Download AntiGout and DMARDs

Anti-Gout Therapy
Goal of Therapy
1. Terminate the acute attack
a. By providing rapid and safe pain reliever
b. For example
i. NSAIDs
1. All other than Aspirin
ii. Glucocorticoid
1. Hydrocortisone
2. Prednisolone
iii. Colchicine
2. Prevent recurrent attacks
a. For example
i. Colchicine
3. Prevent disease progression and complications
a. To avoid complications such as
i. Destructive arthropathy
ii. Tophi
iii. Renal stones
b. For example
i. Allopurinol
ii. Probenecid
iii. Sulphinpyrazone
Symptomatic Reliever
Corticosteroid
Mechanism of Action
Drugs/Infos
1. Prednisolone – oral
2. Hydrocortisone – IV
The idea is, when we ↓the inflammation,
this will ↓ hyperreactivity in which will
therefore ↓ responsiveness to stimuli
So be clear that this drug
1. Cant stop disease progression
2. Only provides symptomatic relieve
Clinical Uses
1. Acute gouty arthritis when patient is
not responsive towards NSAIDs
Side Effects
Inflammatory mediators
1. Inhibits Phospholipase A2 in which involve in the formation of
Arachidonic Acid; precursor of
a. Cyclooxygenase, in return will form
i. Prostaglandin
b. Lypooxygenase, in return will from
i. Leukotriene
Inflammatory cells
1. Inhibits neutrophils migration
2. ↑distribution of lymphocytes and monocytes to lymphoid tissue
3. Inhibit release of proteolytic enzyme by macrophage
Prolonged usage will lead to
1. Systemic effect
a. Cushing syndrome
b. Osteoporosis
c. Cataract
d. Glaucoma
All of these inflammatory mediators formation and action of
inflammatory cells will be halted; therefore will ↓ inflammation
Non-Steroidal Anti Inflammatory Drugs (NSAIDs)
Drugs/Infos
Selective COX2 inhibitors,
such as
1. Diclofenac Sodium
2. Indomethacin
3. Ibuprofen
Only provides
symptomatic relieve, not
stopping the progression of
disease
Mechanism of Action
Selectively inhibits COX2 enzyme
1. COX 2 (inducible enzyme) which converts arachidonic acid into
a. Prostaglandins which involved in
i.
Inflammation
1. Vasodilation (hypereamia)
2. ↑capillary permeability (edema)
a. Inhibition will ↓inflammation
ii.
Pain sensation
a. Directly binds to pain receptor and elicit pain sensation (not
visceral pain)
iii.
Pyrexia (fever)
a. Prostaglandin together with IL-1b stimulates thermostat at the
OVLT to increase temperature set point higher than normal
b. Inhibition will return the temperature set point to normal
Side Effects
1. ↑CVS adverse events
Why? There are two mediators here, which are:
a.
Prostacyclin (PGI2) (synthesis by COX2) on
endothelial cells has effect on
1. Anti-aggregating
2. Anti-proliferative
3. Vasodilatory effect
b. TxA2 (synthesis by COX1) on platelets maintain
homeostasis by
1. Irreversible platelet aggregation
2. Vasconstriction
3. Smooth muscle proliferation
Celecoxib selectively inhibits COX2, therefore, ↓PG12
level, ↑TxA2 level leading to imbalance between these
two mediators
1.
↑in TxA2 will lead to
a. Formation of thrombosis
↑BP due to vasoconstriction
Colchicine
Drugs/Infos
1. No effect on uric acid
level, therefore will
never stop the
progression of disease
Clinical Uses
1. Pain reliever during
acute gouty attack
2. Prevention of recurrent
gout
a. Particularly during
anti-gout therapy
with allopurinol
Mechanism of Action
1. ↓leukocytes migration and release of inflammatory
mediators
a. Bind with intracellular tubulin, inhibiting its polymerization
b. Tubulin wont form microtubule which is important for
cellular movement and phagocytosis
c. Interfere with the production of leukotriene B4
2. ↓leukocytes proliferation
a. Arrests cell division at G1 stage by interfering with
formation of
i. Microtubule
ii. Spindle
b. Affects especially the rapidly dividing cells
Side Effects
1. Acute toxicity
a. Intractable diarrhea
b. Nausea
c. Abdominal pain
2. Low therapeutic margin
Anti-Hyperuriceamic Agents
Drugs/Infos
Allopurinol
1. No analgesic or anti-inflammatory activity
2. ↓concentration of uric acid in the
a. Plasma
b. Tissue
c. Urine concentration
3. Reverses the deposition of urate crystal
4. Inhibits urate stone formation
Clinical Uses
1. Chronic gout with
a. Tophi
b. Nephropathy
2. Secondary gout
a. Cancer pts undergoing chemotherapy
Drug drug Interaction
Only if the cancer pts is having a Azathioprine or
Mercaptopurine regime;
1. Azathioprine  Mercaptopurine  Inactive
metabolite
Conversion of mercaptopurine into inactive metabolite
requires xanthine oxidase, therefore inhibition of xanthine
oxidase activity will lead to ↑in mercaptopurine toxicity
which is pancytopenia
Drugs/Infos
Uricosuric Agents
1. Probenecid
2. Sulfinpyrazone
Mechanism of Action
1. Xanthine oxidase is an enzyme requires in converting hypoxanthine
to xanthine and lastly uric acid.
