Download CNS pharmacology

Introduction to CNS
pharmacology
Dr Caroline Stewart
[email protected]
Learning Outcomes
• List the principal neurotransmitters of the central nervous
system.
• Be aware of the distribution and function of the major
neurotransmitters in the brain.
• Describe the processes involved in chemical transmission
at central synapses.
• Explain the mechanisms by which drugs gain access to the
central nervous system.
What is the central nervous system?
• PNS:
– Autonomic
• Sympathetic
• parasympathetic
– Somatic
• CNS:
– Brain
– Spinal cord
Function of the CNS
• Receive and process information (spinal
cord is usually the conduit)
• Initiate and maintain appropriate
response
– physical
– emotional
Components of the CNS
• Neurones
• Glial Cells
–
–
–
–
Astrocytes
Oligodendrocytes
Ependymal cells
Microglia
• Extracellular space
• Ventricular system (CSF)
Organisation of the CNS
• Sensory system
• Motor system
• Limbic system
Sensory system
Cortex
Specific
projection
Sensory
receptor
Reticular activating
system:
Regulates arousal
and wakefulness
Motor system
Motor cortex
Corticospinal
pathway
(pyramidal tract)
CNS
sensory
system
Extrapyramidal
system
(motor coordination
and posture)
cerebellum
basal ganglia
vestibular nuclei
Sensory
receptor
Polysynaptic
spinal
interneurones
Anterior horn
cell
Skeletal
muscle
Limbic system
Processing of
sensory information
Cortex
Limbic
system
Regulation of emotion
and mood
Hypothalamus
Pituitary
Centres regulating autonomic
function and links to others via
medulla (e.g. BP, HR)
Ganglia
Cingulate gyrus
Anterior nucleus of
thalamus
Thalamus
Para-olfactory
area
Fornix
Mamillary bodies of
hypothalamus
Hypothalamus
Hippocampus
Uncus
Amygdala
Para-hippocampal
gyrus
The synapse
• Transmission of information from one
neurone to another
Chemical messengers
• Neurotransmitter (fast and slow synaptic
transmission)
• Neuromodulator (diffuse, slower action)
• Neurotrophin (long lasting effects on growth
and morphology)
Identifying neurotransmitters
• Localisation
• Release
• Synaptic mimicry
• Synaptic pharmacology
Types of neurotransmitter
• Small molecules
– amino acids (glutamate, GABA)
– biogenic amines (ACh, NA, DA, 5-HT)
• Neuropeptides
– (cholecystokinin, Substance P, enkephalins)
• Diffusable gases
– nitric oxide
• Lipid mediators
– (e.g. endocannabinoids)
• Neurotrophins
– (e.g. nerve growth factor)
• Steroids
Amino acid neurotransmitters
NH2
O
• Glutamic acid (glutamate):
principal excitatory transmitter in
the brain
• Gamma amino butyric acid
(GABA): main inhibitory transmitter
in the brain
HO
• Widely distributed
• Target for general anaesthetics,
anti-epileptics, anxiolytics.
OH O
OH
O
NH2
Cholinergic system
O
O
N+
• Acetylcholine
• Receptors: muscarinic and nicotinic
Motor control
Learning and memory
Attentional processes
NH2
HO
Noradrenergic system
• Noradrenaline/norepinephrine
• Receptors: and -adrenoceptors
OH
OH
Arousal, emotion
Dopaminergic system
• Dopamine
• Receptors:D1 and D2 family
HO
HO
NH2
Motor control
Motivation/reward
Prolactin release
Serotonergic (5HT) system
HO
• Serotonin (5-hydroxytryptamine)
• Receptors: many subtypes 5HT1, 5HT2, 5HT3
mood, sleep, feeding
behaviour and sensory
perception
Analgesia
Neuropeptides
• Synthesised as large precursor polypeptides
• Packaged in large dense core vesicles
• Substance P and opioid peptides found in
spinal cord and higher brain centres
• Play a role in perception of pain
Synaptic transmission (chemical)
Nerve terminal
Metabolites
e.g. decarboxylase
Precursor
nT
Presynaptic receptor
nT
nT
nT
Postsynaptic
receptor
Transporter
Targets for drug action
• Ion channels
• Receptors
• Enzymes
• Transport proteins
Blood brain barrier
Brain receives 2530% of cardiac
output but
capillaries have no
fenestration (holes)
Entry of drugs into brain
• In general, lipid soluble drugs get in, water
soluble drugs kept out
• Brain penetration predicted by oil/water
partition coefficient (relative solubility in
organic solvent compared to water)
• Specific transporters or carrier molecules
present
• In some areas of the brain it is more “leaky”
• area postrema of medulla
• chemoreceptor trigger zone in hypothalamus
Classification of drugs
• By structure e.g. benzodiazepine
• By pharmacological action e.g. monoamine
oxidase inhibitor
• By clinical action e.g. antipsychotic
The End