Download Autacoids-E - BMC Dentists 2011

AUTACOIDS
(LOCAL HORMONES)
PHARMACOLOGY
BY: Dr. Marwa Shaalan
PHARM-D
1
Autacoids
•endogenous compounds;
•play an important role
in the physiological and
pathological processes;
• have very short t1/2;
• have local action.
2
1. Monoamines
a) Histamine
The synthesis and breakdown of histamine
3
•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.
4
In mast cells and basophiles histamine
is located in intracellular granules
together with heparin.
Histamine
- distribution
5
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 .
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7
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Histamine Releasers:
1- drugs (mainly alkaloids
atropine, morphine, reserpine,
tubocurarine in high doses)
•release histamine can cause
bronchoconstriction,
hypotension, itching and skin
rash and other unwanted effects.
8
Naja naja
Folia Urticae
(Leaves of Nettle)
9
Spoilt (putrid) fish
contains histidine!
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FISH
•contains potent
allergens: can
be potentially
dangerous.
•remains
allergenic
despite
cooking.
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Physiological antagonists:
*adrenaline, salbutamol,
and others----inhibit histamine
secretion and produce
bronchodilation
(antiasthmatic effect).
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•Histamine Receptors
H1, H2, H3, H4, and H5
•Histamine’s receptors are
G-protein coupled.
13
1-Stimulation of H1-receptors
Pharmacological actions:
1-Contraction of smooth muscles
(bronchi, uterus and GIT).
2- CVS
- Vasodilatation
of BV
􀂄
- Increased capillary permeability
(oedema)
-Tachycardia : Cardiac stimulation -3-Dilatation of cerebral vessels ( headache,
histamine cephalgia)
4-Exocrine glands: stimulates gastric secretion.
-Stimulation of sensory nerve endings (pain &
itching)
5-Skin : Triple response Skin:
A-Reddness (vasodilatation of capillaries)
B-Wheal (oedema)
C-Flare (stimulation of sensory nerve endings).
6-Release of catecholamines from adrenal
medulla so HISTAMINE AGONISTS
For diagnosis of phaeochromocytoma.
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ANTIHISTAMINIC
H1-receptors
(H1-blockers)
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H1-blockers
•Used in treatment of urticaria
and hay fever.
•Some of them (Mepyramine,
promethazine)
have antiemetic effect too.
16
st
1
generation H1-blockers
(with sedative and Atropine-LIKE effects)
Didimetindene Promethazine
Embramine
Cyproheptadine
Chlorpyramine
(H1&5-HT2)
Clemastine (weak sedation)
17
Hydroxyzine
is an H1-blocker with anxiolytic,
antiemetic,antimuscarinic, and spasmolytic
effects. It is effective in pruritus and urticaria.
18
2nd generation H1blockers
(without sedative and Mcholinolytic effects
Astemizole
Cetirizine
Fexofenadine ,
Loratadine
Terfenadine
prolongation of QT interval
and hypokalemia
19
H1-blockers from
…rd…
3
generation
•Desloratadine
(Aerius® – film-tab. 5 mg; t1/2 27 h)
•Levocitirizine
20
Activation of H2-receptors:
•cardiac stimulation
•stimulation of gastric
acid secretion
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Antagonist of H2-receptors
(H2-blockers) – for the treatment
of peptic ulcer:
•Cimetidine (? …)
•Famotidine
•Nizatidine
•Ranitidine
•Roxatidine
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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.
23
Rang et al.
Pharmacology
– 5st Ed. (2003)
b) Serotonin
(5-Hydroxytryptamine: 5-HT)
Indol derivative
24
25
Structures rich in 5-HT
• GIT (chromaffin cells and enteric
neurons)
• platelets
• CNS
26
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
27
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)
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29
5-HT1-receptors:
•5-HT1A - 5-HT1F
•All subtypes occur in CNS
and cause neural inhibition
•Act by inhibiting
adenylate cyclase
30
Buspirone
•anxiolytic agent
•partial agonist of the
5-HT1A-receptors
•used in anxiety
31
5-HT1D-receptors are
found in some blood
vessels
(a. carotis externa et interna,
meningeal vessels). They
produce vasoconstriction.
pathophysiology of migraine
32
Rang et al.
