AUTACOIDSAUTACOIDS

1.1. HistamineHistamine2.2. Bradykinin & KallidinBradykinin & Kallidin3.3. 5 Hydroxytryptamine (5HT)5 Hydroxytryptamine (5HT)4.4. Autacoids derived from membrane Autacoids derived from membrane

phospholipidphospholipida.a. Eicosanoids – arachidonic acid Eicosanoids – arachidonic acid

(PG, PGI, TXA2, LT)(PG, PGI, TXA2, LT)

b.b. Modified phospholipids – PAFModified phospholipids – PAF

HISTAMINES HISTAMINES

Chemistry:Chemistry:

imidazole ring + amino group imidazole ring + amino group connected by 2 methylene groupsconnected by 2 methylene groups

Synthesis Synthesis

Decarboxylation of amino acid L-histidine Decarboxylation of amino acid L-histidine catalyzed by pyridoxal PO4-dependent L-catalyzed by pyridoxal PO4-dependent L-histidine decarboxylase.histidine decarboxylase.

Ingested from food or formed by bacteria in the Ingested from food or formed by bacteria in the GITGIT

Storage sites:Storage sites: perivascular tissue – mast cellperivascular tissue – mast cell circulation – basophil (bound to chondroitin SO4)circulation – basophil (bound to chondroitin SO4) others – GIT, lungs, skin, heart, liver, neural tissue, others – GIT, lungs, skin, heart, liver, neural tissue,

reproductive mucosa, rapidly growing tissues and reproductive mucosa, rapidly growing tissues and body fluidsbody fluids

Metabolism :Metabolism :

Major pathwaysMajor pathways Deamination – small intestine, liver, kidney Deamination – small intestine, liver, kidney

and monocytesand monocytes Methylation – small intestine, liver, Methylation – small intestine, liver,

skin, kidney, thymus & leukocytesskin, kidney, thymus & leukocytes

N-methylimidazole acetic acid - N-methylimidazole acetic acid - principal urinary metaboliteprincipal urinary metabolite

Metabolism :Metabolism :

Functions:Functions:

1.1. Role in allergic responses – Ag + IgE (bound to mast Role in allergic responses – Ag + IgE (bound to mast cells & basophils)cells & basophils)1.1. Preformed mediatorsPreformed mediators2.2. Most important mechanism of release/controlled by Most important mechanism of release/controlled by

H2 esp. in skin & bloodH2 esp. in skin & blood2.2. Release of other autacoidsRelease of other autacoids3.3. Release by drugs (morphine, urase, amines), Release by drugs (morphine, urase, amines),

peptides, venoms & other agents peptides, venoms & other agents 4.4. Release by urticariasRelease by urticarias5.5. Gastric secretagogueGastric secretagogue6.6. Neurotransmitter Neurotransmitter increased wakefulness, increased wakefulness,

thermoregulationthermoregulation

Selected Actions of Histamine in Selected Actions of Histamine in HumansHumans

Organ TissueOrgan Tissue ActionAction Receptor Receptor CARDIOVASCULARCARDIOVASCULARVascularVascularFacial cutaneousFacial cutaneousForearmForearmGastric mucosaGastric mucosaCarotid arteryCarotid arteryPulmonary arteryPulmonary arteryBasilar arteryBasilar arteryCoronary arteryCoronary arteryOther pre & post cap Other pre & post cap ArteriolesArteriolesPostcapillary venulesPostcapillary venulesHeartHeart

TPRTPR VasodilatationVasodilatation Blood flowBlood flow

Blood flow,relaxationBlood flow,relaxationConstrictionConstrictionRelaxationRelaxationConstrictionConstrictionConstrictionConstrictionVasodilatationVasodilatation PermeabilityPermeability SA rateSA rate Force of contraction Atrial & Force of contraction Atrial & vent automaticity vent automaticity

H1, H2H1, H2H2H2H1, H2H1, H2

H2 (?)H2 (?)H1H1H2H2H2H2H1H1H1H1H2H2H2H2

Selected Actions of Histamine in Selected Actions of Histamine in HumansHumans

Organ TissueOrgan Tissue ActionAction Receptor Receptor RESPIRATORYRESPIRATORY

Bronchiolar smooth muscleBronchiolar smooth muscle Contraction (more prominent)Contraction (more prominent)

RelaxationRelaxation

H1H1

H2H2

GASTROINTESTINALGASTROINTESTINAL

Oxyntic mucosaOxyntic mucosa

GI smooth muscleGI smooth muscle

Gallbladder smooth muscleGallbladder smooth muscle

Acid and pepsin secretion, If Acid and pepsin secretion, If

Relaxation & ContractionRelaxation & Contraction

(more prominent)(more prominent)

Relaxation (?)Relaxation (?)

