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Pharmacodynamics and Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacokinetics in Psychiatric
PharmacotherapyPharmacotherapy
Elizabeth A. Winans, PharmD, BCPPElizabeth A. Winans, PharmD, BCPP
University of Illinois at ChicagoUniversity of Illinois at Chicago
Psychiatric Clinical Research CenterPsychiatric Clinical Research Center
OverviewOverview
Review general pharmacology ofReview general pharmacology of– antidepressantsantidepressants mood stabilizersmood stabilizers
– anxiolyticsanxiolytics stimulantsstimulants
– antipsychoticsantipsychotics Discuss relevant pharmacokinetic Discuss relevant pharmacokinetic
parametersparameters
GABA-BZD receptorGABA-BZD receptor
GABAGABA– inhibitory neurotransmitter which rapidly inhibitory neurotransmitter which rapidly
alters the excitability of other output neuronsalters the excitability of other output neurons
– possesses anxiolytic action within the possesses anxiolytic action within the amygdalaamygdala
– involved with neurotransmitter modulation ininvolved with neurotransmitter modulation in 1/3 of brain impulses1/3 of brain impulses
AnxiolyticsAnxiolytics
Two types of GABA receptorsTwo types of GABA receptors GABAGABAAA
» major binding site for GABAmajor binding site for GABA
» Binding site for anxiolytic agentsBinding site for anxiolytic agents
• GABAGABABB
» does not bind anxiolytics does not bind anxiolytics
» minor GABA binding sitesminor GABA binding sites
GABA-BZD receptorGABA-BZD receptor
"Supramolecular Complex""Supramolecular Complex"– GABA recognition siteGABA recognition site
– BZD recognition siteBZD recognition site
– ClCl-- ion channel ion channel
– picrotoxin binding sitepicrotoxin binding site
Supramolecular Complex Supramolecular Complex
GABA-BZD receptorGABA-BZD receptor
Receptor agonists (e.g., GABA)Receptor agonists (e.g., GABA)– induce the direct opening of the Clinduce the direct opening of the Cl-- channel channel
– ClCl-- influx causes hyperpolarization influx causes hyperpolarization
– hyperpolarization then inhibits cell firinghyperpolarization then inhibits cell firing
GABA-BZD receptorGABA-BZD receptor
Receptor antagonists (e.g., picrotoxin)Receptor antagonists (e.g., picrotoxin)– impedes Climpedes Cl-- entrance into the cell preventing entrance into the cell preventing
hyperpolarizationhyperpolarization
– thus neuron is not inhibited from firingthus neuron is not inhibited from firing
GABA-BZD receptorGABA-BZD receptor
GABA potentiators (e.g., BZDs)GABA potentiators (e.g., BZDs)– augment the flow of Claugment the flow of Cl-- into the cell by into the cell by
increasing the frequency of channel openingincreasing the frequency of channel opening
– benzodiazepines do not act alone but rather benzodiazepines do not act alone but rather act in a synergistic manneract in a synergistic manner with GABAwith GABA
5HT5HT1A1A Receptor Receptor
5HT5HT1A1A is located on both pre- and is located on both pre- and
postsynaptic membranespostsynaptic membranes Coupled with G proteins and adenlylate Coupled with G proteins and adenlylate
cyclasecyclase Buspirone acts as a partial 5HTBuspirone acts as a partial 5HT1A1A agonist agonist
Pharmacokinetics of BZDsPharmacokinetics of BZDs