Pharmacology
– 5st Ed. (2003)
Pathogenesis of migraine and drug treatment
33
The agonist of 5-HT1D-receptors
are highly effective, but expensive,
in acute attacks of migraine:
•Naratriptan
•Rizatriptan
•Sumatriptan
•Zolmitriptan
34
Activation of
5-HT2-receptors
•in CNS produces excitement
•in blood vessels - contraction
and platelet aggregation
•act through phospholipase C/
inositol phosphate pathway
35
Antagonists of
5-HT2-receptors are used:
•for prophylaxis of migraine
- cyproheptadine
- iprazochrome
- methysergide
- pizotifen
•as a peripheral vasodilator
- Naftidrofuryl (Dusodril®)
36
Adverse effects
of methysergide:
•retroperitoneal fibrosis
•renal failure
37
SSRIs (selective serotonin
reuptake inhibitors): Fluvoxamine,
Citalopram, Fluoxetine,
Paroxetine,
Sertraline
are used in
humans
to treat:
•chronic anxiety
•Depression, bulimia
38
5-HT3-receptors
•Located in enteric neurons
and in CNS.
•Act by stimulating
adenylate cyclase.
•Effects are excitatory, causing
GI motility and vomiting.
39
Antagonists of 5-HT3receptors are very
powerful antiemetics:
Dolasetron
Granisetron
Ondansetron
Tropisetron
40
Agonists of
5-HT4-receptors
•Tegaserod (Zelmac®) activates 5-HT4-
receptors in the intestine and stimulates
peristalsis and secretion.
Indication: colon irritable syndrome
41
(eicosi = 20)
2. EICOSANOIDS
(20 carbon atoms!)
•prostanoids
- prostaglandins (PGs)
- thromboxanes (Txs)
•leucotrienes (LTs)
•lipoxins
42
•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.
43
Inflammatory stimulus
Phospholipids
Phospholipase A2
Arachidonic acid
5-lipoxygenase
Cyclooxygenase (Cox)
15-lipoxygenase
Leucotrienes
Lipoxins
Endoperoxides
PGs
TxA2
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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
45
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.
46
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
47
PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
Dorland’s Illustrated
Medical Dictionary
(2003, 2004)
are given for:
•induction of labour
•termination of pregnancy
48
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)
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50
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.
51
Arachidonic acid
Cyclooxygenase (Cox)
(-) >1 g/24 h
Aspirin
Endoperoxides
(-) 100 mg/24 h
Thromboxane A2 synthase
PGs
TxA2
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IL®
COX INHIBITORS
NSAIDs
Nonselective
COX-1/COX-2
inhibitors
COX-2
inhibitors
• Selective (coxibs)
•
Preferential
Selective
COX-3
inhibitors
•Antipyretic
analgesics
53
Pfizer
$2.3
billions
penalty
Coxibs are selective COX-2 inhibitors. They exert
anti-inflammatory, analgesic and antipyretic action
with low ulcerogenic potential.
SIDE EFFECTS: Coxibs can cause
infertility. They have prothrombotic cardiovascular
risk.
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Arachidonic acid
5-Lipoxygenase
Leukotrienes (LTs)
LTC4-
LTD4-
LTE4-
receptor
receptor
receptor
(-)
(-)
Montelukast, Zafirlukast
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3. Platelet activating
factor (PAF)
•PLA2 releases PAF in inflammation.
•PAF causes vasodilatation,
increases vascular permeability,
activates platelet aggregation.
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4. Peptides
A-Endothelins: ET-1, ET-2, RT-3
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B-Kinins (kallikrein,
bradykinin
Cholecystokinin (CCK) –
neuripeptide involved in pathogenesis
of panic reactions
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5. Cytokines –
soluble proteins and glycoproteins
that interact with specific cellular
receptors. Cytokines are involved
in inflammatory and immune
response.
59
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.
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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.
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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
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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.
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•Colony-stimulating factors
- Filgrastim, Molgramustim, Lenograstim
•TNF-alpha (alfa)
•TNF-beta
•VEGF
•PDGF,
•TGF, etc.
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ANY QUESTIONS???
THANK YOU
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