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Autacoids

By Dr Shah Murad

shahmurad65@yahoo.com

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Autacoids(autos>self :coid>remedy)(local

hormones) are naturally occuring substances

having widely different structures and

pharmacological actions.

They include decarboxylated amino

acids(histamine,serotonin),polypeptides(angiote

nsin,kinins,substance P,VIP) and

ecosanoids(PGs,leukotrienes,thromboxanes)

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Common autacoids

Histamine Serotonin Ergot Alkaloids Vasoactive peptides

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Histamine: Storage and Release Immunologic Release:

Most important mechanism Mast cells, if sensitized by surface IgE antibodies,

degranulate when exposed specific antigen  Degranulation:

immediate (type I) allergic reaction calcium-dependent, energy dependent Release components:

histamine ATP other mediators present in granules

 Degranulation may also occurred subsequent to IgG-or IgM-mediated immune reactions

Release regulation: present in most mast cells (not lung)

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Histamine Modulation: immunologic/inflammatory responses Histamine -- following local injury:

local vasodilation

acute inflammation mediator release--

inflammatory cells

neutrophils

eosinophils

basophils

monocytes

lymphocytes

Histamine --

inhibits some T and B lymphocyte function

inhibits release of lysosomal contents

Mechanism of Action:

H2 receptor activation

increasing intracellular cAMP

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 Mechanical/Chemical Release: Histamine displacement:

Morphine, tubocurarine: displacement of histamine from heparin-protein complex

Degranulation: chemical or mechanical injury to mast cells

Physical trauma

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Histamine

It is widely distributed in the body including Mast cells GIT lungs skin and CNS

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Synthesis,storage and release of HISTAMINE

Beta 2,4 imidazole ethylamine(Histamine)is synthesized in the tissues by decarboxylation of histidine.

In the mast cells histamine is stored,bound to heparin.

It is released from mast cells by mechanical

trauma,allergic reactions,ultraviolet radiation and by

various chemicals and

drugs(morphine,tubocurarine,stilbamidine,dextran)

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Overview of Mast Cells and BasophilsMast cells and basophils are the effector cells involved in the

immediate hypersensitivity response . Found in tissues throughout the body, they are particularly associated with blood vessels and nerves and are in proximity to surfaces that border

the external environment . Both contain numerous osmophilic granules that contain heparin

and other proteins that support mediators, including histamine, which alters cellular and vascular reactions.

Secretion of mediators occurs by degranulation during which the contents of the granules are exocytosed. Degranulation is provoked by certain chemical agents, C3a and C5a (two complement components) binding to surface receptors, certain drugs, and the IgE system .

Mast cells and basophils have receptors for IgE antibodies and can be activated to secrete mediators if IgE first binds to these receptors, followed by antigen binding to the Fab fragment of the fixed IgE molecules.

Degranulation can lead to allergic reactions or anaphylactic shock, in extreme cases

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Pharmacological actions

It acts through 2 types of receptors; H1 and H2 receptors.

Gastric,cardiac,probably central and some vascular actions of histamine are mediated through H2 receptors.

All other effects are mediated by H1 receptors. There are species differences in the distribution

of receptors.

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On CVS

Histamine causes relaxation of arterioles,constriction of veins,marked dilatation of capillaries,increased capillary permeability and relaxation of precapillary sphincters.

In man there is usuall fall in BP. Cerebral vessels respond to histamine with

dilatation,causing headache.

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On smooth muscles

It stimulates smooth muscle.

Bronchial smooth muscles are especially

sensitive to large doses of histamine.

Intestinal and ureteral smooth muscles are

contracted.

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Exocrine glands

Histamine by acting on H2 receptors causes the

secretion of large quantities of gastric juice rich

in acid and pepsin.

Gastrin may act through the release of

histamine,as the actions of both are blocked by

H2 receptor antagonists.

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On skin

triple response (of Lewis)  a triphasic skin

reaction to being stroked with a blunt

instrument: first a red line develops at the site

due to histamine release, then a flare develops

around the red line, and lastly a wheal is formed

as a result of local edema.

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On CNS

Large amount of histamine is found in various

CNS structures

It may function as neuro-modulator

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Endocrine glands

Large doses of histamine provoke secretion of

catecholamine from the adrenal medulla.

In acute inflammatory response ,histamine may

initiate early changes such as the axon reflex

and allergic response.

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Histamine and acute anaphylactic shock

During hypersensitivity reactions of the immediate type there is released of histamine from sensitized mast cells or basophils in response to specific antigen.