Variable speed of absorptionVariable speed of absorption All BZDs are highly protein boundAll BZDs are highly protein bound Lipid solubilityLipid solubility Dosing adjustmentsDosing adjustments
– elderlyelderly
– hepatic impairmenthepatic impairment
AntidepressantsAntidepressantsDrugDrug 5HT5HT NENE DADAImipramineImipramine ++++++ ++++ 00DesipramineDesipramine 00 ++++++++ 00FluoxetineFluoxetine ++++++++ 00 00BupropionBupropion ++ ++ ++++NefazodoneNefazodone++++++ ++ 00MirtazepineMirtazepine ++++++ ++++ 00VenlafaxineVenlafaxine ++++++++ ++++ -/+-/+
Mechanisms of ActionMechanisms of Action
Monoamine Oxidase InhibitorsMonoamine Oxidase Inhibitors– blockade of NE, DA, and 5HT degradationblockade of NE, DA, and 5HT degradation
Tricyclic AntidepressantsTricyclic Antidepressants– inhibition of 5HT and NE reuptake; variable inhibition of 5HT and NE reuptake; variable
within classwithin class
– antagonism of alphaantagonism of alpha11-adrenergic, muscarinic -adrenergic, muscarinic
and histaminic receptorsand histaminic receptors
Mechanisms of ActionMechanisms of Action Selective Serotonin Reuptake InhibitorsSelective Serotonin Reuptake Inhibitors
– Inhibition of 5HT reuptakeInhibition of 5HT reuptake– No/minimal effect on NE, No/minimal effect on NE, 11-adrenergic, -adrenergic,
cholinergic or histaminic receptorscholinergic or histaminic receptors 5HT and NE Reuptake Inhibitors5HT and NE Reuptake Inhibitors
– Inhibits 5HT and NE reuptake Inhibits 5HT and NE reuptake – No/minimal effect on NE, No/minimal effect on NE, 11-adrenergic, -adrenergic,
cholinergic or histaminic receptorscholinergic or histaminic receptors
Mechanisms of ActionMechanisms of Action
5HT-2 Antagonist and 5HT Reuptake 5HT-2 Antagonist and 5HT Reuptake InhibitorInhibitor– Minimal affinity for Minimal affinity for 11-adrenergic-adrenergic
– No/minimal effect on histamine and cholinergic No/minimal effect on histamine and cholinergic receptorsreceptors
NE and DA Reuptake InhibitorNE and DA Reuptake Inhibitor– No/minimal effect on No/minimal effect on 11-adrenergic, cholinergic -adrenergic, cholinergic
and histaminic receptorsand histaminic receptors
Mechanisms of ActionMechanisms of Action
Noradrenergic, Specific SerotonergicNoradrenergic, Specific Serotonergic– alphaalpha22 antagonism antagonism
– 5HT5HT2A2A, 5HT, 5HT2C2C and 5HT and 5HT33 antagonism antagonism
– Substantial histamine blockadeSubstantial histamine blockade
Receptor Profile and Side EffectsReceptor Profile and Side Effects
5HT5HT2 2 StimulationStimulation
AgitationAgitation AkathisiaAkathisia AnxietyAnxiety
Panic attacksPanic attacksInsomniaInsomnia Sexual dysfnct.Sexual dysfnct.
5HT5HT3 3 StimulationStimulation
NauseaNausea GI distressGI distress
DiarrheaDiarrhea HeadacheHeadache
Receptor Profile and Side EffectsReceptor Profile and Side Effects
Dopamine StimulationDopamine StimulationAgitationAgitation Aggravation of psychosisAggravation of psychosis
ActivationActivation HypertensionHypertension NE StimulationNE Stimulation
TachycardiaTachycardia AgitationAgitation
InsomniaInsomnia AnxietyAnxiety
Antidepressant PharmacokineticsAntidepressant Pharmacokinetics
Drug Absorption Distribution Metabolism Elimin t1/2
TCAs complete1st passeffect
High PB hepaticCYP 2D6
24 hours
SSRIs complete High PB hepaticFluoxetineactive met.
