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Introduction to CNS pharmacology

Humberto García-Ulloa M.D., MSc., PhD.

Universidad Autónoma de Guadalajara A. C. © 2013


Neuropharmacology
• Is the study of drugs specifically employed
to affect the nervous system
• Entire mechanism is generally unknown
• “Black box”

Universidad Autónoma de Guadalajara A. C. © 2013


Mechanism vs site of action
MECHANISM SITE

Will affect: Neuropharmacologic


*Enzyme agents produce
*Receptor effects by altering
synaptic events.
*Transporter
*Ion channel

Universidad Autónoma de Guadalajara A. C. © 2013


Mechanism of action

transmembrane
abundant
receptors
7 most
amplification
pathway

intracellular
receptors
affect
steroids
may
pµA

Universidad Autónoma de Guadalajara A. C. © 2013 Harvey. Pharmacology. 2012


ELECTRICAL CHEMICAL
SYNAPSES SYNAPSES
notreally abundant Most abundant

GAP junctions Chemical substances


(comunication of 2 cells) (transmitters) released by
presynaptic cell
Allows free movement of
ions from one cell to the Act on receptors of post
other synaptic cells

No synaptic delay NMJ

effect is more
Rapid Universidad Autónoma de Guadalajara A. C. © 2013
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Universidad Autónoma de Guadalajara A.C. © 2013.
atinvokesinteractionofthevesicleand
membrane dockingproteins vesiclefusion
withthemembrane andexocytosis ofthe
neurotransmitter synthesized
cells
within breakdown

withoutcat
Reuptake
there isnot

d
d

STOPthereleased
of
theneurotransmitter

inderect Acting
Drugs Avoid
binds receptorsdirectly
Drug reuptake orbreakd

1
direct acting Idontbindtoreceptors

nqrnotrhansmdftqrme.IE

time
Universidad Autónoma de Guadalajara A. C. © 2013
GABA
POSTSYNAPTIC POTENTIALS inhibitory
neurotrans
EPSP & IPSP Deppress milter
CNS epilepsy
anxiety

Kandel & Shwartz. Principles of Neural Science. 2008

EPSP
Release Neurotransmitter Interaction NT – receptor
activation of Na+ channels Vm depolarizes

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POSTSYNAPTIC POTENTIALS
EPSP & IPSP

Kandel & Shwartz. Principles of Neural Science. 2008

IPSP
Release Neurotransmitter Interaction NT – receptor
increasing Cl- influx and/or K+ eflux Hyperpolarization
IPSP increase negativity beyond the normal Resting
membrane Potential
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PROPERTIES OF ELECTRICAL AND
CHEMICAL SYNAPSES

ELECTRICAL CHEMICAL
IONOTROPIC METABOTROPIC

Agonist None e.g., Ach e.g., Ach

Membrane Connexons Receptor/ Receptor/ G


channel protein
Protein
Speed Instantaneous 1 msec Sec to min
delayedon Releaseof neuro then it acts
postsynaptic cell
Effect Vm Vm Vm, etc
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Universidad Autónoma de Guadalajara A.C. © 2013.
Neurotransmitter Receptors
• Ionotropic receptors (also known as ligand-
gated ion channels) are associated with ion
channels, and change ionic conductance.
• Metabotropic receptors are coupled with
enzymes via G-proteins and other
intermediates. more abundant
Greater amplification
pathway

Universidad Autónoma de Guadalajara A. C. © 2013


cetylcholinereceptor
alsoknown as cholinergic
Consists
of 2types
Nicotinic
Muscarinic

Mi neural
Modulation
pilot of neurotrans
parpeideptors matters
Mz Cardiac
Muscle Typed Slowing HR
muscle contraction andconduct
Ganglionic Type
Mzlglandula
Contraction0
Neural Excitation
Sm and
Cwstype stimulation 0
NeuralExcitation glandular
Universidad Autónoma de Guadalajara A. C. © 2013 secretion
Neurotransmitter
• Neurotransmitter - A substance which is
released locally and causes a change in post-
synaptic potential.
• Neuromodulator - A substance which acts to
modify the response of the synapse to a
neurotransmitter. Thorbytheactionof neurotransmitter
• Co-transmitter- A substance that coexists
with a NT in a given neuron. Acts on synaptic
sites on the same or different cells

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SMALL MOLECULES

CLASS I CLASS III (Amino acids)


• Acetylcholine Glutamate excitatory
Gamma-amino butyric
CLASS II (Amines) acid (GABA) it is very
phosptowerft abundant inthe
• NE Excitatory Inhibitory CNS

• Epinephrine Glycine inhibitory


Excitatory Most abundant in the
spinal cord
• Dopamine Usually CLASS IV
inhibitory
Nitric oxide produce within
• Serotonin both inhibitory healthy Bv
• Histamine Enxffatory
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13
Universidad Autónoma de Guadalajara A.C. © 2013.
Neurotransmitters in CNS
Neurotransmitter Receptors Mechanisms of Signal
Transduction

Acetylcholine Muscarinic 10hChannel


M1, M3, and M5 ↑ IP3 and DAG
M2, and M4 ↓ cAMP; ↑ gK+.
Nicotinic 10hChannel ↑ gCa , gK , and gNa .
2+ + +

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Neurotransmitters in the CNS

Neurotransmitter Receptors Mechanisms of Signal


Transduction
Amino Acids
Gamma- GABAA ion channel ↓ cAMP; ↑ gCl- Inhibitory
aminobutyric GABAB G propteameptors ↑ Ca2+ and gK+
Acid (GABA) (metabotropic)
exitatory
Glutamate and Antagonist Ionotropic Allowflow Nat
excitatoryreceptorsor Ca
receptors seizures
ions ofneurons
into
theirtotreat AMPA and KA
aspartate ofused ↑ gK and gNa causing depolarizati
+ +

NMDA ↑ gCA2+, gK+, and gNa+


exitatory
neurotransmitters
↓ cAMP; ↑ IP3 and DAG
Metab (MGluR)
Glycine Inhibitory Strychnine- ↑ gCl-
insensitive
spinal
cord
Strychnine- Modulate NMDA
sensitive receptors

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Neurotransmitters in the CNS
Neurotransmitter Receptors Mechanisms of Signal
Transduction
Biogenic Amines
Dopamine D1 and D5 ↑ cAMP
D2, D3, and D4 ↓ cAMP
Histamine H1 ↑ IP3 and DAG.
H2 ↑ cAMP
H3 Unknown
Norepinephrine Adrenergic
a1 ↑ IP3 and DAG
a2 ↓ cAMP
b1 and b2 ↑ cAMP
Serotonin (5-hydroxy- 5-HT1 ↓ cAMP; ↑ gK+
tryptamine, or 5-HT) 5-HT2 ↑ IP3 and DAG
5-HT3 ↑ gK- and gNa+
5-HT4 ↑ cAMP

Universidad Autónoma de Guadalajara A. C. © 2013


Neurotransmitters in the CNS
Neurotransmitter Receptors Mechanisms of Signal
Transduction
Peptides
Opioid peptides δ, κ, and μ ↓ cAMP and gCA2+; ↑ gK+
Tachykinins
Neurokinins NK1, NK2, and ↓ gK+; ↑ IP3 and DAG
NK3
Substance P NK1, NK2, and ↓ gK+; ↑ IP3 and DAG
NK3
Hypocretin 1 and 2
(orexins)

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Blood Brain Barrier
• A term used to describe diffusional
barriers retarding the passage of
substances from the central circulation to
nerve cells. Drug should be non ionized and with a low
molecular weight lipidsolvable
• Characteristics which regulate diffusion of
substances through capillaries are
– Molecular weight
– Lipid solubility
– Ionization at physiological pH
C noaltrack H2O CANNOT Cross BBB
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Neuronal Systems in the CNS
• Cognitive processing
• Memory
• Emotional processing
• Sensory processing
• Motor processing

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Cognitive Processing
• Cognitive processing – Interpretation of
sensory information
– Results in motor activity, reasoning,
forethought
– Disorders referred to as delirium
– Altered by antipsychotics, CNS stimulants,
hallucinogens

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Memory
• Memory – Ability to recall events
– Involves many brain structures
– Disorders referred to as dementia
– Altered by cholinesterase inhibitors and
benzodiazepines

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Emotional Processing
• Emotional processing – The conscious
perception of neuronal activity
– Involves limbic structures and frontal lobe
cortex
– Disorders include anxiety, mood disorders,
and schizophrenia
– Altered by anxiolytics, antidepressants,
antipsychotics, and all drugs causing drug
dependence
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Sensory Processing
• Sensory processing
– Vision, hearing, olfaction, touch, pain
– Disorders include sleep disorders, chronic
pain
– Altered by antidepressants, hallucinogens,
anesthetics, analgesics

