Session 6: Immunosuppression, RA and Pharmacology of Airway Control Flashcards
What are some diseases that rheumatologists manage?
Inflammatory arthritis e.g. rheumatoid arthritis (RA)
Systemic lupus erythematosus (SLE)
Systemic vasculitis
Others
What is Rheumatoid Arthritis?
Rheumatoid Arthritis is a chronic autoimmune multi-systemic condition that is a major cause of severe disability, resulting in an inflammation of the synovium. It affects 0.5-3% of the population worldwide and can set in at any age, with women before the menopause being affected 3x more than men. It currently affects about 1% of people in the UK.
Describe the pathogenesis of RA
The chronic synovial inflammation is caused by ongoing T-cell activation and production of rheumatic factor stimulating macrophages via IgG Fc receptors.
Rheumatic factor is a circulating autoantibody that once bound to the Fc region of the IgG results in immune complex formation and resultant inflammatory reaction.
Large amounts of cytokines (mainly IL-1, IL-6 and TNF-alpha) are released by the macrophages to produce an inflammatory response and the result is a widespread, persisting synovitis. They overwhelm the anti-inflammatory mediators (IL-4, TGF-Beta etc)
There is an influx of inflammatory cells to the region and activation of osteoblasts and fibroblasts to produce metalloproteinases (e.g. collagenase).
The result is a thickening of the synovium and joint effusions (from increased vascularity of the region) containing lymphocytes and other inflammatory cells. The hyperplastic synovium spreads from the joint margins to the cartilage surface, and this inflamed synovium is known as a pannus.
The pannus can damage underlying cartilage by blocking its route of diffusion, meaning the cartilage becomes thin and the bone exposed.
Describe the presentation and clinical signs of RA
RA commonly presents as slowly progressing, symmetrical, peripheral polyarthritis developing over weeks to months.
Most patients complain of pain and stiffness in their hand (MCP, PIP and DIP joints) that is worse in the morning that improves with gentle activity.
The patient may feel tired and unwell, sleeping patterns are disturbed, and the joints are warm and tender with some swelling.
Ulnar deviation can occur in the hands and wrists, as well as fixed flexion (boutonniere deformity) or fixed hyperextension (swan neck deformity) in the PIP.
Swelling and dorsal subluxation of the ulnar styloid process can lead to wrist pain and rupture of the finger extensor tendons (which can cause sudden drop in the 4th and 5th digits).
RA can also affect the MTP (metatarsophalangeal) joints in the foot
Describe the diagnosis of RA
Morning stiffness for or greater than 1 hour
Arthritis affecting 3 or more joints
Arthritis of hand joints
Symmetrical arthritis
Synovitis
Blood test – overexpression of IL-6 leads to increased CRP production by liver
Serum rheumatoid factor
Rheumatoid nodules, X-ray changes (however this shows advance disease – ideally want to detect early, treat hard)
Describe the treatment options of RA. What are the treatment goals?
Anti-rheumatoid drugs can broadly be divided into DMARDs and the immunosuppressants.
The most commonly used drugs in initial therapy are DMARDs, which act to halt and may reverse the underlying processes, alongside NSAIDs to reduce to the symptoms. However, with worsening disease, immunosuppressants can also be utilised for the disease.
Don’t start with DMARDs if presentation is atypical e.g. cachexia, fever – consider steroids and further tests
Treatment goals
- Symptomatic relief
- Prevention of joint destruction
- Aim to get patients into remission – so they can live life as if disease-free, with maintenance theapy
- Early use of disease-modifying drugs
Aim to achieve good disease control
Use of adequate dosages
Use of combinations of drugs
Avoidance of long-term corticosteroids (steroids used early down => aim to decrease dosage)
How do rheumatologists deal with SLE and vasculitis?
NB: rheumatologists also deal with multi-system diseases such as SLE and vasculitis. Picture shows malar rash in SLE and ptosis caused by Wegener’s Granulomatosis (inflammatory infiltrates) (see lecture slide)
NB: if a disease affects heart and lungs, it is not multi-system as these two systems are contiguous.
