This power point presentation deals with the different types of neurotransmitters in the CNS and and a breif information about histamine and antihistaminic drugs.

1. PREPARED BY- KESHARI KUMAR SRIWASTAWA
M.PHARM (PHARMACOLOGY) 1ST YEAR

2. NEUROHUMORAL TRANSMISSION IN
CNS

3. WHAT IS THE NERVOUS
SYSTEM ?
The system of the body that deals with
the transmission and conduction of
nerve impulses to and fro between
different parts of the body thereby
coordinating and controlling the
different actions of the body is called
as the nervous sytem.

4. CLASSIFICATION OF THE NERVOUS
SYSTEM

5. What is Neurohumoral Transmission?
It is defined as the transmission of nerve impulses
from a presynaptic neuron to another postsynaptic
neuron by means of humoral agents and these
humoral agents are called as neurotransmitters.
These humoral agents can be:
(i) Biogenic amines
(ii) Amino acids
(iii) Peptides

6. WHAT ARE NEUROTRANSMITTERS?
Neurotransmitters are chemical messengers
that transmit a message from a nerve
cell across the synapse to a target cell. The
target can be another nerve cell, or a muscle
cell, or a gland cell. They are chemicals made
by the nerve cell specifically to transmit the
message.

7. NEUROTRANSMITTERS OF THE CNS
There are three types of neurotransmitters present in the
CNS which are :
1. Inhibitory neurotransmitters :
GABA (Gamma Amino Butyric Acid)
Glycine
Dopamine
2. Excitatotry neurotransmitters :
Glutamate
Aspartate
Histamine
3. Both inhibitory and excitatory eurotransmitters:
Acetylcholine
Noradrenaline
Serotonin (5 –HT)

8. How does neurohumoral transmission
occur?
Neurohumoral transmission in the CNS involves 5
basic steps
1.Biosynthesis of neurotransmitters
2.Storage of neurotransmitters
3.Release of neurotransmitters
4.Interaction of neurotransmitters with specific
receptors
5 Inactivation of the neurotransmitters

10. 1.BIOSYNTHESIS OF
NEUROTRANSMITTERS
• As a rule, the synthesis of small-molecule neurotransmitters
occurs within presynaptic terminals
• The enzymes needed for transmitter synthesis are synthesized
in the neuronal cell body and transported to
the nerve terminal cytoplasm at 0.5–5 millimeters a day by a
mechanism called slow axonal transport.
• The precursor molecules used by these synthetic enzymes are
usually taken into the nerve terminal by transporter proteins
found in the plasma membrane of the terminal.
• The enzymes generate a cytoplasmic pool
of neurotransmitter that must then be loaded into synaptic
vesicles by transport proteins in the vesicular membrane .

12. Schematic diagram of neuron

13. 2. STORAGE OF NEUROTRANMITTERS
Neurotransmitters are stored in synaptic
vesicles, clustered close to the cell
membrane at the axon terminal of the
presynaptic neuron.
The synaptic vesicles are also called as
the neurotrasnmitter vesicles

14. 3. RELEASE OF NEUROTRANSMITTERS
• In response to a threshold action potential or graded
electrical potential, a neurotransmitter is released at
the presynaptic terminal.
• This action potential is of two types:
(i) Inhibitory postsynaptic potential (IPSP) :
This action potential leads to the binding and interaction of an
inhibitory neurotransmitter to the specific receptors on the post
junctional membrane which increases the permeabiloity of the tK+
and Cl- ions
(ii) Excitatory postsynaptic potential (EPSP):
This action potential leads to the binding and interaction of an
excitatory neurotransmitter and increases the permeability of
caations like Na+ ,Ca2+ etc.

17. 4. INTERACTION OF THE NEUROTRANSMITER WITH THE
RECEPTORS
• The released neurotransmitter may then move across the synapse to
be detected by and bind with receptors in the postsynaptic neuron.
• The released neurotransmitters binds with the 2 types of receptors-
1. Ligand gated receptors (LGR)
2. G protein coupled receptor(GPCR)
Depending upon the type of the receptor with which the
neurotransmitter binds they are classifed into 2 types :
(I) Fast neurotranmitters –
Acting on the LGR. eg. Glutamate
(ii) Slow neurotransmitters
Acting on GPCR eg. Histamine
Binding of neurotransmitters may influence the postsynaptic neuron
in either an inhibitory or excitatory way. The binding of
neurotransmitters to receptors in the postsynaptic neuron can trigger
either short term changes, such as changes in the membrane
potential called postsynaptic potentials, or longer term changes by
the activation of signaling cascades.

