DIAZEPAM a SEDATIVE

1. DIAZEPAM a SEDATIVE BY: WicheL Ann MaquiLing

2. STRUCTURE OF DIAZEPAM

3. Diazepam • Diazepam was the second benzodiazepine to be invented by Leo Sternbach of Hoffmann-La Roche, and was approved for use in 1963 • also found in nature: several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines • each mL contains 5 mg diazepam compounded with 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as preservative

4. DEFINITION • drug which belongs to the class of medications known as benzodiazepines that depress activity of the central nervous system • possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties • A sedative is a substance that depresses the central nervous system (CNS), resulting in calmness, relaxation, reduction of anxiety, sleepiness, and slowed breathing, as well as slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes

5. FORM • Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5°C. • odorless and has a slightly bitter taste • very slightly soluble in water, soluble in alcohol and freely soluble in chloroform Drug Forms: • Diazepam rectal gel • Diazepam injection • Diazepam oral solution • Diazepam tablets

7. USES OF DIAZEPAM • It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia. • It is also the first line of defense for a rare disorder called stiff-person syndrome

8. LIST OF USES • Short-term treatment of insomnia • Treatment of tetanus, together with other measures of intensive-treatment • Initial management of mania, together with firstline drugs like lithium, valproate or other antipsychotics • Adjunctive treatment (with antidepressants) of depression with symptoms of anxiety • Adjunctive treatment (with antipsychotics), in patients who develop early extrapyramidal side-effects • Adjunctive treatment of painful muscle conditions • Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures) • Palliative treatment of stiff person syndrome • Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures) • Treatment of overdosage with hallucinogens or CNS stimulants • Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poison), lindane, chloroquine, physostigmine, or pyrethroids • Emergency treatment of eclampsia, along with IV magnesium sulfate • Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy • Used in the treatment for irritable bowel syndrome. • Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome • Treatment of the symptoms of alcohol and opiate withdrawal

9. Mode of action • Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. • It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. • After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day. • In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects

10. MODE OF ACTION • Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity • binds to a specific subunit on the GABAA receptor at a site that is distinct from the endogenous GABA molecule.The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.

11. MODE OF ACTION • Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. • This arises from the hyperpolarization of the post-synaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors

12. Gamma-aminobutyric acid (GABA) - is an inhibitory neurotransmitter found in the nervous systems of widely divergent species - it is the chief inhibitory neurotransmitter in the central nervous system and also in the retina • GABAA receptor - is one of two ligand-gated ion channels responsible for mediating the effects of GABA

13. Side effects Diazepam has a range of side effects which are common to most benzodiazepines. Most common side effects include: • Somnolence • Suppression of REM sleep or dreaming • Addiction • Impaired motor function • Impaired coordination • Impaired balance • Dizziness • Depression • Impaired learning • Anterograde amnesia (especially pronounced in higher doses) • Cognitive deficits • Reflex tachycardia

14. Diazepam (Valium Synthesis)

15. Acetic anhydride

16. Friedel Crafts Acylation

17. Treatment with Aqueous NaOH

18. Acetylation (treatment of amino group with chloroacetyl chloride)

19. Treatment of Ammonia (SN2 reaction)

20. Formation of an Imine (intramolecular reaction of ketone an 1° Amine)