Histamine along with other constituents of the secretary granules is mainly responsible for acute anaphylactic shock

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Histamine, acting on H1-receptors, produces pruritus, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increase in vascular permeability, potentiation of pain, and more.

While H1-antihistamines help against these effects, they work only if taken before contact with the allergen. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life-threatening. Additional administration of epinephrine, often in the form of an autoinjector (Epi-pen), is required by people with such hypersensitivities.

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Therapeutic uses

Histamine was used in past for tests of gastric secretary function and for diagnosis of pheochromocytoma.

BETAZOLE (Histalog) is a synthetic analogue of histamine which stimulate the secretion of gastric acid with fewer side effects as compared to histamine.IT IS USED FOR TEST FOR GASTRIC SECRETION in the dose of 50mg subcutaneously.

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H1 antagonist

An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions. Agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines - other agents may have antihistaminergic action but are not true antihistamines.

In common use, the term "antihistamine" refers only to H1 antagonists, also known as H1-receptor antagonists and H1-antihistamines. It has been discovered that these H1-antihistamines are actually inverse agonists at the histamine H1-receptor, rather than antagonists

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Clinical use of H1-antihistamines

H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include:

Allergic rhinitis Allergic conjunctivitis Allergic dermatological conditions (contact dermatitis) Urticaria Angioedema Diarrhea Pruritus (atopic dermatitis, insect bites) Anaphylactic or anaphylactoid reactions - adjunct only Nausea and vomiting (first-generation H1-antihistamines) Sedation (first-generation H1-antihistamines)

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H1-antihistamines can be administered topically (through the skin, nose, or

eyes) or systemically, based on the nature of the allergic condition.

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First-generation (non-selective, classical)

These are the oldest H1-antihistaminergic drugs and are relatively

inexpensive and widely available. They are effective in the relief of allergic

symptoms, but are typically moderately to highly-potent muscarinic

acetylcholine receptor-antagonists (anticholinergic) agents as well. These

agents also commonly have action at α-adrenergic receptors and/or

5-HT receptors.

This lack of receptor-selectivity is the basis of the poor tolerability-profile of

some of these agents, especially compared with the second-generation H1-

antihistamines.

Patient response and occurrence of adverse drug reactions vary greatly

between classes and between agents within classes.

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Ethylene-diamines

Ethylenediamines were the first group of clinically-effective H1-antihistamines developed.

Mepyramine (pyrilamine) Antazoline

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Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, as well as sedation, are observed in this group but the incidence of gastrointestinal adverse effects is relatively low.

Diphenhydramine Carbinoxamine Doxylamine Clemastine Dimenhydrinate

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Alkylamines

The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site. Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation

EG:Pheniramine Chlorphenamine (chlorpheniramine) Dexchlorpheniramine Brompheniramine Triprolidine

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Piperazines

These compounds are structurally-related to the ethylenediamines and the ethanolamines, and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea, and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group…EG:Cyclizine

Chlorcyclizine Hydroxyzine Meclizine

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Tricyclics and Tetracyclics These compounds differ from the phenothiazine

antipsychotics in the ring-substitution and chain characteristics.

Antidepressants (and tetracyclics), explain the H1-antihistaminergic adverse effects of those drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine was derived from compounds in this group.EG:Promethazine

Alimemazine (trimeprazine) Cyproheptadine Azatadine Ketotifen

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Second-generation and third-generation

(selective, non-sedating)

Second generation H1-antihistamines are newer drugs that are much more selective for peripheral H1 receptors in preference to the central nervous system histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.

Third-generation H1-antihistamines are the active enantiomer (levocetirizine) or metabolite (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions.

Indeed, fexofenadine is associated with a decreased risk of cardiac arrhythmia compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine, respectively.

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Systemic, second-generation

Acrivastine Astemizole Cetirizine Loratadine Mizolastine Terfenadine

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In the 1980's a new group of antihistamines was developed, which has got,

besides its increased efficiency, fewer by effects.

Considering their pharmacokinetic characteristics and effects, the

requirements the modern second generation antihistamine should meet, can

be summarized as follows:

The modern antihistamine should be selective,

Peripheral H1 receptor antagonist,

Should have a low affinity to the H1 receptors of the brain,

Be void of anticholinerg and antiserotonin effect,

Should stabilize the membrane of the mastocytes.

The introduction of modern, second generation antihistamines was started

by terfenadin in 1985, and was followed by astemizole, loratadine and

cetirizine in 1988.

