Pharmacology Kinetics

Dr Lindsey Ferrie [email protected] MRCPsych Neuroscience and Psychopharmacology

School of Biomedical Sciences Pharmacokinetics The mathematics of the processes (ADME) which govern the amount of drug in the body and the way this changes with time.

Absorption • the movement of drug across membranes Distribution • where the drug goes within the body Metabolism • how the drug is broken down Excretion • how the drug is removed from the body

Why do we need to be able to calculate pharmacokinetics parameters?

To ensure that the dosage regimen results in the correct plasma concentration in all patients irrespective of disease state, capacity to eliminate, route of administration, age and other drug therapy General order of ADME processes

Site of administration

1. Absorption (input)

2. Distribution Plasma Tissues

3. Metabolism/Excretion (output)

Urine, Faeces The A in ADME: Absorption • Transfer of an exogenous compound (i.e. drug) from site of administration into the systemic circulation

• Usually involves crossing cell membranes • Passive diffusion down concentration gradient • Active transport (esp. GI tract)

• In general lipid-soluble compounds cross cell membranes more easily and are more rapidly absorbed • However, must also be in solution • Degree of ionization important • ↑unionized = ↑absorbed Absorption – Passive diffusion

– lipid solubility is an important determinant of rate of absorption

– non-polar/ un-ionised substances dissolve in lipid

– ionised species have low lipid solubility

– many drugs are weak acids or bases and therefore exist in both ionised and un- ionised forms

– ratio of ionised : un-ionised determined by pH

Barriers to drug delivery and effect

BBB or Effect other Conc in Volume of target Dynamics: distribution organ Clearance -EC50, slope Absorption Conc in Membrane -Effect delay transport Membrane plasma -Tolerance transport Dose First pass metabolism Bioavailability / First-pass metabolism

Bioavailability: The fraction of the administered dose which enters the systemic circulation. First-pass metabolism: Occurs in both intestine and liver before drug reaches systemic circulation

Bioavailability (F)

• For an iv dose F = 1 • For an extra-vascular dose e.g. oral F = <1

Limitations • Does not consider inter and intra individual variations in; • enzyme activity • Gastric pH • Intestinal motility • Does not consider rate of absorption

Enterohepatic recirculation (HER)

• Drugs that are eliminated in the bile can be reabsorbed in the GI tract • May occur after any route of administration • Secreted into bile which is then stored in the gall bladder and released into duodenum

• Many drugs undergo some degree of EHR: • Hard to generalize characteristics • Examples: morphine, erythromycin, oral contraceptives, lorazepam Parameter of absorption: Area under the curve (AUC)

• Used to estimate bioavailability

• ‘Trapezoidal rule’

• AUC1 = c0 + c1 x Time1-0 2

• AUC1 = 75mg –hr/L

Theoretical plasma concentrations of three drugs with different rates of absorption Cmax: Maximum concentration of compound after administration (mg/mL, ng/mL, etc.) Tmax: Time at which Cmax is reached (hours) Easiest PK parameters to calculate (just look at profile!) 1

0.8 Increased risk of toxicity

Peak concentration (Cmax) 0.6

0.4 Minimum effective conc.

(proportion (proportion of dose) Plasma concentration Plasma 0.2

0 tmax Time 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 Example: Quetiapine IR vs XL

Cmax: 689.19 ng/mL

Cmax: AUC: 381.70 ng/mL 2835.89 ng.h/mL

AUC: 2515.21 ng.h/mL Tmax: Tmax: 2 h 5 h

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 The D in ADME: distribution • Once a compound is absorbed into the systemic circulation, it will distribute into other tissues of the body. • Once equilibrium has been reached between the systemic circulation and a tissue, elimination processes that lower the blood concentration will lead to a parallel decrease in tissue concentration • Half-life in plasma is also elimination half-life from tissues

Following i.v. injection Distribution equilibrium Elimination from plasma Plasma Tissue Plasma Tissue Plasma Tissue Process of drug distribution to tissues

