ic13 drugs for OA, RA, gout Flashcards
what is “osteoarthritis” and what is the etiology of OA
OA is a degenerative joint disease where there is a progressive and irreversible loss of cartilage
it is the most common inflamm joint disorder
inflamm and repetitive activity involving articular cartilage and subarticular bones with secondary effects on synovium, muscle and nerves
what are the risk factors of OA
age, obesity
what are the features of OA
i) joint space narrowing
ii) subchondral sclerosis (thickening of bones affected by OA)
iii) subchondral cysts (fluid filled sacs in one or both of the bones that forms a joint)
iv) osteophyte lipping (osteophytes are bone growths)
v) loose bodies (small fragments of articular cartilage that break off in the knee joint)
what are the types of OA
i) primary generalised OA
ii) erosive inflamm OA
iii) hypertrophic OA
what is the pharmacotx for OA
- pain relief w/wo anti-inflamm
i) paracetamol
ii) non selective NSAIDs (note that diclofenac accumulates in synovial fluid in joints and have longer half life there = incr effect and decr GI s/e)
iii) coxibs
iv) corticosteroids - symptomatic slow acting drugs for OA (SYSADOA)
i) intra-articular hyaluronic acid (HA)
what is the func of hyaluronic acid (HA) and what is the purpose of intra-articular HA in managing OA
HA is a large glycosaminoglycan that is naturally found in synovial fluid
injecting exogenous HA can provide additional shock absorption, traumatic energy dissipation, protective coating of cartilage, lubrication, reduces pain and stiffness
it also induces biosynthesis of HA and extracellular matrix
what is “gout” and what is the etiology of gout
gout is a metabolic disorder where there is hyperuricemia (serum uric acid level >6.8mg/dl) leading to MSU crystal depositions and tophi growths
it is a common inflamm joint disorder >40yo
it might also be attributed to drug induced hyperuricemia (thiazide, loop diuretics, low dose aspirin, cyclosporine)
what are the two main immune system and what are the sub compartments of the immune systems (and so which is the one mainly involved in gout)
- innate immunity
i) complement
ii) phagocytes (neutrophils, macrophages) - adaptive immunity
i) B cells
ii) T cells
phagocytes are the one mainly involved in the inflamm immune responses assoc w gout - phagocytes attempt to phagocytose uric crystals but are unsuccessful and gets damaged which leads to release of factors that recruit even more phagocytic cells which releases even more cytokines, leading to a positive feedback loop of inflamm that leads to severe inflamm and pain thus resulting in gouty arthritis
compare the main compartments of the immune system involved with gout vs RA
gout: phagocyte
RA: phagocyte, Bcells, Tcells (in incr order of involvement)
what happens when immune cells are activated (compare the actions of immune cells in gout vs RA)
i) proliferate
ii) produces cytokines
iii) adhesion and trafficking (eg. migration and movement for phagocytosis)
in gout: activated immune cells mainly result in ii) and iii)
in RA: activated immune cells result in all three
what are the risk factors for gout
i) gender (males:women = 5:1) and tend to only happen after menopause for women and after menopause risk will catch up with men as age incr
ii) age
iii) diet (high purine)
iv) comorbs: HTN, DM, hyperlipidemia
what are the drugs that can induce hyperuricemia
thiazides/ loop diuretics, low dose aspirin, cyclosporine
what are the features of gout
i) high serum uric acid level >6.8mg/dl
ii) monosodium urate (MSU) crystal depositions in joint or cartilage
iii) topaceous gout: tissue growth around extracellular crystal deposits in soft tissue near joints (less common presentation)
what is “tophi”
tissue growth around extracellular crystal deposits in soft tissue near joints
what is the pathophysiology of gout
hyperuricemia -> precipitation of urate crystals in joint -> path 1 and path 2
PATH ONE:
urate crystals in joint lead to complement activation (immune cells are activated) that leads to neutrophil chemotaxis (movement in response to stimulus) -> phagocytosis of crystals by neutrophils [that releases LTB4 and PG and free radicals] -> lysis and activation of neutrophils along with release of crystals -> [ ] and release of lysosomal enzymes contributes to tissue injury and inflamm