H2H2

H1H1

H2 (?)H2 (?)

CUTANEOUS NERVE CUTANEOUS NERVE ENDINGS (Sensory)ENDINGS (Sensory)

Pain & itchingPain & itching

(esp to insect bites & needle (esp to insect bites & needle stings)stings)

H1, H2 (?) H1, H2 (?)

ADRENAL MEDULLA ADRENAL MEDULLA Epinephrine release Epinephrine release H1H1

BASOPHILSBASOPHILS Inhibition of IgE – dependent Inhibition of IgE – dependent degranulationdegranulation

H2H2

Selected Actions of Histamine in Selected Actions of Histamine in HumansHumans

H1, H2H1, H2 - located in post synaptic membrane - located in post synaptic membrane H3H3 – presynaptic – presynaptic H1H1 - predominant in endotracheal & smooth - predominant in endotracheal & smooth

musclemuscle H2H2 - facial veins, carotid a, pulm. a, heart - facial veins, carotid a, pulm. a, heart gastric mucosa, heart, smooth muscle & some gastric mucosa, heart, smooth muscle & some

immune cellsimmune cells H3H3 - several ares in CNS - several ares in CNS Triple responseTriple response - wheal, flare & redness - wheal, flare & redness

H1 RECEPTOR H1 RECEPTOR ANTAGONISTSANTAGONISTS

Pharmacokinetics:Pharmacokinetics: Well absorbed from GIT (oral)Well absorbed from GIT (oral) Onset – 30 minutes, duration – 3 to 6 hoursOnset – 30 minutes, duration – 3 to 6 hours Widely distributedWidely distributed Biotransformed in the liver; microsomal Biotransformed in the liver; microsomal

enzyme inducerenzyme inducer Excretion – kidneysExcretion – kidneys

Adverse Effects:Adverse Effects:

1.1. CNS : sedation, agitation, nervousness, delirium, CNS : sedation, agitation, nervousness, delirium, tremors, incoordination, hallucinations, & tremors, incoordination, hallucinations, & convulsions - common in first generation antihistaminesconvulsions - common in first generation antihistamines

2.2. GIT : vomiting, diarrhea, anorexia, nausea, epigastric GIT : vomiting, diarrhea, anorexia, nausea, epigastric distress, constipationdistress, constipation- dryness of mouth, throat & airway, urinary retention - - dryness of mouth, throat & airway, urinary retention - first generationfirst generation

3.3. Headache, faintnessHeadache, faintness4.4. Chest tightness, palpitations, hypotensionChest tightness, palpitations, hypotension5.5. Visual disturbancesVisual disturbances6.6. Hematological - leukopenia, agranulocytosis, HAHematological - leukopenia, agranulocytosis, HA

Therapeutic Uses:Therapeutic Uses:

1.1. dermatosisdermatosis

2.2. allergic rhinitisallergic rhinitis

3.3. motion sickness & emesismotion sickness & emesis

4.4. Parkinson’s diseaseParkinson’s disease

5.5. EPSEPS

6.6. InsomniaInsomnia

7.7. Adverse reactionsAdverse reactions

Histamine AntagonistsHistamine Antagonists

I. I. First Generation AgentsFirst Generation Agents A. A. EthanolaminesEthanolamines1.1. Carbinoxamine maleateCarbinoxamine maleate2.2. Clemastine fumarateClemastine fumarate3.3. Diphenhydramine HClDiphenhydramine HCl4.4. DimenhydrinateDimenhydrinate B. B. EthylenediaminesEthylenediamines1.1. Pyrilamine maleatePyrilamine maleate2.2. Tripelennemine HCL/citrateTripelennemine HCL/citrate3.3. PPA PPA C. C. AlkylaminesAlkylamines1.1. Chlorpheniramine maleateChlorpheniramine maleate2.2. Brompheniramine maleateBrompheniramine maleate

