AUTACOIDS

(self remedy)

Local hormones
*Histamineneurotransmitters
*Serotonin (5-Hydroxytryptamine)
neurotransmitters
*Endogenous peptides
*Prostaglandins
*Leucotrienes
*Cytokines
 HISTAMINE
Histamine is a basic amine,stored in
mast cells and basophils.
It is held in granules with macroheparin,
and secreted when complement
components C 3a and C 5a interact with
specific receptors,or when antigen
interacts with cell-fixed IgE.
 It produces effects by acting on H1 , H2 , H3
receptors on target cells.
The main actions in humans (and the recep-
tors involved) are:
- stimulation of gastric secretion ( H2 )
- contraction of most smooth muscle other
than of blood vessels ( H1 )
- cardiac stimulation ( H2 )
- vasodilatation ( H1 )
- increased vascular permeability ( H1 )
 Injected intradermally it causes the triple
response:
local vasodilatation and wheal by direct
action of blood vessels,and surrounding
flare due to vasodilatation resulting from an
axon reflex in sensory nerves releasing
a peptide mediator.
 The main pathophysiological roles of
histamine are:
- as a stimulant of gastric acid secretion
( treated with H2- receptor antagonists).
- as a mediator of type 1 hypersensitivity
reactions such as urticaria and hay fever
( teated with H1- receptor antagonists).
The full physiological significance of H3- re-
ceptors is not clear.
ANTIHISTAMINE
 First Generation Agents ( AH1 )
Ethanolamines
-Carbinoxamine maleate (Cardec)
-Clemastine fumarate (Tavist)
-Diphenhydramine hydrochloride (Bena-
dryl)
-Dimenhydrinate (Dramamine)

Ethylenediamines
-Pyrilamine maleate (Nisaval)
-Tripelennamine hydrochloride (PBZ)
-Tripelennamine citrate ( PBZ )

Alkylamines
-Chlorpheniramine maleate (Chlor-Trime
ton / CTM
-Brompheniramine maleate (Dimetane)

Piperazines
-Hydroxyzine hydrochloride (Atarax)
-Hydroxyzine pamoate (Vistaril)
-Cyclizine hydrochloride (Marezine)
-Cyclizine lactate (Marezine)
-Meclizine hydrochloride (Antivert)

Phenothiazines
-Promethazine hydrochloride(Phenergan)

Second Generation Agents

Alkylamines
-Acrivastine (Semprex D)

Piperazines
-Cetirizine hydrochloride
 Pharmacological properties:

-Smooth Muscle
AH1 inhibit most responses of smooth
muscle to histamine.

-Capillary Permeability
AH1 strongly block the action of hista-
mine that result in increased capillary
permeability and formation of edema
and wheal.
-Flare and itch
AH1 suppress both.

-Exocrine glands
AH1 suppress histamine-evoked salivary,
lacrimal,and other exocrine secretions
(atropine-like effect)

Caution : BPH
-Anaphylaxis and Allergy
Edema formation and itch are fairly well
controlled; Hypotension and others are
less controlled ; Bronchoconstriction is
reduced little.

-Central Nervous System

First-generation AH1 can both stimulate
and depress the CNS.
CNS stimulation:
Restless , nervous ,insomnia ,convulsion
CNS depression:
Alertnes ,slowed reaction time, somno-
lence.

Nonsedating AH1 ( second-generation

AH1 ) donot penetrate BBB
and have no effect on muscarinic recep
tors.
-Terfenadine -Cetirizine
-Astemizole
-Loratadine
-Local anaesthetic effect
Some AH1 have local anaesthetic effect.
Promethazine (Phenergan) is especially
active.

