adrenal steroids mineralocorticoids & glucocorticoids munir gharaibeh, md, phd, mhpe faculty of...

Adrenal SteroidsAdrenal Steroids Mineralocorticoids & Mineralocorticoids &

GlucocorticoidsGlucocorticoids

Munir Gharaibeh, MD, PhD, Munir Gharaibeh, MD, PhD, MHPEMHPE

Faculty of MedicineFaculty of Medicine

The Jordan UniversityThe Jordan University

April 2014April 2014

Adrenal GlandAdrenal Gland Cortex Cortex

MineralocorticoidsMineralocorticoids

(Aldosterone)(Aldosterone)

MedullaMedulla Glucocorticoids Glucocorticoids

(E, NE) (Cortisol)(E, NE) (Cortisol)

Sex hormonesSex hormones

(Testosterone, (Testosterone, E2, P) E2, P)

Apr 18, 2023 2Munir Gharaibeh, MD, PhD, MHPE

Mineralocorticoids Mineralocorticoids (Aldosterone)(Aldosterone)Control of synthesis and release:Control of synthesis and release:

- ↑ ↑ Angiotensin III. Angiotensin III. - ↑ ↑ Angiotensin II Angiotensin II - ↑ ↑ KK+ + (the most sensitive stimulator of (the most sensitive stimulator of

aldosterone) aldosterone) - ACTHACTH- ↓ ↓ ECF or blood volume.ECF or blood volume.- Metabolic acidosisMetabolic acidosis


DE DE DehDeh.. CholesterolCholesterol Pregnenolone Pregnenolone

ProgesteroneProgesterone

(21)(21) HydHyd’’ss

Aldosterone Aldosterone (18)(18) corticosterone corticosterone (11) (11) Deoxy- Deoxy-

corticosteronecorticosterone

DE=DE= debranching enzyme; side chain cleavage enzyme; debranching enzyme; side chain cleavage enzyme; desmolasedesmolase

Deh.Deh.= 3= 3ββ-hydroxysteroid dehydrogenase enzyme-hydroxysteroid dehydrogenase enzyme

HydHyd’’ss= Hydroxylases= Hydroxylases


Renin-angiotensin-aldosterone axisRenin-angiotensin-aldosterone axis

AngiotensinogenAngiotensinogen ReninRenin

Angiotensin IAngiotensin I ACEACE

Angiotensin IIAngiotensin II

Aldosterone Aldosterone


Factors/drugs ↑ renin-angiotesin-Factors/drugs ↑ renin-angiotesin-aldosterone:aldosterone:

- Volume depletion (hemorrhage, low NaVolume depletion (hemorrhage, low Na++ intake, dehydration, overuse of intake, dehydration, overuse of diuretics…)diuretics…)

- Upright postureUpright posture- KK++

- ACTHACTH- VasodilatorsVasodilators- Adrenoreceptor antagonistsAdrenoreceptor antagonistsApr 18, 2023 9Munir Gharaibeh, MD, PhD, MHPE

Factors/drugs ↓ renin-angiotesin-Factors/drugs ↓ renin-angiotesin-aldosterone:aldosterone:

- Blood volume expansionBlood volume expansion- Renin release inhibitors (also known as renin Renin release inhibitors (also known as renin

antagonists)antagonists)Aliskiren, Remikerin, Enalkiren, Remikerin, Enalkiren, ββ11-blockers-blockers- ACE inhibitorsACE inhibitorsCaptopril, Enalapril, Benzopril, fosinopril, Captopril, Enalapril, Benzopril, fosinopril,

Lisinopril, RamiprilLisinopril, Ramipril ……- ARB’s (Angiotensin II receptor blockers)ARB’s (Angiotensin II receptor blockers)Candesartan, Losartan, Irbesartan, telmesartan…Candesartan, Losartan, Irbesartan, telmesartan…- Aldosterone antagonistsAldosterone antagonistsSpironolactone, EplerenoneSpironolactone, Eplerenone


