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Autacoids (Local Hormones) and Their Pharmacolo-Gical Modulation
Autacoids (Local Hormones) and Their Pharmacolo-Gical Modulation
HORMONES) AND
THEIR PHARMACOLO-
GICAL MODULATION
(Summary)
Assoc. Prof. Ivan Lambev
E-mail: itlambev@mail.bg
www.medpharm-sofia.eu
Autacoids
•endogenious compounds;
•play an important role
in the physiological and
pathological processes;
• have very short t1/2;
• have local action.
1.
1. Monoamines
Monoamines
a) Histamine
FISH
•contains potent
allergens: can
be potentially
dangerous.
•remains
allergenic
despite
cooking.
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.
•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 H2C NH2
HN N
Histamine and
antagonists of
H1-receptors
(H1-blockers)
H1-blockers
•Used mainly for the
treatment of urticaria
and hay fever.
•Some of them (embramine,
promethazine)
have antiemetic effect too.
H1-blockers from
1 generation
st
prolongation of QT interval
and hypokalemia
H1-blockers from
3 …rd…
generation
•Desloratadine
(Aerius® – film-tab. 5 mg; t1/2 27 h)
•Levocitirizine
Activation of H2-receptors:
•cardiac stimulation
•stimulation of gastric
acid secretion
Antagonist of H2-receptors
(H2-blockers) – for the treatment
of peptic ulcer:
•Cimetidine (? …)
•Famotidine
•Nizatidine
•Ranitidine
•Roxatidine
Mast cell stabilizers prevent transmembrane influx
of calcium ions, provoked by antigen-IgE antibody
reaction on the mast cell membrane. They prevent
degranulation and release of histamine and other
autacoids from mast cells.
Indications: treatment of asthma.
NH
b) 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 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
(a. carotis externa et
interna,
meningeal vessels). They
pathophysiology
produce of migraine
vasoconstriction.
Rang
Rangetetal.al.
Pharmacology
Pharmacology
––55ststEd.
Ed.(2003)
(2003)
Tricyclic antidepressants
Selective 5-HTRIs
Citalopram, Fluoxetine Mianserine**
Selective NARIs Escitalopram, Fluvoxamine Mirtazapine MAO-AIs
- - -
•prostanoids
prostaglandins (PGs)
thromboxanes (Txs)
•leucotrienes (LTs)
•lipoxins
•The eicоsanoids are important
mediators of inflammation
and allergy.
Phospholipids Phospholipase A2
Arachidonic acid
5-lipoxygenase Cyclooxygenase (Cox)
15-lipoxygenase Endoperoxides
Leucotrienes
Lipoxins 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
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.
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
PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
are given for:
•induction of labour
•termination of pregnancy
Main
actions
of the
eicosanoids
Lüllmann,
Lüllmann,Color
ColorAtlas
Atlas
ofofPharmacology
Pharmacology––
22ndEd.
nd
Ed.(2000)
(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 155 Classical
NSAIDs
•Indometacin 60
•Meloxicam 0,8
(Preferential COX-2 inhibitor)
Arachidonic acid
Cyclooxygenase (Cox)
() >1 g/24 h
Endoperoxides Aspirin
() 100 mg/24 h
Thromboxane A2 synthase
PGs TxA2
COX INHIBITORS
Nonselective
(Aspirin-like)
NSAIDs COX-1/COX-2
inhibitors
Selective
COX-2
COX-3
inhibitors
• Selective (coxibs) inhibitors
•Antipyretic
• Preferential
analgesics
Pfizer
$2.3
billions
penalty
Coxibs are selective COX-2 inhibitors. They exert
anti-inflammatory, analgesic and antipyretic action
with low ulcerogenic potential. Coxibs can cause
infertility. They have prothrombotic cardiovascular
risk. The ulcerogenic potential of preferential
COX-2 inhibitors Meloxicam, Nabumetone, and
Nimesulide (Aulin®) is significant.
Inflammatory stimulus
(+)
Phospholipids Phospholipase A2
()
Lipocortin
(+)
Arachidonic acid Glucocorticoids
INFLAMMATION
•alteration NSAIDs
()
•exudation ()Gluco-
corticoids
()
•proliferation
Arachidonic acid
5-Lipoxygenase
Leukotrienes (LTs)
(-) (-)
Montelukast, Zafirlukast
3.
3. Platelet
Platelet activating
activating
factor
factor (PAF)
(PAF)
•PLA2 releases PAF in inflammation.
•PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation.
3. Peptides
a) Vasoconstrictors
Endothelins (ET-1, -2, -3)
Blockers of ET-1 receptors are
indicated for the treatment of PAH
(pulmunary arterial hypertension):
AMBRISENTAN
BOSENTAN
MACITENTAN
b) Vasodilators:
NPY (with NA)
ANP VIP (with ACh)
CGRP Kinins (kallikrein,
SP bradykinin
c) Neuripeptide involved in
pathogenesis of panic reactions
Cholecystokinin (CCK)
5. Cytokines –
soluble proteins and glycoproteins
that interact with specific cellular
receptors. Cytokines are involved
in inflammatory and immune
response.
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.
INTERLEUKINES (ILs)
IL-1 participates in the pathogenesis
of rheumatoid arthritis.
Glucocorticosteroids and
glucosamine depress the synthesis
of IL–1.
IL-2: used i.v. in renal
carcinoma but has ADRs!
IL-11 stimulates
thrombocytopoesis.
IL-18:
•Upregulated INF production
•Enhenced NK cell cytotoxicity
IL-23:
•Anti-viral activity
•Stimulates T-cell, macrophage, and
•NK cell activity.
•Direct anti-tumor effects
•Used therapeuticaly in viral and
autoimmune conditions
INTERFERONS (INFs)
•Interferon alpha-2b (Intron©):
- in chronic hepatitis B and C
- lymphomas, melanomas, etc.
•Interferon beta-1b (Betaferon©)
s.c. in multiple sclerosis.
•Interferon gamma –
in the regulation of
the immune system.
•Colony-stimulating factors
(rHuCSFs):
- Filgrastim, Molgramustim, Lenograstim
(to treat agronulocytosis and leukopenia)
•TNF-alpha (alfa)
•TNF-beta
•VEGF
•PDGF,
•EGF, etc.
Thalidomide
Revemide
Actimide TNF-alfa VEGF Bevacizumab
(–) (–)
(+) (+)
(+) (+)
PDGF EGFR
(–)
(–) Cetuximab
TNF-beta
Colorectal cancer