Transcript Histamine

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
1431 Sofia, 2 “Zdrave” Str., Phone (02) 9172-621
AUTOCOIDS (LOCAL
HORMONES) AND
THEIR PHARMACOLOGICAL MODULATION
Assoc. Prof. Ivan Lambev
E-mail: [email protected]
THEY
•play an important role
in the physiological and
pathological processes
•very short t1/2
•local action
1. Monoamines
• Histamine
• Serotonin (5-HT)
CH2
HN
H2C
NH2
N
Histamine
2-(4-imidazolyl)-ethylamine
Histamine is
a basic amine.
It is formed
from amino acid
histidine by
histidine decarboxylase.
The synthesis and
breakdown of histamine
Essential of Medical Pharmacology – 5st Ed. (2003)
•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 cell and basophiles.
•Non-mast-cell histamine occurs
as a neurotransmitter in CNS.
In mast cells and basophiles
histamine is held in intracellular granules together
with heparin.
Histamine
- distribution
Histamine is released from mast
cells by a secretory process during
inflammatory or allergic reactions
(Ag-Ab reactions).
The secretory process is initiated
by a raise in intracellular Ca2+.
Histamine is released from mast
cells during burns too.
Some drugs (mainly alkaloids
atropine, morphine, reserpine,
tubocurarine) release
histamine by non-receptor
action and can cause
bronchoconstriction,
arterial hypotension and other
unwanted effects.
Naja naja
Folia Urticae
(Leaves of Nettle)
Spoilt (putrid) fish
contains histidine!
FISH ALLERGY
Agents which increase cAMP
(adrenaline, salbutamol
and other beta-adrenoceptor
agonists) inhibit histamine
secretion and produce
bronchodilation
(antiasthmatic effect).
•Histamine produces effects
by acting on H1, H2, H3,
H4 and H5-receptors.
•Histamine’s receptors are
G-protein coupled.
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
CH2
HN
H2C
NH2
N
Histamine and
antagonists of
H1-receptors
(H1-blockers)
H1-blockers
•Use mainly for treatment
of urticaria
and hay fever.
•Some of them (embramine,
promethazine)
have antiemetic effect.
H1-blockers from
1st generation
(with sedative and
M-cholinolytic effects)
promethazine
dimetindene
cyproheptadine
embramine
(H1&5-HT2)
chlorpyramine
clemastine (weak sedation)
H1-blockers from
nd
2
generation
(without sedative and M-cholinolytic effects)
astemizole
cetirizine
loratadine
terfenadine
prolongation of QT interval
and hypokalemia
H1-blockers from
nd
3 generation
•Desloratadine
(Aerius® – film-tab. 5 mg; t1/2 27 h)
•Levocitirizine
Stimulation of H2-receptors:
•cardiac stimulation
•stimulation of gastric
acid secretion
Antagonist of H2-receptors
(H2-blockers) - for treatment
of peptic ulcer:
•Cimetidine (? …)
•famotidine
•nizatidine
•ranitidine
•roxatidine
Mast cell stabilizers
•prevent histamine release
from mast cells
•Are prescribed prophylactically
in allergic asthma
- cromoglycate
- ketotifen
- nedocromil
Rang et al.
Pharmacology
– 5st Ed. (2003)
HO
CH2 H2C NH2
NH
Serotonin
(5-Hydroxytryptamine: 5-HT)
Indol derivative
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, stereotyped behavior,
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
•anxiolytic agent
•partial agonist of the
5-HT1A-receptors
•used in anxiety
5-HT1D-receptors are
found in some blood
vessels
(a. carotis externa et interna,
meningeal vessels). They
produce vasoconstriction.
pathophysiology of migraine
Rang et al.
Pharmacology
– 5st Ed. (2003)
Pathogenesis of migraine and drug treatment
The agonist of 5-HT1D-receptors
are highly effective, but expensive,
in acute attacks of migraine:
•Naratriptan
•Rizatriptan
•Sumatriptan
•Zolmitriptan
Activation of
5-HT2-receptors
•in CNS produces excitement
•in blood vessels - contraction
and platelet aggregation
•act through phospholypase C/
inositol phosphate pathway
Antagonists of
5-HT2-receptors are used:
•for prophylaxis of migraine
- cyprohepatadine
- iprazochrome
- methysergide
- pizotifen
•as a peripheral vasodilator
- Naftidrofuryl (Dusodril®)
Adverse effects
of methysergide:
•retroperitoneal fibrosis
•renal failure
SSRIs (selective serotonin
reuptake inhibitors)
are used in:
•chronic anxiety
•depression
•bulimia
SSRIs include
•fluoxetine
•fluvoxamine
•paroxetine
•sertraline etc.
5-HT3-receptors
•Located in enteric neurons
and in CNS.
•Act by stimulating
adenylate cyclase.
•Effects are excitatory, causing
GI motility and vomiting.
