Search for notes by fellow students, in your own course and all over the country.
Browse our notes for titles which look like what you need, you can preview any of the notes via a sample of the contents. After you're happy these are the notes you're after simply pop them into your shopping cart.
Title: Pharmacology of the Nervous System
Description: Covers the anatomy, physiology and pharmacology of the nervous system.
Description: Covers the anatomy, physiology and pharmacology of the nervous system.
Document Preview
Extracts from the notes are below, to see the PDF you'll receive please use the links above
Nervous System
1
...
2
...
Our brain weighs 1
...
4kg; we have the biggest brain when compared to the
rest of the body but not the biggest brain
...
Humans do not have the best memory
...
One liter of blood
goes through the brain every minute; humans only have 5 liters of blood in their
body
...
It protects itself, physically by
the cranium, a blood brain barrier and buoyancy, surrounded by spinal fluid, can
absorb physical shock
...
CNS
1
...
For
example; sensory nerves that give information to the brain that gives
information of what is happening out there, that is, vision and sound
...
Autonomic nervous system -‐ has to do with the internal environment, it is
completely involuntary
...
The autonomic nervous system has no conscious control
...
• Parasympathetic nervous system OR craniosacrial system – originates
from the base of the cranium and the sacrum
...
This conserves energy, works opposing the sympathetic,
increasing salivation rate, digestive fluids and decreases heart rate
...
It Is involved in the mobilization of energy in response to
stressful situations such as fight or flight
...
• Enteric nervous system is involved in the innervation of the smooth
muscle of the gut (controls intestinal activity)
...
For example; during exercise (perceived to the body as a stressful situation) one
does not feel hungry since the sympathetic NS is activated to a greater extent
than the parasympathetic NS
...
Afferent neurons relay information from the body to the CNS
...
Efferent neurons transmit information from the CNS to the body
...
Spinal cord – 1 billion neurons
...
It is the only way of communication
...
Its job is to conduct sensory
information from the body to the brain and motor actions from the brain
to the body
...
These are reflex actions, where the
spinal cord reacts without consulting the brain
...
Reflex actions are there fore a purpose, if you are going to grab something
jot the body needs to get rid of it immediately
...
Damage of the medulla, respiration stops, and
blood pressure rises, this leads to death
...
For example; during injury, the spinal cord transmits the sensation of
pain from the site of injury to the brain, where it is perceived
...
2
...
Motor and
sensory neurons from the midbrain and forebrain travel through the
medulla
...
If this region is damaged there is immediate death
...
Barbiturates shut down the medulla
oblongata; these are now used to put animals to sleep
...
Pons – the top part of the medulla
...
The pons contains a billion neurons, each connected to
10,000 to 150,000 other neurons
...
4
...
10,000-‐50,000 neurons are
present
...
Each cell is capable of
communicating with another 100,000 cells at the same time
...
• Fine motor contractions: some movements require fine-‐tuning
...
• Posture
...
5
...
• Eye movements
...
• Alertness
...
Diencephalon – made up of 2 structures:
• Hypothalamus – important in controlling autonomic function (hunger,
thirst, body temperature, sleep, etc
...
• Thalamus: relays information from the spinal cord to the cerebral
cortex, involved in awareness, self0awareness and consciousness
...
Functions of the brain are found from patients having a tumor in this particular
part of the brain, animal experimentation and any particular disease with a
particular condition
...
Cerebral Hemisphere – made up of 4 components
...
The central sulcus is the area, which divides the frontal and
parietal lobes
...
The primary sensory cortex receives connections from
sensory modalities such as the skin receptors
...
Damage in this
area will result in loss of social behavior for example; Alzheimer’s
...
§ Occipital lobe – vision
...
What you see with your eyes we see with the back of our
heads, our eyes are simply organs to which light hits, this
information is sent to the brain, processed and an image can be
seen
...
• Basal ganglia – divided into 3 regions, the caudate nucleus, globus
pallidus and putamen collectively known as the corpus striatum
...
Damage may lead to
Parkinson’s disease of Huntington’s chorea
...
It is involved in the entry and formation of new memories
...
Without the hippocampus you cannot form new memories
...
•
Amygdala – present in the temporal lobe and controls any type of
emotion
...
8
...
Damage to this area results in lack of co-‐ordination
between the 2 sides, one half behaves differently form the other half
...
This information is in turn relayed from the
receptors to the brain to be processed by the somatic NS
...
Neurons (nerve cells) – complex, specialized cells that conduct electricity
...
This leads to diseases that are characterized as
neuro-‐degenerated
...
Glia cells – smaller than neurons but more numerous
...
