Adrenal SteroidsAdrenal Steroids Mineralocorticoids & Mineralocorticoids &

GlucocorticoidsGlucocorticoids

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)

Mineralocorticoids (Aldosterone)Mineralocorticoids (Aldosterone)Synthesis: From cholesterolSynthesis: From cholesterolControl of synthesis and releaseControl of synthesis and release- ↑ ↑ in the plasma concentration of in the plasma concentration of

Angiotensin III, a metabolite of Angiotensin III, a metabolite of angiotensin II. angiotensin II.

- ↑ ↑ plasma angiotensin II plasma angiotensin II - ↑ ↑ KK++ blood levels (potassium levels are the blood levels (potassium levels are the

most sensitive stimulator of aldosterone) most sensitive stimulator of aldosterone) - ACTHACTH- ↓ ↓ ECF or blood volume; metabolic acidosisECF or blood volume; metabolic acidosis

DEDE Deh.Deh. CholesterolCholesterol Pregnenolone Pregnenolone

ProgesteroneProgesterone

(21)(21) HydHyd’’ss

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

corticosteronecorticosterone

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

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 antagonists

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

Aldosterone effects:Aldosterone effects:

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 ↓ Volume ↓ VolumeVolume**

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

↑ ↑Ald.Ald.* * ↑Ald.↑Ald.

* * Initial defectInitial defect

Glucocorticoids (Cortisol)Glucocorticoids (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)

DEDE Deh.Deh. 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 inhibitors:Steroid synthesis inhibitors:- 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 feasible radiotherapy or surgery are not feasible and in certain cases of breast cancerand in certain cases of breast cancer

- AminoglutethimideAminoglutethimideSelective desmolase inhibitor and non Selective desmolase inhibitor and non

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

- TrilostaneTrilostane

Competitive inhibitor of 3Competitive inhibitor of 3ββ-hydroxysteroid -hydroxysteroid dehydrogenase enzyme effective in dehydrogenase enzyme effective in Cushing’s syndrome and breast cancerCushing’s syndrome and breast cancer

- KetoconazoleKetoconazole

An antifungal agentAn antifungal agent

An inhibitor of different hydroxylases; An inhibitor of different hydroxylases; inhibits steroidogenesis in adrenals and inhibits steroidogenesis in adrenals and testestestes

Effective in CushingEffective in Cushing’’s syndrome and Ca of s syndrome and Ca of prostateprostate

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

toxictoxicThe therapeutic use of amphenone B is limited

by itstoxicity and by its antithyroid effectCauses severe CNS depression, GIT upset and Causes severe CNS depression, GIT upset and

many skin disordersmany skin disorders- 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 syndromeand in the management of Cushing’s syndrome

Release and transport of glucocorticoidsRelease and transport of glucocorticoids Glucocorticoids receptorsGlucocorticoids receptors

Pharmacological effects/side effects:Pharmacological effects/side effects:- On proteinsOn proteins↑ ↑ Catabolism ↓ anabolismCatabolism ↓ anabolism→ → Osteoporosis; steroid myopathy; delayed Osteoporosis; steroid myopathy; delayed

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

- On CHOOn CHO↑ ↑ blood sugar level ( ↑ gluconeogenesis; ↓ blood sugar level ( ↑ gluconeogenesis; ↓

peripheral utilization of glucose)peripheral utilization of glucose)

- On lipidsOn lipids

↑ ↑ lipolysis lipolysis

Fat redistributionFat redistribution- On electrolytesOn 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:- Also inhibit neutrophil and Also inhibit neutrophil and

macrophage functionmacrophage 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 effectImmunosuppressant effect

Major mechanisms Major mechanisms

↓ ↓ 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)

- Antiallergic effectAntiallergic effect

Supress allergic responseSupress allergic response

↓ ↓ histamine releasehistamine release

↓ ↓ eosinophilseosinophils- CNS manifestationsCNS manifestations

EuphoriaEuphoria

Psychosis Psychosis

Glucocorticoids dosage formsGlucocorticoids dosage forms

Available in all dosage formsAvailable in all dosage forms

Available in many preparationsAvailable in many preparations Structure activity relationshipStructure 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 preparationsGlucocorticoid preparationsShort-actingShort-acting Half-life Half-life AIA AIA Ald.-likeAld.-like

Corisol 10 1 1Corisol 10 1 1Cortisone 10 0.8 1Cortisone 10 0.8 1Corticosterone 10 0.3 30Corticosterone 10 0.3 30Fludrocortisone 10 10 150Fludrocortisone 10 10 150Intermediate-acting:Intermediate-acting:Prednisone 20 4 0.8Prednisone 20 4 0.8Prednisolone 20 5 0.8Prednisolone 20 5 0.8

Half-lifeHalf-life AIA AIA Ald.-Ald.-likelike

Methylprednisolone 20 6 -Methylprednisolone 20 6 -

Triamcinolone 20 6 -Triamcinolone 20 6 -

Beclomethasone 20 6 -Beclomethasone 20 6 -

Long-acting:Long-acting:

Betamethasone 50 25 Betamethasone 50 25 --

Dexamethasone 50 30 -Dexamethasone 50 30 -

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

Clinical uses to glucocorticoids:Clinical uses to glucocorticoids:- Adrenal insufficiency (acute; chronic, Adrenal insufficiency (acute; chronic,

Addisonian crisis, AddisonAddisonian crisis, Addison’’s disease...)s disease...)- Inflammatory conditions (rheumatoid Inflammatory conditions (rheumatoid

arthritis, SLE, arteritis, dermatomycosis, arthritis, SLE, arteritis, dermatomycosis, 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 (hay fever, eczema, Allergic reactions (hay fever, eczema, dermatitis), bronchial asthma, status dermatitis), bronchial asthma, status asthmaticusasthmaticus

- Immunosuppressant effect (organ Immunosuppressant effect (organ transplantation, transplantation,

hemolytic anemia, leukemias, many tumors...)hemolytic anemia, leukemias, many tumors...)- Hypercalcemia associated with Vit. D Hypercalcemia 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 or Many eye, ear, and skin diseases (allergic or inflammatory)inflammatory)

Side effects to glucocorticoids:Side effects to glucocorticoids:- Suppression of hypothalamic-pituitary-adrenal Suppression of hypothalamic-pituitary-adrenal

axisaxis

(major and most dangerous side effect)(major and most dangerous 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…

Strategy in the use of glucocorticoids:Strategy in the use of glucocorticoids:- Use a short-acting steroidUse a short-acting steroid- Use a minimal possible doseUse a minimal possible dose- Give 2/3 of the dose in morning and Give 2/3 of the dose in morning and

1/3 in evening1/3 in evening- Use alternate day therapy which is Use alternate day therapy which is

associated with lee suppression to associated with lee suppression to growth of children and to the growth of children and to the hypothalamic-pituitary-adrenal axis hypothalamic-pituitary-adrenal axis and fewer side effectsand fewer side effects