Practicals: pharmacokinetics

MUDr. P. Potměšil, Ph.D.

1)Quiz

2)Clin. examples and solutions

3)Demonstrations in computer programme

4)Theory

Quiz – questions

1/ What is a biological half-life of drug ?

Quiz – answers, explanations

1/ What is a biological half-life of drug?

After one half-life the concentration of drug will have fallen to half of the initial concentration;

after two half-lives it will have fallen to one quarter of the initial concentration and so on.

Quiz – questions

2/ What is a biological availability (bioavailability)

Quiz – answers, explanations

2/ What is a biological availability (bioavailability)

Bioavailability is the fraction of the administered dose of a drug that reaches the systemic circulation.

Quiz – answers, explanations

2/ What is a bioavailabilityBioavailability can be calculated by comparing the plasma concentration achieved by giving an i.v. dose with the plasma concentration over time following administration of the same dose of a drug given orally.

Rate of drug absorption and first-pass metabolism in the liver are main influences on bioavailability.

Quiz – questions

3/ What is a distribution volume?

Quiz – answers, explanations

3/ What is a distribution volume?

The volume in which a drug would need to be uniformly distributed to produce the same concentration throughout the body as found in plasma.

Vd = Dose / concentration in plasma

Distribution volume (apparent)

Vd is arbitrary value useful as a guide when comparing the relative concentration of the drug in plasma with the rest of the body and should not be thought of as an actual physical volume of fluid.

Distribution volume

Low Vd indicates drug is mainly distributed in plasma, larger indicates drug has been distributed to additional compartments.

Features of drugs that cause them to predominate in each fluid compartment

Intravascular (plasma = 4L)

Interstitial fluid (14 L)

• High mol. weight, bound to albumin:

Warfarin

Benzodiazepines

Penicilin• Low mol. weight,

hydrophilic

Epinephrine

Features of drugs that cause them to predominate in each fluid compartment

Intracellular ( = 42L)

Tissue binding (49 L)

• Low mol. Weight, hydrophobic:

ethanol• Binds to high affinity

site in tissues, high lipid solubility

Digoxin

Tetracyclines

Quiz – questions

4/ What is TDM?

Quiz – answers, explanations

4/ What is TDM?

Therapeutic drug monitoring

For ex.:

•Digoxin (inotropic drug)

•Gentamicin (aminoglycoside antibiotic)

•Valproate (antiepileptic, mood stabiliser)

•Lithium (mood stabiliser)

Clinic example 1:• A 53 yrs old man has swollen ankles,

shortness of breath, fatigue upon mild exercise.

• He is observed:

- severe pitting edema of lower extremities, distended neck veins with prominent pulsation

- Sinus tachycardia 105 beats/min. at rest, normal blood pressure

• He is diagnosed as being in congestive heart failure

• renal function is relatively normal (creatinine CL=115 mL/min)

Clin. Example 1 - continued• If treatment is begun with oral digoxin

(inotropic drug) with a maintenance dose 0,25mg once daily how long should you wait before increasing the dose if his initial response appears inadeaquate?

• You know that biological half-life of digoxin is approx. 36 hours.

a/ approx. 2 hours

b/ approx. 1 day

c/ approx. 2 days

d/ approx. 1 week

Clin. Example 1 - solution• Summary of dosing regimen with digoxin

without use of loading dose

• Initial (starting) dose 0,25mg • Maintenance dose 0,25mg• Dosing interval: 24 hrs. (once daily)• Biol. half life approx. 36 hrs. (1,5 day)

Calculation: steady state concentration wil be in plasma after time of 4-5 biol. half-lives

4 x 36/ 24 = 6 days

Correct answer in test is:

d/ approx. 1 week

Clin. Example : solution using programme PK-SIM

Graph of digoxine dosing without loading dose (in programme PK-SIM)

Dosing of digoxine with loading dose,

normal renal function (progr. PK-SIM)

Graph of digoxine dosing with loading dose normal renal function (in progr. PK-SIM)

Graph of digoxine dosing with loading dose,if renal failure is present (progr. PK-SIM)

Graph of digoxine dosing with reduced loading and maintenance dose and prolonged dosing interval,

severe renal failure is present

Graph of digoxine dosing with reduced loading and maintenance dose and dosing interval 24 hrs,

severe renal failure is present

Clinical example 2:

• Cooperating patient with problems of addiction to alcohol desires to try treatment with acamprosate instead of disulfiram.

• How often should be appropriate to use acamprosate, if we know that biol. half-life of acamprosate is approx. 13 hours?

