autocoids

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AUTOCOIDS
By Shiva
B.Pharmacy Shiva.pharmacist_at_gmail.com
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INTRODUCTION

• Naturally occuring substances termed as local
  harmones which originate from diffuse tissues
  produce intense pharmacological action near their
  site of formation release.
• AutosSelf akos remedy/ medicinal agent.

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CLASSIFICATION

• Based on chemical nature
• 1.BIOGENIC / ENDOGENOUS AMINES Histamine, 5-HT.
• 2.POLYPEPTIDESBradykinin, sub-p.
• 3.LIPID SOLUBLE ORGANIC ACIDS/ PHOSPHO LIPID
  DERIVATIVES
• (A).EICOSINOIDS PGS, PCS, LTS, TXS.
• (B).PAF.

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HISTAMINE

• Tissue amine.
• Histos- Tissue.
• DISTRIBUTION Widely distributed in almost all
  mammal tissues in venom of bees wasps.
• SYNTHESIS In mammals formed by Decarboxylation
  of Histidine in prescence of Histidine
  decarboxylase.
• STORAGE Present in platelets, leucocytes,
  basophills mastcells.
• Mainly in mastcells basophills due to presence
  of his.decarboxylase, specialised storage
  granules.

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MECHANISM OF ACTION

• Acts through 4 receptors viz H1, H2, H3, H4
  all belonging to family GPCR.
• Activation of H1 receptors
• Activation of H2 receptors

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PHARMACOLOGICAL ACTIONS

• CVS (A). BLOOD VESSELS In herbivores Sys
  Pul vasoconstriction.
• In humans Pul.vasodilation.
• Acts by 3 ways (a).Activation of H1 receptors on
  the endothelial cells cause rapid- short lived
  vasodilation.
• (b).Activation of H2 receptors in the vascular
  smooth muscle causes slower but prolonged
  vasodilation.
• (c).Relaxation of smooth muscle of capillaries
  venules leading to their dilation and fall in BP.

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PHARMACOLOGICAL ACTIONS

• (B).BP Therapeutic doses induces hypotension,
  short lived.
• Large doses prolonged hypotension.
• Hypotension left untreated may cause irreversible
  shock death.
• Histamine induced hypotension is partially
  reversed by anti-histaminics completely
  reversed by adrenaline.

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PHARMACOLOGICAL ACTIONS

• TRIPLE RESPONSE When given (20mcg) ID develops a
  triple response
• (a).FLUSH(RED REACTION) Red line r spot develop
  with in 10sec, due to local dilation of
  capillaries venules.
• (b).WHEAL Local swelling due to edema, mottled
  reddening around injury.
• Lasts about 1 1/2min.
• Due to increased permeability of capillaries 7
  post capillary venules with consequent
  xtravasation of fluid.

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PHARMACOLOGICAL ACTIONS

• (c).FLARE Redness with irregular margins spreads
  out from injury.
• Triple response is part of normal reaction to
  injury.
• Its prevention is used to evaluate
  anti-histaminic activity of a new drug.
• (C).HEARTIncreases sinus rate (ve chronotropic
  action)
• Increases the amplitude of ventricular
  contraction (inotropic effect)
• Decreases AV conduction time increases coronary
  blood flow, high conc. induce ven.fibrillation.

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PHARMACOLOGICAL ACTIONS

• (D)SMOOTH MUSCLE Stimulates smooth muscles of
  various tissues by direct action(H1).
• Bronchial Uterine smooth muscle highly
  sensitive.
• GIT Ureteral smooth muscle respond
  moderately.
• Thru H1 receptor gall bladder contraction ,
• H2 receptor gall bladder relaxation.
• H induced bronchospasm antagonised by
  adrenaline, isoprenaline aminophylline but not
  by anti-histaminics r atropine.

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PHARMACOLOGICAL ACTIONS

• ENDOCRINE GLANDS Important physiological
  mediator of gastric acid secretion.
• CNS Doesnt cross BBB, H constituted in 2types
  of cells Histaminergic neurones Mast cells.
• Considered as Waking amine- increase in
  sensitivity of large cerebral areas to excitatory
  inputs.
• IMMUNOMODULATION Increases Humoral Cellular
  immunity by various receptors , H1- cellular
  immunity , H2- Humoral immunity.

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A,D,M,E

• Stable compound absorbed from all sites .
• Rapidly under go first pass metabolism in liver.
• Metabolism varies acc.to animal spcs, sex ,
  organ studied.
• Chemically it is B-Imidazolyl etylamine.
• End products of metabolism include N-Methyl
  imidazole aectic acid, N-acetyl histamine.