*[ ] also further enhances neutrophil chemotaxis
PATH TWO:
urate crystals in joints leads to phagocytosis by monocytes -> release of IL1, TNF and IL6 which leads to neutrophil chemotaxis -> release of proteases from cartilage and synovium -> tissue injury and inflamm
what are the goals of tx and pharmacotx for gout
goals:
i) relieve acute gouty attack
ii) prevent recurrent gouty episodes
pharmacotx:
1. anti inflamm to decr ongoing feedback loop of inflamm and pain during an acute gouty attack
i) non selective NSAIDs
ii) coxibs
iii) glucocorticoids
iv) colchicine (reduce leukocyte migration into joints)
- urate lowering therapy (ULT) to prevent gouty episode
i) xanthine oxidase inhibitors (inhibit production of urate)
ii) uricosuric agents (incr excretion of urate through kidneys)
list eg. of drugs for each drug class that can be used for management of gout
non selective NSAIDs: naproxen, indomethacin
coxibs: celecoxib
glucocorticoids: prednisolone
colchicine
xanthine oxidase inhibitors: allopurinol, febuxostat
uricosuric agents: probenecid
what to note when wanting to start ULT (elaborate on each thing to note)
- do not start ULT during acute attacks but it is to be used instead between attacks to lower plasma level of uric acid
i) starting ULT during attacks will drastically decr plasma uric acid conc which incr the gradient from joint to plasma thus causing an incr mobilisation of crystals out of joints
ii) when crystals are stably within the joints, they are somewhat hidden and protected from immune cell attack vs if they mobilise out of the joint they will get recognised by immune cells which leads to phagocytosis by the immune cells that causes ongoing inflamm and pain
iii) this will make the acute attack worse since there are more mobilisation of crystals out of the cells meaning even more recognition by immune cells and exacerbation of the feedback loop
iv) if use uricosuric agents like probenecid which works by incr excretion of urate out through the kidneys which incr the risk of uric kidney stones formation as the kidney is unable to handle the additional amount of uric acid that is to be excreted bc there is already mobilisation of uric acid out of joints into the blood and out through the kidney during the attack - when ULT is initiated, it is often started with NSAIDs or corticosteroids or colchicine to decr the risk of triggering an acute attack
i) after initial period of incr risk, the agent can be slowly withdrawn and continue monotx with ULT
what is the moa and c/i of NSAIDs for a gouty attack, also list eg. of drugs in this class and identify which would likely be most suitable
moa: inhibit PG synthesis that is assoc w acute inflamm and sensitisation of pain responses, thus inhibiting urate crystal phagocytosis
c/i: low dose aspirin and salicylates (bc they have anti-uricosuric actions by blocking urate secretion that can precipitate gout or make ungoing gout worse)
non selective NSAIDs incl naproxen, indomethacin
coxibs: celecoxib
naproxen has relatively long half life
what is a glucocorticoid used to manage acute gouty attacks
PO or intra articular prednisolone
what is “colchicine”, what is its moa, effect and s/e
colchicine is an alkaloid isolated from colchicum autumnale
moa:
i) binds to tubulin and prevents tubulin polymerisation into microtubules (preventing microtubule polymerisation disrupts the cytoskeletal structure of the cells as it affects the transport of growth factors down the nerves to the muscles)
ii) inhibits leukocyte migration and phagocytosis
iii) inhibits LTB4 and PG production
effect: relieve pain and inflamm in acute gouty attack within 24-36h
s/e: N/V/D, abdominal pain, muscle weakness, abnormal bleeding, pale lips, change in urine amount
why does GI s/e occur due to administration of colchicine and how can we avoid this s/e
it arises bc colchicine is an inhibitor of microtubule polymerisation so at higher conc it will prevent division and proliferation of cells which would have greatest impact on cells along GIT since they are the most rapidly dividing cells
