Corticosteroidi

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Corticosteroidi STORIA 1563 Eustachio scopre
lesistenza delle ghiandole surrenali 1849
Addison attribuisce la pelle bronzea a
malfunzionamento delle ghiandole surrenali 1856
Brown-Sequard rimuove le ghiandole surrenali di
gatti e cani i quali poi moriranno nellarco di
qualche giorno dimostrando cosi limportanza
vitale di queste ghiandole. 1894 Viene scoperta
la suddivisione delle surrenali (corteccia e
midollare). Ladrenalina viene secreta dalla
midollare. 1938 Reichstein isola 29 nuove
sostanze dalla corteccia surrenale e tutte sono
steroidi. 1948 Kendall isola il cortisone 1950
Kendall, Reichstein ed Hench riceveranno il
premio Nobel per la medicina
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For a long period I had from time to time met
with a very remarkable form of general anaemia,
occurring without any discoverable cause
whatever. The disease presented in every instance
the same general character, pursued a similar
course, and, with scarcely a single exception,
was followed, after a variable period, by the
same fatal result. The appetite is impaired or
entirely lost the whites of the eyes become
pearly the pulse small and feeble. The body
wastes, slight pain or uneasiness is from time to
time referred to the region of the stomach, and
there is occasionally actual vomiting, which in
one instance was both urgent and distressing
Neither the most diligent inquiry, nor the most
careful physical examination, tends to throw the
slightest gleam of light upon the precise nature
of the patients malady But with a more or less
manifestation of the symptoms already enumerated,
we discover a most remarkable, and, so far as I
know, characteristic discoloration taking place
in the skin.
Thomas Addison, 1855
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Rev Endocr Metab Disord. 2010 Jun11(2)147-53. Th
e diagnosis of Cushing's syndrome. Carroll TB,
Findling JW. Endocrinology Center (TBC, JWF),
Medical College of Wisconsin, W129 N7055
Northfield Drive Building A, Suite 203, Menomonee
Falls, WI 53051, USA. tcarroll_at_mcw.edu Abstract Sp
ontaneous Cushing's syndrome is well known but
unusual clinical disorder. Many of the clinical
features (central weight gain, glucose
intolerance, hypertension, muscle weakness) are
seen in other common conditions. Recognition of
patients with multiple features, features unusual
for their age (i.e. early onset osteoporosis or
hypertension), patients with features more
specific to Cushing's syndrome (i.e. easy
bruising, facial plethora, and violaceous
striae), and patients with incidental adrenal
mass or polycystic ovary syndrome should prompt
an evaluation for cortisol excess. Late-night
salivary cortisol, 1 mg overnight dexamethasone
suppression testing, or 24 h urine free cortisol
determination have excellent diagnostic
characteristics and should be obtain in patients
with suspected Cushing' syndrome. If this initial
testing is abnormal, further evaluation should be
directed by an endocrinologist experienced in the
diagnosis and differential diagnosis of Cushing'
syndrome.
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Cushings Support Research Foundation
Easy bruising Thinning skin Poor wound
healing Acne Purple striae Hirsutism Female
balding Menstrual irregularity Sleep
disorders Excessive hunger Excessive
thirst Frequent urination Sweating Anxiety Confus
ion Concentration loss Memory loss Depression Suic
idal thoughts Panic attacks
Symptoms Vary And may include any number of
these
Abdominal weight gain Red, round moon
face Thinning extremities Buffalo hump High
blood pressure High blood sugar Muscle
weakness Osteoporosis/Fractures Infections Blood
clots Visual field defects
Illustration from Mayo Clinic Family Health Book,
2d. ed, 1996
Courtesy of www.CSRF.com
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HPA
Ipotalamo
Ipofisi
Surrenali
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I glucocorticoidi sono degli ormoni rilasciati
dale ghiandole surrenali sotto lo stimolo
ipofisario dellACTH e ancor prima dallo stimolo
ipotalamico rappresentato dal CRH. Il
glucocorticoide per eccellenza è il cortisolo.
