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

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

Autacoids

They include:


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


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


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


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) Histamine
Pharmacokinetics:
It is rapidly absorbed after S.C. or I.M. administration.

2. Oxidation by histaminase enzyme. It can not pass B.B.B. but it is present in brain.

Histamine
Histamine
N-methyl transferase
methyl histamine
MAO
methyl imidazole acetic acid.
Major metabolite in urine
Fate
1. Methylation (major metabolic pathway)



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

Present in stomach (responsible for HCl), heart and some vessels.

Histamine
H2 receptors H3 receptors Present presynaptic in brain and in myentric plexus


1.Spasmogenic effect on smooth muscles of bronchi, GIT and large vessels, but arterioles are dilated → headache and flushing2. Hypotension due to arteriolar dilatation, relaxation of precapillary sphincters and increased capillary permeability. Histamine
Actions
H1-Actions
3. Stimulation of adrenaline release from adrenal medulla by direct and reflex action


Itching occurs if histamine is released in the skin and induces pain when deeply injected.
4. Skin
Actions
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.


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


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
Histamine antagonism


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

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



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


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

Actions of anti-histaminic:

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

Antiemetic action and antimotion sickness through inhibiting vomiting center

3.Dimenhydrinate, diphenhydramine, meclizine, cyclizine and promethazine
Actions of anti-histaminic:
4.Diphenhydramine, promethazine, cyproheptadine and Chlorpheneramine
Atropine like 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.

 Conjunctivitis, rhinitis  Urticaria ,itching  Insect stings Uses

1. Allergic disorders as:
Antihistaminic drugs

Uses of Antihistaminic drugs

They are not so effective in bronchial asthma?
Anaphylactic shock and angioneurotic oedema

2. Motion sickness, vertigo and Meniere's disease. 3. Cardiac arrhythmia (antazoline).4. Parkinsonism (due to atropine like action) especially diphenhydramine5. Common Cold (Chlopheneramine)→Sedation & dries the secretions Uses of Antihistaminic drugs



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


Cimetidine (? …)Famotidine NizatidineRanitidine Roxatidine Antagonist of H2-receptors(H2-blockers) – for the treatmentof peptic ulcer: