Pharmaco: RA Flashcards
List the drugs used in RA and their class
Anti-inflammatory agents:
- NSAIDs (short-term pain relief)
- Corticosteroids (low dose bridging therapy)
No role for paracetamol
Conventional Synthetic DMARD (csDMARD)
- Methotraxate
- Sulfasalazine
- Leflunomide
- Hydroxychloroquine
- Ciclosporin
Targeted Synthetic DMARD (tsDMARD)
- Tofacitinib
- Baricitinib
Biologic DMARD (bDMARD)
- Anti-TNF mAb: Infliximab, Adalimumab, Etanercept
- IL-1R antagonist: Anakinra (NA in Sg)
- Anti-CTLA4lg: Abatacept (NA in Sg)
- Anti-CD20: Rituximab
- Anti-IL6 receptor mAb: Tocilizumab
Side effects of glucocorticoids
- Increase CVD risk
- Cataract, glaucoma
- Skin thinning, hirsutism
- Gastric ulcer (if concomitant NSAID)
- Weight gain, fluid retention, Cushing syndrome
- Impaired glucose metabolism, insulin resistance, B-cell dysfunction
- Neuro-psychiatric symptoms, HPA insufficiency
- Osteonecrosis, osteoporosis
- Myopathy
- Infections
[csDMARD - Methotrexate]
Dosage forms
- oral
- SQ
- IM
[csDMARD - Methotrexate]
MOA
Major action:
- Inhibits ATIC enzyme, thereby increasing adenosine levels, activation of adenosine A2a receptors results in anti-inflammatory effects:
- antiproliferative effects on T cells
- inhibition of macrophage functions
- downregulation of pro-inflammatory cytokines, adhesion molecules, chemotaxis, phagocytosis
Minor action:
- inhibits dihydrofolate reductase (DHFR) and thymidylate synthetase, decrease purine synthesis, affect cell replication
[csDMARD - Methotrexate]
Side effects
- GI SEs: N/V/D, Anorexia, Mouth and GI ulcers (stomatitis)
- Hair thinning
- Liver: increase transaminases (therefore need to monitor LFT), hepatic fibrosis, cirrhosis
- Lungs: Fibrosis, pneumonitis
- Haem: bone marrow suppression/myelosuppression, leukopenia
- Derm: photosensitivity, TEN, SJS
[csDMARD - Methotrexate]
Mechanism of side effects
Mechanism: attributed to minor action, at higher dose and long term treatment
MTX inhibits DHFR, reduces levels of tetrahydrofolate and thus decreases synthesis of purines and pyrimidines.
This inhibition leads to a decrease in the production of DNA, RNA and certain amino acids, ultimately disrupting the growth and proliferation of rapidly dividing cells, such as those found in the bone marrow and the walls of GIT, which causes bone marrow suppression and GI disturbances.
[csDMARD - Methotrexate]
How to keep side effects to a minimum?
Concomitant folic acid 5mg/week or folinic acid given 12-24h after methotrexate, can decrease MTX toxicity
Rescue therapy of methotrexate
Folic acid, a synthetic form of the naturally occurring vit B9, helps prevent MTX induced SE by counteracting the reduced levels of tetrahydrofolate
[csDMARD - Methotrexate]
Difference b/w folic acid and folinic acid
Folic acid / Folate
- Cheaper and more commonly used
- However, require high doses as it does not efficiently rescue toxicity
- Folic acid must be converted by DHFR into N5N10-Methylene-FH4 that is essential for cell proliferation (it does not bypass DHFR activity)
Folinic acid (N5-formyl-FH4)
- More expensive
- But more efficient at rescuing MTX toxicity
- Rapidly converted to N5N10-Methylene-FH4 without DHFR activity
[csDMARD - Methotrexate]
(IC16) Contraindications
- Preexisting liver disease
- Immunodeficient syndrome
- Blood dyscrasias
Other precautions/may not prescribe (from the video):
- Liver cirrhosis
- Certain lung conditions
- Pregnant or trying to get pregnant
- Man trying to get someone pregnant
- Significant anemia
- Low WBC
- Breastfeeding
[csDMARD - Methotrexate]
(IC16) Dose adjustment with hepatic or renal impairment
AST/ALT > 3x ULN: 75% of dose
CrCl <50ml/min: 50% of dose
CrCl <30ml/min: avoid use
MTX is 80% excreted renally unchanged
[csDMARD - Methotrexate]
(IC16) DDIs
- NSAIDs/COX-2 inhibitors (incr serum conc. of MTX)
- PPI
- Probenecid
- Vaccines
- Alcohol
[csDMARD - Methotrexate]
(IC16) Use in pregnancy
Teratogenic, embro-fetal toxicity
(exclude pregnancy before starting)
[csDMARD - Methotrexate]
(IC16) Monitoring (side effects and labs)
Side effects:
- Lung: SOB, cough
- GI: N/V, mouth sores, diarrhea
