Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Year 2 - T3 Theme 1 > L14 Pharmacological aspects of immunology; NSAID and corticosteroids > Flashcards

L14 Pharmacological aspects of immunology; NSAID and corticosteroids Flashcards

1
Q

Examples of NSAIDS

A
  • Aspirin
  • Paracetamol
  • Propionic acid derivatives - eg. ibuprofen, naproxen
  • Arylakanoic acids - eg. indometacin, diclofenac
  • Oxicams - eg. piroxicam
  • Fenamic acids - eg. mefanamic acid
  • Butazones - eg. phenylbutazone
  • Coxibs - eg. celecoxib
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What do NSAIDS target

A
  • NSAIDS target a cascade of small molecule inflammatory mediators known as eicosanoids
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Eicosanoid pathway

A
  • During any form of tissue injury, membrane phospholipids are released and converted by phospholipases to arachidonic acid - a poly unsaturated 20 carbon lipid which can then, depending on tissues and inflammatory stimuli, be metabolised to either leukotrienes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the eicosanoid pathway particularly involved in

A
  • Airway responses or prostaglandins
  • Including thromboxanes
    • Prostacyclines
    And prostaglandins – involved in
    Or prosaglandins – through the central intermediate prostaglandin H2
    Prostaglandins include – depending on tissue specific synthases
    • Thromboxanes –which are involved in platelet aggregation and small vessel tone
    • Prostacyclines – which have vasodilator properties
    • And prostaglandins themselves –
    • which are involved in bronchial tone, vascular tone, sensitivity of nerve fibres among other properties
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

NSAID mechanism of action

A
  • All inhibit cyclo-oxygenase
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Isoforms of cox

A
  • COX-1 - Constitutive expression
  • COX-2 - Induced in inflammation
  • COX-3 - CNS only?
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

COX-1 location

A
  • Constitutive expression in all tissues
  • Stomach, kidney, platelets, vascular endothelium
  • Inhibition –> anti-platelet activity, side effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

COX-2 - location

A
  • Induced in inflammation (IL-1)
  • Injury, infection, neoplasia
  • Inhibition –> analgesia and anti-inflammatory actions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

COX-3 - location

A
  • CNS only?

- Inhibited specifically by paracetamol –> antipyretic and analgesic actions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Why is COX 1 important

A
  • Involved in maintenance of vascular supply endothelial junction integrity etc
  • Particularly important seem to be the gastric mucosa and the renal tubules - where inhibition is responsible for much of the side-effects
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is COX 2 induced by

A
  • COX2 is induced by the inflammatory response
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Indications for NSAID therapy

A
  • Short-term management of pain (and fever)
  • As mild analgesics (orally and topically)
  • Mechanical pain of all types
  • Minor trauma
  • Headaches, dental pain
  • Dysmenorrhoea

As potent analgesics (orally, parenterally, rectally)

  • Peri-operative pain
  • Ureteric colic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Anti-inflammatory use of NSAIDs

A
  • Gout

- Inflammatory arthritis eg ankylosing spondylitis, rheumatoid arthritis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Limitations of aspirin use for pain and inflammation

A

Use for pain and inflammation limited by:

  • GI toxicity
  • Tinnitus - mechanism obscure, usually reversible
  • Reye’s syndrome (fulminant hepatic failure in children)

Anti-platelet effect

  • Prophylaxis of ischaemic heart disease
  • Treatment of acute MI
  • Clopidogrel and dipyrimidole (Non-NSAID antiplatelet drugs)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Features of paracetamol (acetaminophen)

A
  • Doesn’t bind COX1 or 2
  • No significant anti-inflammatory action
  • No significant GI toxicity
  • Analgesic/anti-pyretic
  • Dangerous in overdose
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Paracetamol metabolism

A
  • Under normal circumstances, the majority of paracetamol is conjugated in the liver with glucuronide and sulphate but a minority is oxidised by microsomal enzymes to a toxic intermediary which is it self rapidly neutralised by conjugation with glutathione
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Paracetamol metabolism - excess amounts

