Discussing the psychiatric aspects of histamine as a neurotransmitter

1. HISTAMINE
PRESENTED BY : DR JITHIN M
CHAIRED BY : DR INDU V NAIR

2. General Aspects and History
• Histamine (HA), is a monoamine neurotransmitter promoting
wakefulness in the central nervous system.
• Charles Best and colleagues were the first to isolate histamine in
1927.
• In the early 1900s, histamine’s role in immunomodulation and
smooth muscle relaxation was originally described
• The antihistamines were first discovered by the Swiss-born Italian
pharmacologist Daniel Bovet in 1937
• The first nontoxic histamine-blocking drug, pyrilamine was discovered
in 1944.

3. Localization Within the Central Nervous
System
• The principal storage sites of histamine are basophilic leucocytes and
mast cells, which release histamine as part of their reaction to
allergens.
• Other sources include the epidermis, the intestinal mucosa and the
central nervous system.
• histamine is located not only within neurons, but also in interstitial
cerebral mast cells. It is thought that these cells are involved in the
regulation of vascular permeability

4. • Histaminergic neurons are
predominantly located in the tuberal
area of the posterior hypothalamus,
which is known as the
tuberomammillary nucleus
• From this nucleus, the histaminergic
neurons project diffusely into several
brain areas; and their axonal collaterals
give rise to projections, for example to
the forebrain, the cerebellum and the
mesencephalon.
• Functions closely associated with
histaminergic projections are the
regulation of sleep and arousal, and
control of feeding and appetite

5. Biosynthesis and Degradation

6. • Site 1: Histidine is taken up into
histamine-containing neurons and
converted to histamine by
histidine decarboxylase.
No inhibitors of the histidine
decarboxylase are used clinically.
• Site 2: Histamine is accumulated
in storage vesicles by the action of
VMAT.
Reserpine interferes with vesicular
storage of histamine.

7. • Sites 3 and 4: After release
histamine interacts with
postsynaptic receptors.
• Chlorpheniramine and
diphenhydramine possess H1
antagonist properties and are used
as anti-allergy medications.
• H1 antagonists, such as meclizine
(Bonine) and dimenhydrinate
(Dramamine) have proved useful in
the treatment of motion sickness
and vestibular disturbances.

8. • Site 5: Activation of autoreceptors serves
to regulate subsequent release of
histamine.
• Pitolisant is a selective inverse agonist at
the H3 receptor that increases histamine
release, and is used to treat excessive
diurnal sleepiness. There are no
therapeutic products that act as selective
antagonists for H3 receptors.
• Site 6: There is no recapture of synaptic
histamine, and its actions are terminated
by metabolism by histamine n-
methyltransferase. No selective drugs are
used therapeutically to inhibit this
enzyme.
• The metabolite, n-methylhistamine is a
substrate for MAO.

9. HISTAMINE RECEPTORS
• H1 receptors :
• Antagonists of the H1 receptor are
collectively known as
“antihistamines”
• The H1-receptor is a Gq protein-
coupled receptor that activates the
enzyme phospholipase C (PLC) to
produce the second messengers
diacyl glycerol (DAG) and inositol
trisphosphate (IP3).
• results in wakefulness, normal
alertness, and pro-cognitive actions

10. • When these H1 receptors are blocked in the brain, they interfere with
the wake-promoting actions of histamine, and thus can cause
sedation, drowsiness, or sleep
• H1 receptor-expressing cells have been identified in the pyramidal
layer of the hippocampus and in cerebellar Purkinje cells.

11. H2 receptors
• H2 receptors are located postsynaptically
• Histamine 2 (H2) receptors, best known for their actions in gastric
acid secretion and the target of a number of anti-ulcer drugs, also
exist in the brain
• The function of H2 receptors in brain is still being clarified, but
apparently is not linked directly to wakefulness

12. H3 receptors
• H3 receptors are presynaptic and
function as autoreceptors That is, when
histamine binds to these receptors, it
turns-off further release of histamine
• One novel approach to new wake-
promoting and pro-cognitive drugs is to
block these receptors, thus facilitating
the release of histamine, allowing
histamine to act at H1 receptors to
produce the desired effects
• Several H3 antagonists are in clinical
development

13. • There is a fourth type of histamine receptor, H4, but these are not
known to occur in the brain.
• Finally, histamine acts also at NMDA (N-methyl-d-aspartate) receptors
. Interestingly, when histamine diffuses away from its synapse to a
glutamate synapse containing NMDA receptors, it can act at an
allosteric modulatory site called the polyamine site, to alter the
actions of glutamate at NMDA receptors . The role of histamine and
function of this action are not well clarified

14. BIOLOGICAL EFFECTS
• Histamine in mast cells is a potent inflammatory substance depleted
when an allergen binds to the cell surface, cross-linking specific IgE
molecules.
• This mechanism is also present in the nervous tissue; and it seems
most likely that released intracerebral histamine regulates cerebral
circulation and the permeability of cerebral vessels.
• neuronal histamine plays a role as a neurotransmitter.
• Histamine is a major player in the control of sleep and wakefulness.

