CNS Depressants and CNS Depressants and Antidepressants Antidepressants Pamela E. Potter, Ph.D. Pamela E. Potter, Ph.D. Dept. Pharmacology Dept. Pharmacology Midwestern University Midwestern University Arizona College of Osteopathic Arizona College of Osteopathic Medicine Medicine CNS Depressants CNS Depressants Alcohol Alcohol Opium Opium Bromides Bromides- 1800s 1800s Chloral hydrate Chloral hydrate- 1800s 1800s Barbiturates Barbiturates- 1912 1912- 1950s 1950s Benzodiazepines Benzodiazepines- 1961 1961 Zolpidem (Ambien), zalpelon Zolpidem (Ambien), zalpelon (Sonata) (Sonata)- 1990s 1990s- 2000s 2000s
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CNS Depressants and CNS Depressants and AntidepressantsAntidepressants
Pamela E. Potter, Ph.D.Pamela E. Potter, Ph.D.Dept. PharmacologyDept. Pharmacology
Midwestern UniversityMidwestern UniversityArizona College of Osteopathic Arizona College of Osteopathic
Drugs and the GABADrugs and the GABAAAReceptorReceptor
BarbituratesBarbiturates
Increase Increase durationduration of action of GABA of action of GABA Independently opens ClIndependently opens Cl-- channelchannelInhibits other excitatory receptorsInhibits other excitatory receptorsVery low margin of safety Very low margin of safety Low therapeutic index (LDLow therapeutic index (LD5050 vsvs TDTD5050))
EffectsEffects
Diminish awarenessDiminish awarenessDecrease response to stimulationDecrease response to stimulationDecrease cognitionDecrease cognitionDecrease activityDecrease activityDrowsiness, lethargyDrowsiness, lethargyAmnesiaAmnesiaHypnosisHypnosis
Side EffectsSide EffectsCNS depressionCNS depressionrespiratory depression!respiratory depression!dangerous when combined with dangerous when combined with alcoholalcoholphysical dependencephysical dependencesevere withdrawalsevere withdrawal
Overdose Overdose can be can be Fatal!Fatal!
BenzodiazepinesBenzodiazepines
Very commonly prescribed in 1960s Very commonly prescribed in 1960s (housewife’s friend)(housewife’s friend)anxiolyticanxiolytic-- immediate, effectiveimmediate, effectivesedativesedative--hypnotic hypnotic anticonvulsantanticonvulsantintensifyintensify the action of GABAthe action of GABA-- very very safe, even in overdosesafe, even in overdose
The sedative/anticonvulsant action of The sedative/anticonvulsant action of diazepam is shorter than its other effectsdiazepam is shorter than its other effectsTime to peak effect of lorazepam ranges Time to peak effect of lorazepam ranges from 1from 1--6 hrs6 hrs
Cimetidine Inhibition of Cimetidine Inhibition of Benzodiazepine MetabolismBenzodiazepine Metabolism
MidazolamMidazolam +Cimetidine
Erythromycin Decreases Erythromycin Decreases Metabolism of MidazolamMetabolism of Midazolam
MidazolamMidazolam +Erythromycin
CNS DepressantsCNS DepressantsThe effects areThe effects are suprasupra--additiveadditive--i.e., the effects of two together are i.e., the effects of two together are greater than the sum of the two greater than the sum of the two alonealoneBenzodiazepines can produce physical Benzodiazepines can produce physical and psychological dependenceand psychological dependence
Zolpidem (Ambien)Zolpidem (Ambien)
Binds to benzodiazepine receptor Binds to benzodiazepine receptor subtype subtype BZ1BZ1VERY rapid actionVERY rapid action; “blackouts”; “blackouts”Little effect on REM sleepLittle effect on REM sleepApproved for shortApproved for short--term treatment term treatment of insomniaof insomniaZalpelon (Sonata) similarZalpelon (Sonata) similar
AntihistaminesAntihistamines
Diphenhydramine (Benadryl)Diphenhydramine (Benadryl)ChlorpheneramineChlorpheneramine ((ChlorChlor--TrimetonTrimeton))DimenhydrinateDimenhydrinate (Dramamine)(Dramamine)Block H1 receptorBlock H1 receptorVery sedating until tolerance develops Very sedating until tolerance develops