Molti glucocorticoidi di sintesi sono altamente
efficaci nel trattare malattie infiammatorie,
quali asma, reazioni autoimmuni e allergie. I
loro effetti terapeutici sono generalmente
ascrivibili alla forte azione inibitoria sulla
produzione di cellule T così come sulla
inibizione del rilascio di interleuchina 2 e del
suo recettore. Anche le interleuchine
proinfiammatorie 1, 6 e 12, vengono inibite nel
loro rilascio così come per il Tumor necrosis
factor alfa presente nei monociti e macrofagi.
Questi effetti sono mediati dai recettori per i
glucocorticoidi presenti nel citoplasma. Una
volta legati al suo recettore i glucocorticoidi
traslocano nel nucleo e regolano lespressione
genica legandosi specificativamente a sequenze di
DNA con geni detti elementi dei recettori dei
glucocorticoidi. Il recettore dei glucocorticoidi
altera anche lespressione genica attraverso
linterazione diretta con proteine non
recettoriali legate al promotore presente sul
gene. A queste azioni antiinfiammatorie però sono
legati effetti collaterali quali aumento di peso
corporeo, diabete, ipertensione, osteoporosi,
cambiamenti comportamentali e alterazione del
sonno.
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Livelli di cortisolo durante la giornata e
durante I giorni della settimana
The measurement of late-night salivary cortisol,
usually at 2300 to 2400 h, has proven to be a
very useful approach to the diagnosis of
Cushings syndrome.
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Linspiegabile osservazione che ricercatori negli
anni cinquanta vedevano in pazienti a cui
venivano date quantità elevate di cortisone per
os ma avevano piccole concentrazioni di cortisone
nel plasma con un alto livello di cortisolo è
stato finalmente chiarito in anni recenti.
Paradossalmente il composto E (cortisone) che
Kendall usava è una molecola inattiva che
richiede la trasformazione metabolica in
cortisolo per svolgere la sua attività
antinfiammatoria. La conversione sistemica del
cortisone a cortisolo è principalmente per via
epatica attraverso la 11 beta idrossisteroidedeidr
ogenasi 1 (11betaHSD1) che riduce il cortisone a
cortisolo. La 11 beta idrossisteroidedeidrogenasi
2 (11betaHSD2) riconverte il cortisolo in
cortisone ed è generalmente espressa nel tessuto
e dipende dallattivazione del recettore
mineralocorticoideo per attivazione dei
mineralocorticoidi nel rene. Poichè sia
laldosterone che il cortisolo sono entrambi
potenti agonisti mineralocoricoidei lattività
della 11betaHSD2 è richiesta in quei siti dove il
cortisolo deve essere disattivato e quidi
prevenire loccupazione dei recettori
mineralocorticoidei.
11betaHSD1
11betaHSD2
Cortisolo
Cortisone
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Farmaci glucocorticoidei
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Beclometasone
BDP is actually a pro-drug with weak
glucocorticoid receptor binding affinity, that is
hydrolysed via esterase enzymes to an active
metabolite beclomethasone 17-monopropionate
(B-17-MP)
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Beclomethasone 17,21-dipropionate (BDP) is a
topically active corticosteroid used in the
treatment of asthma and rhinitis. It was first
available in 1972 in a pressurized metered-dose
inhaler (MDI) and later in a dry powder inhaler
and an aqueous nasal spray.
19
Numerazione degli atomi di carbonio nello
scheletro degli steroidi
20
Milestones included the discovery that whereas
9a-fluorination increased anti-inflammatory
potency, it also caused excessive protein loss,
potassium loss, sodium retention and oedema. On
the other hand, introduction of a 1,2 double bond
in the A ring (to create prednisone from
cortisone and prednisolone from cortisol) created
derivatives with improved anti-inflammatory
properties and reduced undesirable side effects.
