cushing handout

8/7/2019 Cushing Handout

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Adrenal gland disorder : hyprerfunction (hypercortisolism): Cushing syndrome .

Presented by : Nada Kamal Ragab

PHARM D programPostgraduate studiesCairo university2010

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No. Content

1. History2. Def inition3 . Epidem iology4 . path physiology5 . Etiology6 . Clinical manife st ation7 . D iffe r e nti al diagnosis8 . D iagnosis9 . T r e at me nt10. Evaluation o f th e th e rape utic outco me s11. Pati e nt couns e ling12. Case 13 . M ind plan14 . r efe rance s

hyper function

Hypercortisolism

Cushing syndrome


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1.History :

fig 1: professor Cushing

In 1 93 2, Cushing first described the syndrome emphasized that it was of pituitary origin.

Ten years later, Albright focused his attention on the sugar hormone, which he believed

originated from the adrenal cortex.

After the development of the method for measuring urinary steroids, Daughaday discoveredelevated steroids in the urine of patients with Cushing s disease.

Finally, the end product was identified, and Cushing s syndrome was correctly explained as anexcess of cortisol in the plasma (hypercortisolism).

2 .Defination :

Cushing s syndrome : It refers to the path physiologic hyper function of the adrenal gland onthe cortisol level changes associated with :

exposure to supraphysiologic cortisol Concentrations (endogenous hypercortisolism ) pharmacologic doses of glucocorticoids (exogenous hypercortisolism ).

3.Epidmology:

y Cushing s syndrome from endogenous causes: is a rare condition ,incidence of 2 to 5 casesper 1 million persons per year.

y Patients receiving chronic supraphysiologic doses of Glucocorticoids: such as those withrheumatologic disorders, are at high risk of developing Cushing s syndrome..

y Cushing's syndrome is not confined to humans and is also a relatively common condition in

domestic dogs and horses


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4.Pathophysiology:

y Cushing s syndrome results from the effects of supraphysiologic levels of glucocorticoidsoriginating from either :

1) Exogenous administration or Endogenous overproduction by the adrenal gland

A CTH-dependent (A drenocorticotrophic hormone)

2) Abnormal adrenocortical tissues . A CTH-independent

A CTH-dependentCushing s

A CTH-dependent Cushing ssyndrome

is usually caused byoverproduction of A CTH bythe pituitary gland,

causing adrenal hyperplasia

(Cushing s disease).

Ectopic A CTH syndromerefers to excessive A CTHproduction

resulting from an endocrineor non endocrine tumor,

usually of the pancreas,thyroid, or lung.

(e.g., small-cell lung cancer).


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Cushing's disease refers only to hypercortisolism secondary to excess production of AC TH from acorticotrophic pituitary adenoma .

6.Clinical manifestations:The most common findings:

which are present in 90% of patients, are central obesity and facial rounding.

Fig 2: Cushing patient

Signs & symptoms:

Peripheral obesity and fat accumulation

Facial plethora is caused by an underlying atrophy of the skin and connective tissue

Patients often are described as having moon faces with a buffalo hump.

Hypertension

Psychiatric changes

Cushing induced osteoporosis. ( 40% will present with back pain and 20% will progress tocompression fractures of the spine)

Striae are usually present along the lower abdomen and take on a red to purple color.

patients complain of myopathies and muscular weakness .

Gonadal dysfunction is common with amenorrhea seen in females.

Excess androgen secretion is responsible for females presenting with hirsutism.

7.Diagnosise:

The diagnosis of Cushing s syndrome involves two steps:

(1) Establishing the presence of hypercortisolism, which is relatively easy


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(2) Differentiating between etiologies, which can be quite a challenge

Diagnostic Laboratory Tests Etiology determining Tests

A midnight plasma cortisol. 2 4-hour urine free cortisol. low-dose DST will establish.

(Dexamethasone suppression test)

It indicate the Presence of hypercortisolism

The high-dose D ST. plasma AC TH test. metyrapone stimulation test. CRH stimulation test. inferior petrosal sinus sampling.

It indicate the determination of etiology

A bnormal adrenal anatomy is effectively identified using :

1. high-resolution computed tomography scanning.

2. magnetic resonance imaging.

8. Differential Diagnosis :

Although the diagnosis of Cushing s disease is not a difficult one. at times the clinician will needto differentiate it from syndromes that mimic Cushing s.

Pseudo-Cushing s syndrome , It refers to a group of diseases that can mimic Cushing s disease.

Iatrogenic Cushing s syndrome

Patients with ;

obesity

Depression acute illness of anytype

chronic alcoholism


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Therefore, A ll this can cloud the diagnosis of Cushing s disease.

