Autacoids

Introduction
Autos self Akos remedy Examples: Histamine, 5HT, Bradykinin,
Eicosanoids (PGs, thromboxanes, leukotrienes) and PAF

Histamine

Imidazole + amino group Chief storage site: Mast cell Every tissue contains some amount Synthesis involves de-carboxylation of histidine by a decarboxylase enzyme.

Note: Mast cell in skin, intestinal and respiratory tract mucosa serve as the major storage site, also Basophils.

Histamine
Metabolism involves methylation by Nmethyl transferase. The N methyl-histamine may be converted to N-methyl indole acetic acid by MAO. Also histamine may undergo oxidative deamination with the production of imidazole acetic acid which is later converted to riboside.

Histamine
Functions of endogenous histamine: Hypersensitivity/allergy Gastric acid secretion Neurotransmitter. Systemic effects: Hypotension, flushing,
headache, Edema,

Histamine
GIT Contraction of intestinal smooth
muscle(H1) and gastric acid secretion (H2). Respiratory system Broncho-constriction (H1) Uterus Contraction (H1). Nerve ending stimulation (H1) producing pain and itching.

Histamine
Release of histamine is consequent upon
binding of antigen to the Fc segment of IgE with the increase in cytosolic Ca2+ and fusion of histamine containing vesicles to the plasma membrane. It is presumed that Ca 2+ - calmodulin dependent protein kinase are involved in the fusion and exocytosis processes.

Histamine
Other mediators of histamine release:
PAF, Kinins, LTD4. NB: Release of mediators is enhanced by muscarinic and - adrenergic receptor agonists. B-adrenergic agonists inhibit secretion of the same agents.

Histamine
Agents that stimulate release of histamine

(without prior sensitization) include: amides, amidines, quantenary ammonium compounds, pyridinium, piperidine, Alkaloids, Other agents: vancomycin, morphine, radiocontrast, d-Tubocurarine, succinylcholine, etc.
histamine.

*These histamine liberators do not deplete tissues of non-mast cell

Histamine
Other releasers of histamine: Cold urticaria, solar urticaria, and cholinergic urticaria. Receptors are classified as: H1, H2 and H3 (H4 also) and all are Gprotein coupled with seven membrane spanning domains.

Histamine
H1 results in increase phospho-inostitol
hydrolysis. H2 acts by: increasing cAMP and is involved in gastric acid secretion. H3 located at the pre-synaptic and provides feed back inhibition of histamine, Ach, norepinephine, and 5HT.

Histamine
Histamine receptor agonists: H1: 2 - methyl histamine, 2 Pyridylethylamine, 2 thiazolylethylamine H2: 4, 5 methyl-histamine, Impromidine H3: methyl-histamine

Histamine Antagonism
Histamine antagonism: Physiological Epinephrine. Membrane stabilizers (prevent release) Na chromoglycate Receptor antagonists:

Histamine
H1 antagonists grouped as follows:
Ethanolamines e.g. diphenhydramine Ethylenediamines e.g. pyrilamine Piperazine (e.g. cyclizine) Alkylamines e.g. chlorpheniramine Phenothiazines e.g. promethazine

Antihistamine
Piperidines e.g. *Astemizole, *Terfenadine Miscellaneous e.g. cyproheptadine, loratidine*

*Lack sedating effects and are referred

Antihistamine
H1 blockers are competitive antagonists.
Other effects: sedation (H1) antiemesis (antimuscarinic), antiparkinsonism (antimuscarinic). Blurred vision and urinary retention (anti M), Hypotension (-adrenoceptor blocking action).

Antihistamine
Uses: Anti allergy allergic rhinitis, urticarial, angioedema Motion sickness Nausea and vomiting

Antihistamine
Acute toxicity of antihistamine: Hallucination ) Excitement ) Inco-ordination ) Athetosis Convulsion ) Fixed dilated pupil) Similar to atropine poisoning Urinary retention ) Dry mouth, fever Tachycardia ) Cardiovascular collapse may lead to death eventually.

Antihistamine
Other ADR sedation/Excitation in children Dizziness, tinnitus, inco-ordination Drug allergy Postural hypotension, leukopenia Teratogenesis ?? Agranulocytosis Q-T prolongation, especially with newer generation Anorexia, diarrhea/constipation, dysuria

Antihistamine
Chlorpheniramine An alkylamine, high bioavailability (= 50%) Duration of action = 4-6 hrs Peak plasma concentration = 2-3 hrs Plasma protein binding = 70%

Antihistamines
H2 antagonists: Nizatidine Rantidine, Cimetidine Selective H3 antagonist: Thioperamide,

impromidine and burimamide ( H2 agonist as well). H4 receptor are found on the eosinophils and An agonist of H4 is Clozapine (another e.g clobenpropit). Thioperamide is an antagonist of H3 and H4 receptors.

