AUTOCOIDS

By: Ayema Rehman

Lecturer, MYU
Islamabad

Tripathi KD, Essentials of Medical Pharmacology,

8th Edition, pp. 158-163.
INTRODUCTION

• The term "Autocoid" is derived from the Greek words “autos” (self) and “akos” (healing
substances/remedy/medicinal agents).
• Autocoids are naturally occurring compounds produced by various cells in the body. They have
intense biological activity but generally act locally at the site of synthesis and release (e.g.,
within inflammatory pockets).
• They are also called “local hormones” but differ from circulating hormones because they are
produced by many tissues rather than specific endocrine glands.
CLASSIFICATION OF AUTOCOIDS
The classical autocoids are classified into three major groups:
1.Amine autocoids:
• Histamine
• 5-Hydroxytryptamine (5-HT or Serotonin)
2.Lipid-derived autocoids:
• Prostaglandins (PGs)
• Leukotrienes
• Platelet-activating factor (PAF)
3.Peptide autocoids:
• Plasma kinins (Bradykinin, Kallidin)
• Angiotensin
HISTAMINE
• The term "Histamine" means “tissue amine” (from Greek histos = tissue).
• Chemical name: Imidazole ethylamine
• Produced by basophils and mast cells in response to foreign pathogens
• It is a chemical messenger primarily stored in mast cells and plays a role in wide range
of cellular responses including:
• Allergic and inflammatory reactions
• Gastric acid secretion
• Neurotransmission in parts of the brain
• Histamine has no direct clinical application, but antihistamines that block its action have
important therapeutic uses.
DISTRIBUTION OF HISTAMINE IN THE BODY
•Mast Cell Sites (High Histamine Concentration):
•Pulmonary tissue (mucosa of bronchial tree)
•Skin
•Gastrointestinal tract (intestinal mucosa)
•Non-Mast Cell Sites:
•CNS (neurons)
•Epidermis of skin
•Gastric cells
•Cells in regenerating or rapidly growing tissues
•Basophils (in blood)
HISTAMINE SYNTHESIS
• Histamine is synthesized from the amino acid Histidine through
decarboxylation by the enzyme Histidine Decarboxylase.
HISTAMINE STORAGE & RELEASE
STORAGE
• Stored in granules within mast cells (bound to acidic proteins and heparin -), and basophils, etc
• At the tissue level, it is stored in the skin, lungs, and smooth muscles.
RELEASE
• Released via exocytosis when triggered by:
• Antigen-antibody Reaction
• IgG or IgM immunoreactions
• Mechanical or chemical injury to mast cells
• Certain amines displacing histamine from heparin
METABOLISM OF HISTAMINE
Methylation Pathway:
Histamine → N-methyl
histamine → N-methyl
imidazole-acetic acid
Oxidative Pathway:
Histamine → Imidazole
acetic acid → Imidazole
acetic acid riboside
HISTAMINE RECEPTORS
• Histamine acts through four types of receptors (H₁, H₂, H₃, H₄), all of which are G-protein
coupled receptors (GPCRs).
Receptor Type Location Function
Contraction of smooth muscles,
Smooth muscles (intestine, bronchi,
H₁ Receptor vasodilation, increased capillary
uterus), endothelial cells
permeability
Increases gastric acid secretion,
H₂ Receptor Parietal cells of stomach, heart. positive inotropic & chronotropic
effects on heart
H₃ Receptor CNS Decreases neurotransmitter release,
Chemotaxis of white blood cells
H₄ Receptor Leukocytes
(WBCs)
PHARMACOLOGICAL ACTION
• H – Increased Hypersensitivity (Allergy)
• I – Increased Permeability (Vascular Permeability)
• S – Secretion of Gastric Juice (HCL)
• T – Triple Response (Redness, Flare, Wheal)
• A – Anaphylactic Shock
• M – Muscular Contraction (Bronchioles, GIT etc)
• I – Itching, Inflammation
• N – Neurotransmitter Release Modulation
• E – Endocrine Release of Catecholamine from Adrenal Medulla.
PHARMACOLOGICAL EFFECTS OF HISTAMINE
Blood Vessels:
•Dilates small blood vessels (arterioles, capillaries, venules).
•Constrict large blood vessels (arteries and veins)
•Dilation of cranial vessels can cause pulsatile headaches.
Heart:
•H₂ receptor: Positive chronotropic (increases heart rate) and inotropic (increases force of
contraction) effects.
•H₁ receptor: Decreases atrioventricular (AV) conduction.
Smooth Muscles:
•H₁ receptor: Contracts smooth muscles, leading to bronchoconstriction and increased GI motility.
PHARMACOLOGICAL EFFECTS OF HISTAMINE (CONT.)
Gastric Glands: CNS (H₁ & H₂ receptors):
•H₂ receptor: Increases gastric acid secretion. •Does not cross the blood-brain barrier (BBB).

