Histamine

1. Curative Medical Faculty
Department of Pharmacology
Histamine,Anti-histamine
(Autocoid drugs)
Mohammad Karim Abedy
Master of Pharmacology
M.Pharm, BSc, DIT & DFAS
mail: karimabedy@yahoo.com
BY: MKA
1

2. Autacoids & Autacoids Antagonists
 )Histamine ,prostaglandins & serotonin ‫ها‬ ‫اتاکویید‬
(
 autos(‫)خود‬ & akos(‫)دوا‬
2
 Histamine ,prostaglandins & serotonin are called autacoids.
 Autacoid come from greek: autos(self) & akos(medicinal agent or
remedy).
 They are defined as local hormone i.e. they are released from
tissues upon which they act.
 They differ from hormone in that they are produced by many
tissues rather than specific endocrine glands.
BY: MKA

3. Synthesis, storage & release
 Synthesis: it is synthesized from amino acid histidine.
 ‫ساخت‬
‫کاربوکسیلبشن‬ ‫دی‬ ‫عمل‬ ‫تحت‬ ‫هستیدین‬ ‫اسید‬ ‫امینو‬ ‫از‬
‫میشود‬ ‫ساخته‬ ‫گرفته‬ ‫قرار‬
3
BY: MKA

4. ‫ذخیره‬: In mast cells and basophils, histamine is
complexed in intracellular granules with acidic
protein.
-
‫ها‬ ‫بازوفیل‬ ‫و‬ ‫مست‬ ‫حجرات‬ ‫در‬
‫سازی‬ ‫آزاد‬: it may be primarily in response to
some stimuli as a mediator of inflammation &
allergic reactions.
-
‫زا‬ ‫الرژی‬ ‫مواد‬ ‫مقابل‬ ‫در‬ ‫پاسخ‬ ‫اثر‬ ‫از‬
Stimuli causing histamine release include destruction
of cells as a result of cold, bacterial toxins, bee
sting, venoms or trauma.
4 Synthesis, storage & release
BY: MKA

5. Allergies & anaphylaxis trigger histamine
release.
Its also plays an important physiological
physiological role in
control gastric acid secretion & as
neurotransmitter.
Histamine is metabolised by histaminase
5
BY: MKA

6. Histaminic receptors
‫هستامینک‬ ‫های‬ ‫آخذه‬
.A
Histamine (H1)-receptors
‫های‬ ‫آخذه‬
H1
 H1-receptors are found in the brain, heart, bronchi,
gastrointestinal tract, vascular smooth muscles, and leukocytes
-
‫موقیت‬
 H1-receptors are membrane bound and coupled to G-proteins,
specifically Gq/11, and their activation causes:
-
‫میکانیزیم‬
 increase in phospholipase A2 and D activity
 increases in di acylglycerol and intracellular Ca2+
 increased cyclic guanosine 5′-monophosphate (cGMP)
BY: MKA
6
 Activation of H1-receptors in the brain increases
wakefulness. ‫بیداری‬
 Activation of H1-receptors in vessels causes vasodilation and
an increase in permeability. ‫اوعیه‬ ‫توسع‬

7. .B
Histamine (H2)-receptors
‫ها‬ ‫آخذه‬
H2
 H2-receptors are membrane bound; they are found in the
brain, heart, vascular smooth muscles, leukocytes, and
parietal cells.
-
‫موقیت‬
 The response of H2-receptors is coupled via G αs to
increased cyclic AMP (cAMP) production.
-
‫میکانیزیم‬
 Activation of H2-receptors:
 increases gastric acid production
 causes vasodilation
 generally relaxes smooth muscles.
BY: MKA
7
Histaminic receptors
‫هستامینک‬ ‫های‬ ‫آخذه‬

8. .C
Histamine (H3)-receptors
‫های‬ ‫آخذه‬
H3
 H3-receptors are found in the central nervous system
(CNS) and peripheral nervous system (PNS) at
presynaptic nerve terminals.
-
‫میکانیزیم‬ ‫و‬ ‫موقیت‬
 H3-receptors are membrane bound and coupled to
Gi , their activation increases intracellular Ca2+ and
decreases cAMP.
BY: MKA
8
Histaminic receptors
‫هستامینک‬ ‫های‬ ‫آخذه‬
Stimulation of H3-receptors
 on nerve cells causes a decrease in histamine release
 in the CNS, stimulation of H3 modulates the release of
dopamine, acetylcholine, serotonin, and norepinephrine.
 Activation of H3-receptors on the vagus nerve decreases
acetylcholine (ACh) release.