Effects of AldosteroneEffects of Aldosterone

Receptor-mediatedReceptor-mediated

Acts on distal convoluted tubules in the Acts on distal convoluted tubules in the kidneykidney

- ↑ ↑ reabsorption of Nareabsorption of Na++ → hypertension → hypertension- ↑ ↑ excretion of Kexcretion of K++ & H & H++ → hypokalemia → hypokalemia

& metabolic alkalosis& metabolic alkalosis- ↑ ↑ EC volumeEC volume- ↑ ↑ BPBP


Disorders affecting aldosterone release:Disorders affecting aldosterone release:

* Hypoaldosteronism...rare* Hypoaldosteronism...rare

* Hyperaldosteronism* Hyperaldosteronism

1º 2º1º 2º

↑ ↑ Volume ↓ VolumeVolume ↓ Volume**

↑↑NaNa++ ↓Renin ↑Na ↓Renin ↑Na++ ↑Renin↑Renin

↑ ↑Ald.Ald.* * ↑Ald.↑Ald.

* * Initial defectInitial defect


Glucocorticoids Glucocorticoids (Cortisol)(Cortisol)

Feedback controlFeedback control

CRHCRH

--

ACTHACTH

--

CortisolCortisol



Circadian rhythmCircadian rhythm

PtPt’’s on cortisol therapy...s on cortisol therapy...

Cortisol synthesis (from cholesterol)Cortisol synthesis (from cholesterol)



DE DE DehDeh.. CholesterolCholesterol Pregnenolone Pregnenolone

ProgesteroneProgesterone

(17)(17) HydHyd’’ss

Cortisol Cortisol (11)(11) Deoxy- Deoxy- (21)(21) Hydroxy- Hydroxy-

corticosterone corticosterone progesteroneprogesterone

DEDE= debranching enzyme; side chain cleavage enzyme; = debranching enzyme; side chain cleavage enzyme; desmolasedesmolase

Deh.Deh.= 3= 3ββ-hydroxysteroid dehydrogenase enzyme-hydroxysteroid dehydrogenase enzyme

HydHyd’’ss= Hydroxylases= Hydroxylases


Steroid synthesis Steroid synthesis inhibitorsinhibitors

- o,po,p’’-DDD (Mitotane)-DDD (Mitotane)Causes selective atrophy of Zona Causes selective atrophy of Zona

Fasciculata and Zona ReticularisFasciculata and Zona Reticularis

Useful in RUseful in Rxx of adrenal Ca when of adrenal Ca when radiotherapy or surgery are not radiotherapy or surgery are not feasible and in certain cases of breast feasible and in certain cases of breast cancercancer

- AminoglutethimideAminoglutethimideSelective desmolase inhibitor and non Selective desmolase inhibitor and non

selective aromatase inhibitor, same selective aromatase inhibitor, same uses as mitotaneuses as mitotane


Steroid synthesis Steroid synthesis inhibitorsinhibitors::

- Trilostane:Trilostane:

Competitive inhibitor of 3Competitive inhibitor of 3ββ-hydroxysteroid -hydroxysteroid dehydrogenase enzyme.dehydrogenase enzyme.

Effective in Cushing’s syndrome and breast Effective in Cushing’s syndrome and breast cancer.cancer.

- Ketoconazole:Ketoconazole:

An antifungal agentAn antifungal agent

An inhibitor of different hydroxylases.An inhibitor of different hydroxylases.

Inhibits steroidogenesis in adrenals and testes.Inhibits steroidogenesis in adrenals and testes.

Effective in CushingEffective in Cushing’’s syndrome and Ca of s syndrome and Ca of prostate.prostate.


