This presentation impart a knowledge about Histamine,receptor,and antagonist. Recent advances also mentioned like H3 & H4 receptors role in cognitive impairment etc.

1. Presented by
Moh.Uzair
M.Pharm(Pharmacology) Ist Sem
SPER, Jamia Hamdard New Delhi

2. 1. Histamine 1
2. Biosynthesis of Histamine 2
3. Release of Histamine 3-6
4. Histamine Receptors 7
5. Pharmacological Action 8
6. Drugs acts on H1 Receptor 17
a. First Generation 18
b. Second Generation 19-20
c. Third Generation 21
7. Drugs acts on H2 Receptor 24-33

3. 8. Drugs acts on H3 Receptor & role in Neuro-
- Disease 34-50
a. Schizophrenia
b. Alzheimer Disease
c. Addiction
d. ADHD
9. H4 Receptor 51
10. References 52-53
3

4. Histamine is found in most tissues and
released by mast cells.
 Released during inflammatory or
allergic reaction.
 Synthesized from Histidine.
Act as autacoids means secreted locally
to decrease & increase the activity of
nearby cells.
1

5. 2

6.  The release of histamine from tissues is caused
by the destruction of cells as a result of cold,
bacterial toxins, bee sting venoms, or trauma.
 Allergies, anaphylaxis can also trigger release
of histamine.
3

7.  In mast cells, histamine is stored in granules as
an inactive complex.
 Inactive complex composed of histamine and
the polysulfated anion, heparin,along with
anionic protein.
 Histamine is also known as a neuromodulator,
since it regulates the release of
other neurotransmitter,
like acetylcholine, norepinephrine , and
serotonin.
4

8.  Histamine also has presynaptic receptor(H3)
inhibit the release of histamine.
 Inverse agonist or antagonist of this receptors
may increase histamine leading to wakefulness
and decrease appetite(induces anorexia).
 Pitolisant (tiprolisant) drug approved for
Narcolepsy.
 Ciproxifan drugs antagonist, showing an
exclusively high species-specific affinity at
rodent compared to human H3 receptor.
5

9.  It is well studied as reference compound for H3
receptor in rodent models for neurological
diseases connected with neurotransmitter
dysregulation, e.g. attention deficit
hyperactivity disorder or Alzheimer’s disease.
6

10. 4.Histamine Receptors
H1 H2 H3 H4
Postsynaptic
Gq = ↑Ca++
. BV = Ca ++
dependent NO
release = V.D
. Hypothalamus
Postsynaptic
Gs = ↑CycAmp
. Stomach = ↑Hcl
. Heart
↑Contraction ↑HR
↑Wakeful
ness
↓Appetite
. B.V = V.D
Presynaptic
Gi = ↓CycAmp
↓Histamine
release
H1
H2
↓Effect
Leukocytes
Gi = ↓CycAmp
Chemotaxis
7

11.  Nervous System
 Histamine is a powerful stimulant of sensory nerve
endings may results in pain and pruritis(itching).
 This above results produced by H1 receptor, is
important component of urticarial response to insect
bites and stings.
 Histamine is powerful contractor of visceral smooth
muscles through H1 receptors and results in
bronchoconstriction and abdominal cramps.
8

12.  Glands
 Histamine increases gastric secretion by stimulation
of H2 receptor.
 This action is exerted directly on parietal cells and
mediated by increased cAMP generation and results
in turn activates the membrane proton pump
(H+ , K + ATPase)
9

13.  Autonomic ganglia and adrenal medulla
 These are stimulated and release of Adrenaline occurs,
which can cause a secondary rise in BP.
 CNS
 The histaminergic neurons originate from the
tuberomammillary nucleus ( TMN ) of the posterior
hypothalamus & send projections to most parts of the
brain
 Histamine does not penetrate blood brain barrier- no
central effects are produced on i.v. injection.
 Intracerebroventricular administration produces rise in
BP, cardiac stimulation, behavioral arousal,
hypothermia, vomiting and ADH release
10

14.  The TMN of the
hypothalamus is
the sole source of
histaminergic innervations
of the CNS.
 The most densely
innervated target
of the histaminergic
neurons in the
Hypothalamus.
14

15.  Histaminergic TMN neurons are active during
wakefulness and exert multiple functions.(thus
can be used to treat sleep-wake disorders, like
narcolepsy , via modulation of H3 receptor
function.)
12

16.  Blood vessel
 Histamine causes dilation of small blood vessels and
can results in flushing and hypotension.
 Fall in blood pressure is mediated by both H1 (early;
by release of NO) as well as H2 (delayed and
persistent; direct actions on smooth muscles of
blood vessels) receptors.
 Increases the capillary permeability and results in
exudation of plasma(edema) due to separation
of endothelial cells.
13

