Introduction to CNS Pharmacology, with Anatomy and physiology of CNS, mode of neuro-transmission via action potential and role of major neurotransmitter in the brain with drug design pharmacology of CNS drugs.
2. The Nervous System
The Nervous system is the
master controlling and
communicating system of the
body.
The Nervous system controls and
coordinates all essential functions
of the human body.
3. Functions of Nervous System
Sensory Function: Nervous system uses its millions of
sensory receptors to monitor changes occurring both
inside and outside the body. Those changes are called
stimuli and gathered information is called sensory input.
Integrative Function: The Nervous system process and
interprets the sensory input and make decisions about
what should be done at each moment - a process called
integration.
Motor Function: The Nervous system the send signals to
muscle, glands and organs so that they can respond
correctly such as muscular contraction or glandular
secretion.
4. Structural Classification of
the Nervous System
Central Nervous System: consist
of brain and spinal cord, which act
as integrating and command centers
of the nervous system.
Peripheral Nervous System: it is
the part of nervous system outside
the CNS. They link all parts of the
body by carrying impulses from
sensory receptors to CNS and from
the CNS to appropriate glands or
muscles.
5. Central Nervous System
THE BRAIN
Brain is located within the
cranial cavity of the skull
and consists of the
cerebral Hemisphere,
brain stem and
Cerebellum.
6. Cerebral Hemisphere
The two cerebral hemispheres (the left
and the right side) form the largest part
of the brain, called cerebrum.
Its surface called cerebral cortex, is
convoluted and exhibits elevated ridges
called gyri which are separated by
shallow grooves called sulci. It also has
deeper grooves called fissures which
separates large regions of the brain.
7. Each cerebral hemisphere is divided by some fissure
and sulci into number of lobes which are named for the
cranial bones that lie over them.
The cerebral hemisphere are involved in logical
reasoning, moral conduct, sensory interpretation and
initiation of voluntary muscle activity.
8. The outer surface of the cerebrum is called the
cerebral cortex or grey matter. It is the area of the
brain where nerve cells make connections, called
synapses, that control brain activity. The inner area of
the cerebrum contains the insulated (myelinated)
bodies of the nerve cells (axons) that relay
information between the brain and spinal cord. This
inner area is called the white matter because the
insulation around the axons gives it a whitish
appearance.
9. The cerebrum is
further divided into 4
sections called lobes.
These include the
frontal (front), parietal
(top), temporal (side)
and occipital (back)
lobes.
10. Each lobe has different functions:
The frontal lobe controls movement, speech, behaviour,
memory, emotions and intellectual functioning, such as
thought processes, reasoning, problem solving, decision
making and planning.
The parietal lobe controls sensations, such as touch,
pressure, pain and temperature. It also controls spatial
orientation (understanding of size, shape and direction).
The temporal lobe controls hearing, memory and
emotions. The left temporal lobe also controls speech.
The occipital lobe controls vision.
12. Cerebellum
The cerebellum is the next largest part of the brain. It is
located under the cerebrum at the back of the brain. It is
divided into 2 parts or hemispheres and has grey and white
matter, much like the cerebrum.
The cerebellum is responsible for:
Fine coordinated movement
posture
balance
reflexes
complex actions (walking, talking)
collecting sensory information from the body
13. Brain Stem
The brain stem is a bundle of nerve tissue at the base of
the brain. It connects the cerebrum to the spinal cord
and sends messages between different parts of the body
and the brain.
The brain stem has 3 areas:
midbrain
pons
medulla oblongata
14. The brain stem controls:
breathing
body temperature
blood pressure
heart rate
hunger and thirst
Cranial nerves emerge from the brainstem. These
nerves control facial sensation, eye movement, hearing,
swallowing, taste and speech.
15. The Spinal Cord
The spinal cord is a reflex
center and conduction pathway
which is found in the vertebral
canal.
It extends from the foramen
magnum to L1 or L2.
16. 31 pairs of spinal nerves arise along the spinal cord.
These are "mixed" nerves because each contain both
sensory and motor axons.
The spinal cord carries out two main functions:
It connects a large part of the peripheral nervous system
to the brain. Information (nerve impulses) reaching the
spinal cord through sensory neurons are transmitted up
into the brain. Signals arising in the motor areas of the
brain travel back down the cord and leave in the motor
neurons.
The spinal cord also acts as a minor coordinating center
responsible for some simple reflexes.
17.
18. Neurotransmission by Action
Potential
Nerve signals are transmitted by action potentials that
are abrupt, pulse like changes in the membrane potential
that last a few ten thousandths of a second.
Action potential can be divided into 3 phases. Resting,
depolarization and repolarization.
19. Terminology Associated with Changes in
Membrane Potential
Depolarization- a decrease in the potential difference between the inside and
outside of the cell.
Hyperpolarization- an increase in the potential difference between the inside and
outside of the cell.
Repolarization- returning to the RMP from either direction.
20.
21. In the nervous system, different channel types are responsible for
transmitting electrical signals over long and short distances:
K+ slow leaky channels; mechanically operated Na+ channels
Voltage gated Na+ & K+ channels.
A) Graded potentials travel over short distances and are activated
by the opening of mechanically or chemically gated channels.
B) Action potentials travel over long distances and they are
generated by the opening of voltage-gated channels.
