pharmacology course

2. Local hormones:
 Some substances which were not neurotransmitters, however
acted briefly and at short range on next target cells.
 Local hormone is simply a chemical messenger that carries
information from one cell to another.

4.  An inflammatory mediator is a messenger that acts on blood
vessels and/or cells to promote an inflammatory response.
 The major cell types that produce mediators of acute
inflammation are platelets, neutrophils, monocytes
/macrophages and mast cells.

5. [1] Histamine
 Histamine is an endogenous compound that is synthesized,
stored, and released primarily by mast cells or basophils.
 It is found in most tissues but is present in high concentrations in
tissues in (lungs, skin and gastrointestinal tract).

6.  Histamine is an important mediator of immediate allergic (such
as urticaria) and inflammatory reactions, although it plays only
a modest role in anaphylaxis.

7. Histamine Release
 Histamine is released from mast cells by exocytosis during
inflammatory or allergic reactions through several mechanisms:
 If mast cell and basophil sensitized by IgE antibodies attached
to their surface membranes, degranulate when exposed to the
appropriate antigen.

8.  Degranulation leads to the simultaneous release of histamine,
adenosine triphosphate (ATP), and other mediators that are
stored together in the granules.

10. Clinical uses:
 It is importance in medicine and pharmacology lies in its
pathophysiological actions, the therapeutic usefulness of drugs
that prevent its release from mast cells, and drugs that block the
receptors that mediate the actions of histamine.

11. Effects of histamine can be reduced by:
Epinephrine, have smooth muscle
actions opposite to those of
histamine, but they act at
different receptors.
Cromolyn and nedocromil reduce
the degranulation of mast cells that
results from immunologic triggering
by antigen-IgE interaction.
Represent a third approach to the
reduction of histamine-mediated
responses

13. Clinical uses:
 H1 blockers have major applications in allergies (allergic rhinitis
and urticaria).
 In bronchial asthma, which involves several mediators, the H1
antagonists are largely ineffective.

14.  Diphenhydramine is used for management of vomiting as well
as anti-motion sickness drugs.

15. Toxicity:
 Several of these effects (sedation, antimuscarinic action) have
been used for therapeutic purposes, especially in over-the-
counter remedies.

16. [2] 5-Hydroxytryptamine (5-HT)
 5-Hydroxytryptamine (5-HT) is an important neurotransmitter in
the brain and periphery and also a local hormone.
 Today, the terms ‘5-HT’ and ‘serotonin’ are used
interchangeably.

17.  Serotonin is clearly involved in psychiatric depression and also
appears to be involved in conditions such as anxiety and
migraine; lack of enough serotonin is thought to play a role in
depression, anxiety, mania and other health conditions.

18. [3] Eicosanoid
 Eicosanoid refers to a group of mediators that are generated
from fatty acid precursors as required, and are not stored
preformed in cells.

19.  They are implicated in the control of many physiological
processes, are among the most important mediators and
modulators of the inflammatory reaction and are a very
significant target for drug action.

20. Biosynthesis
 In mammals, the main eicosanoid precursor is arachidonic acid
(AA), a 20-carbon unsaturated fatty acid containing four
unsaturated double bonds, which is released from phospholipid
by phospholipase (PL) action.

22. [A] Prostanoids
 The prostaglandins, thromboxane, and prostacyclin, collectively
termed the prostanoids, are generated from PGH2 through the
action of downstream isomerases and synthases.
 PGE2, PGI2, PGD2, PGF2α and thromboxane A2 are the most
important products of the COX pathway.

24. [1] COX-1 “PGH synthase-1”
 It is present in most cells as a constitutive enzyme (i.e. it is
always present).
 It produces prostanoids that act mainly as homeostatic
regulators (e.g. regulating gastric acid secretion).

25. [2] COX-2 “PGH synthase-2”
 In contrast, PGH synthase-2 (COX-2) is not normally present (at
least in most tissues ) but it is strongly induced by inflammatory
stimuli and therefore believed to be more relevant as a target
of anti-inflammatory drugs.

26.  Put simply, COX-1 generates prostanoids for “housekeeping”
functions, such as gastric epithelial cytoprotection, whereas
COX-2 is the major source of prostanoids in inflammation and
cancer.

27. Prostanoid Receptors
 There are five main classes of prostanoid receptor, all of which
are typical G protein-coupled receptors.
 They are termed PGD, PGF, PGI, PGE and TXA.

28. Prostanoids exert a variety of effects !!
 PGI2 is synthesized in endothelial and vascular smooth muscle
cells  vasodilatation,  platelet aggregation.
 PGF2α causes uterine contraction as well as  intraocular
pressure, apparently by increasing the outflow of aqueous
humor.

29. Thromboxane
 Thromboxane synthesis occurs primarily in platelets, causing
vasoconstriction, and platelet aggregation.
 The vasoconstriction caused by TxA2 aids in the platelet
aggregation because platelets are close to each other, which
leads to greater clot formation.

30. Role of Prostanoids in Inflammation
 Nonsteroidal anti-inflammatory drugs (NSAIDs; exert their
therapeutic effects through inhibition of the COXs, and
antipyretic actions by inhibiting PGE2 synthesis in the
hypothalamus.

31.  Most older NSAIDs, like ibuprofen non-selectively inhibit both
COX-1 and COX-2, whereas the selective COX-2 inhibitors
(celecoxib) inhibit COX-2
 The anti-inflammatory action of the glucocorticoids is largely the
result of inhibition of induction of cyclooxygenase.

34. Clinical Uses:
 Prostaglandins control many physiological functions, such as acid
secretion and mucus production in the gastrointestinal (GI) tract,
uterine contractions, and renal blood flow.

35. Gynaecological and obstetric:
 Both PGE2 and PGF2α have been used as abortifacients in the
second trimester of pregnancy.
 PGE2 (Dinoprostone) is approved for use for induction of labor.

36.  PGE1 analog misoprostol has been used with the progesterone
antagonist mifepristone as a highly effective and safe
abortifacient combination.

37. Pulmonary hypertension and dialysis
 Prostacyclin (PGI2) is approved for use (as epoprostenol) in
severe pulmonary hypertension and to prevent platelet
aggregation in dialysis machines.

38. Peptic ulcers:
 Misoprostol is approved for the prevention of peptic ulcers in
patients who must take high doses of NSAIDs for arthritis and
who have a history of ulcer associated with NSAID use.

39. Ophthalmology
 Latanoprost, a PGF2α derivative, is used extensively for the
topical treatment of glaucoma.

40. [B] Leukotrienes
 Leukotrienes (leuko- because they are made by white cells, and
-trienes because they contain a conjugated triene system of
double bonds,

41. Lipoxygenase-catalyzed pathways
 The main enzyme in this group is 5-lipoxygenase gives rise to
the leukotrienes and is present in leukocytes and other
inflammatory cells such as mast cells.
 Leukotrienes are potent bronchoconstrictors and are secreted in
asthma and anaphylaxis.

42. Leukotriene Receptors
 The leukotriene (LT) receptors are G protein-coupled receptors
that bind and are activated by the leukotrienes.

43. Role of leukotrienes in Asthma:
 Zafirlukast, and Montelucast are
potent competitive antagonist.
 Zileutin  the production of the
leukotrienes

44. Reference
1. Ritter J, Flower RJ, Henderson G, Loke YK, MacEwan DJ, Rang
HP. Rang and Dale's pharmacology.
2. Katzung BG, Masters SB, Trevor AJ, editors. Basic & clinical
pharmacology.