Pharmacology 6: Immunosuppression and RA, and pharmacology of airway control Flashcards
overall mechanism of action of corticosteroids?
inhibitors of gene expression: lipophilic so capable of crossing PM to bind to cytoplasmic receptor.
Forms a hormone-receptor complex which enters nucleus and binds to intra-nuclear receptor and interacts with specific regions of DNA to alter rate of transcription of specific genes.
inhibit all stages of T cell activation
prevent IL-1 and -6 production by macrophages
especially decrease TNF-alpha prod
corticosteroid ADRs?
hypertension
oral candidiasis- increased infection risk as immunocompromised
osteoporosis- as increased osteoclast activity, so may give Vit D supplements
weight gain- moon shaped face and central obesity- Cushing’s syndrome
bruising, purple striae
hyperglycaemia, diabetes
growth suppression in children
gastric ulcers- as transrepression of COX-2 required for PG synthesis in stomach for alkali and mucus prod= protective
mechanism of action of azathioprine (an immunosuppressant)?
cytotoxic antimetabolite that acts selectively on cells with a higher mitotic rate.
primary action= inhibition of purine metabolism, which reduces both DNA and RNA synthesis.
Pro-drug- activated to 6-Mercaptopurine (6-MP)
active form of azathioprine?
6-Mercaptopurine (6-MP)
which enzyme is required for elimination of 6-Mercaptopurine (6-MP)?
TPMT: thiopurine methyltransferase- subject to high rate of genetic polymorphism.
how does expression of enzyme TPMT- thiopurine methyltransferase, affect tment with azathioprine and why?
drug elimination requires this enzyme.
So high levels of enzyme expression will allow rapid elimination, hence undertreatment.
low levels of expression will lead to increased toxicity.
ADRs of azathioprine?
BM suppression, must monitor FBC
increased infection risk
emergence of malignant cell lines, espec increased risk in transplanted patients**
hypersensitivity reactions e.g. dizziness, vomiting, diarrhoea, rash
hepatitis- monitor LFTs
how does cyclophosphamide act as an immunosuppressant?
prodrug activated by CYP450s to produce active alkylating electrophilic cytotoxic metabolites whihc cross link DNA, inhibiting its replication
selectively acts on cells with higher mitotic rate.
suppress both T and B cells
ADRs of cyclophosphamide?
excreted by kidney- can induce bladder cancer due to concentration of acrolein metabolite in urine, acrolein= toxic to bladder epithelium, can cause haemorrhagic cystitis, can be prevented through use of aggressive hydration and/or Mesna, most adjust dose accordingly if renal impairment lymphoma leukaemia infertility teratogenesis
agent of choice in transplant immunosuppression?
mycophenolate mofetil (MM)
ADRs of mycophenolate mofetil?
leuko and neutropenia
myelosuppression
increased infection risk- espec. viral
how does methotrexate work in malignant disease?
acts an an antifolate, with folate being necessary for synthesis of purines and thymidine= precursors to building blocks in DNA synthesis.
Binds to DHFR (dihydrofolatereductase) as competitive reversible inhibitor- which uses folate as a substrate.
folate= role in single carbon transfer reactions central to synthesis of purines and thymidine.
Action selective during S phase of cell cycle in cells with high mitotic activity, so greater toxic effect on rapidly dividing cells e.g. GI and oral mucosa- replicate DNA more frequently.
ADRs of methotrexate?
GI effects as gut mucosa= high mitotic activity- diarrhoea, anorexia, dyspepsia, abdom discomfort, GI ulceration e.g. mouth
may also cause hair loss as hair follicle cells= rapidly dividing
hepatotoxicity, hepatitis- may appear jaundiced, cirrhosis
pulmonary fibrosis and interstitial pneumonitis- dyspnoea, cough, crackles- would show ground glass opacification on CT
BM suppression- may be fatigued, susceptible to infections
monitoring required with methotrexate?
FBC- as BM suppression risk
LFTs- as risk of hepatotoxicity
Us and Es-as mainly eliminated via kidneys
monitor resp symptoms at each visit e..g. dyspnoea and cough, stop tment if pneumonitis supected
dose monitoring if combined with aspirin or other NSAIDs- NSAIDs displace drug from plasma proteins- MTX has 50% protein binding
name 2 diseases sulfasalazine is used in the tment of?
