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MPharm2 SL22105 > Inflammation > Flashcards

Inflammation Flashcards

Acute inflam Adhesion and chemotaxis Manipulation

1
Q

What is inflammation?

A

Normal part of immunity in response to tissue injury
Repair damaged tissue
Self-limiting and beneficial

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2
Q

What are the three stages of inflammation?

A
  • tissue injury (release of histamine)
  • dilation and increased leaking capilliaries
  • phagocytes consume bacteria and debris
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3
Q

Why are infections warm and red?

A

Arteriolar dilatation
Increased blood flow to inflamed tissue

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4
Q

Why do infections swell both acutely and chronically?

A

Leakage of plasma from blood vessels into the tissue
- Plasma extravasation
More chronically
- Cellular accumulation
- Tissue remodelling
- Fibrin deposition

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5
Q

What are the 3 causes of loss of function in long term injuries?

A

Tissue remodelling
Tissue destruction
Fibrin deposition

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6
Q

What are mast cells?

A

Like circulating basophils
Widely distributed throughout connective tissue and mucosal surfaces
- Synthesise and release ‘inflammatory mediators’

Stimuli:
- Mechanical injury to skin
- Type 1 immediate hypersensitivity via IgE (allergy)
- Chemicals: eg. insect bites

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7
Q

What are endothelial cells and their three functions?

A

Blood vessels are lined with endothelial cells
Functions:
- Filteration of fluids
- Blood vessel size regulation (endothelial-derived NO causes arteriolar dilatation)
- hemostasis

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8
Q

What are the 3 points about chemical mediators of inflammation?

A
  • Act on microvasculature and tissues
  • Lowspecificity
  • Synthesised and released from cells and tissues when required
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9
Q

What are the two roles of histamines on blood vessels?

A
  • relaxes arteriolar smooth muscle
  • contraction of venular endothelium = increased permeability
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10
Q

What are the two Eicosanoids and what do they do?

A

Lipid-based signaling molecules that play a role in innate immune response
- Prostaglandins
- Leukotrienes

Prostaglandins involved in vasodilation, pain and fever
Target for commonly used anti-inflammatory medications (eg. aspirin, ibuprofen)

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11
Q

What are Prostaglandins in Fever?

A

Fever results from elevation of the hypothalamic ‘thermostat’

Regulated by production and action of PGE2 in the hypothalamus

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12
Q

What are leukotrienes?

A

Activate the immune system after infection, injury, or contact with allergens
Oedema
- LTC4, LTD4and LTB4 stimulate increased vascular permeability

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13
Q

Why is inflammation beneficial?

A

Increased supply of cells and chemical mediators to site of inflammation and tells body to rest

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14
Q

What is leukocyte migration?

A
  • Leukocytes move from the blood to sites of inflammation and immune activation
  • Directional control is co-ordinated by tissue expression of adhesion molecules
  • On arrival at site they participate in host defence, inflammation and repair
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15
Q

What are the 4 stages of leukocyte diapedesis?

A
  1. circulating
  2. tethering/rolling
  3. firm adhesion
  4. transmigration
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16
Q

What are selectins?

A

Cell adhesion molecules that are glycoproteins

Important in initial ‘tethering’ of leukocytes to vascular cells

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17
Q

What is L-selectin?

A

A key adhesion molecule that regulates both the migration of leukocytes at sites of inflammation and the recirculation of lymphocytes between blood and tissues

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18
Q

What are P-selectins?

A

Key roles in mediating inflammation through promoting adherence of leukocytes to activated platelets and endothelium

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19
Q

What are E-selectins?

A

An adhesion receptor involved in slowing down leukocyte rolling

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20
Q

What are integrins?

A

Integrins are the principal receptors used to bind to the extracellular matrix. They function as transmembrane linkers between the extracellular matrix and the actin cytoskeleton. A cell can regulate the adhesive activity of its integrins from within.

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21
Q

What are integrin ligands?

A

Intercellular adhesion molecule (ICAM) that help the cell to endure pulling forces without being ripped out
- ICAM-2 – basally expressed on endothelium
- ICAM-1 – induced by cytokines IL-1, TNF

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22
Q

What are matrix metalloproteinases?

A

A family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM

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23
Q

What are chemotaxins?

