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AUTACOIDS

Autos: self y akos: relief


“A chemical substance produced by one type of cell that affects
the function of different types of cells in the same region ”.

1. Eicosanoids: Prostaglandins (PG)


Tromboxanes (TX)
Leucotrienes (LT) Generated
“de novo”
2. Nitric oxide (NO) and platelet activating factor (PAF)

3. Polipeptides: Angiotensine and Bradykinin.

4. Amines: Histamine and serotonin stored


HISTAMINE
DISTRIBUTION OF HISTAMINE

Mast cells: Mucosa of the lungs


Digestive track
Skin
Mouth, conjuntiva and nose

Basophils
Neurons (CNS)
Platelets
Biosynthesis and metabolism

Decarboxilase

diaminooxidase N-methyltransferase
Histamine
CH 2 -CH2 -NH2
CH 2 -COOH
N N
N N CH 3

ACIDO 5-IMIDAZOLACETIC 1-METHYLHISTAMINE


Allergen induced histamine release

B cell (plasma)

Histamine Mast cell

Symptoms
1 2 3

4 5 6
Histamine in allergic response
Histamine releasing agents

- Neuromuscular blockers (tubocurarine).

- Morphine

- Antibiotics (vancomicyn, polimixine B)

- Substance P, bradikinine.

- Others: Radiation, bacterial toxins...


Histamine receptors

Types H1 H2 H3

Transducc Gq/11 Gs Gi/o

PLC AC AC
↑Ca++ ↑AMPc ↓cAMP
NO
↑GMPc

Distribution • Lungs • stomach CNS


• endotelial cells parietal cells (presynaptic)
• heart • Vessels
• gi tract • Heart
• sensitive nerves
Pharmacological actions of histamine

Cardiovascular (H1 and H2)

Histamine

H1 endotelial cells H2 smooth muscle

Nitric oxide formation ↑ cAMP

Vasodilation Persistent dilation

Blood pressure decrease


Pharmacological actions of histamine

Stomach (H2 )

Increases secretion of HCl

Sensitive nerve terminals (H1 )

Itching, pain

Respiratory (H1)

Contraction of smooth muscle in the lungs (H1).

Inflammation
Induce IL-10 secretion
Pharmacological actions of histamine

Triple response (Sir Thomas Lewis)


(Intradermic injection triggers triphasic skin reaction )
Red spot: due to capillary dilation

Flare: redness in the surrounding area due to arteriolar dilatation


mediated by axon reflex.

Wheal: due to exudation of fluid from capillaries and venules

3
1

2
Antihistaminic drugs H1

First generation Second generation


Diphenhydramine Cetirizine
Clorpheniramine Ebastine
Mepyramine Loratadine
Doxylamine Terphenadine
Meclizine
Prometacine
Dimenhydrinate

-Pass the blood brain barrier


-Don´t pass the blood brain
-Less specific (5-HT, barrier
cholinergic, adrenergic…)
-More specific
Clinical use of antihistaminics H1

First and second generation

1) Allergies
Rhinitis/ Allergic conjunctivitis
Urticaria/ dermatitis

First generation

2) Kinetosis, dizzyness, emesis, vertigo (Dimenhydrate)

3) Sedation

4) Local anaesthetic (prometazina)

Second generation

5) Inflamation (Cetiricine, inhibit production of LTB4)


Adverse effects of antihistaminics

First generation
- Sedation (if cross blood brain barrier). (Tolerance)

- Antimuscarinic effect; dry mouth, anorexia, nausea…

-Gastrointestinal alterations: nausea

- 5-HT effects: increase of appetite

Second generation

-Arrithmia (terphenadine and asthemizol ).

- Sedation (only Cetiricine)


H2 antagonist drugs

Ranitidine Cimetidine

Therapeutic use: peptic ulcer, gastic mucosal acidosis


Discovery of H1 and H2 receptor subtypes (~70s Sir James Black)

H1?
Respiratory tract alergies Allergie inhibition

Histamine Difenhydramine

H2?
stomach wall HCl secretion
HCl secretion
persist

~1976

Cimetidine HCl secretion Characterization


inhibition of H2 receptors
G Gastrina
K+
LUZ
ATPasa AMPc H2 Histamina
H+ / K+ N. vago

PGE
2
H+ PG PGI 2

Célula parietal

Histamina
G
MOCO
PG
HCO-
3 Célula epitelial
M1 ACh
Célula paracrina
Cimetidina

Cimetidina
Inhibitors of Histamine release
Pharmacological action: prophylaxis of the brocoespasmo
induced by histamine

Therapeutic use: Allergic bronchial asthma and


Histamina Mepiramina induced by exercise
Difenhidramina

(I) Histamine

Cromoglicate sodium Nedocromile