bound TNF (mTNF), which can be cleaved by TNFalpha converting enzyme.
* membrane bound TNF, once cleaved, becomes soluble TNF (sTNF)
233
What happens when TNF is blocked?
* T cell and inflammatory cell apoptosis
* Reduction of inflammatory cytokine production
* Reduction of Paneth cell necroptosis
* Reduction of epithelial cell apoptosis
* Elevation of regulatory macrophages
* Reduce MMP-induced tissue destruction
234
How does TNF signalling occur?
* Both forms of TNF signal through two distinct receptors: TNFR1 and TNFR2.
* TNFR1 is expressed on lymphocytes and enodthelial cells
* TNFR2 is ubiquitously expressed
* mTNF can signal through both, where as sTNF has a greater affinity for TNFR1.
* Activation of TNFR1 results in an intracellular signalling cascade with many effects. The main effect being apoptosis (via caspase-8 pathway), or cytokine secretion (via NF-kB).
* Activation of TNFR2 does not contain a death domain and can result in cell proliferation, migration and cytokine production.
235
Describe T-cell homing and retention in IBD.
* In IBD, T-cells migrate/home towards gut tissues where they accumulate in large numbers and secrete inflammatory cytokines (IL-6, IL-23, TNF).
* T-cell homing to the gut requires an interaction between two molecules; one on the surface of the T-cell and one on the surface of endothelial cells.
* The T-cell surface integrin, α4β7, is a gut specific adhesion molecule that specifically interacts with mucosal vascular adressin adhesion molecule (MAdCAM1) that is expressed in the endothelium.
* T-cells are also retained in the gut tissue through binding of the α4β7 integrin to E-cadherin on the basal membrane of epithelial cells.
236
Describe the mechanism of action of Vedolizumab.
It is an anti-α4β7 antibody blocking the homing and retention of T-cellls to the inflammed gut. The drug binds to the integrin **NOT** the receptor.
237
Describe Sphingosine-1-phosphate signalling, and how drugs can target this.
The S1P receptor controls eggression of immune cells from lymph nodes through a concentration gradient of sphingosine-1-phosphate. S1PR1 agonists can render lymphocytes sensing the S1P gradient and exiting lymph therefore reducing lymphocyte numbers.
238
Describe the mechanism of action of Ustekinumab.
It is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, which are responsible for the inflammation during the pathogenesis of IBDs. Inhibtion of IL-12 and IL-23 supresses the Th1 and Th17 lineage invovled in IBDs.
239
How does Sulfasalazine become activated in the body?
The drug itself is a pro-drug of Mesalazine and Sulfapyradine. They are connected via an azo-bridge which is broken by colonic bacterial azoreductase. Sulfapyradine is absorbed by the colon and further metabolised in the Liver. Mesalazine exters its affect topically on th GI mucosa.
240
What are the contraindications to 5-aminosalicylates?
Hypersensitivity to Sulfapyradine/Sulfonamides or 5-ASAs/salicyates
241
What side effects can occur with 5-aminosalicylates?
Headache, nausea, fever, rash, increased temperature, reversible infertility in men, decreased WBC count, pancreatitis, hepatitis, skin reactions, haemolysis, kidney inflammation
242
What side effects should be reported with 5-aminosalicylates?
sore throat, fever, malaise, jaundice, unexpected non-specific illness, myelosuppression, haemolysis, hepatotoxicity
243
What is the treatment pathway for inducing remission in Crohn's disease?
1. Monotherapy - traditional glucocorticoid (Methylprednisolone, Hydrocortisone. Budesonide - if C/I to others)
2. Add on therapy - Azathioprine OR Mercaptopurine (MTX if not tolerated or low TPMT)
3. Biologics - Infliximab + Adalimumab (then Ustekinumab, then Vedolizumab)
244
What is the treatment pathway for maintaining remission in Crohn's disease?
**DO NOT USE GLUCOCORTICOSTEROIDS OR BUDESONIDE**
1. After surgery - Consider Azathioprine with Metronidazole (or Azathioprine alone if non-tolerant of Metronidazole) - DON'T USE BIOLOGICS OR BUDESONIDE
2. 3 months post op - Offer Azathioprine OR Mercaptopurine (MTX if not tolerated)
245
What is the treatment pathway for inducing remission in mild-moderate Ulcerative Colitis?
* Proctitis - topical (suppository) aminosalicylate. If remission not achieved, consider adding oral aminosalicylate. If further treatment is required, consider adding topical/oral corticosteroid.
* Proctosigmoiditis/distal colitis - topical (enema) aminosalicylate. If remission not achieved in 4 weeks, consider: adding high dose oral aminosalicylate, switching to high oral aminosalicylate + time limited corticosteroid. If further treatment is needed, stop topical treatments and offer oral aminosalicylate and oral corticosteroid
* Extensive colitis - topical (enema) and high dose oral aminosalicylate. If remission not achieved in 4 weeks, stop topical treatment, keep oral and offer time limited oral corticosteroids.
246
What is the treatment pathway for inducing remission in moderate-severe Ulcerative Colitis?
Oral corticosteroids and biologics
247
What is the treatment pathway for acutely severe/hospitalised UC?
