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Autacoids

I- Biologically active amines:  Histamine.  Serotonin (5-HT). IIII- The Eicosanoids:  Prostaglandins (PGs).  Thromboxanes (TXs).  Leukotrienes (LTs).  Lipoxins.

IIIIII- PAF. IVIV- The endogenous polypeptides:

Angiotensins (I & II). Kinins. Substance P. Vasoactive Intestinal peptide (VIP).

V- Cytokines: Interlukins (ILs) including IL1 , IL17. Interferons (IFNs) e.g. IFN-E, IFN-F and IFN-K. Tumor necrosis factor-alpha (TNF-E) & TNF-F.

Histamine
 Histamine is found in most

tissues, in a bound form in granules, in mast cells or basophiles. These mast cells are especially rich at sites of potential tissue injury i.e. skin, lungs, liver, GIT etc.

Release of histamine occurs through:


A- Immunologic reactions:  The mast cells and basophiles, which are previously sensitized by exposure to the antigen, contain antibodies (IgE) attached to their surface membranes.  Re-exposure to the antigen results in antigen-antibody reaction on the walls of these cells.  Influx of calcium ions and  Degranulation of the mast cells and basophiles and release of histamine by exocytosis.

If the release is localized to respiratory passages it may result in asthma. If localized to the skin it results in itching, urticaria and burning. But if generalized release of histamine it may result in anaphylactic shock.

B- Non-immunologic activation: Non It is IgE-independent; does not require energy and is not associated with mast cell degranulation.  Activation may occur by: 1-Drugs: adenosine, morphine, dtubocurarine. 2-The experimental Compound 48/80 (histamine liberator). 3-Mechanical: cold air, exercise, radiation (e.g. X-ray) and mechanical injury of mast cells.

Effects of Histamine: 1- On the C.V.S.: Vasodilatation of small blood vessels due to release of EDRF (NO) from endothelium. This leads to:

 Increase in H.R reflex to hypotension.  Flushing and headache due to V.D.  Edema due to increased capillary permeability.

2- On smooth muscles: Spasmogenic effect (H1 effect), leads to:  Bronchoconstriction.  Contraction of intestinal smooth muscles, and diarrhea in high doses. Contraction of the uterus of a pregnant woman and it may induce abortion.

3- On sensory nerve endings:  Stimulates sensory nerve ending leading to the urticarial response. 4- On secretory tissue:  Stimulates gastric acid secretion, due to activation of H2 receptors on gastric parietal cells (Increases cAMP level and stimulates proton pump).  Stimulates gastric pepsin and intrinsic factor production.

5- On the skin: Intradermal injection of histamine produces a characteristic "Triple response: A) Red spot "Flush", due to V.D of small blood vessels. B) Then a localized edematous 'Wheal' due to increased capillary permeability. C) Then a red irregular Flare surrounding the wheal (due to local arteriolar dilation resulting in V.D in surrounding area).  Pain sensation and itching.

Histamine Receptors  Histamine acts on 3 types of receptors namely H1, H2 & H3.  H1- Rs are present in the SM, endothelium and brain.  H2- Rs are found in gastric mucosa, cardiac muscle, mast cells, and brain.  H3- Rs receptors are presynaptic receptors on nerve terminals in the brain and some other neurons.

Histamine antagonists
1- Histamine release inhibitors (Mast cell stabilizers) as:  Sodium cromoglycate or cromolyn sodium (Intal).  Ketotifen citrate (Zaditen).  Nedocromil sodium (Tilade).  Also glucocorticoids, as dexamethasone and F2-adrenoceptor agonists, as salbutamol.

2- Histamine receptors antagonists: H1 and H2-antagonists: These drugs antagonize histamine competitively. Selective H3-antagonists are not yet available for clinical use.

H1- Receptor antagonists


I - Older H1 antagonists (First H1 (First generation drugs): as Ethanolamines: Diphenhydramine (Benadryl)& Dimenhydrinate (Dramamine)  Ethylenediamines, e.g. mepyramine and antazoline.

Alkylamines, e.g. chlorpheniramine. Piperazines, e.g. cyclizine, meclizine. Phenothiazines, e.g. promethazine (Phenergan). Miscellaneous, e.g. cyproheptadine (Periactin), ketotifen (Zaditen).

II - The second generation H1 H1 antagonists, antagonists, as: Astemizole (Hismanal). Loratadine (Claritin). Terfenadine (Histadin), causes cardiac arrhythmias so obsolete now. Fexofenadine . Cetrizine (zyrtec).

Pharmacological Actions:
1) Antihistaminic action: they action:

oppose, to varying degrees, the effects of liberated histamine by reversible competitive antagonism at the H1 receptors.

2) Other actions: A - Action on CNS: CNS:  Variable degree of CNS depression i.e. sedation, sedation, drowsiness and sleep. sleep.  The newer H1-antagonists are claimed to H1 have little or no sedative action. B - Antimotion sickness effect: e.g., effect: Dimenhydrinate, Diphenhydramine, Promethazine and other Piperazines derivatives.

