CNS Pharmacology

CNS Pharmacology

CNS Pharmacology will deal with- Anesthetics, Preanesthetic medication, Sedative, Hypnotic, Narcotic, Antiepileptic, Analeptics, Analgesic, Anxiolytic, Antidepressants etc.

1. Anesthetics – drugs that produce reversible loss of sensation eg. halothane.
2. Dissociative anesthetic – drug that produces a feeling of dissociation from one’s own body and surroundings including profound analgesia, immobility, amnesia with light sleep.
3. Preanesthetic medication – use of drugs before anesthesia to make it more pleasant and safe.
4. Sedative– drug that subdues excitement and calms the subject without inducing sleep.
5. Hypnotic– drug that induces or maintains sleep
6. Narcotic– drug that induces sleep (refers to opioids – the term is not used now)
7. Antiepileptic drug – drug that is used to control seizures
8. Analeptics– CNS stimulants – drugs that induce CNS stimulation
9. Analgesic– drug that selectively relieves pain without altering consciousness
10. Anxiolytic drugs– group of mild CNS depressants that produce a restful state of mind, without interfering with normal mental or physical functions
11. Antidepressants– drugs that can elevate the mood in depressive illness
12. Antimanic drugs– drugs that stabilize the mood in manic conditions
13. Hallucinogens– (psychotomimetics) drugs that alter mood, behavior, thought and perception in a manner similar to that seen in psychosis.

Chemical messengers in CNS Pharmacology

1. Neurotransmitters: substances stored in the presynaptic area in vesicles. On release lead to excitation or inhibition.
   • Many neurotransmitters have been discovered so far (almost 100).
   • Most important ones are:
     • Biogenic amines — Histamine, 5-HT, Adrenaline, Noradrenaline, Dopamine, ACh
     • AminoAcids – GABA, Glycine, Glutamate, Aspartate
     • Peptides – Somatostatin, Substance P, enkephalin, Endorphin, Oxytocin, Vasopressin, Cholecystokinin, Thyrotrophic hormone, Angiotensin, Vasoactive intestinal peptide, Neuropeptide Y.
2. Neurohormones: Hormone arising from a neuron. Eg: oxytocin, vasopressin.
3. Neuromodulators: Originates from cellular and nonsynaptic sites, influence the general level of excitability without altering the membrane potential. Eg: ammonia, CO₂, Prostaglandins, steroid hormones.
4. Neuromediators: Those that participate in the elicitation of response to a transmitter. Eg:Second messengers cAMP, cGMP, IP₃.

Neurotransmitters in the CNS

Neurotransmitters may be broadly divided into fast neurotransmitters and slow neurotransmitters.

Fast neurotransmitters operate through ligand gated ion channels (eg. glutamate, GABA) while slow neurotransmitters and neuromodulators operate mainly through G-protein coupled receptors (eg. dopamine, neuropeptides, prostanoids).

The same agent (eg. glutamate, 5HT and acetylcholine) may act through both ligand gated channels and G-protein coupled receptors. Many chemical mediators including glutamate, nitric oxide and arachidonic acid metabolites are produced by glia as well as neurons.

Many other mediators (eg. cytokine, chemokine, growth factor, steroids) control log term changes in the brain (eg. synaptic plasticity, remodeling etc.) mainly by altering gene transcription.

• Neurotransmitters are also grouped as large molecule neurotransmitters and small molecule neurotransmitters.
  • Acetylcholine, norepinephrine, dopamine, serotonin, gamma-aminobutyric acid, glycine, glutamate and aspartate are the small molecule neurotransmitters located in the CNS.
    • They are synthesised in the cytosol of the presynaptic terminal and cause most of the responses in the CNS.
    • Their actions on receptors usually occur within a millisecond or less after release.
    • After release they are degraded, diffuse out of the cleft or are absorbed by active transport back into the transmitter vesicles.
  • β-endorphin, vasopressin, oxytocin, growth hormone, enkephalin, substance P, somatostatin, cholecyctokinin, angiotensin II and neurotensin are the large group molecule neurotransmitters.
    • They are very potent, slower to act and present in much smaller quantities than the small molecule neurotransmitters.

The effect of the transmitters on the postsynaptic neuronal membrane is usually to increase or decrease conductance through ion channels. At other times, they stimulate receptor activated enzymes that in turn change the intracellular metabolic processes.

The neurotransmitter (first messenger) links with receptor proteins of the postsynaptic membrane and stimulates or inhibits an intracellular mediator, the second messenger. The second messenger then interacts with various cellular processes to invoke the ultimate action.

Different neurotransmitters and their role in CNS

1. Acetylcholine: Muscarinic M_{1 ­­}–M₅ subtypes and also nicotinic seen in CNS – Forebrain and striatum-inhibitory (muscarinic)
2. Norepinephrine: α₁ and α₂ β₁ and β₂ -mainly in brain stem and reticular formation – control in sleep and wakefulness, mood and emotion, temperature etc.
3. Epinephrine: seen in reticular formation. Role not well established.
4. Dopamine: D₂  subtypes – in basal ganglia and limbic system. Behaviour disturbances, control of movements ( implicated in Parkinsonism) and in hypothalamic – pituitary system.
5. 5-HT – multiple subtypes – sleep and wakefulness, mood and behaviour, appetite and neuroendocrine control.
6. Amino acids – Excitatory – Glutamate and Aspartate – 5 subtypes — NMDA receptor – in dissociative anesthesia, involved in epilepsy and anxiety states.
7. GABA -Inhibitory –  major inhibitory.  Glycine – restricted to spinal cord and retina.
8. Peptides – example is Substance P – in pain perception, opioid peptides (endogenous opioids like endorphins and enkhepalins)– analgesia, behaviour and sedative actions.