immune-mediated toxicities Flashcards
What is drug hypersensitivity reactions (DHR)?
- Activation of immune or inflammatory cells that leads to ADR
- Types of ADR
- Type A: Pharmacologically mediated and predictable based on drug
- Type B (10-15%): DHR
what are the Types of drug hypersensitivity reactions?
- Immune (Allergy)
- Non-immune (Pseudoallergy)
what is immune drug hypersensitivity reaction?
allergy
- Immunologically mediated hypersensitivity reaction to a drug/ antigenic substance in a sensitised person
- Sensitised person when exposed to drug again —> Immune system recognise as threat —> Triggers immune response —> Host tissue damage due to release of inflammatory mediators —> Localised (organ-specific) or generalised systemic reaction
what are the Types of allergic reactions?
note: Atopy: Genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema)
Type I: Immediate hypersensitivity or Atopy
Type II: Antibody-mediated disease
Type III: Immune-complex mediated disease
Type IV: T cell-mediated disease
whats the pathologic immune response for Type I: Immediate hypersensitivity or Atopy?
Th2 cells, lgE antibody, mast cells, eosinophils
whats the pathologic immune response for Type II: Antibody-mediated disease?
lgM, lgG antibodies against cell surface or extracellular matrix antigens
whats the pathologic immune response for Type III: Immune-complex mediated disease?
Immune complexes of circulating antigens, lgM, lgG antibodies deposited in vascular basement membrane
whats the pathologic immune response for Type IV: T cell-mediated disease?
CD4+ T cells (cytokine mediated inflammation), CD8+ CTLs
tell me more about how Genetic disposition can increases susceptibility to drug hypersensitivity syndromes
Variations in genetically determined human leukocyte antigen (HLA) alleles
Genetic factors can influence metabolic deactivation of drugs via phase 1 and 2 metabolism —> Extent of active metabolite remaining
what are the Types of drugs commonly associated with allergic reactions?
- Beta lactam
- Sulfonamide
- Anticonvulsants
- Some chemo agents
- Radiocontrast media
- Chlorhexidine
- ACE/ ARB
- Biologics (proteins)
- NSAIDs
- Insulin
what are the Effectors categories of allergic reactions?
- Innate and adaptive immune systems
- chemical mediators
what are the Effectors (Innate and adaptive immune systems) of allergic reactions?
- Cellular elements: Macrophages, T & B lymphocytes, platelets, mast cells
- Mast cell when exposed again will flare up
- Immunoglobulins: lgE
- Complements: Activates mast cells and inflammatory mediators
- Cytokines
what are the Effectors (chemical mediators) of allergic reactions?
- Histamine: Stored and released from basophils and mast cells
- Platelet-activating factor (PAF) and Thromboxane: Triggers platelets aggregation and clots so hypersensitivity reaction to anticoagulant heparin
- Prostaglandins (PG), Leukotrienes: Dilators or constrictors for bronchoregulation
summarise the Effectors of allergic reactions
- Mast cells release and break down agents which are involved in Type I reaction, Vasodilation —> swelling and hypotension, Increased vessel permeability, Broncho smooth muscle contraction —> Loss of breathing
- Basophils, neutrophils, eosinophils recruited later for delayed sensitivity
what is a life threatening Clinical manifestation of allergic reactions?
- Anaphylaxis
- Acute, life-threatening reaction involving multiple organ systems
- Risk of fatal anaphylaxis greatest within first few hours
- Most common by penicillins, NSAIDs, insulins
what is the signs and symptoms of anaphylaxis?
- Skin: Hives, swelling
- Airway*: Tightness and swelling
- CNS: Anxiety, headache, tunnel vision
- CVS*: Chest pain, low bp, rapid HR
- GIT: N/v, abdominal cramping, diarrhoea
- Serum sickness/ Drug fever
- Alot of antigens in body —> binds with other antibodies to form immune complex which circulates throughout body to trigger inflammation and systemic reactions
- Commonly by antibiotics
- Drug induced autoimmunity
- Common conditions
- Systemic lupus erythematosus (SLE)
- Hemolytic anemia (RBC burst): Commonly by Methyldopa
- Hepatitis: Commonly by phenytoin
- Vasculitis
- Inflammation and necrosis of blood vessel walls
- Limited to skin or involve multiple organs
- Commonly by Allopurinol, thiazide
- Respiratory
- Common conditions
- Asthma: Commonly by NSAIDs
- Fibrotic pulmonary reactions —> Acute and chronic Fibrosis in lungs: Commonly by bleomycin (chemotherapy agent), nitrofurantoin (antibiotic for UTI)
- Common conditions
- Hematologic (blood type reaction)
- High levels of eosinophilia
- Common conditions
- Hemolytic anemia
- Thrombocytopenia
- Agranulocytosis (neutrophil counts drop to dangerous levels)
what is serious cutaneous adverse reaction (SCAR)?