Do not conduct electricity
...
Tumor cells in the nervous
system mostly originate in glia cells are called gliomas
...
It is
composed of actin, microtubules, neurofilaments, etc
...
There are 4 distinct regions:
1
...
They give rise to branches known as dendrites
...
Dendrites (input) – information from other neurons to this neuron
through the dendrites
...
Axon (output) – information from this neuron is relayed to another
through the axon called the conducting unit of the cell
...
Surrounded by myelin sheath formed by glia cells
...
The gaps between myelin sheath cells are called the nodes of
Ranvier
...
Problems associated with myelin include lack of movement since the
speed of conduction slows down – multiple sclerosis
...
There are 2 types:
• Fast transport: compounds that need urgent transport (200-‐
400mm/day)
• Slow transport: compounds that do not need urgent transport (1-‐
8mm/day)
Neurofilaments if the cytoskeleton is arranged in parallel to one another
...
In Alzheimer’s disease, tau protein is in a hyperpolarized state and hence
become dislodged
...
This results in cell not being able to nourish
itself since passage of compounds from one end of the cell to another is
inhibited
...
Anterograde axonal transport: transport that goes down the neuron
...
There are two principles of conduction through neurons:
1
...
2
...
Neurons do not connect to each other randomly, but they connect at
specific, non-‐random points called synapses
...
Not
commonly found in vertebrate brain, more common in invertebrates
...
They are abundant
in the vertebrate nervous system
...
• Multipolar: large number of dendrites radiating from the cell body and
one axon
...
• Pseudounipolar: can be classified as unipolar but usually classified as
bipolar, commonly found in the spinal cord and are involved in reflex
actions
...
These are not usually polarized
...
Functions:
§ Neuron structure
§ Supportive: nourishment, stepping-‐stone between BBB and neuron
...
For example; if a
person becomes blind, neurons in the visual area will migrate to an area
where they are more needed such as the auditory center
...
§ Scavengers: remove cell debris after cell injury – microglia
...
CNS
Oligodendrocytes
PNS
Schwann Cells
Once the cell dies, a glia cell called astrocyte moves to the site of injury/disease
and fill the void
...
BBB
The blood brain barrier is a highly electro chemical system and must be
protected against the introduction of certain chemicals
...
The endothelial cells of the BBB are tightly packed together in order to regulate
tightly what enters and what leaves unlike the endothelial cells of the rest of the
body which are loosely packed and allow molecules to pass freely
...
It is lipophilic in nature and thus substances have to be lipid soluble
...
Heroin and morphine are very lipophilic, the former (heroin) being more
lipophilic than the latter
...
• Amino acids: mechanism
...
• Small molecules: passively
...
• Charged molecules: cannot pass through
...
Diseases such as bacterial meningitis cause breakdown of the BBB
...
It provides a cushioning effect to protect the brain against physical
trauma, removes debris from the brain and makes the brain weigh less
...
There is an abnormal accumulation of CSF in the ventricles or cavities of the
brain
...
Electrical Impulse
Neurons are polarized cells
...
At rest, the voltage inside is -‐70mV with respect to the outside, this is known as
the resting membrane potential
...
This pump removes Na ions from the inside in exchange for
the entry of K ions from the outside
...
The inside of the cell is negative because more positive ions are being removed
than being added and K ions are permeable and can easily leak out
...
Cocaine and ecstasy give rise to depolarization
...
Action potentials are all or none, if reach they fire full strength if not nothing
happens
...
There are 2 kinds of
post-‐synaptic potentials:
• Excitatory (EPSP): results in a depolarization of the post-‐synaptic cell, thus
increase the chances of producing an action potential
...
• Inhibitory (IPSP): result in a hyperpolarization of the post-‐synaptic cell, thus
decrease the chances of producing an action potential
...
Benzodiazepines and sleep inducers cause an increase in the release of GABA,
hence sedating and calming the individual down
...
They are also summated, the more EPSPs, the
more likely the post-‐synaptic neuron will fire, and the more IPSPs the more
likely the post-‐synaptic neuron will not fire, if there is the same number of EPSPs
and IPSPs they will cancel out each other
...
Action Potential
A rapid response characterized by a sudden reversal of charge, in which the
inside of the neuron becomes positive
...
A post-‐synaptic potential is affected by distance whilst an action potential does
not
...
The depolarization that happens at one channel will
initiate the opening of another channel and so on
...
The new positive charge within the cell causes the opening of K+ channels and
thus K+ rushes out of the cell
...
Depolarization comes to a halt
...
It begins when K
channels start closing
...
Sodium channels are of pharmacological importance
...