9.Treatment :

1.Treatment goal:

y The goals of treatment for Cushing s syndrome are to limit morbidity and mortality

y return the patient to a normal functional state by removing the source of hypercortisolismwithout causing any pituitary or adrenal deficiencies.

2 .Treatment strategies :

Iatrogenic Cushing s syndrome

induced by pharmacologic agents, often is indistinguishable from Cushing s disease.

This syndrome can occur from administration :

1.oral, inhaled, intranasal,intra-articular and topical glucocorticoids

2.progestins such as medroxyprogesterone acetate and megestrol acetate.

3 .inhibitor of cytochrome P 45 0 concomitantly with a glucocorticoid can be at higher risk of developing iatrogenic Cushing's syndrome

If exogenous glucocorticoids are beingtaken, plasma cortisol levels canincrease, while corticosterone levelsremain low.

Key note


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A . Non pharmacologic Therapy

1.Surgery

y The treatment of choice for both AC TH-dependent and AC TH-independent Cushing s syndrome

is surgical resection of any offending tumors.

2 .Radiation

y Pituitary irradiation provides clinical improvement in about 50% of patients, but improvementmay not be seen for 6 to 12 months and pituitary-dependent hormone deficiencies can occur.

W HY ?

Because,HP A axis suppression associated with chronic hypercortisolism can result in prolongedadrenal insufficiency lasting for months after surgery and requiring exogenous glucocorticoidadministration

B. Pharmacotherapy :

Pharmacotherapy generally is reserved for patients:

(1) in whom the ectopic AC TH-secreting tumor cannot be localized

(2) who are not surgical candidates

Surgeryradiation

Non

pharmacological

Steroidogenic inhibitorsA drenolytic agentsNeuromodulator of A CTHGlucocorticod receptor blocking

Pharmacological


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(3) who have failed surgery

(4) who have had a relapse after surgery

(5) in whom adjunctive therapy is required to achieve complete remission.

B. 1. Pharmacological classes

1. Steroidogenic inhibitors :

1.Steroidogenic inhibitors

3.Adrenolyticagents

2.Neuromodulatorof ACTH

4.Glucocorticodreceptor blocking


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Drugs 1.Metyrapone 2. Aminoglutethimide Combination of 1 & 2

Mech. Inhibit 11-hydroxylase activity,result in , inhibition of cortisol synthesis .

Inhibit cortisol synthesisby blocking theconversion o f cholesterolto pregnenolene early inthe cortisol pathway.

Combination therapy withMetyrapone andA minoglutethimide

more effective than eitheragent alone for variousetiologies of Cushing s disease

fewer side effects .

useful for inoperable patients.

result in

Side effects

Increase plasma A CTH concentrations because of a

sudden drop in cortisol.Increase A ndrogenic and Mineralcorticoid hormones.

HT

A cne ,Hirsutism

Report after oral admin: N/V/abdominal discomfort

Vertigo/Headache/dizziness / A llergi

c rash

limited efficacy as asingle agent

relapse occurringafter discontinuationof therapy.

y severe sedation,nausea, ataxia,and skin rashes.

Class 1Steriodegenic inhibitors

M etyropone

Aminoglutethimide

Ketoconazole

Etomidate


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2 . A drenolytic agents

A drenolytic agents M itotane

3 .Ketoconazole Inhition a variety of cytochrome P450 enzymes ,11-hydroxylase and 17-hydroxylase .

I t is highly effective in lowering cortisol in Cushing s disease.

p atients can be maintained successfully on thera p y for months to years.

4.Etomidate an imidazole derivative similar to ketoconazole

inhibition of 11-hydroxylase

Because it is only available in a parenteral formulation .

its use is limited to patients with acute hypercortisolemia awaiting surgery.

Adrenolytic Agents

Mitotane:

Inhibit 11-hydroxylation of 11-desoxycortisolInhibit 11-desoxycorticosterone in the adrenal cortex.

The net result :

reduced synthesis of cortisol and corticosterone. decreases the p lasma cortisol concentrations, urinary free cortisol ,cortisol secretion ,p lasma concentrations of the17-substituted steroids.

Degeneration of cells within the zona fasciculata and reticularis occurs with resultant atro p hy of the adrenalcortex. The zona glomerulosa is minimally affected during acute thera p y but can become damaged after long-term

treatment. Because mitotane can severely reduce cortisol p roduction, p atients should be hos p italized beforeinitiating thera p y.


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3. Neuromodulators of A CTH Release

N euromodulators of A CTH ReleaseCyproheptadine

Tretinoin

N euromodulators of ACTH Release

Combination therapy prove more efficacious than any single agent.

Cyproheptadine Tretinoin

Decrease ACTH secretion

y Monitor :

morning plasma cortisol

24-hour urinary free cortisol conc.

reserved for nonsurgical candidates who failmore conventional

y Therapy :Because the response rate is no more than 30% ,patients should

be followed closely for relapses.

