ISHIK UNIVERSITY FACULTY OF DENTISTRY Pharmacology 3rd Class-2016

‘autacoids Histamine and Antihistaminic Agents

Autacoids : They are formed in various tissues of the body and generally act locally at the site of synthesis and release in the body. They have also been called ‘local hormones’ and differ from hormones which are secreted from endocrine glands. The hormones are produced by specific cells (endocrine glands), and are transported through circulation to the distant target organs while autacoids are produced in tissues rather than in glands.

Autacoids Histamine, Hydroxytryptamine (5-HT, serotonin), Prostaglandins, Leukotrienes, and Kinins

Histamine Histamine is an amine formed by the decarboxylation of the amino acid histidine by histidine decarboxylase, an enzyme that is expressed in cells throughout the body, including central nervous system (CNS) neurons, gastric mucosa parietal cells, mast cells, and basophils

Mechanism of Action Histamine released in response to various stimuli exerts its effects by binding to one or more of four types of histamine receptors (H1, H2, H3, and H4 receptors). Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine onophosphate production, causing vasodilation. Histamine H2 receptors mediate gastric acid secretion.

Two important Histamine: H1 & H2 Antiallergic activities of H1 antihistamines, such as inhibition of the release of mediators from mast cells and basophils, involves stimulation of the intracellular activity of the polyphosphatidylinositol pathway. H1 antihistamines involve the down-regulation of nuclear transcription factors that regulate the production of proinflammatory cytokines and adhesion proteins. Stimulation of H2 receptors enhances the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase.

Antihistamines Pharmacological Actions Antihistaminic action: The antihistaminics blocks histamine effects at a variety of sites. They inhibit most responses of smooth muscles to histamine. They antagonize the stimulant actions of histamine smooth muscles of the respiratory system, gastrointestinal tract, the uterus and the blood vessels.

Action on central nervous system: Majority of antihistaminic drugs produce var iable degree of CNS depression i.e. sedation, drowsiness and sleep. Diphenhydramine, promethazine are potent sedatives and is often accompanied by inability to concentrate. terfenadine and astemizole are claimed to have little or no sedative action, Loratidine is claimed to have little autonomic and CNS blocking effects… sedating

Antimotion sickness effect: H1-antagonists. Anticholinergic effects diphenhydramine, promethazine Anticholinergic effects Adrenergic blocking effect: H1- antagonists, specially of phenothiazine subgroups have weak alpha-receptor blocking effect. Antiparkinsonism effects: Because of anticholinergic property, some H1- antagonists have significant suppressant effect on the parkinsonism like symptoms. Local anaesthesia:diphenhydramine and promethazine are occassionally used to produce local anaesthesia in patients allergic to local anaesthetic drugs. Antiserotonin effect: cyproheptadine is promoted as an antiserotonin agent

Pharmacokinetics SE: Absorption in GIT is good. Metabolized in the liver by hydroxylation and glucuronide conjugation, widely distributed throughout the body and excreted in the urine. Adverse Reactions: Sedation except for terfenadine and astemizole fatigue, dizziness, tinnitus, lassitude, blurred vision, diplopia, euphoria, nervousness, tremor and insomnia. SE: loss of appetite, nausea, vomiting, epigastric distress, constipation or diarrhoea and dryness of mouth, bladder disturbances.

Therapeutic Uses Hypersensitivity reactions Motion sickness: promethazine, promethazine chlorotheophyllinate, diphenhydramine, dimenhydrinate, cyclizine and meclizine Antivertigo :cyclizine, cinnarizine, dimenhydrinate, diphenhydramine Antiparkinsonism: diphenhydramine Local anaesthetics: diphenhydramine and tripelennamine

New Antihistamines CETIRIZINE: selective H1antagonist. antihistaminic with a low potential for drowsiness at pharmacologically active doses and with additional antiallergic properties. Indications: allergic rhinitis, seasonal allergic rhinitis, chronic idiopathic urticaria, conjunctivitis. Side effects: headache, dizziness, drowsiness, dry mouth and gastrointestinal discomfort. LEVOCETIRIZINE : a 2-fold higher affinity for human H1-receptors than cetirizine. Oral bioavailability of 85%. Onset of action occurs within one hour.

