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Autacoids = local
hormones
DEFINITION
These are heterogeneous group of
chemical substances with wide spectrum
of biological effects , synthesized by
different tissues and exerting local effect
with no or very minute serum level.
Autacoids' include histamine , serotonin ,
prostaglandins , leukotriens , vaso-active
intestinal polypeptides (VIPs), kinins,
Angiotensin , Nitric oxide (NO),
endothelin,etc.
:Synthesis
Histamine is synthesized by 2
enzymes:
1- Histidine de-carboxylase that
converts histidine to histamine.
This enzyme is inhibited by
methyl histidine.
2- Aromatic amino acid decarboxylase which is non
specific enzyme and inhibited by
methyl-dopamine .
:Release
Histamine is released by the process of degranulation in response to:
1- Immunological reactions : Ag-Ab
complex stimulates mast cell degranulation.
: Metabolism
By 2 routs
1- By histaminase or di-amine
oxidase.
2- By histamine methylating
enzymes.
Histamine acts by
binding to 4
subclasses of
receptors [ H1 , H2 ,
H3 , H4] which
distributed in different
tissues.
Headache , flushing ,
hypotension ,
tachycardia ,
bronchiospasm , GI
upset.
:Contraindications
1- Bronchial asthma .
2- Active peptic
ulcer.
3Pheochromocytoma
.
:Histamine agonists
1- Betazole : Isomer of histamine and acts
on H2 receptor . It is used for diagnosis of
gastric acid secretion but it is
contraindicated in case of bronchial
asthma.
2- Betahistine : It is analogue of histamine
and acts on H1 receptor , it is used in the
treatment of Meneire,s disease . IT should
be used cautiously in patients with
bronchial asthma and pheochromocytoma.
:Histamine antagonists
The action of histamine can be
antagonized by :
1- Physiological antagonist : By
adrenalin .
2- Competitive pharmacological
antagonists : we have H1 and H2
blockers .
3- Mast cells stabilizers (drugs that
prevent mast cell de-granulation )
like chromolyin and nedochromil.
: Classification of H1-blockers
:
1- Ethanolamine group : like Diphenhydramine (allermin)
.
2- Ethylenediamine group : like Antazoline.
3- Alkylamine group: like chlorpheneramine (Histadine).
4- Piperazin group: like Hydroxyzine , cyclizine.
5- Phenothiazines group: like promethazine.
6- Miscellaneous group : like cyproheptadine (periactin)
which used as appetite stimulant especially in children , in
carcinoid syndrome (it has antiserotoninergic effect), in hay
fever , in dumping syndrome after gasterectomy, as
prophylactic in migraine .
Other drugs like acrivastin , clemastin , loratidine ,des, loratidine , ketotifen
Astimazole ,
Terfenadine ,
Fexofenadine,
Cetrizine.
:Clinical indications
Angio-noretic oedema ., - 1
2- Allergic dermatosis ,
3- Urticaria , 4Hay fever ,
5- Motion
sickness , 6- insect bite , 7anaphylactic shock, 8blood transfusion allergic
.reactions
Sedation , dizziness ,
insomnia , blurred
vision, tinnitus ,
.parasthesia
:Drug interactions
:Contraindications of H1 blockers
123456-
:Serotonin metabolism
By mono-amino oxidase enzyme to form 5hydroxy indol acetic acid which is excreted in
the urine in amount of about 3-10 mg /day.
:Pharmacological action of serotonin
Respiratory system:- 2
Serotonin produces a small
direct stimulation to bronchial
smooth muscle in normal
person but produce a
bronchiospasm in patients with
carcinoid syndrome. Serotonin
produces hyperventilation due
to stimulation of bronchial
.sensory nerve endings
Glandular secretion:- 5
Serotonin has little inhibitory
.effects on exocrine glands
:Serotonin syndrome
It is related to the interactions of
serotonin re-uptake inhibitors
with mono-amino oxidase
inhibitors (MAOIs) or interactions
of serotonin agonists with MAOIs.
