Autacoids: Functions and Classes

Autacoids

• Autacoids are biological factors that act locally near their site of synthesis and release.
• They have a brief duration of action and participate in physiological or pathophysiological processes.
• Classes of autacoids include biogenic amines, polypeptides, and lipid-derived autacoids (eicosanoids).

Classes of Autacoids

• Biogenic amines:
  • Histamine
  • Serotonin (5-hydroxytryptamine, 5-HT)
• Polypeptides:
  • Angiotensin
• Lipid-derived autacoids (eicosanoids):
  • Eicosanoids
  • Prostaglandins
  • Leukotrienes
  • Thromboxane

General Physiologic Function

• Modulate blood flow in specific tissues
• Modulate secretory processes (e.g., gastric acid secretion)
• Modulate smooth muscle function (e.g., vascular and bronchial)
• Play a key role in allergy, inflammation, pain, and certain types of drug reactions (e.g., anaphylaxis).

Histamine

• Biosynthesis: Synthesized from dietary histidine by histidine decarboxylase.
• Distribution and storage sites:
  • Mast cells and basophils: stored in vesicles
  • Stomach mucosa: causes gastric acid secretion
  • Lungs and skin: release causes allergic responses
  • CNS: acts as a neurotransmitter
  • Many venoms and insect stings contain histamine

Physiologic and Pathologic Roles of Histamine

• Stimulates gastric acid secretion
• Involved in allergic reactions and anaphylactic shock
• Increases capillary permeability associated with inflammation
• Decreases blood pressure because it relaxes arterioles
• Causes bronchial occlusion and increased mucus secretion associated with asthma
• Causes pain and itching by activating sensory nerves

Histamine Release

• Immune (allergy): binding of antigenic substances to IgE on mast cells or basophils causes degranulation and release of histamine associated with hypersensitivity reactions
• Drugs and chemicals: morphine, tubocurarine, codeine, penicillin
• Physical injury: heat, cold, trauma
• Plant and animal stings

Histamine Receptors

• H1 Receptor:
  • Signal: Gq protein, phospholipase C
  • Response: contraction of GI muscle, bronchoconstriction, dilation of arterioles and capillaries, increased heart rate, increased vascular permeability
• H2 Receptor:
  • Signal: Gs protein, adenyl cyclase
  • Response: gastric secretions, salivary secretion, lacrimation

Histamine Antagonists

• Receptor antagonist
• Release inhibitors
• Physiologic antagonists

H1 Antihistamines

• First Generation: Diphenhydramine, Dimenhydrinate, Hydroxyzine, Meclizine, Promethazine, Cyproheptadine.
  • Unionized at physiological pH, easily cross the blood-brain barrier (BBB), therefore produce CNS side effects (sedation)
• Second Generation: Loratadine, Cetirizine, Fexofenadine.
  • Ionized at physiological pH, difficult to cross BBB, therefore less CNS side effects.

Pharmacologic effects of H1-antihistamines

• Relaxation of contracted bronchiolar smooth muscle
• Relaxation of contracted intestinal smooth muscle
• Inhibition of histamine-induced vasodilation and capillary permeability
• Inhibition of itch sensation
• Sedation (first-generation H1-antihistamines)
• Antimuscarinic effects
• Anti motion sickness (antiemetic) effects

Therapeutic uses of H1-antihistamines

• Treatment of allergic conditions (urticaria, pruritus, allergic reactions, anaphylaxis)
• Prevention of motion sickness
• Sedation induction

Adverse effects of H1-antihistamines

• CNS depression (lethargy, somnolence, ataxia)
• Antimuscarinic effects (dry mouth, urinary retention, intestinal atony)

H2-antihistamines (Cimetidine and Ranitidine)

• Pharmacologic effects: competitively inhibits histamine (H2-receptors) in parietal cells, decreasing gastric acid production
• Therapeutic uses:
  • Ulcer treatment
  • Erosive gastritis
  • Gastroesophageal reflux
• Adverse effects: uncommon when used as recommended
• Drug interactions: inhibits hepatic cytochrome P450 enzymes, prolonging the concentration of drugs metabolized by the liver.

Inhibitors of histamine release

• Cromolyn sodium: inhibits histamine release from mast cells
• Therapeutic uses:
  • Recurrent airway obstruction and heaves in horses
  • Control allergic conjunctivitis (eye drop)
• Physiologic antagonists to histamine:
• Sympathomimetic drugs (Epinephrine, Phenylephrine, Ephedrine)

Serotonin (5-hydroxytryptamine, 5-HT)

• Biosynthesis: From tryptophan via tryptophan hydroxylase and L-aromatic acid decarboxylase.
• Distribution and function:
  • GI tract (enterochromaffin cells): regulates motility
  • Platelets: stores 5-HT and upon activation causes vasoconstriction and platelet aggregation.
  • CNS: acts as a neurotransmitter

Serotonin-receptor modifying drugs

• GI prokinetic agents: increase GI motility by increasing Ach release.
• Cisapride: agonist of 5-HT4 receptor which increases Ach release.
  • Therapeutic uses: gastric/intestinal stasis, reflex esophagitis, constipation
  • Adverse effects: diarrhea, abdominal pain
• Metoclopramide: D2-receptor antagonist and 5-HT3 agonist.
  • Therapeutic uses: vomiting disorders (antiemetic), reflux esophagitis, gastric stasis or hypomotility
  • Adverse effects: restlessness, drowsiness, depression

Cyproheptadine

• 5-HT2 antagonist and H1-antihistamine
• Therapeutic uses: appetite stimulant in cats, treatment of feline asthma and pruritus in cats, managing hives in horses
• Adverse effects: sedation, anticholinergic activity, lethargy.

Eicosanoids

• Derived from membrane phospholipids via phospholipase A2 and arachidonic acid.
• Pathways include cyclooxygenase (prostaglandins, thromboxanes) and lipoxygenase (leukotrienes).

Leukotrienes (LTs)

• Synthesized by lipoxygenase in various cells.
• Pharmacologic effects: potent vasoconstrictors, potent bronchoconstrictors, increase capillary permeability, increased mucous secretion.
• LT antagonists (Montelukast) : used in asthma treatment.

Polypeptides (Angiotensin)

• Mechanism: A series of reactions starting from renin converting angiotensinogen to angiotensin I, then to angiotensin II in the lungs, which causes the body to retain water and salt, leading to vasoconstriction, increasing blood pressure.
• Antagonists of the renin-angiotensin system: ACE inhibitors, Beta1-adrenergic antagonists, Angiotensin I (AT1) receptor antagonists, Renin receptor inhibitors.
  • These drugs counteract the effect of the system, reducing blood pressure or blocking sodium absorption.