Objectives

Colorindex

Extra informationandfurtherexplanation

Important

Doctors’notes

Drugsnames

Mnemonics

Kindlychecktheeditingfilebeforestudyingthisdocument

5: Pharmacology of corticosteroids

1. Defineandclassifycorticosteroids

2. ToCompareVariousCorticosteroids

3. Conceptofmechanismofactionandpharmacological

effectsofcorticosteroids

4. Explaintheclinicalusesofcorticosteroids

5. Todiscusstheadverseeffectprofileofcorticosteroids

To Understand

Biosynthesisofadrenalhormones(onlyfemale’sslides)

أھم شيء تعرفونھ إن تصنیع الھرمونات یبدأ من الكولسترول* **thepharmacologicalpreparationofcortisolishydroxycortisol

*

Corticosteroids

Corticosteroidsaresteroidhormonesproducedbytheadrenalcortex.Theyconsistoftwo

groups:

1- GlucocorticoidsTheyhaveimportant

effectsonintermediary

metabolism, catabolism,

immuneresponses,

growth&inflammation.

2- MineralocorticoidsTheyhavesalt-retaining

activitywhichregulate

Na&Kreabsorptionin

thecollectingtubulesof

thekidney.

**

Introduction to corticosteroids

Mechanismofaction:

Corticosteroidispresent

inthebloodboundtothe

corticosteroidbinding

globulin(CBG)andenters

thecellasthefree

molecule.

Theintracellularreceptoris

boundtothestabilizingproteins,

includingheatshockprotein90(Hsp90)andseveralothers(X).Whenthecomplexbindsa

moleculeofsteroid,theHsp90

andassociatedmoleculesare

released.

TheSteroid– receptorcomplex

entersthenucleusasadimer,bindstotheglucocorticoidresponseelement(GRE)onthegene,andregulatesgene

transcriptionbyRNA

polymerase2andassociated

transcriptionfactors.

TheresultingmRNAis

editedandexportedto

thecytoplasmforthe

productionofproteinthatbringsaboutthefinalhormoneresponse.

• Glucocorticoidstimulategluconeogenesis,asaresult:Bloodglucoserises.

• Insulinsecretionisstimulated→Lipolysisandlipogenesisarestimulated.Withanet

increaseoffatdepositionincertainareas(e.g.,theface(moonfacies),shoulderand

back(buffalohump)

• Theseeffectsoccurwhenthepatientistreatedwith100mgofhydrocortisone or>

forlongerthan2weeks.(Femaleslidesonly)

Effects of steroids

1- Metaboliceffects

§ Glucocorticoidscausemuscleproteincatabolism(↓musclemass).

§ Lymphoidandconnectivetissuefatandskinundergowasting(Fatwasting).§ Cataboliceffectsonboneleadtoosteoporosis§ Inchildrengrowthisinhibited,soitisnotrecommendedforchronicusein

children.

2- Cataboliceffects

3- Immunosuppressiveeffects

• Glucocorticoidsinhibitcellmediatedimmunologicfunctions,especiallydependentonlymphocytes&decreaseinterleukinssecretion.

• Glucocorticoidsdonotinterferewiththedevelopmentofnormalacquiredimmunity

(adaptiveimmunitywhichisagainstaspecificpathogen) butdelayrejection

reactionsinpatientswithorgantransplants.

4- Anti-inflammatoryeffect(Mainuse)

§ Glucocorticoidshaveimportantinhibitory effectsonthedistributionandfunctionof

leukocytes(thatisusedforimmunereaction).

§ Suppressiveeffectontheinflammatorycytokines&chemokines.(Femaleslidesonly)

§ Thesedrugsincreaseneutrophilsanddecreaselymphocytes,eosinophils,basophils

andmonocytes.

§ InhibitphospholipaseA2(Convertsphospholipidsintoarachidonicacidandthenitwillproduceprostaglandinandcytokines)&Prostaglandinssynthesis.

§ Themigrationofleukocytesisalsoinhibited(maleslidesonly)

Overview

5- Othereffects

Glucocorticoidssuchascortisolarerequiredfornormalrenalexcretionofwaterloads.

➤ Butifweuseitforalongtimeitwillaffect:

CNS: Whengiveninlargedosesthesedrugsmaycauseprofoundbehavioral

changes(firstinsomnia&euphoriaorexcitationthendepression).

GIT: Largedosesalsostimulategastricacidsecretionanddecreaseresistancetoulcerformation.