Hypoxanthine  xanthine  uric acid
2. Allopurinol acts as a product inhibitor for xanthine oxidase as it is
the substrate for the enzyme.
3. Allopurinol will be converted into Alloxanthine in which it will inhibit
the activity of xanthine oxidase.
4. Allopurinol will also be metabolized producing and active
metabolite which is Oxypurinol which can also inhibit the activity of
xanthine oxidase. This is therefore made Allopurinol to be able to
produce long lasting effects and allow a sufficient once daily
dosing
Side Effects
1. Hypersensitivity
Precaution
1. Due to its capability to mobilize or resolubilize the urate crystal into
the serum, the initial use of allopurinol is often will lead to an acute
attack of gout
2. This is therefore prevented by concurrent administration of either
Colchicine or NSAIDs together with Allopurinol until the serum level
of uric acid normalizes.
Mechanism of Action
1. Uric acid like many other weak acids is being reabsorbed and
secreted at the 2nd part of Proximal tubule.
2. Uricosuric drugs act by affecting the active transports so that the
net reabsorption of uric acid will be ↓
3. This will lead to
a. ↓size of urate pool
b. ↑uric acid excretion
c. BUT plasma concentration may not be greatly ↓
4. Due to massive excretion of uric acid through urine, renal stone
formation is almost assenting. To avoid this
a. Patient is advised to drink plenty of water
b. Coadminister with urine alkalinizer such as calcium carbonate
Side Effects
1. Hypersensitivity
reaction
Antirheumatic Drugs
Management of Rheumatoid Arthritis
1. Symptomatic reliever
a. NSAIDs
b. Corticosteroid
2. Disease-Modifying Anti Rheumatic Drugs
a. Methotrexate
b. Sulfasalazine
c. Leflunomide
d. Hydroxychloroquine
3. Biological agents
a. TNF A inhibitors
i. TNF A antibodies
1. Chiremic
a. Infliximab
2. Humanized
a. Adalimumab
ii. TNF A soluble receptors
1. Etanercept
b. Interleukin inhibitor
i. Anakinra
Drugs/Infos
Methotrexate
Disease-Modifying Anti Rheumatic Drugs (DMARDs)
Mechanism of Action
Side Effects
Due to a massive inflammatory response in Rheumatoid Arthritis, 1. Mucosal toxicity
inflammatory cells are actively dividing and chemotaxis to
2. Myelosuppression
1. Folate antagonist
synovium of arthritic joints, MTX acts by
3. Hepatotoxicity
2. It is
1. ↓direct inhibition towards cellular proliferation
a. Cytotoxic
2. Stimulates apoptosis in immune inflammatory cells
b. Immunosuppressant
3. ↓chemotaxis of inflammatory cells
4. Inhibition in the synthesis of inflammatory cytokines
Pharmacokinetics
These are achieved through the
Absorption
1. Irreversible inhibition of Dihydrofolate reductase (DHFR)
 70% well absorbed orally
a. This enzyme requires for the conversion of Folic acid 
Distribution
Dihydrofolate and Dihydrofolate  Tetrahydrofolate
 Rapid onset 4-6 weeks
2. Partially reversible inihibiton of Thymidylate synthetase
Metabolism
a. This enzyme requires for the conversion of
 Metabolized into less active
Tetrahydrofolate  Purine/Pyrimidine
hydoxylated metabolites
3.
