Immunosuppressants
- An immune reaction is elicited when the body recognises an antigen to be
foreign.
- Antigens – large molecules, MW > 5000 daltons, multivalent,
consistent charge and molecular profile (proteins, glycoproteins, HMW
carbohydrates)
-
Antigens are processed and presented to T cells by antigen presenting
cells.
-
The immune response is initiated by the interaction of the T cell
receptor with the antigen-MHC complex on the APC. This produces either a
humoral or cellular immune response.
Humoral Immunity
·
This is immunity mediated by antibodies produced by plasma cells
that are derived from B lymphocytes.
·
The humoral immune response occurs in 2 stages
1.
Primary reaction – occurs with the first exposure to antigen. Consists
of a small short-lived rise of IgM.
2.
Secondary reaction – occurs with subsequent exposure to the same
antigen. Greater rise in IgG antibody titre.
·
Function of antibodies
1.
neutralisation of some viruses and of some bacterial toxins
2.
activation of the complement cascade
3.
ingestion of microorganisms
4.
attachment to multicellular parasites, facilitating their killing.
Cellular Immunity
·
This is mediated by activated T cells, which recognises and binds
directly to cells bearing the antigen recognised by the T cell and subsequently
either kills the infected cell (CD8+ cytotoxic T cells) or releases a cascade of
cytokines that activates other components of the immune system such as
macrophages (CD4+ helper T cells).
·
The immune system is the body’s defense mechanism against the
invasion of the body by bacteria, viruses and other foreign material.
·
When it is defective, disorganised or overactive it can produce
disease.
·
The body posesses autoregulatory mechanisms to prevent immune
reactions against self antigens. However, when any of these mechanisms fail,
autoimmune disease results.
·
Immunosuppressive agents are used when the normally protective
immune responses are inappropriately deployed.
Antilymphocyte globulin (ALG)
·
ALG (aka antithymocyte globulin) is prepared by injecting human T
cells into animals to raise antibodies.
·
The active Ig is in the IgG fraction
·
ALG is a polyclonal antilymphocyte antibody
·
Major effect is to prevent antigen from accessing the
antigen-recognition site on the Th cell.
·
Given intraveneously for acute organ rejection and in patients
with high risk of rejecting transplants.
·
Adverse effects – anaphylaxis, serum sickness, production of
anti-animal IgG is common (50%), toxicity to tissues such as RBC and the kidney.
Anti-CD3 monoclonal antibodies
·
Used as adjuvant (2nd line) immunosupprssive therapy in
patients with acute transplant rejection.
·
IgG2a antibodies produced from murine hybridoma cells
·
Given as i.v. bolus 5mg/day for 10-14 days
·
After the 10-14 day course patients develop neutralising antibodies
against the anti-CD3 Ab.
·
These antibodies are targeted specifically at the T cell CD3 receptor,
and when they bind to CD3, antigen is blocked from binding to the T cell antigen
recognition complex adjacent to the the CD3 protein
·
Effect is to reduce T cell participation in acute solid-organ graft
rejection.
·
Adverse effects
1.
hypersensitivity reactions
2.
chest pain, wheezing, dyspnoea
3.
CNS effects – seizures, reversible meningo-encephalitis, cerebral
oedema
Major
Immunosuppresive Drugs
Azothiaprine – major cytotoxic
used for immunosupression + widely used to control tissue rejection in
transplant surgery.
Mechanism:
Metabolised to yield mercaptopurine (6-MP). 6-MP
has no intrinsic activity but requires transformation to 6-thioguanine
nucleotides which interfere with DNA synthesis.
Inhibits lymphocyte clonal proliferation in the induction phase of
immune reaction.
1)
↓ Cell mediated immune reaction (T lymphocytes)
2)
↓ Ab mediated immune reaction (B lymphocytes)
3)
↓ other inflammatory effects that depend on cell division
Pharmakokinetics:
Well aborbed orally. 98% cleared by hepatic
metabolism to 6-MP. Further converted by xanthine oxidase (XO) and
thiopurinemethyl-transferase. T1/2 ~ 12 min.
Note: if given with XO inhibitor (allopurinol), accumulation and
toxicity will occur unless dose ↓ ~30%.