Side effects:
-Sedation
-Mutagenicity
-Drug allergy
-Atropine-like effect.
Other effects of AH1 :
-antimuscarinic: Diphenhydramine
-antiserotonin :Cyproheptadine
-1-adrenoceptor blocker:Promethazine

Third- generation AH1 :

-Levocetirizine
-Desloratadine
-Fexofenadine decrease risk of cardiac
arrhythmia.
Therapeutic uses:
-Diseases of Allergy
-Common Cold
-Motion sickness
-Vertigo / Dizziness
-Sedation
-Anti-emetic
AH2 : Inhibit gastric acid secretion
-Cimetidine: * enzyme inhibitor
(Tagamet) * gynaecomastia
* impotence
-Famotidine (Pepcid)
-Ranitidine (Zantac)
-Nizatidine
-Zolentidine
 SEROTONIN (5-HT)
*Neurotransmitters
*Multiple receptors subtypes
*Local hormone in the gut
*A component of platelet clotting
process
*Play a role in migraine headache
*Mediators of the sign & symptoms of
carcinoid syndrome
Clinical uses:
Serotonin agonist:
*Buspirone (5-HT1A agonist)
anxiolytic.
*Dexfenfluramine (5-HT2C
agonist) appetite suppressant
*Sumatriptan acute migraine
Serotonin-receptor antagonist:
*Phenoxybenzamine
*Cyproheptadine
*Ketanserine
*Ritanserine
*Ondansetron
PROSTAGLANDIN
 MEDIATORS DERIVED FROM
PHOSPHOLIPIDS
The main phospholipid-derived mediators are the
eicosanoids (prostanoids and leukotrienes) and
platelet-activating factor.
The eicosanoids are derivatives of arachidonate
which can be released from phospholipid by phos-
pholipase (PL) action,either in one step by PLA2,or
by two steps PLC then diacylglycerol lipase.
Arachidonate can be metabolised either by one or
two cyclo-oxygenases to give rise to various pros-
tanoids, or by 5-lipoxygenase to give rise to various
leukotrienes.
 Platelet-activating factor ( PAF ) is derived from
phospholipid by PLA2 giving rise to lyso-PAF which
is acetylated to give PAF.
 CLINICAL USE OF PROSTANOIDS

The main established uses are as follows:

*Gynaecological and obstetrical.
-for termination of pregnancy: dinoprostone
(PGE2) given by extra-amniotic route;
gemeprost given by vagina as pessary.
- for induction of labour: dinoprostone locally
in the vagina.
- for postpartum haemorrhage: carboprost
(if no response to other oxytocics).
 Gastrointestinal:
-to prevent gastric and duodenal ulcers in pa
tients taking NSAID :misoprostol (a stable
analogue of PGE2) can be used.

Cardiovascular:
-for the treatment of congenital malformations
of the heart in neonates,the purpose being to
maintain the patency of the ductus arteriosus
prior to surgical correction of the congenital
defect: alprostadil (a preparation of PGE1) is
used,given by intravenous infusion.
-to inhibit platelet aggregation during haemo
dialysis: a short acting PGI2 preparation
epoprostenol, (t 3 min) is used by infusion
if heparin is contraindicated.
Also used for treatment of primary pulmunary
hypertension.
ERGOT ALKALOIDS
Claviceps purpurea produce:
*Ergot alkaloids
*Histamine
*Acetylcholine
*Tyramine
Ingestion of ergot alkaloids in conta
minated grainergot poisoning
(ergotism)
Ergot alkaloids act on several
types of receptors:
* adrenoceptors
*serotonin receptors
*dopamine receptors

In certain receptors ergot alkaloids

can act as agonist,partial agonist
or antagonist
ERGOT ALKALOIDS:
*Bromocriptine
*Ergonovine
*Ergotamine
*Lysergic acid dietylamide (LSD)
*Methysergide
VASOACTIVE PEPTIDE:
Vasoconstrictors & Vasodilators
Vasoconstrictors:
-Angiotensin II
-Vasopressin
-Endothelins
-Neuropeptide Y
-Urotensin
Vasodilators:
-Bradykinin and related kinin
-Natriuretic peptides
-Vasoactive intestinal peptide
-Subtance P
-Neurotensin
-Calcitonin
-Gene-related peptide
-Adrenomedulin