AUTACOIDS ----- PHARMACOLOGY

Autacoids

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Introduction

·         histamine

·         serotonin

·         endogenous peptides

·         prostaglandins

·         leukotrienes

Histamine and Antihistamines

1. Histamine Synthesis

Histamine: Storage and Release

Immunologic Release: 

1.       The most important mechanism for histamine release is in response to an immunological stimulus. 

2.       In mast cells, if sensitized by surface IgE antibodies, degranulate when exposed specific antigen. 

3.       Degranulation means liberation of the contents of the mast cell granules, including .histamine

4.       Degranulation is involved in the immediate (type I) allergic reaction.

Mechanical/Chemical Release:

·         A second type of release occurs following chemical or mechanical injury to mast cells. 

·         In these injuries caused degranulation

·         Mechanism of Action –

·         Histamine mediates its effects by interacting with receptors. 

·         Receptor Types   H_1, H_2, H_3,and H4types. 

Type	Location	Function
H1 histamine receptor	Found on: •       Smooth muscle •       Endothelium •       CNS tissue	Causes: vasodilation Bronchoconstriction bronchial smooth muscle contraction separation of endothelial cells (responsible for hives), and pain and itching due to insect stings; the primary receptors involved in allergic rhinitis symptoms and motion sickness; sleep regulation.
H2 histamine receptor	Located on parietal cells	Primarily stimulate gastric acid secretion
H3 histamine receptor	Found on central nervous system and to a lesser extent peripheral nervous system tissue	Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotonin
H4 histamine receptor	Found primarily in the basophils and in the bone marrow. It is also found on thymus, small intestine, spleen, and colon.	Plays a role in chemotaxis.

Mechanism of action

A.Histamine (H1)-receptors

¤  H1-receptors are membrane bound and coupled to G-proteins, specifically Gq/11, and their activation causes:

n  increase in phospholipase C

n  increases in diacylglycerol and intracellular Ca2+

n  increased cyclic guanosine 5′-monophosphate (cGMP)

                     

¤ Activation of H1-receptors in vessels causes vasodilation and an increase in permeability.

¤  Activation of H1-receptors promotes ( intestinal and Bronchiolar ) smooth muscle contraction

B. Histamine (H2)-receptors

1.     The response of H2-receptors is coupled via Gs to increased cyclic AMP (cAMP) production.

2.     Activation of H2-receptors:

n  increases gastric acid production

n  causes vasodilation

n  generally relaxes smooth muscles.

C.  Histamine (H3)-receptors

1.     H3-receptors are found in the central nervous system (CNS) and peripheral nervous system (PNS) at presynaptic nerve terminals.

2.     H3-receptors are membrane bound and coupled to Gi/o; their activation increases intracellular Ca2+ and decreases cAMP.

3.     Stimulation of H3-receptors

1.     on nerve cells causes a decrease in histamine release

2.     Activation of H3-receptors on the vagus nerve decreases acetylcholine (ACh) release.

D.Histamine (H4)-receptors

1.     H4-receptors are found on hematopoietic cells and in the spleen, thymus, and colon.

2.     Stimulation of H4 receptors increases chemotaxis of mast cells and leukocytes cells toward sites of inflammation.

3.  H4 receptors are coupled to Gi/Go and thereby inhibit the production of cAMP and increase intracellular Ca2+

Histamine antagonists

receptor antagonists: selective blockade of histamine receptors (H₁, H₂, H₃ types)

Histamine (H1)-receptor antagonists

¨ Competitive inhibitors.

¨ Classification:

1.     First-generation agents

2.     Second-generation agents

First-generation agents

n  Chlorpheniramine ,Brompheniramine ,diphenhydramine ,doxylamine ,clemastine ,dimenhydrinate  ,pyrilamine ,meclizine ,cyclizine ,Promethazine

n  These agents produce sedation.

Second-generation agents

A.Non sedating:

1.    Loratadine:

¤  Poor CNS penetration: reduced sedation

¤  Little or no anticholinergic activity

2.    Desloratadine

3.    Fexophenadine

¤  sedative activity is low but dose dependent.