Inhibition
of Aminoimidazolecarboxamide Ribonucleotide
Excretion
Transformylase (AICAR)
 90% excreted unchanged though
These steps are essential in the synthesis of DNA
urine by
o Filtration
o Active secretion
 Therefore requires dose
adjustment in pts with renal
impairment
Clinical Uses
1. Rheumatoid arthritis
2. Lymphoma
3. Leukaemia
Drugs/Infos
Sulfasalazine
Clinical Uses
1. Mild erosive arthritis
a. Often used in combination
Drugs/Infos
Hydoxychloroquine
1. Primarily an anti-malarial drugs
2. Contraindicated in patient with
G6PD deficiency as it may cause
an extensive hemolytic anemia
Clinical Uses
1. Mild non-erosive arthritis
a. Onset in 2-6 months
b. Often used in combination with
other DMARDs
Mechanism of Action
Side Effects
1. Sulfasalazine is being metabolized into
a. Sulfapyridine
i. Being absorbed
ii. Active ingredient
b. 5-aminosalicylic acid
i. Excreted through feaces
ii. Not active
2. Sulfapyridine is believed to have these pharmacological
effects
a. Suppression of T cell and subsequently leading to ↓in B
cells, which therefore
i. ↓in IgM and IgA production with are pathogenic in
rheumatoid arthritis
b. Inhibits the release of inflammatory cytokines which are
produced by macrophages and monocytes believed to
be responsible in the pathogenesis of rheumatoid arthritis
i. IL1
ii. IL6
iii. IL12
iv. TNF a
It is one type of sulfonamide
group of drugs, therefore
susceptible to produce
1. Hypersensitivity reaction
a. Steven Johnson
Syndrome
Mechanism of Action
Side Effects
1. The clear mechanism of action is remain uncertain, but
some ideas have been deliberately proposed
a. Suppression of T lymphocyte responses towards mitogens
b. ↓leukocytes chemotaxis
c. Stabilization of lysosomal enzymes
d. Inhibition of DNA and RNA synthesis
e. Trapping of free radicals
1. Ocular toxicity
a. Due to deposition of
drug on cornea
2. Retinopathy
Drugs/Infos
Leflunomide
1. Newest DMARDs
2. Efficacy comparable to MTX and
sulfasalazine, just most expensive
3. It is
a. TERATOGENIC
b. CYP450 inhibitor
Mechanism of Action
1. Undergoes rapid metabolism in intestine and plasma into its
active metabolite called A77-1726
2. This metabolite will inhibit Dihydroorotate Dehydrogenase
a. An enzyme requires for synthesis of ribonucleotide
3. This will lead to
a. ↓synthesis of ribonucleotide
b. Arrest of stimulated cells in G1 phase of cellular growth
4. Consequently leads to
a. Inhibition of T-cell proliferation
b. Production of IgM by B cells
Side Effects
1. Nausea
2. Diarrhea
3. Altered hepatic function
Drugs/Infos
TNF-a Antibodies
Humanized
 Adalimumab
o Fully human IgG1 anti-TNF monoclonal
antibody
Chiremic
 Infliximab
o 25% mouse and 75% human IgG1 anti TNF
monoclonal antibody
Biological Agents
Mechanism of Action
1. Form complex with soluble TNF-a
2. Therefore prevents its interaction with p55 and
p75 receptors on various tissues
3. This will then ↓function of
a. Macrophages
b. Lymphocytes
Side Effects
1. Opportunistic infections
a. Urinary tract infection
b. Upper respiratory
tract infection
c. Tuberculosis
Infliximab is more
immunogenic
Clinical Uses
1. Rheumatoid arthritis
2. Juvenile arthritis
3. Psoriatic arthritis
4. Crohn’s disease
Drugs/Infos
Soluble TNF-a Receptor
Etanercept
1. Acts as exogenous TNF-a receptor
2. Recombinant fusion protein
Clinical Uses
1. Arthritis
a. Rheumatoid
b. Juvenile
c. Psoriatic
2. Other autoimmune disease
Drugs/Infos
IL-1 Receptor Antagonist
Anakinra
1. Humanized antibody
Mechanism of Action
1. Binds with TNF-a therefore inhibiting it from
binding to bound receptor
a. TNFR1
b. TNFR2
2. Therefore suppressing inflammatory cascade
Mechanism of Action
1. Competitively inhibiting the binding of IL-1 to the
Interleukin-1 type receptor
Side Effects
1. Opportunistic infections
a. Urinary tract infection
b. Upper respiratory
tract infection
c. Tuberculosis
Side Effects
1. GI disturbances
a. Nausea
b. Vomiting