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Topical, second-generation Azelastine Levocabastine Olopatadine

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First-generation antihistamines, which were introduced before the 1980’s, are modestly effective, but would probably not have been approved for use if introduced today because of their sedative and psychomotor side effects. The second-generation antihistamines terfenadine and astemizole were the first non-sedating antihistamines, but are no longer in common use in most countries due to potential cardiac effects.

The second-generation drugs have less propensity to cross the blood-brain barrier than first-generation antihistamines, are thus much less likely to cause sedation, and do not cause dry mouth and urinary dysfunction

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There are currently several next-generation

antihistamines approved or in development . These

drugs are either active metabolites or an enantiomer

(mirror image) of a second-generation antihistamine.

Levocetirizine is currently in use in Europe and the

United Kingdom. Fexofenadine is in use worldwide.

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Systemic, third-generation

Levocetirizine Desloratadine Fexofenadine

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Selected Next-Generation Antihistamines and Their Relationship to Second-Generation Drugs

Next-generation antihistamine- Fexofenadine- Desloratadine- Levocetirizine- Tecastemizole

Chemical relationship to second-generation antihistamine-Metabolite of terfenadine-Metabolite of loratadine-Enantiomer of cetirizine-Metabolite of astemizole

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Antihistamines, among the most commonly prescribed drugs in

the world, have evolved considerably since the first generation

was introduced > 50 years ago. The first generation antihistamines (e.g., chlorpheniramine,

diphenhydramine, promethazine and hydroxyzine) are still widely available and in use today.

These drugs have considerable sedative effects caused by their ability to cross the blood–brain barrier.

The next generation of antihistamines to emerge in the market

were devoid of these sedative effects; however, two

(terfenadine and astemizole) have shown rare but lethal

cardiotoxic side effects. .

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The third generation antihistamines, metabolites of the earlier drugs, have demonstrated no cardiac effects of the parent drugs and are at least as potent.

Many have exhibited superior pharmacokinetic and pharmacological profiles, including an improved onset of action and duration of effect.

The clinical benefit of these newer oral

antihistamines will clearly help improve the

quality of life of patients with chronic allergies

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Serotonin (5-Hydroxytrptamine)

5-Hydroxytryptamine or3-(2-aminoethyl)-1H-indol-5-ol

MOLECULAR FORMULA: C10H12N2O MOLECULAR MASS: 176.215

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Isolated and named in 1948 , It was initially identified as

a vasoconstrictor substance in blood serum – hence

serotonin, a serum agent affecting vascular tone. This

agent was later chemically identified as 5-

hydroxytryptamine (5-HT) by Rapport, and, as the broad

range of physiological roles were elucidated, 5-HT

became the preferred name in the pharmacological field.

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Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables

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In the central nervous system, serotonin is believed to play an important role as a neurotransmitter, in the modulation of anger, aggression, body temperature, mood, sleep, sexuality, and appetite as well as stimulating vomiting.

In addition, serotonin is also a peripheral signal mediator. For instance, serotonin is found extensively in the human gastrointestinal tract (about 80-90% of the body's total serotonin is found in the enterochromaffin cells in the gut).

In the blood, the major storage site is platelets, which collect serotonin for use in mediating post-injury vasoconstriction.

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Neurotransmission

As with all neurotransmitters, the effects of 5-

HT on the human mood and state of mind and

its role in consciousness are very difficult to

ascertain

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5-HT is thought to be released from serotonergic varicosities into the extra neuronal space, in other words from swellings (varicosities) along the axon, rather than from synaptic terminal boutons (in the manner of classical neurotransmission).

From here it is free to diffuse over a relatively large region of space (>20µm) and activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

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5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs.

With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.

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Genetic variations in alleles which code for serotonin receptors are now known to have a significant impact on the likelihood of the appearance of certain psychological disorders and problems.

For instance, a mutation in the allele which codes for the 5-HT2A receptor appears to double the risk of suicide for those with that genotype

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Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, 5-HT reuptake transporter, on the presynaptic neuron.

Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).

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Other functions Recent research suggests that serotonin

plays an important role in liver regeneration and acts as a mitogen (induces cell division) throughout the body

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Pathology If neurons that make serotonin — serotonergic

neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).

Low levels of serotonin may also be associated with intense religious experiences.[10]

Recent research shows that in both patients who

suffer from depression and in mice that model the

disorder, levels of the p11 protein are decreased. This

protein is related to serotonin transmission within the

brain

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The pathway for the synthesis of serotonin from tryptophan

In the body, serotonin is synthesized from the amino acid tryptophan by a

short metabolic pathway consisting of two enzymes: tryptophan hydroxylase

(TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is

the rate-limiting step in the pathway. TPH has been shown to exist in two

forms: TPH1, found in several tissues, and TPH2, which is a brain-specific

isoform.