Effects of steroids

1

Weuseitifwehavelowglucocorticoids

2

weusethemIfwehaveexcessmineralocorticoids

3

Alsousedasdiuretic

4

onlyinmale’sslides

Aldosterone

(Fludrocortisone)

synthetic

Glucocorticoids

Antagonist2

Agonist

MineralocorticoidsGlucocorticoids1

Spironolactone3

Ketoconazole

Mifepristone

Prednisone

Triamcinolone

Dexamethasone

Beclomethasone

Budesonide

Prednisolone

Cortisol

(hydrocortisone)

Aminogluthemide4

Metrapone4

Natural

Glucocorticoids

Glucocorticoids

NaturalCortisol (hydrocortisone) syntheticGlucocorticoids

Pharmacokinetics

• Givenorally,cortisoliswellabsorbedfromGIT.غیر مھم

• Cortisolintheplasmain95%

boundtoCBG(corticosteroidbindingglobulin).

• Itismetabolizedbytheliverandhas shortdurationofactioncomparedwiththesynthetic

congeners.

• Itdiffusespoorlyacrossnormal

skinandmucousmembranes.

• Theirproperties(comparedwith

cortisol)include:

ü Longerhalflifeü Longerdurationofaction.

ü Reducesaltretainingeffectü Betterpenetrationoflipid

barriersfortopicalactivity.

• Betterpharmacokinetics than

NaturalCortisol

Somecommonlyusednaturalandsyntheticcorticosteroidsforgeneraluse(clickheretoseetheoriginalpic)

Agent Activity

Anti-inflammatory Topical Salt-retaining

Short-to-mediumactingglucocorticoids

Hydrocortisone

(cortisol)

1 1 1

Cortisone 0.8 0 0.8

Prednisone* 4 0 0.3

Prednisolone* 5 4 0.3

Long-actingglucocorticoids

Betamethasone* 25-40 10 0

Dexamethasone* 30 10 0

Mineralocorticoids

Fludrocotisone 10 0 250

Effects of steroids

newdrugshasbetteranti-

inflammatoryeffectthancortisol

Thesaltretainingactionisreducedin

thenewdrugswhichisbetter

اللي علیھم نجمة ركزت علیھم الدكتورة

Glucocorticoids

NaturalCortisol (hydrocortisone) syntheticGlucocorticoids

General

information

• It’sthemajornaturalglucocorticoid.• Thephysiologicsecretionofcortisolis

regulatedbyadrenocorticotropic(ACTH)

&secretionratevariesduringtheday

(Circadianrhythm).Peaksinthemorning

andtrough(declines)inmidnight.

Uses

• Beclomethasone& budesonide Have

beendevelopedforuseinasthmaandotherconditioninwhichgoodsurface

activityonmucousmembraneorskinisneededandsystemiceffectsareto

beavoided.

• Rapidlypenetratetheairwaymucosabut haveveryshorthalflivesaftertheyentertheblood,sothatsystemic

effectsandtoxicityaregreatlyreduced.

ADRs(toxicity)

Thecortisolmoleculealsohasasmallbut

significantsalt-retaining(mineralocorticoid)effect.Thisisanimportantcauseof

hypertensioninpatientswithcortisolsecretingadrenaltumororapituitaryACTHsecretingtumor(Cushing'ssyndrome)

• Cushing’ssyndrome(iatrogenic,byhigherdosesmorethan100mg

hydrocortisone dailyformorethan2weekscharacterizedbymoonshape

faceandbuffalohump)

• Increasegrowthoffinehaironface,thighsandtrunk.

• Myopathy,musclewasting,thinningofskin,DiabetesMellitus (becauseofits

effectonbloodglucoselevels).

• Osteoporosis andasepticnecrosisofthehip.(because ofitscataboliceffectsonprotiens)

• Woundhealingimpaired.

• Ingeneralpatientstreatedwithcorticosteroidsshouldbeonhighprotein

andpotassium enricheddiet

• Pepticulcer

• Adrenalsuppression(highcortisolleadstolowACTHlevelsbynegativefeedbackthereforethebodywilldependonthedruginsteadofthenaturalcortisolsecretedbythe

adrenalglands,sotheglandwillbeatrophied)

• Acutepsychosis,depression

• Sub-capsularcataracts(lossoflenstransparency)

• Growthsuppression

• Hypertension

§ Addison’sdisease(chronicadrenalcorticalinsufficiency)

§ Acuteadrenalinsufficiency associatedwithlifethreateningshock,infectionsortrauma.

§ Congenitaladrenalhyperplasia(inwhichsynthesisofabnormalformsofcorticosteroidsarestimulatedbyACTH).

