Download Mechanism of action, Pharmacokinetics, Indications and

This lecture was conducted during the Nephrology Unit Grand
Ground by Medical Student rotated under Nephrology Division
under the supervision and administration of Prof. Jamal Al
Wakeel, Head of Nephrology Unit, Department of Medicine and
Dr. Abdulkareem, Al Suwaida, Chairman of the Department of
Medicine. Nephrology Division is not responsible for the
content of the presentation for it is intended for learning and
/or education purpose only.
Cyclosporine
Presented by:
Hatem Al-Nasser
Medical Student
July 2008
Cyclosporine, the active principle in cyclosporine capsules USP is cyclic
polypeptide immunosuppressant agent consisting of 11 amino acids.
It is produced as a metabolite by the fungus species Tolypocladium Gams.
Each capsule contains the following inactive ingredients: methanol, purified
water, sodium lauryl sulfate and talc.
Mechanism of action
In the cytoplasm, cyclosporine
(CsA) binds to its
immunophilin, cyclophylin
(CpN), forming a complex
between cyclosporine and
CpN. The cyclosporine–CpN
complex binds and blocks the
function of the enzyme
calcineurin (CaN), which has
a serine/threonine
phosphatase activity. As a
result, CaN fails to
dephosphorylate the
cytoplasmic component of the
nuclear factor of activated T
cells (NF-ATc), and thereby
the transport of NF-ATc to the
nucleus and the binding of
NF-ATc to the nuclear
component of the nuclear
factor of activated T cells (NFATn).
The NF-ATc–NF-ATn
complex binds to the
promoter of the interleukin 2
(IL-2) gene and initiates IL-2
production. Consequently, T
cells do not produce IL-2,
which is necessary for full Tcell activation. Therefore It
inhibits T cell activation
Pharmacokinetics:
Cyclosporine absorption is incomplete and some what erratic,
although a new microemulsion formulation improves its
consistency and provides 20-30% bioavailability.
Grapefruit juice increases cyclosporine bioavailability by as much
as 62%.
Cyclosporine is metabolized by CYP3A and consequently is
subject to a large number of drug interactions.
Indications and contraindications:
Cyclosporine capsules USP are indicated for the prophylaxis of organ
rejection in kidney, liver, and heart allogeneic transplants.
It is always to be used with adrenal corticosteroids. The drug may also
be used in the treatment of chronic rejections in patients previously
treated with other immunosuppressive agents.
It is also indicated in RA, SLE, polymyositis, dermatomyositis,
Wegner’s granulomatosis, and juvenile chronic arthritis
Cyclosporine is contraindicated in patients with active ocular infections
and in patients with known or suspected hypersensitivity to any of the
ingredients in the formulation.
Side effects and drug interactions:
The principal adverse reactions of cyclosporine therapy are renal
dysfunction, tremor, hirsutism, hyperkalemia, hepatotoxicity,
hypertension, and gum hyperplasia.
Hypertension which is usually mild to moderate may occur in 50% of
patients following renal transplantation and in most cardiac transplant
patients.
Rare adverse effects include: anxiety, chest pain, constipation,
depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, MI,
night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI
bleeding, visual disturbance, weakness, and wight loss.
Nephrotoxicity increases when the drug is taken with diltiazem, potassium
sparing diuretics and drugs inhibiting CYP3A.
Mycophenolate Mofetil ( CellCept )
Mycophenolate is an immunosuppressant drug used to prevent rejection
in organ transplantation. It was initially marked as the prodrug
mycophenolate mofetil (MMF) to improve oral bioavailability.
More recently, the salt mycophenolate sodium has also been
introduced.
Mycophenolic acid is commonly marketed under the trade names
CellCept (mycophenolate mofetil ; Roche) and myfortic (mycophenolate
sodium ; Novartis)
Mechanism of action:
MMF is converted to mycophenolic acid, the active form of the drug. The
active product inhibits cytosine monophosphate dehydrogenase and,
secondarily, inhibits T cell lymphocyte proliferation; downstream it interferes
with leukocyte adhesion to endothelial cells through inhibition of E-selectin, Pselectin, and intercellular adhesion molecule 1.
Pharmacokinetics:
Mycophenolate is derived from the fungus Penicillum stoloniferum.
Mycophenolate mofetil is metabolized in the liver to its active moiety
mycophenolic acid. It inhibits inosine monophosphate dehydrogenase, the
enzyme that controls the rate of synthesis of guanine monophosphate in the
denovo pathway of purine synthesis used in the proliferation of B and T
lymphocytes.
Mycophenolate is potent and can be in place of the older anti –proliferative
azathioprine. It is usually used as a part of a three compound regimen if
immunosuppressants, also including a calcineurin inhibitor (Cyclosporine or
tacrolimus) and prednisolone.
