Pharmacological aspects of immunology

Question 1

Outline the Cyclooxygenase pathway of the eicosanoid pathway

Answer 1

phospholipids—>arachidonic acid—-> prostaglandin H2 (Cyclo-oxygenases)

• –> thromboxanes (platelet agg, vasocon)
• –> prostaglandins (vasodilation)
• –> prostacyclins (bronchial tone, vascular tone and hyperalgesia etc)

Question 2

How does NSAIDS affect the eicosanoid pathway

Answer 2

It antagonises Cyclo-oxygenase (non-specific COX inhibitors

Question 3

What are the 3 isoforms of COX and the result of inhibiting them

Answer 3

COX1 inhibition- antiplatelet activity
COX2 inhibition- analgesia and anti-inflammatory actions
COX3- relevant to paracetamol

Question 4

In what condition are NSAID’s very effective as an anti-inflammatory

Answer 4

In Gout, uric acid crystal depositions in the joints creating a very painful arthritis

Question 5

Why are prostaglandins important for GI

Answer 5

in the GI prostaglandins E2 and I2 are important for

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

Question 6

Outline NSAID GI Toxicity

Answer 6

NSAID effect prostaglandin production which causes irritation, ulcers and bleeding in the GI, similar effect in the colon

Question 7

Outline NSAID nephrotoxicity

Answer 7

mainly related to changes in glomerular blood flow

• decreases GFR
• sodium retention
• hyperkalemia
• papillary necrosis

Question 8

How does NSAIDS affect people with asthma

Answer 8

They increase bronchospasms as arachidonic acid is shunted down the 5LPO pathway when COX is inhibited which increases leukotrienes production which increases bronchoconstriction

Question 9

How do we prevent NSAID toxicity

Answer 9

Could change the drug, paracetamol?

consider risk factors, renal impairment, previous peptic ulcers?
avoid or dose adjust in renal impairment

consider co-administration of gastroprotection with PPI

Question 10

outline paracetamol properties

Answer 10

minimal anti-inflammatory effects but good analgesic properties
very well tolerated with almost no contraindications
may inhibit COX3
dangerous in overdose.

Question 11

How is paracetamol metabolised

Answer 11

Usually harmlessly removed by phase 2 conjugation reaction in the liver to produce paracetamol sulphate and glucuronide which is excreted.

Question 12

How is paracetamol metabolised in an overdose situation

Answer 12

Phase 2 reaction is very easily oversaturated in which case Phase 1 oxidation reaction is used which produces NAPQI which is hepatotoxic and causes delayed hepatic necrosis

NAPQI then undergoes phase 2 conjugation reaction to make NAPQI glutathione which is excreted.

Question 13

What is the solution to paracetamol overdose

Answer 13

N-acetylcysteine is used to treat paracetamol poisoning, overrides the saturation of the conjugation pathway to harmlessly remove NAPQI

Question 14

What are selective COX-2 inhibitors

Answer 14

once COX 1 was realised to be causing side effects, COX 2 inhibitors were made which also have analgesic and anti-inflammatory properties.

may increase cardiovascular risk

Question 15

What are corticosteroids

Answer 15

endogenous form- cortisol
main functions in:
- carb and protein metabolism
- fluid and electrolyte balance
- lipid metabolism
- psychological effects
- bone metabolism
-profound modulator of the immune response.

Question 16

How do steroid drugs work

Answer 16

They are lipophilic so they cross plasma membranes and bind to the steroid receptor complex, releasing Hsp90, the steroid receptor complex can now cross the nuclear membrane where the receptor affects transcription.

Question 17

How are steroids used clinically

Answer 17

They are used to suppress inflammation of all kinds, particularly in acute disease but also in maintenance therapy e.g. asthma, Crohn’s eczema, sle etc

can be administered systemically (oral) or topically (skin, joint injection, inhaled etc)

Question 18

What are 5 corticosteroids you should know

Answer 18

Hydrocortisone- replacement therapy
                            for hypoadrenalism
prednisolone-anti inflammatory
beclomethasone- anti-inflammatory
dexamethasone- cerebral oedema
triamcinolone-

Question 19

What are side effects of steroid therapy

Answer 19

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

Question 20

outline adrenal supression during corticosteroid therapy

Answer 20

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 the ability to deal with physiological stress e.g. infection

Question 21

What are DMARDS

Answer 21

disease-modifying anti-rheumatic drugs

they target the immune system, used to treat rheumatoid arthritis and other inflammatory diseases such as SLE, eczema and high doses used in chemo.

Question 22

What is methotrexate, what are its main uses and toxicities

Answer 22

A DMARD drug

competitive inhibitor of DHR

reduces t cell activity (and in higher doses tumour synthesis)

main uses

• rheumatoid arthritis
• psoriasis
• Crohns disease

main toxicity

• hepatotoxicity
• leucopenia
• pulmonary fibrosis
• teratogenic

Question 23

What is Azathioprine what are its main uses and toxicities

Answer 23

DMARD drug
Inhibits thiopurine S methyltransferase (TPMT), so also inhibits purine synthesis,

main uses

• rheumatoid arthritis
• psoriasis
• Crohns disease

main toxicity

• hepatotoxicity
• leucopenia
• pulmonary fibrosis
• teratogenic

Question 24

What is ciclosporin what are its main uses and toxicities

Answer 24

Inhibits calcineurin which in turn decreases t lymphocyte activity

similar uses to metho/aza but used more in derm and transplantation

main toxicities

• nephrotoxic
• hepatotoxic
• gum hyperplasia
• hirsutism