Corticosteroids

Darmawan,dr,M.Kes,Sp.PD

Steroids:theworstdrugsforadverseeffects

CorticosteroidsHistorySynthesis

Pharmacological Actions

PharmacokineticsPreparations Therapeutic principlesDosage schedule & Steroid withdrawal

Uses:– Therapeutic– Diagnostic

Adverse reactionsContraindicationsPrecautions during

therapyGlucocorticoid

antagonists

History1855– Addison'sdisease

1856– Adrenalglandsessentialforlife

1930– Cortex>medulla

1932– Cushing’ssyndrome

1949– Henchetal(Steroidsinrheumatoidarthritis)

1952– Aldosterone

Basal secretionsGroup Hormone Daily

secretionsGlucocorticoids • Cortisol

• Corticosterone5 – 30 mg2 – 5 mg

Mineralocorticoids • Aldosterone• 11- deoxycorticosterone

5 – 150 μgTrace

Sex Hormones•Androgen•Progestogen•Oestrogen

• DHEA • Progesterone• Oestradiol

15 – 30 mg0.4 – 0.8 mgTrace

From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

Cholesterol

Pregnenolone

Progesterone

Corticosterone

11-Desoxy-corticosterone

18-Hydroxy-corticosterone

ALDOSTERONE

17-α- Hydroxy pregnenolone

11- Desoxy-cortisol

17- Hydroxy progesterone

21,β hydroxylase

CORTISOL

11,β hydroxylase

Dehydro-epi androsterone

Andro-stenedione Oestrone

Oestriol

TESTOSTERONE OESTRADIOL

ACTH

Glucocorticoid Analogues

PharmacologicalActions• Direct(Intended)Actions

Anti-inflammatoryAnti-allergyAnti-immunity

• PermissiveActions• Lipolyticeffects

• Effectonbp

•Effectonbronchialmuscles

• (e.g.,sympathomimetic amine)

PharmacologicalActions• Negativefeedbackmechanism.• Steroidsanddrugsdesignedtomimicthemaredirectly gene-active.

• Glucocorticoids(e.g.,prednisolone)usedtosuppressinflammation,allergyandimmuneresponses.

• Anti-inflammatorytherapyisusedinmanyillnesses(e.g.,RA,UC,BA,eyeandskininflammations).-Usefulin,say,tissuetransplantationandlymphopoiesis(leukemiasandlymphomas).

• Strikingimprovementscanbeobtained,butsevereadverse,buthighlypredictable,effects areensue.

Adrenals

Kidney

PosteriorPituitary Gland

Hypothalamus

AnteriorPituitary Gland

ACTH

StressCircadian

rhythm

CRH

(-)

Glucocorticoids, Catecholamines, etc..

Glucocorticoids, Catecholamines, etc..

Muscle:Net loss of aminoAcids (glucose)

Liver:Deamination of

proteins into amino acids,

gluconeogenesis (glucose)

Fat Cells:Free fatty

acid mobilization

Heart rate:Increased

Immune system:altered

Hypothalamopituitary adrenal (HPA) axis: Negative Feedback

Corticosteroids are Gene-Active

PharmacologicalActions• Formostclinicalpurposes,syntheticglucocorticoidsareusedbecausetheyhaveahigheraffinityforthereceptor,arelessactivatedandhavelittleornosalt-retainingproperties.

• Hydrocortisone usedfor:orallyforreplacementtherapy,i.v.forshockandasthma,topicallyforeczema(ointment)andenemas(ulcerativecolitis).

• Prednisolone themostwidelyuseddruggivenorallyininflammationandallergicdiseases.

PharmacologicalActions• Betamethasoneanddexamethasone:verypotent,w/osalt-retainingproperties;thus,veryusefulforhigh-dosetherapies(e.g.,cerebraledemas).

• Beclometasone,diproprionate,budesonide:passmembranespoorly;moreactivewhenappliedtopically(severeeczemaforlocalanti-inflammatoryeffects)thanorally;usedinasthma,(aerosol).

• Triamcinolone:usedforsevereasthmaandforlocaljointinflammation(intra-articularinj.).

