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IPT 3 Lectures > Module 3.2.1 (Pharmacology of Drugs used in SLE) > Flashcards

Module 3.2.1 (Pharmacology of Drugs used in SLE) Flashcards

1
Q

What treatments to use for MILD SLE disease?

A

Mild treatments

  • Can limit to oral NSAIDs for anti-inflammatory action
  • Can add hydroxychloroquine to oral NSAIDs for antiinflammatory action when joint and skin manifestations prominant
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2
Q

What is used for suppression of autoimmune diorders such as systemic lupus erythematosus (SLE)?

A

Corticosteroids

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3
Q

What is the MOA of corticosteroids (immunological)?

A
  • Decrease production of T & B lymphocytes, macrophages, eosinophils, monocytes & basophils
  • decrease in IL-1 though 6, IL-8, TNF-γ,cell adhesion factors, GM-CSF
  • Inhibit complement system
  • Less blood removal (increased neutrophil release), therefore susceptible to infection and reactivation of latent infections (herpes, TB)
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4
Q

What is the MOA of corticosteroids (inflammation)?

A

Induces Annexin-1

  • inhibits Phospholipase A2 –> decreased prostaglandins, thromboxanes, leukotrienes

Blocks recruitment of neutrophils

  • decrease transcription of genes for cell adhesion factors

Decrease fibroblast function

Decrease gene expression COX2, NOS2, TNF-α, IL-1 etc

Increase gene expression anti-inflam factors = IL-10, etc

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5
Q

What are some other MOA of corticosteroids? How does being lipophilic effect treatment for SLE?

A

Also inhibit other transcription factors

  • AP-1 & NF-kB
  • NOS2, COX2, pro-opiomelanocortin gene

Being lipophilic

  • enter target cells by diffusion
  • plasma transport mainly protein-bound
  • endogenous (hydrocortisone) on corticosteroid-binding globulin (CBG)
  • delayed response –< takes time to work for SLE
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6
Q

What is the effect of too much corticosteroid in the body?

A

Cushings syndrome

  • Hypertension
  • Possible hyperglycaemia
  • Thinning of skin
  • Easy bruising
  • Poor wound healing #
  • Abdominal fat
  • Osteoporosis
  • -ve nitrogen balance –> increased appetite, increased infection susceptibility
  • Thin arms & legs
  • Muscle wasting
  • Moon face red (plethoric) cheeks
  • Benign intracranial hypertension
  • Cataracts
  • Mood swings
  • Buffalo hump
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7
Q

What do corticosteroids do to increase glucose concentration in the body?

A

Protein degradation –> protein is taken from the muscle –> protein and fat go to liver for gluconeogenesis

  • Long term = decreased collagen, thin skin, visible capillaries and bruising

> decreased glucose uptake to muscle, adipose tissue

> blocks effect of insulin on hepatic glucose output

> increase glycogen in liver

> could develop diabetes mellitus

> induce transcription of liver enzymes (gluconeogenesis)

  • PEPC-Kinase
  • G-6-Pase & Fructose-2,6-diphosphatase
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8
Q

What are the effects of corticosteroids on fat metabolism?

A
  • Increase appetite
  • Increases mobilisation from some reserves (steroid sensitive stores in limbs)
  • Free fatty acids then accumulate in stores that are more resistant to glucocorticoids –> face, trunk of neck, abdomen
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9
Q

What are the effects of corticosteroids on vasculature?

A
  • Decreases permeability of vascular endothelium –> reduces fluid exudation
  • enhances adrenergic vasoconstrictive ability –> decreases vasodilation –> hypertension
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10
Q

What are the effects of corticosteroids on the CNS?

A
  • Hippocampus type 1 receptor
  • Modulates perceptual & emotional function
  • Awakening

> Euphoria/ depression

> Restlessness

> Insomnia

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11
Q

What are the effects of corticosteroids on bone?

A

Decrease bone formation

  • decreases synthesis 1,25 hydroxy-vitamin D3
  • decrease calcium absorption
  • increase urinary calcium

leads to osteoporosis

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12
Q

Properties of hydrocortisone

A
  • Inactive until converted to Hydrocortisone in the liver

> in hepatic disease do not use prodrugs

  • Still has some mineralocorticoid activity
  • Plasma T ½ = 90 min ! yet action initiates 4-6 h
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13
Q

Properties of methylprednisolone

A
  • Still has some mineralocorticoid activity
  • Plasma T ½ = 90 min

> yet action initiates 4-6 h

  • T ½ = 120 min (methylpred)
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14
Q

Properties of dexa/beta methasone

A
  • Very little mineralocorticoid activity
  • Most potent of the orally available forms
  • The fluoride increases potency
  • T ½ = 190 min (dexameth)
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15
Q

What are examples of glucocorticoids? When is high dose required? What is used for subsidiary use?

A

Prednisone, methylprednisolone & Prednisolone

  • High dose at transplantation and acute rejection episodes (500-1000mg/d)
  • Subsidiary use –> minimise allergenic reactions occurring through antilymphocytic globulin or monoclonal antibody use
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16
Q

Is methotrexate used for SLE?

A

Yes, used in many autoimmune disorders

  • Usual dose 7.5 to 15 mg once a week
17
Q

What is the MOA of azathioprine (cytotoxic drugs)? Where is it metabolised?

