Autacoids and Antihistamines






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What is an autacoid?

Autacoids are natually occuring substances that are localized in tissues and act like hormones and cause an effect on smooth muscle such as with vasoconstricting or dialating. They commonly have a short duation of action.
Histamine was the first type of autocoid discovered and main type. Other examples include polypeptides (angiotensin, bradykinin, and kallidin), and lipid derived substances (prostaglandins, leukotrienes, and platelet activating factor).

-Histamine is widely distributed in nature and is found in plants, bacteria, and animals. Nearly all mammalin tissues contain histamine or can form it. In humans the highest concentrations are found in the lung, skin, and intestinal mucosa. Other organs such as the pancreas, spleen, liver, and kidney have a low histmine content. Histamine is synthesized in mammalin tissue by the intracellular decarboxylation of the amino acid histidine. This conversion is catalyzed by histidine decarboxylase. This enzyme is primarly responsible for the synthesis of histamine in human beings. Histamine is found in most tissue in the mast cell and in blood in a related cell, the basophil. These cells synthesize histamine and store it as a proteinaceous complex with heprin or chrondroitin sulfate in membrane bound secretory granuels. Histamine in this form is physiologically inactive but can be dischared from the cell by a process called exocytosis or degranulation.The first step in this process is activation of the cell by an appropriate stimulus, either tissue injury, allergic reaction, or drug foriegn compounds. Once the cell is activated a series of events takes place leading to degranulation.

Where is Histamine stored in, and what induces their release?
Histamine in stored in mast cells and in blood (basophils). Histamine can be released due to tissue injury, allergic reactions, or drugs and foreign compounds.
Video on histamine
1. Histamine is a basic amine that is stored in mast cells and basophils.

2. The interaction between allergen and IgE, bound to the surface of mast cells or
basophils by a surface receptor that binds the Fc fragment of IgE, leads to degranulation of these cells, with release of mediators, including histamine.

3. It acts on H1-, H2-, or H3-receptors on target cells to produce its effects.

4. Histamine has two major pathophysiological roles, which include the stimulation of
gastric acid secretion, which is treated with H2-receptor antagonists, and the mediation of type 1 hypersensitivity reactions such as urticaria and hay fever, which is treated with H1-receptor antagonists.

5. H1-receptors are located in human bronchial muscle and are linked to transduction systems that cause increased intracellular Ca2+, which leads to muscle contraction. H2-receptors are located in acid-secreting stomach cells and in the heart.
HISTAMINES PHYSIOLOGICAL EFFECTS ARE AS FOLLOWS:
5. HR: INCREASES
6. BP: DECREASES
7. SMALL B.V.: DILATION EFFECTS ON SMALL ONES
8. FLUSHING
9. DECREASE IN TPR
10. INCREASE IN CAPILLARY PEARMABILITY
11. “RED” (H1 AND H2), “WHEAL” (H1), AND “FLARE” (H1)
12. LUNGS: INTENSE BRONCHOCONSTRICTION MEDIATED BY H1
13. G.I.: GASTRIC SECRETIONS MEDIATED BY H2
14. NERVES: ITCHING AND PAIN MEDIATED BY H1
15. CNS: REGULATION OF DRINKING, BODY TEMP, BP, AND PAIN (H1-H3

Pharmacologic Effects of Antagonists on H1-receptors:
-As Antihistamine: blocks capillary permeability, dilation of vascular smooth muscle
-As Anticholinergic : dries mucous membranes and decreased salivary secretion
-As Antiserotonergic: block the actions of serotonin or serotonin agonists
-As Antimetic - Antimotion sickness, Meniere’s syndrome ( & other types of vertigo)
- Suppress the itching and pain associated with histamine-mediated reaction at the cutaneous nerve endings (allergic rash)
-Can have sedative effects (with the exception of second generation)
-Can bind to the H1-receptor and prevent the release of histamine or block its action
-In Dentistry: relieves nausea produced by opioids & local anesthesia (can be injected for some local anesthetic -many other drugs are much more effective at producing anesthesia and require less of the drug.)
CONTRAINDICATIONS FOR USE:
-pregnancy, breast feeding
-Adverse Reactions
-CNS Depression (Sedation -> most common side effect; warns of drowsy effects, insomnia*, tremors, nervousness and irritability, palpitation, tachycardia, blurred vision, urinary retention)
-Gastrointestinal (Anorexia, nausea, vomiting, and constipation)
-Anticholinergic (Xerostomia)
-Allergic reactions with high doses (urticarial, eczematous, bullous, or petechial rashes, fixed drug reaction, or anaphylaxis)
-Therapeutic Uses
-Allergic reactions, nausea and vomiting, preoperative sedation, OTC sleeping aids
-SECOND GENERATION Peripheral (Nonsedating) H1-Receptor Antagonist
-Do not cross blood-brain barrier therefore potential for sedation is greatly reduced.
CONTRAINDICATIONS FOR USE:
- concurrent administration w Erythromycin, clarithromycin & ketoconazole: interfere with metabolism of antihistamines
-in some, food can inhibit absorption
-Adverse reactions
Headaches, somnolence, fatigue, and xerostomia


Clinical Uses:
H1 receptors
-To treat or prevent allergic reactions
-Treatment of allergic rhinitis
-Motion sickness
-Nausea and Vomiting

H2 receptors
-Peptic ulcer disease
-Gastric ulcer disease
-Gastroesophageal Reflux Disease
-Hypersecretory disease