Clinical uses of glucocorticoids

Adrenaldisorders

Non-adrenaldisorders5

• Allergicreactions(e.g;bronchialasthma,angioneuroticedema-swellinginlarynx

andrespiratorysystem-,drugsreactions,urticaria,allergicrhinitis)

• Collagen vascular disorders:Auto-immunediseasesagainstconnectivetissues

(e.g;rheumatoidarthritis,systemiclupuserythematous,giantcellarteritis,poly

myositis,mixedconnectivetissuesyndrome)

• Organtransplant:preventionandtreatmentofrejection- immunosuppression.

• GIT disorders: inflammatoryboweldisease,non-tropicalsprue.

• Hematologicdisorders:leukemia,multiplemyeloma,acquiredhemolyticanemia,

acuteallergicpurpura‘auto-immunediseasecausedestructionintheRBCs’.

• Infections: acuterespiratorydistresssyndrome,sepsis-highimmunecellsrelease-

• Neurologicdisorders:tominimizecerebraledemaafterbrainsurgery,multiple

sclerosis

• Pulmonarydisease:e.g;aspirationpneumonia,bronchialasthma,sarcoidosis

accumulationofinflammatorycellsinsidethelungsandlymph

• Thyroid diseases:malignantexophthalmos,subacutethyroiditis

• Renal disorders:nephroticsyndrome

• Miscellaneous: hypercalcemiatosecreteCafromthebody,mountainsickness

5

allofthesediseasesareautoimmunediseases,andhereweuseglucocorticoids asanti-

inflammatorydrug

1

•Localapplication(e.g;aerosolforasthma)

2

•Alternatedaytherapy(toreducepituitarysuppression)toinduce

feedbackmechanismsیوم نستخدمھ ویوم ال

3

•Taperingthedosesoonafterachievingatherapeuticresponse.

4

•Toavoidadrenalinsufficiencyinpatientwhohavehadlongterm

therapy,additionalstressdoses(high dose)mayneedtobegiven

duringseriousillnessorbeforemajorsurgery(toavoidwithdrawal

symptoms)

Methods for minimizing corticosteroid toxicity

Mineralocorticoids

Aldosterone(e.g.Fludrocortisone)

Notes

§ Themajornaturalmineralocorticoidinhuman.

§ Aldosteroneisthemainsalt-retaininghormone,promotesNareabsorption

andthereforewaterreabsorption,Kexcretion,inthedistalconvoluted

tubule&thusitisveryimportantintheregulationofbloodvolume&

bloodpressure.ItssecretionisregulatedbyACTH&bytherenin-

angiotensinsystem.

§ Aldosteronehasshorthalflife&littleglucocorticoidactivity

M.O.A

§ Sameasthatofglucocorticoids.

§ Fludrocortisone: itisamineralocorticoidhasalongdurationofactionand

significantglucocorticoidactivitycomparedtoaldosterone(only maleslides)

Uses

Fludrocortisone isfavoredforreplacementtherapyafteradrenalectomy&in

otherconditionsinwhichmineralocorticoidtherapyisneeded.Andcanbe

givento hypotensivepeopletomaintainnormalNaandwaterlevels.

Corticoids antagonist

Receptorantagonists Synthesisinhibitors

Spironolactone,

eplerenone6

Mifepristone Ketoconazole

6

Aminogluthemide,

Metyrapone

Mechanism

ofaction

• antagonistsof

aldosterone

atitsreceptor

• mineralocorti

coid

antagonist&

K-sparing

diuretic, it

keepstheKin

thebody (only

femaleslides)

Acompetitive

inhibitorof

glucocorticoid

receptorsaswell

asprogesterone

receptors

Itinhibitsthe

cytochromep450

enzymes

necessaryforthe

synthesisofall

steroids

(synthesis

inhibitor)

• Itblocksthe

conversionof

cholesterol

to

pregnelone

• Inhibitsthe

synthesisof

all

hormonally

active

steroids

Indications

usedinthe

treatmentof

primary

aldosteronism, -

theproblemin

theadrenalgland-

(onlyfemale

slides)

usefulinthe

treatmentof

Cushing's

syndrome

* antifungal

* Usedina

numberof

conditionsin

whichreduced

steroid levelare

desirablesuchas:

1. Adrenal

carcinoma

2. Hirsutism

3. Breastcancer

4. Prostate

cancer.

