Autacoids: Histamine, prostaglandins, serotonin, leukotrienes Flashcards
What are autacoids?
Autacoid – from two Greek words
“autos” –self and
“akos” – medicinal agent or remedy
Autacoids have a brief lifetime and act near their site of synthesis – Local hormones
Hormones - act beyond their site of production carried by way of bloodstream for selective action elsewhere in the body e.g. insulin)
- Autocrine – Histamine, Prostaglandins, Serotonin
- Paracrine – Nitric Oxide (NO), Endothelin-1 (ET-1) see CV Notes
- Endocrine – Hormones – Insulin, Thyroxine, Estradiol
What is histamine? what does it do?
Histamine in the body
- stored in mast cells (present in the gut and lungs) and basophils
- Plays a role in allergic/hypersensitivity reactions
(via activation of H1 receptors)
- in neurons in the CNS and peripheral nerves (H1)
- Plays a role as a Neurotransmitter/Neuromodulator
- Stimulates gastric acid secretion (via H2 receptors)
What form is it stored as? How is it released? What type of pathogenesis does it contribute to?
Histamine in the body – stored in mast cells and basophils in secretory granules
In the granules it is bound to a proteoglycan - either heparin sulfate or chondroitin sulfate E
Normally it is released by exocytosis of the secretory granules
Histamine contributes to the pathogenesis of immediate hypersensitivity (minor allergic) reactions. Antihistamines are helpful.
Several mediators contribute to severe anaphylactic reactions - a physiological antagonist (e.g. adrenaline) is more effective in reducing the severity of an anaphylactic reaction by enhancing bronchodilatation, overcoming cardiovascular collapse. Saves Life!
How does histamine release during allergy (hypersensitivity work)?
Acute hypersensitivity and release of histamine and other mediators:
Exposure to antigen
Synthesis of IgE
IgE binds to mast cells in the target organ
Re-exposure to antigen - antigen-antibody interaction on mast cell surfaces
Triggers release of mediators of anaphylaxis
LOOK AT THIS PICTURE AGAIN. FOR THE ABBREVIATIONS.
Is histamine released by some drugs? What inhibits the release of histamine from mast cells?
Histamine may be released directly by certain drugs
- Morphine (opiod analgesics) and d-tubocurarine (skeletal muscle relaxant, competitive antagonist of the NMJ Nicotinic Receptors for ACh)
- displace histamine from the heparin-protein complex in mast cells
Agents that inhibit the release of Histamine from the mast cells are:
- Cromolyn (sodium cromoglycate)
- Theophylline/aminophylline
- ß agonists
What are the three types of histamine receptors and why do we use the blockers for them?
Three types: Why we use H1 and H2 Blockers?
H1 receptors – (contributes to Rhinitis, Urticaria)
coupled to the generation of IP3 and DAG
contribute to minor allergic reactions – hay fever
CLASSICAL ANTIHISTAMINES IS FOR THE H1 RECEPTOR.
H2 receptors (Gastric acid Secretion)
coupled to adenylate cyclase and increases cAMP
activation causes increased gastric acid secretion
H3 receptors (Central Neurotransmitter role)
G-protein coupled
located presynaptically in the brain and in myenteric plexus
What is the summary of major events accompanying stimulation of histamine receptors in man?
Tissue - vascular smooth muscle. Effect - decrease in total peripheral resistance (TPR), fall in BP. Receptor H1 and H2
Bronchial smooth muscle. Contraction (bronchoconstriction). H1
GI mucosa, GI smooth muscle, Gall bladder smooth muscle. acid and pepsin secretion, relaxation and contraction, contraction. H2, H1, H1.
Cutaneous nerve endings. Pain and itching. Mainly H1
Adrenal medulla. Catecholamine secretion. H1.
Basophils. Inhibition of IgE mediated degranulation. H2
For the antihistaminics wha tare the names and duration of hours as well as the sedative effects, antiemetic effects, and antichollinergic effects?
FIRST GENERATION
Dimenhydrinate (gravol). 8 hrs. high (sedative). Medium (antiemetic). High (anticholinergic).
Diphenhydramine (Benadryl). 8. high. medium. high.