Endothelium Plasma protein

Slit junction

Basement membrane Cell membrane

Blood vessel

Interstitium

Tissue cell Factors affecting distribution

Rate of distribution Extent of distribution

Membrane permeability Lipid solubility e.g. Drugs perfuse faster e.g. Ionised lipid insoluble through the highly permeable drugs cannot easily enter cells renal capillaries pH-pKa

Blood perfusion e.g. Drug reaches highly Plasma protein binding vascularised tissues more rapidly e.g. lung/liver Tissue binding

Plasma compartment and proteins

• Drugs with high molecular weight and/or high degree of binding to plasma proteins will tend to stay in the systemic circulation rather than distribute into tissues/organs

• Key drug binding proteins in plasma: • Albumin (HSA) • Produced by the liver • Binds mostly acidic and some neutral drugs • Decreased in malnutrition and cirrhosis • Normal range: 3.5 – 5 g/dL • Alpha 1 acid glycoprotein (AAG) • Also produced by the liver • Binds mostly basic and some neutral drugs • Acute phase protein, elevated in some diseases (cancer), inflammation • Normal range: 0.4 - 1.1 mg/mL

18 Distribution – plasma protein binding

• Extensive plasma protein binding slows drug action and elimination

 A highly plasma protein bound drug will show slower acting and prolonged therapeutic effects

Distribution – tissue binding • Drugs diffuse, or are transported, from the plasma into tissues.

• Tissue can bind drugs – either due to their composition – lipid soluble drugs will accumulate in fat

– via binding to cellular components (proteins, pigments, minerals)

DRUG METABOLISM Phase I Phase II Oxidation Conjugation (CYP P450’s) (glucuronidation)

Conjugation

Metabolites Stable adducts

Polar Non-Polar

Renal elimination Billary elimination (urine) (stools) Phase I Metabolism • usually consist of oxidation (most common), reduction or hydrolysis

• cytochromes P450 are an important group of enzymes but others are involved e.g. plasma cholinesterase

• often introduce/expose a functional group e.g. OH (functionalisation)

• decrease lipid solubility but may increase pharmacological/toxicological activity • a number of benzodiazepines form metabolites which are more pharmacologically active than the parent drug

• Phase I reactions important for activation of pro-drugs

Phase II Metabolism

• conjugation reactions • functional group serves as a point of attack for conjugation systems • large group e.g. glucuronyl, sulphate, acetyl is attached • further decreases lipid solubility and almost always results in pharmacologically inactive metabolite • conjugate excreted in urine or bile

Glucuronidation • commonest conjugation reaction • important for both endogenous compounds e.g. bilirubin and exogenous compounds • mediated by UDP-glucuronyl transferases, an enzyme system with broad substrate specificity • due to their polar nature glucuronides are usually pharmacologically inactive and rapidly excreted

Metabolism of TCAs

• Phase I metabolism converts tertiary to secondary amines • 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 http://medicine.iupui.edu/clinpharm/ddis

The E in ADME: elimination

• 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

First order kinetics

40 /ml) • The rate of elimination is ug proportional to the plasma 30 concentration • Elimination rate quantified by ‘half life’ 20

• The majority of drugs have concentration ( concentration first order kinetics

10 warfarin t1/2 t1/2

0

0 10 20 30 40 50 60 70 Plasma Plasma Time (hours) Elimination parameter: elimination rate constant (ke)

The slope of the log-transformed concentration-time profile Units are 1/time, i.e. hr-1 Theoretical plasma concentration of a first order drug after single or repeated doses Doses

2

1 (proportion of dose) of (proportion

0 Plasma Drug Concentration Plasma Drug Concentration 0 1 2 3 4 5 6 Time (number of half-lives)

Zero order kinetics

200 • The rate of elimination is independent of plasma 150 concentration • A small change in dose can produce a big change in 100 plasma concentration • Rare except if elimination 50 process is saturated (can occur with TCAs)

0 10 Plasma alcohol concentration (mg/dl) concentration alcohol Plasma 0 1 2 3 4 5 6 7 8 9 Time (hours) Elimination parameter: clearance (CL)

• The best measure of the ability of the eliminating organs to remove a compound from the body