Treatment goals
- Symptomatic relief e.g. arthralgia, Raynaud’s phenomenon (excessively reduced blood flow in response to cold or emotional stress) in SLE
- Reduction in mortality-induction of disease remission then maintenance (Wegener’s vasculitis)
- Prevention of organ damage e.g. renal failure in SLE
- Reduction in long term morbidity caused by disease and by drugs
Name some immunosuppressants and DMARDs
Immunosuppressants include Corticosteroids, Azathioprine, Ciclosporin, Tacrolimus and Mycophenolate mofetil
DMARDs include Methotrexate, Sulphasalazine, Anti-TNF agents, Rituximab and Cyclophosphamide (cytotoxic, most potent)
What do Corticosteroids do? Name key adverse reactions
– Inhibitors of Gene Expression
Steroids can be used in high doses in an immunosuppressive role, with their main mechanism of action working as inhibitors of gene expression.
They prevent IL-1 and IL-6 production by macrophages + inhibit all stages of T-cell activation.
The macrophages can’t get to where they can act and lymphocytes are hindered => symptoms reduced, patients feel a lot better
Key adverse effects include
- Weight gain
- Fat redistribution
- Striae, easy bruising, thinning of the skin (the earliest effects seen are skin changes)
- Hair thinning
- Glucose intolerance (hyperglycaemia)
- Adverse lipid profile
- Osteoporosis
- Avascular necrosis
- Infection risk
- Cataract formation, glaucoma
What is Azathioprine, and describe its therapeutic uses
a Cytotoxic Antimetabolite
The main therapeutic uses of Azathioprine in RA, IBD, transplantation and leukaemia is through acting selectively on cells with high mitotic rate. It is used in SLE and vasculitis as maintenance therapy. In RA, there is weak evidence for efficacy. It is also used in bullous skin disease, atopic dermatitis (rarely) and has many other uses as a ‘steroid sparing’ drug (to prevent patients being on steroids for a long time).
The use of Azathioprine enables ‘steroid sparing’. The primary pharmacological action is by Inhibition of Purine Metabolism – which reduces both DNA and RNA synthesis. It is an antimetabolite.
Describe how Azathioprine is broken down in the body? Why is genetic polymorphism so relevant to this drug?
Azathioprine is a prodrug activated to 6-Mercaptopurine (6-MP). 6-MP is a purine analogue that inhibits purine synthesis. Elimination of 6-MP by TPMT (thiopurine methyltransferase) is subject to a high rate of genetic polymorphism for TPMT
High levels of TPMT expression will lead to undertreatment
Low levels of TPMT expression will lead to increased toxicity – likely to develop myelosuppression. It doesn’t mean you can’t give the drug but you may not be able to give the optimal dose!
Therefore need to test this before prescribing!
What are the side effects of Azathioprine?
Main side effects directly relate to its main therapeutic action, especially bone marrow suppression and increased risk of infection and emergence of malignant cell lines.
Bone marrow suppression – monitor FBC
Increased risk of malignancy – especially transplanted patients – Non-Hodgkin’s Lymphoma
Increased risk of infection
Hepatitis - monitor LFT
NB: all immunosuppressants can cause bone marrow suppression, increased risk of malignancy and increased risk of infection. DMARDS are also associated with the above + hepatitis.
What is Cyclophosamide? Describe its mechanism of action and therapeutic uses
Cyclophosphamide – a Cytotoxic Alkylating Agent - DMARD
- Cyclophosphamide is also a prodrug and is activated by CYP450s to produce active alkylating electrophilic cytotoxic metabolites. The main active metabolite is called 4-hydroxycyclophosphamide, which forms DNA crosslinks both between and within DNA strands at guanine N-7 positions, preventing replication.
4-hydroxycycloposphamide exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite).
Wide range of uses as an immunosuppressant and in cancer therapy. It selectively acts on cells with higher mitotic rate. It is excreted by the kidney.
Many immunological effects: suppresses T cell and B cell activity and thus its indications include lymphoma, leukaemia, lupus nephritis, Wegener’s granulomatosis, Polyarteritis nodosum.
What are the ADRs of Cyclophosamide and therefore important considerations?
Cyclophosphamide and its metabolites have a number of major serious ADRs especially induction of bladder cancer (due to concentration of acrolein metabolite – toxic metabolite to bladder epithelium – can lead to haemorrhagic cystitis), lymphoma and leukaemia.
Haemorrhagic cystitis can be prevented through the use of aggressive hydration and/or Mesna
Also associated with infertility and teratogenesis.
Monitoring FBC is important and adjusting the dose for renal impairment is also necessary.
