Lecture 17- Therapeutics (Biologics) Flashcards
What drugs are used as symptoms relief for auto-immune disease?
-Anti-inflammatory drugs: NSAID- Aspirin, ibuprofen and diclofenac
-COX-2 inhibitors: celecoxib
-Steroids:
-Prednisolone etc
#short term use
#IM, injected into the inflamed joint
#slow down progression, preventing further damage to joints
#Long term use should be avoided
Describe the mechanism of action methotrexate?
- Antimetabolite (folate analogue), inhibits cell proliferation
- Increases adenosine level (anti-inflammatory)
- Reduces the production of damaging polyamines
- Induces apoptosis of activated CD4+ and CD8+ T-cells
what is the standard dose for the methotrexate and what is the advantage of this dose range?
- 7.5mg to 25mg weekly Po or SC
- no significant anti-cancer or immunosuppressive effect
what is the advantage of taking methotrexate for RA?
- Reduces inflammation quickly and keeps it under tight control
- Reduces the risk of death from cardiovascular disease in people with RA
- Taking supplements of folic acid reduces side-effects caused by folic acid depletion
Name other synthetic DMARDs, mechanism of action and conditions they are mainly used for?
1) Sulfasalazine (SSZ) – 2-component drug
Sulfapyridine (antibiotic) + 5-amino salicylic acid (anti-inflammatory)
Also used in ulcerative colitis
2) Hydroxychloroquine (HCQ) – antimalarial drug
Used in combination with other DMARDs
A possible mechanism of action: increases lysosomal pH in (immune) cells
Also used for the treatment of SLE
3) Leflunomide – lymphocyte inhibitor
Inhibits de novo pyrimidine synthesis
Most effective in reducing B-cell populations (but significant effect on T-cells too)
what is the purpose of using DMARDs combination therapy in treating RA?
- Combinations of DMARDs – more effective in treating early active RA than the use of single drugs
- Helpful when not possible to use biologic drugs e.g. in patients with recent cancer or chronic infection
- Well tolerated, with no more side effects than the single drug
What is known as the anchor drug for the RA?
Methotrexate- acnchor drug to which other drugs should routinely be added
What is the most effective DMARD therapy and what other treatment should be considered for RA?
- Triple combination of TX + SSZ + HCQ most effective
- Uses steroids in some form
What is the minimum treatment period before required to achieve symptoms control?
8-12 weeks treatment required to achieve improvement of symptoms
List the SE of most DMARD therapy?
- Nausea
- Loss of appetite
- Diarrhoea
- Rash, allergic reactions
- Headache
- Hair loss
- Risk of infections (pneumonia)
- Hepatotoxicity (metabolism)
- Kidney toxicity (route of elimination)
What additional SE that we need to be aware for hydroxychloroquine and leflunoamide?
Hydroxychloroquine – accumulation of the drug in the eye (retinopthay)
Leflunomid – hypertension
what plays the central role in the inflammatory process in RA?
TNF
What are the targets of biologics in RA?
IL-1 IL-6 T cells B cells TNF
Name the TNF blockers?
- infliximab,
- etanercept,
- adalimumab
- golimumab,
- certolizumab pegol
Name the monoclonal antibody against B cells?
Rituximab
Name the T cell co-stimulation inhibitor?
Abatacept
Name the monoclonal antibody against IL-6R?
Tocilizumab
Name the class infliximab belongs to?
partially humanized mouse monoclonal anti-hTNF-a antibody
Name the class etanercept belongs to?
soluble TNF receptor dimer
Name the class adalimumab and golimumab belong to?
human IgG1 monoclonal anti-TNF-a antibody
Name the class Certolizumab pegol belong to?
PEGylated anti-TNF-a monoclonal antibody fragment
Describe the mechanism of action of infliximab?
Neutralizes free, membrane and receptor-bound TNF-a → antibody-dependent cell-mediated cytotoxicity (ADCC)
What other conditions is the infliximab used for?
-Used for the treatment of Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis
How is the infliximab adminstered?
- IV infusion 3mg kg of bodyweight
- repeated every 2 weeks and 6 weeks after the first infusion then every 8 weeks
Describe the mechanism of action of Etanercept?
- Soluble TNF receptor dimer
- Binds free and membrane-bound TNF reducing the accessible TNF in RA → ADCC
What other conditions etanercept is used for?
-used for the treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis
Describe what certolizumab is?
PEGylated Fab’ fragment of humanized anti-TNF-a mAb – no Fc portion
What is certolizumab used for?
Crohn’s disease
What are the consideration for the anti TNF therapy?
Screenied for: tuberculosis (TB), multiple sclerosis, recurrent infection, leg ulcers, heart failure and a past history of cancer
- Live vaccination: against yellow fever, live polio should be avoided
- Anti-TNF therapy can be administered for as long as required
What are some of the reasons for the precluding the use of anti-TNF medications?
- an inadequate clinical response
- Lose their responsiveness over time
- Experience unacceptable side effects
- Have medical issues
Describe the mechanism of action of rituximab?
- Partially humanised anti CD20mAb
- Rituximab opsonized B-cells are attacked and killed by three mechanisms:
1)Complement mediated cytotoxicity
2-3) Antibody-dependent cell mediated cytotoxicity (ADCC) – FcgR/ CR mediated opsonic phagocytosis
4) Apoptosis
What is abatcept ?
-The T cell co-stimulation inhibitor
Describe the mechanism of action of abatcept?
- Competitive inhibitor of CD28
- Increases threshold for T-cell activation
- Suppresses the proliferation of synovial recirculating T cells
- Reduces the level of inflammatory mediators
What is Tociluzimab and what conditions is it used for?
- The IL-6 inhibitor
- Humanized anti-IL-6 receptor monoclonal antibody
- Systemic juvenile idiopathic arthiritis
What is anakinara?
Recombinant IL-1 receptor antagonist
How does the anakinara differ from the native human IL-1RA?
-Differs from native human IL-1ra: it has the addition of a single methionine residue at its amino terminus
What is the fucntion of ankinra in RA?
-Reduces bone erosion
-Decreases osteoclast production
-Blocks IL-1 induced MMP release
from synovial cells
what are the possible adverse effects of the biologic therapy?
-Increased risk of infections:
Upper respiratory tract infections (nasopharyngitis)
Pneumonia
-Urinary tract infections
- Nausea
- Headache
- Hypertension
- Allergic reactions
