1

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 aumnmumu@yahoo.com

aumnmumu2003@Gmail.com

2

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.

3

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”

4

Basic processes of neurotransmitters

The basic processes of synaptic transmission in the central nervous

system are essentially similar to those operating in the periphery

5

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.

6

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

7

Neuro terms

Neuromodulators are released by neurons and by

astrocytes, and produce slower pre- or postsynaptic responses

8

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

9

Neuro terms

Fast neurotransmitters (e.g. glutamate, GABA) operate

through ligand-gated ion channels

10

Neuro terms

Slow neurotransmitters & neuromodulators

(e.g. dopamine, neuropeptides, prostanoids) operate mainly through G-

protein-coupled receptors

11

Anesthetic agents

Drugs used to produce surgical anesthesiahalothane,propofol

12

Anxiolytics and sedatives

Drugs that cause sleep and reduce anxiety, refer to

hypnotics, sedatives, minor tranquillizers

barbiturates, benzodiazepines

13

Antipsychotic drugs

Drugs that are effective in relieving the symptoms of schizophrenic

illness

neuroleptic drugs, antischizophrenic drugs, major tranquillizers

clozapine,chlorpromazine,

haloperidol

14

Antidepressant drugs

Drugs that alleviate the symptoms of depressive illness

monoamine oxidase inhibitors, tricyclic antidepressants,

selective serotonin reuptake inhibitors

15

Analgesic drugs

drugs used clinically for controlling pain

opiates, carbamazepine

16

Psychomotor stimulants

Drugs that cause wakefulness and euphoria

psychostimulants

amphetamine, cocaine caffeine

17

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

18

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).

19

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

20

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).

21

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.

22

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.

23

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.

24

Other transmitters and modulators

• noradrenaline • dopamine, 5-hydroxytryptamine

(5-HT, serotonin) • acetylcholine (ACh)

25

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.

26

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

27

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.

28

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

29

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

30

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.

31

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

32

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

33

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

34

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

35

Anxiolytic and hypnotic drugs

• treat insomnia (hypnotic drugs)o Benzodiazepineso β-Adrenoceptor antagonists

propranololo Zolpidemo Barbiturateso Miscellaneous; chloral hydrate,

meprobamate and methaqualone, diphenhydramine

36

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

37

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).