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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