Cyclophosphamide – important considerations
- Significant toxicity
- Increased risk of bladder cancer, lymphoma and leukaemia
- Infertility – risk relates to cumulative dose and patient age
- Monitor FBC
- Adjust dose in renal impairment
- Mycophenolate mofetil may supercede Cyclophosphamide in lupus nephritis, trial of mycophenolate mofetil versus cyclophosphamide for vasculitis is underway
What is Mycophenolate Mofetil? Describe its therapeutic use and mechanism of aciton
Mycophenolate Mofetil (MM) – a Highly Selective Cytotxic Antimetabolite
MM is the agent of choice in transplant immunosuppression yet can also be used in RA if necessary.
Good efficacy as induction and maintenance therapy for lupus nephritis.
In transplantation medicine drug levels of the active metabolite mcophenolic acid (area under the curve) may be monitored.
Toxicity may be precipitated by both renal and liver disease.
MM is a prodrug, derived from fungus Pencillium stoloniferum used to increase oral bioavailability of Mycophenolic acid (MPA). It has a highly selective action, based on non-competitive inhibition of enzyme (inosine monophosphate dehydrogenase) for de novo synthesis of guanosine; a key metabolic agent with many downstream effects in target cells.
It is highly selective in B and T lymphocytes due to unique requirement of above enzyme to synthesis the purine guanosine. The result is impaired B-cell and T-cell proliferation whilst sparing other rapidly dividing cells – those cells have guanosine salvage pathways.
What are the side effects of MM?
It has serious and common side effects associate with its use, including leukopenia and neutropenia, myelosuppression and increased risk of infection especially viral.
Most serious is myelosuppression
Less serious side effects include nausea, vomiting and diarrhoea (which normally become bearable/goes away over time), metallic taste in mouth
What do Ciclosporin and Tacrolimus do? Explain their mechanism of action and describe their therapeutic indications
Calcineurin Inhibitors Ciclosporin and Tacrolimus – Specific Lymphocyte Signalling Inhibitors
The primary therapeutic indications for these agents are in transplant patients (widely used), inflammatory skin conditions (indicated for atopic dermatitis and psoriasis) and selective use in some RA patients (not commonly used due to concerns about toxicity + gum atrophy)
- Pimecrolimus only available as topical formulation – used in atopic dermatitis.
- Ciclosporin useful in RA/SLE patients with cytopenias as it had no clinical effect on bone marrow.
Both ciclosporin and tacrolimus are active against T-helper cells by preventing the production of IL-2 via calcineurin inhibition; specifically, ciclosporin binds to cyclophilin protein and tacrolimus-binding protein. Both proteins are on the cell wall. These drug/protein complexes then bind to calcineurin.
Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T-cells, which then migrates to start IL-2 transcription so these calcineurin inhibitors lead to reduction in IL-2 synthesis and release.
Why is the use of Ciclosporin and Tacrolimus limited?
Ciclosporin is a polypeptide of 11 amino acids and is produced by the fungus Tolypocladium inflatum Gams, initially isolated from Norwegian soil. The standard preparation is micro-emulsion formulation (Neoral) – more predictable absorption
Tacrolimus is short for Tsukuba macrolide immunosuppressant but it has a narrow therapeutic index.
The ADRs of Calcineurin inhibitors are nephrotoxicity, hypertension, hyperlipidaemia, nausea, vomiting and diarrhoea, hypertrichosis (abnormal amount of hair growth) and hyperuricemia (if patients had gout, could lead to flare up)
These drugs have an important pharmacokinetic profile and these factors affect their oral bioavailability. CYP450 induction and inhibition affects their elimination kinetics – multiple drug interactions are possible. They are also used in combination therapy with other immunosuppressants. Whilst both are still in clinical use, this use has declined due to their toxicity profile.
Describe the CYP450 family including how it affects Ciclosporin and Tacrolimus
Cytochrome P450 is a diverse superfamily of hemoproteins, named because of their properties i.e. bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) which absorbs light at a wavelength of 450 nm when exposed to CO2.
Cytochromes P450 use a plethora of both exogenous and endogenous compounds as substrates in enzymatic reactions.
Cytochrome P450 is the most important element of oxidative drug metabolism. Many drugs may increase or decrease the activity of various CYP isozymes (enzyme induction or inhibition) causing drug reactions e.g. for patients with anti-epileptics, antibiotics can induce the CYP 450 enzymes => increased susceptibility to seizures.
CYP 450 inducers include rifampicin, carbamazepine, phenytoin and omeprazole.
Inhibitors include ciprofloxacin, many antifungals, fluoxetine, paroxetine, HIV antivirals e.g. indinavir, antidepressants etc
Patients should avoid grapefruit/grapefruit juice in the hour before taking Ciclosporin/Tacrolimus as grapefruit is an enzyme inhibitor – can increase the amount of drug that is absorbed into the bloodstream.
