Module 3.2.1 (Pharmacology of Drugs used in SLE) Flashcards
What treatments to use for MILD SLE disease?
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
What is used for suppression of autoimmune diorders such as systemic lupus erythematosus (SLE)?
Corticosteroids
What is the MOA of corticosteroids (immunological)?
- 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)
What is the MOA of corticosteroids (inflammation)?
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
What are some other MOA of corticosteroids? How does being lipophilic effect treatment for SLE?
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
What is the effect of too much corticosteroid in the body?
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
What do corticosteroids do to increase glucose concentration in the body?
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
What are the effects of corticosteroids on fat metabolism?
- 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
What are the effects of corticosteroids on vasculature?
- Decreases permeability of vascular endothelium –> reduces fluid exudation
- enhances adrenergic vasoconstrictive ability –> decreases vasodilation –> hypertension
What are the effects of corticosteroids on the CNS?
- Hippocampus type 1 receptor
- Modulates perceptual & emotional function
- Awakening
> Euphoria/ depression
> Restlessness
> Insomnia
What are the effects of corticosteroids on bone?
Decrease bone formation
- decreases synthesis 1,25 hydroxy-vitamin D3
- decrease calcium absorption
- increase urinary calcium
leads to osteoporosis
Properties of hydrocortisone
- 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
Properties of methylprednisolone
- Still has some mineralocorticoid activity
- Plasma T ½ = 90 min
> yet action initiates 4-6 h
- T ½ = 120 min (methylpred)
Properties of dexa/beta methasone
- Very little mineralocorticoid activity
- Most potent of the orally available forms
- The fluoride increases potency
- T ½ = 190 min (dexameth)
What are examples of glucocorticoids? When is high dose required? What is used for subsidiary use?
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
Is methotrexate used for SLE?
Yes, used in many autoimmune disorders
- Usual dose 7.5 to 15 mg once a week
What is the MOA of azathioprine (cytotoxic drugs)? Where is it metabolised?
- 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
How is azathioprine metabolised? What drugs therefore cant be used with it or the dose has to be lowered?
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
Why can’t 5-ASA drugs (sulfasalazine, mesalazine, etc) be used with azathioprine?
reduces thiopurine methyltransferase activity [TPMT]
- TPMT required to metabolise 6-mercaptopurine.
What are the adverse effects of azathioprine
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
What is the MOA of mycophenolate mofetil/sodium (cytotoxic medication)? IS it more effective than azathioprine? What is it metabolised to?
- 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
What are the adverse effects of mycophenolate mofetil/sodium?
- 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
What is the MOA of cyclophosphamide (nitrogen mustards)? When is it used?
> other nitrogen mustard ifosfamide not used for SLE
> do not breastfeed
- 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
What are the adverse effects of cyclophosphamide (nitrogen mustards)? How to prevent haemorrhagic cystitis?
- 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.
Properties of belimumab (monoclonal antibody)? MOA and what drugs it can be used with?
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
What are the adverse effects of belimumab?
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
Properties of rituximab (monoclonal antibody)? MOA and what drugs it can be used with?
- 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
What are the adverse effects of rituximab?
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
