1. PHARMACOKINETICS 1. Fate of drugs in the body 1.1 absorption
M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008
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

2. 1. FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
Administered
ABSORPTION
Absorbed
DISTRIBUTION
„Hidden“
Volume of distribution
Eliminated
ELIMINATION
Clearance
Acting

3. VOLUME OF DISTRIBUTION
Depends on:
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

4. VOLUME OF DISTRIBUTION
Vd = Amount of drug in body / Concentration of drug in plasma
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)

5. 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.

6. ELIMINATION METABOLIC (biotransformation) ENZYME INDUCTION/ INHIBITION
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

7. 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)

8. and a plate with data Vd= 1000 L, CL = 100 mL/min
Bathtube in a hotel
with two holes, no plugs,
and a plate with data Vd= 1000 L, CL = 100 mL/min

9. 2. The half-life and its uses
the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

10. In most drugs after therapeutic doses:
plasma concentration falls exponentially
Linear kinetics (First order)
The rate of elimination is proportional to the concentration
[t 1/2 is stable]

11. In most drugs after therapeutic doses:
plasma concentration falls exponentially because elimination processes are not saturated
Linear kinetics (First order)
Cmax
[some robustness to dose increase]
Cmin
Elimination is the bigger the higher is the level
The rate of elimination is proportional to the concentration

12. Non-linear (Zero-order, saturation) kinetics
Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin
Non-linear (Zero-order, saturation) kinetics
The rate of elimination is constant
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
[unstable t 1/2 ]

13. elimination is constant, limited
In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated
Cmax
[low robustness to dose increase]
Cmin
elimination is constant,
limited
Non-linear (Zero-order, saturation) kinetics

15. 3. The uses of half-life 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)

16. [t1/2 = h]
Ampicillin - single dose

17. THE USES OF THE HALF-LIFE
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)

18. „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
Plasma concentration
t1/2

19. Why SS is attained after 4-5 half-lifes?
Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life

20. THE USES OF THE HALF-LIFE
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)

21. Elimination of a drug during 5 half-lifes
of initial level
% of total elimination

22. REPEATED ADMINISTRATION OF DRUGS
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

23. Steady-state concentrations are proportional to dose
Linear kinetics - diazepam
toxic
plasma concentrations
daily
therapeutic
daily
daily
Time (days)

24. Non-linear, saturation kinetics - phenytoin
plasma concentrations
toxic
daily
daily
therapeutic
daily
Time (days)

25. REPEATED ADMINISTRATION OF DRUGS
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

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

27. 4. PLASMA CONCENTRATION - EFFECT RELATIONSHIP
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

28. The End

30. Administration of parts of total dose at short intervals
produces smaller fluctuations of drug concentrations (levels)
an omission of a particular dose* does not need to cause an undesirable fall in drug concentrations (levels)
*noncompliance

32. 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 technology BIOAVAILABILITY, bioequivalence
parenteral

33. 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

34. Clinical consequence of the first-pass effect:
limited effect after oral administration
great interindividual differences in dosage

35. BIOAVAILABILITY:
the proportion of drug that reaches the systemic circulation
It is usually calculated from the AUC
(Area Under the Curve)