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Clinical Pharmacology > 8.2 Immunosuppressants > Flashcards

8.2 Immunosuppressants Flashcards

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1
Q

Give some examples of diseases that rheumatologists manage?

A 
inflammatory arthritis (RA)
systemic lupus erythematosus
systemic vasculitis (giant cell arthritis)
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2
Q

what is rheumatoid arthritis?

A 
An autoimmune multi-system disease. Initially localized to synovium. Inflammatory change and proliferation
of synovium (pannus) leading to dissolution of cartilage and bone
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3
Q

what is the inflammatory pannus?

A

aggregation of the inflammatory cells causing the inflammation at the level of the joint. Multiple joints can be affected. Leads to proliferation of inflammatory cells and cytokines. Can lead to erosion of the joint due to dissolution

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4
Q

what is the pathophysiology of rheumatoid arthritis?

A 
Synovitis forms a pannus that releases enzymes causing destruction of cartilage bone and ligaments. Occus in 3 stages. 
1. initiation phase (due to non-specific inflammation). Factors allowing an abnormal immune response, once initiated, become permanent and chronic. These factors are genetic disorders which change regulation of the adaptive immune response.
2. amplification phase (due to T cell activation). Plasma cells derived from B lymphocytes produce rheumatoid factors and ACPA of the IgG and IgM classes. These activate macrophages.
This contributes to local inflammation in a joint, specifically the synovium with edema, vasodilation and entry of activated T-cells. Synovial macrophages and dendritic cells function as antigen-presenting cells by expressing MHC class II molecules, which establishes the immune reaction in the tissue.
3. chronic inflammatory phase, with tissue injury resulting from the cytokines, IL–1, TNF-alpha, and IL–6. Cytokines and chemokines attract and accumulate immune cells, i.e. activated T- and B cells, monocytes and macrophages from activated fibroblast-like synoviocytes, in the joint space.
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5
Q

how does the ratio of proinflammatory factors and antiinflammatory factors vary in a person with RA compared to a person without?

A

Greater ratio of pro-inflammatory factors ( IL-1, IL-6, TNF alpha) to anti-inflammatory factors ( Il-4, TGF beta )

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6
Q

what are metalloproteinases?

A

a catalytic protease enzyme responsible for the erosions in rheumatoid arthritis

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7
Q

what are the clinical criteria used in the diagnosis of RA

A 
Morning stiffness greater than 1 hour 
Arthritis of greater than 3 joints 
Arthritis of hand joints
Symmetrical arthritis
Rheumatoid nodules
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8
Q

what are the non-clinical criteria used in the diagnosis of RA?

A

blood test showing serum rheumatoid factor and anti-CCP antibodies
X ray changes (erosions at the joint)

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9
Q

what are the treatment goals in RA?

A

symptomatic relief

prevention of joint destruction ( cannot reverse previous erosions, just slow progression)

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10
Q

what are the signs and symptoms of systemic lupus erythematosus

A 
mallor rash 
ulcers 
sjogren's syndrome 
GI upset 
extreme fatigue 
arthralgia/myalgia/arthritis/myositis
raynauds 
alopecia
anaemia and other blood abnormalities 
pregnancy complications. 
oedema
hypertension
renal failure
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11
Q

what is a mallor rash?

A

characteristic form of facial rash. It is often seen in lupus erythematosus. butterfly shaped with sparing of the nasolabial folds. Very photosensitive rash

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12
Q

what is vasculitis?

A

Vasculitis is an autoimmune disease that causes inflammation and narrowing of blood vessels (arteries, veins and capillaries).

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13
Q

what are the signs and symptoms of vasculitis

A

general symptoms - Fever, Headache, Fatigue, Weight loss, General aches and pains
GI - Dyspepsia, Ulcers and perforations.
Ears - Dizziness, ringing in the ears and abrupt hearing loss may occur.
Eyes - Giant cell arteritis can cause double vision and temporary or permanent blindness in one or both eyes.
peripheries - Numbness or weakness. The palms of the hands and soles of the feet might swell or harden.
Lungs - SoB, haemoptysis
Skin - Bleeding under the skin can show up as red spots. Vasculitis can also cause lumps or open sores on your skin.

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14
Q

what are the treatment goals of LSE and vasculitis?

A
  • Symptomatic relief e.g arthralgia, Raynaud’s phenomenon
  • Reduction in mortality
  • Prevention of organ damage • Reduction in long term morbidity caused by disease and by drugs
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15
Q

what is the mechanism of action of corticosteroids?