ToleranceTolerance-- AntihistaminesAntihistamines
MSLT SSS
Benzodiazepine Benzodiazepine ToleranceTolerance
Khanna et al, Pharm. Biochem. Behav. 59, 511-519 (1998)
Chlordiazepoxide
Diazepam
Tolerance to PentobarbitalTolerance to Pentobarbital
Khanna et al, Pharm. Biochem. Behav. 59, 511-519 (1998)
Benzodiazepines cause Benzodiazepines cause tolerance to tolerance to EtOHEtOH
Khanna et al, Pharm. Biochem. Behav. 59, 511-519 (1998)
ToleranceTolerance-- AlcoholAlcohol
CarisoprodolCarisoprodol (Soma)(Soma)
SedatingSedating muscle relaxant, in a group that muscle relaxant, in a group that also includes also includes
These act as sedatives in the brain stemThese act as sedatives in the brain stemCarisprodolCarisprodol is converted to is converted to meprobamatemeprobamate(Milltown),(Milltown), which acts like a barbituratewhich acts like a barbiturateNow a very popular drug of abuseNow a very popular drug of abuse
2
Meprobamate (C9H18N2O4)
Conversion of Conversion of CariosprodolCariosprodol to to MeprobamateMeprobamate
/CarisoprodolMeprobamate
CNS Depressants and CNS Depressants and DrivingDriving
At any time, about 5% of people are At any time, about 5% of people are taking prescribed benzodiazepinestaking prescribed benzodiazepinesIn drivers apprehended for impaired In drivers apprehended for impaired driving, 10driving, 10--15% will have 15% will have benzodiazepines in their bloodbenzodiazepines in their bloodThe effect of benzodiazepines on The effect of benzodiazepines on driving performance is variable and not driving performance is variable and not always easy to predictalways easy to predict
CNS Depressants/DrivingCNS Depressants/Driving
Diazepam, Diazepam, flunitrazepamflunitrazepam and and clonazepamclonazepam seem to be the most seem to be the most common drugs reported in drivers common drugs reported in drivers suspected to be impairedsuspected to be impaired
CNS Depressants & Car CNS Depressants & Car AccidentsAccidents
Australian study showed that drivers with Australian study showed that drivers with benzodiazepines in their blood were benzodiazepines in their blood were somewhat more likely (O.R. 4.5 somewhat more likely (O.R. 4.5 vsvs 3.2) to 3.2) to cause a car accidentcause a car accidentThose with BAC > 0.5% had an O.R. of Those with BAC > 0.5% had an O.R. of 34.134.1The odds of having an accident if The odds of having an accident if psychotropic drugs were combined with psychotropic drugs were combined with alcohol was increased 1.7 timesalcohol was increased 1.7 times
CNS Depressants & Car CNS Depressants & Car AccidentsAccidents
Austrian study of drivers injured in car Austrian study of drivers injured in car accidents found:accidents found:36.9% had BAC = .149 36.9% had BAC = .149 ± .054± .0548.1 % of drivers had benzodiazepines, 8.1 % of drivers had benzodiazepines, average drug level 68.7± 62.6 mcg/laverage drug level 68.7± 62.6 mcg/lAnother study found Another study found vigiliancevigiliance impaired impaired after single dose of 5 and 10 mg after single dose of 5 and 10 mg diazepam, 0.5 mg alprazolam, but not diazepam, 0.5 mg alprazolam, but not 10 mg oxazepam10 mg oxazepam
CNS Depressants & Car CNS Depressants & Car AccidentsAccidents
55-- year study showed elderly people year study showed elderly people taking benzodiazepines (Medicaid records) taking benzodiazepines (Medicaid records) 22--4 times more likely to cause an 4 times more likely to cause an automobile accident at higher doses of automobile accident at higher doses of diazepam (diazepam (≥ 20 mg/day)≥ 20 mg/day)