B.     Less Sedating:

1. Acrivastine.
2.  Cetirizine

Pharmacologic properties of Histamine (H1)-receptor antagonists

·        Well absorbed after oral administration.

2nd generation	1st generation
30 min	30 min	Onset
3-24 hours	3-8 hrs	Duration

¨  H1-receptor antagonists are lipid soluble; most first-generation agents cross the blood— brain barrier.

¨  H1-receptor antagonists are metabolized in the liver;

¨  many induce microsomal enzymes and alter their own metabolism and that of other drugs.

Pharmacologic Actions

¨  Many H1-receptor antagonists, especially the1st generation , have muscarinic—cholinergic antagonist activity.

¨  Most of these agents are effective local anesthetics, probably because of a blockade of sodium channels in excitable tissues.

¨  Dimenhydrinate and promethazine are potent local anesthetics.

¨  Injectable 1% diphenhydramine is a safe, inexpensive, and effective local anesthetic for simple dermatological procedures in patients who report “caine” allergies. 

¨  H1-receptor antagonists relax histamine-induced contraction of bronchial smooth muscle and have some use in allergic bronchospasm.

¨  These agents block the vasodilator action of histamine.

¨  H1-receptor antagonists inhibit histamine-induced increases in capillary permeability.

¨  These agents block mucus

¨  H1-receptor antagonists, especially the first-generation agents, frequently cause CNS depression (marked by sedation, decreased alertness, and decreased appetite).

Therapeutic Uses

1. Treatment of allergic rhinitis and conjunctivitis.  

¨  Many antihistamines are used to treat the common cold, based on their anticholinergic properties, but they are only marginally effective for this use.

¨  Diphenhydramine also has an antitussive effect not mediated by H1-receptor antagonism.

2. Treatment of urticaria and atopic dermatitis, including hives
3. Sedatives. Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids.
4. Prevention of motion sickness
5. Appetite suppressants

Adverse effects

¨  (significantly reduced with second-generation agents)

¨  Sedation, dizziness, and loss of appetite.

¨  These agents can cause gastrointestinal upset, nausea, and constipation or diarrhea.

¨  H1-receptor antagonists produce anticholinergic effects (dry mouth, blurred vision, and urine retention).

Histamine (H2)-receptor antagonists

¨  Cimetidine[Tagamet]

¨  Ranitidine[Zantac]

¨  Famotidine[Pepcid AC]

¨  Nizatidine[Axid]

Competitive antagonists at the H2-receptor, which predominates in the gastric parietal cell.

¨  Used in the treatment of:

1.       Gastrointestinal disorders, including heartburn and acid-induced indigestion.

2.       These agents promote the healing of gastric and duodenal ulcers.

3.       Used to treat hypersecretory states such as Zollinger-Ellison syndrome.

Pharmacokinetics

¨  Their elimination is primarily renal.

¨  Cimetidine inhibits cytochrome P-450 and increases the concentrations and the effects of many other drugs.

Adverse effects

¨  H₂ antagonists are generally well-tolerated, except for cimetidine where all of the following adverse drug reactions (ADRs) are common.

¨  Infrequent ADRs include hypotension.

¨  Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash.

¨  Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

H₃-receptor antagonist 

¨  H₃ receptors are primarily found in the brain and are inhibitory autoreceptors located on histaminergic nerve terminals, which modulate the release of histamine.

¨   Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H₁ receptors in the cerebral cortex.

¨   Consequently unlike the H₁ antagonist antihistamines which are sedating, H₃ antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease.

Examples of selective H₃ antagonists

It include:

¨  Clobenpropit , ABT-239 , Ciproxifan , Conessine , A-349/821 , Thioperamide

The chromones:

¨  Cromolyn [Intal]

¨  Nedocromil sodium [Tilade]

  

¨  These are administered by inhalation.

¨  They inhibit the release of histamine and other autocoids from the mast cell.

¨  Each is used prophylactically in the treatment of asthma

¨  they do not reverse bronchospasm.

Adverse effects:

¨  confined to the site of application

¨  Include:

¨  sore throat

¨  dry mouth.

¨  Nedocromil sodium

¨  more effective in reducing bronchospasm caused by exercise or cold air.