C- Anticholinergic effects: effects:  Many H1-antagonists tend to inhibit H1 the muscarinic actions of ACh.  The newer agents as Astemizole has no effect on muscarinic receptors. D- Adrenergic blocking effect: H1effect: antagonists, esp. Phenothiazines have weak alpha-receptor blocking alphaeffect.

E -Antiparkinsonian effect: Some effect: H1-antagonists produce this effect (anticholinergic effect). F - Local anaesthesia: Most of the anaesthesia: H1 antagonists block sodium channels in excitable membranes in the same way as procaine and lignocaine. G -Antiserotonin effect: Drugs, like effect: cyproheptadine is promoted as an antiserotonin agent.

Side Effects: Effects: Sedation, dizziness, insomnia, nervousness, tremors. Antimuscarinic effects e.g. dry mouth, blurred vision, constipation, and dry skin (inhibit sweating). Severe poisoning results in coma and sometimes convulsions.

H2- Receptor antagonists

This group of drugs includes: Cimetidine (Tagamet). Ranitidine (Zantac, Rantidol). Famotidine (Pepcid). Nizatidine (Axid).
 H2-receptor antagonists compete with histamine reversibly at H2-receptor sites and this action is selective, as they do not affect H1- receptors.

Pharmacological Actions:
1-Reduction of gastric acid secretion: This is the most important action. 2-Other effects related to H2receptor blockade: Nizatidine reduces both the H.R and cardiac output in normal persons.

3-Effects unrelated to H2-receptor blockade: Cimetidine can inhibit the cytochrome P450 oxidative drug metabolizing system. Both Cimetidine & ranitidine can inhibit the renal clearance of basic drugs that are secreted by the renal tubules.

Cimetidine binds to androgen receptors and causes antiandrogen effects (gynecomastia, decreased testicular weight) while ranitidine, famotidine and nizatidine do not bind to androgen receptors.

Uses of H2-receptor H2 antagonists:


These drugs are mainly used in: Treatment of gastric and duodenal ulcers. Treatment of gastroesophageal reflux disease and esophageal ulcer.

Treatment of hypersecretory conditions as Zollinger Ellison syndrome (A gastrin-secreting tumor). In high doses, they can control symptoms related to excess acid secretion (in severe GI ulcerations).

Side effects: Most sides effects have been reported with Cimetidine as: Diarrhea, dizziness, headache, and skin rash. Liver toxicity: Cimetidine causes reversible cholestatic effects, while ranitidine causes reversible hepatitis, with or without jaundice.

Endocrine toxicity: Cimetidine binds to androgen receptors, and the antiandrogen effects as: Gynecomastia in men and Galactorrhea in women may occur. Reduction in sperm count and a reversible impotence in patients receiving high doses of Cimetidine.

CNS Dysfunction: delirium, and confusion are most common in old patients receiving Cimetidine. Neutropenia, and other hematological disorders may associate Cimetidine use.

Serotonin
(5-Hydroxytryptamine, 5-HT) Distribution:  About 90% is localized in granules in the enterochromaffin cells of intestinal mucosa.  About 8% is present in blood platelets.  Serotonin is also found in the brain (2%).  It is found in mast cells in rodents, but not in humans.

Serotonin receptors: receptors: The actions of serotonin are mediated through 4 main types of cell membrane receptors (5-HT1 to 5-HT4). 5-HT1 receptors are sub classified into 5-HT1a, 5-HTlb, 5-HTlc and 5HTld receptors.

Serotonin Antagonists:
1-Methysergide: Antagonizes the vasoconstrictor effect of 5-HT as well as its action on a variety of extravascular smooth muscles.

It has been used for migraine prophylaxis and vascular headaches.

2-Cyproheptadine:
It has equal potency at both H1histamine and 5-HT receptors as an antagonist. Used in controlling intestinal manifestations of carcinoid and postgastrectomy dumping syndrome. It has weak anticholinergic and sedative properties.

3-Ketanserin:
A highly selective 5-HT2 antagonist and has no significant action on 5-HT1& 5-HT3 receptors.

It blocks 5-HT2 - induced V.C, platelet aggregation and contraction of airway smooth muscle.

It has adrenergic, H1 and dopaminergic blocking activity. Ketanserin is an effective antihypertensive, but the mechanism of action is not clear.

Actions of 5-HT: 1- On the CVS: a- Blood vessels:


In humans, 5-HT is a powerful vasoconstrictor, constricts veins more than arterioles so blood is accumulated in capillaries resulting in flushing of skin.  Sk. M. vessels and coronaries are dilated (Due to release of NO).

b- Heart rate:  Bradycardia:( H.R) occurs due to activation of chemoreceptor nerve endings in coronaries (Bezold-Jarich reflex).

c -Blood pressure:
 I.V injection of 5-HT produces a triphasic response: An initial decrease in Bl.P. and H.R., (due to activation of chemoreceptors). Followed by a rise in Bl.P, due to peripheral V.C. The third phase is a decrease in Bl.P due to dilatation of skeletal muscle vessels due to release of nitric oxide (EDRF).

d- Blood platelets:  Serotonin causes aggregation of the blood platelets due to activation of surface 5- HT2 receptors.

