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Pharmacology Year 2 > DMARDs > Flashcards

DMARDs Flashcards

1
Q

Provide some examples of csDMARDs

A

Methotrexate
Sulfasalazin
Hydroxychloroquine
Leflunomide,
Cyclosporine

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2
Q

Describe the mechanism of action of methotrexate

A

Antimetabolite
Folic acid analogue which binds to dihydrofolate reductase enzyme & antagonises folic acid. As folic acid is essential to DNA synthesis, MTX impairs cell division , reduces monocytic cell growth & induces apoptosis
Has cytotoxic and immunosuppressant activity
Common first choice drug for RA

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3
Q

Describe the special adverse effects and monitoring for MTX

A

ADVEs: heptox, myelotox, pulmo tox; synergistic BM, liver and pulmo tox with leflunomide; contrad in pregnancy

Monitring: FBC and LFTs, renal function

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4
Q

List some considerations when prescribing methotrexate

A

Once a week therapy. Consideration for implications for compliance
Co-administration of folic acid (not on the same day as methotrexate) reduces GI adverse effects and hepatotxicity

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5
Q

Describe the mechanism of action of leflunomide

A

Anti metabolite
Inhibits pyrimidine synthesis by competitively blocking dihydro-orotate dehydrogenase and thus inhibiting activated lymphocytes.
It has immunosuppressive, immunomodulating and antiproliferative properties. Also has uricosuric effects.

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6
Q

Describe the special advEs and monitoring for leflunomide

A
  • hep, myelo, pulmo tox and BP
  • synergistic BM, liver, lung with MTX
  • monitoring: FBC, LFT, BP (Renal function)
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7
Q

Describe some condirations when prescribing leflunomide

A

CONTRAINDICATED IN PREGNANCY

Washout procedure

  • Due to long half-life of active metabolite, if cessation of leflunomide is required (particularly due to adverse effects or unexpected pregnancy etc) a washout may be required
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8
Q

Describe the MoA of sulfasalazine

A

May act by scavenging the toxic oxygen metabolites produced by neutrophils
Anti-inflammatory and immunosuppressant - usually used if methotrexate is not required first line eg if the patient has low-grade inflammation, few affected joints and no indicators of poor prognosis.

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9
Q

Describe the AdvEs and monitroing for sulfasalazine

A

hep, myelotox; hypersensitivity

Monitor: FBC, LFT (renal function)

Reversible decrease in sperm count has been reported (but safe in female pregnancies)

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10
Q

Describe the MoA of HCQ

A

Inhibits the release of lysosomal enzymes, PML chemotaxis, IL-1 release and the action of phospholipase A2 -> ↓ formation of inflammatory mediators
Monotherapy with hydroxychloroquine may be used if the patient has low-grade inflammation, few affected joints and no indicators of poor prognosis (and therefore doesn’t require methotrexate).

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11
Q

Describe the AdvEs and monitoring required for HCQ

A
  • advEs: retinopathy and GIT
  • monitor: eye exam, renal and LFTs, FBC
  • ONTRAINDICATED IN PREGNANCY
    Monitoring : check complete blood count, renal and hepatic function at baseline
    • may take approximately 2–6 months of treatment before benefit is seen
      Ocular toxicity:
    • Blurred vision is common.
    • Corneal changes (eg oedema, opacities) occur infrequently, are transient or reversible and may cause effects such as blurred vision and halos.
    • Retinopathy is related to daily dose and duration of treatment. Retinal toxicity can lead to vision loss. Damage is irreversible and may progress after stopping hydroxychloroquine.
    • Baseline and regular ophthalmological examination required.
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12
Q

List some examples of biological DMARDs

A
  • Abatacept=Interruption 2nd T cell costimulation signal
  • Tocilizimab=IL-6 cytokine receptor inhibitor
  • Rituximab=B cell blocker(CD 20 monoclonal antibody)
  • JAK inhibitors tofacitinib, baracitinib, upadacitinib

Abatacept, Tocilizimab, Rituximab, JAKs Cautions
- Same as TNF-inhibitors for prescreening and exclusions
- Discontinue Rx if a patient develops serious infection (more likely if on steroids, over 65 years –perhaps etanercept, abatacept, rituximab less infection risk)
- Monitor immunoglobulin levels for those on rituximab
- Monitor full blood count(especially neutrophils), liver function and lipids for those on tocilizimab
- Vaccination against influenza and pneumococcus all RA patients. Ideally also herpes zoster vaccine pre starting boDMARDs and tsDMARDs
- Avoid JAK inhibitors if significant clot and vascular history

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13
Q

Decribe TNFa inhibitors

A

Bind to TNF alpha and inhibit its activity.

TNF alpha is a cytokine involved in inflammatory and immune responses and in the pathogenesis of rheumatoid arthritis, psoriasis and inflammatory bowel disease.

The TNF-alpha antagonists appear to be equally effective in the treatment of rheumatoid arthritis; comparative data are limited (few head-to-head studies).

