Transcript DRUG DOSAGE REGIMENS

DRUG DOSAGE REGIMENS
15th of Dec 2011
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DRUG DOSAGE REGIMENS
• The objective of a dosage regimen in
therapeutics is to prescribe doses, the size
and timing of which will provide the
maximum therapeutic benefit at the minimum
cost in unwanted effects.
• This is achieved by considering the
pharmacokinetic factors that determine the dose
concentration relationship.
• Most drugs show orderly relationship between
the dose rate and both the therapeutic and
unwanted responses
(except for allergic responses).
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Drug Dosage Regimens
• There are 2 significant boundaries :
1) That between dose rates that are
ineffective and those causing the
desired response.
2) That between dose rates causing the
desired response and those causing
toxic effects.
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Drug Dosage Regimens…
• One way of defining the therapeutic
index, which gives expression to the
margin for error dosing, is the ratio
between these boundaries• The multiple by which the just toxic
dose rate exceeds the just effective
dose rate.
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Drug Dosage Regimens…
• The maximal acceptable toxic and
minimal useful effects define a
therapeutic window in the range of
plasma concentrations.
• The therapeutic objective becomes the
prescription of a dosage regimen-:
• That ensures the maintenance of
plasma concentrations lying entirely
within the therapeutic window.
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Drug Dosage Regimens…
• To determine the dosage rate (D/T ) that will
produce any target steady- state plasma
concentration (Css)-:
• Requires knowledge of the fraction absorbed
(F) and elimination clearance (CL). Equation:
D/T=CL X Css
• The clearance can be obtained from-:
• A knowledge of the volume of distribution (V)
and either elimination half life (T1/2) or
elimination rate constant (Kel).
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• To select a dosage regimen that achieves
this dose rate requires 3 further
considerations,
• Providing that the absorption and
elimination are first order exponential
processes and that distribution is
rapid.
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THERAPEUTIC INDEX
• If therapeutic index is large ( e.g. greater than
100, as with benzylpenillin ) wide fluctuations
in concentration are tolerable.
• Consequently, relatively large doses can be
given at long intervals ( relative to t1/2 ).
• If the therapeutic index is small however (
e.g. approximately 3, as with Gentamicin,
Digoxin )-:
• The tolerable dosage regimen is narrow and
fluctuations in the concentration must be
minimized by giving relatively small doses at
short intervals relative to the t1/2.
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URGENCY OF ONSET OF EFFECT:
• A second important consideration is the need for a
loading dose.
• When Clinical circumstances demand an immediate
drug effect but the drug has a long t1/2, it is
necessary to give a larger first dose,
• (loading dose Do) sufficient to produce a therapeutic
concentration after distribution throughout the
distribution volume ( V ).
• The effect of the drug is then sustained by giving a
smaller maintenance dose ( Dm ) at intervals ( T ),
sufficient to keep pace with clearance ( CL ).
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ELIMINATION HALF-LIFE:
• A third consideration is the t1/2, which may
be
 short (less than 1 hour ),
 moderate ( 4-24 h ) or
 long ( more than 24 h ).
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SHORT PLASMA HALF-LIFE:
• If the t1/2 is short and the therapeutic index is
larger (e.g. Penicillins), a very larger dose can
be given at intervals of 4, 6 or 8 hours (D0 = Dm
) i.e. loading dose =maintenance dose
• The lack of toxicity allows us to compensate for
the short t1/2 by enlarging the dose – doubling
the dose adds one t1/2 to the time the plasma
concentration spends in the therapeutic
window.
• The effect persists long enough for a therapeutic
response, although each dose is completely
eliminated before the next is given.
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SHORT PLASMA HALF-LIFE:…
• When the therapeutic index is small, however, a
sustained drug effect can only be attained by
small frequent doses (e.g. soluble insulin, t1/2
less than 9 minute, in diabetic ketoacidosis).
• An even better approach is continuous i/v
infusion (e.g. soluble insulin , oxytocin, t1/2
several minutes, for induction of labour;
Lignocaine for suppression of ventricular ectopic
foci after myocardial infarction ).
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MODERATE PLASMA HALFLIFE:
• If the t1/2 is moderate it is convenient to
give one half of the initial dose every t1/2
(D0 = 2 x Dm).
• Then there is no accumulation
(Trimethoprim every 12 h or Tetracycline
every 8 or 12 h in infections).
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LONG PLASMA HALF-LIFE:
• If the t1/2 is longer than 24h, as 24 h
dosage interval (T) gives much the best
patient compliance.
• The theoretical maintenance dose (Dm)
corresponds with the proportion of the
loading dose (Do) that is eliminated during
that time.
• Do  (D/T ) = T1/2  0.7
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LONG PLASMA HALF-LIFE:
• A patient receiving digoxin, for example, may
show a t1/2 of 2 days.
• 0.7T t1/2= approximately one third. [from
equation Css  (D/V)= t1/2  (0.7 T)]
• Thus a daily dose of 250 microgram would
correspond with a loading dose of 750g.
• Even if no loading dose were given, the amount
in the body would accumulate until the same
steady-state concentration was attained.
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MONITORING OF PLASMA
CONCENTRATION:
• Monitoring of plasma concentrations of a drug is of most
value as an aid to therapy when the therapeutic effect
itself is difficult to quantify over short time periods
( Phenytoin for epilepsy )
OR
• When the therapeutic window is narrow (Gentamicin for
serious infections with Gram-negative bacteria,
