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Clinical Pharmacology, Therapeutics & Intro to Prescribing > Lecture 16- Immunosuppressants > Flashcards

Lecture 16- Immunosuppressants Flashcards

1
Q

Disease rheumatologists manage

A
  • Inflammatory arthritis
    • Rheumatoid and psoriatic
  • Systemic lupus erythematosus (SLE)
  • Systemic vasculitis
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2
Q

Systemic lupus erythematosus (SLE)

A
  • Very common
  • Mimics many disease – multisystemic nature
    • Lungs
    • Heart
    • Blood
    • Skin
    • Brain etc
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3
Q

Rheumatoid arthritis

A
  • An autoimmune multi-system disease
  • Fairly common: UK prevalence 1%
  • Initially localized to synovium
  • Inflammatory change and proliferation of synovium (pannus) leading to dissolution of cartilage and bone
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4
Q

pathogenesis of RA

A

There should be a fine balance between pro-inflammatory and anti-inflammatory mediators

  • In RA overwhelming effect of pro-inflammatory arm
    • IL-1 (fever and malaise) , IL-6 (CRP production by the liver)
    • TNF-alpha etc etc
    • Metalloproteinases- bone erosion
    • T cells- cell mediated immunity
    • B cells- antibodies which direct damage
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5
Q

diagnosis of RA

A

Rheumatoid nodules seen less now as RA is picked up earlier

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6
Q

Treatment goals for RA– via immunosuppressants

A
  • Symptomatic relief
  • Prevention of joint destruction
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7
Q
A
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8
Q

treatment strategy for RA

A

Treatment strategy- drug induced and maintaining remission

  • Early use of disease-modifying drugs (DMARDs)
  • Aim to achieve good disease control
  • Use of adequate dosages
  • Use of combinations of drugs
  • Avoidance of long-term corticosteroids
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9
Q

what are disease-modifying antirheumatic drugs (DMARDs)

A

Disease-modifying antirheumatic drugs (DMARDs) are medicines that are normally prescribed as soon as rheumatoid arthritis (RA) is diagnosed, in order to reduce damage to the joints. Rarely, they can have serious side-effects affecting the blood, liver, or kidneys. DMARDS are usually taken for the rest of your life.

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10
Q

Vasculitis

A

Vasculitis means inflammation of the blood vessels. Inflammation is your immune system’s natural response to injury or infection.

  • Also multisystem e.g. lung, skin, kidney
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11
Q

Treatment goals in SLE & vasculitis – via immunosuppressants

A
  • Symptomatic relief e.g arthralgia (pain in joint), 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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12
Q

Immunosuppressants (some are DMARDs)

A

Cordi Can Make More Angel Cakes, Thanks Love

  • Corticosteroids
  • Methotrexate
  • Azathioprine
  • Ciclosporin
  • Tacrolimus
  • Mycophenolate mofetil
  • Leflunomide
  • Cyclophosphamide
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13
Q

Other disease-modifying anti-rheumatic drugs (DMARDs)

A

Non-biologics

  • Sulphasalazine
  • Hydroxychloroquine

Biologics

  • Anti-TNF agents
  • Rituximab
  • IL-6 inhibitors, JAK inhibitors
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14
Q

general MOA of corticosteroids

A
  • Prevent interleukin IL-1 and IL-6 production by macrophages
  • Inhibit all stages of T-cell activation
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15
Q

Transplantation drugs timeline

A
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16
Q

Azathioprine is an immunosuppressant used to treat

A
  • SLE
  • Vasculitis
  • Atopic dermatitis
  • Bullous skin disease
  • IBD e.g. crohns and acute UC
  • Weak evidence for RA
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17
Q

azarthiprine is known as a

A

Steroid ‘sparing’ drug

Used to wean pts off long term steroids use (steroid ADR- Cataracts, thin skin, osteoporosis, CVS effects)

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18
Q

Pharmacodynamics of azathiprine

A
  • First metabolic step that azathioprine undergoes is conversion to 6-mercaptopurine (6-MP)- an immunosuppressant prodrug
  • 6-MP is metabolised by Thiopurine S-methyltransferase (TPMT)
    • TPMT gene is highly polymorphic
    • Low/absent TPMT levels= risk of myelosuppression
    • Therefore test for TPMT activity required before prescribing
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19
Q

MOA of azathioprine

A
  1. Azathiprine is cleaved to 6-MP
  2. 6-MP is metabolised by TPMT to various molecules e.g. TIMP
  3. TIMP further metapolises to 6-MeMPN (antimetabolite)
  4. which inhibits purine synthesis
  5. DNA and RNA need purines to be made
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20
Q

Adverse drug response: Azathioprine (all immunosuppressants have these adverse effects)

A
  • Bone marrow suppression (monitor FBC)- myelosuppression
  • Increased risk of malignancy
    • Esp in transplanted pts
  • Increased risk of infections
  • Hepatitis
    • Monitor LFT
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21
Q

name 2 drugs which come under the class calcineurin inhibitors (another type of immunosuppressant)

A

: ciclosporin and tacrolimus

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22
Q

uses of calcineurin inhibitors e.g. ciclopsin and tacrolimus

A
  • Transplantation
  • Atopic dermatitis and psoriasis
  • Not often used in rheumatology
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23
Q

Mode of action of calcineurin inhibitors

A
  • Active against helper T-cells, preventing production against IL-2 via calcineurin inhibition
    • Calcineurin exerts phosphatase activity of activates T cells then nucleus factor migration to start IL-2 transcription
  • Drug/protein complexes bind calcineurin
    • Ciclosporin binds to cyclophilin protein
    • Tacrolimus binds to tacrolimus-binding protein
24
Q

