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Introduction:
Fifty years have lapsed since the corticosteroids (CS) were
first employed as anti-inflammatory drugs in the Rheumatic diseases.(1) Initial optimism that these drugs would
revolutionize the treatment of chronic inflammatory diseases like
Rheumatoid arthritis turned to caution and thereafter to unease as the
significant side effect profile of these agents became apparent. CS
represents a classic therapeutic double - edged sword, with their
profound anti-inflammatory activity balanced by serious risk of adverse
effects in long-term, high-dose use.
Mechanism of action of corticosteroids:
CS exert their manifold effects on cells involved in immune
and inflammatory responses primarily by modulating the transcription of a
large number of genes. However they are also able to influence the
translational and post-translational mechanisms by which proteins are synthesized , processed and exported from cells. As a
steroid molecule, glucocorticoids are lipophilic and readily transported
across the blood-brain barrier. They are readily absorbed from the
gastrointestinal tract, and are effective in a wide range of doses that
can be administered orally or parenterally. In fact there is much
controversy regarding the optimum dose, route and the type of
glucocorticoid that is most effective. It is also difficult to determine
bio-equivalence between steroids. In spite of all these limitations,
glucocorticoids remain the mainstay of treatment for all autoimmune
disorders. Extensive research in molecular events of glucocorticoid
function has been the subject of many reviews .
Virtually every cell has glucocorticoid receptors. These
receptors are located on the cell membrane as well as in the cytosol.
When glucocorticoid steroids enter the cell cytoplasm by binding to the
membrane receptor, binding to the carboxyl terminal of the receptor
results in a conformational change. The DNA binding domain on the
receptor with the 2 zinc fingers become activated and the
steroid-receptor complex attaches itself to the DNA after it travels to
the nucleus. Such binding to DNA occur at specific nucleotide sequences,
sites known as glucocorticoid responsive elements. These consensus
sequences can be positive or negative depending on the ultimate effect on
transcription at that promoter location. Accordingly, glucocorticoid
treatment can result in enhanced or repressed transcription of specific
molecules. Glucocorticoids have a wide array of activity and affect
virtually every cell in the immune system. In particular, the cells of
the lymphoid origin are affected. It is indeed an old observation that
lymphopenia occur during glucocorticoid treatment. Function of T and B
cells and macrophages are all affected, as also antigen presenting cells
such as endothelial cells, microglia, and dendritic cells. These drugs
can augment transcription, resulting in enhanced production of one lymphokine, while causing repression and
down-regulation of the production of another.
Some of these activities are dose dependent and therefore
these drugs tend to function differently at different doses.
Glucocorticoids exert their beneficial effects at many levels. Virtually
every cell type in the immune system is affected. Nevertheless, the
macrophages appear to be most sensitive to corticosteroid effects,
followed by B-cells, and then the T-lymphocytes. There are almost 3 times
as many Glucocorticoid receptors on the macrophages as on B-cells and
T-cells. Macrophages once considered as simple scavenging cells, are
today recognized as primary pro-inflammatory cells, especially when
antibodies and complement are involved in mediation of injury.
Macrophages home to sites of antibodies and activated
complement and mediate injury. Corticosteroids down-regulate the
expression of Fc and C3b receptors on macrophages and reduce the
secretion of proinflammatory lymphokines and eicosanoids. Expression of class II
histocompatibility molecules is reduced, which in turn inhibits antigen
presentation. Expression of adhesion molecules is inhibited, which
reduces cell-cell interactions. Endothelial cells no longer permit cell
migration, and inhibition of metalloproteases further reduces breakdown
of the blood-brain barrier .
Clinical use of Glucocorticoids:
There is no consensus among clinicians as to how
corticosteroids are best used in clinical practice. In part, this is a
reflection of the lack of studies to examine the optimal use of these
agents. Most clinicians use oral or intravenous steroids as short or long-term
treatments for a variety of immune mediated disorders.
Oral regimen:
Commonly used agents include prednisolone or dexamethasone.
Prednisolone is usually used in doses of 1 mg/kg, and dexamethasone in
doses of 4 to 16 mg per day. Oral regimens are suited for short or
long-term use. During short-term use, steroids are given for a week or
less and discontinued without a taper. For long-term use, prednisolone is
the preferred drug since its short half-life will lend itself to the
alternate day regimen. They stabilize the blood brain barrier, and affect
mostly macrophage and some B-cell function with limited effects on the
T-cells.
What are the advantages and disadvantages of these agents?
Dexamethasone is more anti-phlogistic, less
mineralocorticoid than prednisone, and therefore a better choice.
However, the long acting nature of the compound (half-life of 36 to 72
hours) does not lend itself to alternate-day regimen (see below).
What is the bio-equivalence of prednisolone and
dexamethasone?
The approximate bio-equivalence is determined by a combination of
relative equivalence and the biological half-life. For example, the
relative equivalence of dexamethasone to prednisolone is 5, since
dexamethasone is 25 fold more potent than hydrocortisone as compared to
prednisolone, which is 5 fold more potent (17). The biological half-life
of prednisolone is 8 hours (8 to 24 hours) as compared to 32 hours for
dexamethasone (32 to 72 hours). Since one half-life of dexamethasone is
equal to 4 half-lives of prednisolone, the biological equivalence of the
two compounds is approximately 40 mg of prednisone to each mg of
dexamethasone, and not 5 mg of prednisolone to 1 mg of dexamethasone as
may be suggested by the relative equivalence. These derivations are approximate,
since the absorption characteristics and biological half-lives of these
compounds are variable from one patient to another.
