pharmacokinetics july 2011

8/4/2019 Pharmacokinetics July 2011

1/52

Pharmacokinetics

Based on the hypothesis that the action of a

drug requires presence of a certain

concentration in the fluid bathing the targettissue.

In other words, the magnitude of response

(good or bad) depends on concentration ofthe drug at the site of action


2/52

Clinical pharmacokinetics ?

Study of the time course of a drugsmovement through the body.

Understanding of what the body does to (orwith) the drug.

Application of Therapeutic Drug Monitoring(TDM) and individualisation of drug therapy.


3/52

Pharmacokinetics (PK) &

pharmacodynamics (PD)

PK - What the body does to the drug?

Absorption; distribution, metabolism,excretion (ADME)

PD - What the drug does to the body? Drug concentration at the site of action orin the plasma is related to a magnitude ofeffect


4/52

Plasma Site

Concen- of

tration ActionEffects

PK PD

Pharmacokinetics (PK) and

pharmacodynamics (PD)

Dose


5/52

Pharmacokinetics vs

Pharmacodynamicsconcept Fluoxetine increases plasma

concentrations of amitriptyline. This is a

pharmacokineticdrug interaction.

Fluoxetine inhibits the metabolism of

amitriptyline and increases the plasmaconcentrationof amitriptytline.


6/52

Pharmacokinetics vs

Pharmacodynamicsconcept If fluoxetine is given with tramadol, serotonin

syndrome can result. This is a

pharmacodynamic drug interaction.

Fluoxetine and tramadol both increaseavailability of serotonin leading to thepossibility of serotonin overload This

happens without a change in theconcentrationof either drug.


7/52

Study of [drug] over time


8/52

Volume of Distribution

An abstract concept

Gives information on HOW the drug isdistributed in the body

Used to calculate a loading dose


9/52


Apparent volume of distribution is thetheoretical volume that would have to be

available for drug to disperse in if theconcentration everywhere in the body werethe same as that in the plasma or serum,the place where drug concentration

sampling generally occurs.


10/52

The Compartment Model

WE can generally think of the body as a

series of interconnected well-stirred

compartments within which the [drug]remains fairly constant. BUT movement

BETWEEN compartments important in

determining when and for how long a drugwill be present in body.


11/52

Distribution

Rate & Extent depend upon

Chemical structure of drug

Rate of blood flow

Ease of transport through membrane

Binding of drug to proteins in blood

Elimination processes


12/52

Partition Coefficients: ratio of solubility of

a drug in water or in an aqueous buffer to its

solubility in a lipophilic, non-polar solvent

pH and ionization: Ion Trapping


13/52

Drug Concentrations May Be

Useful When There Is: An established relationship between

concentration and response or toxicity

A sensitive and specific assay An assay that is relatively easy to perfor A narrow therapeutic range

A need to enhance response/preventtoxicity


14/52

Partitioning into body fat and

other tissues A large, nonpolar compartment. Fat has

low blood supplyless than 2% of cardiac output,

so drugs are delivered to fat relatively slowlyFor practical purposes: partition into body fat

important following acute dosing only for a few

highly lipid-soluble drugs and environmental

contaminants which are poorly metabolized andremain in body for long period of time


15/52

IMPORTANT EFFECTS OF PH

PARTITIONING: urinary acidification will accelerate the

excretion of weak bases and retard that of weak

acids; alkalination has the opposite effects increasing plasma pH (by addition of

NaHCO3) will cause weakly acidic drugs to be

extracted from the CNS into the plasma; reducing

plasma pH (by administering a carbonic anhydraseinhibitor) will cause weakly acidic drugs to be

concentrated in the CNS, increasing their toxicity


16/52

Renal Elimination

Glomerular filtration: molecules below 20 kDapass into filtrate. Drug must be free, not proteinbound.

Tubular secretion/reabsorption: Active transport.Followed by passive & active. DP=D + P. As Dtransported, shift in equilibrium to release morefree D. Drugs with high lipid solubility arereabsorbed passively & therefore slowly excreted.Idea of ion trapping can be used to increaseexcretion rate---traps drug in filtrate.


17/52

Plasma Proteins that Bind Drugs

albumin: binds many acidic drugs and a

few basic drugs

b-globulin and an a1acid glycoproteinhave also been found to bind certain basic

drugs


18/52

A bound drug has no effect!

Amount bound depends on:

1) free drug concentration

2) the protein concentration

3) affinity for binding sites

% bound: __[bound drug]__________ x 100

[bound drug] + [free drug]


19/52

% Bound

Renal failure, inflammation, fasting,

malnutrition can have effect on plasma

protein binding. Competition from other drugs can also

affect % bound.


20/52

An Example

warfarin (anticoagulant) protein bound ~98%

Therefore, for a 5 mg dose, only 0.1 mg of drug is

free in the body to work! If pt takes normal dose of aspirin at same time

(normally occupies 50% of binding sites), the

aspirin displaces warfarin so that 96% of the

warfarin dose is protein-bound; thus, 0.2 mg

warfarin free; thus, doubles the injested dose


21/52


C = D/Vd Vd is the apparent volume of distribution

C= Conc of drug in plasma at some time

D= Total conc of drug in system\

Vd gives one as estimate of how well the drug is

distributed. Value < 0.071 L/kg indicate the drugis mainly in the circulatory system. Values >0.071 L/kg indicate the drug has gotten intospecific tissues.