Steroid synthesis Steroid synthesis inhibitorsinhibitors

- Amphenone BAmphenone BAn inhibitor of different hydroxylases but very An inhibitor of different hydroxylases but very

toxic.toxic.The therapeutic use of amphenone B is limited

by itstoxicity : antithyroid effect, severe CNS severe CNS

depression, GIT upset and many skin depression, GIT upset and many skin disordersdisorders

- Metyrapone (Metopirone)Metyrapone (Metopirone)1111ββ-hydroxylase inhibitor-hydroxylase inhibitorEffective as a diagnostic tool (metyrapone test) Effective as a diagnostic tool (metyrapone test)

and in the management of Cushing’s and in the management of Cushing’s syndromesyndrome


Effects of Effects of GlucocorticoidsGlucocorticoids

- On proteins:On proteins:↑ ↑ Catabolism ↓ anabolismCatabolism ↓ anabolism→ → Osteoporosis; steroid myopathy; Osteoporosis; steroid myopathy;

delayed wound healing; delayed peptic delayed wound healing; delayed peptic ulcer healing…ulcer healing…

- On CHO:On CHO:Diabetogenic: gluconeogenesis; ↓ Diabetogenic: gluconeogenesis; ↓

peripheral utilization of glucose)peripheral utilization of glucose)



- On lipids:On lipids:

↑ ↑ lipolysis lipolysis

Fat redistributionFat redistribution- On electrolytes:On electrolytes:

Aldosterone-like effectAldosterone-like effect

↓ ↓ CaCa++++ absorption from intestine absorption from intestine

↑ ↑ CaCa++++ excretion by kidney excretion by kidney

↑ ↑ Uric acid excretionUric acid excretion



- Antiinflammatory effect: Antiinflammatory effect:

major mechanism: major mechanism:

PhospholipidsPhospholipids Pospholipase A2Pospholipase A2

Arachidonic acidArachidonic acid LipoxygenaseLipoxygenase CyclooxygenaseCyclooxygenase

Leukotreines Leukotreines PG’sPG’s

(SRS-A)(SRS-A)



Other possible mechanisms:Other possible mechanisms:- Inhibition of neutrophil and Inhibition of neutrophil and

macrophage function.macrophage function.- Inhibition of platelet activation factor Inhibition of platelet activation factor

(PAF)(PAF)- Inhibition of tissue necrosis factor or Inhibition of tissue necrosis factor or

receptor (TNF; TNR)receptor (TNF; TNR)- Inhibition of nitric oxide reductase…Inhibition of nitric oxide reductase…



Immunosuppressant effect:Immunosuppressant effect:

↓ ↓ initial processing of Aginitial processing of Ag

↓ ↓Ab formationAb formation

↓ ↓ effectiveness of T-lymphocyteseffectiveness of T-lymphocytes

↓ ↓ lymphocyte induction & proliferationlymphocyte induction & proliferation

↓ ↓ lymphoid tissue including leukemic lymphoid tissue including leukemic lymphocytes (antileukemic effect)lymphocytes (antileukemic effect)


Effects of glucocorticoidsEffects of glucocorticoids

Antiallergic effect:Antiallergic effect:

Supress allergic responseSupress allergic response

↓ ↓ histamine releasehistamine release

↓ ↓ eosinophilseosinophils

CNS effects:CNS effects:

EuphoriaEuphoria

Psychosis Psychosis


GlucocorticoidsGlucocorticoids

Glucocorticoids dosage forms:Glucocorticoids dosage forms:

Available in all dosage formsAvailable in all dosage forms

Available in many preparationsAvailable in many preparations Structure activity relationship:Structure activity relationship:

Major objective: Good antiinflammatory Major objective: Good antiinflammatory effect, less or no aldosterone-like activity effect, less or no aldosterone-like activity

Metabolism:Metabolism:

In the liver by reduction and conjugation In the liver by reduction and conjugation (90-95%); little hydroxylation reactions (90-95%); little hydroxylation reactions (5%)(5%)


Glucocorticoid Glucocorticoid preparationspreparations

Short-actingShort-acting Half-life Half-life AIA AIA Ald.-likeAld.-like

Corisol 10 Corisol 10 1 11 1

Cortisone 10 Cortisone 10 0.8 10.8 1

Corticosterone 10 Corticosterone 10 0.3 300.3 30

Fludrocortisone 10 Fludrocortisone 10 10 15010 150



Intermediate-actingIntermediate-acting Half-life Half-life AIA AIA Ald.-likeAld.-like

