Autacoids

Compiled by
Dr . Jahangir Kaboutari

DVM, PhD Assistant professor of

Pharmacology
Faculty of Veterinary Medicine,
University of Shahrekord, Shahrekord .
Iran
Self remedy
Naturally occurring substances
Local hormones
Localized in tissues ,do not normally circulate
Site of action restricted to the synthesis area
Usually involved in response to injury
Diverse physiopharmacologic activities
Short duration of action
Differ from hormones &neurotransmitters
 classification

Biogenic amines:Hisatmine,5HT
Biogenic peptide:Angiotensin ,kinin
Small peptides:Cytokines
Membrane derived peptides:LTs,PGs,TxA2&PAF
Endotelium derived agents :NO
Histamine

Histidine converts to the Histamine by Histidine

decarboxylase enzyme ,compose of a Imidazole ring
and ethyl amine side chain
)Found in plants and animals) all tissues
Mast cell pool: mast cells& basophiles; plays role in
allergy, shock, inflammation and some side effects of
drugs; slow turn over, storage able
Non mast cell pool: GIT)Entrochromaffin like cells or
ECL of the fundus of the stomach), CNS,
skin/epidermis; rapid turn over; not storage able
Stores in a concentrated form with Heparine,
proteolytic enzymes & other autacoids in storage
granules
Two phasic release: rapid exocytosis of storage
granules form cell followed by release form
granules to the interstitial space
Releasing agents:1- anaphylaxis – allergy: Ca 2+dependent
process ofIgE attachment with surface receptors of mast
cells
physical injuries: -2 severe heating and cooling. skin
scratch and any other agents which cause severe
cellular damage
drugs& chemicals -3: ,Curare, polymixin
morphine,codeine,papaverine,meperidine, atropine, succinyl
choline ,plasma volume expanders, radio contrast medias
Lysosomal enzymes, insect venom's
Endogenous substances: bradykinin, kallidin & substance P
Increase in cAMP: decreases histamine release
 Receptors
H1 agonist :2methylhistidine; endothelium, smooth
muscle cell, nerve ending; contractile, coupled with
phosphlipase
H2 agonist: Betazole; gastric mucosa, cardiac muscle
cell; cAMP coupled
Impromidine:H2 agonist,H3 antagonists
H3:feedback inhibition of NT release
H4:WBCs: chemotactic effect and modulation the
production of eosinophill& mast cells, cytokine
production
H1,H2 presynaptic; H3&H4 :post synaptic
In general histamine constrict large vessels ;dilate
capillaries & venules
 Pharmacologic effects
Species variation; opposite effects in some tissues viaH1&
H2 receptors
CVS:vasoconstriction in large vessels:H1
vasodilatation in small vessels: H1-H2
vascular permeability: H1
Positive intropic ,chronotropic effects:H2
AV node impulse velocity:H1
Hypotension and reflex Positive intropic ,chronotropic
Nep release from nerve endings
:Non vascular smooth muscle
contraction of bronchial smooth muscles:H1
contraction of GIT smooth muscles:H1
contraction of uterine muscle in most spp:H2
Exocrine glands: stimulation of secretion of gastric
salivary, pancreatic and bronchial galnds:H2
Human triple responses due to histamine dermal
injection: local redness )flush), local edema )wheal)
), diffuse redness )flare
 pharmacokinetics
Little oral absorption, rapid distribution and
metabolism
Metabolic pathways: dog & cat: methylatyion and
oxidation; in sheep: oxidative deamination
Indications of histamine: Dx of achlorohydria, triple
responses for evaluation of integrity of sensory
innervations and perfusion sufficiency, Dx of
pheochromocytoma
 Antihistamines
Physiologic: methyl xanthines,catecholamines
Metabolic : Histaminase
Competitive or real antihistamines:H1& H2
receptors blockers
Release inhibitors: Cromolyn , Nedocromil,β
adrenergic agonists
 )H1 blockers )antihistamines
Modification done on the ethyl amine side chain while
imidazoel ring remains intact, competitive
1st generation: Ethyl amines: N substituted: pyrilamine,
tripelennamine
Alkyl amines :C substituted:
chlorpheniramine,brompheniramine
Ethanol amines :O : substituted
diphenhydramine, dimenhydrinate,doxylamine
Piperazines :cyclizine,meclizine,buclizine,hyrdoxyzine
Phenothiazines: promethazine, trimeprazine
Miscellanous :clemastine, antazoline, cyproheptadine
 H1 antagonists
Competitive antagonism for the same receptor
do not prevent histamine release
do not cause physiological antagonism )smooth
)muscle dilatation
)Do not block gastric acid production )blocked by H2
Protect against shock and allergic reactions
.CNS depression, a side effect
Local anesthetic effect
Ethanol amine,ethylendiamines: significant atropine
like effects
Phenothiazines: serotonin &α blocking effects
Ethytlendiamines more potent than ethanol amines
Less sedation in ethanol amines
Less side effects in alkyl amines
More effective in prevention of histamine actions than
in reversing histamine actions
Good oral absorption except in ruminants
 Indication
A ,llergic reactions, hay fever
asthma, motion sickness, common cold, insect
bites, drug induced hypersensitivity,
nutritional laminitis, pregnancy laminitis,
pulmonary emphysema, bloat in ruminants,
acute septic mastitis, gangrenous mastitis,
retained placenta
Use cautiously during pregnancy due to
teratogenic effects
 Side effects
Dose dependent CNS depression or stimulation
GIT disturbances: anorexia, nausea, emesis,
constipation and diarrhea due to long term oral
consumption
Anti cholinergic:xerostomia, mydriasis, tachycardia
,blurred vision
Local anesthetic effects:used for treatment of itching
e.g.. Promethazine
:Drug interactions
Increases the effects of CNS depressant agents
Decrease the effects of hydrocortisone, progesterone,
steroides and androgens
 2 generation of H1 blockers
nd

