Autacoids Presented by: Professor Dr. Imad A-J Thanoon

Autacoids : Agonists, Antagonists Objectives: At the end of the session, students are expected to: Review concepts pertaining to the inflammatory process Define an autacoid Describe the different autacoids in terms of (emphasis on histamine, serotonin, eicosanoids) Distribution/site in the body Synthesis/storage/release/metabolism Factors that stimulate synthesis, release Specific receptors Pharmacologic action/effect of agonists, antagonists and enzyme inhibitors Clinical applications Trivia: How many autacoids are there? Discovery: In this session, we will make use of these autacoids to understand physiologic processes in health, pathologic processes in disease. Knowing all about their distribution/site, synthesis/release/metabolism, factors that stimulate synthesis, release, how they act in the body, what their clinical implications are. This overview will try to cover some of these autacoids that you will take up later this month or semester in the OSI modules. You can appreciate this when you are able to point out possible targets for therapeutic intervention. 2

Definition: Auto = self Coids = Remedy or some times called Local Hormones Why are they very important? Autacoids regulate certain aspects of gastrointestinal (GI), uterine and renal function. These agents also participate in pain, fever, inflammation, allergic reactions, asthma and thromboembolic disorders. The physiological effects of the autacoids are usually restricted to the tissue in which they are formed (local action).

AUTACOIDS Naturally occurring substances Localized in tissues Do not normally circulate Diverse physiological and pharmacological activities Differ from hormones and neurotransmitters Short duration of action Usually involved in response to injury Sites of action restricted to the synthesis area Auto=self, akos=remedy; agents found in the body;eg: histamine, bradykinin, serotonin; 4

Aminoacid derivatives Fatty acid derivatives Autacoids They include: Aminoacid derivatives Histamine Serotonin Endogenous peptides Kinins, Angiotensin Substance P&others Fatty acid derivatives Eicosanoids

Histamine -It is the decarboxylation product of histidine and is present in various tissues as in: Lungs Alimentary tract Blood vessels. Skin

Histamine It is stored in mast cells and basophils with heparin in protein complex

Vancomycin, X-ray contrast media Histamine Histamine release Occurs in response to Injury (as physical trauma) Proteolytic enzymes Snake venom Antigen/antibody reaction. Some drugs can release histamine as morphine, trimethaphan, d-tubocurarine and succinylcholine, Vancomycin, X-ray contrast media

Histamine Pharmacokinetics: Histamine present in diet or formed in large intestine by bacteria is not effective because it is acetylated, bound to intestinal contents and inactivated by (histaminase) enzyme.(So it`s ineffective orally) It is rapidly absorbed after S.C. or I.M. administration.

Histamine Fate 1. Methylation (major metabolic pathway) N-methyl transferase methyl histamine Histamine MAO methyl imidazole acetic acid. Major metabolite in urine 2. Oxidation by histaminase enzyme. It can not pass B.B.B. but it is present in brain.

It acts on specific receptor: Histamine Histamine Receptors It acts on specific receptor: H1 receptors: which present mainly in smooth muscles.

Histamine H2 receptors H3 receptors Present in stomach (responsible for HCl), heart and some vessels. H3 receptors Present presynaptic in brain and in myentric plexus

Histamine Actions H1-Actions 1.Spasmogenic effect on smooth muscles of bronchi, GIT and large vessels, but arterioles are dilated → headache and flushing 2. Hypotension due to arteriolar dilatation, relaxation of precapillary sphincters and increased capillary permeability. 3. Stimulation of adrenaline release from adrenal medulla by direct and reflex action

Actions 4. Skin Itching occurs if histamine is released in the skin and induces pain when deeply injected. If injected intradermally, it produces triple response:  Redness due to capillary dilatation. Spreading flare due to arteriolar dilatation (local axon reflex). Wheal formation due to increased capillary permeability.

Actions H2-Actions 1. Increase gastric acid secretion and pepsin. HCL Pepsin H2-Actions 1. Increase gastric acid secretion and pepsin. 2. Stimulation of heart → tachycardia by direct action on histamine (H2) receptors and by reflex action as a result of hypotension. Uses: (it is rarely used)

Histamine Histamine antagonism The effects of histamine can be antagonized by: 1. Physiological antagonism, e.g. adrenaline. 2. Competitive antagonism. 3.Prevention of histamine release by glucocorticoids (which inhibit antigen/antibody reaction).

Histamine Pharmacokinetics "H1- receptors antagonists (Antihistaminic drugs) Pharmacokinetics  Absorbed orally, metabolized in liver and excreted in urine and milk.  They pass B.B.B. Second generation H1-blockers have minimal CNS actions

They have sedative effect, atropine like action and antiemetic action. Antihistaminic drugs Classification: A- First generation: Dimenhydrinate, diphenhydramine and promethazine They have sedative effect, atropine like action and antiemetic action. Meclizine and cyclizine They are antiemetic but teratogenic Antazoline Anti-arrhythmic action

It has antiserotonin and appetite stimulant action. Antihistaminic drugs A- First generation: Cyproheptadine (periactin) It has antiserotonin and appetite stimulant action.  Chlorpheneramine maleate (analerg).  Clemastine (tavegyl) and chemizole (allercur).  Ketotifen ( used in migaine prophylaxis) Mepyramine. Experimental

Fexofenadine, terfenadine, astemizole, cetirizine and loratadine. Antihistaminic drugs B-Second generation They have minimal sedative effect, no atropine like action, no anti-emetic, no anti-serotonin & long duration e.g. Fexofenadine, terfenadine, astemizole, cetirizine and loratadine.  Terfenadine is withdrawn due to risk of cardiac arrhythmias and is replaced by its active metabolite fexofenadine (considered as a third generation)

Actions of anti-histaminic: 1. H1 blocking action antagonizing spasmogenic effect on smooth muscle (bronchi), skin action, vascular tree and capillary permeability. 2. C.N.S. depressant action → sedation. But toxic doses may produce excitation. Loratadine, terfenadine, fexofenadine and astemizole are excluded from central action.

Actions of anti-histaminic: 3.Dimenhydrinate, diphenhydramine, meclizine, cyclizine and promethazine Antiemetic action and antimotion sickness through inhibiting vomiting center 4.Diphenhydramine, promethazine, cyproheptadine and Chlorpheneramine Atropine like action

Antiparkinsonian action Action of Antihistaminic drugs 5.Diphenhydramine Antiparkinsonian action 6.Cyproheptadine. Antiserotonin action 7. Antazoiline Quinidine like action, membrane stabilizing action and local anaesthetic action.

1. Allergic disorders as: Antihistaminic drugs Uses 1. Allergic disorders as:  Conjunctivitis, rhinitis  Urticaria ,itching  Insect stings

They are not so effective in bronchial asthma? Uses of Antihistaminic drugs Anaphylactic shock and angioneurotic oedema They are not so effective in bronchial asthma?

2. Motion sickness, vertigo and Meniere's disease. Uses of Antihistaminic drugs 2. Motion sickness, vertigo and Meniere's disease. 3. Cardiac arrhythmia (antazoline). 4. Parkinsonism (due to atropine like action) especially diphenhydramine 5. Common Cold (Chlopheneramine)→Sedation & dries the secretions

Adverse effects: Anti-histaminic  Sedation, drowsiness and fatigue.  Hallucination, excitement, convulsions and coma in toxic doses.  Dry mouth, anorexia and nausea, blurred vision & urine retention.

Antagonist of H2-receptors (H2-blockers) – for the treatment of peptic ulcer: Cimetidine (? …) Famotidine Nizatidine Ranitidine Roxatidine 28