S8: immunosuppressants & NSAIDs Flashcards
Describe rheumatoid arthritis
Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone
Increase of pro-inflammatory substances compared to anti-inflammatory substances
Describe the treatment strategy of rheumatoid arthritis
Early use of disease-modifying drugs Aim to achieve good disease control Use of adequate dosages Use of combinations of drugs Avoidance of long-term corticosteroids
Describe the treatment strategy of SLE and vasculitis
Symptomatic relief
Reduction in mortality
Prevention of organ damage
Reduction in long term morbidity caused by disease & by drugs
Describe the mechanism of action of corticosteroids
Prevent interleukin IL-1 and IL-6 production by macrophages
Inhibit all stages of T-cell activation
List indications for azathioprine
SLE & vasculitis – maintenance therapy
Inflammatory bowel disease
Other uses include use as ‘steroid sparing’ drug
Describe the mechanism of action of azathioprine
Cleaved to 6-MP, which is converted to TIMP
-decreases DNA and RNA synthesis
Outline the adverse effects of azathioprine
Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis
List examples of calcineurin inhibitors
Ciclosporin
Tacrolimus
List indications and contraindications for calcineurin inhibitors
Widely used in transplantation
Also atopic dermatitis & psoriasis
Not often used in rheumatology – renal toxicity (check BP & eGFR regularly)
Drug interactions with CYP450 drugs
Describe the mechanism of action of calcineurin inhibitors
Active against helper T cells
Prevent production of IL-2 via calcineurin inhibition
List indications for mycophenolate mofetil
Used primarily in transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis
Maintenance therapy for vasculitis
Describe the mechanism of action and adverse effects of mycophenolate mofetil
Prodrug
Inhibits inosine monophosphate dehydrogenase, which impairs B and T cell proliferation
Adverse effects: nausea, vomiting, diarrhoea & myelosuppression
Describe cyclophosphamide
Alkylating agent – cross links DNA so that it cannot replicate
Suppresses T and B cell activity
Indications: lymphoma, leukaemia, solid cancers, lupus nephritis
Describe adverse effects of cyclophosphamide
Increased risk of bladder cancer, lymphoma & leukaemia
Infertility
Adjust dose in renal impairment
(mycophenolate mofetil safer & as effective in lupus nephritis)
List indications for methotrexate
Gold standard treatment for RA
Other indications: malignancy, psoriasis & Crohn’s disease
Describe the mechanism of action of methotrexate in malignancy & as a DMARD
In malignancy – inhibit dihydrofolate reductase -> reducing FH4 needed for DNA and protein synthesis
DMARD – inhibition of inflammatory mediators, T cells and adenosine
List adverse effects of methotrexate
Mucositis, marrow suppression (both respond to folic acid supplementation)
Hepatitis, cirrhosis, pneumonitis, infection risk
Highly teratogenic, abortifacient
Describe sulfasalazine
Relieve pain, stiffness & fights infection
Inhibition of T cell and neutrophil activity
Release 5-aminosalicylic acid (5-ASA) – immunosuppressive
Outline adverse effects of sulfasalazine
Myelosuppression, hepatitis, rash
Milder side effects: nausea, abdo pain/vomiting
Very few drug interactions & safe in pregnancy
Describe biologicals
Monoclonal antibodies made specifically to block any given substance in the body or to target any specific cell type
Act by TNF-alpha inhibition
ADR: test for latent TB as inhibition of TNF-alpha may reactivate latent disease (TNF is essential in granuloma formation so that TB bacilli are walled off)
Caution with other immunosupressants
Eg. infliximab, golimumab & adalimumab
Describe rituximab
Causes B cell apoptosis – binds specifically to a unique cell-surface marker CD20
Very effective in RA
Describe prostanoids
Prostanoids = prostaglandins, prostacyclin & thromboxanes (PGE2, PGF2a, PGD2, PGI2 & TXA)
Produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control
Act locally at GPCRs & action is often enhanced by local autacoids including bradykinin and histamine
TXA2 and PGI2 have apposing vascular effects; imbalance to prostanoids plays significant role in hypertension, MI and stroke risk
Describe arachidonic acid and prostanoid synthesis
Arachidonic acid derived primarily from dietary linoleic acid – incorporated into phospholipids
Found throughout the body – particularly in muscle, brain, liver & kidney
Describe PGE2 and gastric acid secretion