At low doses, likelihood of accident no At low doses, likelihood of accident no higher than nonhigher than non--drug controldrug controlTCAs (e.g. TCAs (e.g. 125 mg 125 mg amitriptylineamitriptyline) increased ) increased likelihood 5likelihood 5--6 times6 times
Alprazolam ImpairmentAlprazolam Impairment
1 mg alprozolam (Zanax) given 1 hour before the driving test, compared with placebo Neuropsychopharmacology 27, 260-269 (2002)
Zolpidem Impairs DrivingZolpidem Impairs Driving
*
**
EtOH was administered to produce BAC 0.05% on Day 1. Zolpidem or Zapelon were administered during the night, and driving was measured 6 hours later (in the morning)
Triazolam compares to Triazolam compares to EtOHEtOH at at producing impairmentproducing impairment
Alcohol breath measure was 0.13% at time of testing
MoodMood-- antidepressants affect NEantidepressants affect NEMay be involved in anxietyMay be involved in anxietyPain regulationPain regulationLearning and memory Learning and memory Stress depletes NEStress depletes NEAlpha and beta receptorsAlpha and beta receptorsDrugs act on synthesis, uptake Drugs act on synthesis, uptake and breakdownand breakdown
Serotonin PathwaysSerotonin Pathways
Serotonin Serotonin
MoodMooddepression treated with 5HT redepression treated with 5HT re--uptake uptake inhibitorsinhibitors
May promote sleep (May promote sleep (tryptophantryptophan))AnxietyAnxietyObsessive compulsive disorderObsessive compulsive disorderHunger or appetiteHunger or appetitePerception (LSD)Perception (LSD)Many receptor subtypes, targeted by Many receptor subtypes, targeted by newer drugs newer drugs
The Amine HypothesisThe Amine HypothesisThe Amine Hypothesis
PET ScansPET Scans
Treatments for Treatments for DepressionDepression
Inhibit reInhibit re--uptake of NE and 5HTuptake of NE and 5HTAnticholinergic/AntihistamineAnticholinergic/AntihistamineSedation, often significantSedation, often significantNo euphoria/ low abuse potentialNo euphoria/ low abuse potential22--3 weeks to have effect3 weeks to have effect
Irreversibly inhibit MAOIrreversibly inhibit MAO--A, which breaks A, which breaks down NE & 5HT, and MAOdown NE & 5HT, and MAO--B, which B, which breaks down DAbreaks down DA
Used for depression which doesn’t Used for depression which doesn’t respond to other drugs, atypical respond to other drugs, atypical depression, etc...depression, etc...
Side EffectsSide EffectsSevere hypertensive crisis! Severe hypertensive crisis!
MAO in the gut breaks down certain MAO in the gut breaks down certain amines as we eat them, such as amines as we eat them, such as tyraminetyramineTyramineTyramine causes release of NEcauses release of NETyramineTyramine in foods: red wine, beer, aged in foods: red wine, beer, aged cheese, etc…cheese, etc…
SympathomimeticsSympathomimetics (cold medicines) also (cold medicines) also cause cause HTxHTx with MAOIswith MAOIs
Side EffectsSide EffectsTremorsTremorsSedation, excitation, insomniaSedation, excitation, insomniaOrthostatic hypotensionOrthostatic hypotensionDelayed ejaculationDelayed ejaculationFatigueFatigueWeight gain, skin rashWeight gain, skin rashDizziness, blurred vision, constipationDizziness, blurred vision, constipation
SSRIsSSRIsInhibit reInhibit re--uptake of 5uptake of 5--HTHT
Inhibit NE & 5Inhibit NE & 5--HT reHT re--uptakeuptakeVenlafaxine (Effexor)Venlafaxine (Effexor)
SSRIsSSRIs
FluoxetineFluoxetineProzac, Prozac Weekly, genericProzac, Prozac Weekly, genericSerafemSerafem (14 days before menses)(14 days before menses)Antidepressant effect usually takes 3Antidepressant effect usually takes 3--4 4 weeks to developweeks to develop
Antidepressants are NOT mood altering Antidepressants are NOT mood altering drugs, they do NOT cause euphoriadrugs, they do NOT cause euphoria