16a-Hydroxylated compounds retained
glucocorticoid activity without concomitant salt
and fluid retention while 16a-methylation further
increased anti-inflammatory activity. Combining
9a-fluorination, 1-dehydrogenation and
16a-methylation yielded dexamethasone, which was
the most potent nonsalt retaining
anti-inflammatory of its time
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MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI
CORTISONICI
Inibizione della PLA2 da parte dei glucocorticoidi
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Vie di formazione dei macrofagi
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Effetti dei glucocorticoidi sulle cellule
immunitarie
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Meccanismi molecolari di trascrizione del segnale
da glucocorticoidi
Trasferimento nucleo-citoplasmatico e regolazione
trascrizionale del recettore per i
glucocorticoidi GR alfa. Una volta che il ligando
si lega al Gralfa questo si dissocia dalla
proteina heat-shock proteins (HSPs) e trasloca
nel nucleo dove si lega come omodimero al GREs
nelle regioni promotrici di particolari geni del
DNA o interagisce come monomero con unaltro
fattore di trascrizione (TF). (REs response
elements, RNPII RNA polymerase II, GRE
glucocorticoid response element).
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Gli enzimi 11beta-Idrossisteroide deidrogenasi
Gli enzimi della 11betaHSD catalizzano la
interconversione dei glucocorticoidi dalla forma
attiva a quella inattiva. I due isoenzimi sono
chiamati 11bHSD1 e 11bHSD2
Trasmissione del segnale del recettore
mineralocorticoide e glucocorticoide. I
macrofagi contengono recettori per i
mineralocortocidi e i glucocorticoidi ma non per
laldosterone cui necessita lenzima 11beta HSD2.
Per questo motivo i glucocorticoidi circolano a
più alte concentrazioni del mineralocorticoide
aldosterone ed in condizioni normali i recettori
per i mirelalocorticoidi dovrebbero essere
occupati dal cortisolo. In contrasto, le cellule
endoteliali contengono lenzima 11bHSD2 e di
conseguenza I recettori per I mineralocorticoidi
sono normalmente attivati dallaldosterone.
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Attivazione classica e alternativa dei macrofagi.
I fenotipi polarizzati di macrofagi sono
largamente definiti come classici e attivati
alternativamente. I macrofagi attivati
classicamente rispondono allinterferone gamma e
lipopolisaccaridi e giocano un ruolo importante
nel tipo 1 dellinfiammazione, nella distruzione
del tessuto, nelluccisione di parassiti
intracellulari e nella resistenza ai tumori. In
contrasto, i macrofagi attivati alternativamente
rispondono a fattori come linterleuchina 4 o 3 o
10, ai complessi immunitari, al TGF beta e ai
glucocorticoidi e contribuiscono
allinfiammazione di tipo 2, alla rimodellazione
del tessuto, allangiogenesi, alla incapsulazione
dei parassiti e alla progressione del tumore.
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Effetti dei Glucocorticoidi sullosso
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Journal of Endocrinology (2009) 201, 309320
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Tipico dosaggio dei cortisonici per prevenire la
soppressione dellasse ipotalamo-ipofisi-surrene
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Medical management of adrenal disease a
narrative review. Michalakis K, Ilias
I. Department of Endocrinology, E Venizelou
Hospital, 2, Athens GR-11521, Greece. Adrenal
diseases comprise for a variety of medical
endocrine issues, ranging from partial or
complete gland insufficiency, to several kinds of
adrenal hyperfunction, either of congenital or
neoplastic etiology. For hypofunction of the
adrenals (partial or complete) the treatment of
choice is medical the mainstay of treatment is
hydrocortisone. Patients with congenital adrenal
hyperplasia caused by 21-hydroxylase deficiency
are treated with glucocorticoids to control
androgen excess. Most benign neoplastic adrenal
diseases that cause hyperfunction of the gland
are surgically treated, however this may not be
always feasible or effective. For Cushing's
syndrome ketoconazole controls cortisol's
hypersecretion, whereas in case of bilateral
idiopathic hyperaldosteronism spironolactone
controls hypokalemia and hypertension. For
neoplastic adrenomedullary disease surgery is the
treatment of choice medical treatment is used
preoperatively (mainly alpha blockers) and in
case of disease persistence and /or recurrence
(mainly metyrosine). For malignant adrenocortical
disease, surgical removal remains the indicated
treatment, but if the potential for surgical
intervention is limited due to tumor extension,
medical treatment can alleviate symptoms of
hormone hypersecretion mitotane in selected
patients has good results
Endocr Regul. 2009 Jul43(3)127-35.