FEXOFENADINE: a pharmacologically active metabolite of terfenadine, is a non sedating antihistaminic with selective peripheral H1 receptor antagonist activity. Mechanism of Action: Fexofenadine inhibited antigen- induced bronchospasm and histamine release from mast cells. no sedative or other CNS effects. Side effects: headache, fatigue, drowsiness, nausea, tachycardia, palpitations, dry mouth, GIT disturbances, taste disturbances, photosensitivity, dysmenorrhoea and menstrual disorders.

Summary of therapeutic advantages and disadvantages of some H1-histamine receptor blocking agents.

H2-RECEPTOR ANTAGONISTS H2 receptors are responsible for histamine induced gastric acid secretion. H2-receptors antagonists such as cimetidine, ranitidine, famotidin. This will be discussed in Antiulcer Agents topic.

Serotonin and its Antagonists

5-HYDROXYTRYPTAMINE (5-HT, SEROTONIN) Pharmacological Action: Cardiovascular system: 5-HT can directly stimulate or relax smooth muscles via 5-HT1 & 5-HT2 receptors and can influence the release of noradrenaline from adrenergic nerves and stimulate endothelial cells to release prostaglandins. On heart, 5-HT has weakly direct positive inotropic and chronotropic effects, that are mediated by 5- HT1 receptors.

Pharmacological Action Smooth muscle: 5-HT stimulates smooth muscles, it increases the motility of the small intestine, stomach and also large intestine by which peristalsis is increased & diarrhoea can occur. It also constricts bronchial smoothmuscles, but is less potent than histamine. Nerve endings: 5-HT is less potent than histamine in releasing catecholamines from adrenal medulla. 5-HT3 receptors located on various sensory neurons mediate a depolarising response, which may cause pain & itching.

5-HT ANTAGONISTS I. Ergot alkaloids and derivatives Ergotamine : 1-3 mg/day, 0.25-0.5 mg SC/IM Lysergic acid diethylamide (LSD) 2-Bromolysergic acid amide (BOL) Methysergide (Congener of LSD; SANSERT) 2 mg BD-TDS Metergoline II. Antihistaminics Cyproheptadine (PERIACTIN) 4 mg/day (increases the appetite and promotes weight gain) Cinnarizine (STUGERON) 25-50 mg/day III. Phenothiazines Chlorpromazine (LARGECTIL) 25-100 mg/day, IM IV. Selective 5-HT blockers Ketanserin (SUFREXAL) 10-30 mg/day Pizotifen (PIZOTYLINE) 0.5-1 mg/day

Drugs Used to Treat Migraine Headache Migraines present as a pulsatile, throbbing pain; cluster headaches, as excruciating, sharp, steady pain; and tension-type headaches, as dull pain, with a persistent, tightening feeling in the head. Types of migraine: migraine without aura (previously called common migraine). Typically lasts from 2 to 72 hours Migraine with aura (previously called classic migraine.

Drugs Used to Treat Migraine Headache Triptans : The triptans are serotonin agonists, acting at a subgroup of serotonin receptors found on small, peripheral nerves that innervate the intracranial vasculature. rizatriptan , zolmitriptan Ergot alkaloids and derivatives

EICOSANOIDS – PROSTAGLANDINS AND LEUKOTRIENES

Prostaglandins Prostaglandins (PG’s) and leukotrienes (LT’s) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids, which contains 3, 4 or 5 double bonds Unsaturated fatty acid derivatives that act on the tissues in which they are synthesized and are rapidly metabolized to inactive products at the site of action.

prostaglandin analogues PGE1 Misoprostol (CYTOTEC), Rioprostil PGE2 Enprostil, Arbaprostil, Trimoprostil, Dinoprostone (PROSTIN E2) PG I2 Carbacyclin, Iloprost PGF2α -Dinoprost (PROSTIN F2 ALPHA)

Therapeutic uses of prostaglandins Abortion Peptic ulcer Misoprostol is sometimes used to inhibit the secretion of gastric acid and to enhance mucosal resistance to injury in patients with gastric ulcer who are chronically taking nonsteroidal anti- inflammatory agents. Proton-pump inhibitors, such as omeprazole, and H2 antihistamines also reduce the risk of gastric ulcer and are better tolerated than misoprostol, which induces intestinal disorders