Lidocaine, is an anesthetic that
works by doing exactly that
...
Voltage gated ion channels are more specific that ligand gated channels
...
The
latter are more versatile (ligand-‐gated): channels are usually opened/closed by
more than 1 type of ligand
...
Channels must span the entire width of the cell membrane since membranes are
impermeable to polar ions and molecules
...
Ion channels are mainly protein in nature
...
For
example: nicotinic acetylcholine receptor (nAch) is made up of 5 subunits, 2 of
which are exactly the same
...
In old age the γ subunit of the nicotinic receptor is replaced by ε
...
One acetylcholine molecule
(endogenous ligand) or nicotine molecule (exogenous molecule) must bind to
each subunit in order for activation of the receptor to take place
...
Opening of the channel allows positively charged ions to move across it passively
according to their concentration gradient, particularly:
• An influx of Na
• An efflux of K
Drugs act in this same way
...
This
works as follows:
The GABA (Type A) receptor is a protein complex located in the synapses of
neurons
...
A subset of GABA (A)
receptor complexes also contains a single binding site for benzodiazepines
...
This increased conductance decreases the membrane potential of
the neuron (hyperpolarization), resulting in inhibition of neuronal firing
...
Most drugs on the
market bind reversibly to receptors
...
Botox is an injection of Botilium toxin A
...
Its effect lasts 5-‐6 months, until the
receptors replenish themselves
...
GABA (A) receptors contain:
• Ion channels
• 2 binding sites for GABA
• Single binding site for benzodiazepines, promotes binding of GABA,
increase conduction of Cl ions
• Alcohol-‐binding site
Synapses
Neurons communicate via synapses
...
CHEMICAL
ELECTRICAL
Cytoplasmic
Absent
Present
Continuity
Distance of synapse
30-‐50nm
2-‐5nm
(between pre-‐ and
post-‐ membrane)
Presence of ligands
Influenced
Not influenced
(drugs)
Speed of transmission
Fast
Slow
Direction
of
Unidirectional (pre to
Bidirectional
transmission
post only)
Electrical impulses
Gap junctions
...
They
enable communication between one cell and another and form direct
cytoplasmic continuity between one cell and another
...
Chemical impulses
Classified according to the area of the neuron to which they attach
...
Axosomatic synapse: usually produce IPSPs
...
Axodendritic synapse: usually produce EPSPs
...
Axoaxonic synapse: usually modulatory
...
However, the latter still has an important modulatory role
on the action potential
...
This means that IPSPs and EPSPs weaken with distance
...
Indirect effect: neurotransmitter release is at a distance from where receptors
are located
...
These are extremely important for proper brain
function
...
Small neurotransmitters include GABA and acetylcholine
...
Vesicle budding results in their movement down the
axon
...
In Alzheimer’s there is a problem with the microtubules
...
The
enzymes, once synthesized, are packaged into vesicles in the Golgi body and
moved to the pre-‐synaptic terminal via slow axonal transport
...
• The soma – this is because only here is there a mechanism that allows
formation of a peptide bond between different amino acids
...
The number of voltage gated Ca which open depends on the
concentration gradient of Ca ions
...
The process of exocytosis involves the use of SNARE proteins, which may be of 3
types:
1
...
SNAP 25 (Target[T]SNARE)
3
...
A sensor must exist to sense a change in the intracellular concentration of Ca –
this is called synaptotagmin
...
Docking results in opening of the cell membrane to release the neurotransmitter
...
Paralysis occurs if the process of exocytosis is blocked
...
• Tetanus toxin blocks the action of V SNARE protein, thus preventing docking
from occurring and causing paralysis
...
The
more prolonged the action potential, the higher Ca entry rate, the more vesicles
will bind and the more neurotransmitter will be released
...
cAMP) and G-‐
proteins
...
cAMP will activate processes known as cAMP-‐dependent protein
kinase
...
When the protein phosphorylates it will
undergo a conformational change, thus it can open/close a channel
...
It can be present in the
brain: cognitive processing (eg
...
One motor neuron will innervate one muscle fiber
...
Ach diffuses through the cleft until it reaches the motor end plate of the muscle
fiber where it binds to nAch receptors
...
However, the depolarizing effect is enough to cause the opening of Na voltage
gated channels
...
Protein phosphorylation
This can:
• Open a channel
• Modulate effect
• Up regulation or down regulation
This can also be involved in a disease process, for example; tau phosphorylation
...
Consolidation is the process of rehearsal of information to turn short-‐term
memory into long-‐term memory
...
Long-‐term modulatory effect is important in the process of synaptogenesis,
which is the formation of new synapses
...