A

Stimulate directed leukocyte movement

Source of chemotaxins = site of inflammation

Chemotaxins stimulate increased inflammatory cell migration in the tissues, and these inflammatory cells increase the inflammatory cascade.

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24
Q

What are chemokines?

A

Produced in response to IL-1, TNF, bacteria
A large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine receptors

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25
Q

What are H1 receptor antagonists?

A

Block H1 receptors
Anti-histamines
Used for allergies, conjunctivitis, reactions to insect bites

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26
Q

What is cyclo-oxygenase?

A

target enzyme of aspirin
COX-1 Constitutive “Housekeeping enzyme”
- products important in normal function of stomach, intestine, kidney and platelets
- produced at low levels in all tissues

COX-2 Induced
- inresponse to injury

27
Q

What are the 3 side effects of NSAIDs?

A
  1. Gastric irritation
  2. Bleeding
  3. Renal toxicity
28
Q

What are the 2 anti-thrombotic effects of aspirin?

A
  • impair platelet aggregation
  • decreased thrombus formation
    by inhibiting COX
29
Q

What are the 3 ways that anti-inflammatory steroids work?

A
  • Suppress T cell activation and cytokine production
  • Suppress mast cell degranulation
  • Decrease capillary permeability indirectly by inhibiting mast cells and basophils
30
Q

What is the MoA of steroids?

A

Glucocorticoids inhibit neutrophil apoptosis and demargination

Glucocorticoidsbind toglucocorticoid receptors, inhibits histone acetyltransferase and represses inflammatorygeneexpression, increaseexpression of anti-inflammatory genes

31
Q

What is the prevalence of RA?

A

RA is approximately 3 times more prevalent in woman than in men

The overall prevalence of RA in the UK is 0.81%
1.16% for women and 0.44% for men

32
Q

What are the 3 predisposing factors associated with RA?

A
  • Genetic factors
  • Environmental factors
  • Hormones or hormonal deficiencies
33
Q

What are anti-citrullinated protein antibodies?

A
  • ACPAs are autoantibidies common in RA
  • They can be found up to 14 years before onset of symptoms
  • ACPAs can accurately predict the development of RA
34
Q

What are the 5 common symptoms of RA?

A
  • Painful, stiff joints due to inflammatory synovitis
  • Symmetrical swelling in small joints
  • Fatigue
  • Flu-like symptoms
  • Morning stiffness
35
Q

What are some of the extra-articular manifestations of RA?

A

Heart and pericardium
- pericardial effusion
- ischaemic heart disease

Blood
- anaemia (haemolytic)
- neutropenia

kidneys
- amyloid disease

lung and pleura
- pleural disease
- pulmonary disease

36
Q

What are the 3 assessment tools for RA?

A

Radiology
- sharp score
- larsen index

Blood tests
- CRP
- ESR

Disease activity
- ACR
- EULAR response criteria

37
Q

What are 3 radiological signs of early RA?

A
  • Soft tissue swelling
  • Periarticular osteopenia
  • Loss of cartilage
38
Q

What are the 2 radiological signs of severe RA?

A
  • Radial deviation of the carpus and ulnar deviation of the digits
  • Severe erosive damage of MTP Joints of feet
39
Q

What is the outcome of untreated RA?

A

Severe disability
Life expectancy of patients with RA is reduced by an average of 3–18 years

40
Q

What are the poor prognosis markers of RA?

A

Genetics
- The HLA-DRB1 genotype is associated with more severe forms of RA

Laboratory
- High ESR or CRP level at outset
- Positive RF and ACPA

Other
- Early visible erosions
- Adverse socio-economic status
- Smoking

41
Q

What are the 5 categories of RA treatment?

A
  • Analgesics
  • NSAIDS
  • Glucocorticoids
  • csDMARDS
  • bDMARDS
42
Q

What are 3 csDMARDS?

A
  • Methotrexate
  • Sulfasalazine
  • Hydroxychloroquine
43
Q

What is methotrexate?

A

Dose
- Dose ranges from 7.5 to 25 mg, once a week

Onset of Action
- 6-8 weeks

Avoid
- Pregnancy – Teratogenic
- Alcohol
- Sulfa Antibiotics (Sulfasalazine is ok)

Affects cells that rapidly turn over
- Immune cells
- Mucosal cells
- Hair follicles

44
Q

What are 2 common and 3 rare side effects of methotrexate?