one of the signs of anaphylaxis
- Drug rash with eosinophilia and systemic symptoms (DRESS)
- 3 Criteria: Triad of rash, lots of eosinophils, internal organ involvement (commonly hepatitis, interstitial nephritis,interstitial pneumonia,orcarditis (inflammation of heart muscle) etc)
- High mortality rate 10%
- Commonly by Allopurinol, anticonvulsant
what is Mucocutaneous disorders?
one of the signs of anaphylaxis
- Dermatologic emergencies as can progress to cause mucous membrane erosion and epidermal detachment, Commonly by antibiotics (esp sulfonamides)
- Stevens-Johnson syndrome (SJS): Disorder of skin and mucous membrane
- High mortality rate 1-5%
- Toxic epidermal necrolysis (TEN)
- Very high mortality rate 10-70%
- Stevens-Johnson syndrome (SJS): Disorder of skin and mucous membrane
what is the Treatment for anaphylaxis?
- Restore respiratory and CV function
- First line: Epinephrine (adrenaline)
- Acts on alpha and beta receptors to counteract bronchoconstriction and vasodilation (increase bp)
- Epi-pens for those with severe allergies
- Second line (at hospital)
- IV fluids to restore volume/ BP
- Intubation to save airway
- Norepinephrine (noradrenaline) if shock
- Steroids to suppress reaction
- Diphenhydramine (H1) and Ranitidine (H2): Blocks histamine receptors to stop or slow down reaction
- Glucagon (if patient on beta blockers): Help heart beat regularly
what is the treatment for SCAR (serious cutaneous adverse reaction)?
- No known cure
- Just stop drug
- Manage symptoms via supportive care
- Wound care, nutritional support, fluids, temperature regulation, pain management and prevention of infections
- Steroids (controversial)
- IV immunoglobulin and cyclosporine
what is Non-immune (Pseudoallergy)?
- Mimic true allergies but do not involve immune system, not caused by allergen-specific immune responses
- 77% of hypersensitivity reactions
- Release mediators like histamine, prostaglandins, kinins from mast cell, basophil (NOT lgE)
what are some common drugs that cause pseudoallergy?
- Vancomycin
- Infusion reaction aka Red man syndrome if infused too quickly —> So slow down infusion
- Direct release of histamine from mast cells and other mediators
- Itching, flushing, hives
- Onset around neck and face first then progresses to chest and other parts
- ACE/ Sacibitril
- Angioedema
- Inhibition of breakdown of bradykinin —> vasodilation —> increases vascular permeability —> edema, inflammation
- NSAIDs
- NSAIDs induced asthma
- Alter metabolism of prostaglandins esp in lining of lungs —> anaphylaxis
What is autoimmune disease?
- Body attacked by own immune system —> auto antibodies formed
- Risk factors
- Genetic background
- If have variations in genes —> more susceptible to create autoantibodies when stimulated by environmental factors
- Environmental stimuli like smoking and infection
- Genetic background
- At least 80 known autoimmune diseases
what is the Treatment of autoimmune disease?
- Target, block and hence dont activate B cells to produce autoantibodies and T cells to exert cytotoxic effects
- Target cytokines
- Target Kinases
why is autoimmune disease Difficult to treat ?
- Many targets to treat, so many ways for autoimmune disease to continue
- No or lose response to treatment, cannot tolerate treatment, ADR to treatment
- Rare so minimal trials to get drugs approved so available drugs are poorly indicated (most off-label) and costly (not covered under insurance)
- Great variability of treatment among centres
- Having autoimmune disease seen as weakness, so less likely to seek help
what are the Types of autoimmune disease?
note: Organ or not organ specific, depending on type of autoantibody —> to a specific cell or receptor or floating around body
- Systemic lupus erythematosus (SLE) - Non organ specific
- Psoriasis
- Grave disease
- Type 1 DM
- Rheumatoid Arthritis
- Multiple sclerosis
- Sjogren’s syndrome
- Scleroerma
- Systemic vasculitis
how does systemic lupus erythematosus (SLE) happen?