17.  Triple response
 Intradermal injection of histamine may results in
1. Red reaction/Flush(due to vasodilation)
2. Wheal/formation of oedematous patch(exudation of fluid
due to increased permeability)
3. Flare/Red irregular surrounding the wheal(spreading
redness due to axon reflex)
 It is primarily an H1 response.
14

18.  Heart/Cardiovascular system
 H1 receptor stimulation has negative dromotropic
(decreased AV conduction) on isolated heart.
 H2 receptor stimulation increases the force of
contraction on isolated heart.
 Effect on intact heart is not prominent means direct
effects of histamine on in situ heart are not
prominent.
15

19.  These drugs act as competitive antagonist.
 Classified into first generation & second
generation compounds on the basis of CNS
penetration and anticholinergic properties.
 First Gen drugs are highly lipid soluble, cross
the BBB and hence cause sedation &
psychomotor impairment.
 C/I in persons requiring constant attention ,
children and elderly(>65 years).
17

20. a. First Generation Drugs
Moderately Sedating Mildly Sedating
Highly Sedating
• Diphendydramine
•Promethazine
•Hydroxyzine
•Doxepine
• Pheniramine
•Cyprohepatadine
•Meclizine
•Cinnarizine
•Chlorpheniramine
•Mepyramine
•Cyclizine
•Clemastine
18

21.  Based On H1 blocking action
 Allergic condition like itching, urticaria, hay fever
etc.
 Insect bite, ivy poisoning and to prevent adverse
effects due to histamine releasers.
 Based On Anticholinergic properties
 Common cold(to control rhinorrhoea)
 Motion sickness(as prophylactic agent)
 Parkinsonism(Promethazine may be used)
 Acute muscular dystonia
19

22.  Other Uses
 Antihistaminics are drug of choice for idiopathic
pruritis.
 Cinnarizine is used in vertigo
20

23.  These drugs are less lipid soluble, don’t cross
BBB and hence are nonsedating.
 Preferred in persons requiring constant
attention. E.g. Truck drivers etc.
 More potent and more efficacious than first
generation.
 Long acting as compared to first generation.
 All second generation antihistaminics are
metabolized to active products except cetrizine
and mezolastine.
21

24. Second generation Drugs
Systemic Topical
•Cetrizine
•Loratadine
•Rupatadine
•Terfenadine
•Astemizole
•Acrivastine
•Azelastine
•Olopatadine
•Ketotifen
•Alcaftadine
•Bepotastatine
•Emedastatin
•Epinastine
•Levocarbastine
22

25.  Some authorities describe the term 3rd
generation antihistaminics which are
derivatives of the second generation.
Examples-
• Levocetrizine
•Desloratadine
•Fexofenadine
23

26.  These drugs competitively inhibit H2 receptors
in parietal cells, thus inhibiting the acid
secretion.
 ACh and gastrin act partly by causing the
release of histamine, therefore acid secreting
capacity of these agents also is decreased by H2
blockers.
 Histamine is primarily responsible for
nocturnal acid secretion, which is inhibited by
H2 blockers.
24

27. 1. Cimetidine
2. Ranitidine
3. Famotidine
4. Roxatidine
5. Nizatidine
6. Loxatidine
These drugs are used for peptic ulcer, Zollinger -
Ellison syndrome and gastro esophageal reflux
disease(GERD).
25

28.  Cimetidine is not used routinely because:
 It can cross blood brain barrier and result in
mental state changes.
 It inhibits binding of dihydrotestosterone to
androgen receptors that can manifest as
impotence in males.
 It inhibits metabolism of estradiol and
increases serum prolactin levels on long term
use, thus can cause gynaecomastia (in males)
and galactorrhoea (in females).
26

29.  It is a potent inhibitor of CYP enzymes and can
increase plasma concentration of warfarin,
theophylline and many other drugs.
 It is the least potent H2 blocker.
 Ranitidine recently banned in India due to
contamination by cancer causing substance
NDMA( N-nitrosodimethylamine).
27

30. 28
The metabolic degradation of
NDMA produces
formaldehyde and methanol,
and the alkylating intermediate
reacts with nucleic acids and
proteins to form methylated
macromolecules called as O6 -
methylguanine as the likely
proximal carcinogenic
agent.
Pathogenesis Of NDMA Induced Hepatic Carcinoma

31.  Methanol and Formeldihyde are highly toxic to liver
and initiates severe inflammation and
confluent hemorrhagic necrosis.
 These processes results in extreme oxidative
stress and production of reactive oxygen
species (ROS) that further contributes to
hepatocyte damage and necrosis.
 Furthermore, NDMA decreases catalase and
glutathione peroxidase, the major antioxidant
enzymes present in the liver.
29

