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
produces anxiolytic action within the amygdala
involved with neurotransmitter modulation in 1/3 of brain impulses

4. 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

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 manner with GABA

11. 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

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

13. Antidepressants

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

15. 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

16. 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

17. 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

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

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

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

21. Antidepressant Pharmacokinetics

22. Antipsychotics

23. 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

24. 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

25. 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

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

27. Antipsychotic Side Effects

28. Antipsychotic Side Effects

29. 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

30. Mood Stabilizers

31. 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

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

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

34. Mood Stabilizers Pharmacodynamics

35. Mood Stabilizer Pharmacokinetics
Drug
Desired Cp
Distribution
Metabolism
Elimination
Lithium
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

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

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

38. Valproic Acid Pharmacokinetics
Inhibits hepatic metabolism
Occasionally induces hepatic metabolism

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

40. Stimulants

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

42. Stimulant Pharmacokinetics
Drug Onset Duration Meta. Elim.
MPH inactive feces
MPH XR
DXAMP liver urine
Pemoline liver urine

43. Drug Interactions

44. 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

45. 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

46. CYP 450 Inhibitors

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

48. 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

49. Questions ???????