Sensory Nerve Endings: •Intracerebroventricular injection can cause:

•Causes itching when injected intradermally. •Rise in BP

•At high concentrations, it can cause pain. •Cardiac stimulation

•Behavioral arousal
Autonomic Ganglia & Adrenal Medulla:
•Hypothermia
•Stimulates ganglia and releases adrenaline
•Vomiting
(epinephrine). As a result, causes secondary
•Antidiuretic hormone (ADH) release
hypertension
HISTAMINE IN ALLERGIC REACTIONS
• Allergies result from hypersensitivity reactions mediated by IgE antibodies.
• Upon allergen exposure, IgE triggers mast cell degranulation, releasing
histamine → causing inflammatory responses (runny nose, anaphylaxis, etc.).
• Hereditary Factor: If both parents have allergies, the child has a 70% chance of
having them; if only one parent has allergies, the chance is 48%.
 HISTAMINE ANTAGONISTS (ANTIHISTAMINES)
First-Generation H₁ Blockers
(Lipid Soluble, Have Second-Generation H₁ Blockers
anticholinergic activity CNS (Lack anticholinergic effect, Less
Penetration, Sedative Effects) Sedative, Do Not Cross BBB)

• Terfenadine
Highly Sedative Moderately Sedative Mild Sedative (Prodrug)
• Dimenhydrinate • Meclizine • Chlorpheniramine • Fexofenadine
• Diphenhydramine • Buclizine • Dexchlorpheniramine • Loratadine
• Desloratadine
• Promethazine • Cinnarizine • Triprolidine
• Cetirizine
• Pheniramine • Clemastine • Levocetirizine
• Cyproheptadine • Ebastine
• Ketotifen
MECHANISM OF ACTION OF H1 ANTIHISTAMINES
• Act as inverse agonists at H1 receptors → Reduce receptor activity below baseline.
• Block histamine binding → Prevents allergic symptoms.
• First-generation drugs also:
•Block muscarinic (M1) receptors → Anticholinergic effects.
•Block dopamine receptors → Some have anti-nausea effects.
•Block serotonin receptors → Cyproheptadine used for appetite stimulation.
PHARMACOLOGICAL ACTION
1. Anti-Histaminic Action
• Mechanism: Blocks H1 receptors, preventing histamine-induced effects.
• Effects:
• Reduces bronchoconstriction, itching, wheal and flare reaction.
• Does not affect histamine-induced gastric secretion (H2 antagonists are required).

• Uses: Allergic disorders (urticaria, hay fever, conjunctivitis, angioedema).