Slow onset of effectSlow onset of effectLate side effectsLate side effectsLong duration after drug discontinuedLong duration after drug discontinuedHalfHalf--life of 4.7 and 16.7 for fluoxetine life of 4.7 and 16.7 for fluoxetine and and norfluoxetinenorfluoxetine after 3after 3--6 6 mosmosadministrationadministration
Brunswick et al, J. Brunswick et al, J. ClinClin. . PsychopharmPsychopharm. 21: 616. 21: 616--618 (2001)618 (2001)
Drug InteractionsDrug Interactions
Fluoxetine inhibits CYP2D6Fluoxetine inhibits CYP2D6Increases levels of tricyclic antidepressants Increases levels of tricyclic antidepressants (clearance (clearance decdec. 70% or more). 70% or more)Toxicity may occur with TCAs if combined Toxicity may occur with TCAs if combined with fluoxetinewith fluoxetineCYP2D6 inhibition interferes with CYP2D6 inhibition interferes with conversion of some conversion of some opioidsopioids to active to active compounds compounds
Paroxetine (Paxil)Paroxetine (Paxil)
Shorter halfShorter half--life and shorter duration of life and shorter duration of action than fluoxetineaction than fluoxetineLess effect on most hepatic enzymes Less effect on most hepatic enzymes (except CYP2D6), fewer drug (except CYP2D6), fewer drug interactionsinteractionsMore selective than fluoxetine for 5More selective than fluoxetine for 5--HT HT uptakeuptakeMore likely to cause sedationMore likely to cause sedation
Venlafaxine (Effexor)Venlafaxine (Effexor)Blocks both 5Blocks both 5--HT and NE reHT and NE re--uptakeuptakeLong duration of actionLong duration of actionSide effects commonSide effects commonIncreases blood pressure in some Increases blood pressure in some patientspatients
Antidepressant TrendsAntidepressant Trends
Pirraglia et al, Prim. Care Com. J. Clin. Psychiat. 5:153-157 (2003)
Uses of SSRIsUses of SSRIsDepression Depression -- very effectivevery effectivePanic disorderPanic disorderObsessiveObsessive--compulsive disordercompulsive disorderBulimiaBulimiaPMDDPMDDAlcoholismAlcoholism-- recoveryrecoveryPremature ejaculationPremature ejaculation
Side EffectsSide EffectsMild: no cardiac toxicityMild: no cardiac toxicityGI: nausea, loss of appetiteGI: nausea, loss of appetiteWeight loss or gainWeight loss or gainCNS: anxiety, insomnia, or sedationCNS: anxiety, insomnia, or sedationSexual disinterest/dysfunctionSexual disinterest/dysfunctionPhotosensitivityPhotosensitivity
Serotonin SyndromeSerotonin SyndromeWith MAOIsWith MAOIsAgitation, confusion, deliriumAgitation, confusion, deliriumHyperpyrexia, shiveringHyperpyrexia, shiveringDiaphoresis, diarrhea, hyperreflexia, Diaphoresis, diarrhea, hyperreflexia, tremortremorMay progress to convulsions and comaMay progress to convulsions and coma
Discontinuation Discontinuation SymptomsSymptoms
Rare, may last 5Rare, may last 5--8 days 8 days dizziness, ataxia, dizziness, ataxia, parasthesiasparasthesiasfluflu--like symptoms, sleep like symptoms, sleep disturbances disturbances anxiety, agitation, crying spells, anxiety, agitation, crying spells, irritability. irritability. most common with short acting most common with short acting drugs, e.g. drugs, e.g. paroxetineparoxetine
Mirtazapine (Remeron)Mirtazapine (Remeron)
NOT an uptake inhibitorNOT an uptake inhibitorblocks presynaptic blocks presynaptic αα22 receptorsreceptors
blocks 5blocks 5--HTHT2A2A and 5and 5--HTHT33 receptorsreceptorsReduces anxiety, insomnia, nausea, sexual Reduces anxiety, insomnia, nausea, sexual problemsproblems
Antihistamine Antihistamine –– significant significant sedationsedationEffects similar to TCAs, without cardiac Effects similar to TCAs, without cardiac toxicitytoxicity
Ridout et al, Hum. Psychopharm. 18: 261-269 (2003)