since GI s/e are dose limiting, they can be avoided by careful titration (helps ensure compliance)
list the eg. of xanthine oxidase inhibitors, consider what are the structural features, moa, therapeutic target, indications, s/e and any warnings
first line: allopurinol, second line: febuxostat
allopurinol is a structural analog of purines while febuxostat is a synthetic competitive inhibitor of XO and does not have structural similarities to purine
moa: anti-hyperuricemia agents that decr uric acid production by inhibiting xanthine oxidase which is responsible for converting hypoxanthine to xanthine and eventually to uric acid in the purine catabolism pathway
target: <6mg/dl
indications: delibitating gout attacks, chronic erosive arthritis, urate nephrolithiasis
s/e: N/V/D, skin rash, fever, sore throat, abdominal pain, dark urine, jaundice
warning:
i) allopurinol hypersensitivity syndrome (AHS)
ii) severe cutaneous adverse reaction (SCAR)
what are the risk factors of SCAR assoc w xanthine oxidase inhibitors
i) renal impairment (CrCl <60)
ii) thiazide therapy
iii) HLAB*5801 (most common in Han Chinese, Thai, Korean)
list the eg. of uricosuric agents, indications, moa, s/e and cautions
probenecid is a uricosuric agent
indications:
*not first line, given 2-3w after acute gouty attack
i) when allopurinol is c/i in tophaceous gout
ii) freq gouty attacks
moa:
i) inhibits proximal tubule anion transport
ii) inhibits uric acid reabsorption
thus incr uric acid excretion
s/e: N/V, painful urination, lower back pain, allergic rxn, rash
caution:
i) drink plenty of fluid to minimise risk of renal stone formation
ii) keep urine pH >6.0 by administration of alkaline eg. potassium citrate to help decr risk of uric acid kidney stone formation
what is “rheumatoid arthritis” and what is the etiology and risk factors of RA
systemic chronic infamm autoimmune disease that affects many tissues but principally attacking the joints (commonly wrist, hands, elbows, knees) and also extra articular involvement of heart, skin, blood vessels muscles and lungs
primarily targets synovial tissues, bone erosion and joint deformitis
etiology of RA:
i) genetics: strongly assoc w HLA-DR4 molecules which are MHC class II molecules
ii) environment: autoAb (like rheumatoid factor RF and citrullinated protein Ab CPA) against cyclic citrullinated peptides which may contribute to joint lesions
risk factors:
i) women:men = 3:1
what is the pathophysiology of RA
major pathologic changes are caused by cytokine mediated inflamm with CD4 T cells being the principle source of cytokines (TNFalpha, IL1, IL6, IFNgamma) which have effects on osteoclasts, fibroblasts and chondrocytes to produce metalloproteinases, which are implicated in the degradation of the extracellular matrix (ECM), along with other effector molecules and the migration of these polymorphonuclear cells due to the inflamm result in bone and cartilage erosion
what are the autoAb assoc w RA what is the key func of these autoAb
i) rheumatoid factor (RF)
ii) citrullinated protein Ab (CPA)
these autoAb are impt for diagnostic purposes
what are the features of RA
i) bilateral, symmetrical
ii) synovial inflamm (synovitis w chronic inflamm infiltrate, exudate, fibrin) leading to swelling and villous formation of the synovium
iii) formation of the pannus and destruction of the articular cartilage
iv) destruction of adjacent bone due to pannus formation thus resulting in joint deformity
v) formation of rheumatoid nodules
what is a “pannus” formation and “rheumatoid nodules”
pannus is vascular granulation tissue that grows across the cartilage tissue
rheumatoid nodules is a specific type of granuloma characterised by central zone of fibrinoid necrosis
what are the goals of tx for RA and how would RA be managed
goals of tx:
i) remission of sx involving the joints
ii) return of full func
iii) maintenance of remission w DMARD tx
pharmacotx:
1. csDMARDs
i) MTX (first line)
ii) sulfasalazine
iii) leflunomide
iv) hydroxychloroquine (best tolerated)
v) cyclosporin
- tsDMARDs
i) JAKi (tofacitinib, baracitinib) - bDMARDs
i) anti TNFmAb (infliximab, adalimumab, etanercept)
ii) IL1RA (anakinra)
iii) anti IL6R mAb (tocilizumab)
iv) anti CTLA4Ig (abatacept)
v) anti CD20 (rituximab) - anti inflamm
