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

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

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

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

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

Supramolecular Complex

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

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

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

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

Pharmacokinetics of BZDs Variable speed of absorption Lipid solubility All BZDs are highly protein bound Dosing adjustments elderly hepatic impairment CYP p450 isoenzymes

Antidepressants

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

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

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

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

Mechanisms of Action Noradrenergic, Specific Serotonergic alpha2 antagonism 5HT2A, 5HT2C and 5HT3 antagonism Substantial histamine blockade

Receptor Profile and Side Effects 5HT2 Stimulation Agitation Akathisia Anxiety Panic attacks Insomnia Sexual dysfnct. 5HT3 Stimulation Nausea GI distress Diarrhea Headache

Receptor Profile and Side Effects Dopamine Stimulation Agitation Aggravation of psychosis Activation Hypertension NE Stimulation Tachycardia Agitation Insomnia Anxiety

Antidepressant Pharmacokinetics

Antipsychotics

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

3rd Generation- aripiprazole D2 Partial agonist Activity dependent on the endogenous neurotransmitter activity Areas of hyperdopaminergic function- aripiprazole acts as an antagonist Areas of hypodopaminergic function- aripiprazole acts as an agonist

Antipsychotic Pharmacodynamics 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

Antipsychotic Receptor Profile and Side Effects Dopamine Blockade Anticholinergic Antihistaminic (H1) 1-Adrenergic Blockade

Antipsychotic Side Effects

Antipsychotic Side Effects

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, aripiprazole Dosing adjustment in elderly renal and/or hepatic impairment

Mood Stabilizers

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

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

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

Mood Stabilizers Pharmacodynamics

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, autoinduc er 10,11 epoxide 15-28 hours VPA 50-120 mg/ml Rapid in CNS Inhibitor or Inducer 8-17 hours

Factors affecting lithium Cp Impaired Renal Function Pregnancy Sodium balance Medications Diuretics → Na depletion → Li reabsorption Caffeine ↓ lithium levels ACE Inhibitors → ↓ GFR → ↑Li concentration

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

Valproic Acid Pharmacokinetics Inhibits hepatic metabolism Occasionally induces hepatic metabolism

Carbamazepine Metabolism oxidation 10,11 epoxide metabolite → Toxicity X Valproic acid Further metabolism

Stimulants

Stimulants Pharmacodynamics Inhibition of the reuptake of: DA NE Release from the presynaptic neuron 5HT Inhibition of Monoamine oxidase

Stimulant Pharmacokinetics Drug Onset Duration Meta. Elim. MPH 0.5-1 3-6 inactive feces MPH XR 2-3 6-10 DXAMP 1-1.5 8 liver urine Pemoline 4 8 liver urine

Drug Interactions

Pharmacodynamic Drug Interactions Additive side effects secondary to acting on the same neurotransmitter Divalproex and benzodiazepines neurotransmitter system Venlafaxine and b-blockers Serotonin Syndrome Lithium Neurotoxicity MAOIs + numerous drugs SSRIs, TCAs, Stimulants, Antihypertensives

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 John’s wort 3A4 and p-glycoprotein

CYP 450 Inhibitors

Other Pharmacokinetic Interactions Protein binding saturation dilantin, phenytoin, warfarin, VPA Protein binding displacement SSRIs and coumadin Most are measurable interactions

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

Questions ???????