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AUTACOIDS (LOCAL

HORMONES) AND
THEIR PHARMACOLO-
GICAL MODULATION
(Summary)
endogenous compounds;
play an important role
in the physiological and
pathological processes;
have very short t
1/2
;
have local action.
Autacoids
a) Histamine
1. Monoamines
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 basophils.
Non-mast-cell histamine occurs
as a neurotransmitter in CNS.
In mast cells and basophils histamine
is located in intracellular granules
together with heparin.
- distribution
Histamine
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 Ca
2+
.
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.
Folia Urticae
Naja naja
(Leaves of Nettle)

Spoilt (putrid) fish
contains histidine!
contains potent
allergens: can
be potentially
dangerous.
remains
allergenic
despite
cooking.
FISH
Agents which increase cAMP
(adrenaline, salbutamol,
and others) inhibit histamine
secretion and produce
bronchodilation
(antiasthmatic effect).
Histamine produces effects
by acting on H
1
, H
2
, H
3
,
H
4
, and H
5
-receptors.
Histamines receptors are
G-protein coupled.
Stimulation of H
1
-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.
Histamine and
antagonists of
H
1
-receptors
(H
1
-blockers)
N H N
CH
2
C H
2
NH
2
H
1
-blockers
Used mainly for the
treatment of urticaria
and hay fever.
Some of them (embramine,
promethazine)
have antiemetic effect too.
Dimetindene
Embramine
Chlorpyramine
Promethazine
Cyproheptadine
(H
1
&5-HT
2
)
H
1
-blockers from
1
st
generation
(with sedative and
M-cholinolytic effects)
Clemastine (weak sedation)
Hydroxyzine is an H
1
-blocker
with anxyolitic, antiemetic,
antimuscarinic, and spasmolytic
effects. It is effective
in pruritus and urticaria.
Astemizole
Cetirizine
Loratadine
Terfenadine
H
1
-blockers from 2
nd
generation
(without sedative and M-cholinolytic effects)
prolongation of QT interval
and hypokalemia
H
1
-blockers from
3
rd
generation

Desloratadine
(Aerius

film-tab. 5 mg; t
1/2
27 h)
Levocitirizine
cardiac stimulation
stimulation of gastric
acid secretion
Activation of H
2
-receptors:
Cimetidine (? )
Famotidine
Nizatidine
Ranitidine
Roxatidine
Antagonist of H
2
-receptors
(H
2
-blockers) for the treatment
of peptic ulcer:
Cromoglycate per inh.
(Cromolyn USAN)
Ketotifen (p.o.)
Nedocromil per inh.
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. They also inhibit leukocyte
activation and chemotaxis.
Indications: prophylactic treatment of asthma.
NH
O H
CH
2
C H
2
NH
2

b) Serotonin
(5-Hydroxytryptamine: 5-HT)
Indol derivative
Rang et al.
Pharmacology
5
st
Ed. (2003)
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-HT
1
-receptors:

5-HT
1A
5-HT
1F
All subtypes occur in CNS
and cause neural inhibition
Act by inhibiting
adenylate cyclase
Buspirone
anxiolytic agent
partial agonist of the
5-HT
1A
-receptors
used in anxiety
5-HT
1D
-receptors are
found in some blood
vessels
(a. carotis externa et interna,
meningeal vessels). They
produce vasoconstriction.
pathophysiology of migraine
Pathogenesis of migraine and drug treatment
Rang et al.
Pharmacology
5
st
Ed. (2003)
The agonist of 5-HT
1D
-receptors
are highly effective, but expensive,
in acute attacks of migraine:
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan
Activation of
5-HT
2
-receptors
in CNS produces excitement
in blood vessels - contraction
and platelet aggregation
act through phospholipase C/
inositol phosphate pathway
Antagonists of
5-HT
2
-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

2
-adrenergic
blockers
Enzime
inhibitors
Mainly NA-ergic
Desipramine
Nortriptyline
Mainly 5-HT-ergic
Amitriptyline
Clomipramine
Imipramine
Selective NARIs
Reboxetine
Selective 5-HTRIs
Citalopram, Fluoxetine
Escitalopram, Fluvoxamine
Paroxetine, Sertraline
Mianserine**
Mirtazapine
Trazodone
Tricyclic antidepressants
MAO-AIs
Moclobemide
DA&NARIs
Bupropion
5-HT
3
-receptors
Located in enteric neurons
and in CNS.
Act by stimulating
adenylate cyclase.
Effects are excitatory, causing
GI motility and vomiting.
Dolasetron
Granisetron
Ondansetron
Tropisetron
Antagonists of 5-HT
3
-
receptors are very
powerful antiemetics:
Agonists of
5-HT
4
-receptors

Tegaserod (Zelmac

) activates 5-HT
4
-
receptors in the intestine and stimulates
peristalsis and secretion.
Indication: colon irritable syndrome
2. EICOSANOIDS
(20 carbon atoms!)
prostanoids
prostaglandins (PGs)
thromboxanes (Txs)
leucotrienes (LTs)
lipoxins
(
e
i
c
o
s
i

=

2
0
)

The eicsanoids are important
mediators of inflammation
and allergy.


