Drugs Affecting the CNS

• The provided text is about bio-organic and pharmaceutical chemistry, specifically about drugs affecting the central nervous system (CNS).

Drugs Affecting the CNS

• This covers minor tranquilizers, major tranquilizers, antidepressants and antiepileptic/antiparkinsonians
• Also covers stimulants, psychedelics, analgesics and general anesthetics

Minor Tranquilizers

• These include anxiolytics and hypnotics
• Anxiolytics relieve anxiety, while hypnotics treat insomnia
• Benzodiazepines are used for treating acute anxiety and insomnia
• A long acting ½ life of Valium and Librium is 24hrs
• Most sedatives, in addition to being anxiolytic, are anticonvulsant and addictive
• Physical dependence may develop and they are usually safe except when combined with alcohol.

Benzodiazepines

• Benzodiazepines share a core structure consisting of a benzene ring fused to a diazepine ring.
• Examples of benzodiazepines include diazepam (Valium), oxazepam (Serax), lorazepam (Ativan), temazepam, and chlordiazepoxide (Librium), which was the 1st discovered in 1955.

Metabolism of Benzodiazepines

• The process involves phase 1 hydroxylation and further steps.
• For example, Diazepam (Valium) is metabolized into Temazepam via Phase 1 Hydroxylation
• Diazepam is also metabolized to Nordazepam, which is then metabolized to Oxazepam.

Characteristics of Benzodiazepines

• Midazolam has a half-life of 2-4 hours and is used as an intravenous anesthetic and anticonvulsant.
• Zolpidem has a half-life of 2 hours
• Lorazepam, oxazepam, temazepam, and lormetazepam have half-lives of 8-12 hours
• Diazepam and chlordiazepoxide have half-lives of 20-40 hours
• Flurazepam has a half-life of 1 hour

Benzodiazepines: Mechanism of Action

• These drugs act by facilitating the effects of gamma-aminobutyric acid (GABA).
• GABA is an inhibitory neurotransmitter in the CNS
• This occurs mainly in brain tissue
• There exists a close correlation between GABA receptors and benzodiazepine receptors in the brain.

Neurotransmitters

• Key neurotransmitters include amines (acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, melatonin), amino acids (GABA, glutamate, glycine, histamine), neuropeptides (enkephalins, endorphins), peptide hormones (oxytocin, substance P, cholecystokinin, vasopressin, neuropeptide Y), hypothalamic releasing hormones (GnRH, TRH, CRH), lipids (anandamide), and gases (nitric oxide).

Action on receptors

• They bind to receptors to inhibit neurotransmitter release

Classes of Compounds

• Agonists: (e.g. diazepam) produce anxiolytic effects by interacting with the benzodiazepine receptor.
• Antagonists: possess high binding affinity but have no effect on their own
• Antagonists are used to treat benzodiazepine overdose.
• Flumazenil is an example of an antagonist.

Disadvantages

• Interaction with alcohol may cause long-lasting ‘hangover' effects
• May lead to tolerance and dependence.

Abuse of Benzodiazepines

• Benzodiazepines are mainly prescribed for anxiety, panic, sleep or seizure disorders
• Commonly abused benzodiazepines include Xanax (alprazolam), Klonopin (clonazepam), Valium (diazepam), Ativan (lorazepam), and Ambien (zolpidem)
• A withdrawal timeline includes symptoms peaking around week 2, with withdrawal starting 1-4 days after the last dose

Signs of Abuse

• Drowsiness, memory issues, and irritability
• Also slower thinking, increased anxiety, muscle weakness and changes in sleeping and eating patterns

Hypnotics

• Induce sleep, but are not as potent as anaesthetics
• Chloral hydrate, used since the 1830s, is metabolized to active form and trichloroethanol. Tolerance develops.

Barbiturates

• They were originally prescribed to treat insomnia and expanded to treat anxiety, epilepsy and severe migraines
• They depress the Central Nervous System (CNS)

Differences of Baribturates

• Classified according to the time taken for action onset and duration
• Pentobarbital acts in minutes and lasts for 6-12 hrs
• Tolerance develops and they are habit forming, requiring increasing doses
• They have a low therapeutic index, indicating a risk of suicide attempts
• Can be dangerous when taken with alcohol
• Both depress the CNS and are metabolized by the liver
• Can lead to liver failure
• Their use has greatly reduced with the advent of benzodiazepines.

Durations effects are seen

• Effects occur within 20 minutes for very short-acting barbiturates like methohexital
• Effects occur within 40 minutes and last up to 6 hours for short-acting barbiturates such as pentobarbital
• Effects can last several days for long-acting barbiturates like phenobarbital
• Increase in plasma concentration of barbiturates can have effects ranging via sedation to death

Barbiturates vs Benzodiazepines

• Both contain similar effects on the CNS
• Barbiturates: Higher doses can lead to death
• Benzos: Rarely the cause of death when taken alone

Major Tranquilizers

• Neuroleptics (antipsychotics) are used for seriously mentally disturbed individuals to control the manic phase
• Provide sedation while still allowing the patient to be easily aroused
• Used in treatment of schizophrenia, relieves thought disturbance, paranoia, hallucinations, and delusions.
• Best known examples are phenothiazines

Phenothiazines

• Developed in France as antihistamines in 1950s
• They antagonize the dopamine D2-dopaminergic receptor in the brain
• This reduces dopamine levels and helps decrease hallucinations and delusions
• They antagonize the muscarinic cholinergic receptors weakly
• Leading to anticholinergic side effects such as dry mouth, blurred vision, constipation, and urinary retention.