Parenteral use of corticosteroids:
Intravenous administration of corticosteroids permits the
use of large doses of corticosteroids, doses not feasible through oral
formulation. Patients receive 500 to 1000 mg of methyl prednisolone daily
for 3 to 5 days. The prednisolone is mixed in 100 ml of saline and
administered over 2 to 4 hours. Some patients experience metallic taste in
the mouth, but otherwise the drug is well tolerated. Although serious
complications including acute myocardial infarction, acid peptic disease,
pancreatitis, and delayed aseptic necrosis of the femur have all been
reported with this treatment, such occurrences are fortunately rare (18).
Nevertheless, patients should be informed of these possibilities. During
treatment, daily electrolytes, glucose, and amylase should be obtained
and abnormalities if any, corrected during treatment.
Are there any differences between oral and parenteral regimen ?
The Optic Neuritis Treatment Trial would suggest that such differences
exist, at least for treatment of acute optic neuritis.This
multicenter study examined 3 treatment groups for patients with
acute optic neuritis seen within 8 days:
Group 1. Methylprednisololone 250 mg IV q 6
hours for 3 days, followed by prednisolone 1 mg/kg tapered over a total
duration of treatment of 14 days.
Group 2. Oral prednisolone 1 mg/kg , tapered over 14 days
Group 3. Placebo for 14 days. A total of 450 subjects were randomized
into each of the 3 arms.
Improvement of the visual acuity, visual fields, and color
contrast sensitivity were observed in the IV group, evident as early as 2
weeks. By 6 months all groups were similar with regards to improvement of
acuity, and 75% of all subjects had recovered vision to 20/20. What was
however unexpected from this study was the fact that optic neuritis
occurred in the opposite unaffected eye more often in the oral
prednisolone group.
The recommendation after this study was therefore to use IV
steroids, or no steroids at all, for treatment of acute optic neuritis.
Since this study, there has been considerable interest as to whether the
observed differences were a result of the differences in dose or route of
administration. It would appear that the differences were based on the
differences in dose rather than route since administration of 1 gm of
methyl prednisolone by mouth was comparable in efficacy to the same dose
administered IV. Further, it has been shown that disruption of the
gastric mucosa does not occur to any greater degree by administration of
the larger 1 gm dose as compared to 80 mg of prednisolone.
Indications:
Multiple Sclerosis:
Agent Exacerbations:
I.V.Methyl Prednisolone 1gm. IV daily for 3-7
days, followed by an oral steroid taper with Prednisolone:
200mg x 4days then 100mg x 4 days then decreasing by 10mg daily until
off, or Dexamethasone Taper:12mg x 4days then 8mg x 4days then 4mg x
4days.
Specific neuromuscular disorders
Muscle
-
Inflammatory myopathies
Some Muscular dystrophy: Duchenne; ? LGMD 2D
Neuromuscular junction - Myasthenia gravis
Lambert-Eaton myasthenic syndrome
Nerve-
Chronic immune demyelinating polyneuropathy (CIDP)
Vasculitis & Vasculopathies
Usual doses:
Start at high dose then taper
Solu-Medrol (Methylprednisolone): 1 gram IV
daily for 3 to 5 days
Prednisolone: Usually start at 50 mg to 100 mg per day (1 mg/kg/day):
Single daily dose in am
Exception: Myasthenia gravis
Start at lower dose: 10 mg qd
Then gradually increase up to 50 mg qd
With respiratory or bulbar symptoms: Pre treat
using Plasma Exchange Maintenance
Solu-Medrol
Start at 1 gm/week IV for 1 month
Then 1 gm every 2 weeks for 2 months
Taper further by increasing time between doses Prednisolone
Start taper after: 3 to 6 months; or Clinical improvement
Taper slowly by 5 mg every 2 to 6 weeks
Risk of recurrent symptoms with taper: Varies with disease type
Myasthenia gravis: > 90% recurrence if steroids stopped
Inflammatory myopathy: ~ 50% recurrence risk
CIDP: Relapse more common
Disease course > 1 year
Adults > Children
Monitor:
Weight; Blood pressure; Blood glucose & electrolytes;
Ocular exam
Advantages of corticosteroid therapy
Short onset of action (1 to 3 months)
Effective in majority of patients with specific disease indications
Can be used in pregnancy
Disadvantages of corticosteroid therapy
Transient initial severe exacerbation, usually after 1 to 3
weeks (2%).
Many are long-term side effects ( Fewer with intermittent Solumedrol);
Glucocorticoid side effects: Cushingoid
features, Weight gain, Avascular necrosis, Osteoporosis, Myopathy,
Myosin-loss, Type II atrophy, Diabetes, Acne, Striae,
Hyperpsychosis, Pseudotumor
cerebri, Glaucoma, Infection
Drug combinations:
Corticosteroids +Azathioprine: Steroid sparing effects . Cyclophosphamide: Additional efficacy, but
high toxicity.
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