OCTOBER 2011 Drug Therapy Monitoring Definition Drug therapy monitoring also known as Therapeutic Drug Monitoring TDM is a means of monitoring drug levels in the blood Purpose TDM is employed to measure blood drug levels so that the most effective dosage can be determined with toxicit ID: 918710
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Slide1
MONITORING DRUG THERAPY
LAKSHMAN KARALLIEDDE
OCTOBER 2011
Slide2Drug Therapy Monitoring
Definition
Drug therapy monitoring, also known as Therapeutic Drug Monitoring (TDM), is a means of monitoring drug levels in the blood.
Purpose
TDM is employed to measure blood drug levels so that the most effective dosage can be determined, with toxicity prevented. TDM is also utilized to identify noncompliant patients (those patients who, for whatever reason, either cannot or will not comply with drug dosages as prescribed by the physician).
Precautions
Because so many different factors influence blood drug levels, the following points should be taken into consideration during TDM: the age and weight of the patient; the route of administration of the drug; the drug's absorption rate, excretion rate, delivery rate, and dosage; other medications the patient is taking; other diseases the patient has; the patient's compliance regarding the drug treatment regimen; and the laboratory methods used to test for the drug.
Slide3Slide4REASONS FOR MONITORING DRUG TREATMENT
TO SEE WHETHER THERE IS A THERAPEUTIC RESPONSE
TO ASSESS DRUG TOXICITY
TO ASSESS COMPLIANCE
Slide5Examples of easily measurable therapeutic responses
Urine output in patients treated with desmopressin for
diabetes insipidus
Intraocular Pressure in patients treated with timolol eye drops
for glaucoma
Muscle fatigue in patients treated with pyridostigmine for myasthenia gravis
Slide6Monitoring drug treatment
W
ant
our treatments to
work
Do not
wish treatments
to cause harm
. Monitoring drug treatment is one way of seeing that a treatment works, while protecting the patient from
adverse
drug effects.
For
many patients and many treatments clinical evaluation
is
sufficient (e.g. Measuring blood
pressure in a patient
on
antihypertensive
treatment).
When
therapeutic goals cannot always be directly observed
,
monitoring may require blood tests
to determine whether
therapeutic levels
have been
reached.e.g
the measurement
of
the
international normalised ratio (INR) in patients treated
with
warfarin.
Ensure
that the therapeutic
goal (prevention of
thrombosis
is
met)measuring INR
helps to avoid the risk
of
haemorrhage
, which rises steeply as the INR increases
above
2.0.
Slide7Monitoring drug treatment
Monitoring
treatment to anticipate or detect adverse reactions to drugs before they become inevitable or irreversible is
very
important
.
For
a monitoring test for an adverse drug reaction to be useful clinically, it should satisfy
criteria put forward for screening tests. e.g. monitoring in patients treated with clozapine (atypical antipsychotic
associated with agranulocytosis in 0.8% of
patients).
All
patients
taking
clozapine have white cell counts performed weekly for the first 18 weeks of treatment and less often thereafter
.
Clear
criteria exist for when the drug should be
withdrawn
and patients continue treatment only if the white cell count is satisfactory
.
This has
reduced the incidence of clozapine induced agranulocytosis and prevented deaths from a serious adverse reaction
.
Success
is largely the result of
frequent
monitoring at the time when the risk of agranulocytosis is highest
clear guidelines
for action if results are abnormal
.
The adverse reaction evolves slowly enough for once weekly monitoring to
be
effective. By contrast serious hyperkalaemia could occur at any time in
patients
treated for heart failure with spironolactone plus an angiotensin converting
enzyme
inhibitor and evolve rapidly to cause lethal arrhythmia. Thus annual
measurement
would be of little help in avoiding serious
effects
Slide8Factors to take into account when monitoring for an adverse drug effect
The adverse effect
The effect should be potentially serious
The relation between the latent and overt effects should be known
The monitoring test
The test should be safe, simple, precise, and validated
The distribution of test values in the exposed population should be known and suitable cut-off values established
The test should be acceptable to treated patients
A strategy in the face of a positive monitoring test should be agreedThe response to positive tests
An effective intervention should exist
This early intervention should make the outcome better than it would have been with delayed intervention
Evidence for the intervention should be robust
The monitoring strategy
The strategy should reduce morbidity or mortality from the adverse effect
The strategy should be acceptable to patients and professionals
Benefits of monitoring should outweigh the physical and psychological harm
The cost of monitoring should be proportionate
A system for assuring the standards of the monitoring
programme
should exist
Possibility of reducing or removing risks of adverse effects by selection of drug or dosage, or by pretreatment detection of susceptible people, should have been fully explored
Slide9DIFFICULTIES/PROBLEMS
D
etection
of drug induced liver injury.
Statins
can increase serum activity of transaminase in about 3% of patients and rarely can lead to symptomatic hepatic damage
. This
has prompted recommendations for
monitoring. However, guidelines for different statins differ both in recommended frequency of monitoring and advice on the action to take if hepatic abnormalities are detected. Little is understood about the relationship between mild abnormalities of liver function and symptomatic liver injury, since liver function may improve even with continued treatment with
statin
It
is unclear if or when treatment should be
stopped
Infrequent
monitoring as currently recommended is likely to miss most patients who develop the sudden idiosyncratic hepatic reactions
.
Monitoring for liver damage from statins may anyway be unnecessary—a
meta-analysis
examining 112 000 person years of exposure to pravastatin found the frequency
of
abnormal liver function tests (1.4%) to be similar in statin and placebo
arms
and in
the
heart protection study treatment with statins at high dose (40 mg simvastatin)
seemed
safe
.