II.II. Second Generation AgentsSecond Generation AgentsA. A. AlkylaminesAlkylamines AcrivastineAcrivastine

B. B. PiperazinesPiperazines Cetirizines HClCetirizines HCl

C. C. PiperidinesPiperidines AstemizoleAstemizole LevocabastineLevocabastine LoratadineLoratadine TerfenadineTerfenadine FexofenadineFexofenadine

FIRST GENERATION AGENTSFIRST GENERATION AGENTSD. PiperazinesD. Piperazines 1. Hydroxyzine HCl/pamoate 1. Hydroxyzine HCl/pamoate

(long acting) (long acting)

2. Cyclizine HCl/lactate2. Cyclizine HCl/lactate

3. Meclizine HCl3. Meclizine HCl

4. Chlorcyclizine4. Chlorcyclizine

E. E. PhenothiazinesPhenothiazines

1. Promethazine HCl1. Promethazine HCl

Structural ClassStructural Class PrototypePrototype CharacteristicsCharacteristics First Gen. Agents:First Gen. Agents:

1. Ethanolamine1. Ethanolamine Diphenhydramine Diphenhydramine

Significant antimuscarinic Significant antimuscarinic activityactivity

Sedation, somnolenceSedation, somnolence

Incidence of GI symptomsIncidence of GI symptoms

Effective in emesis & motion Effective in emesis & motion

sicknesssickness

2.Ethylenediamine/ 2.Ethylenediamine/

EthylamineEthylamine

PyrilaminePyrilamine

MepyramineMepyramine

PyranesaminePyranesamine

Most specific H1 antagonistMost specific H1 antagonist

Anticholinergic activityAnticholinergic activity

Feeble CNS effectsFeeble CNS effects

Somnolence GI s/s commonSomnolence GI s/s common 3. Alkylamine 3. Alkylamine ChlorpheniramineChlorpheniramine

PheniraminePheniramine

ChlorphenamineChlorphenamine

Most potentMost potent

Not so prone to develop Not so prone to develop drowsinessdrowsiness

More suitable for older patientsMore suitable for older patients

Sedation/CNS stimulationSedation/CNS stimulation 4. Piperazine 4. Piperazine ChlorcyclizineChlorcyclizine Oldest memberOldest member

More prolonged actionMore prolonged action

Incidence of drowsinessIncidence of drowsiness

Structural ClassStructural Class PrototypePrototype CharacteristicsCharacteristics

HydroxyzineHydroxyzine

Long actingLong acting

Widely used for skin allergiesWidely used for skin allergies

CNS depressantCNS depressant

More prominent antipruritic More prominent antipruritic actionaction

CyclizineCyclizine Counters motion Counters motion

sickness (primarily)sickness (primarily)

Meclizine/Meclozine Meclizine/Meclozine Counters motion Counters motion

sickness & emesissickness & emesis

Structural ClassStructural Class PrototypePrototype CharacteristicsCharacteristics

5. Phenothiazine 5. Phenothiazine Promethazine Promethazine AnticholinergicAnticholinergic

Prominent sedationProminent sedation

Counters motion sickness Counters motion sickness primarily antiemeticprimarily antiemetic

Second Gen.AgentsSecond Gen.Agents

1. Piperidine1. Piperidine Terfenadine Terfenadine Highly selective for H1 Highly selective for H1

receptorreceptor

Non-sedatingNon-sedating

(-) anticholonergic action(-) anticholonergic action

(-) pass BBB(-) pass BBB

incidence of S/Eincidence of S/E

2. Alkylamine2. Alkylamine Acrivastine Acrivastine Rapid onset of action (30 mins)Rapid onset of action (30 mins)

(-) anticholinergic effects(-) anticholinergic effects

Reduce both wheal & flare Reduce both wheal & flare responseresponse

Potential to penetrate BBBPotential to penetrate BBB

Skin allergySkin allergy

Allergic rhinitisAllergic rhinitis

3. Piperazine3. Piperazine CetirizineCetirizine Rhinitis, urticariaRhinitis, urticaria

(-) pass BBB (-) pass BBB

H2 RECEPTOR H2 RECEPTOR ANTAGONISTSANTAGONISTS

Pharmacodynamics: Pharmacodynamics:

