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PHARMACOLOGY OF
THE NERVOUS SYSTEMCNS Pharmacology
Mohanad A. Al-Bayati, BVM&S, MS. Physiology, PhD Pharmacology.Assistant Professor of Pharmacology and Toxicology
Department of Physiology and PharmacologyCollege of Veterinary Medicine
University of Baghdad Al-Jaderia, Baghdad
Phone: 0964 7700766550E. Mail [email protected]
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Chemical Transmission and Drug Action in the Central Nervous System (CNS)
Brain function is the single most important aspect of physiology that defines the difference between species.
Disorders of brain function, whether primary or secondary to malfunction of other systems, are a major concern of animal society, and a field in which pharmacological intervention plays a key role. In this lecture, we introduce some basic principles of neuropharmacology that underlie much of the material in the rest of this lesson.
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Neurotransmitter
The original concept of neurotransmission envisaged a substance
released by one neuron and acting rapidly, briefly and at short range on the membrane of an adjacent (postsynaptic) neuron, causing excitation or inhibition.
1. Neuronal Cells2. Non-neuronal Cells “Glial cells and astrocytes”
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Basic processes of neurotransmitters
The basic processes of synaptic transmission in the central nervous
system are essentially similar to those operating in the periphery
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Neuroactive drugs
Neuroactive drugs act on one of four types of target proteins, namely 1. ion channels 2. receptors 3. enzymes 4. transport proteins Four main receptor families5. ionotropic receptors6. G-protein-coupled receptors7. kinase-linked receptors8. nuclear receptors- current drugs target mainly the first two.
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Neuro terms
The terms; refer to chemical mediators that operate over
different timescales. In general:
Neurotransmitters are released by presynaptic terminals
and produce rapid excitatory or inhibitory responses in postsynaptic
neurons
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Neuro terms
Neuromodulators are released by neurons and by
astrocytes, and produce slower pre- or postsynaptic responses
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Neuro terms
Neurotrophic factorsare released mainly by non-neuronal cells and act on tyrosine kinase-linked
receptors that regulate gene expression and control neuronal
growth and phenotypic characteristics
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Neuro terms
Fast neurotransmitters (e.g. glutamate, GABA) operate
through ligand-gated ion channels
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Neuro terms
Slow neurotransmitters & neuromodulators
(e.g. dopamine, neuropeptides, prostanoids) operate mainly through G-
protein-coupled receptors
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Anesthetic agents
Drugs used to produce surgical anesthesiahalothane,propofol
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Anxiolytics and sedatives
Drugs that cause sleep and reduce anxiety, refer to
hypnotics, sedatives, minor tranquillizers
barbiturates, benzodiazepines
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Antipsychotic drugs
Drugs that are effective in relieving the symptoms of schizophrenic
illness
neuroleptic drugs, antischizophrenic drugs, major tranquillizers
clozapine,chlorpromazine,
haloperidol
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Antidepressant drugs
Drugs that alleviate the symptoms of depressive illness
monoamine oxidase inhibitors, tricyclic antidepressants,
selective serotonin reuptake inhibitors
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Analgesic drugs
drugs used clinically for controlling pain
opiates, carbamazepine
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Psychomotor stimulants
Drugs that cause wakefulness and euphoria
psychostimulants
amphetamine, cocaine caffeine
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Psychotomimetic drugs
Drugs that cause disturbance of perception (particularly visual
hallucinations) and of behaviour in ways that cannot be simply
characterized as sedative or stimulant effects
hallucinogens, psychodysleptics
lysergic acid diethylamide,
mescaline phencyclidine
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Cognition enhancers
Drugs that improve memory and cognitive performance
nootropic drugs
1. acetylcholinesterase inhibitors: donepezil,
galantamine, Rivastigmine
2. NMDA receptor antagonists:
memantine,piracetam
(improves cognitive function in animal tests, but not proven in humans).
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Excitatory amino acids
Excitatory amino acids (EAAs), namely glutamate, aspartate, and possibly homocysteate, are the main fast excitatory transmitters in the central
nervous system. Glutamate: is formed mainly from the Krebs cycle
intermediate α-oxoglutarate by the action of GABA transaminase.
There are four main EAA receptor subtypes: • NMDA X blocked by Mg, chlorokynurenate• AMPA X AP-5, CPP, CNQX• Kainate =ionotropic receptors • Metabotropic=G-protein-coupled receptors
EAA receptor antagonists have yet to be developed for clinical use
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Excitatory amino acids
• GLYCINE Strychnine; a convulsant poison
that acts mainly on the spinal cord, blocks both the synaptic inhibitory response and the response to glycine
β-Alanine has pharmacological effects and a pattern of distribution very similar to those of glycine
Tetanus toxin, a bacterial toxin resembling botulinum toxin, acts
selectively to prevent glycine release from inhibitory interneurons in the spinal
cord, causing excessive reflex hyperexcitability and violent muscle
spasms (lockjaw).
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GABA
GABA is the main inhibitory transmitter in the brain
GABAA receptors, which occur mainly postsynaptically, are directly
coupled to chloride channels.the opening of which reduces
membrane excitability. Muscimol is a specific GABAA agonist, and the convulsant bicuculline is an antagonist.
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GABA
Other drugs that interact with GABAA receptors and channels include:
o benzodiazepine tranquillisers, which act at an accessory binding site to facilitate the action of GABA
o convulsants such as picrotoxin, which block the anion channel
o neurosteroids, including endogenous progesterone metabolites, and other CNS depressants, such as barbiturates and some general anesthetic agents, which facilitate the action of GABA.
