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AUTACOIDS (LOCAL
HORMONES) AND
THEIR PHARMACOLOGICAL MODULATION
summary
Autacoids
•endogenious compounds;
•play an important role
in the physiological and
pathological processes;
• have very short t1/2;
• have local action.
•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
- 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 in high doses)
release histamine by non-receptor
action and can cause
bronchoconstriction,
arterial hypotension, and other
unwanted effects.
•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.
H1-blockers
•Used mainly for the
treatment of urticaria
and hay fever.
•Some of them (embramine,
promethazine)
have antiemetic effect too.
H1-blockers from
1st generation
(with sedative and
M-cholinolytic effects)
Didimetindene Promethazine
Cyproheptadine
Embramine
(H1&5-HT2)
Chlorpyramine
Clemastine (weak sedation)
H1-blockers from
nd
2
generation
(without sedative and M-cholinolytic effects)
Astemizole
Loratadine
Cetirizine
Terfenadine
prolongation of QT interval
and hypokalemia
H1-blockers from
…rd…
3
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 They prevent
degranulation and release of histamine and other
autacoids from mast cells. They also inhibit leukocyte
activation and chemotaxis.
Indications: prophylactic treatment of asthma.
Cromoglycate – per inh.
(Cromolyn – USAN)
Ketotifen (p.o.)
Nedocromil – per inh.
Rang et al.
Pharmacology
– 5st Ed. (2003)
HO
CH2 H2C NH2
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
•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
The agonist of 5-HT1D-receptors
are highly effective, but expensive,
in acute attacks of migraine:
•Naratriptan
•Rizatriptan
•Sumatriptan
•Zolmitriptan
Antagonists of
5-HT2-receptors are used:
•for prophylaxis of migraine
- cyproheptadine
- iprazochrome
- methysergide
- pizotifen
•as a peripheral vasodilator
- Naftidrofuryl (Dusodril®)
Adverse effects
of methysergide:
•retroperitoneal fibrosis
•renal failure
SSRIs (selective serotonin
reuptake inhibitors): Fluvoxamine,
Citalopram, Fluoxetine,
Paroxetine,
Sertraline
are used in
humans
to treat:
•chronic anxiety
•Depression, bulimia
5-HT3-receptors
•Located in enteric neurons
and in CNS.
•Effects are excitatory, causing
GI motility and vomiting.
Antagonists of 5-HT3receptors are very
powerful antiemetics:
Dolasetron
Granisetron
Ondansetron
Tropisetron
(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.
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
•misoprostol (used for prophylaxis of
peptic ulcer associated with NSAIDs);
•gemeprost
used for termination
of pregnancy.
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. Most of them
inhibit mainly COX-1
and can cause peptic ulcer,
GI bleeding, bronchial
asthma, and nephrotoxicity.
IL®
COX INHIBITORS
NSAIDs
Nonselective
COX-1/COX-2
inhibitors
COX-2
inhibitors
• Selective (coxibs)
•
Preferential
Selective
COX-3
inhibitors
•Antipyretic
analgesics
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.
INFLAMMATION
•alteration
(-)
•exudation
•proliferation
NSAIDs
(-)Gluco-
corticoids
(-)
4. Peptides
Endothelins: ET-1, ET-2, RT-3
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.
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
[ recombinant human colony stimulating
Factors]:
- Filgrastim, Molgramustim, Lenograstim
Used in cancer
chemotherapy