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19 Cards in this Set
- Front
- Back
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What is the difference between hyperacute, accelerated, acute and chronic rejection?
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Hyperacute
• Occurs rapidly within minutes (often in theatre) • Due to pre-exiting antibodies in recipient reacting against transplanted organ • Results in thrombosis or ischaemic necrosis of allograft • Current immunosuppressants do not stop this Accelerated • Occurs within first few days • Results from prior sensitisation of recipient & immunologic memory for allograft • At risk pts need more intensive immunosuppression at time of surgery Acute • Days to weeks after transplant • Correlates with chronic rejection therefore antirejection Tx usually more aggressive in first 6 months post transplant Chronic • Months or years • Manifests as thickened/blocked blood vessels in kidney/heart, fibrosis in liver/lung • Currently no effective Tx |
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What is the role of corticosteroids in transplants and what are some SE's of chronic use?
What would you counsel the patient on? |
Potent & nonspecific immunosuppressant
• Highest dose given at time of transplantation • 1st line in acute rejection • Use with other agents for 'steroid sparing' effect • Aim to taper dose - abrupt withdrawal can lead to exaggerated immune response & accelerated rejection (done over 3-6 months with monitoring) SEs of chronic use: • Glucose intolerance • Weight gain • Osteoporosis • Hypertension, hyperlipidaemia • Growth inhibition • Acne, hirsutism • Cushingoid features Counselling: • Take in morning with food to minimise insomnia & GI upset • Warn about abrupt discontinuation (acute rejection, adrenal crisis) • SEs |
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What is the role of azathioprine in transplants and what are some of its side effects?
When should it be discontinued? |
• Prodrug converted to 6-mercaptopurine
• Inhibits gene replication & T cell activation • Effective in preventing but not treating rejection SEs: • Haematological (leucopenia, thrombocytopenia, macrocytic anaemia) • Hepatitis • Cholestasis, pancreatitis (rare) Discontinue: • In severe infection • Pts with severe squamous cell skin lesions • Gout is a recognised post-transplant complication commonly treated with allopurinol which blocks metabolism of 6-MP - decrease AZA dose or change to alternative Tx before starting allopurinol |
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What is the role of mycophenolate mofetil in tranplants and what are some of its side effects?
What are some of its drug interactions and counselling points? |
Interferes with purine synthesis & blocks an enzyme responsible for T and B cell proliferation.
• Safe/effective for kidney, heart, liver and lung transplantation SEs: • GI (diarrhoea, abdo pain, N+V) • Hematological (leucopenia, anaemia, thrombocytopenia) • Opportunistic infections • Pancreatitis • Lymphomas Drug interactions: • May increase aciclovir, ganciclovir levels due to competition for renal tubular secretion • Absorption decreased by Mg + Al containing antacids & cholestyramine • Immunosuppressive activity potentiated by tacrolimus • Avoid use with AZA due to bone marrow suppression • No effect on CyA levels • Safe to use with allopurinol Counselling: • May be teratogenic |
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How do calcineurin inhibitors work?
Give some examples.. |
• Block intracellular T cell signals responsible for cytokine production
• Work by downregulating cytokine production without stopping it completely - Useful for body to still be able to combat infection Examples are cyclosporin and tacrolimus. |
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What is the difference between the two available formulations of cyclosporin (Sandimunn + Neoral)?
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NOT equivalent - don't interchange.
Sandimunn • Oral solution + gel caps • GI absorption incomplete & variable • Time to peak concentration variable • Oral absorption is bile dependent • Superceded by newer formulation Neoral • Microparticles dispersed in oils & solvents • Improved BA, less variability • Earlier peak • Reduced dependence on bile for absorption |
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What are some of cyclosporin's drug interactions?
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Cyclosporin is highly protein bound and metabolised by CYP3A4.
Interactions with: • Nephrotoxic drugs - CyA vasoconstrictive effect potentiates nephrotoxicity of other drugs • Inducers/inhibitors of CYP3A4 - Diltiazem used to get therapeutic CyA levels with lower dose |
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What are the adverse effects of cyclosporin and how would you manage it?
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Nephrotoxicity
• Functional: Reversible renal vasoconstriction • Morphological: Chronic interstitial fibrosis, thrombotic microangiopathy • Electrolyte abnormalities (hyperkalemia, hypomagnesaemia) • Conversion to tacrolimus little benefit due to similar SE profile • Attempt to lower dose & augment with other immunosuppressants e.g. MMF • Coadministration of vasodilators (e.g. diltiazem) may reverse renal vasoconstriction - standard Tx Cosmetic complications: • Hirsutism, gingival hyperplasia • Change to tacrolimus Metabolic: • Hyperlipidaemia, glucose intolerance • Compounded by steroid co-admin Neurological • Tremor, headache, seizures |
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Discuss cyclosporin dosing and TDM...