18. RECEPTOR INTERACTION

19. Name of neurotransmitter Receptor with which it
interacts
Type of receptor
GABA (Gamma aamino
butyric acid)
GABA A
GABA B
LGR
GPCR
GLYCINE Closely related to GABA A
receptors
LGR
DOPAMINE D1 ,D2 ,D3,D4,D5, GPCR
GLUTAMATE
NMDA
AMPA
KAINATE
LGR
ASPARTATE NMDA LGR
ACETYLCHOKINE MUSCARINIC
NICOTINIC
GPCR
LGR
NOR ADRENALINE α1 α2 β1 GPCR
SEROTONIN 5HT1,5HT2,5HT4,5HT5,
5HT6,5HT7
5HT3
GPCR
LGR

20. 5. INACTIVATION OF THE
NEUROTRANSMITTERS
• After a neurotransmitter molecule has been recognized by
a post-synaptic receptor, it is released back into the
synaptic cleft. Once in the synapse, it must be quickly
removed or chemically inactivated in order to prevent
constant stimulation of the post-synaptic cell and an
excessive firing of action potentials.
• Some neurotransmitters are removed from the synaptic
cleft by special transporter proteins on the pre-synaptic
membrane. These transporter proteins carry the
neurotransmitter back into the pre-synaptic cell, where it is
either re-packaged into a vesicle and stored until it is once
again needed to transmit a chemical message, or broken
down by enzymes. Serotonin is one neurotransmitter that
gets recycled in this way.

21. • Not all neurotransmitters are recycled by the
presynaptic cell. Neuropeptide
neurotransmitters merely quickly diffuse away
from the receptors into the surrounding
medium. One important neurotransmitter,
acetylcholine, has a specialized enzyme for
inactivation right in the synaptic cleft called
acetylcholinesterase (AChE. AChE is an
enzyme present at all cholinergic synapses
which serves to inactivate acetylcholine by
hydrolysis.
• The inactivation of the neurotransmitter leads
to the termination of its action

23. Factors regulating neurohumoral
transmission
. Neurohumoral transmission is regulated by several
different factors:
1. the availability and rate-of-synthesis of the
neurotransmitter,
2. The release of that neurotransmitter, the
baseline activity of the postsynaptic cell,
3. The number of available postsynaptic receptors
for the neurotransmitter to bind to,
4. The subsequent removal or deactivation of the
neurotransmitter by enzymes or presynaptic
reuptake.

24. MANIFESTATIONS OF CNS STIMULATION (EXCITATION)
AND DEPRESSION (INHIBITION)
CNS Depression CNS Stimulation
Drowsiness Excitement
Sedation Euphoria
Hypnosis Insomnia
Disorientation Tremor
Confusion Twitching
Unconsciousness Convulsions
Coma Coma
Death Death

25. PHARMACOLOGICAL STUDY OF
HISTAMINE

26. WHAT IS HISTAMINE?
• Histamine is a biosynthetic mono amine which
is also an excitatory neurotranmitter of the
brain,spinal cord and uterus
• Histamine is also an autocoid released mainly
from the granules of the mast cells and
basophils of the leukocytes .
• Histamine is an endogeneous substance of the
body which is involved in the local immune as
well as inflammatory responses of the body
and is a prime mediator of itching.

27. CHEMICAL STRUCTURE OF HISTAMINE

28. SYNTHESIS OF HISTAMINE
1. Histamine is synthesized primarily by mast cells,
basophils, histaminergic neurons in the basal ganglia of
the brain and enterochromaffin-like cells (ECL) in the
stomach.
2. Histamine is produced by the decarboxylation of
the basic amino acid histidine in the presence of
the enzyme histidine decarboxylase
3. It is a hydrophilic vasoactive amine
4. The synthesized histamine are later on
metabolized by the enzyme Histamine N-methyl
transferase and diamine oxidase

30. Factors potentiating histamine
release from mast cells
1. Antigen –antibody reactions
2. Certain foods like fish , crab etc.
3. Bile salts
4. Some basic drugs like morphine,
d-TC,dextran ,hydralazine etc.

31. HOW DOES HISTAMINE ACT?
• Histamine exerts its pharmacological action by
acting upon 4 receptors :
H1 Increases Ca levels Gq
Increases IP3/DAG
H2 Increases CAMP Gs
H3 Decreases CAMP Gi (autoreceptor)
H4 Decreases CAMP GI
All these receptors belong to the category of G protein
coupled receptors (GPCR)

32. Pharmacological Actions of Histamine

33. Antihistaminics or histamine receptor
blockers or histamine receptors antagonists
The drugs which act by competitively blocking the
histaminic receptors and show their pharmacological
actions are called as antihistaminics.
They are H1 Antihistaminics
H2 Antihistaminics
H3 Antihistaminics
H4 Antihistaminics

34. H1 BLOCKERS
OR
H1 ANTIHISTAMINICS
OR
HI RECEPTOR ANTAGONISTS

35. Mechanism of action
Competitively Blocks the H1 receptors.
Examples : Cetrizine
Fexofenadine
Loratidine
Rupatidine
Diphenhydramine
Hydroxyzine

38. 1st generation H1 blockers
Pharmacological actions
• CNS depression which leads to sedation,
drowsiness and pshycomotor impairement
• Antiemetic action
• Local anaesthetic action
• Anti parkinsonism action
• Anticholinergic action
• Antiallergic action