The main source of
eicosanoids is arachidonic acid.
It is a 20-carbon unsaturated
fatty acid.
Phospholipase A
2
Phospholipids
Arachidonic acid
5-lipoxygenase
Leucotrienes
Cyclooxygenase (Cox)
Endoperoxides
PGs TxA
2
15-lipoxygenase
Lipoxins
Inflammatory stimulus
PGI
2
(prostacyclin) is located
predominantly in vascular
endothelium. Main effects:
vasodilatation
inhibition of platelet aggregation
TxA
2
is found in the platelets.
Main effects:
platelet aggregation
vasoconstriction
PROSTANOIDS (PGs & Txs)
Several thromboxane
A
2
-receptor antagonists
may be able to restrict further
infiltration of inflammatory cells
in atherosclerotic vessels,
thus stabilizing vulnerable plaques
in the related cardiovascular
diseases.
PGE
1

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.
PGE
2

causes:
contraction of pregnant uterus
inhibition of gastric acid secretion
contraction of GI smooth muscles

PGF
2
main effects:
contraction of bronchi
contraction of myometrium
PGF
2
(dinoprost)
PGE
2
(dinoprostone)
are given for:
induction of labour
termination of pregnancy
PGE
1
(gemeprost)
Dorlands Illustrated
Medical Dictionary
(2003, 2004)
Main
actions
of the
eicosanoids
Lllmann, Color Atlas
of Pharmacology
2
nd
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
Indometacin
Meloxicam
155
60
0,8
(Preferential COX-2 inhibitor)
Classical
NSAIDs
Cyclooxygenase (Cox)
Endoperoxides
PGs TxA
2
(-)
Aspirin
Thromboxane A
2
synthase
(-)
100 mg/24 h
>1 g/24 h
COX-2
inhibitors
Selective (coxibs)
Preferential
Selective
COX-3
inhibitors
Antipyretic
analgesics
Nonselective
(Aspirin-like)
COX-1/COX-2
inhibitors
NSAIDs
COX INHIBITORS
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.
Pfizer
$2.3
billions
penalty
Inflammatory stimulus
(+)
Phospholipase A
2
Phospholipids
Arachidonic acid


(-)
Lipocortin
Glucocorticoids
(+)
alteration
exudation
proliferation
NSAIDs
(-)
(-)
(-)
Arachidonic acid
5-Lipoxygenase
Leukotrienes (LTs)
LTC
4
-
receptor
LTD
4
-
receptor
LTE
4
-
receptor
Montelukast, Zafirlukast
(-) (-)
3. Platelet activating
factor (PAF)
PLA
2
releases PAF in inflammation.
PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation.
4. Peptides
Endothelins: ET-1, ET-2, RT-3
ANP
CGRP
SP
NPY (with NA)
VIP (with ACh)
Kinins (kallikrein,
bradykinin
Cholecystokinin (CCK)
neuripeptide involved in pathogenesis
of panic reactions
soluble proteins and glycoproteins
that interact with specific cellular
receptors. Cytokines are involved
in inflammatory and immune
response.
5. Cytokines
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.
I L-1 participates in the pathogenesis
of rheumatoid arthritis.
Glucocorticosteroids and
glucosamine depress the synthesis
of IL1.
I L-2: used i.v. in renal
carcinoma but has ADRs!
I L-11 stimulates
thrombocytopoesis.
INTERLEUKINES (ILs)
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
I nterferon alpha-2b (Intron

):
- in chronic hepatitis B and C
- lymphomas, melanomas, etc.
I nterferon beta-1b (Betaferon

)
s.c. in multiple sclerosis.
I nterferon gamma
in the regulation of
the immune system.
INTERFERONS (INFs)
Colony-stimulating factors
(rHuCSFs):
- Filgrastim, Molgramustim, Lenograstim
(to treat agronulocytosis and leukopenia)
TNF-alpha (alfa)
TNF-beta
VEGF
PDGF,
EGF, etc.
PDGF EGFR
TNF-beta
(+) (+)
()
VEGF
TNF-alfa
(+) (+)
T
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i
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m
i
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R
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v
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()
Bevacizumab
()
Cetuximab
()