9.- autacoides 3
TRANSCRIPT
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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)
2. Nitric oxide (NO) and platelet activating factor (PAF)
3. Polipeptides: Angiotensine and Bradykinin.
4. Amines: Histamine and serotonin
AUTACOIDS
Generated
“de novo”
stored
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HISTAMINE
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DISTRIBUTION OF HISTAMINE
Mast cells: Mucosa of the lungsDigestive track
SkinMouth, conjuntiva and nose
BasophilsNeurons (CNS)Platelets
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NN
CH2 -CH2 -NH2
CH3
1-METHYLHISTAMINE
NN
CH2-COOH
ACIDO 5-IMIDAZOLACETIC
Biosynthesis and metabolism
Histamine
Decarboxilase
diaminooxidase N-methyltransferase
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Mast cellHistamine
Symptoms
Allergen induced histamine release
B cell (plasma)
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Histamine releasing agents
- Neuromuscular blockers (tubocurarine).
- Morphine
- Antibiotics (vancomicyn, polimixine B)
- Substance P, bradikinine.
- Others: Radiation, bacterial toxins...
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Histamine receptors
Types H1 H2
Transducc Gq/11
PLC↑Ca++
NO↑GMPc
Gs
AC↑AMPc
H3
Gi/o
AC↓cAMP
Distribution • Lungs• endotelial cells• heart• gi tract• sensitive nerves
• stomach
parietal cells• Vessels• Heart
CNS
(presynaptic)
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Pharmacological actions of histamine
Histamine
H1 endotelial cells
Nitric oxide formation
Vasodilation
H2 smooth muscle
↑ cAMP
Persistent dilation
Blood pressure decrease
Cardiovascular (H1 and H2)
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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).
InflammationInduce IL-10 secretion
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1 3
2
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 dilatationmediated by axon reflex.
Wheal: due to exudation of fluid from capillaries and venules
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Antihistaminic drugs H1
First generation Second generation
DiphenhydramineClorpheniramineMepyramineDoxylamine
MeclizinePrometacineDimenhydrinate
CetirizineEbastineLoratadineTerphenadine
-Pass the blood brain barrier
-Less specific (5-HT,cholinergic, adrenergic…)
-Don´t pass the blood brainbarrier
-More specific
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Clinical use of antihistaminics H1
First and second generation
1) AllergiesRhinitis/ Allergic conjunctivitisUrticaria/ dermatitis
First generation
2) Kinetosis, dizzyness, emesis, vertigo (Dimenhydrate)
3) Sedation
4) Local anaesthetic (prometazina)
Second generation
5) Inflamation (Cetiricine, inhibit production of LTB4)
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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)
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H2 antagonist drugs
Ranitidine Cimetidine
Therapeutic use: peptic ulcer, gastic mucosal acidosis
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Allergie inhibition
Histamine
Respiratory tract
stomach wall
alergies
HCl secretion
Discovery of H1 and H2 receptor subtypes (~70s Sir James Black)
Cimetidine
~1976
Characterizationof H2 receptors
Difenhydramine
H1?
H2?
HCl secretionpersist
HCl secretioninhibition
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PG
G
H2
PG
K+
MOCO
HCO3-
Célula parietal
Célula epitelial
LUZ
PGE2
PGI 2
Histamina
Gastrina
Célula paracrina
G
M1 ACh
N. vagoATPasaH+ / K+ AMPc
Histamina
H+
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Cimetidina
Cimetidina
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(I) Histamine
Mepiramina Difenhidramina
NedocromileCromoglicate sodium
Histamina
Inhibitors of Histamine release
Pharmacological action: prophylaxis of the brocoespasmo
induced by histamine
Therapeutic use: Allergic bronchial asthma and
induced by exercise