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    • for treating:
      • nasopharyngeal itching
      • sneezing
      • watery rhinorrhea
      • ocular: itching, tearing, erythema
    • Side effects:-- older H1 antihistamines:
      • sedation
      • visual disturbance
      • urinary retention
      • arrhythmias
  • (Seldane) (Hismanal)
    • Less sedating (reduced ability to cross the blood brain barrier)
    • Important drug-drug interactions:
      • macrolide antibiotics (e.g. erythromycin, clarithromycin (Biaxin)), ketoconazole-class broad-spectrum antifungal drugs, inhibit terfenadine (Seldane) or astemizole (Hismanal) metabolism.
      • Toxic levels of terfenadine (Seldane) or astemizole (Hismanal) may induce potentially fatal cardiac arrhythmias.
      • These new H1 antihistamines are contraindicated for concurrent use with macrolide antibiotics and ketoconazole-class and fungal drugs or in the presence of impaired hepatic function or inpatients predisposed to arrhythmias.

  • :
    • Phenylephrine (Neo-Synephrine) or oxymetazoline (Afrin) reduce nasal congestion/obstruction.
      • Efficacy duration: limited due to rebound rhinitis and systemic effects:
        1. insomnia
        2. irritability
        3. hypertension (seen more commonly with oral alpha adrenergic agonists

  • : -- useful
    • diminishes antihistamines caused sedation
    • enhances antihistamine efficacy in relieving congestion

    • liquid, nasal metered-dose spray:
      • no side effects
      • prophylactic use
        • reduces episodic allergen nasal mast cell activation
      • equal efficacy: cromolyn sodium and nonsedating antihistamines

    • most potent drugs available for management of established rhinitis (seasonal or perennial) and including vasomotor rhinitis
      • topical-to-systemic activity greater for: flunisolide (AeroBid) or budesonide (Rhinocort), compared to beclomethasone (Banceril) or triamcinolone (Aristocort).
    • same efficacy, reduced side effects, compared to same agent administered orally
    • Side effects:
      • local irritation (most frequent)
      • Candida over growth (unusual)
    • Topical high potency glucocorticoids: -- superior efficacy compared antihistamines during pollen season.

    • based on repeated, subcutaneous injections of gradually increasing allergen (specific for the symptom complex)
    • Duration: 3-5 years
    • Contraindications:
      • significant cardiovascular disease
      • unstable angina
    • Cautious use:
      • patients receiving beta adrenergic blockers (due to difficulty in managing possible anaphylactoid responses to treatment)
    • Clinical Management Sequence:
      1. identification of allergens confirmed by allergens-specific IgE skin testing and/or serum assay.
      2. Avoidance of offending allergen
      3. Mild symptoms: prophylaxis with topical cromolyn sodium or single (bedtime) dose of chlorpheniramine (Chlor-Trimeton)or astemizole (Hismanal) or terfenadine (Seldane) (decision based on side effects and presence of other concurrent medications or disease.
      4. Prominent symptoms: Topical beclomethasone (Banceril) or if needed budesonide (Rhinocort) or flunisolide (AeroBid)
      5. Management failure: immunotherapy


Action
Receptor
Location
Smooth muscle contraction
H1
All sm (except vasc.)
Vasodilatation
H1
Endothelial cells (via NO)
Increased Vasc. Permeability
H1 (H2?)
Endothelial cells
Cardiac stimulation
H2
Cardiac muscles
Increased gastric secretion
H2
Parietal cells
Pain and itch Inhibition of transmitter rel.
H1 H3
Sensory nerve endings Nerve ending


AUTOCOIDS AND ANTIHISTAMINES


Drug


Action


Bradykinin


Autocoid that produces pain (B2), vasodilation, stimulate macrophages, mediates bronchoconstriction and increase vascular permeability


Serotonin


Enterochromaffin cells that are located in the GI mucosa produce 5-HT. Released by mechanical stretching and vagal stimulation. 5-HT rls stimulates GI motility and over production is associated with CV, GI, CNS and heart valvular problems (fenfluramine)


Adenosine


1. Vasodilates the coronary artery and is used to perform radionuclide myocardial perfusion imaging and during cardiac catherterizations.
2. Drug of choice for supraventricular tachycardias (short t½)
3. theophylline (Adenosine antagonist) used for asthmatics.
Role in Allergy and anaphylaxis

a. stimulates secrtions
b. constricts sm. muscle (bronchi + intestines)
c. stimulates sensory nerves (itching + pain)
d. dilation of sm muscle in blood vessles (hTN w/rebound tachycardia

e.
dilation and increase permeability of capilaries



Histamine


1. released by trauma, allergy (IgE mediated), anaphylaxis, cold, toxins, venom, Rx.
2. released (heparin, protein, histamine) with several chemical mediators ( leucotrienes, PLA2, prostaglandins, cytokines)
3. MCDP (bee venom), radio contrast media, protamine, d-tubocurare, succinylcholine, morphine, codeine, vancomycin, doxorubicin cause histamine release


Antihistamines


1st generation – antiACh, CNS sedation, short acting

May potentiate other sedating medications


2nd generation – no antiACh, no sedation, long acting


Azelastine


Opthalamic solution with minial anti-cholinergic effects.
Also Tx Allergic Rhinitis



Cromolyn


Mast cell stabilizer; prophylaxis of asthma


Epinastine


Mast cell stabilizer and antihistamine


Promethazine


Most effective antihistamine used, and has anticholinergic effects so its good for motion sickness, local anesthetic action (blocks Na+ channels)


Phenothiazines
"Promethazine"



Used for N/V; blocks the D2 receptors




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