Pharmacological aspects of immunology Flashcards
Outline the Cyclooxygenase pathway of the eicosanoid pathway
phospholipids—>arachidonic acid—-> prostaglandin H2 (Cyclo-oxygenases)
- –> thromboxanes (platelet agg, vasocon)
- –> prostaglandins (vasodilation)
- –> prostacyclins (bronchial tone, vascular tone and hyperalgesia etc)
How does NSAIDS affect the eicosanoid pathway
It antagonises Cyclo-oxygenase (non-specific COX inhibitors
What are the 3 isoforms of COX and the result of inhibiting them
COX1 inhibition- antiplatelet activity
COX2 inhibition- analgesia and anti-inflammatory actions
COX3- relevant to paracetamol
In what condition are NSAID’s very effective as an anti-inflammatory
In Gout, uric acid crystal depositions in the joints creating a very painful arthritis
Why are prostaglandins important for GI
in the GI prostaglandins E2 and I2 are important for
- decrease acid production
- increase mucus production
- increase blood supply
Outline NSAID GI Toxicity
NSAID effect prostaglandin production which causes irritation, ulcers and bleeding in the GI, similar effect in the colon
Outline NSAID nephrotoxicity
mainly related to changes in glomerular blood flow
- decreases GFR
- sodium retention
- hyperkalemia
- papillary necrosis
How does NSAIDS affect people with asthma
They increase bronchospasms as arachidonic acid is shunted down the 5LPO pathway when COX is inhibited which increases leukotrienes production which increases bronchoconstriction
How do we prevent NSAID toxicity
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
outline paracetamol properties
minimal anti-inflammatory effects but good analgesic properties
very well tolerated with almost no contraindications
may inhibit COX3
dangerous in overdose.
How is paracetamol metabolised
Usually harmlessly removed by phase 2 conjugation reaction in the liver to produce paracetamol sulphate and glucuronide which is excreted.
How is paracetamol metabolised in an overdose situation
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.
What is the solution to paracetamol overdose
N-acetylcysteine is used to treat paracetamol poisoning, overrides the saturation of the conjugation pathway to harmlessly remove NAPQI
What are selective COX-2 inhibitors
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
What are corticosteroids
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.
How do steroid drugs work
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.
How are steroids used clinically
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)
What are 5 corticosteroids you should know
Hydrocortisone- replacement therapy
for hypoadrenalism
prednisolone-anti inflammatory
beclomethasone- anti-inflammatory
dexamethasone- cerebral oedema
triamcinolone-What are side effects of steroid therapy
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
outline adrenal supression during corticosteroid therapy
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
What are DMARDS
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.
What is methotrexate, what are its main uses and toxicities
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
What is Azathioprine what are its main uses and toxicities
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
What is ciclosporin what are its main uses and toxicities
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