Adverse Effects:
-Bone marrow suppression
-Diarrhoea
-Skin eruptions
-Mild hepatotoxicity
Cyclophosphamide
Uses as for azothioprine (xplant rejection/ immunosuppression)+
1)
treatment of nephritic syndrome with minimal changes in glomeruli esp.
those sensitive to glucocorticoids
2)
treatment of nephritis due to SLE, Wegner’s granulomatosis, (severe
RA)
Dose: 3 mg/kg/day
p.o.
Mechanism:
Activated by hepatic P-450 mixed function oxidases
to phosphoramide mustard (cytotoxic) and acrolein (causes renal damage).
Inhibits lymphocyte proliferation by alkylating
DNA; more effective after antigen stimulation.
↓ B-cell AB production > ↓ T-cell
mediated immunity
Adverse effects:
- Nausea + vomiting
- Haemorrhagic cystitis (prevent by increasing
fluid intake + sulphydryl donor e.g. N-acetylcysteine or mesna)
Mycophenolate mofetil – ester
product of the Penicillium mould used in conjuction with cyclosporin and
glucocorticoids. Uses as for azothioprine. May be a more effective alternative
in solid organ xplant.
Dose: 1g/ twice per day p.o.
Mechansim:
Mycophenolic acid (active agent) inhibits inosine
monophosphate dehydrogenase (enzyme in purine synthesis). Effects as
azothioprine, but additionally may ↓ pro-inflammatory cytokines.
Adverse effects:
-GI: diarrhoea + haemorrhage
-Bone marrow suppression
-deep seated CMV infection
Pharmakokinetics:
Bioavailability from ester is 94%. Mycophenolic
acid is glucuronidated to
inactive metabolite in liver. T1/2 ~ 18 hrs.
Methotrexate
Glucocorticosteroids
- in immunosuppression
Uses :
1.
Allergic rhinitis
2.
Atopic dermatitis
3.
Acute severe asthma
4.
Chronic asthma
5.
Anaphylaxis
6.
Type II autoimmune diseases – haemolytic anaemia
7.
Immune complex diseases- Type III hypersensitivity/ Rheumatoid
arthritis, SLE
8.
Type IV hypersensitivity reactions- prevent acute graft rejection,
and in severe contact dermatitis
Route and dosage :
Topical (e.g. beclamethasone) or systemic (e.g. prednisolone). There are
appropriate dosing schedules effective in diseases due to all types of
hypersensitivity. Hepatic metabolism (cytochrome P3A4), dosed to minimise HPA
suppression.
Mechanism of action:
Inhibits expression of pro-inflammatory cytokines-IL-2,3 and 6, TNF, GM-CSF
and IFN-gamma
Inhibits production of adhesion molecules- ICAM-1, E-selectin leading to
reduced vascular permeability.
Reduces synthesis of arachidonic acid metabolites (prostaglandins,
leukotrienes) and reduces histamine release.
Adverse effects:
Acute effects- metabolic disturbances (glucose/hypokalaemia), CNS (mood
disorders, insomnia)
Chronic effects- features of Cushing’s syndrome, immunosuppression, risk
of infection, and HPA axis suppression
Cyclosporin
Class: immunosuppresant, cyclic hydrophobic decapeptide.
Uses:
1.
Immunosupresion for solid
organ transplantation
2.
Refractory psoriasis
Route and dosage:
1.
A high dose is given 4-12h before transplantation
2.
Safer to start 14mg/kg/day orally reducing over 3 months to a
maintenance dose of 6mg/kg/day.
3.
In graft-vs.-host disease and bone marrow transplantation iv treatment
3-5mg/kg/day used initially, followed by oral administration for 6-9 months.
Mechanism of action:
1. T-lymphocyte suppresser,
primarily acting on T-helper cells.
2. Inhibits transcription of IL-2 production and pro-inflammatory
cytokines
by T-lymphocytes.
Adverse effects:
1.
Nephrotoxicity
2.
Nausea and GI disturbances
3.
Hyperkalaemia
4.
Hepatotoxicity
5.
Hypertension
6.
Hirsuitism
7.
