Autocoids

Autocoids

HISTAMINE

• HISTAMINE RELEASE:
  • Mast Cells and Basophils
  • Hypothalamus
  • GI mucosa
• HISTAMINE EFFECTS:
  • H₁ RECEPTORS: Phosphoinositol pathway (constrictive) or cGMP (vasodilate)
    • Allergic: increased vascular permeability and vasodilation
    • CV: Decreased blood pressure and reflex tachycardia
    • Local anesthetic effects
    • Smooth Muscle: bronchoconstriction, stimulation of GI muscle. No stimulation of uterine muscle.
    • 2-methylhistamine is an endogenous H₁ agonist.
    
    
    
  • H₂ RECEPTORS: cAMP pathway
    • Allergic: increased vascular permeability and vasodilation
    • GI: Stimulate gastric-acid secretion
    • 4-methylhistamine is an endogenous H₂ agonist.
  • H₃ RECEPTORS: Little known about them. Probably located centrally.
  • Anti-Cholinergic: Dried secretions, blurry vision, urinary retention, constipation, sedation.
  • HISTAMINE METABOLISM:
  • Histidine ------> Histamine (Histidine Decarboxylase)
    • DOPA Decarboxylase will also create histamine, due to similar structure of substrate.
  • Histamine ------> Imidazole Acetic Acid (Diamine Oxidase, or MAO)
  • Imidazole Acetic Acid ------> Methyl Imidazole Acetic Acid (Histamine Methyltransferase) (excreted in urine)
• HISTAMINE LIBERATORS: Things that degranulate histamine granules.
  • Amines and Diamines
    • Morphine
    • Tubocurarine (curare)
  • Large molecules: certain long-chain polymers and dyes.
  • Bacterial endotoxin
  • Compounds that cause general tissue damage: Trypsin, venoms, detergents.
• ANTI-HISTAMINES:
  • EFFECTS: Antagonize H₁ receptors ------> reduce inflammation, redness, swelling. They do not affect H₂ receptors.
    • Treat motion sickness.
    • Local anesthetic properties; pain relief.
  • INDICATIONS:
    • Allergies: Pollinosis, urticaria
    • Motion sickness.
    • Of little value in the common cold; anti-cholinergic properties may improve rhinorrhea.
    • Sedation, anti-anxiety: centrally acting agents only.
  • ADVERSE EFFECTS:
    • Sedation: May be considered adverse effect or primary effect.
      • Centrally acting drugs (3) cause sedation; peripheral drugs (4) don't.
    • GI: Anorexia, nausea, vomiting, constipation, diarrhea, dry mouth and throat.
    • TOXICITY: Hallucinations, ataxia, athetosis, convulsions. Can especially in children taking 20-30 tablets. Symptoms resemble atropine poisoning.
    • CV: When injected IV, antihistamines can mimic anti-arrhythmics and cause heart block.

RENIN-ANGIOTENSIN SYSTEM:

• Prorenin: There is more prorenin in the blood than renin.
• Renin: Renin secretion occurs in the kidney Macula Densa cells. It is stimulated by:
  • Reduced tubular fluid flow ------> reduced delivery of salt to macula densa (lower tubular Na⁺) ------> stimulate release of Renin.
  • beta-receptors stimulate release of Renin.
  • Most drugs which decrease blood pressure also increase Renin, via reflex sympathetic activation.
    • Diuretics also have a direct effect on Renin secretion: lower tubular Na⁺ in Macula Densa ------>
    • higher Renin secretion.
• Angiotensin: Renin converts Angiotensinogen ------> Angiotensin I
  • Structure: It is a decapeptide.
  • Estrogen increases levels of angiotensinogen in blood (increased liver enzymes) ------> potential hypertension.
• Angiotensin Converting-Enzyme (ACE) (dipeptidyl peptidase): In the lung, it converts Angiotensin I ------> Angiotensin II
• Angiotensin II:
  • Actions:
    • Intense vasodilation (G-Protein; phosphoinositol)
    • Promote the release of aldosterone in adrenal gland ------> promote Na⁺ reabsorption in distal tubule ------> higher blood volume.
    • Regulatory negative feedback on the release of Renin.
    • CNS: Stimulate thirst in hypothalamus, stimulate sympathetic outflow.
  • Structure: It is an octapeptide.
  • Angiotensin Receptors:
    • AT1 Receptor: The principle receptor, found in vascular smooth muscle and in adrenal cortex (to release aldosterone). Acts by both IP₃ and cAMP pathways.
    • AT2 Receptor: Actions largely unknown.
• Angiotensin III: Breakdown product of Angiotensin II
  • Structure: Heptapeptide
  • Actions: Promotes aldosterone release. Probably no significant vasoconstrictive effects.