It is a clinical emergency with
high mortality rate and
characterized by rigidity ,
hyperthermia , myoclonus ,
mental changes, tachycardia.
:Serotonin agonists
1- Buspirone : acts on 5-HT1A receptor .It is an anxiolytic
drug ( non benzodiazepines non barbiturates anxiolytic).
2- Dexfenfluramine : Suppresses appetite and used to
body weight.
:Serotonin antagonists
1- Cyproheptadine (periactin): It is H1
and 5-HT2 blocker , used mainly as
appetite stimulant. Other uses include :
Allergic rhinitis , cold urticaria ,
prophylaxis of migraine , in Dumping
syndrome after gasterectomy and in
carcinoid syndrome.
2- Ketanserin: It is 5-HT 2 and -blocker .
It was used in the treatment of
hypertension .
:Migraine Syndrome
It is a syndrome of
recurrent throbbing
unilateral headache with
or without aura ( visual
halos) with nausea ,
vomiting , phonophobia
and photophobia.
:Aetiology
It is poorly understood , it is
precipitated by stress , anger ,
fatigue , diet , rich in chocolate and
cheese , alcohol , menses in female or
using contraceptive , hypoglycemia.
Changes in vascularity between intra
and extra- cranial blood vessels and
stimulation of trigeminal nerve by
calcitonin genes related peptides are
the most popular concept concerning
Aetiology of migraine.
:Treatment of migraine
:Eicosanoids
prostaglandins "PGs" ,
leukotriens "LTs" ,
thromboxanes "TXs" ,
lipoxines "LXs",
isoprostanes, epoxides.
:Synthesis of eicosanoids
1-Arachidonic acid is the source of eicosanoids .
Arachidonic acid is formed by the action of
phospholipase A2 which converts phospholipids in
cell membrane into arachidonic acid.
Arachidonic acid is converted to PGs
endoperoxides by the help of 2 enzymes :
a- Cyclo-oxygenase I "COX I " [ PGH
synthase I] which is widely distributed in body
tissues and has gastro-cytoprotection.]
b-Cyclo-oxygenase II " COX II" [ PGH
synthase II] which is inducible by inflammatory
reactions and concerns with development of renal
function.
vascular smooth- 2
muscles : PGE2 and
PGI2 cause
vasodilatation , while
PGF2 and TX cause
.vasoconstriction
platelets : PGE1- 3
and PGI2 inhibit
platelets
aggregation while TX
induces platelets
.aggregation
Respiratory- 4
system: PGE1 , PGE2
and PGI2 cause bronchi
dilatation while PGF2
and TX cause bronchi
.constriction
Reproductive- 6
system: PGE2 and PGF2
causes contraction of
uterus , PGI2 increases
penile erection.
NOTE: Seminal fluid
containing less than 400
ug/ml of PG is considered
an infertile man
CNS: - 7
-Fever : PGE1 and PGE2 when are
injected into cerebral ventricles , they
increase the body temperature.
PGD2 when infused into cerebral
ventricles produces sleepiness .
- Neurotransmission: PG compounds
inhibit the release of Nor-adrenalin from
post-ganglionic sympathetic nerve
endings.
- Neuro-endocrine: PG compounds
promote the secretion of prolactine , GH,
.TSH, ACTH, FSH and LH
Bone : PGD2- 8
increases bone
turnover (bone
formation and
resorption) .
PG is involved in
bone loss in post.menopausal women
Eyes: PGF2- 9
decreases intra.ocular pressure
Clinical indications of PG
:preparations
1- Reproductive indications:
PGE2 and PGF2 when used in early pregnancy , they
will cause abortion , they terminate pregnancy at any
stage , facilitates labor if given at time of labor.
Advantages of PG over Oxytocin [ which also used in
labor] :
a- PGs are more safe in pregnant women with preeclampsia , cardiac and renal diseases .
b- PGs unlike Oxytocin, having no anti-diuretic effect.