Decrease A CTH secretion

(through inhibition of transcriptional activities)

use has been limited to animal models, and efficacy inhumans is undetermined


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4. Glucocorticoid Receptor Blocking A gents

G lucocorticoid-Receptor Blocking Agents

Mifepristone (RU-486)

y I t is a Progesterone, Androgen and G lucocorticoid receptor antagonist It have 10 times the affinity to that of the cortisol on the glucocorticode rece p tor

y L imited experience in Cushing s syndrome suggests that ;

Mifepristone

is highly effective in reversing

the manifestations of hypercortisolism.

G lucocorticoid Receptor Blocking A gents M ifepristone (RU-486)


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3.Treamtement plans of Cushing syndrome

(A ). In drug-induced Cushing s syndrome :

Management strategy : Discontinuation of the offending agent is the best management option.

Drawback : The withdrawal of the glucocorticoid

result in : adrenal insufficiency & exacerbation of the underlying disease

(B).The treatment of choice for Cushing s Disease:

TTT: has been transsphenoidal resection of the pituitary micro adenoma.

A dvantages: 1. preservation of pituitary function, 2 . low complication rate, 3. high clinical

improvement rate.

The overall ; cure rate of histological proven tumors approaches 98%. Drawback : patients develop Nelson syndrome Caused, by postoperative Hypothalamic

stimulation. Therefore, it should be accompanied by ; hypothalamic inhibition such ascyproheptadine or pituitary radiation .

(C). A drenal A denoma Management :

y Surgical of benign adrenal adenoma is associated with relatively few side effects and a high curerate (95%).

y The gland in the patient with adrenal adenoma is usually A trophic.

Therefore ; steroid replacement is needed both preoperatively and postoperatively .

(D). A drenal Carcinoma Management :

y Surgery: it have an unpredictable and unfavorable outcome.y Radiotherapy : can be used if metastases are discovered.y

Drug Therapy: Mitotane appears to be the drug of choice in inoperable functional andnonfunctional adrenal carcinoma.

y Tumor regression; 35% to 50% occur bet. the 2 nd & 4 th month of therapy. 50% improve clinical response after 5 th months of treatment.


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10.Evaluation of therapeutic outcomes:


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Symptoms often improve immediately after surgery and soon after initiation of drug therapy. However, it may take months for symptoms to resolve following radiation therapy.

Both are essential to identify adrenal insufficiency in patients with Cushing s syndrome. Steroid secretion should be monitored with all drug therapy. corticosteroid replacement given if needed .

patients receiving surgical,medical, or radiation

therapy for resolution of the clinical manifestations

of hypercortisolism .

Close

Monitoring

24 -Hour Urinary FreeCortisol Levels.

Serum cortisol levels

CloseMonitoring


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11.Patient Counseling :

Provide patient education regarding disease state and treatment:

Causes of Cushing s syndrome, including drug-induced etiologies.

How to recognize the clinical manifestations of Cushing s syndrome.

Possible sequelae of Cushing s syndrome.

How to reduce the modifiable cardiovascular and metabolic complications.

Advantages and disadvantages of potential treatment options.

Possible adverse consequences of treatment.

Need for glucocorticoid and mineral corticoid replacement after treatment, if appropriate.

Importance of adherence to therapy.

12 .Case:

EF is a 45 -year-old woman who presents to the dermatologist for evaluation of facial acne. Shehas a history of a 2 5 lb (11. 36 kg) weight gain, irregular menses, and frequent vaginal yeast

infections over the past 2 years. She complains of increased facial hair growth and lowerextremity muscle weakness. Physical examination reveals facial acne, facial hirsutism,truncalobesity, thin skin, and purple abdominal striae.Her past medical history is significant forhypertension, type 2 diabetes mellitus, hyperlipidemia, and rheumatoid arthritis.

Q1. Which findings are suggestive of Cushing s syndrome?

Q2. Is there anything in EF s history that would suggest an exogenous cause of her presumedCushing s syndrome?


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13.Mind plan :

14. References :

1. Pharmacotherapy Handbook.

2. Pathology and Therapeutics for Pharmacists,A basis for clinical pharmacy practice.

3 . Pharmacotherapy Principles & Practice.

4 . Pharmacotherapy : a Pathophysiologic Approach.

C - Central obesity, Cervical fat pads,Collagen fiber weakness, Comedones(acne).

U- Urinary free cortisol and glucoseincrease

S -straie , Suppressed immunity

H- Hypercortisolism , Hypertension,Hyperglycemia, Hirsutism

I - Iatrogenic ( Increased administrationof corticosteroids)N - Noniatrogenic ( Neoplasms).

G - Glucose intolerance, Growthretardation

M nemonic

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