Autacoids

Autacoids
Autacoids are group of endogenous substances that play variety of physiologic and pathologic effects.

A- Biogenic amines: Histamine, Serotonin

B- Eicosanoids: fatty acids derivatives as prostaglandins and thromboxanes.
C- Polypeptides: as angiotensin and Kinnins.

1- Histamine
Synthesis & Metabolism:
)*+,-./012,34 :;<*=>12=-,?@A*-,@* EFG
Histidine 5⎯⎯⎯⎯⎯⎯⎯⎯⎯7 Histamine 5⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯7 methyl histamine 5⎯⎯7 methylimidazole acetic acid (MIAA)
• Oxidation of histamine: occurs by histaminase enzyme
• Synthesized histamine, either stored in special storage sites or metabolized in the liver very.
• small amount is excreted in urine (increased in systemic mastocytosis)
Storage:
l- Mast cell of reticuloendothelial cells, skin, intestine and lung, in mast cell histamine present in a complex
with heparin.
2- Basophil in the blood.
3- cell bodies of histaminergic neurons in the brain, where it acts as a neurotransmitter.
4- Enterochromaffin - like cells (ECL - cells) in the fundus of the stomach.
Released by:
1- Drugs as morphine and D-tubocurarine.
2- Mechanical and chemical injury of mast cells.
3- Proteolytic enzymes as trypsin.
4- Immunologic release

Receptor Type Site Action

H1 • Gq ! PLC • Mainly in • (+) H -receptors in smooth muscle ! histamine increases contraction
1

! IP3 & smooth muscles of smooth muscles of bronchi, GIT and uterus
DAG ! • Vascular • (+) H in vascular smooth muscle ! contraction of large blood
1

#Ca+2 endothelium vessels

• Brain. • powerful stimulation for sensory nerves, ! pain and itching.
• Adrenal medulla: Histamine increases adrenal medullary secretion
• Blood vessels (NO release) ! VD & "Blood pressure
• Gs ! (+) • Vascular • Blood vessels (#c.A.MP).! VD & "Blood pressure
adenyl cyclase smooth muscles. • On the heart: # cardiac contractility & # heart rate.
H2 !#cAMP • Heart & Brain partly by a direct action on receptors and partly reflex due to
• Parietal cells hypotension.
of stomach • (+) H2-receptors in Parietal cells !#gastric secretion
H3 • Gi !(-) • in brain • (+) Presynaptic H -receptors ! modulate transmitter release in CNS
3

adenyl cyclase presynaptically

H4 enzyme !" • in eosinophil
cAMP & neutrophil'

N.P: Triple response: ID injection of histamine produces:

• Redness owing to dilatations of small blood vessels.
• Edema which results from dilatation of microcirculation and exudation of fluid.
• Flare (axon reflex): stimulation of sensory nerve by histamine leads to release of vasodilator
neurotransmitters.
Uses of histamine:
• Histamine aerosol is sometimes used as a provocative test of bronchial hyperreactivity.
• Diagnosis of pheochromocytoma: producing hypertension instead of hypotension

1
Autacoids
Histamine antagonists
1- Physiological antagonism: by adrenaline which is lifesaving in anaphylaxis.
2- Inhibition of histamine release β-stimulants, Cromolyn & corticosteroids
3- Receptor antagonists:
- H1-antagonists (antihistaminic).
- H2-antagonists (anti-ulcer drugs).

- H -antagonists (antihistaminic)
1

(1) First generation agents (2) Second generation agents (3) Third
generation
Promethazine, Cyclizine, Doxylamine Cetirizine Astimazole Fexofenadine
Dimenhydrinate, Diphenhydramine Terfenadine, Loratadine, (metabolite of
terfenadine)
• Rapidly absorbed after orally administration, • Less lipid soluble or no central action. • Metabolites of second-
• Extensively metabolized and highly lipid soluble. • have long t1/2 (given once daily) generation with similar
• Widely distributed all over the body, reaching CNS. • Astimazole and terfenadine may cause efficacy
• Duration of action is short about 4-6 hours. arrhythmias and sudden death • No cardiac toxicity
• Can block autonomic receptors. • No effect on autonomic receptors.

Actions of Antihistaminics
I- Actions related to histamine receptor block:
• By reversible competitive antagonism to histamine on H1-receptor, antihistaminic produce:
- Antiallergic effect.
- Complete antagonism of histamine-induced contraction on GIT and bronchi.
- Partial antagonism of histamine on C.V.S.
II-Actions not related to H1- receptor block: first generation produce the following effects
1- Sedation.
2- Anti-emetic and anti-motion sickness, partly by inhibition of vomiting center and partly by atropine-like
action.
3- Anticholinergic effects (atropine-like action):
• Centrally, they produce antiparkinsonial action as occurs with diphenhydramine.
• Peripherally, dry mouth, blurring of vision and constipation
4- α-adrenergic blocking effect ! orthostatic hypotension. (Promethazine)
5- Anti serotonin action: (cyproheptadine).
6- Local anesthetic action: block Na channels in excitable membranes. diphenhydramine
+

Uses:
1- Allergic condition: Urticaria, allergic rhinitis and drug allergy
• Drugs that are devoid of sedative or muscarinic effects are best given (second and third generation).
3- Nausea and vomiting of pregnancy: cyclizine, meclizine and doxylamine
2- Motion sickness and vestibular disorders:
diphenhydramine and dimenhydrinate “preferred as Antihistaminics with anti-muscarinic effect”
4- Parkinsonism: Diphenhydramine
Side effect:
• Sedation (1st generation).
• Peripheral antimuscarinic effects (1st generation).
• Postural hypotension (1st generation).
• Possible teratogenic effect of doxylamine.
• Excitation and convulsion in children.
• Over dosage may produce excitation, convulsion and coma.
• Astimazole and terfenadine ! cardiac toxicity.