Autacoids

AUTACOIDS (LOCAL HORMONES)

endogenious compounds; play an important role in the physiological and pathological processes;
Autacoids

Two main function

1. Moderate local circulation 2. Influence the process of inflammation

Major classes

1. Endogenous amines : histamine, serotonin 2. Polypeptides : angiotensin, kinins 3. Lipid-derived autacoids : prostaglandins, leukotrienes, thromboxane 4-Cytokine

a) Histamine

1. Endogenous amines
The synthesis and breakdown of histamine


Histamine is presented in high concentration in the skin, and in the mucous layer of the lung and GIT as an autacoid.
At cellular level, it is found largely in mast cells and basophiles.
Non-mast-cell histamine occurs as a neurotransmitter in CNS.



In mast cells and basophiles histamine is located in intracellular granules together with heparin.

Histamine is released from mast cells by a secretory process during inflammatory or allergic reactions (Ag-Ab reactions).
Histamine is released from mast cells during burns too.


Some drugs (mainly alkaloids atropine, morphine, reserpine, tubocurarine in high doses) release histamine by non-receptor action and can cause bronchoconstriction, arterial hypotension, and other unwanted effects.

Folia Urticae

Naja naja
(Leaves of Nettle)


Agents which increase cAMP (adrenaline, salbutamol, and others) inhibit histamine secretion and produce bronchodilation (antiasthmatic effect).

Histamine produces effects by acting on H1, H2, H3, H4, and H5-receptors.

Stimulation of H1-receptors
contraction of endothelium, increasing of vascular permeability and producing type I hypersensitivity reactions (urticaria and hay fever); contraction of smooth muscle of bronchi, GIT, uterus; excitement of CNS.

Histamine and antagonists of H1-receptors (H1-blockers)

H1-blockers
Used mainly for the treatment of urticaria and hay fever. Some of them ( promethazine) have antiemetic effect too.


Hydroxyzine is an H1-blocker with anxyolitic, antiemetic, antimuscarinic, and spasmolytic effects. It is effective in pruritus and urticaria.

Astemizole

Cetirizine
Loratadine Terfenadine
H1-blockers from 2nd generation (without sedative and M-cholinolytic effects)
prolongation of QT interval and hypokalemia



H1-blockers from 3…rd… generationDesloratadine

cardiac stimulation stimulation of gastric acid secretion

Activation of H2-receptors:


Cimetidine (? …)Famotidine NizatidineRanitidine Roxatidine Antagonist of H2-receptors(H2-blockers) – for the treatmentof peptic ulcer:

b) Serotonin (5-Hydroxytryptamine: 5-HT)

Indol derivative
Rang et al. Pharmacology– 5st Ed. (2003)


Structures rich in 5-HT GIT (chromaffin cells and enteric neurons) platelets CNS


Important actions of 5-HT increased GI motility increased platelet aggregation increased microvascular permeability stimulation of nociceptive nerve endings
control of appetite, sleep, mood, hallucinations, pain perception, and vomiting

Clinical conditions in which 5-HT plays a role include:

migraine mood disorders (depressive illnesses) anxiety vomiting carcinoid syndrome (malignant tumors of enterochromaffin cells in intestines)



5-HT1-receptors: 5-HT1A - 5-HT1F All subtypes occur in CNS and cause neural inhibition Act by inhibiting adenylate cyclase


Buspirone is a selective partial agonsist of presynaptic 5-HT1A-receptors. It is an anxyolitic agent, used in anxiety.

5-HT1D-receptors are found in some blood vessels .

Activation of 5-HT2-receptors in CNS produces excitement in blood vessels - contraction and platelet aggregation act through phospholipase C/ inositol phosphate pathway

Antagonists of 5-HT2-receptors are used: for prophylaxis of migraine

- methysergide - pizotifen

SSRIs (selective serotonin reuptake inhibitors): Fluvoxamine, Fluoxetine, Sertraline are used in humans to treat: chronic anxiety Depression


5-HT3-receptors Located in enteric neurons and in CNS. Act by stimulating adenylate cyclase. Effects are excitatory, causing GI motility and vomiting.

Dolasetron Granisetron Ondansetron Tropisetron

Antagonists of 5-HT3- receptors are very powerful antiemetics:

2. EICOSANOIDS Lipid-derived autacoid

prostanoids - prostaglandins (PGs) - thromboxanes (Txs) leucotrienes (LTs) lipoxins


The eicоsanoids are important mediators of inflammation and allergy.The main source of eicosanoids is arachidonic acid. It is a 20-carbon unsaturated fatty acid.

Phospholipase A2

Phospholipids
Arachidonic acid
5-lipoxygenase
Leucotrienes
Cyclooxygenase (Cox)
Endoperoxides
PGs
TxA2
15-lipoxygenase
Lipoxins
Inflammatory stimulus



PGI2 (prostacyclin) is located predominantly in vascular endothelium. Main effects: vasodilatation inhibition of platelet aggregation TxA2 is found in the platelets. Main effects: platelet aggregation vasoconstriction
PROSTANOIDS (PGs & Txs)


Several thromboxane A2-receptor antagonists may be able to restrict further infiltration of inflammatory cells in atherosclerotic vessels, thus stabilizing vulnerable plaques in the related cardiovascular diseases.


PGE2 causes:contraction of pregnant uterusinhibition of gastric acid secretioncontraction of GI smooth musclesPGF2α – main effects:contraction of bronchicontraction of myometrium

PGF2α (dinoprost)PGE2 (dinoprostone)are given for:induction of labourtermination of pregnancy PGE1 (gemeprost)
Dorland’s IllustratedMedical Dictionary(2003, 2004)

Main actions of the eicosanoids

Lьllmann, Color Atlasof Pharmacology – 2nd Ed. (2000)

Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. COX exists in 3 isoforms: COX-1 (constitutive) acts in physiological conditions. COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. COX-3 (in brain)


Aspirin-like drugs inhibit mainly COX-1 and can cause peptic ulcer, GI bleeding, bronchial asthma, and nephrotoxicity.


Inhibiting activity rate (COX-2/COX-1)
Aspirin Indometacin Meloxicam
155 60 0,8
(Preferential COX-2 inhibitor)
Classical NSAIDs

Arachidonic acid

Cyclooxygenase (Cox)
Endoperoxides
PGs
TxA2
(-)
Aspirin
Thromboxane A2 synthase
(-)
100 mg/24 h
>1 g/24 h

COX-2 inhibitors Selective (coxibs) Preferential

Selective COX-3 inhibitors Antipyretic analgesics
Nonselective (Aspirin-like) COX-1/COX-2 inhibitors
NSAIDs
COX INHIBITORS

3. Platelet activating factor (PAF)

PLA2 releases PAF in inflammation. PAF causes vasodilatation, increases vascular permeability, activates platelet aggregation.

3. Peptides

a) Vasoconstrictors


soluble proteins and glycoproteins that interact with specific cellular receptors. Cytokines are involved in inflammatory and immune response.
4. Cytokines –