Example 1: habitual smokers have increased levels of nicotine, leading to and
increase in the nAch receptors in the brain – up regulation of nAch receptors
...
This leads to tolerance – more
receptors need to be filled to have the same effect, meaning more drug must be
administered
...
This however, is a process,
which takes time, and often withdrawal symptoms are encountered, which tend
to have the opposite effects
...
Cholinergic: use Ach as NT
2
...
Serotonergic: use serotonin as NT
4
...
Synthesis of NT in cell body/pre-‐synaptic terminal
2
...
Interaction between NT and its respective receptor
4
...
A substance can only be considered a NT if:
• Synthesized in the neuron
...
• If it is administered exogenously, it must mimic the effect as the
endogenous molecule
...
The nervous system makes use of 2 classes of neurotransmitters:
1
...
Neuropeptides
Acetylcholine
Acetylcholine is a small molecule found in the brain, motor neurons of the spinal
cord, autonomic nervous system, all skeletal nerve junctions and synapses in the
brain, especially around the area known as the nucleus basalis, which feeds
cholinergic projections into the cerebral cortex
...
Acetyl CoA + Choline à Acetylcholine + CoA
Acetyl CoA is formed through the Kreb’s cycle during glucose metabolism
...
The rate-‐limiting step in this reaction is the availability of choline
...
The transport of choline is specific to cholinergic cells only
...
When enzyme
concentrations are low, Ach levels will also be low
...
This is the most efficient enzyme in the human
body: it is capable of breaking down 1000Ach/second
...
This drug does
not pass the blood brain barrier and therefore it never reaches the brain
...
This disease is characterized
by a loss of Ach-‐producing cells in the area of cognitive function, that is, the
hippocampus and cerebral cortex
...
These three drugs bind reversibly to AchR
...
Nowadays they are still used to kill pests
...
Biogenic amines
All the biogenic amines contain an amine group
...
Dopamine
2
...
Adrenaline (epinephrine)
4
...
Histamine
Dopamine, noradrenaline and adrenaline are known as catecholamine because
they contain a catechol and amine group
...
All catecholamines start from tyrosine
...
The enzyme tyrosine hydroxylase catalyzes the conversion of tyrosine to L-‐
dopa
...
L-‐dopa decarboxylase enzyme catalyzes the conversion of L-‐dopa to
dopamine
...
Dopamine β hydroxylase enzyme catalyzes the conversion of dopamine to
noradrenaline
...
The conversion of noradrenaline to adrenaline enquires the enzyme N-‐
methyl transferase and phenylethanolamine
...
Dopaminergic cells (tyrosine hydroxylase and L-‐dopa hydroxylase) only express
the first two enzymes in the cascade
...
Noradrenergic cells (tyrosine hydroxylase, L-‐dopa decarboxylase, and dopamine
B-‐hydroxylase) only adrenergic cells contain the full complement of enzymes
...
It is
rather polar and not lipophilic enough to cross the BBB
...
Parkinson’s), the patient is
administered levodopa instead, which is able to penetrate the BBB and is then
converted to dopamine once it enters the brain
...
Serotonin
Serotonin (or 5-‐hydroxytryptamine) belongs to a group of compounds called
indoles
...
It controls mood, sleep, and appetite
...
In general females have lower
levels of serotonin
...
Synthesis can
only take place in serotonergic cells, since only these will contain the necessary
enzymes from synthesis to take place
...
The latter is important in controlling higher cognitive function such
as sexual behavior
...
The Amino Acid
The amino acids are the most important neurotransmitters
...
The amino acid NTs from part of the cellular component
because they contribute to the metabolic activity of the cell
...
Glutamate
binds to the NMDA receptor
...
It is an excitatory neurotransmitter and therefore causes EPSP
...
A unique drug used in the treatment of Alzheimer’s known as memantine is a
NMDA-‐receptor antagonist and works by blocking glutamate
...
GAD is only expressed in those cells
which produce GABA
...
It is the most important inhibitory NT, it
causes IPSPs at synapses
...
For synthesis, the
neurotransmitters require peptide bonds to be made between two amino acids
...
Once synthesized, neuropeptides are transported to the synaptic area
via slow axomal transport
...
There are over 55 different neuropeptides role, few being insulin, estrogen and
testosterone
...
by axomal transport
...
Slow, unsustained effect
...
May stay in neuron or may diffuse out
into adjacent cells
...
vesicles
...
Methods by which neurotransmitters are removed
1
...
2
...
Re-‐uptake Mechanism
This is most popular method of removal
...
The reuptake mechanism is specific
to the neurotransmitter
...
