Autacoids and Autacoids Antagonist

Histamine It's one of the most important Autacoids. An organic nitrogen compound (formed from amino-acid histidine), involved in: 1. Immune responses (allergic and immune reactions). 2. Regulating physiological function in the → gut and sleep. 3. Acting as a → neurotransmitter.

Location Cells: includes Mast cells (mainly), Basophiles, Neurons and Enterochromaffin-like cells (ECL). Tissue: includes Skin, Lung and GIT.

Release: occur by 2 processes: First:- Energy and Ca+2 dependent degranulation reaction When allergies enter into the body (by eat or breath), result in → trigger immune cells to produce large amounts of IgE, that recognize that food. Some IgE attaches to the → surfaces of mast cells (sensitization). On any subsequent exposure to the same allergen, the allergens interact with the → specific IgE on the surface of the mast cells. In response, the activated mast cells rapidly release → histamine. Depending on the tissue in which they are release, these chemicals will cause a person to have → various symptoms of allergy.

Release Second:- Energy and Ca+2 independent release (displacement) Is induced by: a) Drugs → morphine, tubocuranine, etc. b) Mast cell damage, which is caused by → noxious agents (venom) or mechanical trauma, can release → histamine

Receptors H1, H2, H3 and H4 H1 Mainly in CNS, Smooth muscle cells of airways, GIT, CVS, Endothelial cells and Lymphocytes. H2 Mainly in Parietal cells, Vascular smooth muscle cells. H3 Mainly in CNS and PNS. H4 Mainly in Bone marrow and Immune cells.

Actions 1. Vascular H1 and H2: vasodilatation. H1: ↑ capillary permeability, which is occur by → contraction of endothelial cells of venules. 2. Heart H1:↓ AV conduction. H2: ↑ chronotropy. H2: ↑ inotropy

Actions 3. GI system H1: ↑ intestinal motility and secretions. H2: acid, fluid and pepsin secretions. 4. Lung H1: bronchoconstriction. H1: ↑ mucous viscosity. H1: stimulation of vagal sensory nerve endings → cough and bronchospasm. 5. CNS H1: pain and itching. H1 and H3: neurotransmitters.

We can minimize Histamine reactions by: 1 We can minimize Histamine reactions by: 1. Physiological antagonism → epinephrine. 2. Inhibit the release of histamine → cromolyn. 3. Pharmacological antagonism → antihistamines.

H1-Receptors Antagonists (H1-RA) Mechanism of action: Act by competitive blockade of → H-receptors in the target tissues, result in: ↓ the availability of these receptors for H. This interaction is → reversible, and can be overcome by ↑ H release.

Generations 1st generation (sedating): includes Diphen-hydramine, Doxyl-amine, Terfen- adine, Chloro-phenir-amine, Meclizine and Hydroxine. 2nd generation (non sedating): includes Cetirizine and Loratadine. 3rd generation: includes Fexo-fenadine, Levo-cetrizine and Des-loratadine.

Therapeutic uses 1. Allergic disease → nasal allergies, urticaria and common cold. 2. Systemic anaphylaxis. 3. Anti-emetic: prohylactic for motion sickness → promethazine. 4. Anti-vertigo → meclizine. 5. L.A. → diphen-hydramine and promethazine. 6. Anti-tussive → diphen-hydramine. 7. Ketotifen: oral form to prevent asthma attacks. 8. Other uses: ↓ of tremors and muscle rigidity in Parkinson's disease.

Side effects (↓ in 2nd and 3rd generations) Sedation (1st generation). Dizziness. Lack of coordination. Euphoria. Nervousness. Blurred vision. Urinary retention. Dryness of mouth and respiratory passages.

Uses in dentistry Diphen-hydramine, hydroxyzine and promethazine are used in → conscious sedation procedure and as premedication for deep sedation and G.A. Have L.A. activity, so it can be used for → patients who have allergy to conventional L.A. For management of → systemic anaphylactic reaction.  Treatment of → allergic lesions of oral mucosa.

H2-Receptors Antagonists (H2-RA) Mechanism of action: Competitively blockade the binding of histamine to H2receptors in the gastric parietal cells. Clinical use: Inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. Examples: Cime-tidine. Rani-tidine. Famo-tidine. Niza-tidine

Serotonin Is a monoamine neurotransmitter. One of the most important autocoids, has many physiological roles and clinical applications. It's widely distributed in → plants and animal tissues. In human: 90% → GIT, 8% → platelets and 2% → CNS. Synthesis: Tryptophan a 5-hydroxytryptophan b serotonin (5HT) * a = tryptophan hydroxylase. * b = l-aromatic acid decarboxylase.

Pharmacological actions 1. Cardiovascular system: Small +ve inotropic and +ve chronotropic effect on the heart. Direct vasoconstriction (large arteries). ndirect vasodilatation (NO and PGI2-mediated). *PGI2: prostaglandin - I2. 2. Respiratory system: Small direct stimulation to → bronchial smooth muscle in normal person, but produce → bronchospasm in asthmatic patients. Hypoventilation, due to → stimulation of bronchial sensory nerve endings.

Pharmacological actions 3. GIT: potent stimulation on the → smooth muscle of the gut, which: ↑ the tone. Facilitate peristalsis. Stimulate vomiting. 4. CNS: stimulation of → sensory nerve endings, which lead to → pain and itching. 5. Glandular secretions: little inhibitory effects on exocrine glands. 6. Uterus: large doses → impairs placental blood supply, and may lead to → fetal distress.

Serotonin Agonists 1. Sumatriptan: 5-HT1D agonist, used as → anti-migraine drug. 2. Fluoxetine: selective serotonin reuptake inhibitors, used as → antidepressant drug. 3. Buspirone: 5-HT1D agonist, for → anxiety.

Serotonin Antagonists 1. Cyproheptadine (periactin): H1 and 5-HT2 antagonists, used as → appetite stimulant. *Other uses: allergic rhinitis and cold urticaria. 2. Ondansetron: 5-HT3 antagonists, used in → citotoxic induced nausea and vomiting. 3. Clozapine: 5-HT2A/2C antagonist, for → schizophrenia.

Migraine Syndrome of recurrent pulsatile (throbbing pain) unilateral headache (few hours- few days in duration). Types: 1. Migraine without aura (common). 2. Migraine with aura (classic).

Treatment Drugs used to treat Migraine headache: 1. Non-specific treatment (symptomatic) Analgesics → NSAIDs. Anti-emetic drugs → prochlor-perazine: to control vomiting. Opioids: when other treatments are not successful (rescue medication). 2. Specific migraine therapy Triptans → Suma-triptan, Zolmi-triptan and Almo-triptan. Dihydro-ergotamine. * Both are → 5-HT1D-receptor agonists.

Prophylaxis several drugs are effective in ↓ the frequency and severity of migraine attacks: β-blockers: Propranolol and Nadolol Tri-cyclic anti-depressant: Ami-triptyline Anti-convulsant: Dival-proex. Calcium-channel blocker: Verapamil