Pharmacological aspects of immunology

Question 1

What are the NSAIDs?

Answer 1

Aspirin
Propionic acid derivatives -> ibuprofen, naproxen
Arylalkanoic acids –> indometacin, diclofenac
Oxicams -> piroxicam
Fenamic acids -> mefanamic acid
Butazones -> phenylbutazon

Question 2

Outline the prostaglandin H2 part of the arachidonic acid pathway

Answer 2

Phospholipids -> (phospholipases) -> arachidonic acid -> (cyclo-oxygenases) -> prostaglandin H2 (tissue specific synthases) -> thromboxanes (platelet aggregation / vasoconstriction) + prostaglandins (bronchial tone, vascular tone, hyperalgesia etc) + prostacyclins (vasodilatation).

Question 3

What is the mechanism of action of NSAIDs?

Answer 3

Non-specific inhibitors of cyclo-oxygenases (COX).
3 isoforms:
COX-1 -> constitutive expression –> all tissues
(stomach, kidney, platelets, vascular endothelium).
inhibition → anti-platelet activity, side effects
COX-2 –> induced in inflammation (IL-1) -> injury, infection, neoplasia. inhibition → analgesia + anti-inflammatory actions.
COX-3 –> CNS only? may be relevant to paracetamol.

Question 4

What are the indications for NSAID therapy?

Answer 4

Short-term management of pain (+ fever). as mild analgesics (orally + topically) -> mechanical pain of all types, minor trauma, headaches, dental pain, dysmenorrhoea.
As potent analgesics (orally, parenterally, rectally) ->
peri-operative pain, ureteric colic.

Question 5

NSAIDs’ anti-inflammatory properties are used for which conditions?

Answer 5

Gout

Inflammatory arthritis -> ankylosing spondylitis, rheumatoid arthritis

Question 6

What are the uses and limitations of aspirin?

Answer 6

Pain + inflammation. limited by:
GI toxicity
Tinnitus –> mechanism obscure, usually reversible.
Reye’s syndrome -> fulminant hepatic failure in children.
Anti-platelet effect
Primary + secondary prevention -> stroke + MI
Treatment of acute MI + stroke

Question 7

How can NSAIDs cause GI toxicity?

Answer 7

In GI tract prostaglandins E2 + I2 -> decrease acid production, increase mucus production, increase blood supply.
NSAID inhibition in stomach + duodenum -> irritation,
ulcers, bleeding.
Colitis –> esp. with local preps e.g. rectal diclofenac.
Upper GI bleeding -> relative risk 4.7. biggest risk factor -> previous GI bleed, age, chronic disease (e.g. rheumatoid disease), steroids.
Consider co-administration of gastro-protection with proton pump inhibitor.

Question 8

How can NSAIDs cause nephrotoxicity toxicity?

Answer 8

Due to changes in glomerular blood flow -> decreased GFR, Na 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

Question 9

What effect does aspirin/NSAID have on asthmatics?

Answer 9

10% asthmatics experience bronchospasm -> arachidonic acid shunted down 5LPO pathway when COX is inhibited, increasing leukotrienes.

Question 10

List the non-selective NSAIDs from least potent to most potent (more side effects)

Answer 10

Ibuprofen -> naproxen -> diclofenac -> indometacin

Side effects -> GI, renal, fluid retention

Question 11

What is the effect, contraindications and mechanism of paracetamol?

Answer 11

Not NSAID, minimal anti-inflammatory effects, good analgesic/ anti-pyretic.
Well-tolerated, almost no contraindications.
Doesn’t bind COX1 / 2, weak inhibitor of prostaglandin,
may inhibit COX3 but relevance controversial.
Dangerous in overdose.

Question 12

Outline how paracetamol is metabolised

Answer 12

Paracetamol normally removed via phase 2 conjugation reaction in liver -> paracetamol sulphates + glucuronide -> excretion.
If phase 2 reaction saturated -> shunted down phase 1 oxidation reaction -> NAPQI (hepatic necrosis) -> another phase 2 conjugation reaction -> NAPQI-glutathione -> excretion.

Question 13

How is paracetamol poisoning/overdose treated?

Answer 13

NAC (N-acetylcysteine) overrides saturation of conjugation pathway + enables NAPQI to be harmlessly removed.

Question 14

What is the purpose of selective COX 2 inhibitors?

Answer 14

Selective inhibition of COX-2 in vitro + in vivo.
Anti-inflammatory + analgesic.
Selectivity (GI, platelets) at anti-inflammatory doses.
Comparable efficacy (not superior) to non-selective NSAIDs in acute pain, dysmenorrhoea, inflammatory joint disease.
Controversy -> increased MI risk but may be due to absence of anti-platelet effect.
Only recommended in high-risk patients + after cardiovascular risk assessment.