• multiple choice test

a/ once daily

b/ twice daily

c/ three times daily

Accumulation: dose, dose interval and fluctuation of plasma level

Plasma concentrations of drugs with irregular dosing

Genetic variants in PK

Where can be PK data found?• In section 5.2 „Pharmacokinetic properties“

of SPC = summary of product characteristics

5. Pharmacologic properties

5.1 Pharmacodynamic prop.

5.2 Pharmacokinetic prop.

• SPC is available on the EMA (european medicines agency) web www.ema.europa.eu or web pages of marketing authorisation holder

Recommended literature

• Rang, Dale, Ritter:

Pharmacology 7ed., 2012

• Mark A. Simmons:

Pharmacology - an illustrated review, 2012

Acknowledgements and used literature (information sources)

Lectures, presentations:•Prof. M. Kršiak•MUDr. J. Šedivý, CSc. •Prof. J. Bultas

Books:•Lullman, Mohr:

Color atlas of pharmacology, 2011

•M. A. Simmons: Pharmacology -illustrated review, 2012

Lecture on pharmacokinetics

1. Fate of drugs in the body

1.1 absorption 1.2 distribution - volume of distribution

1.3 elimination - clearance

2. The half-life and its uses

3. The uses of the half-life

4. Plasma concentration-effect relationship

M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008

ABSORPTION

DISTRIBUTION

ELIMINATION

FATE OF DRUGS IN THE BODY

ADMINISTERED

ABSORBED

„HIDDEN“

ELIMINATED

ACTING

WHAT HAPPENS TO DRUGS INSIDE THE BODY

1.1 ABSORPTION

Depends on:

• lipid solubility

• ionization (depends on pH)

non-ionized (non-polar), local changes in the pH

• routes of administration

- per os

- presystemic elimination FIRST-PASS EFFECT

- pharmaceutical technologyBIOAVAILABILITY, bioequivalence

- parenteral

FIRST-PASS EFFECT:

loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation

e.g. in nitroglycerin, morphine

Clinical consequence of the first-pass effect:

• limited effect after oral administration

• great interindividual differences in dosage

BIOAVAILABILITY:

the proportion of drug that reaches the systemic circulation

It is usually calculated from the AUC (Area Under the Curve)

ABSORPTION

DISTRIBUTION

ELIMINATION

FATE OF DRUGS IN THE BODY

ADMINISTERED

ABSORBED

„HIDDEN“

ELIMINATED

ACTING

WHAT HAPPENS TO DRUGS INSIDE THE BODY

- membrane penetration

- protein binding

-plasma proteins

-tissue proteins

ONLY A FREE DRUG ACTS!The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions

1.2 DISTRIBUTION

Depends on:

ABSORPTION

DISTRIBUTION

ELIMINATION

FATE OF DRUGS IN THE BODY

ADMINISTERED

ABSORBED

„HIDDEN“

ELIMINATED

ACTING

WHAT HAPPENS TO DRUGS INSIDE THE BODY

1.3 ELIMINATION:

METABOLIC (biotransformation)

mostly in the liver

ENZYME INDUCTION/ INHIBITION

oxidase enzymes - cytochrom P450 (CYP2D6 etc)

GENETIC POLYMORPHISM

EXCRETION

kidneys metabolites or unchanged (almost completely unchanged e.g. digoxin, gentamycin)

GIT... enterohepatic circulation e.g. tetracyclines

ABSORPTION depends on

- membrane penetration which depends on

-lipid solubility

- ionization (depends on pH)

- routes of administration

DISTRIBUTION depends on:

ELIMINATIONONLY A FREE DRUG ACTS!

FIRST-PASS EFFECT BIOAVAILABILITY- membrane penetration - protein binding

- metabolic

- excretion

FATE OF DRUGS IN THE BODY

ADMINISTERED

ABSORBED

„HIDDEN“

ELIMINATED

ACTING

WHAT HAPPENS TO DRUGS INSIDE THE BODY

protein binding

-plasma proteins

-tissue proteins

ONLY A FREE DRUG ACTS!The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions

VOLUME OF DISTRIBUTION

Depends on:

Because the result of the calculation may be a volume greater than that of the body, it is an APPARENT (imaginary, not actual) volume

For example, Vd of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume)

VOLUME OF DISTRIBUTION

Vd = Amount of drug in body / Concentration of drug in plasma

Clinical importance of volume of distribution:

• When Vd of a drug is big it takes long time to achieve effective plasma concentration of the drug.