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Dosing
• May start immediately prior to surgery or a few days earlier • Keep away from plastic (IV in glass or pvc, liquid mixed in glass container) TDM necessary due to: • Complex/variable PK • Need to evaluate patient compliance • Need to differentiate b/w nephrotoxicity & renal transplant rejection |
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How does tacrolimus work and what are some of its PK properties?
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Similar to CyA but more potent in ability to inhibit IL-2
• IL-2 reduction minimises immune response assoc. with rejection Greater effect than CyA on transforming growth factor beta (implicated in chronic rejection). Used in solid organ transplantation. • Poorly, erratically & incompletely absorbed (take on empty stomach) • Highly protein bound • Highly lipophilic • Metabolised by CYP3A4 |
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What are some of the drug interactions with cyclosporin and tacrolimus?
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• CYP3A4 inhibitors and inducers
• Drugs that decrease absorption (e.g. cholestyramine, Mg/Ca antacids) • Enhanced nephrotoxicity (aminoglycosides, amphotericin, nsaids) • Increased risk of rhabdomyolysis (CyA/Tac inhibit metabolism of statins) • Don't use CyA and Tac together |
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What are some of the adverse effects with tacrolimus?
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• Nephrotoxicity
• Neurotoxicity (headache, tremor, seizures) • Increased risk of infection • Hyperkalemia • Hypomagnesaemia • GI upset • Some reports of recurrence of HepC infection following liver transplantation • Less likely than CyA to cause HT, hypercholesterolaemia • More likely than CyA to cause insulin dependent diabetes |
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Which two drugs are inhibitors of late T-cell function?
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Sirolimus and everolimus.
Structurally related to tacrolimus but different mechnism of action. |
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What is the mechanism of action of sirolimus and what is it's clinical use?
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Disrupts IL-2 receptor signalling - inhibits cytokine driven T-cell proliferation.
Initially used as a substitute for AZA: • Combination with a calcineurin inhibitor & steroids • Lower acute rejection rate at 1 yr Also evaluated as a replacement for calcineurin inhibitors. Sirolimus + CyA: • Exacerbation of CyA SEs including nephrotoxicity • If being given together, separate by 4 hrs • Aim for lower CyA levels than normal Appears to be safe in combination with tacrolimus. |
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What are some of the ADRs with the use of sirolimus?
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• Bone marrow suppression
• Hyperlipidaemia • Hypokalaemia • Hyperglycaemia • Diarrhoea • Abnormal LFTs • Decreased uric acid levels • Hypertension • Increase infectious complications • Delayed wound healing • No increases in malignancy Lacks nephrotoxicity & neurotoxicity seen with calcineurin inhibitors |
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What is OKT3 and how does it work?
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First monoclonal antibody for rejection.
• Treatment of acute rejection • Prophylaxis in high risk pts Must cease CyA/TAC during course - restart 48/24 hrs prior to end of treatment. Mechanism: • CD3 receptor is complexed with the T-cell antigen recognition site • When OKT3 binds to the CD3 receptor, it blocks the ability of cells to become stimulated to foreign antigens |
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What are some of the ADRs associated with OKT3 and their management?
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Primarily associated with first dose:
• Mild-severe flu-like syndrome (fever, chills, headache, N+V, myalgia) • More rarely: APO, encephalopathy, seizures • Increased risk of infectious complications & lymphoma, & intravascular thrombosis Management: • Minimise flu-like syndrome with pre-medication (e.g. steroids, paracetamol, antihistamine) |
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What is the mechanism of action for IL-2 receptor antagonists?
Give examples.. |
Interaction of IL-2 with receptor on T-cells triggers T-cell proliferation & is a key step in acute rejection
Some monoclonal antibodies e.g. daclizumab and basiliximab Daclizumab: • Can be administered with other standard immunosuppressives w/out increase in ADRs • Significant reduction in acute rejections when used • No cytokine release syndrome b/c cells not lysed • Potential to cause lymphoproliferative disorders • No increase in rate of opportunistic infections Basiliximab is similar, but has simpler dosage regimen and cheaper therefore may have an advantage. |
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What is rituximab's role in transplantation?
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Anti-B cell antibody (anti CD-20)
• Being investigated for role in renal transplant of highly sensitised recipients • B-cell mediated rejection not covered by most treatments |