15. • Histamine is also involved in the regulation of the energetic balance
of the body, by regulating glycogenolytic functions. The modulation of
neuronal histamine, for instance by blocking H3 receptors, reduces
food intake
• histamine exerts some endocrine functions because it influences the
secretion of hormones from the pituitary. Together with some
prostaglandines, histamine cooperates in the stimulation of ACTH
secretion. Similar interaction may also play a role in the mediation of
the ACTH response to immunochallenges

16. • The histaminergic innervation of the limbic system suggests that
histamine is influential on different behavioral and cognitive functions
and in the generation and maintenance of emotional states.
• A competitive antagonist of the H2 receptors is the drug LSD and
some changes in the behavior induced by LSD might be coupled to
the inactivation of H2 receptors.

17. ANTIHISTAMINES
Antihistamines are classified into six chemical classes:
• Phenothiazines (e.g., promethazine [Phenergan]),
• piperidines (e.g., cyproheptadine [Periactin]),
• ethanolamines (e.g., diphenhydramine),
• piperazines (e.g., hydroxyzine HCI [Atarax]),
• ethylenediamines (e.g., pyrilamine),
• and alkylamines (e.g., chlorpheniramine [Chlor-Trimeton).

18. • first- and second-generation antihistamines, refers to sedating and
nonsedating agents, respectively.
• nonsedating (i.e., they are substrates of P-glycoprotein)
antihistamines with less arrhythmogenic potential (e.g., fexofenadine
[Allegra], loratadine [Claritin], desloratadine [Clarinex], and cetirizine
[Zyrtec]) have been referred to as thirdgeneration antihistamines.

19. • METABOLISM : Most antihistamines are subject to phase I
metabolism via hepatic cytochrome P450 systems.
• antihistamines are neither potent inhibitors nor inducers of the
cytochrome P450 system.
• The H1-antihistamine terminal elimination half life (t1/2β) ranges
from approximately 2 to 27 hours.
• Pediatric populations rapidly metabolize antihistamines; individuals
who are slow metabolizers may exhibit drug accumulation

20. • ELIMINATION Most antihistamines are excreted largely unchanged in
the urine and feces.
• PHARMACODYNAMICS Histamine is a pleiotropic, low–molecular-
weight amine synthesized endogenously in diverse cell types from L-
histidine by the enzyme histidine decarboxylase.

21. THERAPEUTIC INDICATIONS
• Histamine’s critical role in immunomodulation provides the basis for
its clinical application in allergic rhinoconjunctivitis, asthma, urticaria,
and other allergic or immunological disorders.
• H1 antihistamines are widely prescribed in the treatment of insomnia,
analgesia, akathisia, serotonin syndrome, anxiety, motion sickness,
vertigo, antiemetic, and for bruxism.
• histaminergic systems are critical to wakefulness promotion. Doxepin,
a TCA, is FDA approved for the treatment of insomnia. Doxepin’s
principle pharmacodynamic mode of action in insomnia relates to its
potent antihistaminergic effects. Doxepin induce non-REM sleep by
blockade of H1R.

22. • Oral diphenhydramine is efficacious in the treatment of antipsychotic
induced movement disorders
• Diphenhydramine is indicated by the FDA for the treatment of
antipsychotic-induced parkinsonism, allergic and anaphylactic
reactions, as well as motion sickness.
• Diphenhydramine has historically been prescribed as a nonspecific
sedative for children and the elderly. Reports of paradoxical excitation
as well as cognitive impairment (e.g., anticholinergic effect) reduce its
therapeutic index

23. • Hydroxyzine is indicated for the short-term treatment of anxiety and
tension due to psychological factors
• Promethazine is indicated before or after surgery and as an
antiemetic in postoperative patients. Like diphenhydramine, it is also
used for allergic reactions and to treat motion sickness.
• Promethazine is indicated for sedation in both pediatric and adult
populations.

24. • Cyproheptadine is used to reverse antidepressant-associated sexual
dysfunction or stimulant-induced weight loss or insomnia)and for the
symptomatic treatment of schizophrenia, autistic disorders, and
serotonin syndrome
• H2-receptor antagonist use in psychiatric practice has primarily been
for weight loss in overweight individuals and persons experiencing
antipsychotic-associated weight gain.
• Ecological studies suggested that H2-receptor antagonists could
possibly decrease incident Alzheimer disease

25. • Many antipsychotics have H1-receptor antagonistic properties,
especially low-potency traditional antipsychotics and atypical
psychotics of the “pine” group, e.g. clozapine, olanzapine and
quetiapine. Antipsychotics with high affinity for the H1-receptor are
more sedating, which may be beneficial during acute phase
treatment, but can be detrimental for long-term treatment
• Antidepressants of the tricyclic antidepressant (TCAs) and
noradrenergic and specific serotonergic antidepressant (NaSSA) class
have potent H1-receptor blocking properties, making them more
sedating than most other antidepressants.

26. PRECAUTIONS AND ADVERSE EVENTS
• The most common side effect of first-generation H1-antagonist
receptors is CNS depression, manifesting as sedation, somnolence,
cognitive impairment, and reduction in psychomotor activity.
• The co-administration of alcohol, benzodiazepines, or other CNS
depressants may result in additive sedation, requiring dose
adjustment.
• Other reported CNS side effects include cognitive impairment, blurred
vision, nervousness, and tremors. Other non-CNS side effects
associated with antihistamines are dry mouth, increased appetite,
nausea, vomiting, diarrhea, or constipation.

27. • H1-receptor antagonists also have anticholinergic side effects such as
dry mouth and blurred vision and should be used with caution for
individuals with bladder neck obstruction or enlarged prostate

28. THANK YOU