Hydroxyzine, cyclizine (motion sickness - antiemetic). 6. high. high. medium.
second generations agents - less or no sedation, NO antiemetic or anticholinergic effects
loratadine. Day time (claritin) . 24. very low. none. very low.
What are the main effects and uses for antihistaminics?
To Treat Allergic Reactions
Such as Allergic Rhinitis, Urticaria, Hay Fever, Cold and Drug reactions.
These effects are controlled by classical antihistaminic agents
The H1 blocking agents block most of the actions of histamine listed in the table below. Most cause sedation, drowsiness. So non-sedative 2nd Generation came up.
What are the H1 actions of histamine?
actions - Increased vascular permeability. clinical effect - oedema; extravasation of blood-borne inflammatory mediator substances; physical disruption of epithelial architecture.
vasodilation. erythema; hypotension; nasal congestion and obstruction
smooth muscle contraction. bronchospasm; abdominal pain, vomiting and diarrhea; uterine cramps
stimulation of irritant receptors. itch; pain; sneezing
What are the uses of antihistaminics?
These agents are of little value in the treatment of major anaphylactic reactions (epinephrine used), angioedema, and other life threatening reactions for reasons outlined at the beginning of this lesson
Other effects of some antihistaminics
1) Sedation has been a major problem with many of the antihistaminics. The incidence of sedation with Loratidine is least (t 2nd Generation) to other classical 1st Generation antihistaminics causing sedation (Drugs 29: 34-56, 1985) because 2nd Generation agents [such as Loratidine] do not cause the BBB.
What are other effects of antihistaminics?
Anti-motion sickness
some of the ethanolamines and the piperazine group possess this property (cyclizine)
Anticholinergic
especially the ethanolamines and ethylenediamine
Anti-adrenergic activity
usually quite weak
Anti-serotonin activity (eg. Cyproheptadine Block 5-HT & H1 Receptor – antihistaminic/antiserotonin effects)
Local anesthetic properties
What is a summary of histamine?
Histamine is released from mast cells and is one component involved in immediate hypersensitivity reactions. Because other mediators also play a role, antihistamines are of limited usefulness in severe anaphylactic reactions. Non mast cell histamine plays a role as a neurotransmitter or neuromodulator in the CNS.
Most of the effects of histamine on smooth muscle are mediated by H1 receptors, while H2 receptors modulate gastric acid secretion.
The H1 blocking agents are often classed as first or second generation based on their propensity to induce sedation. H1 blockers such as diphenhydramine is given for hay fever, allergic rhinits, urticaria, Loratidine is a non-sedative. Potent, longer acting day time antihistamine (H1 blocker) since it doesn’t cross the BBB.
H2 blockers are given to gastric acid secretion/ulcer (Ranitidine).
What is the distribution of 5-Hydroxytryptamine (5-HT or Serotonin) XX and what does it do?
Distribution of Serotonin (5-HT) : GIT, Platelets & Brain
(i) Enterochromaffin cells in the GI tract:
approximately 90% of the 5 HT is found in these cells in the GIT.
Carcinoid syndrome is related to tumors of this enterochromaffin tissue. increase GIT Motility & Gastric Secretion.
(ii) Platelets
5-HT found in platelets contributes to Platelet Aggregation. 5-HT released from the Platelets also contributes to vasoconstriction and increase in BP.
(iii) Brain
5-HT is one the major neurotransmitters in the brain.
It plays a role in the regulation of sleep, temperature regulation, depression, and anxiety.
For Serotonin (5-Hydroxytryptamine, or 5-HT) what are the Receptors and Clinical Uses of Serotonin Agonists and Antagonists ?
Drug. 5 - HT receptor. Clinical Use
SEROTONIN AGONISTS
Buspirone. 5-HT(subscript 1A). anxiety, depression
Cisapride [withdrawn] A good prokinetic agent. 5-HT(4). Gastroesophageal reflux disease; To Treat Gastrointestinal hypomotility.
sumatriptan. 5-HT(1B/1D). migraine headaches
SEROTONIN ANTAGONISTS
Clozapine. 5-HT(2). Schizophrenia.
Cyprohetadine. 5-HT(2). Carcinoid syndrome; pruritus; urticaria.
Methysergide. 5-HT(2). carcinoid syndrome; migraine headache.
Ondansetron. 5-HT(3). Nausea and vomiting.
