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Pharmaceutical Pharmacokinetic
process
process
Drug Therapy
Pharmacodynamic Therapeutic
process
process
Monitoring the
Therapeutic Effects of
Drugs :-
1-Monitoring the
therapeutic event in the
individual:A-Anticonvulsant drug
therapy : seizure frequency
Patients should be
encouraged to keep a
diary documenting the
occurrence of seizure in
order to assess the success
of treatment.
B-Anticholiesterase in
myasthenia gravis :
improvement in muscle
power
Patient can assess his
own muscle power by
simple quantitative test.
In case of respiratory
paralysis , test of
pulmonary function e.g.
vital capacity.
Fatigue (Ptosis) in a patient with MG
C-Drugs for angina pectoris
: frequency of attacks
Ability of GTN to prevent
anticipated attack or
shorten its duration.
In assessment of βadrenoceptor blockers or
calcium channel blockers ,
the fall in the number of
GTN tablets a patient has
to take may be used as a
measure of efficacy.
D-Diuretics in the
treatment of oedema :
body weight
Urine volume can be
used , but unreliable
because of errors in
recording or
incontinence.
Daily measurement
of body weight is
more reliable.
E-The treatment of
ulcerative colitis with
glucocorticoids or 5aminosalicylic acid:Improvement in the
systemic effects e.g.
lessening of fever,
general malaise, ,
increase of appetite &
vigor.
Reduction in the
number & severity of
attacks of diarrhoea,
with reduction in the
amount of blood, mucus
& pus.
2-Monitoring the
effects of drug
therapy in the
population:A-Immunization:-the
effect of imunizing the
population against
poliomyelitis can be
monitored by
surveying the
occurrence of this
disease in the
population.
B-Currently
recommended
procedures in
preventive medicine:By encouraging people
to change their life style
the rate of certain
disease will fall
i-Stopping smokingCHD, peripheral
vascular diseases,
chronic bronchitis,
bronchial carcinoma.
ii-Losing weightdiabetes mellitus,
CHD, hypertension ,
osteoarthritis
iii-High -fiber dietdiverticular disease,
irritable bowel
syndrome.
vi-Reducing cholesterol
& saturated fats in the
diet:-CHD
C-Some longterm prophylactic
drug therapies
widely
prescribed:i-Prevention of
pregnancies-oral
contraceptives.
ii-Secondary
prevention of
myocardial
infarctionaspirin, βadrenoceptor
blockers.
iii-Hypertension &
its complicationsantihypertensive
drug therapy.
iv-Diabetes mellitus
& its complicationsdiet, insulin & oral
hypoglycaemic
agents.
2- Monitoring the
Pharmacodynamic
Effects of Drugs:-
In some cases it is not possible to measure the
therapeutic outcome directly.
A pharmacodynamic effect, called surrogate
marker, is measured.
A surrogate marker is defined as an endpoint that
is measured in place of the true end point & that
relates in someway to the end point of primary
interest.
Surrogate markers are cheaper & easier to
measure than true end point & can be measured
more quickly
A-Insulin therapy in diabetes
mellitus: effect on blood
glucose
• Diabetes ketoacidosis is
managed with low- dose
continuous IV infusion of
insulin & frequent
monitoring of blood glucose.
• Measurement of blood glucose allows
alteration of the dose of insulin to
maintain the blood glucose within
reasonable limits to avoid
hyperglycaemia or hypoglycaemia [410mmol/L]
Measurement of urinary
glucose concentration in
patients who cannot measure
their own glucose can be used
to guide therapy. [aim is to
reduce glycosuria to 14-28
mmol/L.
Idea about how good overall
control has been during past
week or month can be
obtained by looking at past
records or by estimation of
HbAIC [raised concentration
suggests poor blood glucose
control over the preceding 2
or 3 months] [normal<6%].
B-Anticoagulant
effect with warfarin :
effect on prothrombin
time
If the international
normalized ratio
[INR] is kept within
accepted therapeutic
limits the chance of
reducing the
likelihood of a
pulmonary embolus
in a patient with deep
vein thrombosis is
increased.
C-Allopurinol in gout :
effect on blood uric acid
Allopurinol reduces serum
uric acid by inhibiting the
conversion of hypoxanthin
to uric acid
Fall of uric acid
concentration is
accompanied by decreased
incidence of acute attacks
of gouty arthritis &
prevention of gouty renal
disease.
