Autacoids vs Hormones

Autacoids

• Autacoids are locally produced biological mediators with short-term effects.
• Autacoids are synthesized in local tissues and rapidly metabolized.
• They exert rapid and localized effects.
• Autacoids are associated with inflammation, pain, and allergic reactions.

Hormones

• Hormones are chemical messengers secreted by endocrine glands and travel through the bloodstream to distant target tissues.
• Hormones are produced by the endocrine system, enter circulation, and affect distant organs.
• They have long-lasting and widespread effects.
• Hormones regulate metabolism, growth, reproduction, and overall homeostasis.

Types of Autacoids

• Amines include Histamine and 5-Hydroxytryptamine.
• Lipids include Prostaglandins, Leukotriens, and Platelet-activating factor.
• Peptides include Bradykinin and Angiotensin.

Histamine

• Histamine, serotonin, and prostaglandins belong to a group of endogenous compounds called autacoids.
• These substances have widely differing structures and pharmacologic activities.
• They are formed by the tissues on which they act, functioning as local hormones.
• Autacoids are produced by many tissues rather than specific endocrine glands.
• Histamine is a chemical messenger primarily generated in mast cells.
• It mediates a range of cellular responses via multiple receptor systems.
• These responses include allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain.
• Histamine itself has no clinical applications, but antihistamines or histamine receptor blockers have therapeutic applications.

Location of Histamine

• Histamine is present in practically all tissues, with significant amounts in the lungs, skin, blood vessels, and the GI tract.
• It is found at high concentrations in mast cells and basophils.
• Histamine functions as a neurotransmitter in the brain.
• It also occurs as a component of venoms and secretions from insect stings.

Synthesis of Histamine

• Histamine is an amine formed by the decarboxylation of the amino acid histidine.
• This process is facilitated by the enzyme histidine decarboxylase.
• The enzyme is active throughout the body in neurons, gastric parietal cells, mast cells, and basophils.
• In mast cells, histamine is stored in granules and if not stored, it is rapidly inactivated by the enzyme amine oxidase.

Release of Histamine

• Stimuli for histamine release from tissues include destruction of cells caused by cold, toxins from organisms, insect and spider venoms, and trauma.
• Allergies and anaphylaxis can also trigger significant histamine release.

Mechanism of Action

• Histamine, when released, binds to histamine receptors (H1, H2, H3, and H4).
• H1 and H2 receptors are widely expressed and are targets for clinically useful drugs.
• Histamine has a wide range of pharmacologic effects mediated by both H1 and H2 receptors.
• H1 receptors produce smooth muscle contraction and increase capillary permeability.
• Histamine promotes vasodilation of small blood vessels by causing the vascular endothelium to release nitric oxide.
• Histamine enhances the secretion of proinflammatory cytokines in several cell types and local tissues.
• Histamine H1 receptors mediate pathological processes, including allergic rhinitis, atopic dermatitis, conjunctivitis, urticaria, bronchoconstriction, asthma, and anaphylaxis.
• Histamine stimulates parietal cells in the stomach, increasing acid secretion via the activation of H2 receptors.

Role in Allergy and Anaphylaxis

• Intravenous injection of histamine produces symptoms similar to anaphylactic shock and allergic reactions including:
  • Contraction of airway smooth muscle
  • Stimulation of secretions
  • Dilation and increased permeability of the capillaries
  • Stimulation of sensory nerve endings
• Symptoms associated with allergy and anaphylactic shock result from the release of mediators like histamine, serotonin, leukotrienes, and eosinophil chemotactic factor of anaphylaxis.

H1 Antihistamines

• Antihistamine refers primarily to classic H1-receptor blockers.
• H1-receptor blockers are divided into first- and second-generation drugs.
• Older first-generation drugs are effective and inexpensive but penetrate the CNS, causing sedation, and interact with other receptors.
• Second-generation agents are specific for peripheral H1 receptors.
• Second-generation antihistamines are made polar by adding carboxyl groups reducing CNS depression.
• Desloratadine, Fexofenadine, and Loratadine show the least sedation among second-generation agents.
• Cetirizine and Levocetirizine are partially sedating second-generation agents.

Actions of H1-Receptor Blockers

• Action of H1-receptor blockers is similar, blocking receptor-mediated response, not the formation or release of histamine.
• Most agents have additional effects by binding to cholinergic, adrenergic, or serotonin receptors.
• Cyproheptadine also acts as a serotonin antagonist on the appetite center, resulting in appetite stimulation.
• Azelastine and ketotifen have mast cell-stabilizing effects in addition to histamine receptor-blocking effects.

