Bez nadpisu

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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. Repeated administration of drugs
4. Plasma concentration-effect relationship
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1. FATE OF DRUGS IN THE BODY
WHAT HAPPENS TO DRUGS INSIDE THE BODY
Administered
ABSORPTION
Absorbed
DISTRIBUTION
Hidden
Volume of distribution
Clearance
ELIMINATION
Eliminated
Acting
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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

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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 that
his actual volume)
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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.

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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)
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Clinical importance of clearance

• Determines the maintenance dose
• Drugs eliminated mainly through the kidney need
  measures (e.g. dosage adjustment) in renal
  insufficiency
• Drugs eliminated mainly through the liver need
  protective measures in liver insufficiency

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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
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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
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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
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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
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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
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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)

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t1/2 1 - 2 h
Ampicillin - single dose
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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)

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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 This
time is independent of dose.
Steady state
Plasma concentration
t1/2
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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
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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)

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Elimination of a drug during 5 half-lifes
of initial level
of total elimination
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3. REPEATED ADMINISTRATION OF DRUGS
STEADY STATE attained after 4-5 half-lifes

• FLUCTUATIONS
• proportional to dose intervals
• blunted by slow absorption

STEADY-STATE CONCENTRATIONS proportional to dose
t1/2
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Fluctuations of concentrations are the bigger the
longer are intervals between administrations (of
parts of total dose)
Time (h)
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• 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
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How to reduce fluctuations in drug concentrations?
by administering

• The total dose in parts at short intervals
  mostly inconvenient

• Sustained-release preparations, infusions

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Steady-state concentrations are proportional to
dose
Linear kinetics - diazepam
toxic
plasma concentrations
daily
therapeutic
daily
daily
Time (days)
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Non-linear, saturation kinetics - phenytoin
plasma concentrations
toxic
daily
daily
therapeutic
daily
Time (days)
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4. PLASMA CONCENTRATION - EFFECT RELATIONSHIP

• Effects of drug
• correlate with plasma concentrations
• Therapeutic Drug Monitoring (TDM)
• do not correlate with plasma concentrations
• hit and run
• tolerance or sensitisation
• active metabolites