Neglected chronic gout
with tophi
D-Carbimazole in
hyperthyroidism : effect on
thyroid hormones
Serum concentrations of T3
& TSH are measured.
Therapeutic effect of
carbimazole can be detected
by a fall in serum T3 , over
treatment will cause a fall in
serum T3 below normal & an
increase in serum TSH above
normal.
E-Bronchodilator therapy in
bronchial asthma: effect on FEV1
& peak flow rate
The effects of salbutamol
inhalor or slow-release
theophylline can be objectively
assessed by measuring their
effect on FEV1 or by measuring
the peak flow rate recorded
during maximal expiration.
Assessment of salbutmol
inhalation is after 10-15min,
ipratropium 45-60min.
F-Cancer
chemotherapy: effect
of tumour markers:The effectiveness of
cytotoxic drug
therapy with
methotrexate can be
monitored by
measuring serum
concentration of
human chorionic
gonadotrophin
G-Lowering the
blood pressure by
antihypertensive
drugs.
H-The
measurement of
intraocular
pressure in
patients with
glaucoma.
Therapeutic drug monitoring is a tool that can
guide the clinician to provide effective and
safe drug therapy in the individual patient.
Monitoring can be used to confirm a plasma
concentration which is above or below the
therapeutic range ,thus minimizing the time
which elapses before corrective measures can
be implemented in the patient
Therapeutic drug monitoring is the measurement of
the serum level of a drug and the coordination of
this serum level with a serum therapeutic range.
The serum therapeutic range is the concentration
range where the drug has been shown to be
efficacious without causing toxic effects in most
people.
Recommended therapeutic ranges can generally be
found in the product inserts for drugs that require
monitoring.
They are also available in books such as the
Physicians Desk Reference, and articles in the
primary medical journals.
Criteria which determine whether measuring
the plasma concentration of a particular
drug may be useful in practice:1-Drugs for which the relationship between
dose & plasma concentration is
unpredictable:-the plasma concentration that
will result from a given dose in a given
individual is unpredictable e.g. phenytoin.
Factors which may alter the relationship
between the dose & plasma concentration
include:-renal & hepatic failure , diarrhoea ,
drug interactions & thyroid dysfunction
2-Drugs for which
there is a good
relationship
between plasma
concentration &
effect:This criterion leads to
the concept of
‘therapeutic range’
which is derived from
plasma concentration
measurements in
large number of
patients.
Drugs with an irreversible or ‘hit & run’
actions e.g. MAOI & alkylating agents are
not suitable.
The development of tolerance may also
restrict the use of the plasma level
estimation.
3-Drugs with a low
therapeutic
index:measurement of
plasma
concentrations of
such drugs will
allow dosage
alterations to be
made in order to
produce optimal
therapeutic effect
or to avoid toxic
effects.
4-Drugs which are not metabolized to active metabolites:-e.g.
procainamide is metabolized to N-acetylprocainamide which is
equally potent .
The extent of metabolism varies according to the acetylator
status[10-40%].
Thus measuring plasma procainamide concentration alone gives
imprecise guide to therapy.
Drugs for which one or two enantiomers comprise a large
proportion of the desired pharmacological response
5-Drugs for which there is difficulty in measuring or
interpreting the clinical evidence of therapeutic or
toxic effects:Nausea & vomiting occur in both digitalis toxicity &
congestive heart failure.
Phenytoin toxicity can occasionally cause an increase
rather than a decrease in the frequency of epileptic
seizures.
Renal failure may occur in patients with G-negative
septicaemia because of the disease or because of the
adverse effects of the gentamicine used to treat it.
If the relationship between the plasma concentration
of a drug and its adverse effects is known, it can be
used to distinguish between drug induced and
disease-induced effects.
6- Drugs with steep dose
response curve for which
a small increase in dose
can result in a marked
increase in desired or
undesired response e.g.
theophylline.
Drugs for which TDM
might not be indicated
include those
characterized by a wide
therapeutic index or
those for which response
can be easily monitored
by clinical signs.