Ciclosporin and Tacrolimus can also cause the amount of potassium in your bloodstream to increase so patients should avoid eating large amounts of foods that have a high potassium content e.g. dried fruit, bananas, tomatoes and ‘low sodium’ salt.
Describe the use of Methotrexate in RA, including its immunosuppressant effects
an antimetabolite
Gold standard treatment for RA. Other indications include malignancy, psoriasis and Crohn’s disease. Also unlicensed roles in: inflammatory myopathies, maintenance therapy in vasculitis, steroid-sparing agent in asthma.
Methotrexate has a very high competitive affinity (x1000) for and reversibly inhibits DHFR (dihydrofolate reductase), which uses folate as a substrate. Therefore methotrexate is considered to act as an antifolate. This action is selective during S phase (during DNA and RNA synthesis), in cells with high mitotic rates (faster rates of DNA replication), e.g. in cancer (malignant and myeloid) and autoimmune disease or in the immune system when there is increased activity is a result of transplantation.
This above action is also responsible for side effects in normal tissue with a high mitotic index e.g. GI and oral mucosa. Therapeutic use needs to be very carefully guided by pharmacokinetic properties and individual patient profile. Dosing typically occurs once per week.
Dihydrofolate reductase catalyses in the conversion of dihydrofolate to the active tetrahydrofolate, the key carrier of one-carbon units in purine and thymidine synthesis. Tetrahydrofolate’s central role in the single carbon transfer reaction central to the synthesis of purines and thymidine, which are essential precursors to building blocks in DNA synthesis. Methotrexate therefore inhibits the synthesis of DNA, RNA and proteins.
Desvribe the pharmacokinetics of Methotrexate
Oral bioavailability of 13-76% (mean 33%) and is commonly administered oral, SC or IM pathway. It is very variable dose dependent – mean intramuscular bioavailability is 76%.
In patients taking oral with partial response or with nausea, swap to subcutaneous => bypassing oral route
WEEKLY not daily dosing (daily dosing is a never event), metabolized to polyglutamates with long half-lives.
Plasma protein binding of about 50%, displaced by NSAIDs.
Elimination is dose dependent.
High doses half-life is approximately 8-10 hours.
Intracellular/Hepatic metabolism to polyglutamates (which can accumulate in cells and actively bind to DHFR, which also can have some effect). It can be retained in cells for weeks – months. This contributes to need for overview in dose regimes.
Renal elimination is mainly (90%) – glomerular active and tubular secretion.
Describe Methotrexate in practice and its ADRs
Well-tolerated
50% of patients continue the drug for >5 years, longer than any other DMARD
improved quality of life
Retardation of joint damage
Anchor drug for DMARD combinations
ADRS
Many serious ADRs:
- Mucositis – responds to folic acid supplementation
- Bone marrow suppression – responds to folic acid supplementation
- Hepatitis
- Cirrhosis
- Pneumonitis (a hypersensitivity reaction)
- Infection risk
- Teratogenic
- Abortifactant
Describe its therapeutic DDIs and hence why clinical monitoring is essential to carry out?
Therapeutic DDRs with other immunosuppressants, anti-cancer drugs and in auto-immune conditions.
Adverse DDIs due to drugs affecting renal blood flow, renal elimination and drugs affecting plasma protein binding (including that of aspirin) e.g. NSAIDs, phenytoin, tetracyclines, penicillin.
In combination with above can lead to increased risk of myelosuppression.
Generally combined with any drug with Hepatic/Renal ADRs will lead to increased risk of ADR including azathioprine and sulfasalazine.
Clinical monitoring – essential to carry out
- Toxicity monitoring is required for methotrexate. This can include baseline CXRs, FBCs (for myelosuppression), LFTs (for hepatic damage) and U&Es and creatinine for renal function.
- Low dose methotrexate can be used to treat RA alongside other DMARDs/steroids and NSAIDs in the long term with careful monitoring
- Regular e.g. monthly FBC, LFT, U+E + creatinine
What are DMARDs and explain the use of methotrexate as a DMARD
DMARDs cover a large group of drugs that have unrelated structures or mechanisms of action yet act to halt the pathogenesis of RA. DMARDs are now initiated as treatment as soon as definite diagnosis has been reached; they may take a while (months) to onset and are covered by NSAIDs initially, yet once therapy begins to work, the level of NSAIDs used is massively reduced.