A

To prevent IL-1 and IL-6 production by macrophages. Il-6 produces CRP which stimulates inflammation
Corticosteroids inhibit all stages of T-cell activation

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16
Q

give some examples of non biologics disease modifying anti-rheumatic drugs

A

sulphasalazine - used in autoimmune GI conditions (crohns)

hydrochloroquine - used in SLE

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17
Q

give some examples of biologic disease modifying anti-rheumatic drugs?

A

Anti-TNF agents
Rituximab
IL-6 inhibitors, JAK inhibitors

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18
Q

what are the indications of azathioprine?

A

SLE and vasculitis as maintenance therapy
RA
inflammatory bowel disease
(steroid sparing drug)

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19
Q

what are the ADRs of azathioprine?

A 
atopic dermatitis
bullous skin disease 
bone marrow suppression - monitor FBC
increase risk of malignancy (all immunosuppressants)
increased risk of infection
hepatitis - monitor LFT
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20
Q

why is azathioprine described as a steroid sparing drug?

A

as long term azathioprine can be used instead of long term corticosteroids and has less burden of treatment associated with their use.

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21
Q

what are some of the ADRs associated with long term steroid use?

A
  • increased appetite – potentially leading to weight gain acne
  • thinned skin that bruises easily
  • increased risk of infections
  • mood changes, mood swings and depression
  • diabetes
  • high blood pressure
  • osteoporosis (weak and brittle bones)
  • withdrawal symptoms caused by suppression of the adrenal glands
  • glaucoma
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22
Q

what test must a patient have before being prescribed azathioprine?

A

TPMT activity test.
azathioprine is metabolised to the active metabolite 6-MP.
6-MP is metabolised by thiopurine methyltransferase (TPMT)
TPMT gene is highly polymorphic and therefore individuals can vary markedly in the activity of TPMT
In individuals with low activity of TPMT there is an increased risk of myelosuppression

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23
Q

what is the mechanism of action of azathioprine?

A

Azathioprine is metabolised to 6-MP
6-MP is metabolised to TIMP.
anti-metabolite decreases DNA and RNA synthesis

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24
Q

what drug class are cyclosporin and tacrolimus?

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A

calcineurin inhibitors (immunosuppressants)