Ginigival hypertrophy
8.
Tremor
9.
Anaphylaxis
10.
Malignancy (Lymphoma)
Pharmacokinetics:
1. Given orally/iv shows variable absorption and hepatic metabolism (cytochrome
P450 3A4) to many inactive metabolites.
2. Bioavailability is 30%.
4.
Peak plasma concentration occur within 1-4h
5.
Renal dysfunction does not affect its clearance but beware of
nephrotoxicity, hence monitor serum urea and cretonne clearance.
6.
Reduce dose in patients with hepatic impairment.
Therapeutic Drug monitoring :
1.
Assayed by radioimmunoassay
2.
Trough plasma concentration of 100-300 ug/L if
iv infusion
3.
Effective immunosuppression at 60-300 ug/L if orally given
4.
Monitor plasma concentration in all, especially in GI disturbances,
hepatic impairment or if patient is receiving nephrotoxic drugs.
Drug interactions :
Many, include Azoles, macrolides and Calcium channel blockers (dilitiazem),
Anabolic steroids.
Disease-modifying anti-rheumatic
drugs (DMARDs)
These suppress the imflammatory process in RA and psoriatic arthritis
and are helpful in progressive disease, perhaps improving extraarticular
manifestations as well as inflammatory joint symptoms and signs. NSAIDs are
usually prescribed first. Treatment with DMARDs is instituted by specialists
once diagnosis and progression of the disease are confirmed. They might work by
inhibiting excess cytokine liberation.
4-6 months’ treatment is required before a full response is seen. If a
drug has produced no effect within 6 months, it should be discontinued.
Methotrexate, gold, penicillamine, azothioprine and sulphasalazine are
similarly effective in RA, but methotrexate tends to be used first because it is
better tolerated. Hydroxychloroquine is also used, but is less potent.
Gold and immunosuppressants (azothioprine, methotrexate) are effective
in psoriatic arthritis.
1.
Methotrexate
Dose 7.5mg once weekly, or 2.5mg 3 times at 12-hourly intervals; up to
20mg according to response.
2.
Azothioprine
Rarely more than 3mg/kg daily, reduced according to response;
maintenance 1-3 mg/kg daily. Consider withdrawal if no response in 3 months.
3.
Sulphasalazine
Initially 5oomg OD, increase by 500mg every week up to 2 or 3g daily in
divided doses.
4.
Penicillamine
125mg PO daily, 1 hour
before food for 1 month as starting dose, then 250mg daily for 1 month,
increasing by 125-250mg every month until a response is achieved. The dose is
reduced by 125-250mg every six weeks to find the minimum effective maintenance
dose once an effect is well-established. Treatment should be discontinued if
there is no improvement within one year. Weekly blood and urine tests are needed
initially, and then monthly during maintenance treatment.
SE: Rashes, nausea and anorexia, not usually a problem if taken before
food or on retiring and low doses are used initially., taste loss, blood
disorders, LE-like and polymyositis-like syndromes and others.
5.
Gold
Sodium aurothiolate weekly by intramuscular injection: 10mg the first
week; 20mg the 2nd; 50mg the 3rd, then 50mg weekly until a
total of 1g has been given. After that a maintenance treatment of 50mg every
month should be given.
SE: mouth ulcers, skin reactions, proteinuria, blood disorders (can be
sudden and fatal); rarely colitis, hepatotoxicity, nephrotic syndrome, alopecia,
peripheral neuritis.
Auronafin is an oral preparation that is less toxic but less effective.
Starting dose 3mg BD, then 6mg OD if the drug is tolerated. 3mg TDS if the
response after 6months is inadequate.
SE: diarrhoea most common; also as aurothiolate.
6.
Hydroxychloroquine
Should not be used in psoriatic arthritis.
Dose initially 400mg daily in divided doses; maintenance 200-400mg.
Avoid in pregnancy/breastfeeding (except for malaria)
Use with caution with neurological disorders, hepatic and renal
impairment, porphyria and the elderly.
SE: headache, GI disturbance and skin reactions; more rarely,
convulsions, retinal damage, hair loss, ototoxicity. Other rare side effects see
BNF.
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