There is evidence that genetic polymorphisms in both these subtypes

influence susceptibility to anxiety and depression.

There is also evidence that ovarian hormones can affect the expression of

TPH in various species, suggesting a possible mechanism for

postpartum depression and premenstrual stress syndrome.

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Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier.

However, tryptophan and its metabolite

5-hydroxytryptophan (5-HTP), from which

serotonin is synthesized, can and do cross

the blood-brain barrier. These agents are

available as dietary supplements and may

be effective serotonergic agents

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One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors

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Serotonergic drugs

Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens

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Psychoactive drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD mimick the action of serotonin at 5-HT2A receptors. The empathogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons

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Antidepressants

The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs

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Some drugs inhibit this re-uptake of serotonin,

again making it stay in the synapse longer. The

tricyclic antidepressants (TCAs) inhibit the re-

uptake of both serotonin and norepinephrine.

The newer selective serotonin re-uptake

inhibitors (SSRIs) have fewer (though still

numerous) side-effects and fewer interactions

with other drugs

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Antiemetics

5-HT3 antagonists such as ondansetron, granisetron, and

tropisetron are important antiemetic agents. They are

particularly important in treating the nausea and vomiting that

occur during anticancer chemotherapy using cytotoxic drugs.

Another application is in treatment of post-operative nausea

and vomiting. Applications to the treatment of depression and

other mental and psychological conditions have also been

investigated with some positive results

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Serotonin syndrome

Extremely high levels of serotonin can have toxic and

potentially fatal effects, causing a condition known as

serotonin syndrome.

such toxic levels are essentially impossible to reach

through an overdose of a single anti-depressant drug,

but require a combination of serotonergic agents, such

as an SSRI with an MAOI.

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Chronic diseases resulting from serotonin 5-HT2B overstimulation

Cardiac fibrosis

In blood, serotonin stored in platelets is active wherever

platelets bind, as a vasoconstrictor to stop bleeding, and

also as a fibrocyte mitotic, to aid healing.

Because of these effects, overdoses of serotonin, or

serotonin agonist drugs, may cause acute or chronic

pulmonary hypertension from pulmonary vasoconstriction,

or else syndromes of retroperitoneal fibrosis or cardiac

valve fibrosis (endocardial fibrosis)

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Serotonin itself may cause a syndrome of

cardiac fibrosis when it is eaten in large

quantities in the diet (the Matoki banana of East

Africa) or when it is over-secreted by certain

mid-gut carcinoid tumors.

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Serotonergic agonist drugs in overdose in

experimental animals not only cause acute (and

sometimes fatal) pulmonary hypertension, but

chronic use of certain of these drugs produce a

chronic pulmonary hypertensive syndrome in

humans, also.

Some serotinergic agonist drugs also cause

fibrosis anywhere in the body, particularly the

syndrome of retroperitoneal fibrosis, as well as

cardiac valve fibrosis

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three groups of serotonergic drugs have been linked with these syndromes.

They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine

and methysergide), the serotonergic appetite suppressant drugs (

fenfluramine, chlorphentermine, and aminorex), and certain anti-

parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-

HT2B receptors. These include pergolide and cabergoline

As with fenfluramine, some of these drugs have been

withdrawn from the market after groups taking them

showed a statistical increase of one or more of the

side effects described. An example is pergolide.

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Amino acid L-tryptophan and SSRI-class antidepressants don’t raise blood serotonin levels>>>>>>>>, they are not under suspicion to cause the syndromes described.

However, since 5-hydroxytryptophan (5-HTP) does

raise blood serotonin levels, it is under some of the

same scrutiny as actively serotonergic drugs

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Illness Caused by lack of serotonin

Obsessive-compulsive disorder (OCD) can be a debilitating disorder with the following two anxiety-related essential features: obsessions (undesirable, recurrent, disturbing thoughts) and compulsions (repetitive or ritualized behaviors).

it may have to do with serotonin, which helps to keep people from repeating the same behaviors over and over again.

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A person who has OCD may not have enough

serotonin. Therefore, many people who have OCD

can function better when they take medicines that

increase the amount of serotonin in their brain

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She has headache

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He also have

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She is crying for her headache

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GIVE THEM PROPER TREATMENT

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ERGOT ALKALODS

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