• Pharmacokinetic factors that cause
variability in plasma drug
concentration are:
• •drug-drug interactions
• •patient disease state
• •physiological states such as age,
weight, sex
• •drug absorption variation
• •differences in the ability of a patient to
metabolize and eliminate the drug
Which drugs fulfill these criteria?
Drugs that fulfill a sufficient number of
criteria to make it worth measuring their
plasma concentrations in monitoring
therapy are listed in A
Some drugs fulfill four of these criteria ,
but have not been shown conclusively to
fulfill the most important criterion [ that
there should be a good relationship
between plasma concentration and the
therapeutic or toxic effects]
These drugs are listed in B.
Indications for measuring plasma drug
concentrations:when in practice such measurement is likely to
contribute significantly to patient care?
1-Individualizing therapy:- to aim for a
particular range within which therapeutic effect
is likely to occur & toxic effects are likely to be
minimized ,which is useful in:A-At the beginning of therapy when the
relationship between dose & plasma
concentration in the individual is uncertain.
B-When rapid changes in renal function alter
the relationship between dos & the plasma
concentration , this is particulary important in
case of digoxin, lithium, aminoglycoside
antibiotics.
C-When another drug alter the relationship
between dose & plasma concentration e.g.
plasma concentration of lithium is increased by
thiazide.
2-In the diagnosis of suspected toxicity:-plasma
concentration above the therapeutic range will
undoubtly reinforce one’s suspicions of toxicity
3-Measuring compliance:- it is the extent
to which the patient follows a prescribed
drug regimen
Extent of compliance varies from 10-92%
Factors which affect compliance:1-The nature of the treatment
a-The complexity of the prescribed
regimen
b-Adverse effects
2-Characteristics of the patient
3-The behavior of the doctor
In general, TDM should not be
performed until plasma drug
concentration has reached
steady state in the patient.
Peak and trough concentrations
are different from one another
for drugs with a short half life
compared to the dosing interval
e.g. antibiotics, for such drugs ,
both a peak and a trough sample
should be collected.
Steady-state drug concentrations provide the best
correlation between serum drug concentrations and
clinical status
Pharmacokinetic principles can be used to
predict the concentration required to
achieve a particular degree of therapeutic
effect
The target concentration strategy is a
process for optimizing the dose in an
individual .
1- choose the target concentration,TC
2-Predict Vd & Cl with adjustment for
factors such as weight & renal function.
3-Give a loading dose or maintenance dose
calculated from TC, Vd & Cl.
4-Measure the patient response & drug
concentration.
5-Revise Vd and/or Cl based on the
measured concentration.
6-Repeat steps 3-5 adjusting the predicted
dose to achieve TC.
Trough samples are generally recommended
for consistency across time if a single
samples are to be collected . Trough
samples should be collected as close to but
before a dose.
Peak should be determined after drug
absorption[generally 2-4hours for oral
administration], for im,sc,0.5-1hour
Most orally administered drugs are rapidly absorbed
and reach peak serum concentrations within 1-2 hours
The Effect of Sample Times on Parameter Values
Patients receiving a drug at a dosing interval longer
than the half-life of the drug will exhibit large
fluctuations between the peak and trough levels.
Shorter intervals lead to less variation
Peak and trough concentrations will not
differ substantially for drugs whose halflives is much longer than the dosing interval
e.g. phenobarbitone, for such drugs a single
sample is generally sufficient
A single sample is also indicated for slow
release preparation, and following a loading
dose, in case of toxicity , a single peak
sample
It is important to avoid withdrawing blood
until absorption is complete [2h after an oral
dose]
Some drugs take several hours to distribute
into tissues e.g. digoxin [6h after last dose]
& lithium[24h after last dose]
When steady state has been reached , a
sample obtained near the mid point of the
dosing interval will usually be close to the
mean steady concentration.