Indications and contraindications:
In general, mycophenolate is used for the prevention of organ transplant
rejection. Mycophenolate mofetil is indicated for the prevention of organ
transplant rejection in adults and renal transplant in children > 2 years;
whereas mycophenolate sodium is indicated for the prevention of renal
transplantation in adults.
Mycophenolate sodium has also been used for the prevention of rejection in
liver, heart, and/or lung transplant. It is also utilized as a steroid sparing
treatment in immune-mediated disorders including immunoglobulin A
nephropathy, small vessel vasculitides, and psoriases.
Its increasing application in treating lupus nephritis has demonstrated more
frequent complete response and less frequent complications compared to
cyclophosphamide bolus therapy, a regimen with risk of bone marrow
suppression, infertility, and malignancy.
Side effects:
The most common side effects with mycophenolate include upset stomach,
nausea, vomiting or diarrhea. Other possible side effects include headache,
dizziness, difficulty sleeping, tremor and, occasionally, rash. These side effects
usually go away with time, but tell a doctor if they persist.
Less common but more serious side effects include a reduction of white blood
cells (increasing the chances of infections), red blood cells that ferry oxygen to
tissues (which may lead to anemia), and platelets that aid clotting (which can lead
to gastrointestinal bleeding). Periodic blood tests can detect reduced blood
counts early on to avoid these problems.
Patients older than 65 may be at increased risk for some side effects, especially
infections and gastrointestinal bleeding. People who have had ulcers or other
serious gastrointestinal conditions should talk with their doctors before taking this
medication.
Studies of transplant patients taking mycophenolate have found it may
increase risk of some cancers such as lymphomas and skin cancers.
Because there may be a similar risk in people with rheumatic conditions
who take mycophenolate for long periods of time, use a sunscreen and
.avoid prolonged sun exposure
Prednisone
Prednisone is an oral, synthetic corticosteroid used for suppressing the
immune system and inflammation. It mimics the action of cortisol
(hydrocortisone), the naturally-occurring corticosteroid produced in the
body by the adrenal glands.
Corticosteroids have many effects on the body, but the most common are
used for their potent anti-inflammatory effects, particularly in those
conditions in which the immune system plays an important role. Such
conditions include arthritis, colitis, asthma, bronchitis, certain skin rashes,
and allergic or inflammatory conditions of the nose and eyes.
Prednisone is inactive in the body and, in order to be effective, first must
be converted to prednisolone by enzymes in the liver. Therefore,
prednisone may not work as effectively in people with liver disease
whose ability to convert prednisone to prednisolone is impaired
Mechanism of action:
Glucocorticoids are naturally occurring hormones that prevent or suppress
inflammation and immune responses when administered at pharmacological
doses. At a molecular level, unbound glucocorticoids readily cross cell
membranes and bind with high affinity to specific cytoplasmic receptors. This
binding induces a response by modifying transcription and, ultimately protein
synthesis to achieve the steroid's intended action.
Such actions may include: inhibition of leukocyte infiltration at the site of
inflammation, interference in the function of mediators of inflammatory
response, and suppression of humeral immune responses. Some of the net
effects include reduction in edema or scar tissue, as well as a general
suppression in immune response. The degree of clinical effect is normally
related to the dose administered.
The anti-inflammatory actions of corticosteroids are thought to involve
phospholipase A2 inhibitory proteins, collectively called lipocortins.
Lipocortins, in turn, control the biosynthesis of potent mediators of
inflammation such as prostaglandins and leukotrienes by inhibiting the
release of the precursor molecule arachidonic acid. Likewise, the numerous
adverse effectsrelated to corticosteroid use are usually related to the dose
.administered and the duration of therapy
Pharmacokinetics:
Prednisone is rapidly absorbed across the GI membrane following oral
administration. Peak effects can be observed after 1—2 hours. The
circulating drug binds extensively to the plasma proteins albumin and
transcortin, with only the unbound portion of a dose active.
Systemic prednisone is quickly distributed into the kidneys, intestines,
skin, liver and muscle. Corticosteroids distribute into the breast milk
and cross the placenta. Prednisone is metabolized by the liver to the
active metabolite prednisolone, which is then further metabolized to
inactive compounds.