•Inhibit gastric acid secretion•(-) effect of gastric motility, emptying time, LES sphincter, pancreatic & mucous secretion

Adverse EffectsAdverse Effects

Cimetidine: headache, dizziness• constipation, diarrhea•skin rashes•alterations of hepatic function•CNS disturbances (elderly & impaired RF)•BM depression – rare•Serum prolactin elevation•Sexual dysfunction & gynecomastia

Ranitidine: Serum prolactin elevation

Drug Interactions:Drug Interactions:

Cimetidine inhibits cyto p-450 – accumulation Cimetidine inhibits cyto p-450 – accumulation of warfarin, phenytoin, theophylline, of warfarin, phenytoin, theophylline, propanolol, diazepam & phenobarbitalpropanolol, diazepam & phenobarbital

Ranitidine – weak inhibitorRanitidine – weak inhibitor Nizatidine & famotidine – do not inhibit Nizatidine & famotidine – do not inhibit

cyto P – 450cyto P – 450 Therapeutic Uses:Therapeutic Uses: Peptic acid disordersPeptic acid disorders

Vasoactive PeptidesVasoactive Peptides

VasoconstrictorsVasoconstrictors—angiotensin —angiotensin II,vasopressin, endothelins, neuropeptide YII,vasopressin, endothelins, neuropeptide Y

VasodilatorsVasodilators—bradykinin, natri-uretic —bradykinin, natri-uretic peptides, vasoactive intestinal peptides,peptides, vasoactive intestinal peptides,

substance P, neurotensin and calcitonin substance P, neurotensin and calcitonin gene-related peptide (CGRP)gene-related peptide (CGRP)

BRADYKININ & KALLIDIN BRADYKININ & KALLIDIN

Peptides that act locally to produce Peptides that act locally to produce pain, vasodilatation, pain, vasodilatation, vascular vascular permeability & PG synthesispermeability & PG synthesis

Synthesis:Synthesis: LiverLiver Percursors: kininogens—SERINE Percursors: kininogens—SERINE

PROTEASES (HMW & LMW)PROTEASES (HMW & LMW)

Pharmacologic Properties Pharmacologic Properties

CVS :CVS :

(+) inotropic & chronotropic effects(+) inotropic & chronotropic effects

vasoconstrictionvasoconstriction Smooth Muscle:Smooth Muscle:

BronchoconstrictionBronchoconstriction GIT:GIT:

Enhanced motilityEnhanced motility

FunctionsFunctions

pain – excites primary sensory neurons & pain – excites primary sensory neurons & provokes release of substance P, provokes release of substance P, neurokinin A & CGRPneurokinin A & CGRP

inflammation - inflammation - permeability in permeability in microcirculationmicrocirculation

production of IL-1 & TNF - production of IL-1 & TNF - respiratory diseaserespiratory disease

Pharmacological Properties Pharmacological Properties 1. CVS – potent vasodilator (10x more than 1. CVS – potent vasodilator (10x more than

histamine)histamine) Stimulate histamine releaseStimulate histamine release

2. Kidney - 2. Kidney - RBF RBF

3. Others:3. Others: spermatogenesis & promotes spermatogenesis & promotes

sperm motility sperm motility

• dilatation of fetal pulmonary arterydilatation of fetal pulmonary arteryclosure of ductus arteriosusclosure of ductus arteriosus

constriction of umbilical vesselsconstriction of umbilical vessels

5 HYDROXYTRYPTAMINE5 HYDROXYTRYPTAMINE(5HT) (5HT)

Found in enterochromaffin cells (90%), Found in enterochromaffin cells (90%), platelets and CNSplatelets and CNS

Sources : tunicates, mollusks, anthropods, Sources : tunicates, mollusks, anthropods, colenterates, fruits, nuts, wasps & colenterates, fruits, nuts, wasps & scorpionsscorpions

Synthesis:Synthesis: TryptophanTryptophan

HydroxytryptophanHydroxytryptophan

5 hydroxytryptamine5 hydroxytryptamine

(Serotonin(Serotonin))