Methotrexate is also called a DMARD because DMARDS can lead to an actual clinical improvement in underlying condition, rather than just act as anti-inflammatories compared with NSAIDs. Methotrexate works as a folic acid antagonist yet works different in malignant and malignant disease
Low dose Methotrexate can be used in combination with other DMARDs/Steroids + NSAIDS (care regarding ADRS!) to treat RA in the longer term. Of those prescribed methotrexate, over 50% continue beyond five years with careful monitoring.
What is Sulfasalazine?
– another DMARD
Unusual drug molecule with an uncertain mechanism of action but has some therapeutic utility in treating both RA and Inflammatory Bowel Disease.
It is made up of 5-aminosalicylate (5-ASA) and sulfapyridine.
- Designed to relieve pain and stiffness (5-ASA = anti-inflammatory) and to fight infection (sulfapyridine = sulphonamide)
The molecule has unique pharmacokinetics in the gut and travels through the length of the upper GI tract as it is poorly absorbed, till it reaches the colon. Then in the colon, bacterial action causes the breakdown of Sulfasalazine into 5-ASA and sulfapyridine.
The active component in treating IBD is 5-ASA. Its precise mechanism of action in treating inflammatory arthritis is unclear and do not act at the COX-2 site. NB: standard NSAIDs themselves can make IBD worse
The drug is poorly absorbed – main activity is within intestine, therefore effective in IBD
What is Asthma?
Asthma is the commonest childhood disease in the developed world, with increasing prevalence in adults.
It is primarily an Th2-driven chronic inflammatory disease that leads to reversible airway obstruction characterised by bronchoconstriction, mucosal oedema and mucus plugging, which can be severely debilitating, leading to life threatening hypoxaemia without therapeutic interventions.
Asthma is also characterised by bronchial hyperresponiveness (abnormally sensitive to bronchoconstrictor stimuli.
Asthma contrasts with COPD, which has different pathogenesis to asthma and is at best, only partially reversible by therapeutics.
Bronchoconstriction leads to increased lower airway resistance. Normally about 40-50% of flow resistance is in the upper respiratory tract, where no gaseous exchange takes place. The remainder of resistance is provided by the trachea and down to 7th generation bronchi.
Describe the immediate and late phases of asthma
Immediate phase:
- In allergic asthma, the initial response to allergen provocation is due to interaction with Mast Cell fixed IgE. This results in the release of histamine and a host of potent spasmogens leading to immediate bronchospasm.
Late Phase
- Co-release of a range of mediators and chemotaxins activate a complex immune system response that bring leucocytes to the area.
This sets off a further chain of events leading to exacerbated bronchospasm and congestion due to epithelial damage, thickening of the basement membrane, oedema and mucus production.
Additionally, the epithelial damage leads to increased exposure of the sensory irritant receptors, which further exacerbates bronchial hyperactivity and sensitivity.
While this dual response to allergen challenge is relevant to symptoms in some atopic individuals, the pathophysiology of ongoing day-to-day symptoms and asthma exacerbations is undoubtedly much more complex and the mechanisms are poorly defined.
Describe the broad categories of asthma therapeutics and the 5-step management plan
2 broad categories
- Bronchodilators or relievers – acute symptomatic relief
- Anti-inflammatories – used to control the inflammatory mechanisms underlying asthma
Depending on the severity of asthma, these two types are commonly used in combination.
Stepwise management of asthma in adults:
- Mild intermittent asthma
- Regular preventer therapy
- Add-on therapy
- Persistent poor control
- Continuous or frequent use of oral steroids
What is meant by Asthma Control and describe ideal individual management of Asthma
Asthma control means:
- Minimal symptoms during day and night
- Minimal need for reliever medication
- No exacerbations
- No limitation of physical activity
- Normal lung function (FEV1 and/or PEF > 80% predicted or best)
- Aim for early control, with stepping up or down as required.
Individual management of asthma can be complex especially as the condition worsens and the whole range of therapeutic options needs to be explored.
An important part of management is to advise the patient to avoid known triggers wherever possible e.g. cigarette smoke, animal dander
This apart, many asthmatics can be primarily and successfully treated with varying combinations of inhaled B2-agonists with glucocorticoids.
Every asthmatic should have a self-management plan with written instructions on and when and how to step-up and step-down treatment.
Leads to better outcomes in terms of day-today control, frequency and severity of exacerbations.
What is the aim of the 5-step approach?
