Module 1.1.1 (Pharmacology of drugs for Rheumatoid Arthritis) Flashcards
Which POTENT NSAID is used for Rheumatoid Arthritis? Why is its use limited? What is the MOA?
> This NSAID can also be used for OA, Acute Gout, AS, Post-OP Pain, Dysmenorrhea
Indomethacin (Indocid)
- Use limit due to high toxicity (35-50%) –> take with food
MOA
- Non-selective COX inhibitor
- Central analgesic effects
- Inhibits PMN motility
Plasma half-life of 2.5 h
What is the prodrug of indomethacin? is it better tolerated than indomethacin?
Sulindac –> 7-15 hours (better tolerated than indomethacin)
Side effects included headache, vertigo, dizziness, mental confusion + usual adverse effects of all NSAIDs
For DMARDS (disease-modifying drugs);
A) What are they?
B) What are some properties?
C) What are some examples?
A)
- Disease-modifying anti-rheumatic drugs (DMARDs) act by altering the underlying disease rather than treating symptoms
B)
- Long term suppressive effect
- Slow onset of action (many months)
C)
- Gold (2-5 months before benefits observed)
- Methotrexate (1-2 months)
- Azathioprine (2-3 months)
- Cyclosporine A (2-4 months)
- Hydroxychloroquine (2-6 months)
- Penicillamine (3-6 months)
- Low dose corticosteroids
- Tocilizumab (1 month but very expensive)
- Leflunomide (1-2 months, de novo pyrimidine inhibitor = decreases joint swelling)
- Etanercept (1-2 months)
- Sulfasalazine (1-3 months, reduces NK activity, antibiotic - sulfapyridine main agent)
- TNFα antibodies (1-2 months)
For Hydroxychloroquine (antimalarial);
A) When is it used
B) MOA
B) What are some side effects
A)
- For remission in RA
- Works after 2 months of treatment ( 50% success)
B)
- Decrease IL-1 synthesis (macrophage): phospholipase A2: chemotaxis
- Initial plasma ½ life ~7 d with terminal ½ life ~32 d
C)
- Retinal toxicity
- Blurred vision, headache, dizziness
- Ophthalmological tests required – annually
- T wave and QRS abnormalities
- Lichenoid skin eruptions, Psoriasis
- Alopecia, hair bleaching.
For Methotrexate;
A) What is the dose usually given and how often is it given?
B) What is the MOA?
C) What are some secondary mechanisms?
A)
7.5-15 mg ONCE A WEEK (low doses)
B)
- Folic acid antagonist
- dihydrofolate reductase inhibitor
- Prevents regeneration of tetrahydrofolate from dihydrofolate – thymidylate synthase block
> thymidylate synthase catalyses UMP —> dTMP reaction
> 2 steps in de novo purine synthesis need folate
> Stops poly-glutamate conjugates forming
> initial treatment = moderate to severe
C)
- 5-lipoxygenase pathway- leucocytes
- decreased IL-1 - macrophages
Ability to suppress the autoimmune component
For Methotrexate;
A) What are some side effects
B) What are some cancers it increases the risk of
C) What is it given with for oral side effects (nausea, diarrhoea, stomatitis)
D) why must there be caution with renal insufficiency and co-administration of renal affecting drugs such as NSAIDs, probenecid, sulfonamides?
A)
- Myelosuppression
- Thrombocytopenia
- Mucositis
- Pneumonitis & pulmonary fibrosis
- Embryos (don’t give to pregnant women)
- Chronic doses leads to hepatic fibrosis & cirrhosis
B)
- 3x melanoma (use sunscreen and stay out of the sun)
- 5x non-Hodgkins lymphoma
- 3x lung cancer
C)
- Leucovorin (folic acid to protect the gut from effects of methotrexate) and divide doses over 24h if oral
D)
- Due to methotrexate being cleared from the kidneys
What are some other uses for methotrexate? What is therapy to recover from high methotrexate levels in the body?