A
  • When excessive amounts of paracetamol is present, both these conjugation reactions are overwhelmed and these toxic intermediates accumulate leading to potentially fatal hepatic necrosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Treatment of paracetamol toxicity

A
  • Relies on the provision of substrates which the body can use to synthesise glutathione
  • The two drugs which are used are NAC and methionine
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is glutathione

A
  • A tripeptide involving cysteine - a non essential amino acid only in that it has to be synthesised from the essential amino acid methionine
  • Can be easily converted to glutathione
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Effects of prostaglandins E2 and I2 in the GI tract

A
  • Decrease acid production
  • Increase mucus production
  • Increase blood supply
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Effects of NSAID inhibition in stomach and duodenum

A
  • Irritation
  • Ulcers (gastric 15-30%, duodenal 10%)
  • Bleeding

Similar effect in the colon
- Colitis - esp with local preps eg. rectal diclofenac

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

How do NSAIDs primarily cause GI toxicity

A
  • Loss of prostaglandins, notably E2 and I2
23
Q

Upper GI bleeding - NSAID risk

A
  • Relative risk 4.7 all users
  • Azapropazone - 23.4
  • Piroxicam - 18
  • Small differences between others
24
Q

Biggest risk for GI bleed

A 
Previous GI bleed 
Also: 
- Age 
- Chronic disease(eg. rheumatoid disease) 
- Steroids
25
Q

What is NSAID nephrotoxicity associated with

A

Primarily related to changes in glomerular blood flow

  • Decreased glomerular filtration rate
  • Sodium retention
  • Hyperkalaemia
  • Papillary necrosis
26
Q

Risk of acute renal failure - NSAID

A
  1. 5 - 1%
    - Avoid or dose adjust in renal failure
    - Avoid in patients likely to develop renal failure
27
Q

What percentage of patients on nsaids experience a bronchospasm

A
  • About 10% of asthmatics experience bronchospasm following NSAID - perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited
28
Q

4 common non-selective NSAIDS - in order of increasing potency and increasing side-effects(GI, renal and fluid retention)

A

Ibuprofen, naproxen, diclofenac and indometacin

29
Q

What can GI toxicity be treated with

A
  • Gastroprotective drugs (misoprstil - PGE1 analogue, or PPI)
  • Avoid in renal failure, dose adjust if necessary
30
Q

Features of COX-2 inhibitors

A
  • Selective inhibition of COX-2 in vitro and in vivo
  • Anti-inflammatory and analgesic in humans
  • Objective evidence of selectivity(GI, platelets) at > anti-inflammatory doses
31
Q

What are the coxibs

A
  • Celecoxib
  • Etoricoxib
  • Rofecoxib
  • Valdecoxib
32
Q

Coxibs - efficacy

A
  • Numerous clinical trial data
  • Comparable efficacy (not superior) to non-selective NSAIDs in

Acute pain
Dysmenorrhoea
Inflammatory joint disease

33
Q

Do coxibs increase risk of MI

A

Cox-2 inhibitors - no activity as antithrombotics
two studies published in 2005
- Increase in rates of MI in clinical trials of celecoxib and rofecoxib
- Data not fully disclosed by companies?
- Relative risk (small 1.56 for celecoxib higher for others) (acute first three months)

34
Q

Main coxib

A
  • Celecoxib
35
Q

BNF advice on coxib usage

A
  • Cyclo-oxygenase-2 selective inhibitors should not be used in preference to non-selective NSAIDs except when specifically indicated (ie for patients who are at particularly high risk of developing gastroduodenal ulceration, performation, or bleeding) and after an assessment of cardiovascular risk
36
Q

Effects of cortisol

A
  • Carbohydrate and protein metabolism
  • Fluid and electrolyte balance(mineralocorticoid effects)
  • Lipid metabolism
  • Psychological effects
  • Bone metabolism
  • Profound modulator of immune response

