1. DR. BADAR UDDINUMAR

2. 
To discuss dosing schedules of drugs
based on pharmacokinetic principles

To discuss therapeutic drug monitoring

3.  Effective
dose: It is the amount of drug
which will produce specific intensity of
effect i.e.; either to treat the disease or
prevent the disease successfully

4.  Median
effective dose (ED50): It is the amount
of a drug which produces the desired
therapeutic effect in 50% of experimental
animals
OR
 It is the dose of a drug required to produce a
specific intensity of effect in 50% of individuals
 It
is measure of effectiveness of a drug

5.  Lethal
dose: It is the amount of a drug which
will kill certain percentage of experimental
animals to whom the drug is administered
 Fatal
dose: When lethal dose reaches 100% or
LD100 is known as fatal dose

6. 
Median lethal dose (LD50): It is the amount
of a drug which is fatal to 50% of the
experimental animals

[i.e.; which kills 50% of the experimental
animals]

It is the measure of acute toxicity of drugs

7.  Initial
loading dose: In some
conditions certain drugs are given in
large doses in the beginning to obtain
an effective blood level rapidly, this is
known as initial loading dose

8.  Maintenance
dose: After achieving a
desired blood level by initial loading
dose, smaller quantity of drug is then
required to maintain the blood level,
this is known as maintenance dose

9.  e.g. initial
loading dose of sparfloxacin
is 400 mg. on the first day then
maintenance dose is 200 mg / day as
single daily dose
 Initial
loading dose of digoxin is 1-1.5
mg the maintained at 0.25 mg once or
twice daily dose

10. Loading Dose
Dose = Cp(Target) x Vd
Dose = Cp(Target) x Vd

11. 
What is the loading dose required for
drug A if;
Target concentration is 10 mg/L
Vd is 0.75 L/kg
Patients weight is 75 kg

Answer is on the next slide




12. 
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

13. 
Maintenance Dose = CL x CpSSav

CpSSav is the target average steady state drug
concentration

The units of CL are in L/hr or L/hr/kg

Maintenance dose will be in mg/hr so for total
daily dose will need multiplying by 24

14. 
What maintenance dose is required for drug A if;

Target average SS concentration is 10 mg/L

CL of drug A is 0.015 L/kg/hr

Patient weighs 75 kg

Answer on next slide

15. 
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

17. 
Effective Dose50 [ED50]

Toxic Dose50 [TD50]

Therapeutic Index

Therapeutic window

20. 
Not all people respond to a similar dose of a
drug in the exact same manner

This variability is based upon individual
differences and is associated with toxicity

21. Drug
Therapeutic Concentration
Range
Aminoglycoside
(gentamicin, tobramycin)
0.5 < - > 8 mg/L
Digoxin
0.5 < - > 8 2.0 ug/L
Phenytoin
10 < - > 8 20 mg/L
Theophylline
10 < - > 8 20 mg/L

22. 
This variability is thought to be caused
by:
• Pharmacokinetic factors contribute to
differing concentrations of the drug at the
target area
• Pharmacodynamic factors contribute to
differing physiological responses to the
same drug concentration -
• Unusual, idiosyncratic, genetically
determined or allergic, immunologically
sensitized responses

25.  The
therapeutic index (also known as
therapeutic ratio), is a comparison (ratio) of the
amount of a drug that causes the therapeutic
effect to the amount that causes death
 Quantitatively, it
is the ratio of median lethal dose
to median effective dose
 It
is an approximate assessment of the safety of
the drugs

26. A
high therapeutic
index is preferable to
a low one
 This
corresponds to a
situation in which one
would have to take a
much higher dose of a
drug to reach the lethal
threshold than the dose
taken to elicit the
therapeutic effect

27.  Larger
the TI greater is the relative safety
of the drug
 For
therapeutic use TI of a drug must be
more than one
A
drug might have different TI
depending on its clinical use
 e.g.; Aspirin used in headache TI is high
 Aspirin used in Rheumatoid arthritis TI is very
low

28.  Drugs
with high TI:
Penicillin [dose up to
48 lac units]
Diazepam [up to 200
mg at once, LD is 750
mg]
 Drugs
with low TI:
Digitalis [digoxin]
Anticancer drugs
Phenobarbitone
Warfarin

29.  In
animal studies, the therapeutic
index is usually defined as the ratio of
the TD50 to the ED50
 The
precision, possible in animal
experiments may make it useful to
estimate the potential benefit of a drug
in humans

30.  The
therapeutic index of a drug in humans is
almost never known with real precision
 Drug
trials and accumulated clinical
experience often reveal a range of usually
effective doses and a different (but
sometimes overlapping) range of possibly
toxic doses

31.  The
clinically acceptable risk of toxicity
depends critically on the severity of the
disease being treated
 For
example, the dose range that provides
relief from an ordinary headache in the great
majority of patients should be very much
lower than the dose range that produces
serious toxicity

32.  However, for
treatment of a lethal
disease such as Hodgkin's lymphoma,
the acceptable difference between
therapeutic and toxic doses may be
smaller

33.  It
is the ratio of the lethal dose to 1%
of population to the effective dose to
99% of the population (LD1/ED99)

34.  This
is a better safety index than the LD50 for
drugs that have both desirable and
undesirable effects, because it factors in the
ends of the spectrum where doses may be
necessary to produce a response in one
person but can, at the same dose, be lethal in
another

35. 
Useful range of concentration over
which a drug is therapeutically
beneficial

Therapeutic window may vary from
patient to patient

36. 
Drugs with narrow therapeutic windows
require smaller and more frequent doses or a
different method of administration

Drugs with slow elimination rates may rapidly
accumulate to toxic levels….can choose to
give one large initial dose, following only with
small doses

38. Some Principles

39. 
An established relationship between
concentration and response or toxicity

A sensitive and specific assay

An assay that is relatively easy to perform

A narrow therapeutic range

A need to enhance response/prevent toxicity

40. 
Lack of therapeutic response

Toxic effects evident

Potential for non-compliance

Variability in relationship of dose and
concentration

Therapeutic/toxic actions not easily quantified
by clinical endpoints

41. 
Assuming patient is at steady-state

Assuming patient is actually taking the drug
as prescribed

Assuming patient is receiving drug as prescribed

Not knowing when the [drug] was measured in
relation to dose administration

Assuming the patient is static and that changes in
condition don’t affect clearance

Not considering drug interactions

42. 
Invasive: blood, spinal fluid, biopsy

Noninvasive: urine, feces, breath, saliva

Most analytical methods designed for
plasma analysis

C-14, H-3

44. At the end of the lecture the students will be able
to
Explain with examples the principles of dosing
schedules of drugs based on pharmacokinetic
principles

Explain with examples the clinical significance
of therapeutic drug monitoring