PharmacologicalActions

1. Carbohydrate

2. Protein

3. Lipid

4. ElectrolyteandH2O

5. CVS

6. SkeletalMuscle

7. CNS

8. Stomach

9. Blood

10. Anti-inflammatory

11. Immunosuppressant

12. Respiratorysystem

13. GrowthandCellDivision

14. Calciummetabolism

StressandTheAdrenalGlands

Actions:Carbohydrateandproteinmetabolism

• Gluconeogenesis– Peripheralactions(mobilizeaasandglucoseandglycogen)

– Hepaticactions

• Peripheralutilizationofglucose

• Glycogendepositioninliver(activationofhepaticglycogensynthase)

Negative nitrogen balance and hyperglycemia

• RedistributionofFat• Buffalohump• Moonface

• Promoteadipokineticagentsactivity(glucagon,growthhormone,adrenaline,thyroxine)

Actions: Lipid metabolism

Actions: Electrolyteandwaterbalance

• Aldosteroneismoreimportant• ActonDTandCDofkidney

– Na+ reabsorption– UrinaryexcretionofK+ andH+

• Addison’sdisease??

• Na+ loss• Shrinkage of ECF• Cellular hydration• Hypodynamic state of CVS• Circulatory collapse,

renal failure, death

• Restrictcapillarypermeability• Maintaintoneofarterioles• Myocardialcontractility

Actions: Cardiovascular system

Mineralocorticoid induced hypertension ??

Na+ sensitize blood vessels to the action of catecholamines & angiotensin

Addison'sdisease:weaknessandfatigueisdueto

Prolongeduse:

Actions: Skeletal MusclesNeeded for maintaining the normal function of Skeletal

muscle

inadequacy of circulatory system

Steroid myopathy

• Direct:– Mood– Behaviour– Brainexcitability

• Indirect:– maintainglucose,circulationandelectrolyte

balance

Actions: CNS

ICP (pseudotumor cerebri) - Rare

Aggravatepepticulcer.Maybedueto:

– Acidandpepsinsecretion

– immuneresponsetoH.Pylori

Actions: Stomach

RBC: HbandRBCcontent(erythrophagocytosis)

WBC:Lymphocytes,eosinophils,monocytes,basophils

Polymorphonucleocytes

Actions: Blood

• RecruitmentofWBCandmonocyte-macrophageintoaffectedarea& elaborationofchemotacticsubstances

• Lipocortin

• ELAM1andICAM-1inendothelialcells

• TNFfromphagocyticcells

• IL1frommonocyte-macrophage

• FormationofPlasminogenActivator

• ActionofMIFandfibroblasticactivity

• ExpressionofCOXII

Actions: Anti-inflammatory

Immunosuppressiveandanti-allergicactions

• Suppressesalltypesofhypersensitivityandallergicphenomenon

• AtHighdose: Interferewithallstepsofimmunologicalresponse

• CausesgreatersuppressionofCell-mediatedimmunity (graftrejectionanddelayedhypersensitivity)

• Transplantrejection: antigenexpressionfromgraftedtissues,delayrevascularization,sensitisationofTlymphocytesetc.

• InhibitcelldivisionorsynthesisofDNA• Delaytheprocessofhealing• Retardthegrowthofchildren

Actions: Growth and Cell division

• Intestinalabsorption

• Renalexcretion

• Excessivelossofcalciumfromspongybones(e.g.,vertebrae,ribs,etc)

Actions: Calcium metabolism

• Not bronchodilators• Mostpotentandmosteffectiveanti-inflammatory• Effectsnotseenimmediately(delay6ormorehrs)• Inhaledcorticosteroidsareusedforlongtermcontrol

Actions: Respiratory system

PreparationsDrug Anti-inflam. Salt retaining Topical

Cortisol 1 1.0 1Cortisone 0.8 0.8 0Prednisone 4 0.8 0Prednisolone 5 0.3 4Methylpredni-solone

5 0 5

Intermediate actingTriamcinolone 5 0 5Paramethasone 10 0 -Fluprednisolone 15 0 7

PreparationsDrug Anti-inflam. Salt retaining Topical

Long actingBetamethasone 25-40 0 10Dexamethasone 30 0 10MineralocorticoidsFludrocortisone 10 250 10DOCA 0 20 0

Stimuli Part Principal product

Angiotensin II Zona glomerulosa

ACTH Zona fasiculata & reticularis

Sympathetic nervous system

Medulla

Synthesis

Aldosterone

CortisolAdrenal androgens

Adrenaline &Nor-adrenaline

Thank You