Psychobiology Research Group 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

Pharmacokinetics

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

Pharmacokinetics and Pharmacodynamics 5

Pharmacokinetics Absorption Metabolism Elimination  General principles  Clinically relevant examples

Theoretical plasma concentrations of three drugs with different rates of absorption Time Plasma concentration (proportion of dose) t Peak concentration (C max ) max Increased risk of toxicity Minimum effective conc. AUC

Absorption of TCAs t max  tertiary amines: hours  secondary amines:4 - 8 hours Clinical relevance:  shorter t max leads to higher C max  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

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

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

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

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

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

14 Datto et al Clinical Therapeutics 31, 492

Drugs 15

Fluoxetine 16

Drug Metabolism 17 O Type 1 metabolism Cytochrome P450’s Oxidation etc Type 2 metabolism Conjugation Gluconurilation etc Conjugation Polar species Elimination Biliary elimination Non-polar species

Metabolism of TCAs - 1 Type 1 metabolism converts tertiary to secondary amines, eg.  AmitriptylineNortiptyline  ImipramineDesipramine  ClomipramineDesmethylclomipramine 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

Metabolism of fluoxetine 19 Morphine Morphine glucuronate Cytochrome P450 2D6

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CYP 450 – 1A2 interaction examples Substrates:  Tertiary amine TCAs  Clozapine Inhibitors  Fluvoxamine, Ciprafloxacin Inducers  Brocolli, Brussel sprouts, tobacco, modafanil 24

CYP 450 – 2D6 interaction examples Substrates  TCAs, paroxetine, haloperidol, risperidone Inhibitors  Fluoxetine, paroxetine  Duloxetine  Cimetidine, sertraline Inducers  Dexamethasone 25

CYP 450 – 3A4,5,7 interaction examples Substrates  Many and varied drugs  Dexamethasone, tamoxifen Inducers  St John’s wort  Glucocorticoids 26

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

Time (hours) Plasma alcohol concentration (mg/dl) Zero order kinetics 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)

Time (hours) Plasma warfarin concentration (ug/ml) 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 t 1/2

Theoretical plasma concentration of a first order drug after single or repeated doses Time (number of half-lives) Plasma Drug Concentration (proportion of dose) Doses

Effect of reduced metabolism of a drug on its steady state concentration Time (hours) Plasma drug concentration t = 4 hours (due to reduced clearance) 1/2 t = 2 hours 1/2

Half lives of TCAs Amitriptyline Imipramine Clomipramine Nortriptyline Desipramine DMC Lofepramine Half Life (hours - approx) Metabolite Nortriptyline Desipramine DMC Desipramine

“…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

Effect of varying dose and frequency of administration of a first order drug Time (number of half-lives) Plasma drug concentration Half dose, same freq. Control Half dose, twice as often Increased risk of side effects

Half lives of SSRIs - 1 Note inter-drug and -individual variation Fluoxetine and paroxetine  t 1/2 increases with dose and time Fluoxetine Sertraline Citalopram Paroxetine Fluvoxamine Half life (hrs) (Active metab.) ( ) 25 (66) 36 (?)

Half lives of SSRIs - 2 Clinical 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

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