- Apoptosis of cells releases cell contents including nucleic acids which float around body —> DNA and RNA act as autoantigens —> SLE kicks in: Autoantibodies formed anywhere in body which binds with nucleic acids —> immune complex formed and interact with APCs with MHC —> MHC presents immune complexes to T cells and stimulate B cells to produce more autoantibodies —> activate cytokines and symptoms
- Autoantibodies and antiphospholipid antibodies produced
where can systemic lupus erythematosus take place?
- Multi-system as immune complex can be anywhere in body
- Complexes collect in smaller vessels —> blockage in brain, kidney, joints and hands, CVS —> diseases
what are the risk factors of systemic lupus erythematosus?
- More prevalent in females, non-white, African descent than asian
- Strong genetic disposition
- UV light
- Epstein-Barr virus
- Pollution
- Drugs (refer to drug-induced lupus)
what is the clinical physical presentation for systemic lupus erythematosus?
note: Disease fluctuates with periods of remission, flares and progression in 70% of patients
- Skin diseases appear in 50-70% of patients
- Rheumatoid arthritis: Affects joints
- Neurological disease
- Serostitis: Inflammation of serous membrane (pleura, pericardium, peritoneum), affects heart, lungs
- Fever, aching alot
- Lupus nephritis —> Kidney failure
- Only cure is transplant
- Neuropsychaitric lupus
- Stroke
- CVS
- Note that statin has DDI with some lupus medications
what is the clinical presentation lab signs for systemic lupus erythematosus?
- Full blood count decreased due to:
- Hemolytic anemia —> RBC decrease
- Leukopenia —> WBC or lymphocytes decrease as autoantibodies destroy WBCs
- Thrombocytopenia —> Platelets decrease as autoantibodies destroy platelets
- Immunologic
- High Autoantibodies
- Antinuclear antibody (ANA)
- Antidouble-stranded DNA (dsDNA)
- Anti-Smith antibody (anti-Sm)
- Antinuclear ribonucleoprotein (anti-RNP)
- Low complement (C3, C4, CH50) when immune complexes activate the complement system, leading to complement protein cleavage and consumption
- High antiphospholid antibodies —> Antiphospholid syndrome in 40% of SLE patients
- Lupus anticoagulant
- Anticardiolipin
- Anti-beta2 glycoprotein I
- High Autoantibodies
what is the clinical implications of having high antiphopholipid antibodies in someone with systemic lupus erythematosus?
- Risk of thrombosis (blood clot)
- High risk of preggo morbidity: Might be reason for high occurrence of miscarriage
what can be done for someone with high antiphopholipid antibodie?
preggos
- Nothing can be done :(
- Put on parental anti-coagulant
non preggos
- Primary thromboprophylaxis: Asprin to get rid of clots
- Secondary thromboprophylaxis: Warfarin (NOT USED FOR PREGGOS)
- Hydroxychloroquine has protective effect in suppressing clotting factors
what is the treatment goals for systemic lupus erythematosus?
- Goal: Remission where disease is inactive so minimal symptoms
- Prevent flares and other organ involvement, slow disease, reduce use of steroids, improve QOL, minimise ADR
- Need to treat comorbidities too
- Lifestyle and support groups for mental health
how to minimise risk factors of systemic lupus erythematosus ?
- stop Smoking
- Sun protection
- Exercise
- Diet: Monitor lipids, glucose
what are the pharma agents for systemic lupus erythematosus?
- Hydroxychloroquine
- Corticosteroid: Prednisone, Glucocorticoids
- NSAID: Aspirin
- Biologic: Belimumab (more approved) and Rituximab (reserved as alternative for severe diseases)
- Immunosuppressants
- Mycophenolate mofetil
- Azathioprine
- Methotrexate
- Calcineurin inhibitors (cyclosporine, tacrolimus)
which is first line for systemic lupus erythematosus ?
Hydroxychloroquine
how does hydroxychloroquine work to treat sle?
works by limiting APCs and decreasing activation of T cells and thus B cells to prevent autoantibodies from being produced
Interferes with cytokine production
Prevent flares, improve long term survival
what is the dosage of hydroxychloroquine for sle?
<5mg/kg/day and try to keep at minimal dose for minimal ADR
Onset 4-8 weeks
is hydroxychloroquine safe for sle preggos?
Minimal ADR so safe for preggos
what is the adr for hydroxychloroquine?
prolonged usage (>20y) have risk of retinal toxicity so need eye exams
what corticosteroids can be used for sle?
Prednisone, Glucocorticoids
how does Prednisone, Glucocorticoids help with sle?