Respiratory- 4
indications: PGE2
is used as aerosol
to relieve
. bronchiospasm
GIT indications :- 5
PGE1 analogue
(Misoprostol)is
cytoprotective and
used for treatment
.of gastric ulcer
Dinoprost = PGF2
Dinoprostone = PGE2
Alprostadil = PGE1
Epoprostenol = Prostacyclin =
PGI2
Misoprostol = PGE1 analogue
Latanoprost = PGF2 ( eye
preparation)
Leukotriens
Potent biologically active
compounds are synthesized from
arachidonic acid with the help of
5-lipo-oxygenase in neutrophiles ,
monocytes , macrophages and
keratinocytes.
LTs present in brain , heart , lung
and spleen . The slow reacting
substance A released as result of
immunological reactions contains
LTC4 , LTD4 and LTE4
1- CVS : These
agents reduce
myocardial
contractility and
coronary blood flow.
Blood : LTB4 is a- 4
potent chemo
attractant of
neutrophiles , LTC4
and LTD4 are chemo
attractant of
.eosinophiles
: Lipoxins
Act on specific
receptor on PMN
cells , inhibits NK
cells.
PAF:
Has role in
Pathophysiology of
asthma and shock.
Lexipafant is PAF
antagonist and used in
management of acute
. pancreatitis
It is synthesized by a family of
enzymes that are collectively
called nitric oxide synthase,
NOS Three isoforms of NOS
have been identified.(NOS-1,
NOS-2, NOS-3). These isoforms
are heme-containing
flavoproteins employing Larginine as a substrate Nitric
oxide generation. Activation of
NOS by the influx of
extracellular calcium and
Vascular Effects
Nitric oxide., it is released by
acetylcholine and other endotheliumdependent vasodilators. Infusion of NOS
inhibitors increases vascular tone and
elevates mean arterial pressure.
Vasodilatation mediated of cGMP
synthesis results in smooth muscle
relaxation. Also it a potent inhibitor of
neutrophiles adhesion to the vascular
endothelium.
Respiratory Disorders
Pulmonary artery
hypertension: NO is approved
for this indication, and acute
respiratory distress syndrome,
use for defective gas
exchange in the newborn .
Increased urinary
excretion of nitrate, is
reported in gramnegative bacterial
infection, resulting in
exaggerated
hypotension, This
hypotension is reversed
by NOS inhibitors.
Atherosclerosis
In vitro, NO carriers and donors
and cGMP analogs inhibit smooth
muscle cell proliferation. In addition,
it may blocks the oxidation of lowdensity lipoproteins (LDL) and thus
preventing the formation of foam
cells in the vascular wall.
Platelets
Nitric oxide is a potent
inhibitor of platelet
adhesion and aggregation.
NO affects blood
coagulation by enhancing
fibrinolysis via an effect on
plasminogen.
Organ Transplantation
Inflammation:
NO promotes edema and vascular
permeability, dietary L- arginine
supplementation exacerbates arthritis.
Psoriasis lesions, airway epithelium in asthma,
and inflammatory bowel lesions in humans all
demonstrate elevated levels of NO. Also it
stimulates the synthesis of inflammatory
prostaglandins by activating cyclo-oxygenase
isoenzyme II (COX-2).
Hypertension associated
with pregnancy.
Manifestation of pre- eclampsia
result from inadequate
physiological response of
pregnancy and combined with
deficiency of NO and
prostacyclin. enhancement of
NO level through nutritional
supplement of L- arginine may
be effective.
b- Kinins
(bradykinin):
It is a well known
vasodilator , it is 10
times more
vasodilator than
histamine
Other vasodilators:
Substance P (also plays role
in pain perception),
Neurotensin ,
PGI2,vasoactive intestinal
peptide (VIP), calcitonin
gene related peptide which
is the strongest vasodilator
discovered yet.
V2 = Anti-diuretic effect.