Lithium carbonate for prophylaxis of manicdepressive psychosis, Lignocaine for cardiac
dysrhythmias).
• It must be recognized that the therapeutic window is
a guide to those plasma concentrations at which
benefit generally outweighs hazard.
• The plasma concentration boundaries vary between
individuals.
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CONCENTRATION/ EFFECT AND
TIME/EFFECT RELATIONSHIPS:
• For many drugs the position of the
concentration/effect curve during both an
increase and decrease in concentration is
superimposable ( e.g during and subsequent to
drug infusion ).
• This is seen with neuromuscular blockade
produced by Suxamethonium.
• After i/v administration the drug rapidly gains
access to the neuromuscular junction and the
onset and offset of effect here is rapid.
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CONCENTRATION/ EFFECT AND
TIME/EFFECT RELATIONSHIPS:…
•
•
Some drugs exhibit anti-clockwise hysteresis.
This means that the magnitude of effect for a
given plasma concentration is greater during
offset than during onset of the effect.
• Reasons include-:
1. Delay in distribution- the site of action is in a
deep tissue compartment (e.g. peak Digoxin
effect is approximately 6 h after peak plasma
concentration).
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CONCENTRATION/ EFFECT AND
TIME/EFFECT RELATIONSHIPS:…
• Reasons include:- (cont..)
2. Delay in pharmacological response-there is an
interval between drug reaching its site of action
and its measured effect ( e.g. peak warfarin
concentrations are followed by rapid inhibition
of Prothrombin formation but there is a delay of
approximately 1 day before there is a reduction
in blood coagulation ).
3. Formation of active metabolites ( e.g.
Diazepam metabolism to several
pharmacologically active benzodiazepines ).
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CONCENTRATION/ EFFECT AND
TIME/EFFECT RELATIONSHIPS:…
• The opposite phenomenon of clockwise
hysteresis can also be seen.
• In this case the magnitude of effect for a
given plasma concentration is greater
during onset than offset of the effect.
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CONCENTRATION/ EFFECT AND
TIME/EFFECT RELATIONSHIPS:…
• Reasons include-:
1. Physiological homeostatic mechanisms-these return the
perturbed system to normal but there is a delay in their
onset ( e.g. decrease in BP with a vasodilator drug
countered by reflex tachycardia ).
2. Tolerance- the drug effect declines with time.
• This may occur over minutes, days or even weeks.
• Tolerance may have a pharmacokinetic basis ( e.g.
increased clearance with phenobarbitone ) or a
pharmacodynamic basis ( e.g. change in sensitivity of
neurones in the CNS to Morphine).
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Summary
• Pharmacokinetics is the quantitative science
underlying drug disposition
• The handling of most drugs can be described by
a one compartment model, with parameters of
volume and elimination rate proportional to
concentration (first-order process)
• The half-life of a drug = 0.7 times the apparent
volume of distribution divided by the clearance
• Continuous or intermittently repeated drug
administration results in accumulation until a
steady state is reached.
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Summary…
• At steady state, rate of drug input = rate of
drug output.
 Rate of drug input is bioavailable dose
per unit time and
rate of drug output is clearance times
steady-state concentration
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Summary…
• The handling of a lipid-soluble drug given
intravenously is better described by a
model incorporating a peripheral and a
central compartment (Twocompartment model)
• For some drugs metabolism is saturated at
the prevailing concentration so the
concentration decays at a constant rate
(zero-order process)
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Summary…
• The therapeutic index is the ratio of the drug
dose rate that is just toxic to the drug dose rate
that just produces the desired response
• The therapeutic window is bounded by the
plasma concentrations that define the maximal
acceptable toxic and minimal useful effects
• A dosage regimen of a drug is dictated by its
therapeutic index, desired urgency of onset of
effect and elimination half-life.
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Summary of pharmacokinetic
terms and symbols
• A (mg)
-the amount of a drug in the body
at a particular time
• Css (mg/L)
-the mean plasma drug
concentration when a steady state is attained
• C (mg/L)
-the concentration in the
main/central/plasma compartment at a particular
time after the previous dose
• Co (mg/L)
-the concentration at zero time,
assuming complete absorption with no
elimination; obtained by back extrapolation
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Summary of pharmacokinetic
terms and symbols…
• CL (L/h)
-drug clearance; the volume of
fluid (blood, plasma or water) that contains the
mass of drug eliminated in unit time
• CLcr (L/h)
-clearance of endogenous
creatinine; a useful measure of kidney function
that approximates to GFR
• D (mg)- dose of drug
• F –fraction of dose absorbed from site of
administration; the bioavailability
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Summary of pharmacokinetic
terms and symbols…
• Ka (/h) -absorption rate constant; reciprocally
related to the time for 50% absorption
• Kel (/h) -elimination rate constant; reciprocally
related to the time for 50% elimination
• t1/2 (h) -elimination half-time; the time for C to
decrease by one half or the time for 50%
elimination
• T (h)
-interval between doses during a
course of drug treatment
• V (L)
-apparent distribution volume; the size
of the conceptual compartment in which the drug
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is distributed
Exercise
• What is Drug dosage regimen?
• Write short notes on the following:

Therapeutic index & therapeutic
window

Loading dose & maintenance dose

Dose; dosage & course
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