•In such cases a loading dose may be given to boost the amount of drug in the body to the required level. This is followed by administration of lower maintenance dose.

METABOLIC (biotransformation)

mostly in the liver

the drug is made more hydrophilic – this increases its excretion in the urine

EXCRETIONmostly by the kidneys

metabolites or unchanged

GIT... enterohepatic circulation e.g. tetracyclines

CLEARANCE

Clearance (CL) is the volume of plasma totally cleared of drug in unit of time (ml/min/kg)

CLtot total

CLR renal

CLH hepatic

CLNR nonrenal (= Cltot - CLR)

Bathtube in a hotel

with two holes, no plugs,

and a plate indicating Vd= 1000 L, CL = 100 mL/min

How would you regulate supply of water (water tap) to fill the bath in order to take a bath soon and for a longer time?

Example – analogy for utilization of information on volume of distribution (Vd) and clearance (CL):

the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

Volume of distributiont ½ = 0,69 .Clearance

Linear kinetics (First order)

[t 1/2 is stable]

In most drugs after therapeutic doses:

plasma concentration falls exponentially

The rate of elimination is proportional to the concentration

In most drugs after therapeutic doses:plasma concentration falls exponentially because elimination processes are not saturated

[some robustness to

dose increase]

Elimination is the bigger the higher is the level

Cmax

Cmin

Linear kinetics (First order)

The rate of elimination is proportional to the concentration

Elimination processes are saturated e.g.:

in alcohol, after higher doses of phenytoin, theophyllin

[unstable t 1/2 ]

Non-linear (Zero-order, saturation) kinetics

For example, in alcohol the rate of metabolism remains the same at about 1 g of alcohol for 10 kg of body weight per hour

The rate of elimination is constant

In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated

elimination is constant, limited

Cmax

Cmin

Non-linear (Zero-order, saturation) kinetics

[low robustness to dose increase]

Kinetics

Half-life(plasmatic)

for anytherapeutic

dose

Robustnessto doseincrease

Predictability

Linear (First-order) stable good good

Non-linear(saturation,zero-order)

unstable poor poor

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

•to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and

•when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

[t1/2 = 1 - 2 h]

Ampicillin - single dose

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

• to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and

• when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

THE USES OF THE HALF-LIFE

„PRINCIPLE OF 4-5 HALF-LIFES“:

If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes

The time to attain the steady state is independent of dose.

Steady state

t1/2

Pla

sma

conc

entr

atio

n

Interval Administered Initial plasmaconcentration atthe beginning of

intervalmicrog/ml

Remains atthe end of

intervalmicrog/ml

[Eliminatedduringinterval

microg/ml]

1. 100 mg 100 50 50

2. 100 mg 150 75 75

3. 100 mg 175 88 88

4. 100 mg 188 94 94

5. 100 mg 194 97 97

Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life

Why Stead State is attained after 4-5 half-lifes?

T1/2 as a guide to asses:

1/ At a single-dose: duration of drug action

2/ During multiple dosing:

•to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and

•when a steady state is attained (in 4-5 half-lifes)

3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

THE USES OF THE HALF-LIFE

Elimination of a drug during 5 half-lifes

of initial level % of total elimination

TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose

FLUCTUATIONS• proportional to dose intervals• blunted by slow absorption

STEADY-STATE LEVELS (CONCENTRATIONS)proportional to dose

t1/2

REPEATED ADMINISTRATION OF DRUGS

Steady-state concentrations are proportional to dose

Linear kinetics - diazepamplasma concentrations

daily

daily

daily

Time (days)

toxic

therapeutic

Time (days)

therapeutic

toxic

plasma concentrationsNon-linear, saturation kinetics - phenytoin

daily

daily

daily

TIME TO STEADY STATE (attained after 4-5 half-lifes) independen of dose

FLUCTUATIONS• proportional to dose intervals• blunted by slow absorption

STEADY-STATE LEVELS (CONCENTRATIONS)proportional to dose

t1/2

REPEATED ADMINISTRATION OF DRUGS

How to reduce fluctuations in drug concentrations?

by administering drugs slowly, continually, e.g.:slow i.v. injection, infusion, sustained–release (SR) tablets, slow release from depots

(e.g. from patches transdermally, depot antipsychotics injected i.m.)

by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient)

or

Effects of drug

• correlate with plasma concentrations

Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some antiepileptics)

• do not correlate with plasma concentrations

- „hit and run“

- tolerance or sensitisation

- active metabolites

The *.ppt set of this lecture will appear at:

http://vyuka.lf3.cuni.cz

1st Teaching Unit (ID9234)