Precautions
- Demyelinating disorders: eg MS—contraindicated; TNF-alpha antagonists may increase disease activity
- Heart failure: contraindicated in moderate or severe heart failure (NYHA class III–IV) and left ventricular ejection fraction <50%; use cautiously in mild disease as TNF-alpha antagonists may worsen heart failure
- History of blood dyscrasias: rare cases of serious blood dyscrasias (some fatal) have been reported; monitor complete blood count regularly
- Respiratory disease: may be at increased risk of interstitial lung disease with TNF-alpha antagonists
- Psoriasis: exacerbation and change in type of psoriasis has occurred
- Antibodies against double-stranded DNA (eg lupus): TNF-alpha antagonists are associated with the formation of autoantibodies. They may worsen or induce a lupus-like syndrome
- Infection: Contraindicated in serious or untreated infection, eg sepsis, abscess, hepatitis B, active TB (before completing TB treatment). May reactivate inactive hepatitis B and latent TB (begin TB treatment before starting a TNF-alpha antagonist). Careful when prescribed with other agents that affect the immune system
- Malignancy: Contraindicated if there is a history of lymphoproliferative disease within the last 5 years. There are reports of metastatic melanoma after use of TNF-alpha antagonists in patients whose melanoma was treated several years previously. TNF alpha affects cellular immune response and its inhibition may affect development of malignancies
- Surgery: Consider the increased risk of perioperative infections with TNF-alpha antagonists.

Adverse effects:
- Infections (may be serious, eg invasive fungal infections)
- rash, itch
- headache
- autoantibodies
- psoriasis, eczema
- lupus-like syndrome (rare with etanercept and golimumab)
- blood dyscrasias (eg thrombocytopenia, neutropenia, rarely pancytopenia)
- malignancies (including skin cancers and lymphomas)
- demyelination
- interstitial lung disease
- vasculitis
- heart failure, or worsening of existing disease (infrequent with adalimumab, infliximab and certolizumab)

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14
Q

Describe JK inhibitors

A
  • Janus Kinase inhibitor (member of the tyrosine kinase group of enzymes)
  • Janus Kinase is crucial for signal transduction of interleukins
  • Integral for lymphocyte activation and proliferation
  • Blocks cytokine pathways that lead to lymphocyte activation

Adverse Effects:
- Infections including opportunistic
- Increased liver enzymes, diarrhoea, nausea, rash, headache

Warnings:Increased risk of GI perforation, eg diverticular disease, NSAIDs—tofacitinib may add to the risk of GI perforation

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15
Q

Describe CTLA4 protein

A

Abatacept works by binding to two signal molecules (CD80 and CD86) on antigen-presenting cells, thereby preventing them from activating T cell.

It is made up of the extra cellular part of the human cytotoxic lymphocyte-associated antigen (CTLA-4) linked to a fragment of human immunoglobulin G.

Side effects
- Infection
- Infusion related reactions
- malignancies and auto-immune conditions

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16
Q

Describe rituximab

A
  • Chimeric monoclonal antibody that binds to CD20 on B lymphocytes.
  • In chronic inflammatory diseases it suppresses immune response and inflammation by reducing T cell activation and resulting cytokine production.
  • Side effects
    - Infection risk
    - Injection related reactions
    - Lymphopenia, neutropenia, thrombocytopenia , anaemia
    - Arrhythmias, heart failure, Angina, myocardial infarction
    - progressive multifocal leucoencephalopathy (requires cessation of treatment and prolonged monitoring)
17
Q

Describe the paradigm of modern e.g. RA treatment and ladder of prescribing in arthritis

A

Modern RA treatment
- Treatment should be goal-oriented and governed by a strategic treatment approach
- Primary target for treatment of RA: Remission or low disease activity (especially if disease has been progressing without treatment, remission may not be possible)
- Patients should be closely monitored using composite disease activity measures
- Treatment should be adapted if the treatment aim is not reached within preferably 3 or 6 months

Phase I treatment
- MTX, and if not, leflunomide or sulfasalazine ^[used more than HCQ due to efficacy in reducing radiological damage]
- may be used in conjunction with short-term steroids

Phase II
Move to biologics or alternative csDMARD depending on prognostic factors.

18
Q

Discuss use of HCQ (in SLE)

A

MoA: Decreases Toll-like receptors 9,8,7 and 3 activation by alkalinisation of the lysosome

SE:

  • Adverse events ;Drug rash(usually first month, means that drug cannot be used long-term, occurs in about 1% of patients), GI(nausea/diarrhoea)
  • Tox and monitoring:
  • Neurotoxicity+- myotoxicity, myasthenia syndromes, Eye monitoring (but OCT scans can detect early retinopathy which is uncommon unless higher dose used over many years in renal patients). Consider adverse effects a genuine concern if renal issues presence

Dosing:
- Start 6.5mg/kg body weight/day. Reduce maintenance dose 5mg/kg/day

19
Q

Describe the common indications, contraindicatons and side effects of boDMARDs

A

All in RA
All seronegative except tocilizumab, rituximab, anakinra, abatacept.

Contraindications:
Current infections (TB, hepatitis, HIV)
Exposure to serious infections (hepatitis, HIV)
Malignancy (breast cancer)
Multiple Sclerosis
HF

SEs:
Infections
Rash, itch
Headache
Auto-Ab
Psoriasis, eczema
Blood dyscrasia
Malignancies
Demyelination
Interstitial lung disease
Vasculitis
HF

Note: rituximab requires Ig monotrong, certolizumab-pegol is safe for pregnancy, and tocilizumab needs monitoring of LFT, FBC, WCC

Pharmacology Year 2 (16 decks)

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