Soluble Gases
Certain soluble gases are also capable of neurotransmission
...
Nitric acid is involved in many processes, such as the contraction of intestinal
wall and dilating the blood vessels
...
Carbon monoxide in small quantities is important in brain activity, such as cGMP
(cyclic guanosine monophosphate) function, although not much is known about
this
...
Acetylcholine
Acetyl CoA + Choline = Acetylcholine + CoA
Acetylcholine = Acetate + Choline
1
...
2
...
3
...
4
...
Inhibition of the AchE enzyme can occur by certain drugs in order to increase the
Ach concentration
...
• Niostigmine (does not pass the BBB) – it binds with both sites reversibly –
indicated for myasthenia gravis
...
Acetylcholine is constantly being broken down and synthesized in the body
...
A drug called vesamicol has the ability to inhibit the packaging of Ach into
synaptic vesicles
...
This drug is only used experimentally, not clinically
...
This ensures
that Ach will be present when required
...
About 20% of Ach is stored in the axon
...
The two types of Ach stores the synapse:
1
...
Another reserve store vesicles containing Ach that acts as a reserve
(40%)
There are also drugs that inhibit Ach release:
• Alpha-‐bungarotoxin a toxic protein derived from snake venom
...
• Botulin toxin produced by Clostridium botulinum, which is highly toxic
and lethal in very small quantities
...
In humans, most cholinergic innervation occurs in a certain area, called the
nucleus basalis of meynert
...
Acetylcholine Receptors
There are two types:
1
...
2
...
There are various sub-‐types of each receptor
...
Muscarinic Acetylcholine Receptors (mAchRs)
• Receptor subtypes from M1 to M5: M1, M3, M5 M1 like, M2, M4 are M2
like
...
M1 like G-‐Protein are predominantly bound to G proteins of class Gq
which use:
Upregulation of phospholipase C
Inositol triphospholipase and intracellular calcium as a signaling
pathway
...
M2 like receptors act via the Gi type receptor causing:
• A decrease in cAMP in the cell
• Inhibition of voltage gated Ca2+ channels
• Efflux of K+ as a signaling pathway
•
•
M1 receptor
• Location: Neural (CNS: cortex, hippocampus; Ganglia: enteric autonomic),
Gastric (parietal cells)
• Cellular function: depolarization and excitation (slow EPSP)
• Functional Effects: CNS excitation (cognitive functions and memory)
Gastric acid secretion
GI motility
• Agonists: Ach, pilocarpine (partially selective)
• Antagonists: atropine (used to dilate the pupil), pirenzepine (partially
selective)
M2 receptor
• Location: Cardiac (atria, conducting tissue)
Neural (pre-‐synaptic terminals)
• Cellular Effects: Hyperpolarization and inhibition (slow IPSP)
• Functional Effects: Cardiac inhibition
Pre-‐synaptic inhibition
Neural inhibition
• Agonists: Ach, Bethamesol
• Antagonists: atropine gallamine (partially selective)
M3 receptor
• Location: Glandular (exocrine glands, smooth muscle, vasicular
endothelium)
• Cellular function: Secretion
Smooth muscle contraction
Vasodilation
• Agonists: Ach
• Antagonists: atropine, HHSD (hexahydrosiladifenol)
M4 receptor
• Location: mainly in the brain
• Agonists: Ach, muscarin
• Antagonists: atropine, hyoscine
M5 receptor
• Not well known
The non-‐selective antagonists are known to cause adverse effects such as dry
mouth and blurred vision
...
• Inotropic, therefore fast synaptic events
• Bring about depolarization
• Allow the passage of Na+, K+ and Ca2+ ions
• Occur along the entire width of the cell membrane
How is muscle contraction brought about?
This is done by the release of Ach into the synaptic cleft
...
The binding of Ach to these receptors alone is not enough for
the end plate to reach threshold
...
Na+ enter the cell, producing significant
depolarization to result in an end plate, which will in turn lead to muscle
contraction
...
Alpha and beta can only be of one variant
...
Alpha
can be of 8/9 different variants (alpha 8 has only been found in chickens) while
beta can be of 3 different types
...
•
Homomeric: composed of one same subunit (can function on its own)
The general mechanism of action of the nAchR is the same: two Ach molecules
bind to two alpha subunits in the receptor, the channel opens up and Ca= ions
are able to pass through
...
Agonists and Antagonist:
• All nicotine receptors bind both Ach and nicotine as agonists
...
• Mecamylamine is an example of an antagonist for neuronal alpha4beta2
(everywhere in the brain but mostly in the mesolimbic dopaminergic
pathway – it is the receptor that causes addiction) and alpha 7 receptors
(concentrated in hippocampus)
...