9. 
Histamine (H4)-receptors
‫های‬ ‫آخذه‬
H4

‫میکانیزیم‬ ‫و‬ ‫موقیت‬
 H4-receptors are found on hematopoietic cells and in
in the spleen, thymus, and colon.
 Stimulation of H4 receptors increases chemotaxis of
mast cells and leukocytes cells toward sites of
inflammation.
 H4 receptors are coupled to Gi/Go and thereby inhibit
the production of cAMP and increase intracellular
Ca2+
BY: MKA
9
Histaminic receptors
‫هستامینک‬ ‫های‬ ‫آخذه‬

10. Type Location Function
H1 histamine receptor
Found on:
• Smooth muscle
• Endothelium
• CNS tissue
Causes:
vasodilation
Bronchoconstriction
bronchial smooth muscle
contraction separation of
endothelial cells (responsible for
hives), and pain and itching due to
insect stings;
the primary receptors involved in
allergic rhinitis symptoms and
motion sickness;
sleep regulation.
BY: MKA
10
H2 histamine receptor Located on parietal cells
Primarily stimulate gastric
acid secretion
H3 histamine receptor
Found on central nervous
system and to a lesser extent
peripheral nervous system
tissue
Decreased neurotransmitter
release: histamine,
acetylcholine, norepinephrine,
H4 histamine receptor
Found primarily in the
basophils and in the bone
marrow. It is also found on
thymus, small intestine,
spleen, and colon.
Plays a role in chemotaxis.

11. Effects of histamine
1.↑production of nasal & mucus secretion (H1)
2. Bronchial smooth muscle (H1) → bronchoconstriction.
3. Sensory nerve endings (H1) →cause itching & pain.
4. Stomach (H2) →↑gastric acid secretion.
5. Heart (H1& H2) →↑rate & force of contraction.
6.Arterioles (H1& H2) →vasodilatation.
7. Capillaries (H1)→ vasodilatation &↑ permeability result in
redness, wheal formation & flare “triple response”.
11
BY: MKA

12. Actions of histamine
12
BY: MKA

13. Anti-histamines

‫هستامینک‬ ‫انتی‬ ‫تعریف‬
:
۱
-
‫جلوگیری‬ ‫آخذه‬ ‫در‬ ‫هستامین‬ ‫شدن‬ ‫وصل‬ ‫از‬
۲
-
‫مست‬ ‫حجرات‬ ‫از‬ ‫هستامین‬ ‫سازی‬ ‫آزاد‬ ‫از‬
They are classified into :
1: H1-blockers
a: Sedative Anti-Histaminic ‫مسکن‬
b: Non Sedative Anti-Histaminic ‫مسکن‬ ‫غیر‬
2- H2-blockers
1: H1-blockers Pharmacokinetics
 Are absorbed from the GIT.
 Can also be given parenterally & topically.
 Most of them appear widely distributed throughout the body, but some
do not penetrate the BBB,
 Are most effective when use prophylactically.
 Most of the them are metabolized extensively in the liver.
13

14. Histamine (H1)-receptor antagonists ‫انتاگونیست‬
‫یک‬ ‫هستامین‬ ‫آخذه‬ ‫ها‬
 Competitive inhibitors.
 Classification:
1. First-generation agents ‫مسکن‬
2. Second-generation agents ‫مسکن‬ ‫غیر‬
BY: MKA
14

15. First-generation agents
 Groups:
1. Alkylamines
2. Ethanolamines
3. Ethylenediamines
4. Piperazines
5. Tricyclics
BY: MKA
15

16. 1. First-generation agents
1.Alkylamines
Alkylamines include
Chlorpheniramine
Brompheniramine
These agents produce slight
sedation.
BY: MKA
16

17. 2. Ethanolamines:Include
diphenhydramine
doxylamine
clemastine
dimenhydrinate
(combination of diphenhydramine and 8-
chlorotheophylline)
Ethanolamines produce marked sedation;
doxylamine is marketed only as a sleeping aid.
Ethanolamines also act as antiemetics.
BY: MKA
17

18. 3. Ethylenediamines Include:
Pyrilamine
antazoline.
Ethylenediamines produce
moderate sedation and can
cause gastrointestinal upset.
BY: MKA
18

19. 4. Piperazines
Include
meclizine
cyclizine.
Piperazines produce marked adverse
gastrointestinal effects and moderate
sedation.
These agents have
A.Anti-emetic
B. Anti-vertigo activities.
BY: MKA
19

20. 5. Phenothiazines
include
promethazine.
Phenothazines produce marked sedation.
These agents have antiemetic activity.
Phenothiazines are also weak
α-adrenoceptor antagonists.
BY: MKA
20

21. 6. Methylpiperidines
include
cyproheptadine.
have antihistamine, anticholinergic, and
antiserotonin activities.
BY: MKA
21

22. 2.Second-generation agents
1.Piperidines
 Loratadine [Claritin]
 Desloratadine [Clarinex]
 Poor CNS penetration: reduced sedation
 Little or no anticholinergic activity
 Desloratadine:
 is the active metabolite of loratadine
 has about 15-fold greater affinity for the H1 receptor than
the parent compound
 Fexophenadine:
 is structurally different than the other piperidine antihistamines,
 sedative activity is low but dose dependent.
BY: MKA
22

23. 2. Clemastine
 is a second-generation ethanolamine
 longer duration of action than dimenhydramine
it has some antiemetic activity.
3. Alkylamines:
A. acrivastine.
 Acrivastine is not associated with cardiac effects.
B. Cetirizine [Zyrtec]
 Cetirizine is not associated with cardiac abnormalities.
 Cetirizine has poor penetration into the CNS.
 Cetirizine is less sedating;
 it is ineffective for motion sickness or antiemesis.
BY: MKA
23

24. Pharmacologic properties
of Histamine (H1)-receptor antagonists
 well absorbed after oral administration.
2nd generation
1st generation
30 min
30 min
Onset
3-24 hours
3-8 hrs
Duration
BY: MKA
24

25. Pharmacologic Actions
 Many H1-receptor antagonists,
especially the ethanolamines, phenothiazines, and
ethylenediamines, have
muscarinic — cholinergic antagonist activity.
 Most of these agents are effective local anesthetics,
probably because of a blockade of sodium channels in
excitable tissues.
 Dimenhydrinate and promethazine are potent local
anesthetics.
BY: MKA
25

26.  H1-receptor antagonists relax histamine-induced
contraction of bronchial smooth muscle and have
some use in allergic bronchospasm.
 These agents block the vasodilator action of
histamine.
 H1-receptor antagonists inhibit histamine-induced
increases in capillary permeability.
 These agents block mucus secretion and sensory nerve
stimulation.
BY: MKA
26

27.  H1-receptor antagonists,
especially the first-generation agents, frequently
cause CNS depression
(marked by sedation, decreased alertness, and
decreased appetite).
BY: MKA
27

28. Therapeutic Uses
1. Treatment of allergic rhinitis and conjunctivitis.
 Clemastine is approved for the treatment of
rhinorrhea.
 Many antihistamines are used to treat the common
cold, based on their anticholinergic properties, but
they are only marginally effective for this use.
 Diphenhydramine also has an antitussive effect not
mediated by H1-receptor antagonism.
BY: MKA
28

29. 2. Treatment of urticaria and atopic dermatitis
3. Sedatives.
Several (doxylamine, diphenhydramine) are marketed
marketed as over-the-counter (OTC) sleep aids.
4. Prevention of motion sickness
5. Appetite suppressants
BY: MKA
29

30. Adverse effects
 (significantly reduced with second-generation agents)
1. CNS effects:Sedation, dizziness, and loss of appetite.
2. These agents can cause gastrointestinal upset, nausea,
and constipation or diarrhea.
3. H1-receptor antagonists produce anticholinergic
effects (dry mouth, blurred vision, and urine
retention).
4. Two second-generation H1 antagonists, astemizole
and terfenadine
(a prodrug of fexofenadine) were discontinued or
removed from the market because they were
associated with ventricular tachycardias.
30

31. BY: MKA
31

32. Histamine (H2)-receptor antagonists
Cimetidine [Tagamet]
Ranitidine [Zantac]
Famotidine [Pepcid AC]
Nizatidine [Axid]
Competitive antagonists at the
H2-receptor,
which predominates in the gastric
parietal cell.
BY: MKA
32

33.  Used in the treatment of:
1. Gastrointestinal disorders, including acid-induced
indigestion.
2. These agents promote the healing of gastric and
duodenal ulcers.
3. Used to treat hypersecretory states such as Zollinger-
Ellison syndrome.
BY: MKA
33

34. Adverse effects
 H2 antagonists are generally well-tolerated, except for
cimetidine where all of the following adverse drug
reactions (ADRs) are common.
 Infrequent ADRs include hypotension.
 Rare ADRs include: headache, tiredness, dizziness,
confusion, diarrhea, constipation, and rash.
 Additionally, cimetidine may also cause gynecomastia
in males, loss of libido, and impotence, which are
reversible upon discontinuation.
BY: MKA
34

35.  Side effects: some adverse effects observed with
first generation antihistamines
35
BY: MKA

36. ‫مندی‬ ‫حوصله‬ ‫و‬ ‫توجه‬ ‫از‬ ‫تشکر‬
‫تان‬
BY: MKA
36