Gated Channels Are Involved in
Neuronal Signalling
22.
23. Action Potential Conduction
Movement of the AP along the axon at high speed is called
conduction. A wave of action potentials travel down the axon.
Each section of the axon is experiencing a different phase of the AP
(see figure).
24. Factors Influencing Conduction
Speed of APs
The resistance of the
membrane to current leak
out of the cell and the
diameter of the axon
determine the speed of AP
conduction.
Large diameter axons
provide a low resistance to
current flow within the axon
and this in turn, speeds up
conduction.
Myelin sheath which wraps around vertebrate axons prevents current leak out of
the cells. Acts like an insulator, for example, plastic coating surrounding electric
wires.
However, portions of the axons lack the myelin sheath and these are called
Nodes of Ranvier. High concentration of Na+ channels are found at these nodes.
F8-6
25. Saltatory Conduction
• When depolarization reaches a
node, Na+ enters the axon
through open channels.
• At the nodes, Na+ entry
reinforces the depolarization to
keep the amplitude of the AP
constant, but slows the current
flow due to a loss of charge to
the extracellular fluid.
• However, it speeds up again when the depolarization encounters the next node.
•The apparent leapfrogging of APs from node to node along the axon is called
saltatory conduction.
•Diseases which destroy the myelin sheath (demyelinating disorders) can cause
paralysis or other problems.
26. Synaptic Transmission
Excitatory postsynaptic potentials (EPSP) and Inhibitory
postsynaptic potentials (IPSP) are inputs that
depolarize/hyperpolarize the postsynaptic cell bringing it
closer/away from firing an action potential.
EPSP are caused by opening of channels that are
permeable to Na and K.
Neurotransmitters: Ach, Dopamine, Serotonin
IPSP are caused by opening of Cl channels
Neurotransmitters: GABA and Glycine
27. Neurotransmitters
Acetylcholine
Serotonin
Norepinephrine
Dopamine
GABA
Glutamate
Most drugs that affect the central nervous system (CNS)
act by altering some step in the neurotransmitters
mediating the physiological and pathological responses
in neuropharmacology.
28. Acetylcholine
Myasthenia gravis is characterized by skeletal muscle
weakness and fatigability resulting from a reduced
number of Ach receptors on muscle end plate (due to
autoimmune antibodies against acetylcholine receptors
at neuromuscular junction). Diagnosis and treatment
invloves acetylcholine esterase inhibitors (neostigmine)-
prolong the action of acetylcholine at muscle end plate.
Ach esterase inhibitors (Tacrine)-Alzheimer’s Disease
Anticholinergic (Benztropine) in Parkinson’s Disese
29. Serotonin
Involved in mood, depression and pain regulation.
Activities modified by:
Antidepressants
CNS Stimulants
30. Dopamine
Involved in movement, attention, learning, motivation,
reward
Overactive Dopamine
Schizopherina (Antipsychotics)
Loss of Dopamine
Parkinson Disease (Levodopa)
31. GABA
Main inhibitory neurotransmitter in CNS
Anxiety Disorders (Benzodiazepine)
Huntington’s Chorea that involves loss of neurons that
utilize GABA.
32. Glutamate
High concentrations of glutamate lead to neuronal cell
death by mechanisms that have only recently begun to
be clarified. The cascade of events leading to neuronal
death is thought to be triggered by excessive activation
of NMDA or AMPA/kinase receptors, allowing significant
influx of Ca2+ into neurons. Because of their widespread
distribution in the CNS, glutamate receptors have
become targets for diverse therapeutic interventions. For
example, a role for disordered glutamatergic
transmission in theetiology of chronic neurodegenerative
diseases and in schizophrenia has been postulated.
33. CNS Drug Design
Pharmacology
As is evident from the previous literature, a large number
of agents have been developed to treat neuropsychiatric
diseases. With few exceptions these agents offer
primarily symptomatic improvement; few are truly
disease modifying. For example, the use of L-dopa to
treat Parkinson disease alleviates the symptoms
effectively but the disease continues to progress.
Similarly, although antipsychotics and antidepressants
are often efficacious, the symptoms tend to recur.
Moreover, many drugs developed to treat CNS diseases
are not uniformly effective: Approximately one-third of
patients with severe depression are “treatment-resistant.
34. Furthermore, the complexity of the brain and its neuronal
pathways results in significant risk of side effects, even
when the most biochemically selective agent is
administered. Studies of treatments for neurodegenerative
disease are even more difficult. With current diagnostic
capabilities, it is difficult to detect a significant change in the
rate of progression of cognitive decline in patients with
Alzheimer’s disease in less than a year. One way to
circumvent the long time necessary to detect a biological
meaningful result is through the use of surrogate markers
(e.g., a decrease in serum cholesterol for improved
cardiovascular morbidity and mortality). Regrettably, there
are relatively few useful surrogate markers for CNS
diseases.
35. Impact of Genomics on CNS
Drug Discovery
The sequencing of the human genome has the potential to
significantly change drug discovery in the CNS. Thus,
genetic testing may predict the likelihood that a given
individual will develop a particular disease, will respond
to a particular therapy, or will suffer side effects
from a particular treatment paradigm. Genetic testing
may be particularly important in the case of CNS
diseases, where the etiology is likely to be multigenic.
Molecular approaches will likely speed development of
more and improved animal models that better mimic
humandisease.