2 Overview of DMARDs Flashcards by Cindy Liu

What is an auto-immune disease?

Immune system produces inappropriate response against own cells resulting in
inflammation and damage

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What is a potential cause of auto-immune diseases

Environmental trigger in genetically susceptible individuals (SNPs in important
immune regulating process genes)

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What are main drug targets to INHIBIT for treatment of RA

Cytokines
Pro-inflammatory signalling
COX-2
Antigen presentation
T-cell activation

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What is a drug target to STIMULATE for the treatment of RA

CTLA4

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What are drug targets to destroy for RA treatment (2)

Rapidly proliferating cells (T)
Adaptive cells (T and B)

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What are some symptomatic treatments of RA (3)

Non-pharmacological
Analgesics
Anti-inflammatory drugs (non-steroidal, corticosteroids)

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When are DMARDs started

Early in combination with NSAIDs or GC

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What is the effect of DMARDs

Delayed efficacy on symptoms

Long term outcome improvement by slowing disease progression

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What are some synthetic DMARDs (4)

Methotrexate and Leflunomide (anti-metabolites)
Hydroxychloroquine
Sulfasalazine

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What are some biological DMARDs (4)

TNF-a inhibitors
IL-6 inhibigots
Rituximab
Abatacept

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What is methotrexate

Analogue of folic acid (Vitamin B9)

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What is the drug target of methotrexate

DIhydrofolate reductase)

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What are the pharmacokinetics of methotrexate (4)

Given orally
Lower doses compared to cancer
Long half life in RBC
Renally eliminated

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What does methotrexate form in RBC and WBCs

Polyglutamate derivatives

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What is the MOA for methotrexate (3)

Inhibits the synthesis of thymidylate and purine nucleotides
Essential for DNA synthesis and cell proliferation
Lymphocytes are highly susceptible

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What is the toxicity of methotrexate (5)

1) Bone marrow suppression = higher risk of infections
2) Liver accumulation -= hepatotoxicity
3) Mouth Ulcers
4) Nausea
5) Pneumonitis (particularly year 1, elderly and diabetic high risk)

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What is the drug target of leflunomide

Dihydroorotate dehydrogenase

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What is the MOA of leflunomide (2)

Inhibits de novo pyrimidine synthesis

Essential for DNA/RNA synthesis, cellular proliferation

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What are the pharmacokinetics of leflunomide (3)

Converted to teriflunomide
Protein binding > 99%
Metabolism by gut/liver 14 day half-life

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Is leflunomide a pro-drug

Yes

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What are some toxicities for leflunomide (6)

Gastro-intestinal 
Skin rash, alopecia
Minor infections
Liver function abnormality
Peripheral neuropathy
Pneumonitis

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What is the drug target of sulfasalazine?

Unknown

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What is the in vivo MOA of sulfasalazine

Unkonwn

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What are some in vitro MOAs of sulfasalazine

Inhibit various inflammatory mediators
Inhibit nuclear factor kappa B activation
Reduce synthesis of inflammatory mediators (IL-2, IL-1, chemookine)

What are the pharmacokinetics of sulfasalazine (2)

Converted to 5-aminosalicylic acid | Poor bioavailability, surprisingly works in joints

Is sulfasalazine a pro-drug

Yes

What are some toxicities of sulfasalazine (7)

``` GI rash headache dizziness depression reversible infertility in males thrombocytopenia ```

What is the drug target of hydroxychloroquine

Lysosomes

What is the MOA of hydroxychloroquine

Increased intracellular lysosome pH Diminished lysosome enzyme processing of immune signalling proteins Inhibits TLR9 signalling in dendritic cells, peptide loading for MHC Prevents activation of innate immune cells, stops presentation to lymphocytes

What are the pharmacokinetics of hydroxychloroquine (3)

Orally administered Long half life > 40 d Renal excretion

What are the toxicities of hydroxychloroquine

Corneal deposits Retinal toxicity (dose and time dependent) GIT

2 main MOA of conventional DMARTs

Inhibition of RNA synthesis and cellular proliferation | Inhibition of intracellular signalling in immune cells

What is a missing target for effective RA treatment

Signalling mediators

What are some biological DMARDs

Infliximab Tocilizumab Rituximab Abatacept

What are antibodies

Large MW proteins

How are antibodies delivered

SC injection into interstitial space of hypodermis

What are the pharmacokinetics of antibodies

Slow absorption into the systemic circulation Transport via lymphatics Long half-life of days

How are antibodies broken down

``` Degradation by proteolysis Fcy receptor-mediated clearance Target-mediated clearance Non-specific endocytosis Formulation of immune-complexes (ICs) Complement- or Fc receptor-mediated clearance mechanisms ```

How are antibodies eliminated

Smaller peptides excreted in urine <30kDa

What are some TNF-a inhibitors

``` › Etanercept (Enbrel) › Infliximab (Remicade) › Adalimumab (Humira) › Certolizumab (Cimzia) › Golimumab (Simponi) ```

What is the MOA of TNF-a inhibitors

Reduced NKFB signalling | Diagram

What is the drug target of TNF inhibitors

Extracellular TNF or TNFR or membrane-bound TNF

What are the pharmacokinetics of TNF inhibitors

Large molecules, not orally bioavailable | Infliximab given via IV injection, all others via SC

What are toxicities of TNF inhibitors

Injection site reactions common Infections - especially opportunistic bacteria and fungi Recurrence of latent infections (TB and HBV) Increased risk of malignancy Demylinating disease and Congestive heart failure

Drug target of tocilizumab (IL-6)

IL-6 receptor

What is the MOA of tocilizumab (4)

Binds to IL-6 receptor Blocks IL-6 from binding at the cell surface receptor Prevents JAK-STAT3 intracellular signalling Reduces cellular survival and proliferation

What are the pharmacokinetics of tocilizumab

IV administration | Long half-life

What are some toxicities of tocilizumab (4)

Abnormal liver function Neutropenia (increased risk of infection, including cellulitis) Increased cholesterol (both HDL and LDL) Increased risk of GI perforation

What is the drug target of rituximab

CD20 on B-cells

What is the MOA of rituximab

Binds to CD20 on B-cells | ADCC - cell death

What are the pharmacokinetics of rituximab

IV, stat, fortnightly then 6 monthly | Long half-life

What are some toxicities of rituximab (6)

``` Headache Fever Chills Stomach pain Nausea Diarrhoea ```

What happens at the end of immune response

CTLA4 upregulation on T-cells

What happens after CTLA4 upregulation

CTLA4 binds to CD80/CD86

What does abatacept bind to as a CTLA4 agonistic antibody

CD80/CD86

What is the MOA of abatacept

Inhibits CD80/86 on APC preventing activation and proliferation of T-cells Inhibits T-cell mediated cytokine release

What are the pharmacokinetics of CTLA4 inhibitors

SC (weekly) IV (monthly) 13d half-life

What are some toxicities or abatacept

Hypersensitivity | Respiratory function worsening in COPD and headache

What are the 3 main MOA for biological DMARDs

Ligand blockade Receptor blockade Depletion