Therapeutic Uses of H1-Receptor Blockers

• Useful in treating and preventing allergic reactions caused by antigens acting on immunoglobulin E antibody.
• Oral antihistamines are the drugs of choice in controlling symptoms of allergic rhinitis and urticaria.
• They manage anaphylactic reactions to control urticaria, itching, and edema.
• Antihistaminics only partially protect against hypotension.
• Ophthalmic antihistamines like azelastine, olopatadine, and ketotifen treat allergic conjunctivitis.
• H1-receptor blockers are not suited for treating bronchial asthma, since histamine is only one of several mediators.
• Antihistaminics are used in common cold formulas, providing symptomatic relief by decreasing rhinorrhea and sneezing.

Motion Sickness and Nausea Uses

• Antimuscarinic agents, H1-receptor blockers such as diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine prevent symptoms of motion sickness.
• The antihistamines are more effective if taken prior to expected travel.
• They prevent or diminish nausea and vomiting, blocking central H1 and M1 muscarinic receptors.
• Meclizine treats vertigo associated with vestibular disorders.

Somnifacients

• First-generation antihistamines such as diphenhydramine and doxylamine, are used for insomnia.
• First-generation H1 antihistamines are contraindicated for individuals working in jobs that demand wakefulness.
• Second-generation antihistamines have no value as somnifacients.

Pharmacokinetics

• H1-receptor blockers are absorbed well orally with maximum serum levels at 1 to 2 hours.
• Plasma half-life is 4 to 6 hours, except for meclizine and second-generation agents (12 to 24 hours allowing for once-daily dosing).
• First-generation H1-receptor blockers are distributed in all tissues, including the CNS.
• First-generation and some second-generation (desloratadine and loratadine) H1 antihistamines are metabolized by the hepatic cytochrome P450 system.
• Cetirizine and levocetirizine are excreted largely unchanged in urine and fexofenadine in feces with the onset of action within 1 to 3 hours.
• Azelastine, olopatadine, ketotifen, alcaftadine, bepotastine, and emedastine target tissue delivery and are available in ophthalmic formulations.
• Azelastine and olopatadine have intranasal formulations.

Adverse Effects

• First-generation H1-receptor blockers have low specificity, interacting with histamine, muscarinic cholinergic, α-adrenergic, and serotonin receptors.
• Adverse reactions include:
  • Sedation caused by chlorpheniramine, pheniramine, diphenhydramine, hydroxyzine, and promethazine.
• Diphenhydramine can cause paradoxical hyperactivity in some children.
• Elderly patients may experience fatigue, dizziness, lack of coordination, and tremors.
• Second-generation H1 antihistamines are specific for peripheral H1 receptors.
• First-generation antihistamines cause dryness in the nasal passage and oral cavity.
• Most common adverse reaction associated with second-generation antihistamines is headache.
• Topical formulations of diphenhydramine can cause local hypersensitivity reactions such as contact dermatitis.

Drug Interactions

• Interaction of H1-receptor blockers with other CNS depressants potentiates the effects.
• The effectiveness of cholinesterase inhibitors are decreased in the treatment of Alzheimer's disease.
• Patients with MAOIs should not take antihistamines.

Overdoses

• Acute poisoning of H1 receptor blockers is relatively common in young children.
• Effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions.
• It may lead to coma and cardiorespiratory system collapse if untreated.

Other Uses

• Antihistaminics provide symptomatic relief through anticholinergic action in cough formulas but have no cough-suppressant property.
• Antihistaminics with anticholinergic activity can be used in the initial stages of Parkinson’s disease.

Histamine H2-Receptor Blockers

• Histamine H2-receptor blockers have little affinity for H1 receptors.
• H2-receptor blockers inhibit gastric acid secretion treating ulcers and heartburn.
• Types of H2 receptor blockers include:
  • Cimetidine
  • Ranitidine
  • Famotidine
  • Nizatidine

Selective Action

• Histamine H2 receptor antagonists act selectively on H2 receptors in the stomach without affecting H1 receptors.
• They are competitive antagonists of histamine which are fully reversible.
• These drugs treat peptic ulcers, acute stress ulcers, and gastroesophageal reflux disease.
• Drugs such as cimetidine, ranitidine, famotidine, roxatidine, and nizatidine inhibit basal, food-stimulated, and nocturnal secretion of gastric acid reducing acid secretion by approximately 70%.
• Cimetidine limited utility and adverse drug effects, was the first H2 receptor antagonist.