- Suppress immune system
- Useful for stopping flares and decreasing inflammation
are the adrs dangerous for Prednisone, Glucocorticoids for the treatment of sle?
yes
ADR: Hyperglycemia, hypertension, osteoporosis, skin atopy for topical steroids
so Low does and for short-term use due to ADR
is prednisone, Glucocorticoids for the treatment of sle safe for preggos? why?
Not safe for preggos (but not super high) due to adr
how can nsaids: aspirin help with sle?
Symptom control with its anti-inflammatory (joint) and analgesic properties
what to be mindful about when giving aspirin to someone with sle?
Caution in worsening lupus nephritis (so consider kidney function before prescribing)
how does biologiv belimumab and rituximab help with sle?
note: Belimumab (more approved) and Rituximab (reserved as alternative for severe diseases)
Suppress immune system by disrupting B cells
what adrs does belimumab have for the treatment of sle?
ADR: Irritation at injection sites
what immunosuppressant can be used for sle?
IV/PO Cyclophosphamide: For severe organ involvement to get it under control initially (induction therapy)
is immunosuppressant safe for preggos?
- Not safe for preggos UNLESS mama really in danger
- 😖Affects fertility rates
does immunosupressnats have better response in whites or asians or afticans or hispanic?
Good response in white and asians (can use lower dose) compared to african and hispanic patients
whats the adr for belimumab for sle?
Hemorrhagic cystitis (inflammation and bleeding in the bladder), Bladder cancer
what is mycophenolate mofetil used for in sle?
Maintenance therapy to get steroid dose down
what is the adr for mycophenolate mofetil for sle?
Large GI side effects
can preggos use mycophenolate mofetil for sle?
- Highly teratogenic so not safe for preggos
- Does not affect fertility
how can azathioprine be used for sle?
Maintenance therapy to get steroid dose down
- On list of genetic test
- Test to check if drug will get metabolised and cause toxicity
is azathioprine safe in emergency use and preggos?
- Safe in emergency cases, low teratogenic risk so relatively ok if used after first trimester
- Does not affect fertility
what are the secondary agents used in sle?
Methotrexate
Calcineurin inhibitors (cyclosporine, tacrolimus)
can preggos take methotrexate ?
- 😖Teratogenic, Not safe for preggos
- 😖Affects fertility
which of the sle meds are teratogenic? (aka preggos cannot take)
Corticosteroid
Immunosuppressants
Mycophenolate mofetil
Methotrexate
just rmb, preggos cannot take corn in imm, mymome
which of the sle meds affect fertility?
Immunosuppressants
which of the sle meds are safe for emergency use?
Azathioprine
which of the sle meds are safe for preggos?
Hydroxychloroquine
Azathioprine (low teratogenic risk, so ok to use after first trimester)
which of the sle meds do not affect fertility?
Mycophenolate mofetil
Azathioprine
how common is drug-induced lupus?
10-15% of SLE
how does drug-induced lupus occur?
Drug look like protein and presented by APCs to T cells to trigger immune response
what are the main drugs that cause drug-induced lupus?
Procainamide, Hydralazine, Quinidine (moderate incidence)
what does TNF alpha inhibitors cause?
- TNF alpha inhibitors cause TNF alpha antagonist induced lupus-like syndrome (TAILS)
- Same presentation as lupus
how to treat drug-induced lupus?
- STOP DRUG, symptom control with steroids
- If condition doesnt improve, may be idiopathic lupus instead of drug-induced
how to evaluate therapeutic outcomes for sle?
- Patient verbally says
- Monitor ADR, comorbidities development
- Measures of disease activity to check change in status of levels
- urinalysis/ renal function, anti-dsDNA antibodies, complement levels, C-reactive proteins, full blood count, liver function test
- Measure lab values every 1-3 months with active disease, 6-12 months if stable
- Antibodies are either present or not, doesnt fluctuate with disease activity —> So not measured
what is the purpose of immunosuppression?
To suppress immune systems to prevent cell damage and inflammation
when should one carry out immunosuppression?
- Autoimmune conditions so it stops attacking itself
- Solid organ transplants so it does not attack the foreign organ
- Stem cell/ bone marrow transplants which develop new cell lines —> For blood cancers, blood disorders (sickle cell), bone marrow issues (aplastic anemia)
what to target to suppress whole immune system?
- B cells, APCs, T cells, Mediators (eg. cytokines)
- Inhibit some step in proliferation or activation
how to Suppress immune system for transplant ?
- Induction therapy
- Maintenance therapy
what is the induction therapy used to suppress immune system?