• Example Drugs: Diphenhydramine, Cetirizine, Loratadine.
2. Anti-Cholinergic Action
Mechanism: Some H1 blockers also inhibit muscarinic (M) receptors, reducing acetylcholine effects.
(parasympathetic effects) This leads to:
• Dry mouth (due to decreased saliva production)
• Urinary retention (reduced bladder contraction)
• Blurred vision (due to pupil dilation and reduced focus)
Effects:
• Reduces nasal secretions (useful in common cold).
• Prevents motion sickness and reduces vertigo. e.g., diphenhydramine, meclizine
• Relieves drug-induced dystonia (antipsychotic-induced extrapyramidal symptoms). e.g., diphenhydramine
Uses: Motion sickness, pre-anesthetic medication, Parkinsonism.
Example Drugs:
•High: Promethazine, Diphenhydramine, Dimenhydrinate
•Low: Chlorpheniramine, Hydroxyzine, Triprolidine
•Minimal/Absent: Fexofenadine, Loratadine, Cetirizine
3. Anti-Parkinsonian Action
• Mechanism: Central anticholinergic
effect reduces tremors and rigidity.
• Uses:
• Mild symptomatic relief in early
Parkinson’s disease.
• Treats drug-induced dystonia (caused
by antipsychotics).

• Example Drugs: Promethazine,

Diphenhydramine.
4. Anti-Serotonin Action
• Mechanism: Blocks 5-HT2 receptors, inhibiting serotonin effects.
• Effects:
• Increases appetite (by reducing serotonin-induced satiety).
• Reduces vascular headaches.

• Uses:
• Appetite stimulation (Cyproheptadine is used in underweight individuals).
• Migraine prophylaxis.

• Example Drug: Cyproheptadine.

5. Anti-Vertigo Action
• Mechanism:
• Suppresses vestibular system
• Blocks calcium influx in vestibular sensory cells.

• Uses:
• Ménière’s disease.
• Vestibular vertigo & motion sickness.

• Example Drugs:
• Cinnarizine (most effective for vertigo).
• Dimenhydrinate, Meclizine.
6. Anti-Emetic Action
• Mechanism:
• Blocks histamine and muscarinic receptors in the vomiting center (CTZ).
• Suppresses nausea & vomiting.
• Uses:
• Motion sickness.
• Postoperative nausea & radiation sickness.
• Pregnancy-related vomiting (morning sickness).
• Example Drugs:
• Promethazine (most widely used).
• Meclizine, Diphenhydramine, Dimenhydrinate.
7. Local Anesthetic & BP Effects
Membrane Stabilization (Local Anesthesia):
• Strong: Pheniramine, Promethazine, Diphenhydramine
• Not used clinically due to irritation
BP Effects:
• IV injection causes hypotension (smooth muscle relaxation, α-blockade)
• Oral administration has no significant effect
THERAPEUTIC USES OF H1 ANTIHISTAMINES
•Allergic Disorders → Urticaria, hay fever, anaphylaxis (adjunct), atopic dermatitis.
•Motion Sickness & Nausea → Meclizine, Promethazine.
•Parkinsonism & Drug-Induced Extrapyramidal Symptoms → Diphenhydramine.
•Insomnia & Anxiety → Hydroxyzine, Diphenhydramine.
•Common Cold & Cough Relief → Chlorpheniramine, Diphenhydramine.
ADVERSE EFFECTS OF H1 ANTIHISTAMINES
Category Adverse Effects
Sedation, dizziness, tremors, paradoxical hyperactivity
CNS
(children)
Anticholinergic Dry mouth, blurred vision, urinary retention, constipation
Cardiovascular Hypotension, dizziness, reflex tachycardia
Nausea, vomiting, epigastric distress, weight gain
Gastrointestinal
(cyproheptadine)
CNS depressants (↑ sedation), MAOIs (↑ anticholinergic
Drug Interactions
effects), Alzheimer’s drugs (↓ effectiveness)
Allergic Reactions Contact dermatitis (topical diphenhydramine)
Overdose Hallucinations, seizures, coma, cardiorespiratory collapse
PHARMACOKINETICS OF H1 ANTAGONISTS
Absorption:
• Well absorbed orally and parenterally.
Distribution:
• First-generation: Crosses BBB → CNS effects.
• Second-generation: Does not cross BBB.
Metabolism:
• Liver metabolism (CYP enzymes), excreted in urine.
• Cetirizine and levocetirizine excreted unchanged.
Half-life:
• First-generation: 4–8 hours (short duration).
• Second-generation: 12–24 hours (long duration).