Long-‐term
heavy smokers build up a dopamine reserve, thus are less likely to suffer from
Parkinson’s disease
...
The disease results in no cognitive function and decreased memory
...
Myasthenia gravis is an autoimmune disease which the body produces
antibodies against nAchRs
...
In this case AchEI
are used to increase the amount of Ach
...
It increases the Ach and
GABA inside the brain
...
Almost always
dementia is developed by time
...
It is most common in people over
55 years
...
Ach is implicated in memory function, therefore if one damages cholinergic
neurons, one might get memory impairment
...
GABA (gamma-‐aminobutyric acid)
GABA is the most important inhibitory neurotransmitter in the mammalian CNS
...
It may be
excitatory in some insects
...
It is
widely distributed in the brain and also in the PNS
...
The enzyme, which catalyzes
the reaction, is called glutamic acid decarboxylase (GAD)
...
In absence of the co-‐factor the GAD will not function
...
However it is very unlikely to have this deficiency since Vitamin B6 is
found in many foodstuffs
...
Once GABA is synthesized it is transported into the vesicles via transporter
mechanisms
...
It is then destroyed in the
mitochondria of neurons or glia cells via the action of enzyme-‐GABA-‐
Transaminase (GABA-‐T)
...
Step 2 involves the conversion of NAD to NADH+
...
Those that block pyroxidal-‐5-‐phosphate, and therefore block the activity
of GAD
...
For example; isoniazid
...
Those that directly compete with glutamate for the GAD enzymatic site
...
For example; allylglycine
...
These are drugs that are used in epilepsy to lower glutamate
concentrations and reduce the incidence of seizures such as;
• Gamma-‐vinyl GABA
• Sodium valproate – also used in mania
There are those, which inhibit the re-‐uptake of GABA, they also increase the
GABA concentration in the synaptic cleft and is therefore useful in controlling
epilepsy and seizures
...
GABA receptors
Two main GABA receptors:
• GABA (a) – ionotropic
• GABA (b) – metabotropic
GABA ( c ) also exists but is only present in the retina, it is shown to be very
similar to GABA (a), they are both ionotropic and have similar structures
...
It gates a chloride channel
...
Chloride ions will enter the intracellular space, bringing about a
hyperpolarization
...
It’s a multi-‐complex channel, other than the GABA site there are other sites,
which include:
• Benzodiazepine site
• Barbiturate site
• Anesthetic site
• Picrotoxin site
• Neurosteroid site
• Alcohol site
Binding a particular ligand with its receptor site changes the conformation in
such a way that it will hate the channel
...
• THIP
• Isoguvacine
• Gaboxadol
Antagonists include:
• Bicuculline (competitive)
• Picrotoxin (non-‐competitive)
GABA receptor sub-‐types:
• Made up of 3 subunits: alpha, beta and gamma
...
• All 5 subunits are arranged to surround a central Cl-‐ channel
...
• Benzodiazepine binding sites are found at either alpha –gamma or beta-‐
gamma interface
...
Activation of the GABA (b) results in inhibition of
secondary messenger systems, hence leading to a decrease in cAMP
...
The changing K+
concentrations hyperpolarize the cell at the end of an action potential
...
These receptors are completely distinct from the GABA (a), they do not share the
same agonists and antagonists
...
Benzodiazepine site
Benzodiazepines are CNS depressants and have various uses, such as muscle
relaxants, sedatives/hypnotics and anxiolytics
...
Although it is an old drug, it is still
commonly used
...
There are about 55 different benzodiazepines
...
One important feature
characteristic of benzodiazepines is that they are allosteric modulators; this
means that alone benzodiazepines have no direct effect o the Cl-‐ channel
...
They do this by increasing the
frequency of channel opening, resulting in more Cl-‐ ions entering the cell per
time, thus, a greater hyperpolarization and inhibitory effect
...
They also have the potential for dependence
...
They aid in sleep, and
whens topped suddenly they suffer from rebound insomnia
...
The normal dose of diazepam is 5mg and the lethal dose is
2g
...
The patient feels a
sense of well being and euphoria
...
Diazepam acts on both with equal efficacy
...
Barbiturate site
These were the drugs of choice before benzodiazepines
...
They act on the GABA (a)
receptor and facilitate the action of GABA like benzodiazepines
...
Barbiturates do not require the presence of GABA to cause opening of the Cl-‐ ion
channels, they open directly
...
Drowsiness -‐> Sleep -‐> Reversible Coma -‐> Irreversible Coma -‐> Death
For example, after a high consumption of alcohol, one will move through the
spectrum until sleep
...