5-hydroxyindole acetaldehyde5-hydroxyindole acetaldehyde

5-hydroxyindole acetic acid5-hydroxyindole acetic acid acid 5-hydroxytrytophol acid 5-hydroxytrytophol(principal metabolite)(principal metabolite)

N-acetyl-N-acetyl- 5-HT 5-HT

MelatoninMelatonin

Antagonists:Antagonists:

1. Clozapine: Reduce incidence of EPS

High affinity for dopamine receptors Reduced negative symptoms of schizophrenia

2. Risperidone: D2 receptor blocker Reduced negative symptoms of schizophrenia Low incidence of EPS

1. Clozapine:• Reduce incidence of EPS• High affinity for dopamine receptors• Reduced negative symptoms of schizophrenia

2. Risperidone:• D2 receptor blocker• Reduced negative symptoms of schizophrenia• Low incidence of EPS

3. Methysergide: used for diarrhea & malabsorption in patients with carcinoid tumors

Cyproheptadine:

• H1 blocker• Weak anticholinergic and mild CNS

depressant• Used for skin allergies, cold urticaria• Counteract the sexual side effects of

SSRI’s

LIPID-DERIVED LIPID-DERIVED AUTOCOIDS AUTOCOIDS

EicosanoidsEicosanoids

formed from PUFA (AA)formed from PUFA (AA) release from cellular stores by PLA2release from cellular stores by PLA2 human platelets – DAG lipasehuman platelets – DAG lipase coupled to G proteinscoupled to G proteins

EFA (diet) EFA (diet) Esterified acid Esterified acid Arachidonic acidArachidonic acid in cell lipid in cell lipid PLA2 PLA2

LipoxygenaseLipoxygenase Cyclooxygenase X ASA, indomethacin Cyclooxygenase X ASA, indomethacin

12-HPETE12-HPETE 5-HPETE 5-HPETE

8484

12-HETE12-HETE 5-HETE 5-HETE LTA4 LTA4 LTC4LTC4

LTB4LTB4 LTD4LTD4

LTE4LTE4

LTF4LTF4

CycloxygenaseCycloxygenase

PGG2PGG2

PGH2PGH2

PGG2 PGE2 PGF2PGG2 PGE2 PGF2 PGD2 TXA2 PGD2 TXA2

PGF1PGF1 TXB2 TXB2

Inhibitors of Biosynthesis Inhibitors of Biosynthesis

1.1. drugs that reduce the availability of Cadrugs that reduce the availability of Ca

2.2. glucocorticoids – induce lipocortin glucocorticoids – induce lipocortin synthesis which inhibits PLA2synthesis which inhibits PLA2

3.3. ASA & related NSAIDASA & related NSAID

Pharmacological Pharmacological Properties Properties

Therapeutic Uses Therapeutic Uses

1.1. PGE1 (Misoprostol) – suppress gastric PGE1 (Misoprostol) – suppress gastric ulcerationulceration

2.2. PGE1 & PGI2 – improve harvest and storage of PGE1 & PGI2 – improve harvest and storage of platelets for therapeutic transfusionplatelets for therapeutic transfusion

- improve blood flow & tissue oxygenation in - improve blood flow & tissue oxygenation in neonates (ductus arteriosus – vasodilatation)neonates (ductus arteriosus – vasodilatation)

33. PGE1 – treatment of impotence. PGE1 – treatment of impotence

PLATELET ACTIVATING PLATELET ACTIVATING FACTOR (PAF) FACTOR (PAF)

Synthesized by platelets, Synthesized by platelets, neutophils,monocytes, mast cells, neutophils,monocytes, mast cells, eosinophils, renal mesangial cells, eosinophils, renal mesangial cells,

renal medullary cells & vascular renal medullary cells & vascular endothelial cellsendothelial cells

Pharmacological Pharmacological Properties Properties

A. CVS:A. CVS: Potent vasodilatorPotent vasodilator

vascular permeability 1000x more than vascular permeability 1000x more than histamine/bradykininhistamine/bradykinin

B. Leukocyte:B. Leukocyte: ChemotaxisChemotaxis

C. Smooth Muscle:C. Smooth Muscle: ContractionContraction Airway resistance & responsiveness to other Airway resistance & responsiveness to other

bronchoconstrictorsbronchoconstrictors

D. StomachD. Stomach Potent ulcerogenPotent ulcerogen