22/52

V

Volume 100 L

Clearance

10 L/hr

Volume of Distribution, Clearance and

Elimination Rate Constant


23/52

V

Volume 100 L (Vi)

Clearance10 L/hr

V2

Cardiac and

Skeletal Muscle

Clearance =

Volume of blood cleared of drug per unit time

Volume of Distribution =

Dose_______Plasma Concentration


24/52

VVolume 100 L (Vi)

Clearance10 L/hr

V2

Cardiac andSkeletal Muscle

Clearance = 10 L/hrVolume of Distribution = 100 LWhat is the Elimination Rate Constant (k) ?


25/52

CL = kV

k = 10 Lhr -1 = 0.1 hr -1

100 L

10 % of the Volume is cleared (of drug) per hour

k = Fraction of drug in the body removed per hour


26/52

CL = kVIf V increases then k must decrease as

CL is constant


27/52

Loading Dose

Dose = Cp(Target) x VD


28/52

Important Concepts

VD is a theoretical Volume anddetermines the loading dose

Clearance is a constant and determinesthe maintenance dose

CL = kVD

CL and VD are independent variables

k is a dependent variable


29/52

Question

What is the loading dose required fordrug A if;

Target concentration is 10 mg/L

VD is 0.75 L/kg

Patients weight is 75 kg


30/52

Answer: Loading Dose of Drug A

Dose = Target Concentration x VD

VD = 0.75 L/kg x 75 kg = 56.25 L Target Conc. = 10 mg/L

Dose = 10 mg/L x 56.25 L

= 565 mg This would probably be rounded to 560 or

even 500 mg.


31/52

How are [drug] measured?

Invasive: blood, spinal fluid, biopsy

Noninvasive: urine, feces, breath, saliva

Most analytical methods designed for

plasma analysis

C-14, H-3


32/52

Clearance Ability of organs of elimination (e.g.

kidney, liver to clear drug from the

bloodstream Volume of fluid which is completely

cleared of drug per unit time

Units are in L/hr or L/hr/kg

Pharmacokinetic term used indetermination of maintenance doses


33/52

Maintenance Dose

Calculation

Maintenance Dose = CL x CpSSav

CpSSav is the target average steady statedrug concentration

The units of CL are in L/hr or L/hr/kg

Maintenance dose will be in mg/hr so for totaldaily dose will need multiplying by 24


34/52

Question

What maintenance dose is required fordrug A if;

Target average SS concentration is 10mg/L

CL of drug A is 0.015 L/kg/hr

Patient weighs 75 kg


35/52

Answer

Maintenance Dose = CL x CpSSav

CL = 0.015 L/hr/kg x 75 = 1.125 L/hr

Dose = 1.125 L/hr x 10 mg/L= 11.25 mg/hr

So will need 11.25 x 24 mg per day= 270 mg


36/52

Half-Life and k

Half-life is the time taken for the drugconcentration to fall to half its original

value The elimination rate constant (k) is the

fraction of drug in the body which is

removed per unit time.


37/52

Drug Concentration

Time

C1

Exponential decay

dC/dt C

= -k.CC2


38/52

Log Concn.

Time

C0

C0/2t1/2

t1/2

t1/2

Time to eliminate ~ 4 t1/2


39/52

Steady-State

Steady-state occurs after a drug has been givenfor approximately five elimination half-lives.

At steady-state the rate of drug administrationequals the rate of elimination and plasmaconcentration - time curves found after eachdose should be approximately superimposable.

Accumulation to Steady State


40/52

100

187.5194

175

150

75

87.5 9497

50

200

100

Accumulation to Steady State

100 mg given every half-life


41/52

C

t

Cpa

Four half lives to reach steady state

Wh i S d S (SS) ?


42/52

What is Steady State (SS) ?Why is it important ?

Rate in = Rate Out

Reached in 4 5 half-lives (linearkinetics)

Important when interpreting drugconcentrations in TDM or assessingclinical response


43/52


44/52

Therapeutic Window

Useful range of concentration over which a drug istherapeutically beneficial. Therapeutic windowmay vary from patient to patient

Drugs w/ narrow therapeutic windows requiresmaller & more frequent doses or a differentmethod of administration

Drugs w/ slow elimination rates may rapidlyaccumulate to toxic levels.can choose to giveone large initial dose, following only with smalldoses


45/52

Shape different for IV injection


46/52

Conc. Vs. time plots

C = Co - kt ln C = ln Co - kt


47/52

Clearance

Volume of blood in a defined region of the

body that is cleared of a drug in a unit time.

Clearance is a more useful concept in realitythan t 1/2 or kel since it takes into account

blood flow rate

Clearance varies with body weight Also varies with degree of protein binding


48/52

AUC: IV Administration


49/52

AUC

For IV bolus, the AUC represents the total

amount of drug that reaches the circulatory

system in a given time. Dose = CLT AUC


50/52

AUC: Oral Administration


51/52

Bioavailability

The fraction of the dose of a drug (F) that

enters the general circulatory system,

F= amt. Of drug that enters systemic circul.

Dose administered

F = AUC/Dose


52/52

Bioavailability

A concept for oral administration

Useful to compare two different drugs or differentdosage forms of same drug

Rate of absorption depends, in part, on rate ofdissolution (which in turn is dependent on

chemical structure, pH, partition coefficient,surface area of absorbing region, etc.) Also first-pass metabolism is a determining factor

pharmacokinetics july 2011

Documents