Neuropharmacology IIAntidepressants and SedativesDepressionA frequent problem, affecting up to 5% of the populationCommon presentations include low mood, loss of energy, disinMay also include weight loss, sleep disturbance, or psychosiShould be considered in patients with atypical dementia and Diagnosis of Depression - DSM-IVFive of the following present during the same 2-week period depressed moodmarkedly diminished interest or pleasure in all, or almost asignificant weight loss when not dieting or weight gaininsomnia or hypersomniapsychomotor agitation or retardationfatigue or loss of energyfeelings of worthlessness or excessive or inappropriate guildiminished ability to think or concentrate, or indecisivenesrecurrent thoughts of death, recurrent suicidal ideation or The symptoms cause clinically significant distress or impairThe symptoms are not due to the direct physiological effectsThe symptoms are not better accounted for by BereavementPathophysiology of depressionAt present, mechanism is unknown - may be more than one mechNo useful biomarkers or imaging abnormality during lifeStudy of postmortem brain has not revealed any consistent stMajority of the currently available medications were discoveMost current theories are based on “amine hypothesis”Biogenic aminesTurnover of Biogenic AminesClasses of AntidepressantsTricyclics and heterocyclicsSelective serotonin reuptake inhibitors (SSRI’s)BupropionNonselective MAO inhibitorsNon-pharmacological therapyECTPsychotherapyTricyclics and heterocyclics - Clinical pharmacologyLarge family of structurally related compoundsMultiple pharmacological actionsTherapeutic effect probably due to ability to block reuptakeAll may be sedating, although some much more than othersMany of these drugs have anticholinergic (anti-muscarinic) aTricylics and heterocyclics - pharmacokinetics and toxicityAll are primarily metabolized by the liver, and undergo firsBiochemical half-lives range from 4 to more than 24 hours, bOverdose of tricylics (more than 1 gram) is often lethal dueSome commonly used tricylics and heterocyclicsAmitriptiline (Elavil®)Inhibits serotonin & NE reuptakeProminent anticholinergic effectsMetabolite is nortriptylineDesipramine (Norpramine®)Inhibits NE reuptakeMild anticholinergic effectsTrazodone (Desyrel®)HeterocyclicInhibits serotonin reuptakeMinimal anticholinergic effectsSedatingSelective Serotonin Reuptake Inhibitors (SSRI’s)Act by inhibition of presynaptic reuptake of serotonin in ceNot as sedating as many of the tricylic compoundsAlso do not have the anticholinergic side effects of the triSome are potent inhibitors of P450 enzyme systems, and may lSome commonly used SSRI’sFluoxetine (Prozac®)Sertaline (Zoloft®)Citalopam (Celexa®)Paroxetine (Paxil®)All are potent inhibitors of serotonin reuptakeAdverse effects: anxiety, tremorOverdose of SSRI alone is rarely lethalShould not be administered with nonselective MAO inhibitorsSuicide as an adverse effect?BupropionStructurally related to the tricyclics, but seems to have a Not sedating or anticholinergic, but does sometime induce haAlso effective in treating tobacco addictionMAO InhibitorsNon-selective, irreversible enzyme inhibitors - long duratioTherapeutic effect is due to is enhancement of CNS amine levMajor adverse effects are due to excessive accumulation of aTyramine: the “cheese effect.”Drug interactions: SSRI’s, sympathomimeticsSafe in carefully controlled circumstances, but “real world”Treatment of depressionMany patients will not report symptoms of depression unless Patients who are depressed may be suicidal - it is essentialThe response of an individual patient to a particular antideIn severely depressed patients, ECT often produces a rapid iSedatives and hypnoticsUsed to reduce anxiety, or induce sleepVery commonly prescribedTwo principal chemical classes:BenzodiazepinesBarbituratesBoth work by enhancing activity of the inhibitory neurotransGABA (-aminobutyric acid)Principal inhibitory transmitter of the mammalian brainReceptors:GABAA: ligand gated ion channels, regulate chloride ion, at GABAB : G-protein coupled receptorsEffects of benzodiazepines and barbiturates on GABA ReceptorBoth drugs bind to GABAA receptor subunits, but at differentNeither one binds to the agonist siteBenzodiazepines increase the frequency of channel opening, bBarbiturates prolong the duration of channel openingBenzodiazepinesMore than a dozen benzodiazepines are marketed in the USThey are distinguished primarily by their profiles of distriToxicity is mainly excessive sedation.After chronic use, withdrawal seizures may occur, especiallyFlumazenil: a benzodiazepine antagonist, blocks effects of oBarbituratesAlso distinguished largely by half-life and duration of actiToxicity is excessive sedation, but unlike benzodiazepines, Biochemical half lives range from 3 hours (methohexital) to Redistribution is a key mechanism regulating duration of theRedistributionRedistribution is a mechanism which limits the duration of aEffect is greatest when:Agent is administered rapidly (e.g., intravenous)Agent is highly lipophilicCan lead to very short duration of action (minutes) even thoClinical use of sedativesAnxiolytic useUsually a medium to long acting benzodiazepine, such as diazHypnotic useUsually a short to medium acting benzodiazepine, such as temSedative use (for surgical procedures)A short acting benzodiazepine, such as midazolamA short acting barbiturate, such as thiopentalAdministered intravenously, and action terminated by redistrTolerance, cross-tolerance, and addictionChronic use of sedatives of either class (benzodiazepine or Both also induce tolerance to ethanol, which acts in part thBoth benzodiazepines and barbiturates may produce dependenceRapid withdrawal from either class of sedatives may lead toStandaert 1 March 2005 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: ¾ depressed mood ¾ markedly diminished interest or pleasure in all, or almost all, activities ¾ significant weight loss when not