32.  NDMA decreases serum and liver
concentrations of ascorbic acid, another major
antioxidant.
 The persistent treatment of NDMA further
increases oxidative stress and lipid
peroxidation that enhances hemorrhagic
necrosis and collapse of liver parenchyma.
 The extensive panlobular and multilobular
necrosis lead to massive hepatic necrosis,
which in turn initiates mitosis and hepatic
regeneration.
30

33.  On the other hand, the resting HSCs(Hepatic
Stellets Cells) transform into myofibroblast like
cells and start extensive synthesis of connective
tissue proteins.
 This causes deposition of mature collagen
fibrils in the extracellular matrix of the liver
and results in hepatic fibrosis.
 All these processes lead to condensation of
hepatic reticulin framework, production of
granulation tissue, and ultimately scar
formation.
31

34.  The ischemic consequences of the hepatic tissue
and confluent necrosis amplify the process of
nodular regeneration and drive towards to liver
cirrhosis.
 The repeated tissue repair and regeneration
process can lead to aberrations and mutations in
genes and end up in development of HCC(
Hepatocellular carcinoma).
 Alternatively, the methyl carbonium ions
produced during metabolic degradation of NDMA
methylate the hepatocyte DNA that results in gene
mutation and trigger HCC.
32

35. 33
The metabolic activation and
detoxification of NDMA cause
hepatocyte injury, inflammation,
neutrophilic infiltration, and
massive hepatic necrosis, which
results in oxidative stress and
production of reactive oxygen
species. These processes induce
activation of hepatic stellate cells
and increased synthesis of
connective tissue components,
especially collagens that end up
in hepatic fibrosis. The chronic
liver injury and perpetual
fibrosis lead to liver cirrhosis,
which could develop into
hepatocellular carcinoma

36.  Histamine H3 receptor (H3R) antagonists/inverse
agonists have revealed potential to treat diverse
disease states of the central nervous system (CNS)
including Alzheimer’s disease (AD), attention-
deficit hyperactivity syndrome (ADHD),
schizophrenia, obesity, pain, epilepsy, narcolepsy,
substance abuse, etc
34

37.  AD is a chronic and progressive neurodegenerative
brain disease.
 In AD the histamine production is diminished but in
early stage histamine production is paralleled by
build up of neurofibrillary tangles (NFT) in the
Tuberomammillary Neuron.
 A significant loss of large-sized histamine
containing neurons in the rostral TMN was
observed where numerous NFT were found,
indicative of a central histaminergic
dysfunction.
35

38.  Central histaminergic fibres originating from the
TMN in the posterior hypothalamus widely projects
into different brain areas including the cerebral
cortex, thalamus, basal ganglia, amygdala, and
hippocampus, where histamine is crucially
associated with a large number of basic
physiological functions including sensory and motor
functions, cognition, attention, learning, and
memory.
36

39.  Blockade of human H3 autoreceptor by
Thioperamide evokes the increase of the
neuronal histamine release.
 The neurotransmitter modulates cognition
processes via both human H1 and H2 receptors
or via cholinergic and GABAergic interneurons
either directly via excitation of neocortical
pyramidal neurons and thalamic relay neurons
or indirectly via excitation of ascending
cholinergic neurons.

40.  Amyloid plaque, consisting of extracellular deposits
of β-amyloid protein in selective areas of brain such
as cortex, hippocampus, amygdala and subcortical
nuclei etc.
 Neurotoxicity in AD results from excessive
formation of Aβ protein.
 Familial AD(rare) results from mutations in the
genes for amyloid precursor protein(APP) which
causes an increase in Aβ formation.
38

41.  NFT arising from hyperphosphorylation of tau,
a microtubule-associated protein.
 Activation of cellular path- ways that inhibit
tau kinase signaling and subsequent tau hyper-
phosphorylation is considered to be the most
feasible strategy to prevent tau aggregation
and associated pathological effects.
 Suppression of tau protein can also block Aβ-
induced apoptosis there by reducing cognitive
deficits.
39

42.  ADHD is a disorder most prevalent in children
characterized by persistent carelessness,
hyperactivity, and impulsivity.
 In preclinical models, pharmacological
alterations that antagonize the cholinergic
system or enhance the various neurotrans-
mitter systems like DA, orexin, cannabinoids
systems including histamine cause
hyperactivity [an increase in locomotor activity
(LA)] that accompanies various neurological
disorders including ADHD ).
40

43.  Recently, H3R antagonist (carnicine, a stable
analog of the naturally occurring dipeptide
carnosine) attenuated hyperlocomotion in an
ADHD-specific model with neonatal habenula
lesion without having an effect on attention-
deficit.
41

44.  Schizophrenia, a chronic debilitating neurological
syndrome characterized by positive (e.g., hallucination
and delusion), negative (e.g., paucity of emotion and
motivation), and impaired cognitive symptoms.
 Dysregulation in DA and other neurotransmitter
systems are involved in the development of the
disease.
 Current pharmacotherapy for schizophrenia consists of
first generation (FGA) and second generation (SGA)
antipsychotics, which mainly act by DA antagonism in
CNS mediated mainly by DA D2- receptors
42