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Eventi avversi da cortisonici
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Effetti dei cortisonici sul sistema nervoso
centrale
Psychiatry Clin Neurosci. 2009 Oct63(5)613-22. C
entral nervous system effects of natural and
synthetic glucocorticoids. Fietta P, Fietta P,
Delsante G. Psychiatry Department, Hospital of
Lodi, Lodi, Italy. pierluigi.fietta_at_ao.lodi.it Abs
tract Natural glucocorticoids (NGC)
physiologically modulate body homeostasis and
coordinate adaptive responses to stress,
involving almost all organs and tissues,
including brain. Since their therapeutic
availability, synthetic GC (SGC) have been
successfully prescribed for a variety of
diseases. Mounting evidence, however,
demonstrated pleiotropic adverse effects (AE),
including central nervous system (CNS)
disturbances, which are often misdiagnosed or
underestimated. The aim of the present study was
therefore to review and discuss the CNS effects
of both NGC and SGC. A detailed search was
carried out of the available literature using the
PubMed (US National Library of Medicine)
database. Cortisolemia plays a crucial role in
control of behavior, cognition, mood, and early
life programming of stress reactivity.
Hypercortisolemia or SGC treatments may induce
behavioral, psychic and cognitive disturbances,
due to functional and, over time, structural
alterations in specific brain target areas. These
AE are generally dose and time dependent
(infrequent at prednisone-equivalent doses lt20
mg/day) and usually reversible. Pediatric
patients are particularly susceptible. Behavioral
changes, including feeding and sleeping
modifications, are common. Psychic AE are
unpredictable and heterogeneous, usually
mild/moderate, severe in 5-10 of cases. Manic
symptoms have been mostly associated with short
SGC courses, and depressive disorder with
long-term treatments. Suicidality has been
reported. Cognitive AE peculiarly affect
declarative memory performance. Physiologic
levels of NGC are essential for efficient brain
functions. Otherwise, hypercortisolemia and SGC
treatments may cause dose-/time-dependent
neuropsychic AE and, over time, structural
alterations in brain target areas. Clinicians
should carefully monitor patients, especially
children and/or when administering high doses
SGC. PMID 19788629 PubMed - indexed for MEDLINE
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Cardiovasc J Afr. 2009 Jul-Aug20(4)233-6. Cortic
osteroid therapy for primary treatment of
Kawasaki disease - weight of evidence a
meta-analysis and systematic review of the
literature. Athappan G, Gale S, Ponniah
T. Caritas St Elizabeth Medical Centre, Tufts
School of Medicine, Boston, USA.
ganeshathappan_at_gmail.com OBJECTIVE
Corticosteroids are the treatment of choice in
most forms of vasculitis. However, their role in
the primary treatment of Kawasaki disease (KD) is
controversial. Our aim was to conduct a
meta-analysis to assess the clinical course and
coronary artery outcome of adding corticosteroids
to standard therapy intravenous immunoglobulin
(IVIG) aspirin in patients with acute KD.
METHODS We included randomised trials comparing
the addition of corticosteroids to conventional
primary therapy for Kawasaki disease. RESULTS A
total of four studies were identified, which
included 447 patients. The meta-analysis revealed
a significant reduction in re-treatments with
IVIG in patients receiving corticosteroid plus
standard therapy compared with standard therapy
alone odds ratio (OR) 0.48 95 confidence
interval (CI) 0.24- 0.95. There was however no
significant reduction in the incidence of
coronary artery aneurysms among patients who
received corticosteroid therapy plus standard
therapy, compared with standard therapy alone for
either up to a month (OR 0.74 95 CI 0.23-2.40)
or over one month (OR 0.74 95 CI 0.37-1.51).
Similarly no significant differences between
treatment groups were noted in incidence of
adverse events (OR 0.81 95 CI 0.05-0.88).
CONCLUSION The inclusion of corticosteroids in
regimens for the initial treatment of Kawasaki
disease decreased rates of re-treatment with
intravenous immunoglobulin. However the addition
of corticosteroids to standard therapy did not
decrease the incidence of coronary aneurysms or
adverse events.