PGE2 contributes to regulation of acid secretion in parietal cells
Prostacyclin contributes to maintenance of blood flow and mucosal repair
Describe cyclooxygenase enzymes
COX-1: constitutively active across most tissues
COX-2: inducible in chronic inflammation, constitutively in brain, kidney and bone
List homeostatic functions of COX-1 and COX-2
COX-1: GI protection, platelet aggregation & vascular resistance
COX-2: renal homeostasis, tissue repair and healing, reproduction & inhibition of platelet aggregation
List pathological functions of COX-1 and COX-2
COX-1: chronic inflammation, chronic pain & raised BP
COX-2: chronic inflammation, chronic pain, fever, blood vessel permeability
Describe NSAIDs
Have antipyretic, analgesic and anti-inflammatory properties
Mode of action: inhibition of COX -> decreased prostaglandin, prostacyclin & thromboxane synthesis
Compete with arachidonic acid for hydrophobic site of COX enzymes
Describe the analgesic action of NSAIDs
Local peripheral action at site of pain
Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2
Decreased PGE2 synthesis in dorsal horn -> decreased neurotransmitter release -> decreased excitability of neurones in pain relay pathway
Full analgesia after several days dosing
Describe the anti-inflammatory action of NSAIDs
NSAIDs reduce production of prostaglandins released at site of injury
Symptomatic relief with COX inhibition – little effect on underlying chronic condition
Describe the antipyretic action of NSAIDs
Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated
Results in a reduction in temperature
Describe COX selectivity of NSAIDs
Differentiated by their selectivity
COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses
Aspirin, ibuprofen, naproxen, diclofenac, celecoxib, etericoxib (increasing COX-1 selectivity -> increasing COX-2 selectivity)
What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (GI system)
Adverse effects: dyspepsia, nausea, peptic ulceration, bleeding and perforation, exacerbation of IBD
-decreased mucus & bicarbonate secretion, increased acid secretion
-decreased mucosal blood flow -> enhanced cytotoxicity and hypoxia
Warnings: elderly, prolonged use, smoking, alcohol, history of peptic ulceration, H. pylori
Important drug interactions: aspirin, glucocorticoid steroids, anticoagulants
What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (renal)
Adverse effects: reversible decrease in GFR & decrease renal blood flow, increased BP due to inhibition of prostaglandins
Warnings, contraindications: underlying CKD, heart failure
Important drug interactions: ACEi, ARBs, diuretics
Describe selective COX-2 inhibitors
Less GI ADRs, renal ADRs similar to non-selective
Do not share antiplatelet action but inhibit PGI2
Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment
(NB: ALL NSAIDs increase risk of MI)
List examples of selective COX-2 inhibitors
Celecoxib
Etoricoxib
Describe NSAIDs and protein binding
Displace other bound drugs -> increases free drug concentration
-sulfonylurea: hypoglycaemia
-methotrexate: accumulation and hepatotoxicity
-warfarin: increased risk of bleeding
Competitive displacement of some other drugs – likely dose adjustment needed & increased monitoring
List indications for NSAID use
Inflammatory conditions Osteoarthritis Postoperative pain Topical use on cornea Menorrhagia
Describe paracetamol
Antipyretic action, use for mild to moderate analgesia and fever
At therapeutic doses generally well tolerated with fewer common ADRs
COX-2 selective inhibition in CNS – decrease pain signals to higher centres
Very little anti-inflammatory action
Describe NAPQI
Highly reactive metabolite
At normal therapeutic doses, conjugation with glutathione renders NAPQI harmless
When hepatic glutathione is limited, NAPQI causes cell death by necrosis and apoptosis
Describe paracetamol overdose
Can be asymptomatic for many hours
First: nausea, vomiting, abdominal pain; maximal liver damage occurs at 3-4 days
Treatment: glutathione thiol replacement – i.v. N-acetylcysteine
Can’t give glutathione itself because it can’t get into the hepatocytes
List mechanisms by which NSAIDs can cause GI adverse drug reactions
Decreased mucus secretion
Decreased bicarbonate secretion
Reduced mucosal blood flow
pH partitioning & accumulation of NSAID at gastric mucosa
-inhibition of PGE2 and PGI2 major factor in these ADRs
Which prostanoids show apposing platelet aggregatory action?
PGI2 & TXA2
PGI2 inhibits platelet aggregation
TXA2 contributes to platelet aggregation