LARS sedation, mean maximum change from baseline ± SEM on Day 2, *p>0.05
Bupropion (Wellbutrin) Bupropion (Wellbutrin)
Inhibits DA reInhibits DA re--uptakeuptake((ZybanZyban))-- extended release, smoking extended release, smoking cessationcessation
Side EffectsSide EffectsCNS stimulation, anxiety, but not sedatingCNS stimulation, anxiety, but not sedating
May cause May cause seizuresseizures ((espesp with TCAs)with TCAs)
May work where others haven’t May work where others haven’t Few sexual side effects Few sexual side effects
Antidepressant TrendsAntidepressant Trends
Pirraglia et al, Prim. Care Com. J. Clin. Psychiat. 5:153-157 (2003)
Driving ImpairmentDriving ImpairmentElderly drivers taking TCAs about 2x more Elderly drivers taking TCAs about 2x more likely to be involved in an accidentlikely to be involved in an accident**
Studies using standard driving tests Studies using standard driving tests designed to investigate antidepressant designed to investigate antidepressant effectseffectsDriving 62 mi on a highway at 59 mph and Driving 62 mi on a highway at 59 mph and a steady lateral position a steady lateral position SDLP measuredSDLP measured
**LeveilleLeveille et al, et al, EpidemiolEpidemiol. 5: 591. 5: 591--598 (1994)598 (1994)**Ray et al, Am. J. Ray et al, Am. J. EpidemiolEpidemiol. 136: 873. 136: 873--883 (1992)883 (1992)
SDLPSDLP
SDLP rises SDLP rises exponetiallyexponetially as BAC risesas BAC risesBAC over 0.5 mg/ml correlates with BAC over 0.5 mg/ml correlates with increased fatal accidentsincreased fatal accidentsBAC of 0.5 mg/ml causes a 2.4 cm. BAC of 0.5 mg/ml causes a 2.4 cm. change in SDLPchange in SDLPTest other drugs against this criteriaTest other drugs against this criteria
TCAs and drivingTCAs and driving
Meta analysis of 10 studiesMeta analysis of 10 studiesAcute doses of Acute doses of
Caused changes in SDLP equivalent to BAC Caused changes in SDLP equivalent to BAC 0.8 mg/ml0.8 mg/mlBUT after 1 week treatment tolerance had BUT after 1 week treatment tolerance had developed to the effectdeveloped to the effect
RamaekersRamaekers, JG, J. , JG, J. ClinClin. . PsychiatPsychiat. 64:20. 64:20--29 (2003)29 (2003)
TCAs and DrivingTCAs and Driving
BAC 0.8 mg/ml
Ramaekers, J, J. Clin. Psychiat. 64:20-29 (2003)
SSRIs and DrivingSSRIs and DrivingFluoxetine and Fluoxetine and paroxetineparoxetine (SSRIs) (SSRIs) considered nonconsidered non--sedating, have never sedating, have never been shown to affect drivingbeen shown to affect drivingVenlafaxine also does not affect drivingVenlafaxine also does not affect drivingNefazodone has some effect, but Nefazodone has some effect, but tolerance develops rapidlytolerance develops rapidly
SSRIs and DrivingSSRIs and Driving
Ramaekers, J, J. Clin. Psychiat. 64:20-29 (2003)
Ridout et al, Hum. Psychopharm. 18: 261-269 (2003)
Mirtazapine increases Mirtazapine increases reaction timereaction time
Fluoxetine/Fluoxetine/BDZsBDZs
Ramaekers, J, J. Clin. Psychiat. 64:20-29 (2003)
BAC 0.8 mg/ml
Somnolence/DrivingSomnolence/Driving
Ramaekers, J, J. Clin. Psychiat. 64:20-29 (2003)
SummarySummary
TCAs can significantly impair driving, TCAs can significantly impair driving, especially if combined with alcoholespecially if combined with alcoholSSRIs in general do not affect driving SSRIs in general do not affect driving abilityability-- but might increase the effects of but might increase the effects of BDZsBDZs or alcoholor alcoholMirtazapine causes somnolence, but Mirtazapine causes somnolence, but driving studies have not been donedriving studies have not been doneThere are no studies for There are no studies for bupropionbupropion, , although impairment is highly unlikelyalthough impairment is highly unlikely