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GABA
GABAB receptors are G-protein-coupled receptors linked to
inhibition of cAMP formation.They cause pre- and postsynaptic inhibition by inhibiting Calcium channel opening and increasing K+ conductance. Baclofen is a GABAB receptor agonist used to treat spasticity. GABAB antagonists are not yet in clinical use.
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Other transmitters and modulators
• noradrenaline • dopamine, 5-hydroxytryptamine
(5-HT, serotonin) • acetylcholine (ACh)
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Other transmitters and modulators
• 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).
drugs that act partly or mainly on noradrenergic transmission in the CNS include antidepressants, cocaine and amphetamine. Some antihypertensive
drugs; clonidine, methyldopa, act mainly on noradrenergic transmission in the CNS.
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Other transmitters and modulators
• Dopamine• Parkinson's disease is associated with a
deficiency of nigrostriatal dopaminergic neurons. • Behavioral effects of an excess of dopamine
activity consist of stereotyped behaviour patterns
1. dopamine-releasing agents; amphetamine 2. dopamine agonists; apomorphine. • Hormone release from the anterior pituitary
gland is regulated by dopamine, especially prolactin release (inhibited) and growth hormone release (stimulated).
• Dopamine acts on the chemoreceptor trigger zone to cause nausea and vomiting
• Antogonized by bromocriptin
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Other transmitters and modulators
• 5-Hydroxytryptamine
– various behavioural responses (e.g. hallucinatory behaviour, 'wet dog shakes')
– feeding behaviour – control of mood and emotion – control of sleep/wakefulness – control of sensory pathways,
including nociception – control of body temperature – vomiting.
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Other transmitters and modulators
• Drugs acting selectively on 5-HT receptors or transporters include: – 'triptans' (sumatriptan), 5-HT1D
agonists used to treat migraine.– 5-HT2 antagonists (ketanserin) used
for migraine prophylaxis. – selective serotonin uptake inhibitors
(fluoxetine) used to treat depression.
– ondansetron, 5-HT3 antagonist, used to treat chemotherapy-induced emesis
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Other transmitters and modulators
• AcetylcholineMuscarinic receptors appear to
mediate the main behavioral effects associated with ACh, namely effects
on arousal and on learning and short-term memory.
Muscarinic antagonists (e.g. scopolamine) cause amnesia
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Other transmitters and modulators
• PURINES; nociception• HISTAMINE ; food and water intake,
and thermoregulation, nausea - vomiting, motion sickness and middle ear disorders
• MELATONIN; sleep disorders• NITRIC OXIDE; inhibitory and
excitatory effects on neurons.
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General anesthetic agents
• LIPID THEORY; Anaesthetic potency is closely correlated with lipid solubility, interaction with the lipid membrane bilayer
• Effect on Ion channel; interaction with ligand-gated membrane ion channels• enhance the activity of inhibitory
GABAA receptors, and many inhibit activation of excitatory receptors such
as glutamate and nicotinic acetylcholine receptors
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General anesthetic agents
• Anesthesia involves three main neurophysiological changes: unconsciousness, loss of response to painful stimulation and loss of reflexes
• Intravenous anesthetics : thiopental, etomidate) maintenance of anesthesia combination with muscle relaxants and analgesics.
• Inhalational anaesthetics (gases or volatile liquids) for maintenance of anaesthesia. – volatile liquids halothane, sevoflurane– halothane hepatotoxicity– inhalational anaesthetics trigger malignant
hyperthermia
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Local anesthetics and other drugs affecting sodium channels
drugs block voltage-sensitive sodium channels and inhibit the generation of
the action potentialby preventing the voltage-dependent
increase in Na+ conductance Drug are amphiphilic molecules with a
hydrophobic aromatic group and a basic amine group
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Local anesthetics
• Local anesthetics may be infiltrated into soft tissue (e.g. of gums) or to block a nerve or nerve plexus.
• Coadministration of a vasoconstrictor (e.g. adrenaline) prolongs the local effect.
• Lipid-soluble drugs (e.g. lidocaine [lignocaine]) are absorbed from mucous membranes and are used as surface anesthetics.
• Bupivacaine has a slow onset but long duration. It is often used for epidural blockade (e.g. to provide continuous epidural blockade during labour) and spinal anaesthesia. Its isomer levobupivacaine is less cardiotoxic if it is
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Anxiolytic and hypnotic drugs
• treat insomnia (hypnotic drugs)o Benzodiazepineso β-Adrenoceptor antagonists
propranololo Zolpidemo Barbiturateso Miscellaneous; chloral hydrate,
meprobamate and methaqualone, diphenhydramine
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Antipsychotic drugs
– first-generation ('typical') antipsychotics (chlorpromazine, haloperidol, fluphenazine, flupenthixol, clopenthixol)
– second-generation ('atypical') antipsychotics (clozapine, risperidone, sertindole, quetiapine, amisulpride, aripiprazole, zotepine).
All antipsychotic drugs are antagonists at dopamine D2-receptors, but most
also block other monoamine receptors, especially 5-HT2. Clozapine also blocks
D4-receptors
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Antidepressant drugs
• theory of depression is the monoamine hypothesis
• tricyclic antidepressants and monoamine oxidase inhibitors.
Main type of drug– monoamine uptake inhibitors (tricyclic
antidepressants, selective serotonin reuptake inhibitors and others)
– monoamine oxidase (MAO) inhibitors – miscellaneous ('atypical')
antidepressants, mainly non-selective receptor antagonists (e.g. trazodone, mirtazepine).