25
what are the indications of cyclosporin and tacrolimus?
widely used in transplantation atopic dermatitis psoriasis
26
what are the ADRs of cyclosporin?
renal toxicity - need to check BP and eGFR regularly
27
give some examples of CYP P450 inducers?
rifampicin carbemazepine phenytoin omeprazole
28
give some examples of CYP P450 inhibitors?
``` ciprofloxacin many antifungals fluoxetine paroxetine HIV antivirals (indinavir) ```
29
what is the mechanism of action of cyclosporin and tacrolimus
- Active against helper T-cells, preventing production of IL-2 via calcineurin inhibition - Ciclosporin binds to cyclophilin protein - Tacrolimus binds to tacrolimus-binding protein - Drug/protein complexes bind calcineurin - Calcineurin exerts phosphatase activity of activated T-cells then nuclear factor migration starts IL-2 transcription
30
what are the indications of mycophenolate mofetil?
transplantation - may monitor mycophenolic acid | induction and maintenance therapy in the treatment of lupus nephritis and vasculitis
31
what is the mechanism of action of mycophenolate mofetil?
Inhibits inosine monophosphate dehydrogenase (required for guanosine synthesis) Impairs B- and T-cell proliferation Spares other rapidly dividing cells (due to guanosine salvage pathways in other cells) Is a prodrug
32
what are the ADRs of mycophenolate mofetil?
nausea, vomiting, diarrhoea mucositis myelosuppression
33
what are the indications of cyclophosphamide?
effective in inducing remission in many autoimmune conditions – Lymphoma, leukaemia, solid cancers – Lupus nephritis – Wegener’s granulomatosis (ANCA-vasculitis)
34
what is the mechanism of action of cyclophosphamide?
Alkylating agent -cross links DNA so that it cannot replicate Many immunological effects: – suppresses T cell activity – suppresses B cell activity
35
what are the pharmacokinetics of cyclophosphamide?
Cyclophosphamide is excreted by the kidney so require good renal function
36
what is haemorrhagic cystitis?
inflammation of the urinary bladder that results in bleeding. An ADR of cyclophosphamide
37
how does cyclophosphamide cause haemorrhagic cystitis?
Acrolein, a metabolite of cyclophosphamide is toxic to the bladder epithelium and can lead to hemorrhagic cystitis
38
how is haemorrhagic cystitis prevented in cyclophosphamide use?
aggressive hydration and/or Mesna
39
what are the important considerations when prescribing cyclophosphamide?
• Mycophenolate mofetil safer and as effective in lupus nephritis • Significant toxicity – increased risk of bladder cancer, lymphoma and leukaemia – Infertility: Risk relates to cumulative dose and patient age – monitor FBC – Adjust dose in renal impairment
40
what drugs may be co-prescribed with cyclophosphamide to reduce the occurrence of ADRs?
Mesna - reduces risk of haemorrhagic cystitis | Gonadotropin receptor antagonist - give to women to protect eggs and prevent infertility
41
what are the indications of methotrexate?
rheumatoid arthritis malignancy psoriasis crohn's disease Unlicensed roles: Inflammatory myopathies, vasculitis, steroid-sparing agent in asthma abortifacient in ectopic pregnancy - double dose
42
what are myopathies?
Myopathies are diseases of skeletal muscle which are not caused by nerve disorders. These diseases cause the skeletal or voluntary muscles to become weak or wasted.
43
what is the mechanism of action of methotrexate with cancer treatment?
• Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR) • The affinity of methotrexate for DHFR is 1000X that of folate for DHFR. • Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis • Methotrexate therefore inhibits the production of tetrahydrofolate and inhibits the synthesis of DNA, RNA and proteins • Methotrexate acts during DNA and RNA synthesis hence cytotoxic during S-phase of the cell cycle. Greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
44
what drugs must be prescribed alongside methotrexate?
contraceptive for women of childbearing age | folic acid supplementation - helps prevent mucositis and myelosuppression
45
what are the pharmacokinetics of methotrexate?
* Administered PO, IM or S/C • In patients taking PO with partial response or with nausea then swap to s/c * WEEKLY NOT DAILY DOSING, metabolites have long half lives * 50% protein bound -NSAIDs displace * Renal excretion
46
what are the benefits of treatment with methotrexate?
``` gold standard for treatment of RA well tolerated 50% of patients continue the drug for >5 years, longer than any other DMARD Improved QOL Slows development of joint damage Anchor drug for DMARD combinations ```
47
what are the ADRs associated with methotrexate?
* mucositis * marrow suppression/ myelosuppression * Highly teratogenic, abortifacient * hepatitis, cirrhosis, * pneumonitis * infection risk
48
what is the mechanism of action of sulfasalazine
T-cell - inhibition of proliferation, possible T cell apoptosis, inhibition of IL-2 production Neutrophil - reduced chemotaxis and reduced degranulation so cannot release cytokines and produce inflammation
49
what is sulfasalazine?
A conjugate of a salicylate (5aminosalicylic acid, 5ASA) | and a sulfapyridine molecule
50
what are the indications of sulfasalazine?
crohns disease - sulfasalazine is poorly absorbed and therefore its main activity is within the intestine so good for inflammatory bowel diseases
51
what are the ADRs of sulfasalazine?
``` • Mainly due to sulfapyridine moiety – myelosuppression – hepatitis – Rash • Milder side effects – nausea – abdo pain/vomiting ```
52
why is sulfasalazine more preferable than other immunosuppressants?
* Long term blood monitoring not always needed * Very few drug interactions * No carcinogenic potential • Safe in pregnancy
53
what are biologicals?
* Extracted from living systems e.g. whole blood + blood components, stem cell therapy * Recombinant DNA technology producing substances that are (nearly) identical to the body's own key signalling proteins e.g. growth hormone, erythropoietin * Monoclonal antibodies “custom-designed“ made specifically to block any given substance in the body, or to target any specific cell type * Receptor constructs (fusion proteins), usually based on a naturally- occurring receptor, acting to block it
54
what are the effects of blocking TNF-alpha?
``` Decrease Inflammation - decrease Cytokine cascade - decrease Recruitment of leukocytes to joint. Prevents elaboration of adhesion molecules and production of chemokines Decrease Angiogenesis - decrease VEGF levels Decrease Joint destruction - decrease MMPs and other destructive enzymes - decrease Bone resorption and erosion - decrease Cartilage breakdown ```
55
give a common indication for anti-TNF therapy
to treat latent TB - as identified by the quantiferon test. TNF-alpha is essential for development and maintenance of granulomata. TNF-alpha is released by macrophages in response to mycobacterium Tb infection
56
what drug class is rituximab?
monoclonal antibody
57
what is the indication of rituximab?
RA
58
what is the mechanism of action of rituximab?
binds specifically to a unique cell- surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type Rituximab causes B cell apoptosis
59
what is the function of B cells?
present antigen to T cells produce cytokines | produce antibodies

Clinical Pharmacology (26 decks)

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