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Motor processing
• Motor processing
– Control of motion and posture
– Disorders include Parkinson’s disease, and
degenerating and demyelization diseases
– Altered by antiparkinsonian drugs, CNS
stimulants, sedative-hypnotics

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Universidad Autónoma de Guadalajara A. C. © 2013
Acetylcholine
• Acetylcholine is widely distributed in the
CNS, important pathways being:
– Basal forebrain (magnocellular) nuclei, which
send a diffuse projection to most forebrain
structures, including the cortex.
– Septohippocampal projection
– Short interneurons in the striatum and nucleus
accumbens

Universidad Autónoma de Guadalajara A. C. © 2013


Acetylcholine
• Dementia
• Parkinson

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Norepinephrine
• Noradrenergic pathways, running mainly in
the medial forebrain bundle, and
descending spinal tracts, terminate
diffusely in the cortex, hippocampus,
hypothalamus, cerebellum, and spinal
cord.
• The actions of noradrenaline are mainly
inhibitory (b-adrenoceptors), but some are
excitatory (a- or b-adrenoceptors).
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Norepinephrine
• Noradrenergic transmission is believed to
be important in
– The “arousal” system, controlling wakefulness
and alertness
– Blood pressure regulation
– Control of mood (functional deficiency
contributing to depression).

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Dopamine
• There are three main dopaminergic pathways
– Nigrostriatal pathway, important in motor control
– Mesolimbic/mesocortical pathways, running from
groups of cells in the midbrain to parts of the limbic
system, especially the nucleus accumbens, and to the
cortex; they are involved in emotion and drug-induced
reward systems.
– Tuberohypophyseal neurons running from the
hypothalamus to the pituitary gland, the secretions of
which they regulate.

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Dopamine
• Parkinson’s disease is associated with a
deficiency of nigrostriatal dopaminergic
neurons.
Fof dopamine levels Used
for
treatment
of parkinsons

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5-Hydroxytryptamine (5-HT in the CNS)
serotonin
• 5-HT neurons are concentrated in the
midline raphe nuclei in the pons and
medulla, projecting diffusely to the cortex,
limbic system, hypothalamus, and spinal
cord, similar to the noradrenergic
projections.

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5-Hydroxytryptamine (5-HT in the CNS)

• Functions associated with 5-HT pathways


– Feeding behavior
– Control of mood and emotion
– Various behavioral responses (e.g.,
hallucinatory behavior, “wet-dog”shakes)
– Control of sleep-wakefulness
– Control of sensory pathways, including
nociception
– Vomiting

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Excitatory Amino Acids (EAAs)
• EAAs, namely glutamate and aspartate,
are the main fast excitatory transmitters in
the CNS.
• There are four main EAA receptor
subtypes:
association
ChannelsNat
– NMDA Depolarization
– AMPA their 10h of Into
with flow10ns
– Kainate allow cat
or neurons
– Metabotropic
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Inhibitory Amino Acids:
GABA and Glycine
• GABA is the main inhibitory transmitter in
the brain.
• It is present fairly uniformly throughout the
brain; there is very little in peripheral
tissues. This ion channel contains complex receptors
for
several drugs
Its receptors Inotropic GABA GABAA
Metabotropic GABA GABAB
• GABA is formed from glutamate, by the action of GAD (glutamic acid decarboxylase). Its action is
terminated mainly by reuptake, but also by deamination, catalysed by GABA transaminase.

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Inhibitory Amino Acids:
GABA and Glycine
• Drugs that interact with GABAA-
receptors and channels include:
– Benzodiazepine tranquillizers, which act at an
accessory binding site to facilitate the action
of GABA
– Neurosteroids, including endogenous
progesterone metabolites, and other CNS
depressants, such as barbiturates, which
facilitate the action of GABA.
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Inhibitory Amino Acids:
GABA and Glycine
• Glycine is an inhibitory transmitter mainly
Activation of
in the spinal cord, acting on its own this receptor
hyperpolarization membrane
receptor, structurally and functionally
similar to the GABAA-receptor.
• The convulsant drug strychnine is a
competitive glycine antagonist. Tetanus
toxin acts mainly by interfering with glycine
release.

Universidad Autónoma de Guadalajara A. C. © 2013


Summary
• Neuropharmacology
• Mechanism vs site of action
• Preganglionic and postganglionic neuron
• EPSP and IPSP
• Types of receptors
• Neurotransmitter and characteristics

Universidad Autónoma de Guadalajara A. C. © 2013

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