When considered with evidence about muscle damage from
statins,
the findings
imply
that these drugs can be used without any regular
monitoring (conclusion
of
a
retrospective analysis of 1014 patients in primary care, where the occasional finding
of
abnormal laboratory values rarely resulted in drug
discontinuation).
A
policy of non-monitoring would prevent
unnecessary
discontinuation of
statins.
Slide10Product information on drugs often suggests monitoring of one kind or another but does not specify the frequency of testing or the strategy to adopt if tests are positive, and many of the proposed tests fail to satisfy the criteria
listed
.
There is a need for better
evidence on which to base
monitoring
strategies
.
Meanwhile, adverse reactions will often be prevented more effectively (and economically) by educating prescribers and increasing patients' awareness than by empirical blood test monitoring.
After
all, rational therapeutics demands a more careful approach to drug treatment than simple opportunistic measurement in the outpatient clinic.
BMJwww.bmj.com
BMJ 327 : 1179
doi
: 10.1136/bmj.327.7425.1179 (Published 20 November 2003)
Editorial
Munir
Pirmohamed
, professor of clinical
pharmacology
Robin E Ferner
, clinical
pharmacologist
Slide11TDM is a practical tool that can help the physician provide effective and safe drug therapy in patients who need medication.
Monitoring
can be used to confirm a blood drug concentration level that is above or below the therapeutic range, or if the desired therapeutic effect of the drug is not as expected.
If
this is the case, and dosages beyond normal then have to be prescribed, TDM can minimize the time that elapses.
TDM
is important for patients who have other diseases that can affect drug
levels
Or
who
take other medicines that may affect drug levels by interacting with
drug
being tested
.
As
an example, without drug monitoring, the physician cannot be sure if a patient's lack of response to an antibiotic reflects bacterial resistance, or is the result of failure to reach the proper therapeutic range of antibiotic concentration in the blood.
In
cases of life-threatening infections, timing of effective antibiotic therapy is critical to success. It is equally crucial to avoid toxicity in a seriously ill patient. Therefore, if toxic symptoms appear with standard dosages, TDM can be used to determine changes in
dosing.Blood demonstrates drug
action
at
any specific
time. drug
levels examined from
Urine
reflect the presence of a drug over many days (depending on the rate of excretion).
Slide12Therapeutic Drug Monitoring: Therapeutic And Toxic Range
Drug Level∗
Use
Therapeutic
Level∗
Toxic
∗Values are laboratory-specific
∗∗Concentration obtained 30 minutes after the end of a 30-minute infusion.
Acetaminophen
mg/ml
Analgesic,
antipyretic
Depends on
use
>250
Amikacin mg/
ml
Antibiotic
12-25 mg/
ml∗∗
>25
Aminophylline ng/
ml
Bronchodilator
10-20 mg/ml
>20
Amitriptyline ng/
ml
Antidepressant
120-150
ng
/ml
>500
Carbamazepine
mg/ml
Anticonvulsant
5-12 mg/ml
>12
Chloramphenicol
mg/ml
Antibiotic
10-20 mg/ml
>25
Digoxin ng/ml
Cardiotonic
0.8-2.0 ng/ml
>2.4
Slide13entamicin
Antibiotic
4-12 mg/L
>12
mg/L
Lidocaine
Antiarrhythmic
1.5-5.0 mg/ml
>5 mg/mlLithium mEq/LAntimanic
0.7-2.0
mEq
/L
>2.0
Nortriptyline ng/
ml
Antidepressant
50-150
ng
/ml
>500
Phenobarbital mg/
ml
Anticonvulsant
10-30 mg/ml
>40
Phenytoin mg/ml
Anticonvulsant
7-20 mg/ml
>30
Procainamide mg/
ml
Antiarrhythmic
4-8 mg/ml
>16
Propranolol ng/ml
Antiarrhythmic
50-100 ng/ml
>150
Slide14Quinidine mg/ml
Antiarrhythmic
1-4 mg/ml
>10
Theophylline mg/
ml
Bronchodilator
10-20 mg/ml
>20Tobramycin mg/mlAntibiotic4-12 mg/ml∗∗>12Valproic acid mg/ml
Anticonvulsant
50-100 mg/ml
>100
Values are laboratory-specific
∗∗Concentration obtained 30 minutes after the end of a 30-minute infusion.
Blood specimens for drug monitoring can be taken at two different times: during the drug's highest therapeutic concentration ("peak" level), or its lowest ("trough" level). Occasionally called residual levels, trough levels show sufficient therapeutic levels; whereas peak levels show poisoning (toxicity). Peak and trough levels should fall within the therapeutic range.
Slide15Preparation
In preparing for this test, the following guidelines should be observed:
Depending on the drug to be tested, the physician should decide if the patient is to be fasting (nothing to eat or drink for a specified period of hours) before the test.
For patients suspected of symptoms of drug toxicity, the best time to draw the blood specimen is when the symptoms are occurring.
If there is a question as to whether an adequate dose of the drug is being achieved, it is best to obtain trough (lowest therapeutic concentration) levels.
Peak (highest concentration) levels are usually obtained one to two hours after oral intake, approximately one hour after intramuscular (IM) administration (a shot in the muscle), and approximately 30 minutes after intravenous (IV) administration. Residual, or trough, levels are usually obtained within 15 minutes of the next scheduled dose.
Risks
Risks for this test are minimal, but may include slight bleeding from the blood-drawing site, fainting or feeling lightheaded after blood is drawn, or accumulation of blood under the puncture site (hematoma).
Resources
Books
Pagana
, Kathleen
Deska
.
Mosby's Manual of Diagnostic and Laboratory Tests
. St. Louis: Mosby, Inc., 1998.
Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. All rights reserved.