KININS

KININS
Two major isoforms: Bradykinin Lysyl-bradykinin. Source: kininogen from the liver Kininogenase cleaves nonapeptide bradykinin from kininogen*
*Plasma HMWK or tissue LMWK

Synthesis of Bradykinin
HMWK Hageman factor* Kallikrein** ~ ~ Prekallikrein Bradykinin
*Hageman factor is activated by exposure to damaged tissue(inhibited by C1 inhibitor) **Kallikrein is inhibited by C1 inhibitor and 2 macroglobulin

KININS
Formed from circulating kininogen by
Kallekrein* (a protease). Metabolism involves kininase I & II** T ~ 15 seconds.
Both agents circulate as pre~ HMWK & prekallikrein to protect from effects of kinin. Hageman factor sets up the cascade ff its activation by tissue injury ** The carboxyl terminal Arginine is removed by Carboxypeptidase thus inactivating it

KININS
Receptors: B1 & B2 B2 is constitutive in all normal tissues B1 is up-regulated in reaction to injury. B2 is G-protein coupled and activates PLA2 and PLC. The stimulated PLA2, librates arachidionic acid from membrane bond phospholipids
which in turn may be metabolized to other potent mediators of inflammation.

KININS
Effects: -Vasodilation* directly
and synthesis of PGE2 and PGI2. and through release of EDRF

-Venocostriction and contraction of

endothelial cell resulting in EDEMA. -Release of mediators of Inflammation broncho-spasm

KININS
Other effects: Pain (B1), bone re-absorption (B1) Asthma, RBF, Destruction of blood-brain barrier.

Serotonin (5HT)

Serotonin (5HT)
High concentrations in entero-chromaffin cells of: GI, Platelets* and CNS. (*Lacks synthetic ability)

Serotonin (5HT)

Biosynthesis

Tryptophan (Tryptophan lydroxylase) (oxygen, pteridine) Hydroxytryptophan (decarboxylase) 5HT

Serotonin (5HT)
Metabolism: MAO and aldehyde dehydrogenase To form 5-HIAA. Action in the CNS is terminated by an
uptake process.

Serotonin (5HT)
5HT plays a role in: mood, headache, sleep, temperature regulation pain perception, blood pressure regulation and platelet function.

Serotonin (5HT)
Receptors: 5HT1-7 5HT1: (A, B, D, E, F) 5HT2: (A, B, C) 5HT5: (A, B)

Serotonin (5HT)
Some are G-protein coupled: Gi/Go (1A,. 2A,) Gq (2A) Gs (4,6,7)

Serotonin (5HT)
Effects: Vasoconstriction (2A) Release of EDRF and vasodilation: (5HT). Hypotension and bradycardia (5HT3) Smooth muscle contraction (2A, C, 4) Vascular muscle relaxation (5HT7) Bronchoconstiction. Emesis (5HT3, Area postrema). Behaviour (aggression, anxiety, depression).

Serotonin (5HT)
SSRI: E.gs fluoxetine Prevent 5HT re-uptake and used for depression. 5HT agonists: LSD (Lysergic Acid Diethylamide), Buspirone, sumatriptan, cisapride (5HT4 to stimulate, GI motility).

Serotonin (5HT)
Antagonists: Ondansetron (5HT3), Clozapine (5HT2 and5HT7) Methylsergide(5HT2A/2C), Cyproheptadine (5HT2A)

Ondansetron
A selective 5HT3 receptor antagonist. Uses include: Treatment and prophylaxis of

emesis/nausea of cancer chemotherapy Treatment and prophylaxis of emesis/nausea post-operatively

Ondansetron
Preparations: Ondansetron HCl exists as
white powder usually mixed with Dextrose or N/saline and Available as oral, IV or IM

Ondansetron
Mechanism*: Antagonist at the 5HT receptor: -Chemorecptor trigger zone or -Area Postrema in the brain. Both Dopamine and 5HT receptors are found here
*It is not known for certain whether action is central or peripheral or both

Ondansetron
PHK: Plasma binding is about 75-80% Extensively metabolized (95%) in the liver by hydroxylation* Followed by: sulphation and glucuronidation T1/2 averages 5.5 hours and prolonged in hepatic diseases. (> 12hours) Renal excretion of parent drug is about 5%
* Major enzyme is CYP3A4, others include: CYP2D6, CYP1A2.
-

Ondansetron
Unwanted effects: Headache Constipation Flushing Arrhythmias Bradycardia Hypotension seizures