This document summarizes several classes of autacoids and their physiological roles and clinical applications. It describes how histamine is stored in mast cells and basophils and released during inflammatory reactions, causing effects via H1-H5 receptors. H1 antagonists are used to treat allergies while H2 antagonists are used for ulcers. Serotonin is found in the GI tract and platelets and acts on multiple receptor subtypes to influence various functions. SSRIs are used as antidepressants by blocking serotonin reuptake. Prostaglandins, thromboxanes, and leukotrienes are derived from arachidonic acid and mediate inflammation. COX inhibitors including NSAIDs and coxibs are used

2. AUTACOIDS
• endogenious compounds;
• play an important role in the physiological and
pathological processes;
• have very short t1/2;
• have local action.

3. 1. Monoamine
 a) Histamine
• Histamine is presented in high concentration in the
skin, and in the mucous layer of the lung and GIT.
• 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 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

6.  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.
 Agents which increase cAMP (adrenaline, salbutamol, and
others) inhibit histamine secretion and produce
bronchodilation (antiasthmatic effect)

7. • Histamine produces effects by acting on H1, H2, H3, H4,
and H5-receptors which are G-protein coupled

8. Stimulation of H1-receptors
• contraction of endothelium
• increasing vascular permeability
• producing type I hypersensitivity reactions (urticaria
and hay fever);
• contraction of smooth muscle of bronchi, GIT, uterus
• excitement of CNS

9. H1-blockers
• Used mainly for the treatment of urticaria and hay fever.
• Some of them (embramine, promethazine) have
antiemetic effect too.

10. a. 1st generation
 have sedative and M-cholinolytic effects
Dimetindene
Embramine
Chloropyramine
promethazine
Cyproheptadine (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

11. b. 2nd generation
 without sedative and M-cholinolytic effects
Cetirizine
Loratadine
Terfenadine
Astemizole
prolongation of QT
interval
and hypokalemia

12. c. 3rd generation
• Desloratadine (Aerius® – film-tab. 5 mg; t1/2 27 h)
• Levocitirizine

13. Activation of H2-receptors
• cardiac stimulation
• stimulation of gastric acid secretion

14. Antagonist of H2-receptors
(H2-blockers)
 for the treatment of peptic ulcer
• Cimetidine
• Famotidine
• Nizatidine
• Ranitidine
• Roxatidine

15. 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.
 Ketotifen -p.o
 Nedocromil – per inh

16. b) Serotonin
 (5-Hydroxytryptamine: 5-HT) Indol derivative
Structures rich in 5-HT
• GIT (chromaffin cells and enteric neurons)
• platelets
• CNS

17. 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

18. 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.

19. 5-HT1D-receptors are found in some blood
vessels They produce vasoconstriction. pathophysiology of migraine
The agonist of 5-HT1D-receptorsare highly
effective, in acute attacks of migraine, but expensive:
• Naratriptan
• Rizatriptan
• Sumatriptan
• Zolmitriptan

20. 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- s/e- retroperitoneal fibrosis renal failure
 - pizotifen
• as a peripheral vasodilator
 - Naftidrofuryl (Dusodril®)

21. SSRIs (selective serotonin
reuptake inhibitors)
 Fluvoxamine, Citalopram, Fluoxetine, Paroxetine,
Sertraline
 are used in humans to treat:
• chronic anxiety
• Depression,
• bulimia

22. Monoamine Reuptake Inhibitors α2-adrenergic
blockers
Enzyme
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

23. 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

24. Agonists of 5-HT4-receptors
• Tegaserod (Zelmac®) activates 5-HT4-receptors
in the intestine and stimulates peristalsis and
secretion.
 Indication: colon irritable syndrome

25. 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

26. Phospholipase A2
Phospholipids
Arachidonic acid
5-lipoxygenase
Leucotrienes
Cyclooxygenase (Cox)
Endoperoxides
PGs TxA2
15-lipoxygenase
Lipoxins
Inflammatory stimulus

27. 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

28.  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.

29. 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 terminationof pregnancy.

30.  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

31. PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
 are given for:
• induction of labour
• termination of pregnancy

32. Main
actions
of the
eicosanoids
Lüllmann, Color Atlas
of Pharmacology –
2nd Ed. (2000)

33. 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)

35. Aspirin-like drugs inhibit mainly COX-1
and can cause peptic ulcer, GI bleeding,
bronchial asthma, and nephrotoxicity.
 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

36. COX-2
inhibitors
• Selective (coxibs)
• Preferential
Selective
COX-3
inhibitors
•Antipyretic
analgesics
Nonselective
(Aspirin-like)
COX-1/COX-2
inhibitors
NSAIDs
COX INHIBITORS

37. Arachidonic acid
5-Lipoxygenase
Leukotrienes (LTs)
LTC4-
receptor
LTD4-
receptor
LTE4-
receptor
Montelukast, Zafirlukast
(-)
(-)

38. Inflammatory stimulus
(+)
Phospholipase A2
Phospholipids
Arachidonic acid
(-)
Lipocortin
Glucocorticoids
(+)

39. 3. Platelet activating factor (PAF)
• PLA2 releases PAF in inflammation.
• PAF causes vasodilatation, increases vascular
permeability, activates platelet aggregation

40. 4. . Peptides
• a) Vasoconstrictors- - angiotensin 2, vassopressin,
endothelins, neuropeptide y
• B) vasodolators – bradykinin, natri-uretic peptides,
vasoactive intestinal peptides, substance p,
neurotensin &calcitonin gene-related peptide (CGRP)
 C) ) Neuripeptide involved in pathogenesis of
panic reactions - Cholecystokinin (CCK)

41. 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.

42. 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.

43.  IL-18:
• enhances 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

44. 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.

45. • Colony-stimulating factors
 (rHuCSFs):
 - Filgrastim, Molgramustim, Lenograstim
 (to treat agronulocytosis and leukopenia
• TNF-alpha (alfa)
• TNF-beta
• VEGF
• PDGF,
• EGF, etc.

46. PDGF EGFR
TNF-beta
(+) (+)
(–)
VEGF
TNF-alfa
(+)
(+)
Thalidomide
Actimide
Revemide (–)
Bevacizumab
(–)
Cetuximab
(–)