AUTACOIDS (LOCAL

HORMONES) AND
THEIR PHARMACOLO-
GICAL 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.
 Folia Urticae
Naja naja (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 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
1st generation
(with sedative and
M-cholinolytic effects)
Dimetindene Promethazine
Embramine Cyproheptadine
Chloropyramine (H1&5-HT2)
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 2 nd generation
(without sedative and M-cholinolytic effects)

Astemizole Loratadine
Cetirizine Terfenadine

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.

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 Enzime
blockers inhibitors
DA&NARIs
Bupropion

Tricyclic antidepressants

Mainly NA-ergic Mainly 5-HT-ergic

Desipramine Amitriptyline
Nortriptyline Clomipramine
Imipramine

Selective 5-HTRIs
Citalopram, Fluoxetine Mianserine**
Selective NARIs Escitalopram, Fluvoxamine Mirtazapine MAO-AIs
Reboxetine Paroxetine, Sertraline Trazodone 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-HT3-
receptors 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
 2. EICOSANOIDS
(20 carbon atoms!)
(eicosi = 20)

•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 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

PGF2α – main effects:

•contraction of bronchi
•contraction of myometrium
 Dorland’s Illustrated
Medical Dictionary
(2003, 2004)

PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
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 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
(-) Gluco-
•exudation
corticoids

•proliferation
(-)
 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) 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