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Pharmacokinetics and Phamacogenetics

Pharmacokinetics and Phamacogenetics. Hamish McAllister-Williams PhD, MD, FRCPsych Reader in Clinical Psychopharmacology Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service. Declaration of Interests. I have received: Speaker fees from:

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Pharmacokinetics and Phamacogenetics

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  1. Pharmacokinetics and Phamacogenetics Hamish McAllister-Williams PhD, MD, FRCPsych Reader in Clinical Psychopharmacology Newcastle University Hon. Consultant Psychiatrist Regional Affective Disorders Service

  2. Declaration of Interests • I have received: • Speaker fees from: • Astra Zeneca, BMS, Eli Lilly, GSK, Janssen-Cilag, Lundbeck, Organon, Pfiser, Wyeth • Consultancy fees from: • Astra Zeneca, BMS, Cyberonics, Eli Lilly, Janssen-Cilag, Lundbeck, Servier, Wyeth • Independent investigator led research support from: • Astra Zeneca, Eli Lilly and Wyeth

  3. Pharmacokinetics

  4. Barriers to drug delivery and effect BBB or other Effect Conc in target organ Half-life • Pharmacodynamics: • EC50, slope • Effect delay • Tolerance Clearance Volume of distribution Conc in plasma Absorption Membrane transport Membrane transport First pass metabolism Dose

  5. Pharmacokinetics and Pharmacodynamics

  6. Pharmacokinetics • Absorption • Metabolism • Elimination • General principles • Clinically relevant examples

  7. Increased risk of toxicity Peak concentration (Cmax) Minimum effective conc. max Theoretical plasma concentrations of three drugs with different rates of absorption 1 AUC 0.8 0.6 Plasma concentration (proportion of dose) 0.4 0.2 0 Time t

  8. Absorption of TCAs • tmax • tertiary amines: 1 - 3 hours • secondary amines: 4 - 8 hours • Clinical relevance: • shorter tmax leads to higher Cmax • most side effects (e.g. sedation, postural hypotension, membrane stabilisation) are dependent on the plasma concentration • therefore give sedative TCA all in one dose at night (and postural hypotension occurs while lying down!) • secondary amines often associated with fewer side effects

  9. Quetiapine IR vs XL Datto et al. 2009 Clinical Therapeutics 31, 492

  10. Quetiapine IR vs XL Datto et al. 2009 Clinical Therapeutics 31, 492

  11. Quetiapine IR vs XL Datto et al. 2009 Clinical Therapeutics 31, 492

  12. Quetiapine IR vs XL Datto et al. 2009 Clinical Therapeutics 31, 492

  13. Sedation with quetiapine IR and XL Before treatment After 5 days treatment Datto et al. 2009 Clinical Therapeutics 31, 492

  14. Drugs

  15. Fluoxetine

  16. Drug Metabolism Type 1 metabolism Cytochrome P450’s Oxidation etc Type 2 metabolism Conjugation Gluconurilation etc Conjugation O Non-polar species Polar species Biliary elimination Elimination

  17. Metabolism of TCAs - 1 • Type 1 metabolism converts tertiary to secondary amines, eg. • Amitriptyline Nortiptyline • Imipramine Desipramine • Clomipramine Desmethylclomipramine • Tertiary amines generally more potent 5-HT uptake blockers, secondary amines more potent NA uptake blockers • Up to 70% of clomipramine may be converted to desmethylclomipramine • may lead to lack of efficacy in OCD

  18. Metabolism of fluoxetine Cytochrome P450 2D6 Morphine glucuronate Morphine

  19. http://medicine.iupui.edu/clinpharm/ddis

  20. CYP 450 – 1A2 interaction examples • Substrates: • Tertiary amine TCAs • Clozapine • Inhibitors • Fluvoxamine, Ciprafloxacin • Inducers • Brocolli, Brussel sprouts, tobacco, modafanil

  21. CYP 450 – 2D6 interaction examples • Substrates • TCAs, paroxetine, haloperidol, risperidone • Inhibitors • Fluoxetine, paroxetine • Duloxetine • Cimetidine, sertraline • Inducers • Dexamethasone

  22. CYP 450 – 3A4,5,7 interaction examples • Substrates • Many and varied drugs • Dexamethasone, tamoxifen • Inducers • St John’s wort • Glucocorticoids

  23. Elimination of drugs • Primarily via the kidney • Metabolism of drug usually has to occur first to produce a water soluble compound • This is usually the rate limiting step • Factors slowing metabolism will increase the elimination time • Kinetics • Usually ‘first order’ • Influences the dosing schedule • Influences the possibility of withdrawal problems

  24. The rate of elimination is independent of plasma concentration A small change in dose can produce a big change in plasma concentration Rare except if elimination process is saturated (can occur with TCAs) 200 150 Plasma alcohol concentration (mg/dl) 100 50 0 0 1 2 3 4 5 6 7 8 9 10 Time (hours) Zero order kinetics

  25. 40 30 Plasma warfarin concentration (ug/ml) 20 10 t1/2 t1/2 0 0 10 20 30 40 50 60 70 Time (hours) First order kinetics • The rate of elimination is proportional to the plasma concentration • Elimination rate quantified by ‘half life’ • The majority of drugs have first order kinetics

  26. Theoretical plasma concentration of a first order drug after single or repeated doses Doses 2 1 Plasma Drug Concentration (proportion of dose) 0 0 1 2 3 4 5 6 Time (number of half-lives)

  27. t = 4 hours (due to reduced clearance) 1/2 t = 2 hours 1/2 Effect of reduced metabolism of a drug on its steady state concentration Plasma drug concentration 0 4 8 12 16 20 24 Time (hours)

  28. Metabolite Nortriptyline Desipramine DMC Half lives of TCAs Half Life (hours - approx) Amitriptyline Imipramine Clomipramine 16 12 18 Nortriptyline Desipramine DMC 60 50 45 Lofepramine 5 Desipramine

  29. “…prescribing phenothiazines and tricyclic antidepressants three times a day is simply a public display of pharmacological ignorance…” R.E. Kendell (1993) Companion to Psychiatric Studies, 5th Ed. p 419

  30. Increased risk of side effects Half dose, twice as often Control Half dose, same freq. Effect of varying dose and frequency of administration of a first order drug 1.8 1.6 1.4 1.2 1 Plasma drug concentration 0.8 0.6 0.4 0.2 0 0 1 2 3 4 5 6 Time (number of half-lives)

  31. Half lives of SSRIs - 1 Half life (hrs) (Active metab.) • Note inter-drug and -individual variation • Fluoxetine and paroxetine • t1/2 increases with dose and time Fluoxetine Sertraline Citalopram Paroxetine Fluvoxamine 45-72 (150-200) 25 (66) 36 (?) 10-20 15

  32. Half lives of SSRIs - 2Clinical Relevance • Fluoxetine/norfluoxetine long half life consequences: • 5+ weeks to steady state • late emergence of plasma level dependent side effects • prolonged washout period • N.B. delayed CYP2D6 inhibition • benefit for poor compliers • little risk of discontinuation syndrome • Paroxetine short half life • SSRI most prone to discontinuation • N.B. also anti-cholinergic

  33. Pharmacokinetics Conclusions • A knowledge of pharmacokinetics can improve the clinical usage of drugs e.g. by: • minimising side effects associated with Cmax • split dosages • choice of drug (secondary versus tertiary TCA, IR vs XR) • adjusting dosages appropriately for age and sex • avoiding pharmacokinetic interactions • being aware of discontinuation phenomena

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