Question 15

What are the functions of cortisol (hydrocortisone)?

Answer 15

Endogenous glucocorticoid:
Carbohydrate + protein metabolism
Fluid + electrolyte balance (mineralocorticoid effects)
Lipid metabolism
Psychological effects
Bone metabolism
Profound modulator of immune response

Question 16

How is the mechanism of action corticosteroids?

Answer 16

Steroid receptors in cytoplasms complexed with Hsp90 -> steroids cross cell membrane + bind to steroid receptor complex releasing Hsp90 -> steroid:receptor complex can now cross nuclear membrane -> in nucleus steroid receptor binds to specific gene regulatory sequences + activates transcription.
Steroids reduce immune activation by altering gene expression e.g. in T + B cells + cells of innate immune system. delayed onset of action so must be taken regularly.

Question 17

What are the immunomodulation effects of steroids?

Answer 17

Cell trafficking -> lymphopenia, monocytopenia (redistribution), neutrophilia + impaired phagocyte migration.
Cell function -> T cell hypo-responsiveness, inhibited B cell maturation, decreased IL1, IL6, TNFa production (monocytes), widespread inhibition of Th1 + Th2 cytokines, inhibition of COX - prostaglandins, impaired phagocyte killing, ↓collagenases, elastases etc.
Don’t effect immunoglobulin levels + complement.

Question 18

Outline the clinical use of steroids

Answer 18

Suppress inflammation of all kinds, esp. in acute disease + maintenance therapy.
Asthma, Crohn’s / UC, eczema, MS, sarcoid, allergy, rheumatoid arthritis, SLE etc.
Replacement therapy in hypoadrenalism.
Myriad preparations + routes:
Systemic -> oral + parenteral
Topical -> skin, joint injections, inhaled, enteric coated, rectal.

Question 19

What are the corticosteroid drugs and their potency, lipid solubility, systemic use and typical use?

Answer 19

Hydrocortisone -> low potency, good lipid solubility, replacement rx + occasionally treatment, skin + joints.
Prednisolone -> medium, good, anti-inflammatory, enemas.
Beclomethasone -> medium, poor, topical use for asthma + Crohn’s.
Dexamethasone -> high, good, systemic use for cerebral oedema.
Triamcinolone -> high, poor, topical use for skin + joints

Question 20

What are the side effects of steroid therapy?

Answer 20

Early -> weight gain, glucose intolerance, mood change, suppression of ACTH release.
Later -> proximal muscle weakness, osteoporosis, skin + body shape changes, hypertension, cataracts, adrenal suppression.

Question 21

What are the effects of adrenal suppression during corticosteroid therapy?

Answer 21

After prolonged therapy adrenal cortex atrophies + endogenous production takes some time to recover upon cessation.
Abrupt withdrawal below replacement dose reduces ability to deal with physiological stress e.g. infection + may precipitate an adrenal crisis -> steroid warning card, tail dose slowly, increase dose during acute illness + prior to surgery.

Question 22

What is the risk of steroid therapy?

Answer 22

Risk related to cumulative dose.
Phagocytic defects (early risk):
bacterial infection –> S. aureus, enteric bacteria etc.
fungal infection –> candida, aspergillus.
Cell mediated defects (later risk):
intracellular pathogens -> TB, varicella, listeria, pneumocystis.

Question 23

What are disease-modifying anti-rheumatic drugs (DMARDS) used for?

Answer 23

Targets immune system.
Rheumatoid arthritis, transplantation, myriad other autoimmune + inflammatory disorders, sometimes in higher doses for chemotherapy.
Distinguished from NSAIDs, steroids + biologics.

Question 24

What are the uses and toxicities of the DMARD methotrexate?

Answer 24

Competitive inhibitor of DHR -> anti-folate action.
Folate needed for purine synthesis in DNA.
Reduces T cell activity + tumour synthesis in higher doses.
Rheumatoid arthritis, psoriasis, Crohn’s.
Hepatotoxicity, leucopenia, pulmonary fibrosis, teratogenic.
Weekly dosing (errors have caused major toxicity).

Question 25

What are the uses and toxicities of the DMARD azathioprine?

Answer 25

Inhibits TPMT so inhibits purine synthesis.
Similar indications to methotrexate, more widely used in transplantation than metho.
Toxicities similar to metho -> GI upset very common.

Question 26

What are the uses and toxicities of the DMARD cyclosporins?

Answer 26

Inhibits calcineurin -> reduces T cell activity.
Similar indications to aza/metho, used more in dermatology + transplantation.
Nephrotoxic, hepatotoxic, gum hyperplasia, hirsutism.
Tacrolimus (newer formulation) is easier to take + available for topical use (esp eczema).