Antagonists of 5-HT3receptors are very
powerful antiemetics:
dolasetron
granisetron
ondansetron
tropisetron
Agonists of 5-HT4-receptors
•Tegaserod (Zelmac®) activates 5-HT4receptors in the intestine and stimulates
peristalsis and secretion.
Indication: colon irritable syndrome
(eicosi = 20)
2. EICOSANOIDS
(20 carbon atoms!)
•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.
IL®
Inflammatory stimulus
Phospholipids
Phospholipase A2
Arachidonic acid
5-lipoxygenase
Cyclooxygenase (Cox)
15-lipoxygenase
Leucotrienes
Lipoxins
Endoperoxides
PGs
TxA2
PROSTANOIDS (PGs & Txs)
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
PGE1
•alprostadil (prodrug – used to maintain
the patency of the ductus arteriosus in neonates
with congenital heart defects, and for treatment
of erectile dysfunction by injection
into the corpus cavernosum of the penis);
•misoprostol (used for prophylaxis of
peptic ulcer associated with NSAIDs);
•gemeprost
used as pessaries to soften the uterine
cervix and dilate the cervical canal prior to
vacuum aspiration for termination of pregnancy.
PGE2 causes:
•contraction of pregnant uterus
•inhibition of gastric acid secretion
•contraction of GI smooth muscles
PGF2α – main effects:
•contraction of bronchi
•contraction of miometrium
PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
Dorland’s Illustrated
Medical Dictionary
(2003, 2004)
are given for:
•induction of labour
•termination of pregnancy
Main
actions
of the
eicosanoids
Lüllmann, Color Atlas
of 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)
This has relevance for the
mechanism of action of
NSAIDs. The most of
them 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
Arachidonic acid
Cyclooxygenase (Cox)
(-) >1 g/24 h
Aspirin
Endoperoxides
(-) 100 mg/24 h
Thromboxan A2 synthase
PGs
TxA2
Inflammatory stimulus
(+)
Phospholipase A2
Phospholipids
(-)
Lipocortin
(+)
Arachidonic acid
Glucocorticoids
INFLAMMATION
•alteration
NSAIDs
(-)
•exudation
•proliferation
(-)Gluco-
corticoids
(-)
3. Platelet activating
Factor (PAF)
•PLA2 releases PAF in inflammation
•PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation
4. Non – hormonal peptides
Opioid peptides
•dynorphin (μ, δ, κ)
•enkephalin (μ, δ)
•endorphin (μ, δ, κ)
•nociceptin – ORL1 (tolerance)
ANALGESIA
μ – on supraspinal level
κ – on spinal level
δ – mainly on peripheral level
NB: Metamizole (Analgin®)
stimulates the secretion of beta-endorphin
(Vlaskovska M, Surcheva Sl, Ovcharov R, 1989).
– strong
long – acting
vasoconstrictors
Endothelins
ЕТ-1, ET-2 и Е-3
ЕТА-receptors: >>> vasoconstriction
ЕТB-receptors: 30 s vasodilatation
ET-1 plasma levels increase in
vascular spasm and acute myocardial
infarction.
Angiotensin II
AT1-
AT2-
receptor
receptors
•Vasoconstriction
•Proliferative effects
•Vasodilation
•Antiproliferative
effects
Secretion of aldosterone
IL®
Angiotensinogen
Catepsin G
Renin
Angiotensin I
ACE
Angiotensin II
Sartans
(-)
AT1-
receptor
AT2-
receptor
(-)
synthesis
(-)
Beta –
blockers
ACE
inhibitors
(-)
ACE
(kininase II)
Cytokines Regulatory peptides
of inflammation
and allergic reactions
Cytokines act together (“as a team”)
on: endothelium, leucocytes,
mastocytes, fibroblasts, stem cells
and osteoclasts.
Cytokines control their proliferation,
differentiation and/or activation by
receptor mechanism.
IL-1 participates in pathogenesis
of rheumatoid arthritis.
Glucocorticosteroids and
glucosamine depress the synthesis
of IL–1.
IL-2 (Aldesleukin) – i.v.
in renal Ca.
IL-11 stimulates
thrombocytopoesis
•Interferon alpha-2b
©
(Intron ):
- in chronic hepatitis B and C
- lymphomas, melanomas etc.
•Interferon beta-1b
©
(Betaferon )
s.c. in multiple sclerosis
•Inerferon gamma –
in the regulation of
the immune system
•Colony-stimulating factors
(rHuCSFs):
- Filgrastim, Molgramustim
•Erythropoetin:
- Epoetin alpha et beta
•TNF-alpha; TNF-beta
Thalidomide
Actimide
Revemide
PDGF
(-)
VEGF
TNF-alpha
(+)
(-)
Avastin®
(+)
(+)
(+)
(–)
TNF-beta
TGF-beta