Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacotherapy

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Pharmacodynamics and Pharmacokinetics in
Psychiatric Pharmacotherapy

• Elizabeth A. Winans, PharmD, BCPP
• University of Illinois at Chicago
• Psychiatric Clinical Research Center

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Overview

• Review general pharmacology of
• antidepressants mood stabilizers
• anxiolytics stimulants
• antipsychotics
• Discuss relevant pharmacokinetic parameters

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GABA-BZD receptor

• GABA
• inhibitory neurotransmitter which rapidly alters
  the excitability of other output neurons
• possesses anxiolytic action within the amygdala
• involved with neurotransmitter modulation in 1/3
  of brain impulses

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Anxiolytics

• Two types of GABA receptors
• GABAA
• major binding site for GABA
• Binding site for anxiolytic agents
• GABAB
• does not bind anxiolytics
• minor GABA binding sites

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GABA-BZD receptor

• "Supramolecular Complex"
• GABA recognition site
• BZD recognition site
• Cl- ion channel
• picrotoxin binding site

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Supramolecular Complex
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GABA-BZD receptor

• Receptor agonists (e.g., GABA)
• induce the direct opening of the Cl- channel
• Cl- influx causes hyperpolarization
• hyperpolarization then inhibits cell firing

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GABA-BZD receptor

• Receptor antagonists (e.g., picrotoxin)
• impedes Cl- entrance into the cell preventing
  hyperpolarization
• thus neuron is not inhibited from firing

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GABA-BZD receptor

• GABA potentiators (e.g., BZDs)
• augment the flow of Cl- into the cell by
  increasing the frequency of channel opening
• benzodiazepines do not act alone but rather act
  in a synergistic manner with GABA

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5HT1A Receptor

• 5HT1A is located on both pre- and postsynaptic
  membranes
• Coupled with G proteins and adenlylate cyclase
• Buspirone acts as a partial 5HT1A agonist

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Pharmacokinetics of BZDs

• Variable speed of absorption
• All BZDs are highly protein bound
• Lipid solubility
• Dosing adjustments
• elderly
• hepatic impairment

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Antidepressants

• Drug 5HT NE DA
• Imipramine 0
• Desipramine 0 0
• Fluoxetine 0 0
• Bupropion
• Nefazodone 0
• Mirtazepine 0
• Venlafaxine -/

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Mechanisms of Action

• Monoamine Oxidase Inhibitors
• blockade of NE, DA, and 5HT degradation
• Tricyclic Antidepressants
• inhibition of 5HT and NE reuptake variable
  within class
• antagonism of alpha1-adrenergic, muscarinic and
  histaminic receptors

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Mechanisms of Action

• Selective Serotonin Reuptake Inhibitors
• Inhibition of 5HT reuptake
• No/minimal effect on NE, ?1-adrenergic,
  cholinergic or histaminic receptors
• 5HT and NE Reuptake Inhibitors
• Inhibits 5HT and NE reuptake
• No/minimal effect on NE, ?1-adrenergic,
  cholinergic or histaminic receptors

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Mechanisms of Action

• 5HT-2 Antagonist and 5HT Reuptake Inhibitor
• Minimal affinity for ?1-adrenergic
• No/minimal effect on histamine and cholinergic
  receptors
• NE and DA Reuptake Inhibitor
• No/minimal effect on ?1-adrenergic, cholinergic
  and histaminic receptors

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Mechanisms of Action

• Noradrenergic, Specific Serotonergic
• alpha2 antagonism
• 5HT2A, 5HT2C and 5HT3 antagonism
• Substantial histamine blockade

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Receptor Profile and Side Effects

• 5HT2 Stimulation
• Agitation Akathisia Anxiety
• Panic attacks Insomnia Sexual dysfnct.
• 5HT3 Stimulation
• Nausea GI distress
• Diarrhea Headache

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Receptor Profile and Side Effects

• Dopamine Stimulation
• Agitation Aggravation of psychosis
• Activation Hypertension
• NE Stimulation
• Tachycardia Agitation
• Insomnia Anxiety

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Antidepressant Pharmacokinetics
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Antipsychotic Pharmacodynamics

