Antidepressants and Sedatives-Drugs, Medicine And Pathophysiology-Lecture Notes, Study notes of Pathophysiology

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Neuropharmacology II Antidepressants and Sedatives Depression • A frequent problem, affecting up to 5% of the population • Common presentations include low mood, loss of energy, disinterest in activities • May also include weight loss, sleep disturbance, or psychosis • Should be considered in patients with atypical dementia and chronic pain Diagnosis of Depression - DSM-IV • Five of the following present during the same 2-week period and represent a change from previous functioning: depressed mood markedly diminished interest or pleasure in all, or almost all, activities significant weight loss when not dieting or weight gain insomnia or hypersomnia psychomotor agitation or retardation fatigue or loss of energy feelings of worthlessness or excessive or inappropriate guilt diminished ability to think or concentrate, or indecisiveness recurrent thoughts of death, recurrent suicidal ideation or a suicide attempt • The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. • The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). • The symptoms are not better accounted for by Bereavement Pathophysiology of depression • At present, mechanism is unknown - may be more than one mechanism. • No useful biomarkers or imaging abnormality during life • Study of postmortem brain has not revealed any consistent structural or neurochemical abnormality • Majority of the currently available medications were discovered empirically • Most current theories are based on “amine hypothesis” docsity.com Biogenic amines Turnover of Biogenic Amines Dopamine – S yn thes is: tyros in e L-DO PA d op am ine – Origin: substantia nigra, ventral tegmental area – Targets: basal ganglia, cerebral corte x u Norepinephrine – S yn thes is: d op am in e N orepinep h rin e – Origin: locus c eruleus – Targets: cerebral cortex u Ser otonin – Synthesis: tryptophan 5-H TP serotonin – Origin: raphe nuclei – Targets: cortex, basal ganglia, hippocampus, brainstem T H A A D C Dβ H T PH A A D C docsity.com • In severely depressed patients, ECT often produces a rapid improvement and may be the best initial treatment Sedatives and hypnotics • Used to reduce anxiety, or induce sleep • Very commonly prescribed • Two principal chemical classes: Benzodiazepines Barbiturates • Both work by enhancing activity of the inhibitory neurotransmitter, GABA GABA (γ-aminobutyric acid) CH2 CH2 CH2 COOH NH2 Glutamic Acid GABA Succinic semialdehyde GAD GABA-T • Principal inhibitory transmitter of the mammalian brain • Receptors: GABAA: ligand gated ion channels, regulate chloride ion, at least 15 different subunit proteins GABAB : G-protein coupled receptors Effects of benzodiazepines and barbiturates on GABA Receptors β γ α β α GABA BDZ GABA docsity.com • Both drugs bind to GABAA receptor subunits, but at different sites. • Neither one binds to the agonist site • Benzodiazepines increase the frequency of channel opening, but do not alter conductance or duration of opening • Barbiturates prolong the duration of channel opening Benzodiazepines • More than a dozen benzodiazepines are marketed in the US • They are distinguished primarily by their profiles of distribution and half-life. • Toxicity is mainly excessive sedation. Examples of some benzodiazepines trade name t1/2 - hours typical application midazolam Versed 1 - 3 IV - brief sedation for procedure triazolam Halcion 2 - 4 hypnotic - may produce amnestic syndrome temazepam Restoril 10 - 17 hypnotic lorazepam Ativan 10 - 20 hypnotic, sedative diazepam Valium 30 - 60 hypnotic, sedative flurazepam Dalmane 50 - 100 old hypnotic - not recommended • After chronic use, withdrawal seizures may occur, especially with short half-life agents • Flumazenil: a benzodiazepine antagonist, blocks effects of other benzodiazepines Barbiturates • Also distinguished largely by half-life and duration of action. • Toxicity is excessive sedation, but unlike benzodiazepines, often leads to respiratory depression which may be fatal. • Biochemical half lives range from 3 hours (methohexital) to 100 hours (phenobarbital) • Redistribution is a key mechanism regulating duration of the biological effect of barbiturates (and benzodiazepines) when administered rapidly. docsity.com Redistribution • Redistribution is a mechanism which limits the duration of action • Effect is greatest when: Brain Blood Muscle, adipose tissue and other organs Agent is administered rapidly (e.g., intravenous) Agent is highly lipophilic • Can lead to very short duration of action (minutes) even though biochemical half life is longer (hours). Clinical use of sedatives • Anxiolytic use Usually a medium to long acting benzodiazepine, such as diazepam, administered orally. • Hypnotic use Usually a short to medium acting benzodiazepine, such as temazepam, administered orally - but note that all hypnotics lose efficacy if taken daily. • Sedative use (for surgical procedures) A short acting benzodiazepine, such as midazolam A short acting barbiturate, such as thiopental Administered intravenously, and action terminated by redistribution. Tolerance, cross-tolerance, and addiction • Chronic use of sedatives of either class (benzodiazepine or barbiturate) induces tolerance to all members of the class, and cross-tolerance to members of the other class. docsity.com