Autacoids

Objective

At the end of this lecture, student will be able to

• Explain autacoids

• Describe the pharmacology of histamine

• Discuss the pharmacology of antihistamine

Content

• Autacoids

• Histamine

                                Introduction

                                Synthesis

                                Release

                                Histamine receptors

                                Pharmacological action

                                Pathophysiological role

                                Antihistamine

Autacoids

• Autacoid: derived from Greek: autos-self, akos-healing substance or remedy

• These are diverse substances produced by a wide variety of cells in the body, having intense biological activity, but generally act locally at the site of synthesis and release

• Also known as local hormones

• Autacoids are involved in a number of physiological and pathological processes

• Even serve as transmitters or modulators in the nervous system

Classification of autacoids:

1. Amine autacoids Histamine, 5-Hydroxytryptamine (Serotonin)

2. Lipid derived autacoids: Prostaglandins, Leukotrienes, Platelet activating factor

3. Peptide autacoids: Plasma kinins (Bradykinin), Cytokines (interleukins, INFo., GM-CSF etc)

Histamine

• Synthesized in 1907 & later isolated from mammalian tissue

• Tissue amine

• Present in animal tissues, certain plants, venoms

• Manifestations of certain allergic reactions

• Mediator of hypersensitivity, phenomena and tissue injury reactions

• Play important physiological roles

• Present mostly within storage granules of mast cells (Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs and placenta)

• Non mast cell histamine occurs in brain, epidermis, gastric mucosa and growing regions

• Synthesis, storage and destruction

• Histamine is imidazolylethylamine

• Synthesized from amino acid histidine

• Degraded rapidly by oxidation and methylation

• IgE antibody is produce and get bound to receptor-1 on the surface of mast cell

• An binds to Ab and forms An-Ab complexs

• ca²⁺ induce Exocytosis for release of histamine

Histamine receptor

Pharmacological action of Histamine

Blood vessels:

• Dilatation of smaller blood vessels (arterioles, capillaries and venules)

• Vasodilatation is partly indirect mediated through EDRF

• Large arteries and veins are constricted mediated by H₁ receptor

• ↑se capillary permeability due to separation of endothelial cells which leads to exudation of plasme (H₁ receptor)

•       Intra dermal inj: Elicits triple response

                Red spot: due to intense capillary dilatation

                Wheal: due to exudation of plasma

Flare: redness in surrounding area due to arteriolar dilation

Heart (H₁ receptor):

• ↑se  HR, FOC, +ve chronotropy and +ve inotropy

• Smooth muscle (H₁ receptor): Bronchoconstriction, uterus and intestinal smooth muscle (abdominal cramps) constriction

• Glands (H₂ receptor): ↑se gastric secretions

• Sensory nerve ending (H₁ receptor): stimulated cause itching, pain etc

• Adrenal medulla (H₂ receptor): increase the release of AD produce secondary hypertension

• CNS(H₁ & H₂ receptor): does not penetrate BBB & no central effects are seen

Pathophysiological role of Histamine

• Gastric secretions: ↑se HCl secretion in stomach and cause ulcers (H2 receptor)

• Allergicphenomena: Mediate by hypersensitivity reactions leads to urticaria, angioedema, bronchoconstriction and anaphylactic shock

• As transmitter: initiates the sensation of itch and pain at sensory nerve ending,  act as a transmitter in regulating body temperature, CVS function, Thirst, Hormone release from anterior pituitary

• Inflammation: mediator of vasodilatation and other changes that occur during inflammation and promotes adhesion of leukocytes to vascular endothelium

Uses of Histamine 

•       Histamine has no therapeutic use. Only for experimental use

•       Contraindications: in asthmatic and ulcer patients

Antihistamines or H₁ antagonists 

•       These drugs competitively antagonize actions of histamine at the H1 receptors

•       Classification of antihistamines

                All antihistamines have similar action, but differs in sedative property

1. Highly sedative: Diphehydramine, Promethazine, Hydroxyzine
2. Moderately sedative: Pheniramine, Cyproheptadine, Cinnarizine
3. Mild Sedative: chlorpheniramine, Cyclizine, Dexchlorpheniramine
4. Non sedative (Second generation antihistamines): Cetirizine, Loratadine, Levocetirizine 

Pharmacological action of H₁ antagonists 

•       Histamine antagonism:

Blocks:  histamine induced bronch, intestinal and uterus contraction

                                Triple response-especially wheal, flare and itch

                                Fall in BP

                                Release of Adr from adrenal medulla

                                Constriction of larger blood vessel

•       Anti allergic action: Immediate hypersensitivity (type I reactions) are suppressed

                Urticaria, itching and angioedema are well controlled

                Anaphylactic fall in BP is only partially prevented

•       CNS: Older antihistamines produce variable degree of CNS depression

                Sedative antihistamine causes CNS depression

                Stimulant effects like restlessness and insomnia

                Excitement and convulsions are frequently seen at toxic doses

                Effective in preventing motion sickness

                Controls vomiting of pregnancy

                Reduce tremor, rigidity of parkinsonism

•       Anticholinergic action: antagonize muscarinic actions of Ach

•       Local anaesthetics: it has membrane stabilizing property

•       BP: cause a fall in BP on i.v. injection

•       H₁ antihistaminics are well absorbed from oral and parenteral routes

•       Metabolized in the liver

•       Excreted in urine

•       Widely distributed in the body and enter brain

•       Newer compounds penetrate brain poorly

•       Duration of action of most agents is 4 to 6 hours, except meclizine, loratadine, cetirizine and fexofenadine which act for 12-24 hours or more

Side effects and toxicity of H₁ antagonists 

•       Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common

•       Impairment of psychomotor performance

•       Few individuals become restless, nervous and are unable to sleep (Second generation compounds are largely free of CNS effects)

•       Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision due to anticholinergic property

•       Epigastric distress and headache are also common

•       Local application can cause contact dermatitis

•       Acute overdose produces central excitation, tremors, hallucinations, muscular incordination, convulsions, flushing, hypotension, fever and some other features of belladonna poisoning

•       Death is due to respiratory and cardiovascular failure

Advantages of second generation H₁ antagonists 

•       Higher H₁ selectivity

•       No anticholinergic side effects

•       Absence of CNS depressant property

•       Additional antiallergic mechanisms apart from histamine blockade

•       Inhibit late phase allergic reaction by acting on leukotrienes or by anti platelet activating factor effect

•       Advantage of not impairing psychomotor performance

•       No sleepiness, Do not potentiate alcohol or benzodiazepines

Uses of H₁ antagonists 

•       Allergic disorders: Antihistaminics do not suppress AG:AB reaction, but block the effects of released histamine-are only palliative (allergies, e.g. itching, urticaria, seasonal hay fever, allergic conjunctivitis and angioedema of lips, eyelids, etc)

•       Pruritides

•       Common cold, Cough

•       Motion sickness, Vertigo

•       Preanaesthetic medication

•       Parkinsonism

•       Acute muscle dystonia

•       As sedative, hypnotic, anxiolytic

Summary

•       Histamine is an amine autacoid

•       Mediator of hypersensitivity , phenomena and tissue injury reactions

•       Betahistine is histamine receptor analogue

•       Antihistamines competitively antagonize actions of histamine at the H1 receptors

•       Antihistamines are commonly used in Allergic disorders