45.  But also by D3R and/or D4R, serotonin receptor (5-
HTR) subtypes (5-HT2AR/5-HT2CR) and/or via
modulation of the glutamatergic system which may
evoke extrapyramidal (mainly FGAs) and/or serious
metabolic disorders.
 H3R antagonist could be a pervasive therapeutic
strategy owing to its pro-cognitive property.
 Histaminergic innervations into the brain areas
closely associated with the development of
schizophrenia raises the possibility of H3R
antagonists influencing its pathophysiology.
43

46.  H3R antagonists, enjoy the advantage of
enhancing DA release from PFC(Prefrontal
cortex).
 Thus may have a sparing effect on prefrontal
function over strong DA antagonizing
antipsychotics.
 H3R antagonist ciproxifan also reduced LA in
methamphetamine induced chronic
sensitization model.
44

47.  Addiction is a complex condition, a brain
disease that is manifested by compulsive
substance use despite harmful consequence.
 One common mechanism for addiction caused
by various drugs of abuse is thought to be the
activation of brain’s reward circuitry.
 Circuitry pathway is connected to the ventral
tagmental area (VTA) of the midbrain and their
targets in limbic forebrain especially nucleus
accumbens(NAc) where neurons release
Dopamine to make you feel pleasure.
45

48.  However, other neurotransmitter systems
including histamine are known to modulate the
psychotropic effects of rewarding drugs.
 The fact that histamine also modulates
mesolimbic DA transmission suggests that
histaminergic drugs may be tried
therapeutically in drug addiction.
 Nucleus accumbens (NAc) the main region
involved in addiction, receive only weak his-
taminergic innervations, very high densities of
H3Rs which are present here.
46

49.  Striatum contains one of the highest densities
of H3Rs in the brain.
 Mainly, striatal H3Rs are located
postsynaptically in the GABAergic efferent
neurons where they are co-localized with D1
and D2 receptors.
 They are also located presynaptically on
dopaminergic terminals in the striatum where
they have an inhibitory role on DA release.
47

50.  Histamine can also activate mesolimbic
dopaminergic system possibly via presynaptic
H3Rs located on DA terminals or
postsynaptically on GABAergic neurons in
striatum or through H1 Rs located on striatal
cholinergic interneurons.
 Addictive drugs modulate the histamine levels
in the brain.
 For instance, alcohol affects histamine levels in
the brain by modulating histamine synthesis,
release and turnover.
48

51.  Acute injection of cocaine increases histamine
levels and histamine-N-methyl transferase
activity in the striatum and NAc and opioids
(e.g., morphine) increases turnover of neuronal
histamine via opioid receptors.
 On the other hand, histaminergic system can
modulate behavioral effects of various drugs of
abuse including cocaine, amphetamines,
opioids, and alcohol.
 All addictive drugs stimulate LA (psychomotor
stimulant effects).
49

52.  Locomotion activation by
amphetamine/methamphetamine and other
dopaminergic agonists was attenuated by H3R
block- ade by Thioperamide and Ciproxifan.
50

53.  H4 receptor have been shown to play a role
inflammatory conditions by virtue of their
presence on the membrane of eosinophils and
mast cells.
 Although no selective H4 ligand is available.
51

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Laurence L.Brunton by Randal A, Skidgel,
Allen P. The McGraw-Hill Companies, Page
No 912-915.
2. Lippincott’s Illustrated Reviews :
Pharmacology 5th edition, Series Editor
Richard A. Harvey. By Michelle A. Clark.
Wolters Kluwer|Lippincott Williams &
Wilkins, Page No 550-551.
52

55. 3. Joseph George, Mutsumi Tsuchishima
& Mikihiro Tsutsumi(08 Jan 2019). Molecular
mechanisms in the pathogenesis of N-
nitrosodimethylamine induced hepatic
fibrosis. Nature Research (subsidiary
of Springer Nature)
4.https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC5895478/
5. https://www.nature.com/articles/srep40541
6.https://www.sciencedirect.com/topics/psycho
logy/histamine
53

56. 7.https://www.thehindu.com/news/national/dr
ug-regulator-cautions-against-over-the-
counter-use-of-ranitidine/article29511521.ece
8. Divya Vohora* and Malay Bhowmik (23 Oct
2012).
Histamine H3 receptor antagonists/inverse
agonists on cognitive and motor processes
:relevance to Alzheimer’s disease, ADHD,
schizophrenia, and drug abuse. Frontiers in
Systems Neuroscience. Volume 6|Article 72 |
1 . www.frontiersin.org
54

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57