1. Autocrine & Paracrine Pharmacology (Part II)
Prof. Alhaider Department of Pharmacology College of Medicine

2. OBJECTIVES At the end of lecture the Students should be able to:
1- Specify storage sites of histamine
2- Explain the synthesis, release & inactivation of histamine
3-List histamine receptors regarding:
Type, major location, major biologic effects
4-Explain the clinical uses of histamine receptors antagonists.

3. Continue
5- Describe the synthesis of Eicosanoids 6- Classify drugs that inhibit synthesis of eicosanoids 7- Enumerate the pharmacological actions of eicosanoids 8-Enumerate the clinical uses of PGs analogs

4. H istamine
Neurotransmitter
Allergic & Inflammatory reactions
Gastric acid secretion

5. Highest amounts in mast cells
Storage Sites
Highest amounts in mast cells
Basophils
Skin
Lung
Intestinal mucosa
Stomach
Brain

6. Biosynthesis

7. Inactivation Histamine Imidazole N-methyltransferase
Methyl histamine (Oxidation)
Methyl imidazole acetic acid
Imidazole N-methyltransferase
Diamine oxidase

8. -ve presynaptic autoregulation
H 1
H 1 +
H 2 +
H 3 +
H 3
-ve presynaptic autoregulation

9. RELEASE
Primary mechanism, during allergic reactions on sensitizing [ IgE antibody interacts with antigen on the surface of mast cells ]
Mast cells are degranulated and release histamine and leads to allergic reactions.
It also has some role in acute inflammation ,on injury it causes local vasodialtion and leakage of plasma, anti bodies and inflammatory cells.
Its release is modulated by binding to H3 presynaptic receptors

10. Continue
Enzymes as trypsin or drugs as morphine or other chemicals can liberate histamine
Tissue injury by trauma or burn

11. acute allergic responses secretion of gastric acid
Histamine receptors
Receptor Type
Major Tissue Locations
Major Biologic Effects H1
smooth muscle, endothelial cells
acute allergic responses H2
gastric parietal cells
secretion of gastric acid H3
central nervous system
neurotransmission H4
mast cells, eosinophils, T cells
regulating immune responses

12. Effects Of Histamine Pain, itching, hives الطفح الجلدي
Hypotension, tachycardia, flushing and bronchoconstriction تحصل في حالات فرط الحساسية
Headache, visual disturbances, increase
skin temperature
Excessive secretion of gastric acids and diarrhea
Bronchoconstriction, dyspnea,

13. Histamine receptors antagonists

14. Physiologic antagonists: Histamine effects can be reduced by physiologic antagonism such as epinephrine which acts on different receptors but produces effects opposite to histamine especially in anaphylaxis. Therefoe, Epinephrine is the drug of choice for Anaphylaxis (فرط الحساسية) Specific receptor blockage: Of Blocking of histamine receptors. But in most of the cases these blockers specific in their binding and blocking activity.

15. First generation H1 receptor Blockers (CNS)
First generation H1 receptor Blockers (CNS). Diphenhydramine , cyclizine , promathazine Second generation H1 receptor blockers (Pero Loratidine Citrizine

16. Has a Sedating effect Clinical uses : Diphenhydramin
(First generation)
H1 antagonists ( Blockers )
Has a Sedating effect
Clinical uses :
Insomnia
Motion sickness
Cold medication
Allergy

17. Loratadine (Second generation)
H1 antagonists
Non-sedating effect
Clinical uses
Allergic conditions as :
allergic rhinitis
Conjunctivitis
Urticaria

18. Inhibitor of gastric acid secretion Used in the treatment of
Cimetidine
H2 antagonists
Inhibitor of gastric acid secretion
Used in the treatment of
peptic ulcers

19. BETAHISTINE
H3 antagonists
Used in treatment of
vertigo in middle ear

20. Eicosanoids

22. INHIBITORS OF EICOSANOIDS

23. Drugs Corticosteroids Zileuton NSAIDs Phospholipids Arachidonic Acid
Phospholipase A2
Arachidonic Acid
Prostaglandins
Thromboxane (TXA2)
Prostacyclin
Cyclooxygenase
Leukotrienes
Lipoxygenase
Corticosteroids
Zileuton
NSAIDs

24. Actions of prostaglandins (Very Important)
Causes vasodilatation of vascular smooth muscle cells
Causes inhibition of platelets aggregation
Sensitize neurons to cause pain
Induce labor
Decrease intraocular pressure
Acts on thermoregulatory center of hypothalamus
Acts on kidney to increase glomerular filtration
Acts on parital cells of stomach to prevent gastric mucosa

25. Comparison in actions between
Prostaglandins
Thromboxane A2

26. Vascular smooth muscles:
Prostaglandins
Thromboxane A2
Potent vasoconstrictor.
Potent vasodilators .

27. Blood: TXA2 inhibit platelet aggregation
a potent inducer of platelet aggregation.
Prostaglandins
inhibit platelet aggregation

28. Inflammation:
Both play important role in inflammatory reactions.

29. Bronchial smooth muscle:
-Prostaglandins ( bronchorelaxation )
-Thromboxane
(bronchoconstriction)

30. Uterine smooth muscle:
Prostaglandins increase uterine contractions → Menstruation/ Dysmenorrhea آلام الطمث/ Labor contractions

31. GIT smooth muscle:
- Prostaglandins
GIT
motility

32. GIT secretions:
Prostaglandins
↓acid secretion
 Mucin secretion

33. Kideny
Prostaglandins increase renal blood
flow and diuresis.

34. Central and peripheral nervous systems
Fever

35. Clinical uses of prostaglandins analogs
( Synthetic prostaglandins )

36. Carboprost
Abortion
Induce abortion in first trimester.

37. Carboprost cont. PGF “less used nowadays “
2) Treatment of postpartum haemorrhage
( vasoconstriction + uterine muscle contraction)

38. Latanoprost (↓ IOP by enhancing outflow of the aqueous humar)
eye drops /in treatment of open angle glaucoma.
(↓ IOP by enhancing outflow of the aqueous humar)

39. Misoprostol
Treatment of Peptic ulcer

40. Prostaglandin Antagonists have very important clinical uses e
Prostaglandin Antagonists have very important clinical uses e.g: NSADS (Aspirin; Paracetamol; Brufen). Also, Leukotriene antagonists have an important value for treating asthma الربو

41. Thank you