- Liver: jaundice
- Dermatologic toxicity
- Infections
Labs:
- FBC
- LFT (AST, ALT, albumin, bilirubin) - incr transminases, also may affect dosing
- SCr (dose adjustment when CrCl <50ml/min, avoid use when CrCl <30ml/min)
[csDMARD - Sulfasalazine]
MOA
Unknown, but poorly absorbed so may be mediated by effect in gut microflora, leading to changes in immune response:
- Decreased IgA and IgM rheumatoid factors
- Suppression of T and B cells, and macrophages
- Decrease in inflammatory cytokines (e.g., IL-1B, TNF, IL-6)
- (IC16) Modulates leukotrienes, inhibits TNF
[csDMARD - Sulfasalazine]
Metabolism
Metabolized to sulfapyridine (active) + 5-aminosalicylic acid
[csDMARD - Sulfasalazine]
Side effects
- GI: Nausea and vomiting, dyspepsia
- CNS: Headache, dizziness
- Derm: Rash
- Hemolytic anemia
- Neutropenia
- Reversible infertility in men
(IC16)
- Genitourinary: Oligospermia (reversible), urine discoloration
[csDMARD - Sulfasalazine]
(IC16) Contraindications
- Sulfonamide allergies
- Caution in G6PD deficiency
[csDMARD - Sulfasalazine]
(IC16) DDIs
- Iron
- Antibiotics
- Warfarin
[csDMARD - Sulfasalazine]
(IC16) Pregnancy Status
B, may use
[csDMARD - Sulfasalazine]
(IC16) Monitoring: side effects and labs
Side effects
- N/V
- Rash
- Infection
Lab
- FBC
[csDMARD - Leflunomide]
MOA
Inhibits dihydroorotate dehydrogenase
- Decrease in pyrimidine synthesis and growth arrest at G1 phase
- Inhibit T cell proliferation and B cell autoantibody production
- Inhibit NF-kB activation pro-inflammatory pathway
DHODH plays a key role in the de novo synthesis of the pyrimidine
(IC16): decrease lymphocyte action
[csDMARD - Leflunomide]
Metabolism
Rapidly converted to active metabolite, teriflunomide
[csDMARD - Leflunomide]
Side effects
- GI: Diarrhea, nausea
- Liver: incr transaminases (elevation of liver enzymes)
- Derm: Alopecia, skin rash
- CNS: headache
- Haem: myelosuppression
- Weight gain
- Teratogenic
[csDMARD - Leflunomide]
(IC16) Contraindication
- Preexisting liver disease
- ALT > 2x ULN
- Immunodeficient states
[csDMARD - Leflunomide]
Half-life, implications
Leflunomide has very long half-life (detectable years after last dosing)
- Cholestyramine (bile salt binding resin) is used to wash-out the drug (e.g., before pregnancy - since it is teratogenic)
If using Leflunomide, then cholestyramine is a drug interaction (IC16)
[csDMARD - Leflunomide]
(IC16) Dose adjustment in liver impairment
ALT > 2x ULN: avoid use
[csDMARD - Leflunomide]
(IC16) Pregnancy status
Teratogenic
(exclude pregnancy before starting)
[csDMARD - Leflunomide]
(IC16) Monitor SEs and Labs
Side effects:
- Diarrhea
- Hair loss
- Jaundice
- Infection
Labs:
- FBC
- LFTs (AST, ALT, albumin, bilirubin)
[csDMARD - Hydroxychloroquine]
MOA
Hydroxychloroquine is an anti-malarial agent
- Effective anti-inflammatory agent (but least potent DMARD)
- Reduced MHC Class II expression and antigen-presentation, (IC16) inhibit complement-dependent antigen-antibody reactions
- Reduced TNF-a and IL-1, and cartilage resorption
- Antioxidant activity
- (IC16) inhibit locomotion of neutrophils, chemotaxis of eosinophils
[csDMARD - Hydroxychloroquine]
Side effects
- Nausea and vomiting
- Stomach pain
- CNS: headache, dizziness
- Hair loss
- Ophthalmic: Ocular toxicity, retinopathy
- Derm: photosensitivity, hyperpigmentation
- Metabolic: hypoglycemia
- Neuropsychiatric symptoms
- CVS: QT prolongation
Best tolerability out of the DMARDs
[csDMARD - Hydroxychloroquine]
(IC16) Contraindications
- Preexisting retinopathy
- Caution in G6PD deficiency
[csDMARD - Hydroxychloroquine]
(IC16) Pregnancy status
C
[csDMARD - Hydroxychloroquine]
(IC16) Monitoring
Eye exam (ophthalmoscopy)
[tsDMARD - Tofacitinib]
MOA
Non-selective JAK inhibitor, block JAK/STAT activation of gene transcription, thereby blocking cytokine production
- binds to JAK proteins inside cells to prevent JAKs from transphosphorylating the associated cytokine and growth factor receptor
[tsDMARD - Tofacitinib]
Dosage form
Small molecule kinase inhibitors, administered orally
[tsDMARD - Tofacitinib]
What is another indication that Tofacitinib is also approved for?