SAMPLING TIMES AND TARGET RANGES FOR TDM ASSAYS .TABLE 1
DRUG
MINIMUM
PLASMA/SERUM
VOLUME (mL )
Amitriptyline
(+ nortriptyline)
APPROXIMATE TIME TO
STEADY STATE (DAYS)
RECOMMENDED
SAMPLING TIME
TARGET
RANGE
10-7
pre-dose
250-100µg/L
Caffeine
0.2
2
2-1h post-dose
36-12mg/L
Carbamazepine
0.5
4-2
pre-dose
12-4mg/L
Clomipramine (+norclomipramine)
2.0
42-28
pre-dose
800-150µg/L
Desipramine
2.0
14-10
pre-dose
250-100µg/L
Digoxin
0.5
7-5
24-6h post-dose
2.0-0.8µg/L
Dothiepin (+ nordothiepin)
2.0
7
pre-dose
300-100µg/L
Ethosuximide
0.5
14-7
pre-dose*
100-40mg/L
Fluoxetine (+ norfluoxetine )
2.0
42-28
pre-dose
800-150µg/L
Gabapentin
0.5
2-1
pre-dose
20-2mg/L
Imipramine (+ desipramine)
2.0
7
pre-dose
300-150µg/L
Lamotrigine
0.5
6-4
pre-dose
4-1mg/L
Nortriptyline
2.0
14-10
pre-dose
150-50µg/L
Phenobarbitone
0.5
20-10
pre-dose*
40-15mg/L
Phenytoin
0.5
35-7
pre-dose*
20-10mg/L
Theophylline - adults (1 )
Theophylline - neonates (2 )
0.5
0.5
2
2
4-2h post-dose
4-2h post-dose
20-10mg/L
10-5mg/L
Valproic acid (3 )
0.5
3-2
pre-dose
up to 100
mg/L
The process of therapeutic monitoring takes
effort.
First pharmacist and physician develop initial
dosing recommendations.
Involvement of clinical pharmacist in therapeutic drug
monitoring & interpretation.
The management of therapy using plasma concentration
•
•
•
•
•
•
Information required
Time of sample in relation to last dose
Duration of treatment with the current dose
Dosing schedule
Patient - Age, weight, sex, height, smoker
Clinical - Drug requirements, clinical status (renal serum creatinine; cardiac - cardiac output, liver, etc
• Other drug therapy
• Relevant disease states
• Reason for request e.g. lack of effect, routine
monitoring, suspected toxicity
Calculate initial loading dose or maintenance
regimen and make recommendations
• Then organize sample collection and analysis .
Accurate Timing in necessary
• Second, someone (nurse, med tech) must take the
blood.
• Someone (lab tech, you) must assay the drug
concentration in the blood.
• Evaluate pharmacokinetically the analytical result
and recalculate dosing regimen recommendations
Organize further samples if necessary, repeat as
necessary
• You must communicate your interpretation and
your recommendations for dosage regimen change
to the physician. This will allow for informed
dosage decisions.
• You must follow through to ensure proper
changes have been made.
• You must continue the process throughout
therapy.
Therapeutic drug monitoring, in many cases,
will be part of your practice. It can be very
rewarding.
A retrospective survey
carried out at the
Massachusetts General
Hospital showed that
whilst prior to the use of
digoxin monitoring
13.9% of all patients
receiving this drug
showed evidence of
intoxication , following
introduction of
monitoring this fell to
5.9%.
A significant difference
with regard to length of
stay in the hospital
between patients on
gentamicin who were
monitored and their
dosage regulated
consequently versus
those who were not
(DeStache, 1990)
Effect of artifact on TDM results
Artifact
Sequela
Drug
All
drugs
Serum
separator
tubes
Aminogl Glass tubes
ycosides
Digitalis Red
stoppers
Silicon gel can bind
drug,decreasing
concentration
Glass bind drug,
decreasing concentration
Stoppers may bind drug,
decreasing concentration
Identification and
quantization
performed on an
emergency basis of
toxic substances in
patients after toxic
episode
Why Measure Drug Levels?
Indications of “Drug screen”
1-It is carried out for drugs or
toxins for which plasma
concentration data may influence
treatment. e.g. phenobarbitone,
ethanol, ethylene glycol, isopropyl
alcohol, paraquat, salicylates,
thiophylline,
Why Measure Drug Levels?
2-Multiple drug ingestion
3-History unreliable [Patient may
try to hide drug poisoning by
withholding or altering information.]
4-Patient in delirium or coma of
unclear aetiology.
5-Determine drug abuse
Objectives:1-Identification of
specific drug
2-To indicate when
antagonists to be
used
3-Aid in the
estimation of
prognosis
Assay Techniques



Spectrophotometric
Immunoassay
Chromatographic
Awareness of relative
specifity, sensitivity
& precision of these methods.
