AntiInflammatory&

ImmunosuppressiveDrugs1
I3Fall2011
SusanMasters,Ph.D.

PharmacologyinI3
Week2

Antiinflammatory
andimmunosuppressive
drugs1&2

Week6

Antifungaldrugs

Week4

Antibacterialdrugs1
Antibacterialdrugs2
Antibacterialdrugs3

Week7

Antiviraldrugs1

Week5

Drugsformycobacterial
infections

Week8

Antiviraldrugs2
Antiparasiticdrugs

TheInflammatoryCascade
Perceivedthreat

Tissueinjury

Adaptiveimmune
system

Infection

22

Leukocyte&endothelialcellactivation

11

Inflammatorymediators

Inflammation(redness,edema,
warmth,pain,tissuedestruction)

Innateimmune
system

Antiinflammatory&Immunosuppressant
Drugs

NSAIDS
Acetaminophen
Antihistamines
Corticosteroids

Immunosuppressants
Newerbiologicagents
Drugsforgout

InhibitorsofEicosanoidProduction
Zileuton
montelukast,
zafirlukast
PhospholipaseA2

NSAIDS (including
aspirin)

5-ASA (IBD)

Arachidonicacid
Lipoxygenase
Lipoxygenaseproducts
(leukotrienes)

Inflammatoryeffects
(esp.inasthma)

Cyclooxygenase(COX)
Prostaglandins&thromboxanes

Inflammatoryeffects

IBD, inflammatory bowel disease; 5-ASA, 5-amino salicylic acid

Homeostatic
functions

NotableNSAIDS

aspirin

naproxen (Naprosyn, Ale

ibuprofen (Motrin, Advil)

indomethacin (Indoc
ketorolac (Toradol)
- parenteral (IM)
celecoxib (Celebrex)

NSAIDTherapeuticEffects
Antipyretic,
Analgesic

Antithrombotic
(aspirinonly)
0

Antiinflammatory

Dailydoseofaspirin(g)

Nacetylaminophenol
Acetaminophen(Tylenol;AKAparacetamol)
antipyretic,analgesicNOTantiinflammatory

NSAID&AcetaminophenToxicity
NSAIDS:Disruptionof
homeostaticfunction
GIupset&ulcers(esp.COX1)
Acuterenalfailure(COX1&2)
Thrombosis(COX2)
Bleeding(COX1,esp.aspirin)
Impairedlabor(COX1&2)

Aspirin&acetaminophen:
verydangerousinoverdose
Aspirin:salicylatepoisoning
Acetaminophen:liverfailure

Aspirin:Reyesyndrome
Syndromeofhepaticinjury&
encephalopathyinkidstreated
withaspirinafteraviralillness

NSAIDS:Rare
hypersensitivityreaction
Excessiveshuntingof
arachidonicacidproducts
tolipoxygenasepathwaywhen
COXisblocked

AcetaminophenToxicity
Acetaminophen

glucuronide

UDP glucuronosyltransferase

Sulfotransferase
sulfate

CYP2E1

Acetylcysteine
(antidote)
Glutathione-Stransferase
glutathione

Liver failure
protein

TheInflammatoryCascade
Perceivedthreat

Adaptiveimmune
system

Tissueinjury

Leukocyte&endothelialcellactivation

NSAIDS, acetaminophen

Antihistamines

Inflammatorymediators

Inflammation(redness,edema,
warmth,pain,tissuedestruction)

Infection

Innateimmune
system

IgEMediatedMastCellDegranulation
RestingMastCell

ActivatedMastCell

Histamine
Proteases
Heparin

Histamine

Histidine

Histidine
decarboxylase

Histamine

H1 receptor

vascular permeability
venulevasodilation
pruritus

Cimetidine,
ranitidine

H2 receptor

gastric acidsecretion

H1HistamineAntagonists(Antihistamines)
Prototype

Properties

Lowaffinityfor
Loratadine(Claritin)
muscarinicreceptors,
Fexofenadine(Allegra) doesntcrossBBB

Diphenhydramine
(Benadryl)

ClinicalUses
Allergicreactions

Allergicreactions,dystonic
Muscarinicantagonist,
rxtntodopamineblockers,
crossesBBB
OTCsleepaid,antiemetic

However,inthecaseofseverehypersensitivityreactions,including
anaphylaxis,drugsofchoiceare:Epinephrine(need1
vasoconstrictionand2bronchodilation)andcorticosteroids!