i) NSAIDs (for short term relief of pain and stiffness + PPI to reduce GI s/e)
ii) corticosteroids (to bridge anti-inflamm tx w DMARD tx)
are bDMARDs more potent than csDMARDs
no, they are often used as adjuncts to csDMARDs to reduce dose of csDMARDs
what is the drug class, structure, advantages, indication, formulation types, moa and s/e (what is the rationale behind the s/e and how to manage the s/e) of MTX
MTX is a csDMARD
structure: folic acid analog
advantages:
i) long term efficacy
ii) acceptable toxicity
iii) low cost
iv) assoc w significantly lower mortality
indication: often combined w other csDMARDs for optimal effects
formulation types: PO, SQ, IM
moa:
i) major: incr adenosine levels by inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase or IMP cyclohydrolase (ATIC)
ii) minor: inhibits dihydrofolate reductase and thymidylate synthetase
inhibition of ATIC causes decr purine synthesis and incr adenosine synthesis thus the resulting incr in extracellular adenosine levels and subsequent activation of A2a receptor has antiproliferative effects on Tcell and macrophage func, leading to anti inflamm effects due to decr in proinflamm cytokines, adhesion molecules, chemotaxis and phagocytosis + inhibition of DHFR also decr DNA methylation, decr purine synthesis, decr pyrimidine synthesis
s/e:
i) N/V, mouth and GI ulcers
ii) hair thinning
iii) leukopenia
iv) hepatic fibrosis
v) pneumonitis
(s/e occurs due to the minor pathway of MTX moa which at high doses will decr proliferation of other normal cell types as well eg. GI and hair follicular cells which are the two most rapidly proliferating cells thus most likely to be affected)
(s/e can be minimised by concom folic acid or folinic acid 12-24h after MTX)
what is the rescue therapy for MTX toxicity and what is the rationale behind it
using folate
i) MTX inhibits DHFR which converts folate into folinic acid which is impt for production of nucleic acids like adenine, guanine, thymidine, methionine, serine which are all impt for cell proliferation
ii) thus folinic acid would be the best for rescue therapy for MTX toxicity since it would be rapidly converted into N5,N10-methylene FH4 and bypass DHFR activity
iii) but folate is much cheaper than folinic acid thus more commonly used
iv) but also means folate need higher doses else it would not efficiently rescue toxicity due to the depletion of N5,N10-methylene FH4 as DHFR is inhibited by MTX
what is the drug class, metabolism, moa and s/e of sulfasalazine
sulfasalazine is a csDMARD
metabolism: into sulfapyridine (active) and 5-aminosalicylic acid
moa: unknown but poorly absorbed so may be mediated by effect on gut flora and leads to
i) decr IgA and IgM rheumatoid factors
ii) suppression of T and B cells and macrophages
iii) decr in inflamm cytokines TNFalpha, IL1, IL6
s/e:
i) N/V
ii) HA
iii) rash
iv) hemolytic anemia
v) neutropenia
vi) reversible infertility in men
what is the drug class, metabolism, moa, s/e and warning for leflunomide
leflunomide is a csDMARD
metabolism: rapidly converted into teriflunomide (active metabolite)
moa:
i) inhibits dihydroorotate dehydrogenase
ii) decr pyrimidine synthesis and growth arrest at G1 phase
iii) inhibits T cell proliferation and B cell autoAb production
iv) inhibits NF-KB activation pro inflamm pathway
s/e:
i) D
ii) elevation of liver enzymes
iii) alopecia
iv) weight gain
v) teratogenic
warning:
i) very long half life (for years)
ii) leflunomide is recycled through the bile (released in bile and reabsorbed through small intestine) thus can use colestyramine, a bile salt binding resin, to wash out and incr excretion of leflunomide when needed (eg. before pregnancy)
what is the drug class, additional indication, moa and s/e of chloroquine and hydroxychloroquine
chloroquine and hydroxychloroquine are csDMARD
they are also antimalarial agents
moa:
i) decr MHC class II expression and thus decr Ag presentation
ii) decr TNFalpha and IL1 and cartilage resorption
iii) has antioxidant activity
s/e:
i) N/V, stomach pain
ii) dizziness
iii) hair loss
iv) ocular toxicity
*note that hydrochloroquine is the best tolerated although not best efficacy (MTX)
what is the “JAK STAT pathway”