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Duchenne muscular dystrophy (DMD) is a disease
linked to the X-chromosome which affects 1 in
3,600-6,000 newborn males. It is manifested by
the absence of the dystrophin protein in muscle
fibres, which causes progressive damage leading
to death in the third decade of life. The only
medication so far shown to be effective in
delaying the progression of this illness are
corticosteroids, which have been shown to
increase muscle strength in randomised controlled
studies long-term studies have demonstrated that
they prolong walking time and retard the
progression of respiratory dysfunction, dilated
cardiomyopathy and scoliosis. Several potential
drugs are now being investigated. Genetic
therapy, involving the insertion of a dystrophin
gene through a vector, has proven effective in
animals but not humans. Currently under clinical
study is Ataluren, a molecule that binds
with ribosomes and may allow the insertion of an
aminoacid in the premature termination codon, and
exon-skipping, which binds with RNA and excludes
specific sites of RNA splicing, producing a
dystrophin that is smaller but functional. There
are also studies attempting to modulate other
muscular proteins, such as myostatin and
utrophin, to reduce symptoms. This paper does not
address cardiomyopathy treatment in DMD patients.
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Endogenous Cushings syndrome results from
excessive glucocorticoid production with a
failure of the normal negative feedback effect on
the hypothalamo-pituitaryadrenal axis. It is
traditionally divided into ACTHdependent and
ACTH-independent Cushings syndrome. In the
majority of cases, it is caused by an adenoma in
the pituitary gland secreting ACTH hormone
(Cushings disease),
The medical therapy of hypercortisolaemia in
Cushings syndrome is predominantly based on the
inhibition of adrenal steroidogenesis at one or
more enzymatic sites, or alternatively by
antagonism of the glucocorticoid receptor or the
suppression of ACTH. Oral therapy with
ketoconazole and metyrapone are the most frequent
steroidogenic enzyme inhibitors currently in use.
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Kawasaki disease
Vascoliti
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Br J Haematol. 2010 Jun149(5)638-52. Epub 2010
Apr 12. The optimal use of steroids in paediatric
acute lymphoblastic leukaemia no easy
answers. McNeer JL, Nachman JB. Section of
Paediatric Haematology/Oncology, University of
Chicago Comer Children's Hospital, Chicago, IL,
USA. Abstract Glucocorticoids are an integral
component of therapy for acute lymphoblastic
leukaemia (ALL), but usage differs between
cooperative group protocols. All groups use
glucocorticoids during induction but vary on
whether to use dexamethasone or prednisone.
Issues to consider in the choice of induction
steroid include impact on event-free and overall
survival, acute morbidity such as infection risk,
diabetes, and behavioural disturbances and
long-term complications such as avascular
necrosis. It is generally agreed that
dexamethasone is the steroid of choice for groups
using a delayed intensification phase, but dosing
schedules (intermittent versus continuous) vary.
There is no consensus on the potential benefit of
steroid administration during maintenance
therapy.
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Tossicità da corticosteroidi
I glucocorticoidi sono farmaci molto efficaci
contro la leucemia però ad essi sono associati
eventi tossici importanti. - Le tossicità a
breve termine sono mialgia, miopatia, infezioni,
iperglicemia, problemi comportamentali,
soppressione dellasse ipotalamo-ipofisi-ghiandole
surrenali possono terminare alla sospensione del
trattamento. - La necrosi avascolare dellosso è
di particolare gravità perchè ha un grande
impatto nella qualità della vita per il resto
della vita del paziente.
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• INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
• METIRAPONE (inibitore della 11b-idrossilazione)
• TRILOSTANO (inibitore della 3 b-idrossisteroide
  deidrogenasi)
• KETOCONAZOLO (Blocca la rottura della catena
  laterale del colesterolo)

Il metirapone blocca la sintesi del cortisolo
attraverso linibizione della steroid
11ß-hydroxylase. Questo fatto stimola lipofisi a
produrre ACTH la quale aumenta nel plasma i
livelli di 11-deoxycortisol levels. Quando un
eccesso di ACTH è la causa di ipercortisolismo,
il test del metirapone aiuta a vedere se la causa
è lACTH ipofisaria o è di natura ectopica ovvero
non-ipofisaria.