Picrotoxin Site (Inhibitory)
Binding of picrotoxin to its site at the GABA receptor leads to closing the Cl-‐
channels; hence prevent hyperpolarization of the cell
...
Neurosteroid site
Steroids do not only affect the body but can also affect the brain
...
Like barbiturates they directly affect the opening of the channel by increasing its
opening time, hence increasing the entry of Cl-‐ ions and causing a greater
polarization
...
Glutamate
Glutamate is the most important excitatory NT in the brain
...
It is present in high quantities almost
everywhere inside the brain
...
Synthesis, Removal and breakdown
It is synthesized in both neurons and glia cells by 2 main pathways:
• In neurons: it is synthesized from alpha-‐ketoglutarate by the action of the
enzyme alpha-‐ketoglutarate transferase
...
• In glia cells (astrocytes): glutamate is specifically synthesized from
glutamine by the action of an enzyme called glutaminase
...
Once synthesized, it is transported into vesicles and released by exocytosis
...
Once inside, the breakdown of glutamate
occurs in 2 ways, which are the reverse production mechanism:
• Glutamate -‐> alpha-‐ketoglutarate by the enzyme glutamic dehydrogenase
...
Glutamate receptors
4 different types of receptors:
1
...
Alpha-‐amino-‐3-‐hydroxyl-‐5-‐methyl-‐4isoxazole-‐propionate (AMPA)
3
...
Metabotropic Glutamate Receptor (secondary messenger linked receptor)
The former 3 are ionotropic
...
However, only NMDA receptor also allows the passage
of Ca++ ions
...
They give hallucinations and are more often used recreationally producing the
same effects as LSD
...
At rest, the channel of this receptor is open but is blocked by extracellular Mg++
ions
...
If and only when these ligands bind together,
then they will be able to expel the Mg++ ion that is the blocking agent to the
outside
...
If enough ions pass through, depolarization of the neurons occurs, give rise to
EPSP
...
It is both ligand-‐gated and voltage dependent
...
It requires co-‐activation by two ligands (glutamate and glycine)
The NMDA receptor is very important in memory function and is involved in long
term potentiation, a process that occurs in the hippocampus and is in an NMDA-‐
dependent process
...
Initiation and maintenance of epileptic fits (convulsions)
...
2
...
This causes Alzheimer’s disease
...
Memantine is a partial NMDA antagonist
...
Glycine
Glycine is an inhibitory NT in the CNS, mainly found in the spinal cord, brainstem
and retina
...
An enzyme called serine hydroxymethyl transferase catalyzes this reaction
...
Once synthesized, glycine is stored in vesicles and released by exocytosis
...
When glycine receptors are activated Cl-‐ ions enter the neuron via
ionotropic receptors, causing hyperpolarization and IPSPs
...
The main antagonists at this receptor are strychnine and bicuculline
...
Serotonin
Serotonin is also known as 5-‐hydroxytryptamine
...
It is derived from tryptophan, serotonin is primarily foynd in
the GI tract, platelets, and in the central nervous system (limbic area, mort
importantly the amygdala)
...
Only 1-‐2% of total serotonin is produced in sertonergic cells located in the brain
...
Physiological
• Mood
• Anxiety
• Aggression
• Attention
• Cognition
• Suicidal tendency
2
...
Psychiatric Disorders
• Depression
• Autism
• Alcoholism
• Schizophrenia
•
Anxiety
90% of the human serotonin is located in the enterocchromaffin cells in the gut
where it is used to regulate the intestinal movements
...
In fact, low CNS serotonin
levels primarily characterize depression
...
Tryptophan does not enter the brain directly but it enters via the LNAA
transporter
...
This process occurs by a
short metabolic pathway consisting of two enzymes: tryptophan hydroxylase
(TPH) and 5-‐HTP decarboxylase
...
TPH has
been shown to exist in two forms: TPH1, found in several tissues and TPH2,
which is a brain specific isoform
...
Thus, it decreases the levels of serotonin
...
It treats delirium
...
It
is found in foods such as turkey, cheddar, eggs, yogurts, nuts and fish
...
Selective serotonin Reuptake Inhibitors (SSRIs) are the gold standard
antidepressant drugs, indicated in first line treatment for depression
...
Thus,
more serotonin will remain in the synaptic cleft and exert its effects on
receptors
...
These too block the
reuptake mechanism
...
These side effects are not associated with the SSRIs
...
Once serotonin is transported back into the cell, it is degraded in the
mitochondria by an enzyme called mono-‐amino oxidase in a one step reaction
...