Piperidine group:astimazole, terfenadine,

loratadine, fexofenadine, certirizine
Less sedative and anticholinergic effects
Terfenadine &astimazole :cardiac arrhythmic
potential especially in the presence of P450
enzyme inhibitors and discard form market
 H2 blockers
Burimamid, Metiamide, Ranitidine )Zantac), Cimetidine
))Tagamet), Nizatiidne) axid) Famotidine)Pepcid

Substitution done on the imidazole while ethyl amine

side chain remains intact: less lipophlicity, less BBB
penetration, no sedative effects
Block all phases of gastric acid secretion due to histamine,
gastrin &Ach, decrease food induced acid secretion up to
90%,decrease pepsin secretion
Treatment of duodenal ulcer, stress related gastritis & peptic
ulcer
Good oral absorption
Ranitidine, Cimetidine: twice daily or once dose
nightly
Famotiidne ,nizatiidne: once daily orally
Rare side effects: diarrhea , muscular pain, dizziness,
temporary dermal rashes ,hypergasrtinaemia
Cimetideine : decreases libido and gynaecomastia
)rare),P450 enzyme inhibition and increase the
effects of anticoagulants & tricyclic anti depressants
,some time headache in geriatrics
 )Serotonin)5HT
Source: plants (banana, pineapple, plums) & animals
(mollusks, arthropods, animal venoms& stings ,mammals
(platelets,.(not in mast cells
Biosynthesis: Hydroxylation of tryptophan, then
decarboxylation to serotonin(5-hydroxy tryptamine;5-HT).
Rapidly absorbed into secretory granules. Accumulated in
.platelets, degradation by oxidative deaminaion
In pineal gland converts to Melatonin by N-acetylation and 5
methylation
Uses: .No therapeutic use. Antagonists are highly useful
Neurotransmitter in the CNS
Precursor of melatonin
Induces sleep, Intestinal motility
Involved in Temperature regulation
)Affects mood and behavior )humans
Deficiency causes depression: serotonin specific
reuptake inhibitors )SSRIs);
Fluoxetine,Sertraline,Puoxetine use as
antidepressant drugs
Vasodilator in skeletal muscle vessel bed
Involved in hemostasis :platelet aggregation
Inhibitory NT in satiety center: antagonist like
Cyproheptadine use as appetizer agents
.Constricts bronchial & uterine smooth muscles
5HT of insect venom and toxins stimulates sensory
nerve terminals: pain and itching
Do not crosses BBB,5HTP crosses BBB: stimulates
afferent nerve endings, ganglionic cells and adrenal
medullary cells
Direct stimulation of intestinal smooth muscle and
ENS: increases GIT motility
P stimulation and vasoconstriction; Vasodilation via ∑
EDRF
Stimulates peripheral nociceptors
 5HT agonist& antagonists
5HT1D agonists: Sumatriptan; migraine treatment
5HT2 antagonists :Dihydroergotamine, Methyl sergide,
Cyproheptadine, Ketanserin,Ketotifen, Pizotifen;non
specific antihistaminic andα blocker agents,
Dihydroergotamine, Methyl sergide:migraine preventive
agents, others used for the control of symptoms of carcinoid
syndrome
5HT3 antagonists:Ondansteron , Granisetron,Tropisetron;
ant emetic agents especially in cancer chemotehrapy
5HT4 agonist:Metoclopramide, Cisapride ;stimulates
peristaltic movement of GIT,Tegserod: used for IBS control