- Use high potency, short course therapy as soon as possible to stop any existing damage and prevent worsening of autoimmune conditions or prevent organ rejection
- Get rid of lymphocytes (T and B cells) via lymphocyte depleting agents to cause cell lysis
- Antithymocyte globulin (ATG): Mainly targets T cells
- Alemtuzumab (off-label): Binds to T cells and triggers apoptosis
- Use immune modulators to prevent activation and proliferation of T cells
- Basiliximb
what is the maintenance therapy used to suppress immune system?
Target T cell activation, can combine for stronger suppression —> Need to do therapeutic drug monitoring to ensure enough suppression but not till toxicity levels
what are the agents used for maintenance therapy used to suppress immune system?
- Calcineurin inhibitors: Cyclosporin, Tacrolimus
- Metabolised in liver and other tissues, so not to be taken with CYP450 inhibitors like fluconazole or they wont get metabolised and instead accumulate —> Toxicity
- Antimetabolites: Mycophenolate, Azathioprine
- Not primarily metabolised by CYP450
- Corticosteroids
- mTOR inhibitors: Sirolimus, Everolimus
- Biologics: Adalimumab, Belatacept
- Not primarily metabolised by CYP450
How to carry out transplant
- Patient selection: Match HLA and blood type as closely as possible
- Use intensive induction therapy to avoid initial rejection
- 70% of patients use biologic therapy to delay use of calcineurin inhibitors as can cause kidney damage and to minimise duration of usage
- Use multiple maintenance therapy
- Common combi: Calcineurin inhibitor + glucocorticoids + mycophenolate
- Avoid using Calcineurin inhibitor and mTOR which can increase nephrotoxicity
- Reduce dosage or replace drug if toxicity > benefits
what are the Immune related Complications when taking immunosuppressants?
- Opportunistic infections (Occur more frequently and more severe with weakened immune systems)
- Bacteria, viral, fungal, parasites
- Cancers because also suppress T regulated Cells so cannot recognise and kill abnormal cells
- (Main) Skin cancer: Esp common in patients with transplant induced immunosuppression
- Lymphoproliferative disorders: Due to messing with lymphoid cells
- Donor-related or recurrent cancer
what are the non-Immune related Complications when taking immunosuppressants?
- Bone marrow suppression
- Esp with Azathioprine, Mycophenolate
- Hepatotoxicity
- Esp with Azathioprine, Mycophenolate
- Renal toxicity
- Esp with Cyclosporin, Tacrolimus —> Worst in combi with mTOR inhibitors
- Avoid use of ACEi, diuretics that can cause renal toxicity
- Hypertension, Hyperlipidaemia, Hyperglycemia (to psot-transplant DM so impt to monitor blood sugar levels)
- Esp with Steroids, Calcineurin inhibitors (due to causing vasoconstriction and Na retention)
- First line for Calcineurin hypertension: Dihydropyridine Ca channel blockers
what is the pharmacist role when counselling someone taking immunosuppressants?
- Monitor for complications (of disease, transplant, medications)
- Medication management
- Medication access
- DDI
- CYP450 3A and p-glycoprotein substrates: Calcineurin inhibitors (tacrolimus, cyclosporins), mTOR inhibitors
- Therapeutic drug level monitoring
- Just right level: Avoid toxicity yet ensure sufficient conc to continue immunosuppression
- Patient education
- Improve adherence
- Increase safety
whats the issue of taking Steroids issue: Long term use >3months?
- HPA Axis suppression
- Hypothalamus produces corticotropin release hormone to anterior pituitary which produces adrenocorticotropic hormone to adrenal cortex which produces cortisol
- Steroids is cortisol —> Inhibits whole access via negative feedback and prevents production of CRH and ACTH
- Ok if on exogenous steroids, but once steroids stopped, inactivation of HPA axis inactivated over time will not be able to recover function —> Adrenal suppression
- Solution: SLOWLY withdraw from steroids, Consider tapering off steroids after use for 2 weeks
what are the side effects of taking Steroids issue: Long term use >3months?
- Myopathy: Muscle weakness
- Hypertension
- Dyslipidemia
- Pneumocystis jiroveci pneumonia (PJP): Lung fungal infection —> Need PJP prophylaxis (treatment to prevent disease)
- Osteoporosis
- HPA Axis suppression
what does steroids do?
- Have powerful anti-inflammatory and immunosuppressive effects
- Decrease activation of T lymphocyte cells
what are steroids used in?
Asthma, COPD, autoimmune diseases, transplants, inflammatory bowel disease, eczema, cancer/pain