A

Common
- Malaise
- Nausea

Rare
- Fever
- cough
- SOB

45
Q

What is hydroxychloroquine?

A

Anti-malarial medication found useful for the treatment of inflammatory arthritis

Increases intracellular pH
Interferes with cell’s ability to degrade and process proteins

Dose & Administration
- Dose ranges from 200 – 400 mg per day

46
Q

What are 3 common and 2 rare side effects of hydroxychloroquine?

A

Common
- Rash
- nausea
- cognitive effects

Rare S/E
- Ocular
- heart

47
Q

What is sulphasalazine?

A

Anti-inflammatory: Salicylic Acid
Antibiotic: Sulfapyridine

Takes 6-8 weeks to work

48
Q

What are 4 common and 2 rare side effects of sulphasalazine?

A

Common S/E:
- Nausea,
- Abd pain
- Rash
- Headaches

Rare S/E:
- Hypersensitivity reaction

49
Q

What is leflunomide?

A

Newer csDMARD
A pro-drug that inhibits the activity of dihydro-orotate dehydrogenase, used for de novo synthesis of pyrimidines.

Given daily – ranges from 10-20 mg per day

50
Q

What are 4 common side effects of leflunomide?

A

Common S/E
- GI upset
- Hypertension
- Alopecia
- Rash

51
Q

What are the 6 types of biologics?

A
  • TNF Inhibitors
  • T-Cell Co-Stimulatory Blockade
  • IL-6 Inhibition
  • IL-1 Inhibition
  • JAK Inhibition
  • B-Cell Depletion
52
Q

What are the risks of TNFs?

A

High risk of infections

53
Q

What is rituximab?

A

B cell depleting monoclonal anti-CD20 antibody
- B cell apoptosis

54
Q

What is abatacept?

A

Binds to the costimulatory molecules on antigen-presenting cells, thereby blocking interaction with T cells

55
Q

What are the 3 types of surgery for RA?

A
  • Synovectomy
  • Arthroplasty
  • Spinal stabilisation
56
Q

What is steroidal structure?

A

Steroids have a basic 4 ring structure (6:6:6:5) with side-chains.

57
Q

What are glucocorticoids?

A

Cortisol and cortisone are a stress hormones.
They promote gluconeogenesis.
Prednisolone and methylprednisolone are synthetic derivatives.

Excessive used can result in Cushing’s Syndrome, whilst sudden withdraw can result in adrenal insufficiency.

58
Q

What are NSAIDs?

A

NSAIDs are anti-inflammatory drugs which reduce the production of leukotrienes (lipids used to mediate the inflammatory response)
They work by inhibiting COX-1 and -2

59
Q

What is Aspirin?

A

Aspirin is an irreversible, selective COX-1 inhibitor.
Drug disappears from the blood rapidly but extended duration of action.
Effect is potentiated by caffeine.
Long-term low doses reduces blood clotting
Not recommended for use in children due to risk of Reyes’ syndrome

60
Q

What is ibuprofen?

A

Reversible inhibitor of COX-1 and -2.
Analgesic, anti-inflammatory and antipyretic activity is largely due to COX-2 inhibition.
Only the S-enantiomer is active (the enantiomer which is shown). Naproxen is manufactured as the S-enantiomer, all others as the racemate.
Some risk of ulcers (due to COX-1 inhibition).

61
Q

How is ibuprofen activated?

A

Ibuprofen is given as a racemic mixture, conversion is specifically R to S.
Acyl-CoA esters can acylate other proteins (gives rise to allergic reactions and other toxicities)

62
Q

What is diclofenac?

A

Diclofenac shows is a stronger inhibitor of COX-2 than COX-1 (~10x)
Use increases risk of cardiovascular complications
Reduced risk of ulcers (due to lower activity against COX-1)
Duration of action is 6-8 hours (despite a short half-life)

63
Q

What are selective COX 2 inhibitors?

A

Increased risk of cardiovascular complications.
Effectiveness for pain-relief is similar to that of Ibuprofen, Naproxen, and Aspirin.
Naproxen has a lower cardiovascular risk (and is much cheaper) but less widely used.

MPharm2 SL22105 (8 decks)

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