24 hoursFluox. daysParoxetine
Venlafaxine complete widelyLow PB
hepaticactivemetabolites
5 hours
Nefazodone complete1st passeffect
loose PB hepaticactivemetabolites
2-4 hours
Mirtazepine complete high PB hepaticactivemetabolites
20-40hours> in women
Antipsychotic Antipsychotic PharmacodynamicsPharmacodynamics
Traditional antipsychoticsTraditional antipsychotics DopamineDopamine22 receptor blockade = Efficacy receptor blockade = Efficacy 22 adrenergic, histamine, and muscarinic receptor adrenergic, histamine, and muscarinic receptor
blockade = Side effectsblockade = Side effects
Atypical vs. Traditional Antipsychotics Atypical vs. Traditional Antipsychotics Pharmacological DifferencesPharmacological Differences ““Limbic selectivity” for DALimbic selectivity” for DA22 receptor blockade receptor blockade High ratio of 5HTHigh ratio of 5HT22 receptor binding to DA receptor binding to DA2 2 receptorsreceptors
AntipsychoticAntipsychoticPharmacodynamicsPharmacodynamics
Clinical Definition of “Atypical”Clinical Definition of “Atypical” Efficacy against positive and negative Efficacy against positive and negative
symptomssymptoms Lower risk of EPS Lower risk of EPS Estimated lower risk Tardive DyskinesiaEstimated lower risk Tardive Dyskinesia Improved cognitive functionImproved cognitive function Little/no effect on serum ProlactinLittle/no effect on serum Prolactin
Antipsychotic Receptor Profile Antipsychotic Receptor Profile and Side Effectsand Side Effects
Dopamine BlockadeDopamine Blockade Anticholinergic Anticholinergic Antihistaminic (HAntihistaminic (H11))
11-Adrenergic Blockade-Adrenergic Blockade
Antipsychotic Side EffectsAntipsychotic Side Effects
Drug Clz Risp Olz Quet
sedation ++ + ++ ++
orthostasis +++ ++ ++ ++
prolactin 0 ++ + 0
wt gain +++ ++ +++ +
Antipsychotic Side EffectsAntipsychotic Side Effects
Drug Clz Risp Olz Quet
LFTs + + + +
EPS 0/+ ++ + 0/+
TD 0/+ 0/+ 0/+ ?
seizures +++ + + +
Pharmacokinetics of Pharmacokinetics of AntipsychoticsAntipsychotics
ADME profilesADME profiles All are readily absorbedAll are readily absorbed All are metabolized by the hepatic cytochrome All are metabolized by the hepatic cytochrome
P450 systemP450 system prone to drug interactionsprone to drug interactions
TT1/21/2 is generally 20 hours except: is generally 20 hours except: ziprasidone, quetiapine ziprasidone, quetiapine
Dosing adjustment in elderly renal and/or hepatic Dosing adjustment in elderly renal and/or hepatic impairmentimpairment
Lithium MOALithium MOA
Alteration in cellular electrochemical Alteration in cellular electrochemical microenvironmentmicroenvironment
Facilitation of reuptake of NE and DAFacilitation of reuptake of NE and DA Decreased production and release of Decreased production and release of
catecholaminescatecholamines Facilitation of tryptophan (TRP) uptakeFacilitation of tryptophan (TRP) uptake
Valproate MOAValproate MOA
Inhibiting GABA degradationInhibiting GABA degradation Stimulating its synthesis and releaseStimulating its synthesis and release Directly enhancing its postsynaptic effectsDirectly enhancing its postsynaptic effects
Carbamazepine MOACarbamazepine MOA Reported to decrease the turnover of Reported to decrease the turnover of
GABA, NE and DAGABA, NE and DA Inhibits the second messenger adenlyate Inhibits the second messenger adenlyate
cyclasecyclase
Mood Stabilizers Mood Stabilizers PharmacodynamicsPharmacodynamics
Drug InhibitsAdenylate
cyclase
PITurnover
Ca+
InfluxInhib.