Antineoplastic (cancer) agent
- Childhood ALL
- Choriocarcinomas, osteosarcomas, brain
- Choriocarcinomas, osteosarcomas, brain
Organ transplant
Psoriasis
Crohn’s disease (not UC)
Ectopic pregnancy
New therapy to recovery from high methotrexate = glucarpidase Reduces 95% of methotrexate in body
Provide FIVE examples of Anti-TNFa drugs
- Etanercept
- Infliximab
- Adalimumab
- Golimumab
- Certolizumab pegeol (PEGylated anti-TNF = helps to keep drug in body longer)
EIAGC
Can be used with methotrexate
> all TNFa drugs –> psoriasis may get worse
For Anti-TNFa drugs;
A) What are some properties and issues of etanercept
B) What are some properties and issues of infliximab
C) What are some properties and issues of adalimumab
D) What are some properties of golimumab
E) What are some properties of certolizumab pegol
A)
- Fusion protein –[TNF receptor–Fc IgG1]: MW 150kDa
- Lymphotoxin-α binding alone (unique)
- Synoviocytes, osteoclasts & chondrocytes
- Potent (low doses)
Fewer side effects:
- Site reactions – itching, swelling, pain
- Metastatic melanoma risk (as for all TNFα drugs)
- Allergic reaction – urticaria
- Immune response (vaccines) –> don’t use vaccines while on this drug
- Inject sc only 1 to 2x week. (if 1x use double dose)
- S.c. inject 1/2 life > 3days
B)
- Anti-TNF-α monoclonal: MW 149 kDa !
- 8-10 d ½ life – inject IV every 4-8 weeks !
- Combine with methotrexate – good 2 year prognosis
Issues:
- Infections & anti chimeric antibody prodn (75% human, 25% mouse)
- Dormant infections reactivate- eg TB, hepatitis B
- Infusion site (erythema, eczema, itching, pain, swelling), vertigo
- Serum sickness, dizziness, abdominal pain, vomiting, fever
- Psoriasis may get worse –> common to all TNFa drugs
C)
- Anti-TNF-α monoclonal: MW 148 kDa
- 2-week ½ life
- sc inject – every 2 weeks
- Fully humanised –> no mouse component (longer to autoantibody gen) –> decreased anaphylaxis
- Administer with methotrexate
- Also used in psoriasis (ask if psoriasis gets worse or treats it??) and IBD
- Adverse effects same as infliximab + hyperlipidemia
D)
- Monthly injections (subcutaneous); 2-week ½ life
- Administer with methotrexate
E)
- Rapid onset with 2 to 4-week dosing
- Administer with methotrexate
ALL TNFa antibodies classed as clinically equivalent
patients have pain with SC injections, and compliance is issue with these drugs – initiatives to reduce injections assist here
For Anakinra;
A) What is it? How is it created?
B) Properties and dose
C) Adverse effects
D) Contraindications
E) How long to see results
A)
- IL-1 receptor antagonist
- Created using E.coli recombinant DNA techniques
B)
- MW 17 kDa
- Inject only (sc) 100mg/day
- Peak plasma = 3-5h after sc
- Term ½ life = 4-6 h
C)
- Injection site (erythema, ecchymosis, inflammation)
- Headache;
- Risk of serious infection
- Neutropenia
D)
- Do not use with TNF-α drugs
> Infection risk >> greater, no increase in relief
E)
- 2 weeks to see effects
For Tocilizumab;
A) What is it?
B) what is it used with?
C) Dose
D) Adverse effects
A)
- IL-6 targeting antibody
- Most abundant IL in synovial joints of RA patients & systemic juvenile idiopathic arthritis (JIA)
B)
- Better with concurrent methotrexate
C)
- IV Dose 1x4 weekly (4mg/kg)
D)
- Possible 5 fold # AST & ALT levels (transient)
- Increased LDL levels, hypertension, headache, dizziness
- Neutropenia
For Tofacitinib;
A) What is it? MOA?
