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