Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacotherapy Elizabeth A. Winans, PharmD, BCPP University of Illinois at Chicago Psychiatric Clinical

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


"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


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


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 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


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


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


VPAVPA 50-120 50-120

mg/mlmg/ml

Rapid in Rapid in

CNSCNS

Hepatic, Hepatic,

Inhibitor Inhibitor or or

InducerInducer


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

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Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacotherapy Elizabeth A. Winans, PharmD, BCPP University of Illinois at Chicago Psychiatric Clinical