2- Effect on Sm. m. of GIT and

bronchi: Serotonin is a direct spasmogenic agent, causes contraction of Sm. m. of the GIT, and bronchi. It controls the gastrointestinal motility. Excessive secretion (from tumors as carcinoid syndrome), results in severe diarrhea and flushing.

3-Effect on nervous system: Like histamine, serotonin is a potent stimulant of pain and sensory nerve endings. Serotonin is anxiogenic and plays an important role in initiation of migraine attack.

Eicosanoids
 Eicosanoids are autacoids derived from arachidonic acid. They include: 1-Prostaglandins (PGs), 2-Thromboxanes (TXs), 3-Leukotriens (LTs), 4-Lipoxin and other related compounds.

Biosynthesis:
Activation of the enzyme phospholipase-A2 with hydrolysis of cell membrane phospholipids and release of free arachidonic acid.

PGs, and TXs are formed by the cyclooxygenase pathway and LTs are produced via the 5lipooxygenase pathway.

Effects of PGs, TXs and LTs: 1- On Bl.V.: Bl.V.:


PGE2 & PGI2:  Arteriolar V.D, maintaining

pulmonary blood flow; also maintain the potency of the ductus arteriosus until the time of its closure. Renal V.D, rennin release and increase in GFR & Na+ and water excretion TXA2 TXA2 produces V.C. V.C.

2- Blood Platelets:

TXA2: is a potent stimulant of


platelet aggregation.

PGI2: inhibits platelets


aggregation. The balance between TXA2 & PGI2 maintain normal blood flow..

3- Uterus: Many PGs, including PGE2 & PGF2 , produce contraction of the uterus and may result in abortion (Oxytocic effect).

4- GIT: PGE2 & PGI2 Decrease gastric


acid secretion and Increase the secretion of the protective mucin layer that covers the gastric mucosa (cytoprotective effect).

PGs may lead to diarrhea and


intestinal colic (due to motility). gastric

5- Bronchi: Bronchi:
 PGE2 & PGI2 produce

bronchoprotective effect but PGF2 and LTs produce bronchoconstriction.

LTs: LTC4, LTD4 and LTE4 form

the SRS-A that produce asthmatic attacks.

They cause bronchoconstriction, V.C, increased vascular permeability, mucous hypersecretion, and chemotactic activity for leucocytes (hence their name).

6- Role in inflammation:

PGs & LTs are considered among


the important mediators of inflammation. They produce:

V.D. of capillaries (redness).


Increase capillary permeability and edema.

Pain sensation (Sensitize nerve endings to histamine& serotonin) Producing fever (Pyrogenic effect due to stimulation of HRC in hypothalamus). LTB4 has a chemotactic activity for leucocytes (Attract leucocytes to inflammatory site).

Uses of Eicosanoids:
 PGE1 (Alprostadil) is given to maintain the potency of ductus arteriosus in pulmonary hypertension or pulmonary artery stenosis.  PGE2 (Dinoprostone) pellets for induction of abortion in second trimester, induction of labor (Dinoprostone gel) and treat postpartum bleeding.  PGF1 (Enzaprost) is used for induction of abortion.

Misoprostol (Cytotec), a synthetic PGE1 analogue, is used for prevention of aspirinlike drugs-induced ulcer. Latanoprost is a PGF1 analogue used for treatment of open angle glaucoma.

Inhibition of Eicosanoids biosynthesis and actions: Achieved by : actions: 1- Glucocorticoids: as hydrocortisone and dexamethasone.  These drugs block Eicosanoids synthesis, by stimulating the synthesis of the inhibitory proteins 'Lipocortins', which inhibit phospholipase-A2.

 They inhibit the biosynthesis of PGs, TXs, LTs, and other related Eicosanoids as well as PAF.

2-Non-steroidal antiinflammatory drugs (NSAIDs): e.g. aspirin, indomethacin, & paracetamol. They block both PGs, and TXs formation by inhibiting cyclooxygenase activity.

3-Zileuton: It is 5-lipoxygenase
inhibitor reducing the biosynthesis of LTs. 4-Montelukast and Zafirlukast are leukotriene receptor blocking agents (Used for treatment of bronchial asthma).

Platelet Activating Factor (PAF) PAF is a phospholipid-derived


mediator, synthesized by the action of phospholipase A2. It is a potent pathophysiologic mediator of asthma and shock.

Intradermal injection of PAF in human skin produces an immediate painful reaction, which can be blocked by i.d. injection of H1-antagonists.

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