Mono-‐Amine Oxidase A
2
...
However, the type A
mostly degrades serotonin while type B mainly degrades dopamine and
noradrenaline
...
It has now been discontinues, but it was used in clinically obese individuals
because it is an appetite suppressant
...
However, it is not used anymore since it is associated with valvular
heart disease
...
All are metabotropic except 3, which is ionotropic
...
Variant A is important in anxiety, sleep
and thermoregulation
...
This drug shows very important anxiolytic properties
...
Benzodiazepines can also act as
anxiolytics
...
Sedation
is not always a disadvantage, such as in insomniac patients
...
5-‐HT2 also reduces anxiety
...
There are drugs of choice to prevent vomiting produced by cancer
chemotherapy
...
• 5-‐HT-‐1A agonist delay onset of REM sleep
• 5-‐HT-‐2 antagonists suppress REM sleep
People who are deprived of REM tend to show very aggressive behavious
...
The functins of
REM sleep are not fully understood but theories include its role in memory
consolidation and importance of neural development, especially in neonatal
development
...
Drugs of abuse
SSRIs reduce alcohol intake in alcohol-‐dependent rates
...
Anxiolytic Activity
5-‐HT-‐1A agonists such as buspirone and gepirone, have these effects
...
Aggression
5-‐HT-‐1A and to a lesser extent 5-‐HT-‐1B and 5-‐HT1C agonists suppress
aggression in animal models
...
It was
subsequently withdrawn due to cardiac valve damage
...
It is most important is
schizophrenia and Parkinson’s and attention deficit disorders
...
Similar effects of schizophrenia are encountered with the administration of some
drugs like LSD
...
It comes out at the age of about twenty and is more
common in males
...
Nigro-‐striatal pathway
This is associated with locomotive activity
...
It starts from the substantial
nigra and branches to the striatum (caudate nucleus and putamen)
...
Damage to this area results in Parkinson’s
disease, that is, the neurodegeneration in the substantial nigra, Thus
dopaminergic cells will die much earlier than normal, thus associated with
problems of voluntary movement
...
Mesolimbic pathway
It is associated with reward
...
Stimulation of this pathway makes one feel good Stimulation of this pathway
occurs when one is hungry and we eat, when one is thirsty and we drink
...
Most abused/addictive drugs and some
food stimulate this particular pathway
...
Tubero-‐infindibular (hypothalamus) pathway
This pathway regulates lactation and fertility
...
Parkinson’s occurs where there is a decrease in dopamine in striatum
...
Dopamine is also found in the body
...
It is a good vasodilator used in renal impairment
to produce renal vasodilation
...
It is finally converted to dopamine
...
A drug known as reserpine (experimentally used) blocks the entry of dopamine
into vesicles
...
This
result in empty vesicles, thus the overall dopamine concentrations are low, thus
giving rise to Parkinson’s like effects
...
Two major degradation pathways exist for dopamine
...
•
•
•
•
But because dopamine, as well as a biogenic amine, is also catecholamine,
dopamine is also inactivated by reuptake via the norepinephrine transporter
(NET), presumably on neighbouring norepinephrine neurons, the enzymatic
breakdown by catechol-‐o-‐methyl transferse (COMT)
...
They are classified into 2
classes:
• D1 like: D1 (D1A) and D5 (D1B)
• D2 like: D2 (D2A), D3 (D2B), D4 (D2C)
They are all metabotropic
...
The D2 like, activation is coupled to Gi protein which directly inhibits the
formation of cAMP by inhibiting adenylate cyclase
...
Only a
few drugs are selective like bromocryptine and haloperidol that act almost
exclusively on the D2 receptor
...
accumbens
• N
...
accumbens • Olfactory
• Cortex
• Olfactory
tubercle
Amygdala
tubercle
Agonists and Antagonists
Dopamine agonists such as dopamine, amphetamine, bromocriptine, increase
levels of dopamine thus suitable for Parkinson’s
...
An individual, in theory, cannot suffer from both schizophrenia and Parkinson’s
at the same time
...
Nicotine, which
takes as little as 7 seconds to reach the brain, stimulates the release of dopamine
...
Smoking does, in fact, protect an
individual from getting Parkinson’s, since they build up dopaminergic reserves
...
However,
once it has developed the persons decline tends to be much steeper
...
To treat schizophrenia drugs known as
neuroleptics/antipsychotics are used such as clozapine and risperidone
...
Title: Pharmacology of the Nervous System
Description: Covers the anatomy, physiology and pharmacology of the nervous system.
Description: Covers the anatomy, physiology and pharmacology of the nervous system.