Transcript АВТАКОИДИ

AUTACOIDS (LOCAL
HORMONES) AND
THEIR PHARMACOLOGICAL MODULATION
(Summary)
Assoc. Prof. Ivan Lambev
E-mail: [email protected]
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. Monoamines
a) Histamine
The synthesis and breakdown of histamine
•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.
Naja naja
Folia Urticae
(Leaves of Nettle)
Spoilt (putrid) fish
contains histidine!
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
HN
H2C
NH2
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
1st generation
(with sedative and
M-cholinolytic effects)
Promethazine
Dimetindene
Cyproheptadine
Embramine
(H1&5-HT2)
Chlorpyramine
Clemastine (weak sedation)
Hydroxyzine is an H1-blocker
with anxyolitic, antiemetic,
antimuscarinic, and spasmolytic
effects. It is effective
in pruritus and urticaria.
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 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.
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 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
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 phospholipase C/
inositol phosphate pathway
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
Monoamine Reuptake Inhibitors
α2-adrenergic
blockers
Enzime
inhibitors
DA&NARIs
Bupropion
Tricyclic antidepressants
Mainly NA-ergic
Desipramine
Nortriptyline
Selective NARIs
Reboxetine
Mainly 5-HT-ergic
Amitriptyline
Clomipramine
Imipramine
Selective 5-HTRIs
Citalopram, Fluoxetine
Escitalopram, Fluvoxamine
Paroxetine, Sertraline
Mianserine**
Mirtazapine
Trazodone
MAO-AIs
Moclobemide
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-HT4-
receptors 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.
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
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
PGF2α – main effects:
•contraction of bronchi
•contraction of myometrium
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)
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
•Indometacin 60
•Meloxicam 0,8
(Preferential COX-2 inhibitor)
Classical
NSAIDs
Arachidonic acid
Cyclooxygenase (Cox)
(-) >1 g/24 h
Aspirin
Endoperoxides
(-) 100 mg/24 h
Thromboxane A2 synthase
PGs
TxA2
COX INHIBITORS
NSAIDs
Nonselective
(Aspirin-like)
COX-1/COX-2
inhibitors
COX-2
inhibitors
• Selective (coxibs)
•
Preferential
Selective
COX-3
inhibitors
•Antipyretic
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
(+)
Phospholipase A2
Phospholipids
(-)
Lipocortin
(+)
Arachidonic acid
Glucocorticoids
INFLAMMATION
•alteration
(-)
•exudation
•proliferation
NSAIDs
(-) Gluco-
corticoids
(-)
Arachidonic acid
5-Lipoxygenase
Leukotrienes (LTs)
LTC4-
LTD4-
LTE4-
receptor
receptor
receptor
(-)
(-)
Montelukast, Zafirlukast
3. Platelet activating
factor (PAF)
•PLA2 releases PAF in inflammation.
•PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation.
3. Peptides
a) Vasoconstroctors
Endothelins: ET-1, ET-2, ET-3
b) Vasodilators:
ANP
CGRP
SP
NPY (with NA)
VIP (with ACh)
Kinins (kallikrein,
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
Actimide
Revemide
PDGF
(–)
VEGF
TNF-alfa
(+)
(–)
Bevacizumab
(+)
(+)
(+)
EGFR
(–)
(–)
TNF-beta
Cetuximab
Colorectal cancer