Transcript lec.7-426
ANTIANXIETY Antianxiety agents, formerly called minor tranquilizers, and known also as anxiolytic and tensiolytics, are used to control neuroses and stress. Drowsiness is the most common untoward effect of antianxiety agents. Anxiety is an emotional state characterized by a disquietude of mind and a fearful anticipation events which may be brought on by stressful events in normal life. Major Uses • • • • • • • A. Anxiety state B. Insomnia C. Epilepsy D. Muscle spasticity E. Induction of amnesia F. Adjunct in alcohol withdrawal G. For differential psychiatric diagnosis. Classification According to their chemical structure, antianxiety agents can be divided into five classes: 1. 2. 3. 4. 5. benzodiazepines- - GABA receptor modulators: Diazepam, Alprazolam. Non – benzodiazepines: Alpidem. Propanediol carbamates: Meprobamate. Antihistaminic: hydroxyzine. Miscellaneous - 5HT agonists: Buspirone. 1. Benzodiazepines • In 1990 diazepam and lorazepam were in the top 20 most frequently used generic drugs. • Benzodiazepines are not general depressants of the CNS like barbiturates and other sedatives and hypnotics. • They don’t induce true anaesthetic effect, since awareness is still present and total muscular relaxation is not obtained even in with large doses. • It is believed that they exert at least some of their action via GABA- mediated inhibitory neurotransmission by binding to a specific site on GABAA receptor. • Benzodiazepines are orally absorbed. 1) 3H-1,4-benzodiazepines Chlordiazepoxide (librium) • Indications: anxiety, parenteral for preanesthetic use, status epilepticus, chemotherapy induced N/V, acute alcohol withdrawl, psychogenic catatonia, chronic insomnia • 0.5, 1.2 mg tablets, oral solution concentrate, injection 7-Chloro-2-methylamino-5-phenyl-3H1,4-benzodiazepine-4-oxide CH3 NH N Cl N O Chlordiazepoxide HCl Librium®, Mitran®, Reposans® Synthesis Structure Activity Relationship a) b) c) In ring A an electron – withdrawing group such as Cl, Br, NO2, NO2, or CN at position 7. A methyl Group is attached to the nitrogen atom in position 1 in ring B. However, substituents at position 1 that are metabolically are still clinically useful e.g. Flurazepam. Replacement of the carbonyl function with two hydrogens in position 2 gives medazepam, less potent than diazepam. d) Replacement of one of the hydrogen with a OH group on position 3 lower the activity on the one hand and aids elimination on the other. Introduction of a carbonyl function in the 3 position increases the duration of action and also favours formation of water soluble salts. c) d) e) f) g) h) A phenyl substituent at the 5, position. α-pyridyl derivative and cycloalkyl substituent at 5 position give potent compounds. Electronegative substituents such as Cl or F at the ortho and disubstituted in both ortho positions in ring C. Derivatives with additional rings joining the diazepine nucleus at the 1 and 2 positions are generally more active than the corresponding 1-methylbenzodiazepines. Replacement of the benzene ring by heteroaromatic (e.g. pyrazole) resulted in compounds with interesting anxiolytic properties ( e.g. ripazepam). Saturation of the 4,5- double bond reduces potency, as does a shift of the unsaturation into the 3,4-position. Diazepam (valium) 7- Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one Synthesis • • • • • Uses: It is used for the control of anxiety and tension state, the relief of muscle spasm. It is also helpful in combating withdrawal symptoms in chronic alcoholics. It has shown effectiveness in certain types of epilepsy and in labour it has many advantages over other drugs. It is metabolized to nordiazepam which is also active with half – life of 60 hrs. Assay: A sample (0.5) is dissolved in glacial acetic acid (80ml). The solution is titrated with 0.1 N perchloric acid and the end point is determined potentiometrically. Dose: 5 to 30mg daily in divided doses. Metabolism • Biotransformation of benzodiazepines takes place in the liver by microsomal – metabolizing system. N-demethyation gives active metabolite with longer life than the parent drug. Diazepam and Chlorzepate to active metabolite such as N-desmethyl diazepam (nordiazepam). • Hydroxylation at position 3 followed by glucuronidation is the main metabolic pathway. Mode of action 2. Non-benzodiazepines Alpidem (Ananxyl) • It is an imidazopyridine antianxiety agent with anticonvulsant properties. • It is the first non-benzodiazepine anxiolytic to show selectivity for omega-1 modulatory site of the GABA receptors. • It is similar to benzodiazepines, but is significantly better tolerated with lower abuse potential. 3. Propandiol Carbamates • MOA: a carbamate derivative that has multiple CNS sites of action by inhibiting neurotransmission in the thalamus and limbic system, inhibits multi-neuronal spinal reflexes. Acts like benzodiazepines, but less selective and higher abuse potential. • It is also used as a sedative and hypnotic.. • 200, 400 and 600 mg tablets CH3 O H2N O O H3C NH2 O Meprobamate - Equanil®, Miltown®, Neuramate® 4. Antihistaminic • Indications: Skin allergies (pruritis). Also anxiety and tension, prior to dental procedures, acute emotional problems, alcoholism, anxiety caused by heart disease, parenteral antiemetic and analgesia • MOA: subcortical area CNSdepressant, a rapid-acting true ataraxic (calmative). H1 Antagonist • 10,25, 50, 100 mg tablets and capsules, syrup, oral suspension injection N O OH N Cl Hydroxyzine - Atarax®, Vistaril® 5. Miscellaneous • Buspirone HCl - Buspar® • 5-H Agonist • Indications: management of anxiety disorders. • MOA: Unknown, has affinity for serotonin 5-HT1A and D2-dopamine receptors, but has NO anticonvulsant activity nor muscle relaxant properties • No tolerance or withdrawal issues: 5, 10, 15 mg tablets • Oxidative liver metabolism with active metabolites. • Often takes 3-4 weeks to see results