Endogenous cortisol from the adrenal cortex
Extensive regulatory functions including the most profound global modulator of the immune response

37
Q

How do corticosteroids function

A
  • Steroid receptors are found in the cytoplasm complexed with a heat-shock protein
  • Steroids cross the cell membrane and bind to the steroid receptor complex, releasing Hsp90
  • The steroid:receptor complex can now cross the nuclear membrane
  • In the nucleus, the steroid receptor binds to specific gene regulatory sequences and activates transcription
38
Q

Overall effect of corticosteroids

A
  • Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system
  • Their onset of action is delayed and they must be taken regularly
39
Q

Immunomodulation by steroids - cell trafficking

A
  • Lymphopenia, monocytopenia (redistribution)

- Neutrophilia and impaired phagocyte migration

40
Q

Immunomodulation by steroids - cell function

A
  • T cell hyporesponsiveness
  • Inhibited B cell maturation
  • Decreased IL1, IL6 and TNFalpha production (monocytes)
  • Widespread inhibition of Th1 and Th2 cytokines
  • Inhibition of COX - prostaglandins
  • Impaired phagocyte killing
  • Decreas ein collagenases, elastases etc

Don’t affect immunoglobulin levels and complement

41
Q

Clinical use of steroids

A

To suppress inflammation - asthma, crohn’s/UC, eczema, MS, sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis

To suppress specific immunity - graft injection

Replacement therapy in hypoadrenalism

– Because of these functions, they are widely used to suppress inflammation and specific immunity

42
Q

How are steroids administered

A
  • Systemic (oral and parenteral)

- Topical (skin, joint injections, inhaled, enteric coated, rectal)

43
Q

Features of hydrocortisone

A
  • Low potency
  • Good lipid solubility
    Systemic use - Replacement Rx
    Topical use - skin, joints
44
Q

Features of prednisolone

A
  • Medium potency
  • Good lipid solubility
    Systemic use - anti-inflammatory
    Topical use - enemas
45
Q

Features of beclomethasone

A
  • Medium potency
  • Poor lipid solubility
    Topical use - asthma, crohn’s
46
Q

Features of dexamethasone

A
  • High potency
  • Good lipid solubility
    Systemic use - cerebral oedema
47
Q

Features of triaminiclone

A
  • High potency
  • Poor lipid solubility
    Topical use - skin, joints
48
Q

Side effects of steroid therapy - early

A
  • Weight gain
  • Glucose intolerance
  • Mood change
  • Suppression of ACTH release
49
Q

Side effects of steroid therapy - later

A
  • Proximal muscle weakness
  • Osteoporosis
  • Skin changes
  • Body shape changes
  • Hypertension
  • Cataracts
  • Adrenal suppression
50
Q

Adrenal suppression during corticosteroid therapy

A
  • High-dose exogenous corticosteroids suppress endogenous production within 1 week
  • After prolonged therapy, the adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation
  • Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress - eg infection - and may precipitate an adrenal crisis
51
Q

Steroid use - precautionary measures

A
  • Steroid warning card
  • Tail dose slowly
  • Increase dose during acute illness and prior to surgery
52
Q

Link between steroids and infection

A

Steroids also increase risk of infection:

  • 71 placebo controlled trials of prednisolone
  • Consistently report increased risk of infection which is related to total accumulative dose
  • Eg. for prednisolone > 700 mg (= 10-20 days of a standard dose)
53
Q

Risk of infection with steroid use - phagocytic defects

A

Phagocytic defects - risk occurs early

  • Bacterial infection - S. aureus, enteric bacteria etc
  • Fungal infection - candida, aspergillus
54
Q

Risk of infection with steroid use - cell mediated defects

A 
Cell mediated defects - risk occurs later 
Intracellular pathogens 
- TB 
- Varicella 
- Listeria 
- Pneumocystis

Year 2 - T3 Theme 1 (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions