This document discusses histamine, including its sources, functions, receptors, and modulating drugs. Some key points: - Histamine is produced in mast cells and basophils from histidine and stored in granules. It is released during allergic reactions and causes effects via four receptor types (H1-H4). - H1 receptors mediate smooth muscle contraction, vasodilation, increased capillary permeability. H2 receptors stimulate gastric acid secretion. - Antihistamines competitively block H1 receptors, relieving allergy symptoms. First-generation drugs cross the blood-brain barrier, causing sedation as a side effect. - Histamine has roles as a neurotransmitter and

1. HISTAMINE
PHARMACOLOGY

2. To Know
• Source and metabolism of Histamine
• Biological functions of histamine
• Pharmacodynamics of histamine
• Histamine modulating drug (Clinical
Pharmacology)

3. Histos (tissue) amine
• What happens when blunt trauma, heat,
cold or allergens (chemicals) is applied to
the skin?
- Swelling, Hives, redness, itch

4. SOURCE
• when a sensitized animal was injected
with an allergen, the immediate response
was similar to those of poisoning by
histamine
• Postulate: endogenous histamine
contributed to immediate hypersensitivity
reaction.
• Thereafter histamine was isolated from
tissues of liver and lungs
• thereby establishing that it is a naturally

5. • Hence the name histamine from the Greek
name for tissue histos.
• Tissue derived amine
• structure of histamine- a hydrophilic
molecule consisting of an imidazole ring
and an amino group connected by two
methylene groups.
• Hence it is called aminoethylimidazole.

6. Structural formula of histamine

7. • Histamine is widely and evenly distributed
throughout the animal kingdom and is
present in snake venoms, bacteria and
plants.
• Almost all mammalian tissues contain
histamine in varying amounts from less
than 1 to 100 micrograms/g.
• Plasma and other body fluid
concentrations are low, but the CSF
contains significant amount.
.

8. • The mast cell and the basophills are the
predominant storage sites for histamine
The tissue distribution of histamine is
identical to the mast cell distribution
• Skin, Bronchial mucosa, Gut mucosa, and
other mucosal surfaces
• The non-mast cell stores of histamine :
enterochromaffin cells, blood platelets,
neurons of the CNS and cells in rapidly
regenerating tissues
•

9. Synthesis and storage
• formed from the decarboxylation of Histidine by
the enzyme L-Histidine decarboxylase.
• The mast cells and the basophils contain this
enzyme and store the formed histamine in their
secretory granules
• The turn over rate of histamine is slow, thus
when depleted in the granules, it takes weeks
before the concentration can return to normal.

10. • The turn over rate of histamine is slow,
thus when depleted in the granules, it
takes weeks before the concentration can
return to normal.
• The non-mast cell stores of histamine
includes enterochromaffin cells, blood
platelets, neurons of the CNS and cells in
rapidly regenerating tissues

11. metabolism
• Two major pathways for the metabolism of
histamine exist in the body.
• The first and the more important is the ring
methylation of histamine by histamine-N-
methyltransferase to form the N-
methylhistamine.
• This is further oxidized by monoamine
oxidase to N-methylimidazoleacetic acid.

12. • Alternatively, histamine may undergo
oxidative deamination by nonspecific
enzyme deamine oxidase to yield
imidazolacetic acid
• which is then converted to imidaloacetic
acid and a riboside.
• These metabolites are excreted in the
urine

13. Release.
• Histamine can be released from its stores
by three different mechanisms.
- (i) Immunologic release
- (2) Chemical release
- (3 ) Mechanical release

14. Immunologic release
- Most important mechanism of histamine
release by mast cells and basophills.
- Initial exposure to allergen induces –
sensitisation - production of antibodies
which bind to surface IgE of mast cells and
basophills
- On further exposure, allergen binds with
antibodies attached to IgE on the cell
membranes.
- The IgE-antibody-allergen complex
activates the signal transduction system in
the membrane of the sensitized cell.

15. - with the ultimate degranulation of
histamine from its stores.
• Histamine is released with other
inflammatory mediators each contributing
to the allergic response as a whole. during
such allergic reactions.
• The release of histamine only partially
explains the biological effect observed
following immediate hypersensitivity
reactions.

16. Chemical release
• following direct effect of certain agents or
drugs on the mast cells or the basophils.
without prior sensitization of the mast cell.
• intravenous injection of drugs like
tubocurarine, succinylcholine, morphine,
radio-contrast media and certain
carbohydrate expanders, which may lead
to anaphylactic reactions.

17. • Venoms may contain histamine releasing
peptides.
• These peptides activate the secretory
responses by causing a rise in intracellular
calcium ions.
• Some peptides are ionophores and
facilitate entry of calcium ions into the cell
• others act on specific G protein-coupled
receptors to activate various enzymes
which ultimately culminate in the
mobilization of stored calcium and
eventual histamine release.

18. Mechanical release
• cold and nonspecific cell damage e.g.
trauma, scratching may be cause direct
mechanical injury to histamine containing
cells.
• .

19. triggers of histamine release
• Immunologic
- Anaphylactic triggers
- Antigen specific, IgE mediated
- Anaphylactoid triggers
• Chemical
- Organic bases
- Morphine
- Tubocuravine
- Succinylchloride
- Contrast media used in radiography
- Dextran
- Vancomycin (an antibiotic)
- Complement (C5a, C3a)
- Some neuropeptides
- Venom from insects (e.g. mastoparan from wasps)

20. Histamine in disease
• Increased systemic release of histamine is
found in diseases caused by excessive
proliferation of the mast cells e.g.
enterochromaffin cell tumor, carcinoid
tumors, systemic mastoblastosis.
• excessive histamine release : urticaria,
priritus, headaches, weakness,
hypotension, flushing and a variety of
gastrointestinal disorders such as
peptic ulceration, diarrhea

21. Pharmacological effect of
histamine
• Contracts some smooth muscles : bronchi
and gut,
• but markedly relaxes others : blood
capillaries
• Increases capillary permeability.
• potently stimulates gastric secretion.
• stimulation of nerve endings (pain,
itching).
• chemotaxis of inflammatory cells

22. Pharmacodynamics of
Histamine
• four distinct classes (H1,H2,H3,H4) of
receptors
• They are all G protein-coupled receptors
with different pharmacological
characteristics and location in the body

23. The H1 receptor
• couples to Gq and activates the PLC-IP3-
Calcium ion pathway
• Activation of the H1 receptor on the vascular
endothelium stimulates the calcium mobilizing
pathway.
• Results in activation of Calcium-calmodulin-
dependent enzymes (Nitric oxide synthethase)
• Inreases synthesis of nitric oxide (a potent
vasodilator) thereby relaxing the nearby
smooth muscle.
• Stimulation of the same H1 receptor on bronchial
and enteric smooth muscles will mobilize the
calcium but cause contraction of the smooth
muscles.

24. The H2 receptors
• coupled to Gs to activate the adenylyl
cyclase -cyclic AMP-protein- kinase A
pathway.
• Vis H2 receptors, histamine the parietal
cells to increase gastric secretion, pepsin
and intrinsic factor output
• Blockade of this receptor not only
eliminates gastric acid secretion in
response to histamine, but also causes
nearly complete inhibition of responses to
gastric and vagal stimulation

25. The H3, and H4 receptors
• coupled to Gi/ and inhibit the adenylyl
cyclase.
• H3 receptors pre-synaptic auto-receptors
that mediated feedback inhibition of the
release and synthesis of histamine in the
brain.
• The are expressed in white blood cells
where they appear important in
chemotaxis of inflammation.

26. Histamine as a neurotransmitter
• evidence that histamine functions as a
neurotransmitter in the CNS include:
- Histamine, Histidine decarboxylase, and
enzymes of catabolism of histamine are in
the CNS
• Histaminergic neurons are located in the
tuberomamillary nucleus of the
hypothalamus and project to major areas
of the brain.
• Histamine receptors are found in specific
areas of the brain.

27. CNS effects
• Histamine increases wakefulness via H1
receptors, thus probably explaining the
sedative effect of H1 blockers.
• Histamine via H1 receptors inhibits
appetite.
• Histamine has been implicated in
regulation of drinking, temperature,
secretion of ADH, blood pressure,
perception of pain, aggression, mood,
locomotion and other behaviors in mice

28. The Triple Response of Lewis
• When injected intradermally, histamine
elicits characteristic phenomenon first
observed by Lewis (1927).
(i) flush- a localized red spot extending a
few millimeter around the site of injection
that appears within a few seconds after
injection and reaches maximum within a
minute.
- It is caused by the direct vasodilatating
effect of the histamine (H1 receptor-
mediated nitric oxide production).
• .

29. (ii) flare- a brighter red flush or flare
extending beyond the injection spot by
about 1cm developing more slowly,
caused by the histamine-induced
stimulation of the axon reflexes that leads
to reflexive vasodilatation and
(iii) wheal- noticeable in about minutes and
occupies the same area as the original red
spot-flare.
• This reflects the histamine-induced
increase in capillary permeability

30. Histamine shock
• large doses (anaphylaxis) of histamine
causes profound and progressive fall in
blood pressure.
• dilated arterioles and increased capillary
permeability trap large amounts blood
from circulation.
• peripheral tissues suffer from reduced
delivery of arterial blood nutrients and
other consequents of clinical shock.

31. Nerve endings
• Histamine stimulates nerve endings to
generate and modulate sensation.
• Primes the nerve sensation to painful
stimulus
• It acts on nerve endings of the autonomic
system to elicit the flush component of the
triple response.

32. Histamine Receptor Antagonists.
• Some physiological and pathological processes
are mediated by histamine through its receptors.
• several drugs with histamine receptor blocking
capacity (antihistamines) can modulate these
histamine mediated effects for therapeutic
purposes
• Applicable to treat diseases ranging from
common allergy to anaphylaxis, peptic ulcer,
motion sickness etc.
• The pharmacological properties of the individual
groups of the antihistamines are described
below.

33. H1 receptor antagonists
• The drugs in this group are all reversible competitive
inhibitors of the H1 receptors.
• They inhibit most of the H1 receptor mediated effects
they
• -reverse the smooth muscle contraction in the bronchial
tree,
• -reverse vasodilatating effects in the capillaries,
• -block the increased capillary permeability and formation
of edema,
• - block the itching, flare and wheal formation in the skin
and
• - suppress the histamine-evoked salivary, lacrimal and
other exocrine secretions-an anti-muscarinic-like effect.

34. Side effects
• Therapeutic doses of the first generation H1
receptor antagonists is usually accompanied
with central nervous system depression resulting
in diminished alertness, slowed reaction times,
somnolence and even sedation.
• the second generation antihistamines are largely
excluded from the brain due their inability to
cross the blood brain barrier, hence devoid of
the CNS side effects.
• The various H1 receptors antagonist based on
their chemical structures, therapeutic and side
effects are as follows:

35. Dibenzoxepin tricyclics
• Doxepin - a remarkably potent H1 receptor
antagonist with pronounced tendency to
cause sedation and antimuscarinic-like
effect.
• It is also an antidepressant drug hence it is
better tolerated in depressed patient

36. Ethanolamines
• diphenhydramine, clemastine fumarate-
also produce pronounced sedative and
antimuscarinic-like effect.

37. Other groups
• Alkylamines (Chlorpheniramine - piriton)- produce
variable sedative effects
• Piperazines (cyclizine, meclizine, cetirizine)- They are
used in the treatment of motion sicknesss
• Phenothiazines (promethazine-phenergan) it has
additional antiemetic effect.
• Piperidines (cyproheptadine, Terfanadine)
• Unlike first-generation H1-receptor antagonists, the
second-generation compounds (such as astemizole,
cetirizine, loratadine, and terfenadine) do not cross the
blood-brain barrier readily and are thus comparatively
free of central nervous system effects.

38. Therapeutic uses
• Allergic diseases: They are most useful in the
treatment of allergy that present with sumptoms of
rhinitis, urticaria and conjunctivitis.
• Their effect is confined to the suppression of symptoms
attributable to histamine released by the antigen-
antibody reaction.
• In complex allergies like bronchial asthma, histamine
antagonists have limited efficacy due to the involvement
of several other autocoids in the pathophysiology of
bronchial asthma.
• For the same reason, in the treatment of anaphylaxis in
which other autocoids apart from histamine are involved,
the mainstay of therapy is epinephrine; histamine
antagonists have an adjuvant role.

39. • The best anti-allergic results with
antihistamines are obtained in seasonal
rhinitis (hay fever, pollinosis) when
rhinorrhea, sneezing, itching of eyes, nose
and throat are relieved by antihistamines.
• Allergic skin diseases also respond well to
antihistamines. Urticaria, edema and
itching components of some of these
dermatoses respond well to
antihistamines.

40. Motion sickness
• although the mainstay of the treatment of motion
sickness is the muscarinic antagonist,
scopolamine, milder forms of the sickness can
be treated with H1 antihistamines with fewer
side effects.
• Cyclizine, meclizine and promethazine are most
relevant.
• Promethazine has additional antiemetic effect.
• Hence it can be used as an adjuvant to treat
nausea and vomiting subsequent to
chemotherapy or radiotherapy of malignancies..

41. Vestibulopathy (Meniere’s disease)
• It is associated with vertigo, dizziness due
to a disorder of the inner ear (vestibular
system). Antihistamines (meclizine,
cetirizine) are of particular benefit.

42. Local anesthesia
• Block sensitisation effect of histamine on
nerve endings
• May block Na ion channel in excitable
tissues
• May replace conventional LA drugs in
patients sensitive to them

43. Sedation
• The tendency of drugs in this group (the
first generation antihistamines) to cross
the blood brain barrier to cause sedation
has led to their use as hypnotics.
• They are present in various proprietary
remedies for insomnia sold over the
counter.

44. Antiparkinsonism effect
• Diphenhydramine suppress
extrapyramidal (dystonic reaction) side
effects of antipsychotics

45. Side effects/ Toxcity of H1
antagonists
• Antimuscarinic effects toxicity (atropine-
like) -Dry mouth, urinary retention, bluured
vision
• Excitation and convulsion in children
• Postural hypotension

46. Effects of H1 Antagonists
• Sedation (OTC sedatives)
• Antinausea and antiemesis (motion sickness,
pregnancy)
• Antiparkinsonism (Dystonic reactions to
antipsychotics)
• Anticholinergic (allergic rhinorrhea)
• Vasodilation ( alpha adrenergic receptor block-
like effect
• 5HT receptor blocking effect
• Local anesthetic effect

47. Drug-drug interaction
• Ventricular arrhythmias when terfanadine
or astemizole was combined with
macrolides or antifungal drugs or other
inhibitors of CYP3A4
• Combination with CNS depressants
potentiate their effects

48. H2 receptor antagonists
• The H2 receptor antagonists inhibit gastric acid
production by reversibly competing with
histamine for binding to H2 receptors on the
membrane of the parietal cells.
• Presently the drugs in this group available for
clinical use are the cimetidine, ranitidine,
famotidine and nizatidine.
• All but nizatidine have significant first pass effect

49. Pharmacodynamics
• Highly selective to H2 receptors located on
parietal cells.
• Significantly block stimulation of parietal
by histamine released by ECL cells
following vagal of gastrin stimulation –
basal or fasting gastric secretion
• Modestly reduce direct stimulation of
parietal cells by vagal or gastrin
stimulation (meal-induced stimulation)

50. • The major side effect of cimetidine is its
ability to reduce testosterone binding to
the androgen receptor and inhibit a
cytochrome P enzyme responsible for the
hydroxylation of oestriol.
• This results in galactorrhea in women,
gynaecomastia, oligospermia and
impotence in men.

51. Drug interactions
• Cimetidine and Ranitidine interacts with
metabolism of substrate drugs of
cytochrome P450 (2C9, 2D6,3A4)
• Interaction is less for famotidine and
nizatidine
• They inhibit gastric first pass metabolism
of ethanol especially in women

52. H3 receptor and its ligands
• The H3 receptors are localized presynaptically on
histaminergic neurons in the brain as autoreceptors
regulating histamine release from the presynaptic
membrane.
• They are also found on a variety of neurons in the brain
as heteroreceptors including noradrenergic,
serotoninergic, GABAergic and glutamatergic neurons.
• The H3 receptor ligands are still undergoing several
studies in animal models to understand the role of these
receptors in different behaviors.
• They have been found to be beneficial in animal models
of convulsion, learning and memory, state of alertness.
• Their potential therapeutic values are speculated from
the effects observed in animal models.

53. H4 receptor and its ligands
• the H4 receptors are mainly expressed on the
surface of the cells of the hematopoetic system
notably the mast cells, the basophils and
eosinophils where they are thought to mediate
the chemotaxic effect of pro-inflammatory
agents.
• Hence H4 receptors antagonists are promising
new anti-inflammatory drugs which are still at the
early stage of drug development.