Psoriatic arthritis (PsA)
[tsDMARD - Tofacitinib]
Side effects
- Cytopenia: including neutrophils, lymphocytes, platelets, NK cells
- Immunosuppression: opportunistic infections, incr risk of herpes zoster infection esp in asian popln
- Anemia (bc tsDMARDs can affect JAK2 activation by erythropoietin)
- Hyperlipidemia (metabolic): incr in total, LDL, HDL, cholesterol, and triglycerides (bc JAK-STAT pathway involved in lipid pathway and control) => monitor lipid panel
[tsDMARD - Tofacitinib]
Can tofacitinib be combined with csDMARDs or bDMARDs?
- Can combine with MTX for mod-severe RA
- tsDMARD cannot be combined with bDMARD => risk of additive effects, high risk of immunosuppression and opportunistic infections
[tsDMARD - Tofacitinib]
Tofacitinib carries high risk for:
Tofacitinib carries high risk for major adverse cardiovascular events (MACEs) and malignancy (for individuals with the risk factors)
Note that bDMARD and tsDMARD carry similar risk for malignancy
tsDMARD along with IL-6 inhibitor, Tocilizumab, also carries risk for thrombosis and gastrointestinal perforation
[tsDMARD - Tofacitinib]
What are some risk factors for cardiovascular events and malignancies that must be considered when intending to prescribe a JAK-inhibitor?
CVD risk factors:
- Age >65
- Hx of current or past smoking
- Other CVD risk factors: diabetes, obesity, hypertension
Malignancy risk factors:
- Other risk factors for malignancy: current of hx of malignancy other than successfully treated NMSC
Risk factors for thromboembolic events:
- Risk factors for thromboembolic events (hx of MI, HF, cancer, inherited blood clotting disorders, hx of blood clots)
- Pts taking combined hormonal contraceptives or HRT
- Pts undergoing major surgery
- Pts who are immobile
[tsDMARD - Tofacitinib]
Risk factors for gastrointestinal perforation
- Diverticulitis
- > 65y
- Glucocorticoid use
- NSAID use
[bDMARD]
Why are bDMARDs tried before tsDMARD?
bDMARDs are more specific and selective for certain cytokine pathways, hence less risk of broad-spectrum adverse effects compared to tsDMARDs
[bDMARD]
Generally explain what are bDMARDs?
- made by molecular biologic techniques
- administered via SC injection or IV infusion
- binds to cytokines or their receptors to downregulate/inhibit their function, thereby reducing immune and inflammatory response
[bDMARD - TNF signaling blockers]
Name the TNF signaling blockers
Infliximab, Adalimumab, Golimumab, Etanercept
(From most to least immunogenic)
[bDMARD - TNF signaling blockers]
Compare the MOA of Infliximab, Adalimumab, Golimumab, and Etanercept
Infliximab, Adalimumab, Golimumab:
- Chimeric / Recombinant human IgG1 that binds to TNF-a
Etanercept:
- Recombinant TNFR2-IgG1-Fc protein (decoy TNFR2 receptor IgG1 fusion protein) that intercepts, and binds to TNF-a, TNF-B, and lymphotoxin-A
- NOT a monoclonal antibody
[bDMARD - TNF signaling blockers]
Compare the administration of Infliximab, Adalimumab, Golimumab, and Etanercept
Infliximab: IV infusion
Adalimumab: SC (may self-administer)
Golimumab: IV/SC
Etanercept: SC (may self-administer)
[bDMARD - TNF signaling blockers]
Compare the half-lives of Infliximab, Adalimumab, Golimumab, and Etanercept
Infliximab: 8-9.5 days
Adalimumab: 14 days
Golimumab: 12 +/- 3 days
Etanercept: 70h
[bDMARD - TNF signaling blockers]
Side effects
- Respiratory infection
- Skin infection
- Increased risk of lymphoma
- Optic neuritis
- Exacerbation of multiple sclerosis
- Leukopenia
- Aplastic anemia
Immunocompromised
[bDMARD - TNF signaling blockers]
(IC16) Contraindication
NYHA Class III and IV Heart Failure
[bDMARD - IL1 signaling blockers]
Which drug?