SEROTONIN: Effects

• EFFECTS:
  • CV: Mixed vasoactive effects. Direct vasoconstriction, plus vasodilation in skeletal muscle. Also causes platelet aggregation.
  • GI: Diarrhea, as is often seen with Carcinoid Tumor.
• RELEASE: Primarily released from enterochromaffin cells of the GI tract.

VASOPRESSIN (ADH):

• STRUCTURE: Nonapeptide, stored in hypothalamus and released through posterior pituitary.
• RECEPTORS:
  • V₁ Receptor: Vascular receptor, causing vasoconstriction.
    • Associated with phosphoinositol / Ca⁺² increase.
  • V₂ Receptor: Tubular receptor. Increased permeability to water in distal tubule ------> increased water reabsorption.
    • Associated with cAMP increase.
• Diabetes Insipidus: Congenital lack of secretion of ADH ------> no water retention in kidneys ------> profuse fluid loss. Vasopressin is used to treat Diabetes Insipidus.

ERGOT ALKALOIDS: Methysergide, LSD, Ergonovine, Ergotamine

• ACTIONS: Prolonged vasospasm, hallucination, uterine smooth muscle contraction.
  • ERGOTISM: Prolonged vasospasm caused by ergot alkaloids which, if untreated, may lead to ischemia and gangrene.
• PHARMACOLOGY:
  • 5HT₁-Receptor agonist and/or antagonist, depending on the drug.
  • alpha-agonist.
  • Dopamine agonist.

KININS: Kallidin, Bradykinin

• METABOLISM: Ultimate product is bradykinin
  • Kallikreins convert Kininogen (alpha₂-globulin) ------> Bradykinin or Kallidin, depending on tissue.
  • Kallidin ------> Bradykinin
• ACTION: Wide variety of actions:
  • Pain, vasodilation. Responsible for the flushing associated with carcinoid tumors.
  • Some responses mediated by prostaglandins and/or NO.

EICOSANOIDS:

• CYCLOOXYGENASE PRODUCTS: Inhibited by NSAID's.
  • Prostaglandin E₁ (PGE₁): Wide variety of effects.
    • Maintain patent ductus arteriosus before birth.
  • Prostaglandin E₂ (PGE₂):
    • CV: Potent vasodilator.
    • GI: Cytoprotective effects in gastric mucosa (increased mucous, HCO₃^-)
    • Causes pain and sensitized nerve endings.
  • Prostaglandin F_2alpha (PGF_2alpha): Essential promotor of uterine contractions during labor. Also stimulates GI muscle and vascular smooth muscle.
    • CV: Vasoconstrictor
    • Bronchoconstriction
  • Prostacyclin (PGI₂): Works via cAMP.
    • CV:
      • It inhibits platelet aggregation and elicits vasodilation.
      • Antagonizes the effects of Thromboxane A₂.
      • It is released by vascular endothelial cells.
    • GI: Cytoprotective effects in gastric mucosa (increased mucous, HCO₃^-)
  • Thromboxane A₂ (TXA₂): Works via IP₃ (increase Ca⁺²).
    • It is produced by platelets -- not endothelial cells.
    • CV: It promotes vasoconstriction and is essential for platelet aggregation.
• LIPOXYGENASE PRODUCTS:
  • Leukotriene B₄ (LTB₄):
    • It causes intense bronchoconstriction. Receptors are antagonized by Zafirlukast and Zileuton.
    • Chemotaxis
    • Allergic reactions.
  • Hydroxyeicosatetaraenoic Acid (HETE's): Implicated in inflammation, chemotaxis.
• ADVERSE EFFECTS: Nausea, vomiting, diarrhea. Fever, bronchoconstriction.
• ASPIRIN (NSAID): It inhibits cyclooxygenase
  • LOW DOSE: It is more specific for thromboxane derivatives (TXA₂), thus low doses are given for prophylaxis for CAD.
  • HIGH DOSE: It is more specific for prostaglandin derivatives, thus high doses are used for anti-inflammatory properties. High doses are not as effective for CAD prophylaxis.