RA
IBD
ADRs of sulfasalazine?
nausea abdom pain diarrhoea vomiting, nausea fatigue headache myelosuppression hepatitis allergic rash- anaphylaxis so must do LFTs and FBC regularly
ADRs of B2 agonists used as relievers in asthma?
skeletal muscle tremor tachycardia dysrhythmia palpitations headache
features of temporal (giant cell) arteritis?
malaise
jaw claudication
severe peri-orbital headache
giant cell arteritis can affect other arteries of head and neck,large vessel vasculitis, no infection
=inflammation of temporal arteries= terminal branches of ECA, chronic inflammatory process,severe pain if patient tries to brush their hair, medical emergency as inflammation can spread to involve ICA- opthalmic artery- central artery of retina- sudden blindness
why is azathioprine associated with increased risk of skin cancer?
causes accumulation of 6-thioguanine in patient’s DNA, which might trigger cancer on exposure of patient to UV light
people giant cell arteritis is most common in?
women
aged >35
what is given to all patients prescribed steroids for >3wks in case patient requires tment in an emergency?
blue steroid card- patients may enter an addisonian crisis if suddenly stop their steroid medication as steroids will have been suppressing release of ACTH from anterior pituitary that normally stimulates steroid release from adrenals, so HPA axis suppression, so on stopping steroids, endogenous prod of steroids may be so low with adrenal insufficiency that an addisonian crisis results= patient may be very confused, hypotensive, nausea, vomiting, severe abdominal pain, seizures
most common cause of an addisonian crisis?
abrupt withdrawl of steroid medication
how is giant cell arteritis treated?
initial dose of prednisolone= 40–60 mg daily (the higher dose being used if visual symptoms occur). Treatment should be continued until remission of disease activity and doses are then reduced gradually to about 7.5 –10 mg daily for maintenance. Relapse is common if therapy is stopped prematurely. Many patients require treatment for at least 2 years and in some patients it may be necessary to continue long-term low-dose corticosteroid treatment.
indications for methotrexate?
RA- used in combination with other DMARDs to provide best outcome, and with biologics e.g. etanercept and infliximab.
malignancy
Crohn’s
Psoriasis
unlicensed roles= maintenance therapy in vasculitis
how is methotrexate thought to work in tment of inflammatory diseases e.g. RA?
increases adenosine, through inhibition of enzymes involved in purine metabolism, which is a potent, endogenous anti-inflammatory mediator that inhibits neutrophil adhesion, phagocytosis, and superoxide generation.
MTX also causes apoptosis of activated CD4 and CD8 T cells, but not of resting T cells.
when might adenosine be given IV to treat a patient?
for arrhythmias e.g. re-entry, as short t1/2 <10s, acts on alpha 1 adrenoceptors at AV node, and enhances K+ conductance, hyperpolarising cells so conduction at AV node slowed/prevented.
how often is methotrexate given and why?
once weekly as metabolites (polyglutamates) are long lived- long t1/2s
2.5 mg tablets, may take up to 8 for tment of moderate to severe active RA= max wkly dose 20mg
if a patient is take methotrexate once weekly, what else must they also take once weekly?
folic acid= as MTX antagonises folate action in body, so taken NOT on same day as MTX as folate would then be ineffective
folate required for DNA synthesis and repair, and for rbc synthesis to prevent anaemia.
what is it important to note if thinking of commencing a young woman on methotrexate?
it is teratogenic as inhibits folate action, so can cause neural tube defects
hence pregnancy should be avoided until at least 3mnths post stopping of MTX tment
indications for sulphasalazine?
RA
inflammatory bowel disease
immunological effects of sulphasalazine?
T cells- inhibit proliferation
possible result in apoptosis
inhibition of IL-2 production
neutrophils- reduced chemotaxis and degranulation
drug class for sulphasalazine?
aminosalicyclate
combination of 5-aminosalicylic acid (‘5-ASA’) and sulfapyridine; sulfapyridine acts only as a carrier to the colonic site of action in treating IBD but still causes side-effects.
sulfapyridine important in RA as absorbed into blood so can have sytemic effects.
other drugs apart from sulphasalazine that are aminosalicylates?
balsalazide
olsalazine
sulphasalazine has sulphonomide component= sulfapyridine- absent from other drugs
indications for azathioprine?
IBD
SLE
vasculitis- maintenance therapy here and in SLE
RA
what must be monitored if patient on azathioprine?
FBC
factors limiting use of biologics in RA?
expense
profile of ADRs e.g. …
important drug-drug interactions of aspirin, in terms of treating a patient with RA?
corticosteroids= PDs, both drugs increase risk of gastric ulcer formation as inhibit PG production in stomach necessary for mucus and alkali production, aspirin= inhibits COX, and corticosteroids= transrepression of COX-2. methotrexate= PKs, aspirin reduces excretion of MTX NSAIDs= increase SEs as both inhibit COX in stomach.
X-ray changes with RA?
bony erosions
joint subluxation following tendon rupture due to inflammation
osteopenia