Difficulties & limitations
1-Some compounds may be active at
low concentration which are not
detectable by available techniques.
2-Some compounds are heat labile and
break apart before detection e.g LSD,
psilocybin
3-Some compounds are distributed to
compartments other than the tested
compartment e.g. LSD, pesticides
4-Some evaporate in extraction or
concentration e.g. solvents
Sampling:1-Blood:-
Blood– Specimen most often
used for medicolegal cases
Useful in case of paracetamol,
salicylates,
carboxyhaemoglobin,
methanol, ethylene glycol
• – Disadvantages: invasive, drugs
only detected for short time,
analysis of blood is labor intensive
and relatively expensive
Advantage:
when
individual
suspected of
being
intoxicated on
alcohol (exact
concentration
determined
and related to
levels
determined to
cause
impairment)
BAC(mg/L)
Clinical effect
50-100
Sedation,↑reaction times
100-200
Impaired motor function,
slurred speech, ataxia
200-300
Emesis, stupor
300-400
coma
>500
Respiratory depression,
death
2-Urine:performed when the
blood concentration of
the compound is too
low for detection by
conventional measures
, rapidly eliminated or
have high volume of
distribution e.g.
phenothiazines,
benzodiazepines,
antihistamines, TCA
• • Advantages: most widely used, readily
available, non-invasive, drugs/metabolites tend to
concentrate in urine, easily handled and analyzed,
little cost
• • Disadvantages: drugs/metabolites only indicate
past use, subject to adulteration or substitution,
short detection times (12 hours to 2-3 weeks—2-5
days for most drugs
• In an attempt to avoid detection of illicit
drug use, some people who are asked to
give a urine sample for drug screening will
attempt to substitute the urine of another
person or adulterate their urine specimens,
using either commercially available
adulterants or home-brew recipes.
3-Hair:-cocaine, opiates,
once incorporated into hair ,
drugs remain there
indefinitely (previous 3
months), due to absence of
metabolism in hair and
uniform growth rate(1
cm/month)
Strand of hair cut into
sections gives information in
the pattern of drug use
• – Advantages:Longer
detection times (weeks and
months), impossible to
adulterate or substitute, easily
collected
• – Disadvantages: much
higher cost, very recent or
infrequent drug use likely
not detected, alcohol use
cannot be detected, not all
donors have long enough
hair, exposed to environment
(passive contamination)
• – Research is showing that
darkly pigmented hair more
readily incorporates and
retains drugs than does light
pigmented hair.
4-Sweat :-detects cocaine, heroin
5- Saliva:-Marijuana , cocaine , opiates
• – Rarely used
• – FDA has approved a saliva test for monitoring
alcohol use
6-Breath:– Not as good as blood,
but useful when ethanol
abuse suspected.
– Advantages:readily available, noninvasive.
– Disadvantage:must have a calibrated
breath alcohol testing
device with qualified
personnel to perform test
• Results Interpretation
• Time of sample collection, time of
administration of toxin,time of appearance of
toxic effects or death should be interpreted in
relation to pharmacokinetic parameters of
toxin absorption, distribution, metabolism and
elimination.
When did the donor use this substance?
Specimen dependent
Urine: drugs detectable for about 2-5 days
Exceptions: cannabinoids, long-acting
barbituarates, benzodiazepines
Cannabinoid: light user=10 days; chronic
user=month or more
Benzodiazepines: 15 days or more
Did donor use an illicit substance or can
the result be innocently explained?
passive exposure,
available by prescription
How much of the drug did the
donor use?
– Nearly impossible to answer
when urine is the specimen
• Differing levels of hydration
– Not enough known about
hair yet
– Blood: estimate of drug can
calculated by employing
published pharmacokinetic data
Is the donor continuing to use the
substance?
– The shorter the detection time for a
substance, the easier the answer to this question
becomes.
– If the donor’s urine is retested seven to 10
days after initial test and the analyte is a
substance with a short detection time, a second
positive test can be presumed to mean that the
donor is continuing to use the drug.
Two components make up the process of
therapeutic drug monitoring:•Assays for determination of the drug
concentration in plasma.
•Interpretation and application of the
resulting concentration data to develop a
safe and effective drug regimen.