1. AUTACOIDS
(LOCAL HORMONES) PHARMACOLOGY
BY: Dr. Marwa Shaalan
PHARM-D

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

3. 1. Monoamines
a) Histamine
The synthesis and breakdown of histamine 3

4. 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.

5. In mast cells and basophiles histamine
is located in intracellular granules
together with heparin.

6. 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 .

7. 7

8. 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.

9. Folia Urticae
Naja naja
(Leaves of Nettle)

10. Spoilt (putrid) fish contains histidine!

11. FISH contains potent allergens: can be potentially dangerous. remains
allergenic
despite
cooking.

12. Physiological antagonists:
*adrenaline, salbutamol,
and others----inhibit histamine
secretion and produce
bronchodilation
(antiasthmatic effect).

13. Histamine Receptors
H1, H2, H3, H4, and H5
Histamine’s receptors are
G-protein coupled.

14. 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. 􀂄

15. ANTIHISTAMINIC
H1-receptors
(H1-blockers)

16. H1-blockers Used in treatment of urticaria and hay fever.
Some of them (Mepyramine,
promethazine)
have antiemetic effect too.

17. 1st generation H1-blockers
(with sedative and Atropine-LIKE effects)
Didimetindene
Embramine
Chlorpyramine
Promethazine
Cyproheptadine
(H1&5-HT2)
Clemastine (weak sedation)

18. effects. It is effective in pruritus and urticaria.
Hydroxyzine
is an H1-blocker with anxiolytic, antiemetic,antimuscarinic, and spasmolytic
effects. It is effective in pruritus and urticaria.

19. Fexofenadine , Loratadine Cetirizine 2nd generation H1-blockers
(without sedative and M-cholinolytic effects
Astemizole
Fexofenadine ,
Loratadine
Terfenadine
Cetirizine
prolongation of QT interval
and hypokalemia

20. H1-blockers from 3…rd… generation Desloratadine
(Aerius® – film-tab. 5 mg; t1/2 27 h)
Levocitirizine

21. stimulation of gastric acid secretion
Activation of H2-receptors:
cardiac stimulation
stimulation of gastric
acid secretion

22. Antagonist of H2-receptors (H2-blockers) – for the treatment
of peptic ulcer:
Cimetidine (? …)
Famotidine
Nizatidine
Ranitidine
Roxatidine

23. Indications: prophylactic treatment of asthma.
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.

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

26. Structures rich in 5-HT GIT (chromaffin cells and enteric neurons)
platelets
CNS

27. 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

28. 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) 28

29. 29

30. 5-HT1-receptors: 5-HT1A - 5-HT1F All subtypes occur in CNS
and cause neural inhibition
Act by inhibiting
adenylate cyclase

31. Buspirone anxiolytic agent partial agonist of the 5-HT1A-receptors
used in anxiety

32. 5-HT1D-receptors are found in some blood vessels
(a. carotis externa et interna,
meningeal vessels). They
produce vasoconstriction.
pathophysiology of migraine

33. Pathogenesis of migraine and drug treatment
Rang et al.
Pharmacology
– 5st Ed. (2003)
Pathogenesis of migraine and drug treatment

34. The agonist of 5-HT1D-receptors
are highly effective, but expensive,
in acute attacks of migraine:
Naratriptan
Rizatriptan
Sumatriptan
Zolmitriptan

35. Activation of 5-HT2-receptors in CNS produces excitement
in blood vessels - contraction
and platelet aggregation
act through phospholipase C/
inositol phosphate pathway

36. 5-HT2-receptors are used:
Antagonists of
5-HT2-receptors are used:
for prophylaxis of migraine
- cyproheptadine
- iprazochrome
- methysergide
- pizotifen
as a peripheral vasodilator
- Naftidrofuryl (Dusodril®)

37. Adverse effects of methysergide: retroperitoneal fibrosis
renal failure

38. SSRIs (selective serotonin reuptake inhibitors): Fluvoxamine,
Citalopram, Fluoxetine,
Paroxetine,
Sertraline
are used in
humans
to treat:
chronic anxiety
Depression, bulimia 38

39. 5-HT3-receptors Located in enteric neurons and in CNS.
Act by stimulating
adenylate cyclase.
Effects are excitatory, causing
GI motility and vomiting.

40. powerful antiemetics:
Antagonists of 5-HT3-
receptors are very
powerful antiemetics:
Dolasetron
Granisetron
Ondansetron
Tropisetron 40

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

42. (eicosi = 20) 2. EICOSANOIDS (20 carbon atoms!) prostanoids
- prostaglandins (PGs)
- thromboxanes (Txs)
leucotrienes (LTs)
lipoxins
(eicosi = 20)

43. 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

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

45. 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

46. 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.

47. PGE2 causes: PGF2α – main effects: contraction of pregnant uterus
inhibition of gastric acid secretion
contraction of GI smooth muscles
PGF2α – main effects:
contraction of bronchi
contraction of myometrium

48. Dorland’s Illustrated
Medical Dictionary
(2003, 2004)
PGE1 (gemeprost)
PGF2α (dinoprost)
PGE2 (dinoprostone)
are given for:
induction of labour
termination of pregnancy

49. 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)

51. inhibit mainly COX-1 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.

52. Aspirin Arachidonic acid Cyclooxygenase (Cox) (-) >1 g/24 h
Endoperoxides
(-)
100 mg/24 h
Thromboxane A2 synthase
PGs
TxA2

53. COX INHIBITORS NSAIDs Nonselective COX-1/COX-2 inhibitors Selective
IL®
Nonselective
COX-1/COX-2
inhibitors
NSAIDs
Selective
COX-3
inhibitors
Antipyretic
analgesics
COX-2
inhibitors
Selective (coxibs)
Preferential

54. 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.

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

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

57. 4. Peptides
A-Endothelins: ET-1, ET-2, RT-3

58. B-Kinins (kallikrein, Cholecystokinin (CCK) – bradykinin
neuripeptide involved in pathogenesis
of panic reactions

59. 5. Cytokines – soluble proteins and glycoproteins
that interact with specific cellular
receptors. Cytokines are involved
in inflammatory and immune
response.

60. (“as a team”) on: Cytokines act together endothelium, leucocytes,
mastocytes, fibroblasts, stem cells
and osteoclasts.
Cytokines control their proliferation,
differentiation and/or activation by
receptor mechanism.

61. 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.

62. IL-18: IL-23: Upregulated INF production Enhenced NK cell cytotoxicity
Anti-viral activity
Stimulates T-cell, macrophage, and
NK cell activity.
Direct anti-tumor effects
Used therapeuticaly in viral and
autoimmune conditions

63. Interferon alpha-2b (Intron©):
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.

64. Colony-stimulating factors
- Filgrastim, Molgramustim, Lenograstim
TNF-alpha (alfa)
TNF-beta
VEGF
PDGF,
TGF, etc.

65. ANY QUESTIONS???
THANK YOU