CNS Pharmacology - General consideration

CNS Pharmacology

·         The mammalian nervous system is divided into two major divisions, the central nervous system and peripheral nervous system

·         The CNS consists of spinal cord and brain whereas the peripheral nervous system contains sensory and motor nerves.

·         The major functional unit of CNS is the neuron or nerve cell. A typical neuron has four morphologically defined regions, the dendrites, the cell body, the axon and the presynaptic terminals to the axon.

·         The dentrites have several branches like extensions given by the cell body that serve as a major information receiving apparatus of the neuron.

·         The cell body contains important cell organelles.

·         The cell body gives to axon, the conducting unit of neuron, transmitting an electrical impulse (action potential) from its initial segment at cell body to other end at the presynaptic terminal

·         Axon branch near their ends into several specialized endings called presynaptic terminals.

·         The presynaptic terminal contains synaptic vesicles which contain a chemical transmitter for neurotransmission.

·         The presynaptic terminal of an axon usually contacts the receptive surface of an adjacent nerve or muscle cell or the nerve cells dentrites, but sometimes also on the cell body or occasionally on the terminal end of another cell’s axon.

·         The site of contact of presynaptic terminal with adjacent cell is called the synapse and the space between these two cells is called synaptic cleft.

·         Information in the form of an impulse originating in a single neuron can be propagated to the next neuron or muscle cell through a chemical transmission process called neurotransmission.

·         Neurotransmitter is a chemical that is released in the synapse and carries out the function of propagation of nerve impulse. It excites or inhibits the postsynaptic neuron or effector organ.

Steps in neurotransmission

1.       Axonal conduction

2.       Neurotransmitter release

3.       Receptor events – Excitatory post synaptic potential

-          Inhibitory postsynaptic potential

4.       Initiation of post synaptic activity

5.       Destruction or dissipation of transmitter – Metabolic degradation, Reuptake mechanism, diffusion

Criteria to make a chemical as neurotransmitter

1.       The compound is present in neurons in CNS tracts

2.       The compounds when administered produces effects similar to those of neuronal stimulation

3.       The compound is demonstrably released by electrical stimulation

4.       The neurons are capable of synthesizing the compound from precursor molecules

5.        The compounds action could be terminated by enzymatic degradation and/or uptake into neuronal or glial cells.

6.       Inhibitors of enzymatic breakdown or uptake produce effects similar to the administered transmitter and neuronal stimulation.

7.       Specific receptor site antagonist of the compound block the actions of the transmitter or its release by electrical stimulation.

8.       Each of the steps in the neurotransmission pathway may be modified by drugs.

Classification of neurotransmitters

1.       Excitatory amino acids – Aspartate and Glutamate

2.       Inhibitory amino acids – Glycine and GABA

3.       Quaternary choline ester – Acetyl choline

4.       Monoamines / amines – Noradrenaline, adrenaline, dopamine, 5-Hydroxytryptamine and    

                                             histamine. 

5.       Neuro peptides – Opioids

Excitatory amino acids

·         Glutamate and Aspartate

·         Excitatory amino acid neurotransmitters mediate excitatory synaptic transmission in the CNS.

·         They are found in very high concentration in brain and are widely distributed in virtually every region of the CNS.

·         There are four main excitatory amino acid receptor subtypes - NMDA, AMPA, Kianate and metabotrophic receptors.

·         The dissociative anaesthetic agents, ketamine, phencyclidine and Tiletamine reduce the excitatory effects of glutamate and aspartate, especially the latter.

Inhibitory amino acids

GABA

·         γ- aminobutyric acid (GABA) is a major inhibitory transmitter at all levels of the brain.

·         GABA has two main receptor subtypes – GABA_A AND GABA_B

·         GABA_A receptors directly coupled to chloride channels, opening of which reduces membrane excitability

·         GABA_B receptors located mainly on presynaptic terminals belonging to G- protein coupled receptor super family and act via both second messenger and regulation of ion channels and are mainly responsible for presynaptic inhibition.

