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Glucocorticoid Withdrawal Syndrome

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Hypersecretion of endogen or chronic administration the same hormon ... Fatigue, hypersomnia, lethargy and hyperphagia. Hypercoritsolism 2/3 patient depression. ... – PowerPoint PPT presentation

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Title: Glucocorticoid Withdrawal Syndrome


1
Glucocorticoid Withdrawal Syndrome
  • CME Review article 18 2004
  • Z.Hochberg
  • Presents by
  • Chen T.T.

2
Introduction
  • Hypersecretion of endogen or chronic
    administration the same hormon tolerance or
    dependence.
  • Termination Hormon deficiency -withdrawal
    syndrome.
  • Endocrine withdrawal synd. changes HPAx and
    centr. Opiate, Noradrenal a. dopaminergic system
    of the brain.

3
Introduction
  • High dose glucocorticoid suppressed HPA axis.
  • Osteoporosis, cataract formation, increase BP.
  • Increase glucose level
  • Increase cholesterol level
  • Myopathy
  • Avascular necrosis
  • Growth retardation.

4
Clinical manifestation
  • Anorexia
  • Weight loss
  • Nausea and vomiting
  • Headache
  • Lethargy, fever, myalgia, arthralgia,
  • Skin desquamation
  • Postural hypotension.

5
Tolerance, dependence and addiction
  • Tolerance Functional adjustments of target
    tissue signal transduction systems and/or form
    metabolic adjustment associated with increased
    catabolism and disposition of the drug taken
    chronically.

6
Tolerance, dependence and addiction
  • Progressive decreased response to the effect of a
    drug, necessitating ever-larger doses to achieve
    the same effect.
  • Addiction Psychological and physiological
    dependence with clear adverse behavioral and
    social consequences, mainly with regard to drugs
    of abuse.

7
Withdrawal syndrome after discontinuation of
glucocorticoid therapy
  • Glucocorticoid control the activity of
    autoimmune, inflammatory, allergy and neoplasm of
    the hematopoietic system.
  • High therapy dose control suppress the HPA axis
    and exert numerous CNS effect- anxiety, insomnia,
    impairment of cognition , euphoria, mania,
    depression and psychosis.

8
Withdrawal syndrome after discontinuation of
glucocorticoid therapy
  • Relapse of illness.
  • HPA axis and POMC-derived peptide secretion
    remain suppressed for long time.
  • Nonspesific withdrawal syndrome could develop
    even receiving physiological replacement dose.
  • Psychologic dependence.
  • Syndrome could occur during weaning pharmacologic
    high dose therapy while replacement is adequat.

9
Withdrawal synd. After correction of
hypercotisolism in Cushing synd.
  • Successful surgery of Cushing synd. Patient feels
    worse.
  • Atypical depressive disorder develops in over
    half of postoperative patient, ¼ of patient for
    up to 1 year while still glucocorticoid
    replacement.

10
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11
Possible mechanism of the Glucocorticoid
withdrawal Synd
  • Corticotropin-Releasing hormone suppressed.
  • Patient with Cushings disease show markedly
    decreased CRH in CSF.
  • Hypersecretion of CRH? Hypercortisolism -?
    melancholia
  • Glucocorticoid induced hyperactivity of CRH
    neuron in the amygdala -? arousal, fear response
    and anxiety.

12
Possible mechanism of the Glucocorticoid
withdrawal synd
  • Hyposecretion of CRH plays the important role in
    pathogenesis of atypical depression.
  • Abrupt glucorticoid withdrawal -? psychopathology
    ? long standing hypoactivity of central CRH
    neuron.
  • Fatigue, hypersomnia, lethargy and hyperphagia.
  • Hypercoritsolism ? 2/3 patient depression.

13
Vasopressin
  • Adrenal insufficiency elevated plasma
    vasopressin, normalized by glucocorticoid
    replacement.
  • Cushing synd. suppress vasopressin with increase
    frequency urination.
  • Improved short-and long term memory processes,
    mood, concentration of depressed patient.
  • Oxytocin impair memory performance.
  • Glucocorticoid withdrawal induced disturbance of
    vasopressin and oxytocin neurons.

14
Neurotransmitters
  • Glucocorticoid treatment increase dopamine
    release in nucleus accumbens associated with the
    Euphoric state.
  • Acute stress dopamine release from mesolimbic
    systemin defensive responses.
  • But prolonged exposure to stress ---gt inhibition
    of the mesolimbic dopanergic system.

15
Neurotransmitters
  • Chronic hypercotisolemia( animal )? central
    noradrenegic system is inhibited.
  • Adrenalectomy increase norepinephrine release in
    brain and periphere, cortisol. Replacement blunt
    this change.
  • Chronic cortisolism inhibit periphere
    sympathoadrenal activity.
  • Cushings synd. decrease glucose up take rate in
    all brain, except striatum.

16
Neurotransmitters
  • Post op patient of Cushing synd.? increase panic
    behavior together with increased sympathoadrenal
    activity? normalized after steroid replacement.
  • Corticosteroid withdrawal -gt Panic and increased
    central noradrenergic activity. When the function
    of noradrenagenic neuron recover, symptoms of
    anxiety subsided.

