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204: The immune system > Pharmacological aspects of immunology > Flashcards

Pharmacological aspects of immunology Flashcards

1
Q

NSAIDS

A

Large, chemically diverse family of drugs

  • aspirin
  • paracetamol
  • propionic acid derivatives
  • arylalkanoic acids
  • axicams
  • fenamic acids
  • butazones
  • coxibs
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2
Q

NSAID mechanism of action

A

All inhibit cyclo-oxygenase

Three isoforms of cyclo-oxygenase

  • COX-1 constitutive expression
  • COX-2 induced in inflammation
  • COX-3 CNS only
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3
Q

COX-1

A

Constitutive expression- all tissues

Stomach, kidney, plateletse, vascular endothelium

Inhibition -> anti-platelet activity, side effects

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4
Q

COX-2

A

Induced in inflammation (IL-1)

Injury, infection, neoplasia

Inhibition -> analgesia and anti-inflammatory actions

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5
Q

COX-3

A

CNS only?

Inhibited specifically by paracetamol -> antipyretic and analgesic actions

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6
Q

Indications for NSAID therapy

A

Short term management of pain (and fever)

As mild analgesics

  • mechanical pain of all types
  • minor trauma
  • headaches, dental pain
  • dysmenorrhoea

As potent analgesics (orally, parenterally, rectally)

  • peri-operative pain
  • ureteric colic

As anti-inflammatories

  • gout
  • inflammatory arthritis e.g. ankylosing spondylitis, rheumatoid arthritis
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7
Q

Aspirin

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

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8
Q

Paracetamol

A

Doesn’t bind COX1 or 2

No significant anti-inflammatory action

No significant GI toxicity

Analgesic/ anti-pyretic

Dangerous in overdose

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9
Q

NSAID GI toxicity

A

In the GI tract prostaglandins E2 and I2

  • decrease acid production
  • increase mucus production
  • increase blood supply

NSAID inhibition in stomach and duodenum

  • irritation
  • ulcers
  • bleeding

Similar effect in the colon
- colitis- esp with local preps

Upper GI bleeding
- relative risk 4.7 all users

Biggest risk factor for GI bleed is previous GI bleeds

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10
Q

NSAID nephrotoxicity

A

Primarily related to changes in glomerular blood flow

  • decreased glomerular filtration rate
  • sodium retention
  • hyperkalaemia
  • papillary necrosis

Acute renal failure 0.5-1%

Avoid or dose adjust in renal failure

Avoid in patients likely to develop renal failure

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11
Q

Asthma and aspirin

A

About 10% of asthmatics experience bronchospasm following NSAID

Perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited

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12
Q

Preventing NSAID toxicity

A

Treatment with
- gastroprotective drugs (misoprostil- PGE1 analogue, or proton pump inhibitor)

Avoid in renal failure, dose adjust if necessary

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13
Q

Selective COX-2 inhibitors

A

Selective inhibition of COX2 in vitro and in vivo

Anti-inflammatory and analgesic in humans

Objective evidence of selectively (GI, platelets) at > anti-inflammatory doses

The ‘coxibs’

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14
Q

Coxibs efficacy

A

Numerous clinical trial data

Comparable efficacy to non-selective NSAIDs in

  • acute pain
  • dysmenorrhoea
  • inflammatory joint disease
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15
Q

Coxibs increase risk of MI

A

Cox-2 inhibitors- no activity as antithrombotics

Increased rates of MI in clinical trials of celecoxib and reofecoxib

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16
Q

Corticosteroids

A

Cortisol (hydrocortisone)- predominant endogenous glucocorticoid

  • carbohydrate and protein metabolism
  • fluid and electrolyte balance
  • lipid metabolism
  • psychological effects
  • bone metabolism
  • profound modulator of immune response
17
Q

Immunomodulation by steroids

A

Cell trafficking

Cell function

Don’t effect

  • immunoglobulin levels
  • complement
18
Q

Immunomodulation by steroids- cell trafficking

A

Lymphopenia, monocytopenia (redistribution)

Neutrophilia and impaired phagocyte migration

19
Q

Immunomodulation by steroids- cell function

A

T cell hyporesponsiveness

Inhibited B cell maturation

Decreased IL1, IL6 and TNFa production (monocytes)

Widespread inhibition of Th1 and Th2 cytokines

Inhibition of COX- prostaglandins

Impaired phagocyte killing

Decrease collagenases, elastases etc

20
Q

Clinical use of corticosteroids

A

To suppress inflammation
- asthma, Crohn’s/ UC, eczema, multiple sclerosis, sarcoid, allergy, RA, SLE

To suppress specific immunity
- graft rejection

Replacement therapy in hypoadrenalism

21
Q

Steroid preparation

A

Different routes of administration

  • systemic (oral and parenteral)
  • topical (skin, joint injections, inhaled, enteric coated, rectal)

Different drugs

  • different potencies
  • different pharmacokinetics
22
Q

Hydrocortisone

A

Potency: low

Lipid solubility: good

Systemic use: replacement Rx

Topical use: skin, joints

23
Q

Prenisolone

A

Potency: medium

Lipid solubility: good

Systemic use: anti-inflammatory

Topical use: enemas

24
Q

Beclomethasone

A

Potency: medium

Lipid solubility: poor

Topical use: asthma, crohn’s

25
Q

Dexamethasone

A

Potency: high

Lipid solubility: good

Systemic use: cerebral oedema

26
Q

Triaminiclone

A

Potency: high

Lipid solubility: poor

Topical use: skin, joints

27
Q

Early side effects of steroid therapy

A

Weight gain

Glucose intolerance

Mood change

Suppression of ACTH release

28
Q

Later side effects of steroid therapy

A

Proximal muscle weakness

Osteoporosis

Skin changes

Body shape changes

Hypertension

Cataracts

Adrenal suppression

29
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 e.g. infection and may precipitate an adrenal crisis

30
Q

Steroids and infection risk

A

Phagocytic defects

  • bacterial infection: S. aureus, enteric bacteria
  • fungal infection: candida, aspergillus

Cell mediated defects
- intracellular pathogens: TB, varicella, listeria, pneumocystis

204: The immune system (19 decks)

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