Autacoids in Medical Pharmacology

Autacoids

• Definition: Local hormones, heterogeneous substances with different structures and diverse pharmacological actions.

Histamine

• Chemistry: Formed from amino acid "Histidine" by decarboxylation, stored in mast cells and basophils.
• Functions:
  • Inflammation
  • Immediate allergic reaction
  • Neurotransmitter and neuromodulator
• Release:
  • Immunologic reaction (Allergy)
  • Mechanical injury
  • Inflammation
  • Chemical release (e.g., morphine, trimethaphan, succinylcholine)
  • Toxins (e.g., snake venom)

Histamine Receptors

• H1: Endothelium, smooth muscles, brain, and skin
• H2: Gastric mucosa, cardiac muscle, brain, and endothelium
• H3: Presynaptic neurons
• H4: Leukocytes, bone marrow, and blood
• Intracellular receptor mechanism:
  • H1: Increase IP3 and DAG, nitric oxide release, and vasodilatation
  • H2: Increase cAMP, calcium, and gastric HCl and pepsin
  • H3: Decrease cAMP, decrease transmitter release
  • H4: Decrease cAMP, chemotactic effect on eosinophils and mast cells

Histamine Agonists and Antagonists

• Agonists:
  • H3: Treatment of obesity, antipsychotics
  • H4: Allergic rhinorrhea
• Antagonists:
  • Physiologic antagonists: Adrenaline
  • Histamine release inhibitors: Cromolyn, Nedocromil
  • Adrenal steroids: Inhibit antigen-antibody reaction
  • Pharmacologic competitive antagonists:
    • H1: Doxylamine, Diphenhydramine, Loratidine
    • H2: Burimamide
    • H3: Clobenpropit, Tiprolisant
    • H4: Diphenhydramine, Cetrizine, Loratidine

Antihistaminics (H1 Receptor Blockers)

• Classification:
  • First generation: Sedating, lipophilic, and penetrate CNS
  • Second generation: Less sedating, less lipophilic, and less CNS penetration
• Pharmacodynamics:
  • Reversible competitive blockers at H1 receptors
  • Block effects of histamine: Vasodilatation, hypotension, increased capillary permeability
  • Sedation, antiemetic, and antiparkinsonian effects
• Pharmacokinetics:
  • Lipid soluble, metabolized by liver microsomal enzymes, and excreted through renal and milk
• Therapeutic uses:
  • Allergic reactions
  • Nausea and vomiting of pregnancy
  • Motion sickness prophylaxis
  • Sedative-hypnotic
• Adverse effects:
  • Sedation, dizziness, CNS depression, dry mouth, constipation, and urine retention

Serotonin (5-HT)

• Chemistry: Formed from amino acid "L-tryptophan" by hydroxylation and decarboxylation
• Functions:
  • Neurotransmitter
  • Gastrointestinal tract:
    • Contraction of smooth muscles
    • Stimulates ACh release
  • Cardiovascular system:
    • Vasoconstriction
    • Platelet aggregation
    • Reflex bradycardia

Serotonin Receptors

• 5-HT1A and 5-HT1B: CNS
• 5-HT2: CNS, platelets, and smooth muscles
• 5-HT3: CNS, peripheral nerves, and vagal afferent
• 5-HT4: GIT (ENS)

Serotonin Agonists and Antagonists

• Agonists:
  • 5-HT1A: Buspirone, Triptans
  • 5-HT2: Appetite suppressant
  • 5-HT4: Prokinetic
• Antagonists:
  • 5-HT2: Cyproheptadine, Methysergide
  • 5-HT3: Ondansetron, Granisetron

Ergot Alkaloids

• Chemistry: Derivatives of "Lysergic acid"
• Classification:
  • Natural alkaloids
  • Semisynthetic derivatives
• Pharmacokinetics:
  • Ergotamine: Poor oral absorption, delayed onset, and prolonged duration
  • Ergometrine: Complete oral absorption, short duration, and no CNS distribution
• Pharmacodynamics:
  • Ergotamine:
    • Alpha-1 adrenoceptor: Partial agonist
    • 5-HT2: Partial agonist
    • Oxytocic effect
    • Stimulates CIC and CTZ
  • Ergotoxine:
    • Alpha-1 adrenoceptor blocker
    • Inhibits VMC
    • Oxytocic effect
    • Stimulates CIC and CTZ

Ergot Alkaloids (continued)

• Uses:
  • Ergotamine: Acute attack of migraine
  • Ergotoxine: Senile cerebral insufficiency, peripheral vascular disease
  • Ergometrine: Postpartum hemorrhage, subinvolution of uterus
  • Methylergometrine: Treatment of postpartum hemorrhage
• Adverse effects:
  • Ergotamine: Cold extremities, tingling, numbness, gangrene, hypertension, and nausea
• Contraindications:
  • Ergotamine: Coronary heart disease, peripheral vascular disease, hypertension, pregnancy, liver disease, and renal disease

Migraine Headache

• Definition: Paroxysmal, unilateral headache
• Clinical picture:
  • Aura: Visual, sensory, and motor manifestations
  • Headache: Vasodilatation of cerebral blood vessels, unilateral, throbbing, and lasts for several hours
• Prophylaxis:
  • Avoid precipitating factors
  • Serotonin antagonists
  • Propranolol
  • Amitriptyline
  • Flunarizine
• Treatment:
  • Mild attack: Analgesics, antiemetics
  • Severe attack: Ergotamine or Dihydroergotamine + Caffeine, Sumatriptan, or Triptans