The stepwise approach to dosing aims outlined in e-BNF to minimise the effect of long-term high dose glucocorticoids. The aim of corticosteroid sparing is however beset by management of other potential side-effects in using theophylline and the less effective leukotrienes or cromoglycate.
Treatment of asthma has a 5-step approach. Patients should start at the step most appropriate to the severity of their asthma; once asthma is controlled, stepping down is recommended, ensuring patients are on the lowest possible doses of the inhaled steroid medication.
Before initiating to a new therapy, it is important to check compliance with existing therapies, check inhaler technique and elimination of any trigger factors.
Describe the 3rd step
Addition of inhaled long acting B2-agonist (LABA) (add-on therapy)
Before initiating a new drug therapy, re-check patient’s medication compliance, check inhaler technique (is it the right inhaler? Are they still using it correctly?), eliminate trigger factors.
First choice: long-acting B2-agonists (formoterol, salmeterol)
Add-in LABA when patients not controlled on 400mcg/day ICS (flat ICS dose-response curve)
Long-acting B2 agonists reduce asthma exacerbations, improve asthma symptoms and improve lung function. But they are NOT anti-inflammatory on their own and must always be prescribed in conjunction with an inhaled steroid (can be used alone in COPD).
Describe the action of B2 agonists (bronchodilators)
B2 agonists were especially developed to exploit the prevalence of B2 receptor in bronchial smooth muscle. B2 receptors are coupled to G(s) proteins.
This leads to an increase in cAMP levels and a consequent decrease in intracellular Ca2+, reduces binding of Ca2+ by light myosin chains (these changes inactivate myosin light chain kinase and activate myosin light chain phosphatase), thus reducing the binding of calcium to troponin and preventing muscle constriction.
B2 agonists also lead to increases in Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation
Predominant action is on airway smooth muscle (relieving/preventing bronchoconstriction) but potentially inhibit mast cell degranulation if only used intermittently (this effect is lost if use of B2 agonist is regular)
On regular use of B2-agonists, mast cell degranulation in response to allergen increases.
How does variation in half life determine therapeutic choice?
Fast-acting bronchodilators such as salbutamol or terbutaline (duration of action 3-5 hours) act immediately – so are used as relievers. Inhaled Formoterol (duration of action 12 hours) also has a fast onset of action, similar to salbutamol. As Formoterol is fast-activing, it can be used as a reliever – studies have shown it reduces rate of exacerbations by up to 50%.
Longer lasting agents (12 hours) such as formoterol and salmeterol (slower onset) are often given in adjunct with anti-inflammatories where corticosteroid therapy does not provide adequate control of asthma.
Also indicated for treatment of nocturnal asthma (a marker of poor asthma control).
Describe the mechanism of action of corticosteroid
Glucocorticoids provide a cornerstone for the longer-term management of chronic asthma and depending on its severity can be administered by inhalation or, in severe cases, orally. Their action in suppressing gene transcription (GRE gene) in a very wide range of pro-inflammatory structural cells (transactivation) is impressive. This effectively reduces the infiltration of the lung by the eosinophils and other cells that execute the exaggerated immune response – corticosteroids also act to repress the inflammatory responses seen (transrepression) – prevent transcription of inflammatory mediators.
Additionally they act to increase the expression of B2-receptors and anti-inflammatory interleukin proteins. They induce apoptosis in a range of inflammatory cells and reduce the number of mast cells in respiratory mucosa.
Asthma can be eosinophilic or non-eosinophilic asthma and corticosteroids have a better treatment response to patients with eosinophilic asthma compared to non-eosinophilic patients.
Optimal effects are seen after weeks/months of therapy. Inhaled corticosteroids improve symptoms, lung function, reduce exacerbations and prevent death.
Describe the pharmacokinetics of corticosteroids including the systemic availability of inhaled drugs
Pharmacokinetics: glucocorticoids are normally administered by inhalation with 10-50% of dose delivered to the lungs depending on the inhaler device.
A major proportion of drug is deposited in the upper airway and/or swallowed to be removed by the liver.
Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.
Lipophilic substituents on D-ring lead to a combination of three key properties:
- A very high affinity for the GCS receptor
- Increased uptake and dwell time in tissue on local application
- Rapid inactivation by hepatic biotransformation following systemic absorption
- VERY POTENT!
Systemic absorption of inhaled drugs
- Beclomethasone absorbed through gut and lungs
- Budesonide and fluticasone undergo extensive first-pass metabolism.
- Lung absorption is still relevant and at high doses all ICS have the potential to produce systemic side effects such as renal suppression, potential bone loss etc.