Adrenocortical

cancer(steroid

producingtumor)

inconjuction with

otherdrugs

Adrenalcancer,whensurgicaltherapy

isimpracticalor unsuccessfulbecause

ofmetastasis

6

onlyinmale’sslides

Summary

Corticosteroids

MOA:

1. Corticosteroidispresentinthebloodboundtothecorticosteroidbinding

globulin(CBG)andentersthecellasthefreemolecule

2. Theintracellularreceptorisboundtothestabilizingproteins,includingheat

shockprotein90(Hsp90)andseveralothers(X).Whenthecomplexbindsa

moleculeofsteroid,theHsp90andassociatedmoleculesarereleased.

3. TheSteroid– receptorcomplexentersthenucleusasadimer,bindstothe

glucocorticoidresponseelement(GRE)onthegene,andregulatesgene

transcriptionbyRNApolymerase2andassociatedtranscriptionfactors.

4. TheresultingmRNAiseditedandexportedtothecytoplasmfortheproduction

ofproteinthatbringsaboutthefinalhormoneresponse.

Effectsof

steroids:

Metaboliceffects, Cataboliceffects, Immunosuppressiveeffects

Anti-inflammatoryeffect, CNS,GIT.

Glucocorticoids (NaturalCortisol(hydrocortisone),syntheticGlucocorticoids)

• Beclomethasone&budesonide Havebeendevelopedforuseinasthma, haveveryshorthalf

livesaftertheyentertheblood,sothatsystemiceffectsandtoxicityaregreatlyreduced.

ADRs effects

Cushing’ssyndrome

Increasegrowthoffinehaironface,thighsandtrunk.

Myopathy,musclewasting,thinningofskin,DiabetesMellitus

Osteoporosis

Growthsuppression

Hypertension

Clinicalusesof

glucocorticoids

Adrenaldisorders (e.g.Addison’sdisease,Congenitaladrenalhyperplasia)

Non-adrenaldisorders (e.g.Allergicreactions, Organtransplant,

Hematologicdisorders)

Mineralocorticoids

• Aldosteroneisthemainsalt-retaininghormone,promotesNareabsorption.

• Fludrocortisoneisfavoredforreplacementtherapyafteradrenalectomy&inotherconditions

inwhichmineralocorticoidtherapyisneeded

Corticoidsantagonist

• Receptorantagonists (Spironolactoneantagonistsaldosterone,Mifepristonecompetitiveinhibitor

ofglucocorticoid receptors)

• Synthesisinhibitors(KetoconazoleItinhibitsthecytochromep450enzymesnecessaryforthe

synthesisofallsteroids, Metrapone Inhibitsthesynthesisofallhormonallyactivesteroidsby

blockingtheconversionofcholesteroltopregnelone)

MCQs

Q1:Whichoneofthefollowingisthemostimportanttherapeuticpropertyofglucocorticoidsinclinicalpractice?A.Metaboliceffect.B.Immunosuppressant.C.Anti-inflammatory.

Q2;Whichoneofthefollowingisthemainmechanisminwhichglucocorticoidsactasanti-inflammatorydrugs?A.Blocktheactionofcytokinesandchemokines.

B.InhibitphospholipaseA2andprostaglandinsynthesis.

C.Inhibitthemigrationofneutrophilsandleukocytes.

Q3:Whichcorticosteroidspossessthehighestmineralocorticoidfunction?A.Hydrocortisone.B.Fluprednisolone.C.Fludrocortisone.

Q4:Corticosteroidsareusefulinthetreatmentofallofthefollowingdisordersexcept:A. Addisondisease.B.Allergicrhinitis.C.Cushingsyndrome.D.Inflammatoryboweldisease.

Q5:Allofthefollowingadverseeffectscommonlyoccurwithglucocorticoidtherapyexcept:A. Glaucoma.B.Increasedriskofinfection.C.Hypotension.D.Peripheraledema.

Q6:Osteoporosisisamajoradverseeffectcausedbytheglucocorticoids.Itisduetotheirabilityto:A.Increasetheexcretionofcalcium.B.Inhibitabsorptionofcalcium.C.Decreasecollagensynthesis.

Q7:Achildwithsevereasthmaisbeingtreatedwithhighdosesofinhaledcorticosteroids.Whichofthefollowingadverseeffectsisofparticularconcern?A. Hypoglycemia.B.Hirsutism.C.Growthsuppression.

Q8:Thediagnosisofcongenitaladrenalhyperplasia(CAH)isconfirmedinachild.ThisconditioncanbeeffectivelytreatedbyAdministering:A.Glucocorticoid.B.Androgenantagonist.C.ketoconazoletodecreasecortisolsynthesis.