39. 1st generation H1 blockers
Pharmacokinetics
Absorption : Well absorbed orally and parentrally
Distribution: widely distributed throughout the body
Metabolism : Extensively in liver
Elimination: Urine

40. 1st generation H1 blockers
Adverse effects
1. Common side effects- sedation , drowsiness,,lack of
concentration , fatigue,headache, incoordination
2. Gastrointestinal side effects- Nausea,vomitting, loss
of appetite and epigastric disturbances.
3. Anticholinergic side effects : dryness of mouth ,
blurring of vision, constipation and urinary retention
4. Teratogenic side effects_ are observed i some animals
5. Allergic reactions: Rarely observed especially contact
dermatitis on topical applications
6. Terfenadine causes plymorphic ventriculatr
tachycardia.

41. 1ST generation H1 blockers
Uses
1. Allergic diseases
2. Common cold
3. Preanaesthetic medication
4. Antiemetic (eg, Promethazine,
diphenhydramine,dimenhydrinate are used for the prophlaxis of
motion sickness)
5. Parkinsonism ( eg. Promethazine and diphenhydramine are used
for the tratment for the treatment of drug induced
parkinsonism)
6. Cinnarizine , dimenhydrinate, ,meclizine are used to control
vertigo in Meniere’s disease and control other types of vertigo.
7. Sedative and hypnotic
Note
The 1st generation H1 blockers shuold not used in case of truck
driver and people doing operative machinery work

42. 2nd generation H1 blockers
These drugs are highly selective for H1 receptors
and possess the following properties :
(i) Have no anticholinergic effect
(ii) Lack antiemetic effect
(iii) Do not cross BBB hence cause minimal or no drowsiness
(iv) Do not impair psychomotor performance
(v) Not relatively expensive.

43. 2nd generation H1 blockers
Uses
1. Various allergic condtions like rhinits,dermatitis,
conjuctivitis,urticaria,eczema,drug and food allergies.
2. For allergic rhinitis– Fexofenadine,
cetrizine,mezolastine,or rupatidine is used orally.
3. Azelastine is used as nasal spray in allergic rhinitis.
4. For urticaria ,atopic dermatitis,and other skin allergies
fexofenadine,cetrizine, mezolastine,loratidine,and
ebastineare useful.
5. Azelastine and levocetrizine are available as eye drops for
allergic conjuctivitis.

44. H2 BLOCKERS OR H2 ANTIHISTAMINICS
OR H2 RECEPTOR ANTAGONISTS

45. MECHANSM OF ACTION
• Competitively block the H2 receptors in the parietal cells or
oxyntic cells in the stomach.
• Inhibit gastric acid secretion by suppressing the 3 phases of
acid secretion (i.e basal ,cephalic and gastric)
• They are mainly helpful in preventing nocturnal acid secretion.
• They prevent the acid secretion due to the stimulation of
acetychokine , gastrin and food etc.
• Examples : Cimetidine (prototype drug)
Rantiidne
Famotidine (most potent)
Nizatidine (nearly 100% bioavailibility)

46. Adverse effects
1. Antiandrogenic effect (shown by Cimetidine)
2. Gynaecomastia
3. Galactorrhea
4. Impotence
5. Nizatidine shows some adverse effects like
bradycarrdia, lacrimation,salivation and
diarrhoea

47. Uses
1. Gastric and duodonal ulcer
2. NSAID induced ulcer.
3. GERD( Gastroesophageal reflux disorder)
4. Zolinger- Elison syndrome
5. Aspiration pneumonia

48. H3 RECEPTOR BLOCKERS

49. Mechanism of action
Blocks the H3 receptors in brain and promotes the release of
histamine in brain and thereby promotes wakefullness.
Examples: Thioperamide
Pitolisant
Teprolisant
Uses
1. Narcolepsy
2. ADHD (Attention deficit hyperactivity disorrder)
3. Alzheimer’s Disease
4. Schizphrenia

50. H4 RECEPTOR BLOCKERS

51. Mechanism of action
Blocks the H4 RECEPTORS.
Examples JNJ 7777120
VUF-6002
A987306
A943931
Pimozide
Uses.
1.By inhibiting the H4 receptor, asthma and allergy may be
treated.
2.The highly selective histamine H4 antagonist VUF-6002 is
orally active and inhibits the activity of both mast cells and
eosinophils in vivo, and has antiinflammatory and
antihyperalgesic effects.

52. Some important drugs
• Betahistine a histamine analogue is used orally to
treat vertigo in Mennier;s disease.Common side
effects are nausea,vomitting, headaxhe,pruritus.it
should be avoided in patients with asthma and
peptic ulcer.
• Cetrizine is the active metabolite of hydroxyzine.
• Terfenadine is the fastest acting antihistaminic. Its
active metabolite is fexofenadine.
• Asteimazole is the slowest and fongest acting
antihistaminic.
• Asteimazole posseses the maximum topical activity

53. Thank You