Prednisone 20 4 Prednisone 20 4 0.8 0.8

Prednisolone 20 5 Prednisolone 20 5 0.8 0.8

Methylprednisolone 20 6 Methylprednisolone 20 6 - -

Triamcinolone 20 6 Triamcinolone 20 6 - -

Beclomethasone 20 6 Beclomethasone 20 6 - -



Long-acting:Long-acting: Half-lifeHalf-life AIA AIA Ald.-likeAld.-like

Betamethasone 50 Betamethasone 50 25 -25 -

Dexamethasone 50 Dexamethasone 50 30 -30 -

** Plasma half-life; Nuclear half-life** Plasma half-life; Nuclear half-life


Clinical uses to Clinical uses to GlucocorticoidsGlucocorticoids- Adrenal insufficiency Adrenal insufficiency (acute; chronic, (acute; chronic,

Addisonian crisis, AddisonAddisonian crisis, Addison’’s disease...)s disease...)

- Inflammatory conditions Inflammatory conditions (rheumatoid (rheumatoid arthritis, SLE, arteritis, dermatomyositis, arthritis, SLE, arteritis, dermatomyositis, cerebral edema, ulcerative colitis, cerebral edema, ulcerative colitis, rheumatic carditis, active chronic rheumatic carditis, active chronic hepatitis, proctitis, acute gout...)hepatitis, proctitis, acute gout...)

- Allergic reactions Allergic reactions (hay fever, eczema, (hay fever, eczema, dermatitis), bronchial asthma, status dermatitis), bronchial asthma, status asthmaticusasthmaticus


Clinical uses to Clinical uses to GlucocorticoidsGlucocorticoids- Immunosuppression:Immunosuppression: (organ (organ

transplantation, transplantation,

hemolytic anemia, leukemias, many hemolytic anemia, leukemias, many tumors...)tumors...)

- Hypercalcemia Hypercalcemia associated with Vit. D associated with Vit. D intoxication or sarcoidosis or intoxication or sarcoidosis or hyperparathyroidism or cancer...)hyperparathyroidism or cancer...)

- Many eye, ear, and skin diseases (allergic Many eye, ear, and skin diseases (allergic or inflammatory)or inflammatory)


Side effects of Side effects of GlucocorticoidsGlucocorticoids- Suppression of hypothalamic-pituitary-Suppression of hypothalamic-pituitary-

adrenal axis (major and most dangerous adrenal axis (major and most dangerous side effect)side effect)

- CushingCushing’’s syndromes syndrome- Salt & water retention, edema, ↑ BP, Salt & water retention, edema, ↑ BP,

obesityobesity- Peptic ulcer disease and GIT ulcerationsPeptic ulcer disease and GIT ulcerations- OsteoporosisOsteoporosis- Diabetes mellitusDiabetes mellitus- ↑ ↑ incidence of viral and fungal infectionsincidence of viral and fungal infections- ↓ ↓ wound healing and skin atrophy and wound healing and skin atrophy and

myopathymyopathy- Suppression of growth of childrenSuppression of growth of children- Cataract…Cataract…


Strategies in the use of Strategies in the use of GlucocorticoidsGlucocorticoids

- Use a short-acting steroid.Use a short-acting steroid.

- Use the minimal possible dose.Use the minimal possible dose.

- 2/3rd of the dose in morning and 1/3rd in 2/3rd of the dose in morning and 1/3rd in evening.evening.

- Use alternate day therapy which is Use alternate day therapy which is associated with less suppression to associated with less suppression to growth of children and to the growth of children and to the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-adrenal axis and fewer side effectsfewer side effects


adrenal steroids mineralocorticoids & glucocorticoids munir gharaibeh, md, phd, mhpe faculty of...

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