Anakinra
[bDMARD - IL1 signaling blockers]
MOA
Anakinra is a recombinant IL-1 receptor antagonist, binds to IL-1 receptor and blocks signaling
It is less effective than TNF signaling blockers
In normal circumstances, endogenous IL-1 receptor antagonist protein regulates the IL receptor function by inhibiting it
[bDMARD - IL1 signaling blockers]
Protein structure in comparison to endogenous IL-1 receptor antagonist
Differs from sequence of the endogenous protein by one methionine added to the N-terminus and not being glycosylated (no PTM)
[bDMARD - IL1 signaling blockers]
Dosage form of Anakinra
SC
[bDMARD - IL1 signaling blockers]
Side effects
- Infections
- Injection site reactions
[bDMARD - IL6 signaling blockers]
Which drug?
Tocilizumab
[bDMARD - IL6 signaling blockers]
MOA
Tocilizumab is a humanized mAb binds irreversibly at the IL-6Ra chain, prevents binding of IL-6 to IL-6Ra and homodimerization of IL-6RB signaling
[bDMARD - IL6 signaling blockers]
Dosage form of Tocilizumab
IV
[bDMARD - IL6 signaling blockers]
Side effects
- Infections
- Skin eruptions
- Stomatitis
- Fever
- Neutropenia
- Increase in ALT/AST
- Hyperlipidemia
[bDMARD - IL6 signaling blockers]
CYP interactions
NOT the typical CYP interaction, because biologics are cleared by proteolytic enzymes, hence we would not expect to see interaction with liver CYP enzymes
- IL-6 reduces expression of CYP450 enzymes
- Hence Tocilizumab which inhibits IL-6 receptors, would increase the expression of CYP450 enzymes
- Indirectly causes decrease serum concentration of drugs that are CYP450 substrates (include CYP450, 3A4, 1A2, 2C9 substrates)
[bDMARD - IL6 signaling blockers]
Tocilizumab carries risk of:
IL-6 inhibitor, Tocilizumab, along with tsDMARD carries risk for thrombosis and gastrointestinal perforation
[bDMARD - IL6 signaling blockers]
Due to risk of thrombosis, Tocilizumab should be avoided in:
pt with history of thrombotic events
[bDMARD - IL6 signaling blockers]
Risk factors for gastrointestinal perforation
- Diverticulitis
- > 65y
- Glucocorticoid use
- NSAID use
[bDMARD - CTLA4-FcLgG1]
Which drug?
Abatacept
[bDMARD - CTLA4-FcLgG1]
MOA
Abatacept is a recombinant fusion protein with CTLA4-FcLgG1, binds to CD80 and CD86 and prevents CD28 activation, thereby inhibiting T cell activation
suppress T cells
[bDMARD - CTLA4-FcLgG1]
Dosage form
SC/IV
[bDMARD - CTLA4-FcLgG1]
Side effects
- Respiratory infection in COPD
- Increase lymphoma incidence
[bDMARD - Anti-CD20]
Which drug?
Rituximab
[bDMARD - Anti-CD20]
MOA
Rituximab is a chimeric mAb IgG1 directed at CD20 on pre- and mature B cells, depletes CD20+ B cells, (induce killing of normal and malignant B cells that express CD20); blocks antigen presentation, autoantibody, and cytokine level
[bDMARD - Anti-CD20]
Dosage form
IV Rituximab
[bDMARD - Anti-CD20]
Side effects
- Rash in first dose
- Respiratory infection in COPD
[bDMARD - Anti-CD20]
Rituximab also report risk of:
Gastrointestinal perforation (but mainly IL-6 inhibitor, Tocilizumab and tsDMARD tofacitinib)
- Evaluate abdominal pain or vomiting