• Traditional antipsychotics
• Dopamine2 receptor blockade Efficacy
• ?2 adrenergic, histamine, and muscarinic receptor
  blockade Side effects
• Atypical vs. Traditional Antipsychotics
  Pharmacological Differences
• Limbic selectivity for DA2 receptor blockade
• High ratio of 5HT2 receptor binding to DA2
  receptors

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AntipsychoticPharmacodynamics

• Clinical Definition of Atypical
• Efficacy against positive and negative symptoms
• Lower risk of EPS
• Estimated lower risk Tardive Dyskinesia
• Improved cognitive function
• Little/no effect on serum Prolactin

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Antipsychotic Receptor Profile and Side Effects

• Dopamine Blockade
• Anticholinergic
• Antihistaminic (H1)
• ?1-Adrenergic Blockade

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Antipsychotic Side Effects
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Antipsychotic Side Effects
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Pharmacokinetics of Antipsychotics

• ADME profiles
• All are readily absorbed
• All are metabolized by the hepatic cytochrome
  P450 system
• prone to drug interactions
• T1/2 is generally 20 hours except
• ziprasidone, quetiapine
• Dosing adjustment in elderly renal and/or hepatic
  impairment

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Lithium MOA

• Alteration in cellular electrochemical
  microenvironment
• Facilitation of reuptake of NE and DA
• Decreased production and release of
  catecholamines
• Facilitation of tryptophan (TRP) uptake

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Valproate MOA

• Inhibiting GABA degradation
• Stimulating its synthesis and release
• Directly enhancing its postsynaptic effects

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Carbamazepine MOA

• Reported to decrease the turnover of GABA, NE and
  DA
• Inhibits the second messenger adenlyate cyclase

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Mood Stabilizers Pharmacodynamics
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Mood Stabilizer Pharmacokinetics
Drug Desired Cp Distribution Metabolism Elimination
Lithium 0.6-1.0 mEq/L No PB kidneys, thyroid None Renally, 18-20 hours
CBZ 6-12 mg/ml Complete Hepatic, autoinducer 10,11 epoxide 15-28 hours
VPA 50-120 mg/ml Rapid in CNS Hepatic, Inhibitor or Inducer 8-17 hours
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Factors affecting lithium Cp

• Impaired Renal Function
• Pregnancy
• Sodium balance
• Medications
• diuretics
• caffeine

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CBZ Pharmacokinetics

• Oxidation to CBZ-10,11-epoxide
• valproic acid
• Potent enzyme inducer
• antidepressants, anticonvulsants, antipsychotics
• Autoinduction
• serum level should stabilize within 4 weeks

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Valproic Acid Pharmacokinetics

• Inhibits hepatic metabolism
• Occasionally induces hepatic metabolism

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Carbamazepine Metabolism
Carbamazepine
oxidation
10,11 epoxide metabolite
? Toxicity
X
Valproic acid
Further metabolism
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Stimulants Pharmacodynamics

• Inhibition of the reuptake of
• DA
• NE
• Release from the presynaptic neuron
• DA
• NE
• 5HT
• Inhibition of Monoamine oxidase

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Stimulant Pharmacokinetics

• Drug Onset Duration Meta. Elim.
• MPH 2 3-6 inactive feces
• DXAMP 1-1.5 8 liver urine
• Pemoline 4 8 liver urine

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Pharmacodynamic Drug Interactions

• Additive side effects secondary to
• acting on the same neurotransmitter
• neurotransmitter system
• Lithium Neurotoxicity

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Cytochrome P450 Systems

• Inhibitors of the CYP p450 system
• numerous antidepressants
• wide range of substrates effected
• Inducers of the CYP p450 system include
• carbamazepine, rifampin, INH, phenytoin
• St Johns Wort 3A4 only

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CYP 450 Inhibitors
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Other Pharmacokinetic Interactions

• Protein binding saturation
• dilantin, phenytoin, warfarin
• Protein binding displacement
• valproic acid
• Most are measurable interactions

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Indications for Cp monitoring

• non-responders for dosage adjustment
• suspicion of non-compliance
• to avoid toxicity (especially in the elderly)
• overdose
• if adverse effects limit further dosage increases
• patients with absorption abnormalities
• document response

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• Questions ???????