TheMightyCorticosteroids
Perceivedthreat

Infection

Corticosteroids
Adaptiveimmune
system

Tissueinjury

Innateimmune
system

Corticosteroids
Leukocyte&endothelialcellactivation

Corticosteroids
Corticosteroids

Inflammatorymediators

Inflammation(redness,edema,
warmth,pain,tissuedestruction)

GlucocorticoidsRegulateTranscription
Cortisol

Cortisol

Cortisol
GR

NUCLEUS

transcription (eg, lipocortin)

IP
HSP

GR

HSP

Cortisol Cortisol
GR
GR

or

transcription (IL-1, IL-2,

TNF- , IF-)

GRE

mRN A
Proteins

mRN A

GR,glucocorticoidreceptor;HSP,heatshockprotein;IP,immunophilin;GRE,glucocorticoidreceptor

CorticosteroidsInhibitEicosanoid
Production
Corticosteroids

Lipocortin

PhospholipaseA2

Corticosteroids
inhibit induction
of COX-2 expression

Arachidonicacid
Lipoxygenase
Lipoxygenaseproducts
(leukotrienes)

Cyclooxygenase(COX)
Prostaglandins&thromboxanes

GlucocorticoidsArePowerfulImmuno
suppressants

Corticosteroidsaffectnearlyeveryfacetofimmunefunction,
althoughlessinhibitionofhumoralarmthancellmediatedarm;
theyalsoinduceapoptosisinrapidlydividingleukocytes

ClinicalUseofGlucocorticoids

Selflimitedreaction
(eg,poisonoak)

Acuteflareofa
chronicinflammatory
conditionororgan
rejectionreaction

ToxicityofChronicSystemic
Glucocorticoids

Cushings
syndrome

Fatredistribution
Hypertension
Glucoseintolerance
Impairedwoundhealing
Osteoporosis(preventwithbisphosphonates)
Cataracts
Gastriculcers(preventwithomeprazole,misoprostol)
Riskofinfection
CNSeffects,includingpsychosis
Growthinhibitioninchildren

www.sd-neurosurgeon.com/diseases/pit_tumors.html

AdrenalSuppressionwithChronic
SystemicGlucocorticoids
Hypothalamus

CRH
prednisone
Anterior
pituitary

ACTH

Adrenalcortex

cortisol,
aldosterone

SomeCorticosteroids
Forms
Available

RelativeAnti
Inflammatory
Activity

RelativeSalt
Retaining
Activity

Oral,parenteral,
topical

Cortisone

Oral

0.8

0.8

Prednisone

Oral

0.3

Triamcinolone

Oral,injectable,
topical,inhaled

Dexamethasone

Oral,injectable,
topical

30

Oral

250

Agent
Cortisol(hydro
cortisone)

Fludrocortisone
(mineralocorticoid)

Summary
Inhibitorsoftheproductionoractionofinflammatory
mediators(NSAIDS,antihistamines,presumably
acetaminophen)providesymptomaticreliefwithreasonable
safetyinmostpeoplebutdonotameliorateongoingimmune
reaction;
Corticosteroidshavepowerfulantiinflammatoryand
immunosuppressantactionsbutchronicuseproducesmuch
toxicity

ReminderStudyingPharmacology
Drugnames(focusonprototypes;useflashcards,tables)
Unusualchemicalstructures(eg,antibody,receptor,cytokine)
Mechanismsofaction
Clinicaluses
Pharmacokinetics(eg,notablerouteadministration,elimination)
Adverseeffects(predictable,unusual,teratogens)
Druginteractions(eg,CYP450inducers,inhibitors,narrow
therapeuticwindowANDaCYPsubstrate)

EicosanoidsAsDrugs

(AdditionalinfothatwillNOTbetestedinI3)

DrugName

AnalogOf

ClinicalUse

Epoprostenol

PGI2

Pulmonaryhypertension

Dinoprostone

PGE2

Medicalabortion,relaxuterinecervixin
preparationforinductionoflabor

Misoprostol

PGE1

Pepticulcer,medicalabortion

Alprostadil

PGE1

Maintainapatent(open)ductusarteriosus
inneonateswithcertaincardiac
malformationsuntilemergencysurgery;
erectiledysfunction

Carboprost

PGF2

Laborinduction

Latanoprost

PGF2

Glaucoma