These inactive metabolites, as well as a small portion of unchanged
drug, are excreted in the urine. The plasma elimination half-life is 1
hour whereas the biological half-life of prednisone is 18—36 hours
Indications:
Endocrine disorders: primary or secondary adrenocortical
insufficiency (hydrocortisone or cortisone is the first choice; synthetic
analogs may be used in conjunction with mineralocorticoids where
applicable; in infancy mineralo-corticoid supplementation is of
particular importance); congenital adrenal hyperplasia; hypercalcemia
.associated with cancer; non-suppurative thyroiditis
Rheumatic disorders: as adjunctive therapy for short-term
administration (to tide the patient over an acute episode or
exacerbation) in: psoriatic arthritis, rheumatoid arthritis, including
juvenile rheumatoid arthritis (selected cases may require lowdose maintenance therapy), ankylosing spondylitis, acute and
subacute bursitis, acute nonspecific tenosynovitis, acute gouty
arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis,
.epicondylitis
Collagen diseases: during an exacerbation or as
maintenance therapy in selected cases of: systemic lupus
erythematosus, systemic dermatomyositis (polymyositis),
acute rheumatic carditis
Dermatologic diseases: pemphigus; bullous dermatitis
herpetiformis; severe erythema multiforme (Stevens-Johnson
syndrome); exfoliative dermatitis; mycosis fungoides; severe
psoriasis; severe seborrheic dermatitis
Allergic states: control of severe or incapacitating allergic
conditions intractable to adequate trials of conventional
treatment: seasonal or perennial allergic rhinitis; bronchial
asthma; contact dermatitis; atopic dermatitis; serum sickness;
drug hypersensitivity reactions
Ophthalmic diseases: severe acute and chronic allergic and inflammatory
processes involving the eye and its adnexa such as: allergic corneal marginal
ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse
posterior uveitis and choroiditis, sympathetic ophthalmia, allergic
conjunctivitis, keratitis, chorioretinitis, optic neuritis, iritis and iridocyclitis
Respiratory diseases: symptomatic sarcoidosis; Loeffler’s syndrome not
manageable by other means; berylliosis; fulminating or disseminated
pulmonary tuberculosis when used concurrently with appropriate
antituberculous chemotherapy; aspiration pneumonitis
Hematologic disorders: idiopathic thrombocytopenic purpura in adults;
secondary thrombocytopenia in adults; acquired (autoimmune) hemolytic
anemia; erythroblastopenia (RBC anemia); congenital (erythroid)
hypoplastic anemia
Neoplastic diseases: for palliative management of: leukemias and
lymphomas in adults, acute leukemia of childhood
Edematous state: to induce a diuresis or remission of proteinuria in
the nephrotic syndrome, without uremia, of the idiopathic type or that
due to lupus erythematosus
Gastrointestinal diseases: to tide the patient over a critical period of the
disease in: ulcerative colitis, regional enteritis
Nervous system: acute exacerbations of multiple sclerosis
Miscellaneous: tuberculous meningitis with subarachnoid block or
impending block when used concurrently with appropriate antituberculous
chemotherapy; trichinosis with neurologic or myocardial involvement
Contraindications/precautions:
abrupt discontinuation
breast-feeding
cataracts
children
coagulopathy
Cushing's syndrome
diabetes mellitus
diverticulitis
fungal infection
GI disease
glaucoma
heart failure
hepatic disease
herpes infection
hypertension
hypothyroidism
infection
inflammatory bowel disease
measles
myasthenia gravis
myocardial infarction
osteoporosis
peptic ulcer disease
psychosis
renal disease
seizure disorder
surgery
thromboembolic disease
tuberculosis
ulcerative colitis
vaccination
varicella
viral infection
visual disturbance
Absolute contraindications are in italics
Side effects:
abdominal pain
acne vulgaris
adrenocortical insufficiency
amenorrhea
angioedema
anorexia
anxiety
appetite stimulation
arthralgia
avascular necrosis
bone fractures
cataracts
constipation
Cushing's syndrome
depression
diabetes mellitus
diaphoresis
diarrhea
dysmenorrhea
ecchymosis
edema
EEG changes
emotional lability
erythema
esophageal ulceration
euphoria
exfoliative dermatitis
exophthalmos
fever
fluid retention
gastritis
growth inhibition
headache
heart failure
hirsutism
hypercholesterolemia
hyperglycemia
hypernatremia
hypertension
hypocalcemia
hypokalemia
hypotension
(HPA) suppression
immunosuppression
impaired wound healing
increased intracranial pressure
infection
insomnia
lethargy
menstrual irregularity
metabolic alkalosis
mood lability
myalgia
myopathy
nausea/vomiting
ocular hypertension
optic neuritis
osteoporosis
palpitations
pancreatitis
papilledema
peptic ulcer
peripheral neuropathy
petechiae
phlebitis
physiological dependence
pseudotumor cerebri
psychosis
restlessness
retinopathy
seizures
sinus tachycardia
skin atrophy
sodium retention
striae
thrombocytopenia
thromboembolism
thrombosis
urinary incontinence
urinary urgency
urticaria
vertigo
visual impairment
weakness
weight gain
weight loss
withdrawal
Thank you
Done by: Hatem AL-Nasser