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ADR

• Due to pharmacological actions hypotension,
  visual disturbances, dyspnea, diarrhoea.
• Man, Gunea pig- extremely sensitive.
• Rats Mice highly resistant.
• Large dose causes severe nausea, gripping,
  headache sweating.
• USESStudy of gastric acid secretion.

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ANTI-HISTAMINICS

• Certain phenolic ether anti-histaminic
  properties.
• CLASSIFICATION By two ways Clinically
  Chemically.
• (A).CLINICAL CLASSIFICATION
• 1.POTENT SEDATIVE Diphenhydramine,
  Promethazine.
• 2.POTENT LESS SEDATIVE Cyclizine, Meclizine.
• 3.LESS POTENT LESS SEDATIVE Antazoline,
  Cinnarizine.
• 4.NON SEDATIVE Loratidine, Cetirizine.

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CHEMICAL CLASSIFICATION

• General formula
• Based on configuration of X classified as
• 1. ETHANOLAMINES(XO) Diphenhydramine,
  Doxylamine.
• 2.ETHYLENE DIAMINES(XN) Mepiramine,
  Antazoline.(show negligible anti-cholinergic
  anti-emetic efcts)
• 3.ALKYL AMINES (XC) Chloropheneramine,
  Triprolidine.
• 4.PIPERAZINES (XC in conjunction with
  piperazine ring) Cinnarizine, Cetirizine.

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CHEMICAL CLASSIFICATION

• 5.PHENO THIAZINES (XN as apart of
  phenothiazine nucleus) Promethazine,
  Trimeprazine, show potent anti-emetic effect.
• 6.PIPERIDINES Loratadine, Fexofenadine.
• 7.DIBENZOXYPINES Doxepine (Tricyclic anti
  depressant) shows potent anti-histaminic
  properties.

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H- ANTAGONISTIC ACTIONS

• 1.ANTI-HISTAMINIC ACTIONS Competatively block
  H at various sites.
• Antgonize stimulant action of H on Smooth
  muscle of GIT, bronchi, uterus bld.ves.
• Reduce H induced triple response.
• Anti-allergic anti-inflammatory actions
  involve (a). Inhibition of release of
  mediators from mastcells, basophills.
• (b).Down regulation of H1-receptors.
• Dont antgonize CVS actions of H.

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ANTAGONISTIC ACTIONS

• OTHER ACTIONS Related to their blocking of 5-HT
  A1-Adreno receptors.
• 1.SEDATION HYPNOSIS CNS depression common
  side effect.
• Induce varying degrees of sedation, drowsiness
  sleep.
• 2.CNS STIMULATION Stimulation is less ,
  conventional doses of Promethazine cause
  restlessness, tremors insomnia.

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ANTAGONISTIC ACTIONS

• 3. ON ANS First gen. anti-histaminics show
  muscarinic blocking activity, second gen.
  anti-histaminics doesnt show these actions.
• 4.ANTI-EMETIC ANTI-MOTION SICKNESS
  Diphenhydramine Promethazine block
  histaminergic signals from the vestibular nucleus
  to vomiting center.
• 5.ANTI-PARKINSONIAN EFFECTS Central
  anti-muscarinic actions useful in treating
  parkinsonism.

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ANTAGONISTIC ACTIONS

• 6.CVS Rapid IV administration of
  Diphenhydramine, Antazoline may produce dose
  related prolongation of QT interval due to
  membrane stabilising effect.
• 7.LOCAL ANAESTHESIA Promethazine,
  Diphenhydramine exhibit local anaesthetic
  activity.
• A,D,M,E Well absorbed orally parenterally.
• Anti-histaminic effect starts with in 15-30 min,
  peaks by 1hr lasts for 3-6hrs.
• Meclizine- action persists for 12-24hrs.

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ANTAGONISTIC ACTIONS

• A,DM,E First gen compounds metabolised by CYP3A4
  in liver.
• H1-antagonists induce hepatic microsomal enzymes,
  facilitating their own metabolism.
• ADR Mild,
• 1.CNS Sedation Hypnosis, Fatigue.
• In children less than 2yrs- Promethazine cause
  Apnoea.
• ANTI-MUSCARINIC EFFECTS Dry mouth, blurred
  vision, bladder disturbances rarely impotence.

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ADR

• GIT Nausea, vomiting, epi-gastric distress.
• MISC May produce allergic manifestations despite
  of their anti-allergic anti-inflammatory
  properties.

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THERAPEUTIC USES

• Used in treatment of 1.Allergic disorders,
• 2.Reagenic allergy,
• 3. Allergic conjunctivitis ,
• 4. Mastocytosis,
• 5.Other uses (a).As hypnotics,
• (b).As anti-emetics,
• (c).In parkinsonism,
• (d).In motion sickness
  vertigo,
• (e).Anti-tussives,
• (f).Local anaesthetics.
  

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