GlutamateRelease
GlutamateAMPA
blocker
Lithium X X X
CBZ X X X X
VPA X
Lmtg X X
Top X
Mood Stabilizer PharmacokineticsMood Stabilizer Pharmacokinetics
DrugDrug Desired Desired CpCp
DistributiDistributionon
MetabolisMetabolismm
EliminatioEliminationn
LithiumLithium 0.6-1.0 0.6-1.0
mEq/LmEq/L
No PBNo PBkidneys, kidneys, thyroidthyroid
NoneNone Renally,Renally,
18-20 18-20 hourshours
CBZCBZ 6-12 6-12 mg/mlmg/ml
CompleteComplete Hepatic,Hepatic,
autoinducautoinducerer
10,1110,11 epoxide epoxide
15-28 15-28 hourshours
VPAVPA 50-120 50-120
mg/mlmg/ml
Rapid in Rapid in
CNSCNS
Hepatic, Hepatic,
Inhibitor Inhibitor or or
InducerInducer
8-17 8-17 hourshours
Factors affecting lithium CpFactors affecting lithium Cp
Impaired Renal FunctionImpaired Renal Function PregnancyPregnancy Sodium balanceSodium balance MedicationsMedications
– diureticsdiuretics
– caffeinecaffeine
CBZ PharmacokineticsCBZ Pharmacokinetics
Oxidation to CBZ-10,11-epoxideOxidation to CBZ-10,11-epoxide– valproic acidvalproic acid
Potent enzyme inducerPotent enzyme inducer– antidepressants, anticonvulsants, antidepressants, anticonvulsants,
antipsychoticsantipsychotics AutoinductionAutoinduction
– serum level should stabilize within 4 weeksserum level should stabilize within 4 weeks
Valproic Acid Valproic Acid PharmacokineticsPharmacokinetics
Inhibits hepatic metabolismInhibits hepatic metabolism Occasionally induces hepatic metabolismOccasionally induces hepatic metabolism
Carbamazepine MetabolismCarbamazepine Metabolism
10,11 epoxide metabolite10,11 epoxide metabolite
CarbamazepineCarbamazepine
Further metabolismFurther metabolism
ToxicityToxicity
XXValproic acidValproic acid
oxidationoxidation
Stimulants PharmacodynamicsStimulants Pharmacodynamics
Inhibition of the reuptake of:Inhibition of the reuptake of:– DADA– NENE
Release from the presynaptic neuronRelease from the presynaptic neuron– DADA– NENE– 5HT5HT
Inhibition of Monoamine oxidaseInhibition of Monoamine oxidase
Stimulant PharmacokineticsStimulant Pharmacokinetics
DrugDrug OnsetOnset DurationDuration Meta.Meta. Elim.Elim.
MPHMPH 22 3-6 3-6 inactiveinactive fecesfeces
DXAMPDXAMP 1-1.51-1.5 8 8 liverliver urineurine
PemolinePemoline 44 8 8 liverliver urineurine
Pharmacodynamic Drug Pharmacodynamic Drug InteractionsInteractions
Additive side effects secondary toAdditive side effects secondary to– acting on the same neurotransmitteracting on the same neurotransmitter
– neurotransmitter systemneurotransmitter system Lithium Neurotoxicity Lithium Neurotoxicity
Cytochrome P450 SystemsCytochrome P450 Systems
Inhibitors of the CYP p450 systemInhibitors of the CYP p450 system– numerous antidepressantsnumerous antidepressants
– wide range of substrates effectedwide range of substrates effected Inducers of the CYP p450 system include:Inducers of the CYP p450 system include:
– carbamazepine, rifampin, INH, phenytoincarbamazepine, rifampin, INH, phenytoin
– St John’s Wort 3A4 onlySt John’s Wort 3A4 only
CYP 450 InhibitorsCYP 450 Inhibitors
Rank 1A2 2D6 3A4High Fluvox Fluoxe
ParoxeNefazFluvoxFluoxe
Mod Fluoxe Serta
Min ParoxNefazVenlaf
NefazVenlafFluvox
Venlaf
enla
Other Pharmacokinetic Other Pharmacokinetic InteractionsInteractions
Protein binding saturationProtein binding saturation– dilantin, phenytoin, warfarindilantin, phenytoin, warfarin
Protein binding displacementProtein binding displacement– valproic acid valproic acid
Most are measurable interactionsMost are measurable interactions
Indications for Cp monitoringIndications for Cp monitoring
non-responders for dosage adjustmentnon-responders for dosage adjustment suspicion of non-compliancesuspicion of non-compliance to avoid toxicity (especially in the elderly)to avoid toxicity (especially in the elderly) overdoseoverdose if adverse effects limit further dosage increasesif adverse effects limit further dosage increases patients with absorption abnormalitiespatients with absorption abnormalities document responsedocument response
Questions ???????Questions ???????