A
  • Prevent clonal expansion of T & B lymphocytes
  • Purine antimetabolite
  • Metabolised in Erythrocytes and liver to active 6-mercaptopurine then enters cells & metabolised to 6-thioguanine & 6-thioinosinic acid
  • Substrate for HGPRT –> generate fraudulent purine nucleotides

multiple mechanisms:

> inhibition of de novo purines

> disrupts membrane glycoprotein synthesis

> Incorporation of false purines in DNA –> causes mitosis to fail

18
Q

How is azathioprine metabolised? What drugs therefore cant be used with it or the dose has to be lowered?

A

Metabolised by xanthine oxidase –> (6-thioinosinic acid to thiouric acid (inactive))

  • Therefore no allopurinol/febuxostat while on azathioprine
  • or cut azathioprine to 25% of normal dose
19
Q

Why can’t 5-ASA drugs (sulfasalazine, mesalazine, etc) be used with azathioprine?

A

reduces thiopurine methyltransferase activity [TPMT]

  • TPMT required to metabolise 6-mercaptopurine.
20
Q

What are the adverse effects of azathioprine

A

Common

  • GI tract disorders, nausea, vomiting, mouth ulcers, diarrhoea, pancreatitis, hepatotoxicity
  • Loss of hair (alopecia) - reversible

Uncommon

  • Bone marrow suppression –> Leucopenia +Thrombocytopenia + Anaemia (dose-limiting effect)
  • Increased infections
  • Cancers – lymphomas, skin
21
Q

What is the MOA of mycophenolate mofetil/sodium (cytotoxic medication)? IS it more effective than azathioprine? What is it metabolised to?

A
  • Uncompetitively and reversibly inhibits IMPDH

> blocks de novo purine synth only (not salvage)

  • depletes lymphocytes and monocytes (1 to 10 µM)

active form: Mycophenolic acid (MPA): active-18h ½ life

More effective than azathioprine – more cell specificity

> MPA metabolised to inactive glucuronides – renal excretion

22
Q

What are the adverse effects of mycophenolate mofetil/sodium?

A
  • 10% of patients experience increased infections
  • Angina pectoris – atrial fibrillation
  • Cancers – lymphomas, skin

Common

  • GI tract bleeding, nausea, vomiting (take with food to lessen), mouth ulcers, diarrhoea (36%), hepatotoxicity, fatigue
  • Hypertension, headache
  • Blood disorders – neutropenia, thrombocytopenia, anaemia, leucopenia
23
Q

What is the MOA of cyclophosphamide (nitrogen mustards)? When is it used?

> other nitrogen mustard ifosfamide not used for SLE

> do not breastfeed

A
  • Alkylates DNA
  • B cells recover slowly from this insult
  • Bi-functional = mutagenic and cytogenic
  • Mostly for Autoimmune disorders, or Bone marrow transplants
  • When azathioprine not tolerated
  • Many CYPs -mainly CYP2B activated1, CYP3A4 activated
  • Oral or IV
  • T ½ = 4 hours (parent) serum metabolites detected for 72 hours
  • Crosses BBB
24
Q

What are the adverse effects of cyclophosphamide (nitrogen mustards)? How to prevent haemorrhagic cystitis?

A
  • Alopecia, sterility, leukaemia, nephrotoxicity, anorexia
  • Early menopause, increased bladder cancer risk
  • Metallic (or loss of) taste, dark skin & nails
  • Myelosuppression

Prevent hemorrhagic cystitis (acrolein metabolite) –> drink lots of water/fluid to prevent HC. Give MESNA which binds to acrolein and prevents HC.

25
Q

Properties of belimumab (monoclonal antibody)? MOA and what drugs it can be used with?

A

Specifically for SLE

  • Targets B-lymphocyte stimulator protein (BAFF)
  • IV infusion 10mg/kg 2 weekly, then 4 weekl
  • Do not use with other monoclonals eg anti-CD20 or cytotoxics
  • OK to use with azathioprine,methotrexate ,NSAIDs,cortico’s ,hydroxychloroquine
26
Q

What are the adverse effects of belimumab?

A

Hypersensitivity responses

  • Angioedema, dyspnoea, rash, urticaria, fever, bradycardia, hypotension, nausea, headache, myalgia
  • Use of antihistamine and paracetamol may limit the effects above

Increased infection risk

  • Leucopenia

Depression and anxiety

27
Q

Properties of rituximab (monoclonal antibody)? MOA and what drugs it can be used with?

A
  • More for RA and cancers with overexpressed CD20 (non-hodgkin’s lymphoma). Used for SLE recently many countries (off-label)
  • IgG1 targets B-lymphocyte CD20
  • As off label – doses unclear for IV infusion
  • Depletes functioning B-cells from circulation
  • Do not use with other monoclonals eg anti-BAFF or cytotoxics
  • OK to use with azathioprine,methotrexate ,NSAIDs,cortico’s ,hydroxychloroquine
28
Q

What are the adverse effects of rituximab?

A

Hypersensitivity responses

  • Angioedema, dyspnoea, rash, urticaria, fever, chills, bradycardia, hypotension, nausea, headache, myalgia
  • Use of antihistamine and paracetamol may limit the effects above

Increased infection risk

  • Neutropenia, lymphopenia

Arrhythmias

IPT 3 Lectures (26 decks)

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