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Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacotherapy

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

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Pharmacodynamics and Pharmacokinetics in Psychiatric Pharmacotherapy

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

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

  3. 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 in1/3 of brain impulses

  4. 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

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

  6. Supramolecular Complex

  7. 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

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

  9. 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 mannerwith GABA

  10. 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

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

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

  13. 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

  14. 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

  15. 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

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

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

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

  19. Antidepressant Pharmacokinetics

  20. 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

  21. 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

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

  23. Antipsychotic Side Effects

  24. Antipsychotic Side Effects

  25. 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

  26. 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

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

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

  29. Mood Stabilizers Pharmacodynamics

  30. Mood Stabilizer Pharmacokinetics

  31. Factors affecting lithium Cp • Impaired Renal Function • Pregnancy • Sodium balance • Medications • diuretics • caffeine

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

  33. Valproic Acid Pharmacokinetics • Inhibits hepatic metabolism • Occasionally induces hepatic metabolism

  34. Carbamazepine Metabolism Carbamazepine oxidation 10,11 epoxide metabolite  Toxicity X Valproic acid Further metabolism

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

  36. Stimulant Pharmacokinetics Drug OnsetDuration Meta. Elim. MPH 2 3-6 inactive feces DXAMP 1-1.5 8 liver urine Pemoline 4 8 liver urine

  37. Pharmacodynamic Drug Interactions • Additive side effects secondary to • acting on the same neurotransmitter • neurotransmitter system • Lithium Neurotoxicity

  38. 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 only

  39. CYP 450 Inhibitors

  40. Other Pharmacokinetic Interactions • Protein binding saturation • dilantin, phenytoin, warfarin • Protein binding displacement • valproic acid • Most are measurable interactions

  41. 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

  42. Questions ???????

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