1. IV corticosteroids
2. Consider IV Ciclosporin or surgery if non-tolerant of corticosteroids
3. If there is little improvement after 72 hours, consider adding IV Ciclosporin to the corticosteroid
4. If Ciclosporin in C/I, Infliximab is an option.
248
What is the treatment pathway for maintaining remission in mild-moderate UC?
Proctitis/Proctosigmoiditis - Consider the following: topical aminosalicylate (suppository/enema), oral and topical aminosalicylate or oral aminosalicylate alone (this may be less effective)
Distal and extensive colitis - Offer a low maintenance dose of oral aminosalicylate
All areas - Consider Mercaptopurine OR Azathioprine (if remission isn't maintained by aminosalicylates)
249
What are keratinocytes and what do they do?
They are the main cell type in the epidermis. They are rich in lipids and keratin, have stem cells enabling rapid proliferation and self renewal. They are responsible for replenishing tissue and acting as a microbial barrier also.
250
What are Merkel cells and what do they do?
They are 'pressure cells'. They respond to changes in pressure as they are attached to nerves.
251
What are melanocytes and what do they do?
They synthesise melanin from tyrosine and protect from UV rays. They are loacted in the basal region of the epidermis.
252
What are Langerhans cells and what do they do?
They are immune cells (dendritic cells). They initiate the adaptive immune response from skin microbes.
253
Describe the structure of the dermis.
* middle skin layer, made up of fibrous and elastic tissue
* supportive and cushioning tissue consisting of collage, elastin and fibrin
* structures found: nerve endings, blood vessels, lypmh vessels, pilorector muscles, hair follicles, sweat and sebaceous glands
254
# subcutaneous
Describe the structure of the hypodermis.
* subcutaneous fat layer acting as a: mechanical protector, thermal insulator and an energy store
255
Why are skin-resident microbial communities helpful?
* Educate and prime adaptive immunity - tune local cytokine production, epigenetically prime APCs to educate adaptive immunity, influence Treg cells in epidermis
* Directly inhibit pathogen growth - occupy space and nutrients, produce AMP/bacteriacidal compounds, inhibit S. aureus biofillm formation
* Enhance host innate immunity - increase AMP production, decrease inflammation after injury, strengthen epidermal barrier
256
Describe the first stage of wound healing (haemostasis).
* microvascular injury - blood seeps into wound
* injured vessels contract
* coagulation cascade activated by tissue factor
* clot forms and platelets aggregate
* platelets trapped in clot release growth factors (PDGF, IGF, TGFbeta) which attract and activate fibroblasts, macrophages and endothelial cell
* serotonin is also released which increases vasacular permeability
257
Describe the second stage of wound healing (early inflammation phase).
* complement activated
* neutrophils infiltrate within 24-48hrs
* diapedesis into wound and phagocytose bacteria and foreign particles
* dying cells cleared by macrophages and are extruded to wound surface
258
Describe the third stage of wound healing (late inflammatory phase).
* blood monocytes arrive and become macrophages (48-72hrs)
* macrophages are key for repair as they release cytokines and growth factors which recruit fibroblasts, keratinocytes and endothelial to repair damage
* collagenases arrive and degrade tissue
* lymphocytes enter the wound after ~72hrs and help with remodelling
259
Describe the fourth stage of wound healing (proliferative phase).
* fibroblasts migrate - proliferate and construct new ECM
* new collagen is synthesised
* angiogenesis occurs - capillary sprouts invade clot and organise microvascular network
* granulation tissue formation
* epithelialisation - single layer of epithelial cells migrate from wound edge to form covering
260
Describe the fifth stage of wound healing (remodelling phase).
* matrix matures and remodels
* fibronectin and hyaluronic acid break down
* collagen bundles increase in diameter and strength
* collagen becomes more organised and shrinks to bring wound margins closer
* fibroblasts and macrophages undergo apoptosis
* capillary outgrowth halted and blood flow reduced
* scar formation
261
What is atopic dermatitis?
A chronic skin disorder (a type of Eczema) with flare ups and remissions. It is a Type 4 hypersensitivity reaction. It typically occurs in an atopic traid with hay fever and asthma.
262
Describe the aietology of Atopic dermatitis.
* defects in skin barrier and a lack of anti-microbial peptides
* occurs from a defect in the filaggrin gene
* stimulation of B-cells in the skin tissues cause mast cells to continuously produce allergens which irritate the skin causing itchiness and inflammation
263
What is irritant contact dermatitis?
* exposure to skin by acute toxic insult or cumulative damage from irritants
* detergents and solvents strip the skin of natural oils
* excess handwashing, dribble rashes, nappy rashes
* not a hypersensitivity reaction
264
What is allergic contact dermatitis?
* type 4 hypersensitivity reaction
* over time of exposure, immune responses build up
* nickel, rubber, perfumes, preservatives
265
What treatments are available for contact dermatitis?
* avoid irritants and allergens
* emollients
* topical corticosteroids
* oral corticosteroids
* Alitretinoin for chronic hand contact dermatitis refractory to steroids
266
What is seborrheic dermatitis?
* rash on the skin's sebaceous zones (face, scalp, chest, ears, skin folds, arm pit, groin)
* due to the overgrowth of Malassezia yeasts
267
What treatments are available for seborrheic dermatitis?
* Infants - emollients or mineral oils (for scalp), topical steroids with anti-fungal (for body)
* Adults - anti-yeast shampoos (Ketoconazole, Selenium sulfide), topical corticosteroids, oral anti-fungals