• Total body CL = sum of all organ CL processes • i.e. Total CL = Hepatic CL + Renal CL + all other CL

• May be defined as the volume of plasma (or blood) cleared of the compound per unit of time (typically expressed as L/hr in clinical pharmacokinetics, but can be any volume/time)

After IV dosing: After oral dosing: 퐼푉 퐷표푠푒 푂푟푎푙 푑표푠푒×퐹 퐶퐿 = 퐶퐿 = 퐼푉 퐴푈퐶0→∞ 푂푟푎푙 퐴푈퐶0→∞

• Dose/AUC after oral administration gives CL/F (often called oral clearance) • Can also be calculated by: CL = Ke x Vd Elimination parameter: half-life

• Time it takes for concentration of a compound to reach 50% of its current value • Units are time (i.e. hours, minutes, days) 0.693 퐻푎푙푓 푙푖푓푒 = 푘푒

• Rule of thumb: It takes 5 half-lives for a compound to reach steady-state (rate in=rate out) after chronic exposure

• Note: Remember can calculate a rate constant and half-life for absorption, distribution, and elimination processes Half lives of TCAs

Half Life Metabolite (hours - approx)

Amitriptyline 16 Nortriptyline Imipramine 12 Desipramine Clomipramine 18 DMC

Nortriptyline 60 Desipramine 50 DMC 45

Lofepramine 5 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

1.8

Increased risk of side 1.6 effects

1.4 Half dose, 1.2 twice as often 1 Control 0.8

0.6 Half dose, 0.4 same freq.

0.2 Plasma drug concentration drug Plasma

0 0 1 2 3 4 5 6 Time (number of half-lives) Half lives of SSRIs - 1

Half life (hrs) (Active metab.) Fluoxetine 45-72 (150-200) • Note inter-drug and individual variation

• Fluoxetine & paroxetine Sertraline 25 (66) • t1/2 increases with dose and time

Citalopram 36 (?)

Paroxetine 10-20

Fluvoxamine 15 Half lives of SSRIs - 2 Clinical Relevance • Fluoxetine/norfluoxetine - long half life • 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: Special considerations

40 Pregnancy pharmacokinetics

• Absorption • Nausea and vomiting in pregnancy • Distribution • Plasma volume increased by 50% but reduced protein binding • Decrease in total plasma concentration but greater free (or active) drug may offset • Metabolism and elimination • Cytochrome P-450 system induced • GFR increased 50% • ? Effects in practice on steady state concentrations • All psychotropic drugs pass through placenta • The fetal : maternal ratio varies

Ageing Pharmacokinetics

• Renal function • Reduced glomerular filtration by 20-50% • Important for drugs predominantly renally excreted (e.g. lithium) • Hepatic function • Up to 30% reduction in liver volume • Reduced liver blood flow • Reduced CYP450 activity • Reduced serum proteins • Body composition • Increased body fat and decreased body water

42 Problems in the frail elderly

ADR’s are more harmful

• Delirium with Ach effects

• Falls & # with postural hypotension due to adrenergic block

• Lithium tremor disabling

Beware additive effects of drugs (pharmacodynamic interactions)

A single drug may not cause harm BUT additive ADRs may and be missed

Many drugs have anticholinergic effects (inc. warfarin, prednisolone, benzos, ampicillin, ISMO, ranitidine, opioids) (Carnahan et al 2006) Beware additive effects of drugs (pharmacodynamic interactions) Some formulae for adverse effects

Paroxetine + prednisone + furosemide =anti-cholinergic delirium

Citalopram + NSAID + Prednisone = GI bleeding Risk:Benefit ratio in the elderly • Adverse effects are more likely and potentially more serious • Hence lower doses (‘start low and go slow’) • And fewer prescriptions • But biological age ≠ chronological age and treat vigorously if ‘young’

Summary You should now be able to:

• Describe why drug metabolic processes are so important to the function and responses of the body. • Detail the key phases of drug metabolism; using specific examples of the processes involved and the outcome on the drug molecule itself. • Describe situations in which normal metabolic processes will change and the effect this will have on drug disposition.

Summary - kinetics • 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