17
Neurotransmitters
  • Thus,
  • Major depression hyperadrenegic and
    hypercortisolemic.
  • Depressed Cushing patient Hypoadrenergic and
    hypercoticolemic
  • Patient after glucocorticoid withdrawal
    Hypernoradrenergic and hypocortisolemic.

18
Pro-opiomelanocortin
  • CRH and Vasopressin stimulate serum level of
    lipotropin, MSH and Beta-endorphin.
  • Glucoriticoid supppress pituitary and
    hypothalamic POMC expression.
  • Hence, some of the symptoms of Cushing synd.
    Related to deficiency of these peptids.
  • So some of CNS symptoms of glucocorticoid
    dependence and withdrawal are related to those of
    opiate withdrawal.

19
Interleukin and Prostaglandins
  • Acute phase of gluc. withdrawal and the flu like
    syndrome?IL-6, TNF-alpha and IL 1beta increased.
  • Exogenous administration of IL-6 ? Flu like synd.
  • PGE2 and PGI2 may induce many of the feature of
    the flu like synd.

20
Nicotine
  • Habitual smoker- dose dependent increase plasma
    cortisol after smoking 2 cigarette and fall in
    plasma cortisol level with withdrawal of nicotine
    stimulus.
  • Nicotine withdrawal? change of CRH and cortisol
    level.
  • Thus cigarette cessation program ?
  • 1-2 ACTH injections help smoker stop.

21
Therapeutic approaches to glucocorticoid
withdrawal
  • 2 Option to minimize postoperative withd.synd.
  • 1. Normalize cortisol secretion Pre- Op. with
    medical suppression of steroidegenesis.
  • 2. High-dose glucocorticoid replacement therapy
    Post0-Op and tape it off gradually.

22
Therapeutic approaches to glucocorticoid
withdrawal
  • Sucessful withdrawal of a long term low dose
    glucocort. Therapy depends on the recovery of
    ther pituitary adrenal axis.
  • Assess by a low dose ACTH stimulation and CRH
    stimulation tests.
  • Fluoxetine- effective for Tx of glucocorticoid
    and androgen withdrawal synd.

23
Withdrawal syndrome of other steroid hormones.
  • Estrogen and Progestins
  • Estrogen potent stimuli to HPA axis.
  • Manisfestation of withdrawal synd.
  • Hot flushes and autonomic hyperactivity, also
    fatigue, irritability, anxiety and depression
    even psychosis.

24
Withdrawal syndrome of other steroid hormones.
  • Supra physiological gonadal steroid levels of
    pregnancy and withdrawal from these high levels
    to hypogonadal state-?mood symptoms-gt post partum
    depression.
  • 60 mild depression.
  • 13 Fullfledged depression.

25
Withdrawal syndrome of other steroid hormones.
  • Estrogens are psychoactive and change mood.
  • Psychological and physiological dependence-
    Replacement therapy promotes feeling of well
    being.
  • Premenstrual dysphoric disorder (PMDD)-Premens.
    Irritability, fatique and mood change associated
    with increase and decrease in levels of estrogen
    and progresterone.

26
Withdrawal syndrome of other steroid hormones
  • Abuser of anabolic steroid of athletes could be
    up 100 times greater than therapeutic replacement
    doses.
  • Have severe psychologic and behavioral side
    effect, including aggressive and violent
    behavior.
  • Withdrawal and dependence Decreased sexual
    drive, also in a flu like synd that mimics in
    many ways, the glucocorticoid withdrawal synd.

27
Withdrawal syndrome of other steroid hormones
  • 23 of anabolic user reported major mood
    syndromes mania, hyponamia, and depression.

28
Common mechanisms possibly underlying steroid
hormones withdrawal synd.
  • Symptoms or signs of endocr. withdr. Syndrome are
    different.
  • Fear and anxiety decrease steroid hormonal
    level.
  • Euphoric Glucocorticoid, estrogen and androgen
    overdosing.
  • Depression in vice versa.

29
Common mechanisms possibly underlying steroid
hormones withdrawal synd.
  • Labile mood and paranoid idea
  • Withdrawal symptoms from different classes of
    drugs of abuse- common sign of mood disturbance
    and flu like symptoms.
  • Clonidine ameliorate the withdrawal syndrome from
    glucocorticoid, anabolic steroid as well as those
    of menopause.

30
Common mechanisms possibly underlying steroid
hormones withdrawal synd
  • High dose glucocorticoid suppress POMC-expression
    with conceivable adjustment of that system to a
    new steady state that is abruptly changed after
    withdrawal.
  • Sex steroid modulate POMC-related peptid
    secretion and opioid peptide activity- Effect of
    naloxone on neg. feed back of gonadotropins.

31
Common mechanisms possibly underlying steroid
hormones withdrawal synd
  • Mesolimbic dopaminergic system is known to
    participate in the opiate withdrawal syndrome.
  • Relatively short-term dependence and addiction to
    drugs Resulte from adaptation in specific
    target cells-caused by prolonged exposure to a
    supraphysiological level of drug or hormone
    abuse.
  • Acute opiate exporure inhibits neuronal cAMP ,
    whereas chronic exporure leads to a compensatory
    cAMP upregulation.

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