Q9:ApatientwithAddisondiseaseisbeingtreatedwithhydrocortisonebutisstillhavingproblemswithdehydrationandhyponatremia.Whichofthefollowingdrugswouldbebesttoaddtothepatient’stherapy?A. Dexamethasone.B.Fludrocortisone.C.Prednisone.

Q10:Amalepatientisplacedonanewmedicationandnotesthathisbreastshavebecomeenlargedandtendertothetouch.Whichmedicationishemostlikelytaking?**A. Hydrocortisone.B.Spironolactone.C.Eplerenone.

** An adverse drug reaction to spironolactone is gynecomastia due to its effects on androgens and progesterone in the body. Eplerenone may be a suitable alternative if the patient is in need of an aldosterone antagonist but has a history of gynecomastia.

1)

C

2)

B

3)

C

4)

C

5)

C

6)

B

7)

C

8)

A

9)

B

10)

B

MCQs

Q11:Whichcorticosteroidspossessthelowestsaltretainingeffect?A. Hydrocortisone.B.Prednisone.C.Dexamethasone.

Q12:ComparingtoCortisol/Hydrocortisone,thesyntheticglucocorticoidsarepreferredtobeuseddueto:A. Rapidonsetofaction.B.Mineralocorticoideffect.C.Betterpenetrationoflipidbarrier.

Q13:PatientswhoaretreatedbyHydrocortisone,theirdietshouldberichin:A. Carbohydrates&Na.B.Proteins&K.C.Fats&Cl.

Q14:49yearsoldpatientwhoisoncortisoltherebyfor2years.Heisgoingtomajorsurgeryaftersystemicinfection.Howcanhisdoctoradjustthedoseofcortisolbeforesurgery?A. Taperingthedosebeforethesurgerytothehalf.

B. Givehimthedrugdailyinsteadofalternatedaythereby.

C. Givehimadditionalstressdosebeforethesurgery.

Q15:Whichiscontraindicatedinapatientwithhyperkalemia?A. Aldosterone.B.Ketoconazole.C.Spironolactone.

Q16:Whichoneofthefollowingsyntheticsteroidshowspredominantlyanti-inflammatoryeffect?A. Hydrocortisone.B.Prednisone.C.Dexamethasone.

Q17:Whichoneofthefollowingdrugsactbyinhibitingthesynthesisofcorticosteroids?A.Aldosterone.B.Ketoconazole.C.Spironolactone.

Q18:AllofthefollowingarestrategiestominimizethedevelopmentofHPAaxissuppressionwithcorticosteroidtherapyexcept***:A. Alternate-dayadministrationoftherapy.

B. Usingthelowestdoseofcorticosteroidthatadequatelycontrolssymptoms.

C. Administrationoftwo-thirdsofthedailydoseinthemorningandone-thirdintheafternoon.

Q19:WhichofthefollowingpatientswouldmostlikelyhavesuppressionoftheHPAaxisandrequireaslowtaperofcorticosteroidtherapy****?A. Apatienttaking40mgorallyofprednisonedailyfor7daystotreatanasthmaexacerbation.

B. Apatienttaking10mgorallyofprednisonedailyfor3monthsforrheumatoidarthritis.

C. Apatientusingbeclomethasonenasalspraydailyfor6monthsforallergicrhinitis.

D. Apatientreceivinganintra-articularinjectionofmethylprednisoloneforosteoarthritis.

*** Administration of two-thirds of the dose in the morning and one-third in the afternoon is a strategy to mimic the normal diurnal variation of cortisol secretion. However, it is not a strategy to prevent suppression of the HPA axis. All of the other methods will help prevent the likelihood of suppression of the HPA axis.

**** Correct answer = B. Suppression of the HPA axis usually occurs with higher doses of corticosteroids when used for a duration of 2 weeks or more. Although the dose of prednisone is higher in the asthma patient, the duration of therapy is short, so the risk of HPA axis suppression is lower. The risk of HPA axis suppression is low with topical therapies like intranasal beclomethasone and with one-time joint injections.

11)

C

12)

C

13)

B

14)

C

15)

C

16)

C

17)

B

18)

C

19)

B

:قادة فريق علم األدوية

اللولو الصليهم - جومانا القحطاني - فارس النفيسة -

: الشكر موصول ألعضاء الفريق املتميزين

References:

1- 436doctorsslidesandnotes

2- 435pharmacologyteamwork

@pharma436pharma436@outlook.com Yourfeedback

روان سعد القحطانيحني باشيخري الشثريرميا البراك