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204-theme 1 > L14. Pharmacological aspects of immunology (Theme 1) > Flashcards

L14. Pharmacological aspects of immunology (Theme 1) Flashcards

1
Q

examples of NSAIDS

A

Large, chemically diverse family of drugs:

Aspirin

Paracetamol

Propionic acid derivatives - e.g. ibuprofen, naproxen

Arylalkanoic acids – e. g indometacin, diclofenac

Oxicams - e.g. piroxicam

Fenamic acids - e.g. mefanamic acid

Butazones - e.g. phenylbutazone

Coxibs e.g. celecoxib

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2
Q

what is the Eicosanoid pathway

A

Study slide 6

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3
Q

what do nSAIDS all do

A

They antagonise cyclooxygenase stopping the conversion of arachidonics and Prostaglandins H2 to thromboxanes

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4
Q

what are the 3 isoforms of cyclo-oxygenases

A

COX-1 - Constitutive expression

COX-2 – Induced in inflammation

COX-3 – CNS only?

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5
Q

what are the 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
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6
Q

what are NSAID used for

A

for gout

inflammatory arthritis e.g- ankylosing spondylitis, rheumatoid arthritis

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7
Q

what is Aspirin used for

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

action 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 (see later slides)

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9
Q

how is paracetamol metabolised

A

see slide 17

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10
Q

describe 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 (gastric 15-30%, duodenal 10%)
  • Bleeding

Similar effect in the colon
-Colitis – esp with local preps e.g. rectal diclofenac

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11
Q

describe 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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12
Q

study slide

A

21

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13
Q

describe NSAIDs in increasing toxicity

A

Ibuprofen- naproxen- dielofenae - indomethacin

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14
Q

how can you prevent NSAID toxicity

A

Is an NSAID the answer (paracetamol, opioids?)

In terms of GI toxicity
Treatment with
Gastroprotective drugs (misoprostil – PGE1 analogue, or proton pump inhibitor)

Avoid in renal failure, dose adjust if necessary

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15
Q

describe selective 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

The ‘coxibs’:

  • celecoxib
  • etoricoxib
  • rofecoxib
  • valdecoxib
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16
Q

what is the efficacy of coxibs

A

Numerous clinical trial data

Comparable efficacy (not superior) to non-selective NSAIDs in

  • Acute pain
  • Dysmenorrhoea
  • Inflammatory joint disease
17
Q

GI side effects of COXIBs

A

lower than for NSAIDs

18
Q

do coxibs increase the risk of MIs

A

Cox-2 inhibitors – no activity as antithrombotics

Two studies published in 2005

↑ 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)

19
Q

which coxib do we need to know

A

Celecoxib:cyclo-oxygenase-2 selective inhibitors should not be used in preference to non-selective NSAIDs except when specifically indicated (i.e. for patients who are at a particularly high risk of developing gastroduodenal ulceration, perforation, or bleeding) and after an assessment of cardiovascular risk’

20
Q

give an example of a corticosteroid

A

Cortisol (hydrocortisone) – predominant endogenous glucocorticoid

  • Carbohydrate and protein metabolism
  • Fluid and electrolyte balance (mineralocorticoid effects)
  • Lipid metabolism
  • Psychological effects
  • Bone metabolism
  • Profound modulator of immune response
21
Q

mechanism of action of corticosteroids

A
  • steroid receptors are found in the cytoplasm complexed with a heat-shock protein HSp90
  • steroids cross the cell membrane and bind to the steroid receptor complex releasing Hsp90

the steroid-receptor complex can now cross the nuclear membrane

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

22
Q

Immunomodulation by steroids

A

Cell trafficking

  • Lymphopenia, monocytopenia (redistribution)
  • Neutrophilia and impaired phagocyte migration
Cell function
-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
↓collagenases, elastases etc

Don’t effect

  • Immunoglobulin levels
  • Complement
23
Q

clinical use of steroids

A

To suppress inflammation
Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosis etc etc

To suppress specific immunity
Graft rejection

Replacement therapy in hypoadrenalism

24
Q

routes of admin-steroids

A

Systemic (oral and parenteral)

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

25
Q

different drug properties

A

Different potencies

Different pharmacokinetics (esp lipid solubility and half-life)

26
Q

side effects of steroid therapy

A

Early:

  • Weight gain
  • Glucose intolerance
  • Mood change
  • Suppression of ACTH release

Later:

  • Proximal muscle weakness
  • Osteoporosis
  • Skin changes
  • Body shape changes
  • Hypertension
  • Cataracts
  • Adrenal suppression
27
Q

describe the suppression of adrenals 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:

  • Steroid warning card
  • Tail dose slowly
  • Increase dose during acute illness and prior to surgery
28
Q

steroids increase the risk of

A

infections:
Early: Phagocytic defects:

  • Bacterial infection – S. aureus, enteric bacteria etc
  • Fungal infection – candida, aspergillus

Cell mediated defects

  • Intracellular pathogens
  • TB
  • Varicella
  • Listeria
  • Pneumocystis

204-theme 1 (15 decks)

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