The word autacoids is derived from Greek: autos – self, akos – healing substance/remedy.
Definition
- Autacoids are substances formed in various tissues, have complex physiological and pathological actions and act locally at the site of synthesis.
- They have a brief action and are destroyed locally. Hence they are called local hormones and differ from true hormones which are produced by specific cells and reach their target tissues through circulation.
- They are involved in a number of physiological and pathological processes.
Classification of autacoids is shown in Table 3.1.1.
HISTAMINE AND ANTIHISTAMINICS
Histamine
Histamine: (tissue amine) (Histo = tissue)
- It is a biogenic amine formed in many tissues. It is also found in the venom of bees, wasp and other stinging secretions.
- Dale established relation between action of histamine and allergic reactions.
- First synthesized in 1907.
Synthesis, storage, distribution and degradation
- Histamine is formed by the decarboxylation of the amino acid (histidine) (Fig. 3.1.1).
- Tissue rich in histamine are: lungs, skin, intestine, liver and placenta. It is stored in the granules of the mast cells and basophiles in an inactive form.
- Non-mast cell histamine found in brain (serves as a neurotransmitter), epidermis and in growing region.
- Degranulation of the mast cells (Fig. 3.1.2) release histamine which is quickly degraded by deamination and methylation.
Mechanism of Action
- Histamine produces its effects by acting on the histamine receptors. Three subtypes are known.
- – H1 : present in lungs, gut, blood vessels, nerve endings and brain.
- – H2 : stomach (gastric glands), heart, blood vessels and brain.
- – H3 : CNS.
Actions
CVS: Histamine dilates small blood vessels resulting in hypotension accompnied by reflex tachycardia. But cerebral blood vessels dilate producing severe throbbing headache.
Triple response: Intradermal injection of histamine elicits triple response comprising of:
- Red spot: at the site (flush): due to local capillary dilation.
- Flare: redness surrounding the ‘flush’ due to arteriolar dilatation.
- Wheal: local edema due to the escape of fluid from the capillaries.
This response is accompanied by pain and itching.
Smooth muscle: Histamine causes contraction of the non-vascular smooth muscles. Thus bronchospasm and increased intestinal motility are produced. Actions on other visceral smooth muscles like uterus are insignificant in human.
Glands: Histamine is a poweful stimulant of the gastric acid secretion-(acts through H2 receptors). It also stimulates pepsin and intrinsic factor secretion.
CNS: It dose not crosses BBB
- Direct injection in brain produces hypertension and behavioral arousal.
- Histamine functions as a neurotransmitter in the CNS.
Skin
Sensory Nerve endings :
- Histamine stimulates sensory nerve endings causing pain and itching.
- Intradermal injection of histamine produces triple response.
Adverse reactions: They include: hypotension, flushing, tachycardia, headache, wheals, bronchospasm and diarrhea.
Uses: Histamine is of no therapeutic value. It is occasionally used in some diagnostic tests like.
- Testing gastric acid secretion : To test the acid secreting ability of the stomach. But now pentagastrin is preferred for this purpose.
- Diagnosis of pheochromocytoma : Histamine releases catecholamines and rises BP – now not used.
- Testing pulmonary functions : To test bronchial hyperreactivity.
Histamine substitutes: Betazole is a H2 agonist and can be used in gastric function tests. Betahistine is a H1 agonist used to control vertigo in Meniere's disease.
Antihistaminics
- Histamine antagonists can be H1 receptor blockers and H2 receptor blockers.
- Drugs that competitively block H1 histamine receptors are conventionally called the ‘antihistaminics’. H2 blockers are used in the treatment of peptic ulcer.
- Classification of H1 receptor blockers are shown in Table 3.1.2.
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Actions
- Blockade of histamine actions: H1 receptor antagonists block the actions of histamine on H1 receptors. They block the histamine induced effects on smooth muscles of the gut, bronchi, blood vessels and triple response.
- Antimotion sickness effects: Several antihistamines prevent motion sickness and vomiting due to other labyrinthine disturbances. Some of them also control vomiting of pregnancy.
- Anticholinergic actions: Many of the H1 blockers have anticholinergic property.
- Sedation: Antihistamines cause CNS depression; sedation, dizziness, inability to concentrate and disturbances of coordination are common. Alcohol and other CNS depressants potentiate this action. Some patients may experience CNS stimulation resulting in tremor, restlessness and insomnia.
- Antiparkinsonian effects: Some of them suppress tremors, rigidity and sialorrhea probably due to their anticholinergic properties.
- Other actions: Antihistamines also have local anesthetic effects in high doses. Some of them also block α1 adrenergic and 5-HT receptors.
Pharmacokinetics
- Antihistaminics are well-absorbed.
- They are widely distributed in the body.
- Histamine is metabolised in the liver and excreted in the urine.
- Dose and route of administration see in Table 3.1.3.
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Adverse reactions: They are mild and on continue use tolerance develops:
- Sedation, dizziness, motor in coordination, inability to concentrate making driving dangerous (while on antihistaminics).
- Anticholinergic effects like dryness of mouth, blurred vision, constipation and urinary retention may be troublesome.
- Epigastric pain and headache can also occur.
- Many of them are teratogenic (toxic to fetus).
Newer non-sedative antihistaminics
- They are also called IInd generation antihistaminics and have the following advantages over classical antihistaminics:
- – No sedation because they poorly cross the blood-brain barrier.
- – No anticholinergic side effects as they are pure H1 blockers and do not block cholinergic receptors.
- – Some of them like astemizole are long-acting.
- However, the therapeutic indications of these agents are limited to allergic disorders like allergic rhinitis and chronic urticaria. They are more expensive.
- Terfenadine can very rarely cause fatal ventricular arrhythmias; erythromycin and ketoconazole potentiate this cardiotoxicity.
Uses
- Allergic reactions: Antihistaminics are useful for the prevention and treatment of symptoms of allergic reactions. They are effective in allergic rhinitis, conjunctivitis, hayfever, urticaria, pruritus, some allergic skin rashes and pollinosis.
- – Though they prevent bronchospasm induced by histamine, antihistaminics are not useful in bronchial asthma as many other mediators are also involved in the pathogenesis of bronchial asthma. Moreover, antihistaminics render the respiratory secretions more thick making it difficult to remove it and through it out.
- Common cold: Antihistaminics reduce rhinorrhea and afford symptomatic relief in common cold.
- Cough: Due to postnasal drip can be controlled by antihistaminics like diphenhydramine.
- Motion sickness: Given 30–60 minutes before journey, antihistaminics prevent motion sickness. They are also useful in treating vertigo of Meniere's disease and other vestibular disturbances. Cinnarizine is preferred.
- Antiemetic: Promethazine is used to prevent drug induced and postoperative vomiting. It has also been used in ‘morning sickness’.
- Preanesthetic medication: For the sedative, anticholinergic and antiemetic properties, promethazine has been used as preanesthetic medication.
- Parkinsonism: Some of them are useful in drug induced parkinsonism due to their anticholinergic action.
- Hypnotic: The sedative antihistamines are sometimes used to induce sleep. Hydroxyzine has been used as an anxiolytic.