B) Adverse effects?
C) Dosing?
A)
Janus kinase inhibitor (JAK1, 2 & 3)
- Important induction system in joint inflammation (pro-inflammatory cytokine production)
- Prevention of cell proliferation via JAK-STAT induction systems in nucleus
- May induce apoptopic pathways in lymphocytes
- ⇩ activation of T-lymphocytes
B)
- liver damage
- Increased lipid blood levels
- Cancer risk
- Decreased heart rate and gut perforations (induction systems not unique to joints)
C)
- Dosing 5mg oral tablets bd
For Gold Salts (aurothiomalate);
A) MOA?
B)Dosing schedule
C) Where does the build-up of gold occur?
D) half-life?
E) side effects?
A)
IM injection-induced remission via
- Decreased mitogen-induced lymphocyte proliferation
- Decreased release and activity of lysosomal enzymes
- Decreased production of O2 radicals/metabolites
- Decreased chemotaxis from neutrophils
- Decreased mast cell mediator release
> Auranofin does all the above is orally given and decrreases IL-1 and TNF-a induction
B)
- Weekly then monthly injections (start with low dose)
C)
- Gold builds in synovial joints, circulating macrophages (reticuloendothelial cells)
D)
- 7 day 1/2 life but increases with treatment
E)
- 1 in 3 (serious: 30% of these = 1 in 10 overall)
- Lesions of mucous membranes (mouth) – grey/blue deposits
- exfoliating dermatitis & other rashes
- Peripheral neuropathy
- Nephrotoxicity –> proteinuria
- Hepatitis
- Encephalopathy
Oral auranofin (high levels of the drug in the gut)
- nausea, vomiting,diarrohea, dyspepsia, stomatitis, conjunctivitis
For D-Penicillamine;
A) What are some properties? What makes it unique?
B) How is it excreted?
C) What are some adverse effects?
A)
- Decreased collagen formation, rheumatoid factor & immune complex – synovial fluid & blood
> one of the few drugs that decrease RF
- effectiveness over many weeks to months
- adverse effects affect 40% of patients
- Chelating ability- possible role
> Wilson’s disease, Pb poisoning, cystinuria
- Cysteine substitute – more soluble complexes.
- Doses start low = gradual increase
B)
- Excretion – 80% renal, mostly metabolites
C)
Similar to Gold (such as neuropathy, nephropathy) with the follow extra considerations
- Allergy to penicillin
- G.I. Tract
> Taste disturbances
> Nausea, vomiting, anorexia
- Blood
> Leukopenia – aplastic anaemia – stop immediately !
> Autoimmune conditions
- Rashes, stomatitis
- Proteinuria (20%)
- Goodpasture’s syndrome (Pulmonary haemorrhage)
For leflunomide;
A) MOA?
B) Properties?
C) Toxicity
D) What is it used in?
E) Adverse effects?
A)
- Pro-drug
- De novo pyrimidine synthesis inhibitors
- Dihyroorotate dehydrogenase (DHDH ) –> blocker of de-novo pyrimidine
- Lymphocytes – cell division blocked
- Inhibits CYP2C9 (phenytoin / warfarin interact)
B)
- Long half-life (> 2 weeks)
- Loading doses [100 mg/d – 3days-then 5-25 mg/d)
C)
- Toxicity – liver – co-therapy with other liver-damaging drugs can cause severe liver failure*
- teratogenic ADEC(X) - 6 months wash out using cholestyramine (binds bile salts in the gut and reduces the period of washout)
- No breast-feeding
D)
- useful in RA and Psoriatic arthritis– decreased joint swelling
- *eg with Methotrexate - increased hepatotoxicity
E)
- In addition to Hepatic
- (usual array of N V D) !
- Hair loss
- Weight loss
- Weakness
- Headache
- Dizziness
- Pneumonia
- Increased risk of interstitial lung disease (Japan evidence)
- Peripheral Neuropathy
Summary
