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

2. Overview u Review general pharmacology of –antidepressantsmood stabilizers –anxiolyticsstimulants –antipsychotics u Discuss relevant pharmacokinetic parameters

3. GABA-BZD receptor u 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

4. Anxiolytics u Two types of GABA receptors  GABA A »major binding site for GABA »Binding site for anxiolytic agents GABA BGABA B »does not bind anxiolytics »minor GABA binding sites

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

6. Supramolecular Complex

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

9. GABA-BZD receptor u 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 –benzodiazepines do not act alone but rather act in a synergistic manner with GABA

11. 5HT 1A Receptor u 5HT 1A is located on both pre- and postsynaptic membranes u Coupled with G proteins and adenlylate cyclase u Buspirone acts as a partial 5HT 1A agonist

12. Pharmacokinetics of BZDs u Variable speed of absorption u All BZDs are highly protein bound u Lipid solubility u Dosing adjustments –elderly –hepatic impairment

13. Antidepressants Drug5HTNEDA Imipramine+++++0 Desipramine0++++0 Fluoxetine++++00 Bupropion++++ Nefazodone++++0 Mirtazepine+++++0 Venlafaxine++++++-/+

14. 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 alpha 1 -adrenergic, muscarinic and histaminic receptors

15. Mechanisms of Action u Selective Serotonin Reuptake Inhibitors –Inhibition of 5HT reuptake –No/minimal effect on NE,  1 -adrenergic, cholinergic or histaminic receptors u 5HT and NE Reuptake Inhibitors –Inhibits 5HT and NE reuptake –No/minimal effect on NE,  1 -adrenergic, cholinergic or histaminic receptors

16. Mechanisms of Action u 5HT-2 Antagonist and 5HT Reuptake Inhibitor –Minimal affinity for  1 -adrenergic –No/minimal effect on histamine and cholinergic receptors u NE and DA Reuptake Inhibitor –No/minimal effect on  1 -adrenergic, cholinergic and histaminic receptors

17. Mechanisms of Action u Noradrenergic, Specific Serotonergic –alpha 2 antagonism –5HT 2A, 5HT 2C and 5HT 3 antagonism –Substantial histamine blockade

18. Receptor Profile and Side Effects u 5HT 2 Stimulation AgitationAkathisiaAnxiety Panic attacksInsomniaSexual dysfnct. u 5HT 3 Stimulation NauseaGI distress DiarrheaHeadache

19. Receptor Profile and Side Effects u Dopamine Stimulation AgitationAggravation of psychosis ActivationHypertension u NE Stimulation TachycardiaAgitation InsomniaAnxiety

20. Antidepressant Pharmacokinetics

21. Antipsychotic Pharmacodynamics u Traditional antipsychotics  Dopamine 2 receptor blockade = Efficacy  2 adrenergic, histamine, and muscarinic receptor blockade = Side effects u Atypical vs. Traditional Antipsychotics Pharmacological Differences  “Limbic selectivity” for DA 2 receptor blockade  High ratio of 5HT 2 receptor binding to DA 2 receptors

22. Antipsychotic Pharmacodynamics u 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

23. Antipsychotic Receptor Profile and Side Effects u Dopamine Blockade u Anticholinergic u Antihistaminic (H 1 ) u  1 -Adrenergic Blockade

24. Antipsychotic Side Effects

26. Pharmacokinetics of Antipsychotics u ADME profiles  All are readily absorbed  All are metabolized by the hepatic cytochrome P450 system  prone to drug interactions  T 1/2 is generally 20 hours except:  ziprasidone, quetiapine  Dosing adjustment in elderly renal and/or hepatic impairment

27. Lithium MOA u Alteration in cellular electrochemical microenvironment u Facilitation of reuptake of NE and DA u Decreased production and release of catecholamines u Facilitation of tryptophan (TRP) uptake

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

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

30. Mood Stabilizers Pharmacodynamics

31. Mood Stabilizer Pharmacokinetics Drug Desired Cp Distributi on Metabolis m Eliminatio n Lithium0.6-1.0mEq/L No PB kidneys,thyroidNoneRenally, 18-20 hours CBZ 6-12 mg/ml CompleteHepatic, autoinduc er 10,11 epoxide 15-28 hours VPA50-120mg/ml Rapid in CNSHepatic, Inhibitor or Inducer 8-17 hours

32. Factors affecting lithium Cp u Impaired Renal Function u Pregnancy u Sodium balance u Medications –diuretics –caffeine

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

34. Valproic Acid Pharmacokinetics u Inhibits hepatic metabolism u Occasionally induces hepatic metabolism

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

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

37. Stimulant Pharmacokinetics DrugOnset DurationMeta.Elim. MPH2 3-6 inactivefeces DXAMP1-1.5 8liverurine Pemoline4 8liverurine

38. Pharmacodynamic Drug Interactions u Additive side effects secondary to –acting on the same neurotransmitter –neurotransmitter system u Lithium Neurotoxicity

39. Cytochrome P450 Systems u Inhibitors of the CYP p450 system –numerous antidepressants –wide range of substrates effected u Inducers of the CYP p450 system include: –carbamazepine, rifampin, INH, phenytoin –St John’s Wort 3A4 only

40. CYP 450 Inhibitors

41. Other Pharmacokinetic Interactions u Protein binding saturation –dilantin, phenytoin, warfarin u Protein binding displacement –valproic acid u Most are measurable interactions

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

43. u Questions ???????