·         Barbiturates and benzodiazepines increase binding of GABA to its receptors.

·         Bicuculline blocks GABA receptor and picrotoxin closes the chloride channel.

Glycine

·         Another inhibitory CNS neurotransmitter occurs mainly in spinal cord interneuron and also in brain stem.

·         These are ionic receptors that increases the chloride ion conductance

·         Nuxvomica, strychnine and brucine antagonizes Glycine at the spinal cord interneuron.

Quaternary Choline ester

Acetyl choline (Ach)

·         Ach is present at all levels of brain and spinal cord.

·         Both nicotinic and muscarinic (M₁, M₂, M₃, M₄) cholinergic receptors occur in CNS, but central effects are usually mediated via muscarinic receptors.

·         Nicotinic receptor is ionic receptor, while all muscarinic receptor subtypes are G- protein coupled receptors.

·         Cholinergic neurons are involved in cortical aroused response and on learning and short term memory.

·         In most, instances Ach have an excitatory effect on CNS however some neurons show inhibitory response.

Amines

Nor adrenalin

·         The receptors are α (α₁ and α₂) and β (β₁, β₂ and β₃).

·         All receptor subtypes belong to G-protein coupled receptor super family

·         The action of noradrenalin in the CNS is mainly inhibitory but some are excitatory

·         Nor adrenergic transmission is believed to be important in control of mood and blood pressure and functions related to learning, memory, sleep wake cycle, arousal, alertness etc.,

·         Functional deficiency of noradrenalin results in depression.

Adrenalin

·         Adrenalin is found only in very low concentration and it is of minor importance

·         The exact function and physiological role of adrenalin in the CNS is not clear but it has been postulated to play a role in control of blood pressure.

Dopamine

·         Dopamine is an important neurotransmitter as well as precursor of noradrenalin in the CNS.

·         There are two main families of dopamine receptors D1 (D₁ & D₂), D₂ (D₂, D₃, D₄)

·         D₂ family is pharmacologically more important and control most of the central functions of dopamine (motor control, vomiting, inhibition of prolactin secretion)

·         Apomorphine produces emesis by its stimulant action of D₂ receptor and metaclopramide on the other hand is a specific dopamine antagonist used extensively in dogs and cats as an antiemetic.

·         The secretion of prolactin from the lactophores of the anterior pituitary is inhibited by dopamine. Bromocriptine is an agonist for dopamine receptors, which has been used to suppress prolactin secretion in pseudopregnancy in dogs.

5- Hydroxy tryptamine / Serotonin

·         Although brain contains only about 1% of the total body 5- HT contents, it occupies an important position in CNS.

·         Although there are 14 5HT receptor subtypes only 5 subtypes (5HT_1A, 5HT_1B, 5HT_1D, 5H_T2 and 5H_T3) have been associated with CNS functioning.

·         All are G-protein coupled receptors except 5HT₃ which is directly linked to ionic channels.

·         5HT is involved in regulation of several aspects of behavior, sleep wake cycle, temperature control, pain perception, depression, sexual activity, aggressiveness and hypothalamic control or release of pituitary hormones.

·         Ondansetron  - antagonist of 5HT₃ receptor is an antiemetic.

Histamine

·         Present in brain in much smaller amounts

·         H₁, H₂, H₃ are histamine receptors. H₁ is the most predominant receptor.

·         Histamine plays a role in regulation of food and water intake, thermoregulation and hormone release.

Peptide transmitters

Opioid peptides

·         These are endogenous peptides with opiate (morphine) like effects.

·         They bind with high affinity with opioid receptors. The receptors are µ, δ, σ and κ

·         The three distinct families of opioid peptides are endorphins, enkephalins and dynorphines and each derived from different precursor.

 µ - Analgesia, cough suppression, respiratory depression, cardiovascular depression, physical dependence

δ – Analgesia, indifference

κ – Analgesia, sedation and ataxia

σ – Euphoria, hallucination, excitement and analgesia.