IC13 drugs for gout, OA, RA Flashcards
normal plasma urate concentration?
2-7mg/dL
drug induced hyperuricaemia?
thiazide or loop diuretics
low dose aspirin
ciclosporin
MOA of colchicine
use for acute attacks
reduces leukocyte migration into the joint
1) binds to tubulin (cytoskeleton)
2) prevents tubulin polymerisation into microtubules
3) inhibits leukocyte migration and phagocytosis
4) inhibits leukotriene B4 (LTB4) and prostaglandin (PG) production.
what NSAIDs are contraindicated for gout?
aspirin and salicylates
induce kidney retention of uric acid [23-27]. However, low-dose aspirin used for cardiovascular prophylaxis should be continued during the treatment of a gout flare despite this effect
which gc recommended for gout
prednisolone
SE of colchicine
gi side effects (due to effects on proliferation of gi wall): n/v, diarrhoea, abdo pain
muscle weakness
pale lips
change in amount of urine.
risk of myopathy, neuropathy, pancytopenia (blood dyscrasia related to bleeding) esp in renal or hepatic impairment
caution for colchicine
renal impairment
esp crcl<30 or for prolonged duration increases toxicity
drug drug interaction w pgp cyp3a4 inhibitors and inducers.
- macorlides, azoles, antiarrhythmic (verapamil, diltiazem…)§, rifampin, atorvastatin
onset of colchicine
relief pain in 24 to 36 hours
MOA of allopurinol and febuxostat and use
uric acid synthesis inhibitors
used to prevent recurrence
DO NOT USE during acute attacks
allopurinol (and xanthine oxidase inhibitor) warning
allopurinol hypersensitivity syndrome (AHS)
severe cutaneous adverse reaction (SCAR) warning (allopurinol > febuxostat)
febuxostat = MACE warning
risk factors for SCAR
renal impariment;: crcl <60, thiazide therapy, hlab5801 genotype (common in han Chinese)
reduce dose if renally impaired
side effect of xanthine oxidase inhibitors
maculopapular rash (related to hypersensitivity),
n/v, diarrhoea, stomach pain
fever, sore throat
dark urine
jaundice
probenecid use?
uricosuric agent
increases uric acid excretion
used to prevent recurrence
DO NOT USE during acute attacks, may increase risk of uric acid kidney stone formation
moa of uricosuric agents
inhibit proximal tubule anion transport
inhibit uric acid re-absorption
increase uric acid excretion
when to start probenecid
2-3 weeks after flare
probenecid pracutions and C/I
1) take plenty of fluid (≥2L of water) to minimise renal stone formation (CONTRAINDICATED in PMH urolithiasis)
2) keep urine pH > 6 by administration of alkaline (eg potassium citrate)
risk of hemolytic anaemia in patients w g6pd deficiency
not recommended if crcl<50
SE of probenecid
n/v
painful urination
lower back pain
allergic reaction
rash
proBACK(pain)neACID(urine = pain)
another drug for oa other than nsaids
include MOA
intra articular hyaluronic acid (slow-acting)
moa: shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain and stiffness
induces biosynthesis of HA (in the synovial fluid) and extracellular matrix
methotrexate mechanism of action
major: increase adenosine levels due to AICAR and/or ATIC inhibition
minor: inhibits (i) dihydrofolate reductase and (ii) thymidylate synthetase.
overall effects: increased extracellular adenosine level and activation of adenosine A2a receptor =
(i) antiproliferative effects on T cells
(ii) inhibition of macrophage functions,
(iii) decrease in pro-inflammatory cytokines, adhesion molecules, chemotaxis, phagocytosis.
side effects of methotrexate (related to mechanism)
inhibition of dihydrofolate reductase reduces the proliferation of other cell types (due to reduced purine and therefore DNA synthesis), more specifically those that are rapidly proliferating: skin and GI
- n/V
- mouth and GI ulcers
- hair thinning
management of potential side effects of methotrexate
administration of folic or folinic acid or folate 12-24 hours after mtx to decrease toxicity.
differences between management of mtx toxicity with folate vs folinic acid
folate = cheaper but require high doses due to depletion of n5, n10 methylene FH4
vs
folinic acid = rapidly converted to n5,n10 methylene FH4 = more efficient at rescuing toxicity s dihydrofolate reductase activity is bypassed
sulfasalazine mechanism of action
metabolised by sulfapyridine and 5aminosalicylic acid
= effect on gut flora = decrease IgA, IgM rheumatoid factors, suppression of T and B cells, macrophages, decrease in inflammatory cytokines (eg IL1beta, TNF, IL6)
side effects of sulfasalazine
GI: nausea, dyspepsia
CNS: headache, dizzy
Derm: rash
Haem: agranulocytosis, neutropenia, hemolytic anaemia
Genitourinary: oligospermia (reversible infertility in men),
urine discolouration
Infection
MOA of leflunomide
converted to teriflunomide
= inhibit dihydroorotate dehydrogenase
=
(i) decrease pyrimidine synthesis and arrest G1 phase
(ii) (decrease t cell, b cell) inhibit T cell proliferation, B cell autoantibody production
(iii) inhibit NF-KB activation of pro-inflammatory pathway
caution and management for leflunomide
very long half life (years)
can manage with colestyramine (bile salt binding resin) to wash out (eg before pregnancy)
TERATOGENIC
side effects of leflunomide
GI: diarrhoea, nausea
CNS: headache,
liver: increase transaminases
derm: alopecia, rash
heme: myelosuppression
Infection
moa of hydroxychloroquine
reduced MHC class II expression and antigen presentation
reduced TNF, IL1 and cartilage resorption
antioxidant activity
SE of hydroxychloroquine
gi: n/v, stomach pain
ophth: retinopathy
derm: photosx, hyperpigmentation, hairloss
cvs: qtc prolongation
metabolic: hypoglycaemia
cns: headache, dizziness, neuropsychiatric smx
ADR of tofacitinib
cytopenia of neutrophils, lymphocytes, platelets, NK cells
= immunosuppression = opportunistic infections (eg herpes zoster)
anemia (affect jak2 activation by erythropoietin)
hyperlipidemia
TO(lesterol)fA(nemia)ci(topenia)tinib
MOA of tofacitinib
JAK janus kinase pathway inhibitor
- blocks cytokine production by blocking JAK/STAT activation of gene transcription
what are the bDMARDS
TNF: infliximab, adalimumab, etanercept, (GOLIMUMAB)
IL1: anakinra
IL6: tocilizumab
CD20 rituximab
CD28 abatacept
side effects of TNF blockers
infection: resp and skin
autoimmune: multiple sclerosis
malignancy: increased risk of lymphoma
ophth: optic neuritis
heme: leukopenia, aplastic anemia
C/I for TNF blockers
live vaccination
hep B
monitoring for TNF blockers
screen for latent or active TB
side effect of anakinra
infections
injection site reactions
side effect of tocilizumab
stomatitis
skin eruptions
increase ALT/AST (transaminases)
fever, infections,neutropenia
sTOmach ci(skin) li(ver) zu mab (neutropenia, fever, infection)
tocilizumab interactions
cyp450:
1A2, 2C9, 3A4
