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B.Pharm Lab. Instruction Manuals

APHE Anatomy, Physiology, and Health Education

Pharmacy study material

# 3.5.3 Pharmacology I

## Lab 8 Determination of the prolongation action of Diazepam on Pentobarbitone induced sleeping time (Cont'd...)

### Theory (cont'd...)

The physiological sleep inducers are adenosine and the hormone melatonin. Melatonin is secreted by the epithalamus gland. It's concentration is high in the dark and it induces sleep by inhibiting the RAS.

When the brain is performing, it uses high level of ATP, which generates the adenosine. When significant amount of adenosine accumulated in the brain, it binds with the A1 receptor and inhibits the cholinergic neurons of reticular activating system, those are involved in arousal.

There is another one mechanism which maintain balances between brain excitations and inhibition that is essential for normal brain performance. Complications arise with too much excitations of brain include convulsions, anxiety, high blood pressure, restlessness and insomnia. There are physiological inhibitor of neuronal cell like $\gamma$-amino butyric acid (GABA), glycine etc. GABA is a neurotransmitter, present in most of the synapses (40%) in central nervous system and inhibits the post synaptic neurons by opening the chloride (Cl$^-$) channel followed by the hyper-polarization of the neuron. It acts by binding with the ligand gated ion channel (GABA$_A$ receptors) in the site of the receptor, located between $\alpha 1$ and $\beta 2$ subunits. Thus GABA inhibits the neurons present in the region of RAS and inhibits the state of stimulation of those neurons.

Insomnia is a sleep disorder, when it is difficult for one to fall asleep. The possible causes of insomnia include stress, excessive caffeine intake, mood disorders, shift work, pain or other medical issues, drugs etc.

When one is incapable of maintaining the balance between the state of excitation and inhibition, GABA agonists are given from the outside. Based on the GABA$_A$ receptors inhibitory action, barbiturates, benzodiazepine (BZDs) and non BZDs groups of drugs are used for the treatment of insomnia and other central nervous system disorders like convulsions, anxiety, epilepsy etc.

Barbiturates, the first generation hypnotics, has higher affinity towards the ionotropic GABA$_A$ receptors and act by decreasing waking, increasing slow-wave sleep and enhancing the intermediate stage situated between slow-wave sleep and paradoxical sleep, at the expense of this last sleep stage. Barbiturates can induce sleep in absence of GABA as well as it is capable of stimulating the GABA binding sites of GABA$_A$ receptors. Pentobarbitone further inhibits the glutamate mediated depolarization of post synaptic neurons.