it is an intracellular signal transduction pathway that can be triggered by numerous cytokines and lead to additional production of pro and anti inflamm cytokines and destructive enzymes
many cytokine receptors involve the JAKSTAT pathway and involve a number of different functions like T cell proliferation and other aspects of immune response
involves JAK1, JAK2, JAK3, TYK2 with JAK1 being the most common receptor involved in RA
list eg. of JAKi and note whether they are selective
tofacitinib inhibits JAK1, JAK2, JAK3
baracitinib inhibits JAK1, JAK2
what is the indication, moa, s/e and caution for JAKi
indication:
i) combi tx with MTX for moderate to severe RA
ii) monotx in cases of intolerance to MTX
iii) psoriatic arthritis
moa: janus kinase pathway inhibitor
i) blocks cytokine production by blocking JAK STAT activation of gene transcription
s/e:
i) cytopenia (neutrophils, lymphocytes, PLT, NK)
ii) immunosuppression = opportunistic infections (incr risk of herpes zoster infection esp in asians)
iii) anemia (affects JAK2 activation by EPO)
iv) hyperlipidemia (bc incr in total, LDL, HDL, cholesterol, TG)
(immunosuppression most common s/e)
warning: do not combine w bDMARDs bc risk of great additive effect and too great of an immunosuppression
list the types of bDMARDs that are suitable for management of RA (drug class, formulation type, structure)
- TNF signalling blocker
i) infliximab (IV): chimeric IgG1 (25% mouse)
ii) adalimumab (SQ): human IgG1
iii) etanercept (SQ): decoy TNFR2 receptor IgG1 fusion protein (intercepts TNF alpha and beta)
iv) golimumab (IV): human IgG1 - IL1 signalling blocker
i) anakinra (SQ): modified human IL1 RA protein (differs from sequence of endogenous protein by one methionine added to N terminus and is not glycosylated) - IL6 signalling blocker
i) tocilizumab (IV): humanised IgG1 (reversible antagonist of IL6)
compare between the different naming for biologics
li = target immune system
xi = chimeric
mu = human
zu = humanised (but not fully human)
what are the eg. of TNF signalling blockers (formulation type) and what are their indications, s/e, c/i and monitoring
TNF signalling blockers are infliximab (IV), adalimumab (SQ), etanercept (SQ)
indication: RA pts who do not respond well with csDMARD and is given in combi w MTX
s/e:
i) resp infection
ii) skin infection
iii) incr risk of lymphoma, optic neuritis
iv) exaceration of multiple sclerosis
v) leukopenia
vi) aplastic anemia
c/i:
i) live vaccination
ii) hep B
monitoring: i) screen for latent or active TB
what are the eg. of IL1 signalling blocker (formulation type) and what are their moa and s/e
anakinra (SQ) is a IL1 receptor antagonist
moa: binds to IL1 receptor and blocks signalling
s/e:
i) infections
ii) inj site rxn
*note that it is less effective than anti-TNFs
what are the eg. of IL6 signalling blocker (formulation type) and what are their moa and s/e
tocilizumab (IV) is a anti-IL6mAb
moa: humanised mAb directed at IL6Ralpha chain, prevents binding of IL6 to IL6Ralpha and homodimerisation of IL6Rbeta signalling
s/e:
i) infections
ii) skin eruptions
iii) stomatitis
iv) fever
v) neutropenia
vi) incr ALT/AST
vii) hyperlipidemia
viii) interacts w 3A4, 1A2, 2C9 substrates
what is interesting about the ddi of tocilizumab
tocilizumab is a protein based bDMARD and thus is largely cleared by proteolytic breakdown by proteolytic enzymes and thus would not expect them to have cyp interactions
but IL6 decr expression of cyp enzymes and tocilizumab’s inhibition of IL6 will result in an incr of cyp enzymes thus give rise to potential ddi
what is an eg. of antiCTLA4 Ig (formulation type) and what is its moa and s/e
abatacept is an anti-CTLA4 Ig (IV)
moa:
i) recombinant fusion protein w CTLA4-Fc IgG1, binds to and inhibits CD80 and CD86 thus preventing CD28 activation on T cells (T cell therapy)
s/e:
i) resp infection in COPD
ii) incr lymphoma incidence
what is an eg. of antiCD20 (formulation type) and what is its moa and s/e
rituximab is an antiCD20 Ig (IV)
moa:
i) chimeric IgG1 directed at CD20 on pre and mature B cells thus leading to depletion of CD20 B cells (B cell therapy)
ii) blocks Ag presentation, auto Ab and cytokine levels
s/e:
i) rash in first dose
ii) resp infection in COPD