Adverse drug response calcineurin inhibitors

A
  • Renal toxicity
  • Gum hypertrophy (ciclosporin)
25
Q

Contraindication calcineurin inhibitors

A

Renal problems

26
Q

Drug-drug interactions calcineurin inhibitors

A

Multiple due to cytochrome P450

27
Q

Mycophenolate mofetil comes under the class

A

immunosuppressant

28
Q

Mycophenolate mofetil uses

A
  • Primarily in transplantation
  • Good efficacy as induction and maintenance therapy for lupus nephritis/vasculitis maintenance
29
Q

Mode of action Mycophenolate mofetil

A
  • Prodrug derived from fungus penicillium stoloniferum
  • 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)
30
Q

Adverse drug response MM

*

A
  • GI: nausea, vomiting, diarrhoea
  • Myelosuppression (bone marrow failure)
31
Q

Contraindication (MM)

A

Pregnancy

32
Q

name a drug under the class alkylatong agents used to treat various cancers

A

Cyclophosphamide

33
Q

Cyclophosphamide uses

A
  • Lupus nephritis
  • Lymphoma, leukaemia, solid cancer
  • Wegener’s granulomatosis (ANCA-vasculitis)
34
Q

Pharmacodynamics of cyclophosphamide

A
  • Prodrug
  • Converted in the liver (cytochrome P450) to active forms
  • Main metabolite is 4-hydroxycyclophosphamide
    • 4-hydroxycyclophosphamide exists in equilibrium with its tautomer, aldophosphamide
    • Most of the aldophosphamide is oxidised to make carboxyphosphamide
    • Small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)
    • Carboxyphosphamide excreted in the kidneys
    • Acrolein (another metabolite of cyclophosphamide) is toxic to the bladder epithelium and can lead to haemorrhagic cystitis
      • This can be prevented through the use of aggressive hydration and/or Mesna
35
Q

Mode of action of cyclophosphamide

*

A
  • Cytotoxic agent- alkylating agent- cross links DNA so that it cannot replicate
    • Suppresses T and B cell activity
36
Q

Adverse drug response cyclophosphamide

A
  • Increased risk of bladder cancer, lymphoma and leukaemia
  • Infertility: risk relates to cumulative disease and pt age
37
Q

Contraindication cyclophosphamide

A

Adjust dose in renal impairment

38
Q

methotrexate is an

A

antimetabolite

drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis

39
Q

uses of methotrexate

A
  • Malignancy e.g. ALL
  • Gold standard treatment for early stage RA
  • Psoriasis
  • Crohn’s disease
  • Unlicenced roles: inflammatory myopathies, vasculitis, steroid sparing agent in asthma

Well tolerated, improves QOL, stops retardation of joint damage, anchor drug for DMARD combinations

40
Q

Pharmacokinetics methotrexate

A
  • Mean oral bioavailability is 33% (13-76%)
  • Mean intramuscular bioavailability is 76%
  • 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 (never dose methotrexate daily everrrr), metabolized to polyglutamates with long half lives (30hours)
  • 50% protein bound -NSAIDs displace
  • Renal excretion
41
Q

what to remember with methotrexate

A
  • WEEKLY NOT DAILY DOSING (never dose methotrexate daily everrrr), metabolized to polyglutamates with long half lives (30hours)
42
Q

methotrexate :Mode of action for cancer

A
  • Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR)
  • 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 unit in purine and thymidine synthesis- therefore anti-folate therapy
    • Therefore inhibits synthesis of DNA , RNA and proteins
  • Acts in the S phase of the cell cycle (DNA and RNA synthesis)–> greater toxic effect on rapidly dividing cells which replicate their DNA more frequently
43
Q

methotrexate :Non-malignant mode of action

A
  • Mechanisms is not via anti-folate action
  • Mechanism unclear
44
Q

Adverse drug response methotrexate

A
  • Mucositis (respond to folic acid)
  • Myelosuppression (respond to folic acid)
  • Hepatitis
  • Pneumonitis
  • Infection risk
45
Q

Contraindication methotrexate

A

Pregnancy (teratogenic and abortifacient)

46
Q

‘Biologics’- novel therapeutics

A
  • 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
47
Q

name a drug under the class anti-TNFa

A

adalimumab (humira) , infliximab

48
Q

uses of anti-TNFa

A

TNF inhibitors are drugs that help stop inflammation. They’re used to treat diseases like rheumatoid arthritis (RA), juvenile arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, ulcerative colitis (UC), and Crohn’s disease

49
Q

Mode of action TNfa

A
  • Block TNF-a, therefore redcuing
    • Inflammation and Cytokine cascade
    • Recruitment of leukocytes to joint
      • elaboration of adhesion molecules
      • production of chemokines
    • Angiogenesis and VEGF levels
    • Joint destruction, MMPs and other destructive enzymes, bone resorption and erosion
    • Decrease cartilage breakdown
50
Q

adverse drug response Anti-TNFa

A
  • TB reactivation is a risk
    • TNFa released by macrophages in response to M TB infection
    • TNFa is essential for development and maintenance of granulomata
    • Need to screen for latent TB before anti-TNF treatment
51
Q

contraindications anti-TNFa

A
  • Pregnancy
52
Q

rituximab is a

A

biologic which depletes b cells

53
Q

uses of rituximab

A
  • RA
  • Good safety data
54
Q

mode of action rituximab

A
  • Binds 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 other types
  • Causes B cell apoptosis
  • B cells
    • Present antigens to T cells
    • Produce cytokines
    • Produce antibodies
  • therefore B cell activity reduced
55
Q

Adverse drug response: rituximab

A
  • GI: nausea, vomiting, diarrhoea
  • Myelosuppression (bone marrow failure)

Clinical Pharmacology, Therapeutics & Intro to Prescribing (39 decks)

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