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TTTTherapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring

Clinical Toxicology Lines Series

Dr: Dr: Dr: Dr: Maha AlMaha AlMaha AlMaha Al----MazrouaMazrouaMazrouaMazroua

Head of Dammam Poison Control Center

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herapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring

Clinical Toxicology Lines Series

MazrouaMazrouaMazrouaMazroua

Head of Dammam Poison Control Center

Dr: Ahmed RefatDr: Ahmed RefatDr: Ahmed RefatDr: Ahmed Refat

Toxicology Consultant Dammam PCC

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Antidote Courseـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ

herapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring herapeutic Drug Monitoring CourseCourseCourseCourse


Toxicology Consultant Dammam PCC

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Therapeutic Drug Monitoring Course

IIII---- IIIIntroductionntroductionntroductionntroduction

Therapeutic drug monitoring and pharmacogenomics are both clinical toxicology

related areas within the clinical laboratory. Although each

laboratory medicine, the two fields overlap significantly. This course provides an overview of each

of these laboratory sub-disciplines and discusses the utility, rationale, and practice of each one.

The course is intended for clinical toxicologist, clinical laboratory health care personnel and other

technologists and technicians who are responsible for monitoring, prescribing and administering

therapeutic medications.

IIIIIIII---- CCCCourse Outlineourse Outlineourse Outlineourse Outline

A: Therapeutic Drug Monitoring� Introduction

� Therapeutic Drug Monitoring Definition

� Pharmacogenomics Definition

� Basic Pharmacokinetics

� Drug Concentration Over Time

� Drug Metabolism

� Drug Elimination

� Half-life

� Bioavailability

� Protein Binding

� Protein Availability and Drug Dosing

� Other Factors Affecting Drug Absorption and Distribution

� Given what you have learned thus far, which of the follo

true?

� Steady State

� Steady State Example

� Sampling

� Peak and Trough Sampling Times

� Why TDM?

� Unexpected Concentrations

� A physician needs to prescribe a drug to a patient but the drug has a narrow therapeutic

window. He is concerned about possible toxic effects. To asse...

� TDM For All Drugs?

� When is TDM Not Useful?

� Alternative to TDM

� Examples of Drugs That are Monitored by TDM

� TDM for Antibiotics

� TDM for Anticonvulsants

� TDM for Immunosuppressants

� TDM for Cardiac Medications

� TDM for Theophylline

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Dr: Ahmed Refat &

Therapeutic Drug Monitoring Courseــــــــــــــــــــــــــــــــــــــــــــ

herapeutic Drug Monitoring Course


related areas within the clinical laboratory. Although each is considered a sub


disciplines and discusses the utility, rationale, and practice of each one.

ended for clinical toxicologist, clinical laboratory health care personnel and other


A: Therapeutic Drug Monitoring………………………………………………………………...5

Therapeutic Drug Monitoring Definition

Pharmacogenomics Definition

Drug Concentration Over Time

Protein Availability and Drug Dosing

Other Factors Affecting Drug Absorption and Distribution

Given what you have learned thus far, which of the following statements below do you think is

Peak and Trough Sampling Times

Unexpected Concentrations

A physician needs to prescribe a drug to a patient but the drug has a narrow therapeutic

concerned about possible toxic effects. To asse...

When is TDM Not Useful?

Examples of Drugs That are Monitored by TDM

TDM for Anticonvulsants

TDM for Immunosuppressants

TDM for Cardiac Medications


& Dr: Maha Al-Mazroua


Therapeutic drug monitoring and pharmacogenomics are both clinical toxicology-

is considered a sub-discipline within


disciplines and discusses the utility, rationale, and practice of each one.

ended for clinical toxicologist, clinical laboratory health care personnel and other


………………………………………………………………...5

wing statements below do you think is

A physician needs to prescribe a drug to a patient but the drug has a narrow therapeutic

� � � � � � � � � � � � � � � � � � � � Clinical Toxicology Lines Clinical Toxicology Lines Clinical Toxicology Lines ــــــــــــــــــــــــــــــــــــــــــــ

2

� Albuterol is a fast-acting bronchodilator used acutely during asthma attacks. Which of the

reasons below explains why TDM for albuterol is not availab...

� Laboratory Methods

� PETINIA

� FPIA

� Chemiluminescenc

B: Pharmacogenomics…………………………………� Individualized Medicine

� Polymorphism and CYP450

� CYP450s

� CYP2D6

� Metabolizers

� Enzyme Abnormalities and Drugs

� Clinical Utility

� Warfarin Metabolism

� A person who is classified as an ultrarapid metabolizer (UM) would need of a drug metabolized

by that enzyme.

� CYP450 Induction and Inhibition

� A patient is taking cimetidine for a stomach ulcer. This drug inhibits CYP2D6. The patient is

now prescribed amphetamine for narcolepsy. Amphetamine i...

� Genotype versus Phenotype

� TDM and PGx

� The Bottom Line

C: Individualized TDM Drug Profiles

D: References:……………………………………………………………………………………...47

E: Practical Settings:


Dr: Ahmed Refat &


acting bronchodilator used acutely during asthma attacks. Which of the

reasons below explains why TDM for albuterol is not availab...

………………………………………………………………………….17

Polymorphism and CYP450

Enzyme Abnormalities and Drugs

A person who is classified as an ultrarapid metabolizer (UM) would need of a drug metabolized

CYP450 Induction and Inhibition

A patient is taking cimetidine for a stomach ulcer. This drug inhibits CYP2D6. The patient is

now prescribed amphetamine for narcolepsy. Amphetamine i...

Genotype versus Phenotype

Profiles……………………………………………………………..23

……………………………………………………………………………………...47




acting bronchodilator used acutely during asthma attacks. Which of the

……………………………………….17

A person who is classified as an ultrarapid metabolizer (UM) would need of a drug metabolized

A patient is taking cimetidine for a stomach ulcer. This drug inhibits CYP2D6. The patient is

……………………………………………………………..23

……………………………………………………………………………………...47

� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � ــــــــــــــــــــــــــــــــــــــــــــ

3

IIIIIIIIIIII---- CCCCourse ourse ourse ourse contentcontentcontentcontent

Introduction

Therapeutic drug monitoring and pharmacogenomics are both

within the clinical laboratory. Although each is

the two fields overlap significantly. In this course, we w

laboratory sub-disciplines and discuss the utility, rationale, and practice of each one.


Therapeutic Drug Monitoring (TDM) is a branch of clinical chemistry that specializes

measurement of medication levels in

measurements of drugs and/or their metabolites. These measurements are

patient serum samples. TDM can be contrasted with urine drug

performed to detect or monitor drug abuse or check patient compliance when a drug with high abuse

potential has been prescribed. Determining actual concentrations are less important for urine drugs of

abuse screening. Providing accurate concentrations for TDM,

concentrations provided with TDM allow clinicians to adjust medication dosages as well as

patient's drug metabolism response and their compliance or dosing regimen.

Pharmacogenomics DefinitionPharmacogenomics (usually abbreviated PGx) is the study of how variations in the human

genome affect a given individual's response

handled by a specific person given

Basic Pharmacokinetics In order to discuss TDM and PGx we need to also introduce the concept of pharmacokinetics.

Pharmacokinetics is the study of drug disposition in the body: It

the circulation, how long they remain in the blood, and how they are ultimately eliminated from the

body. TDM is the clinical assessment of a drug's pharmacokinetic properties. Physicians and

toxicologist, pharmacists often need to establish that a

concentration yet does not reach a toxic concentration.

factors that determine a drug's disposition in the body. These factors ultima

therapeutic drug monitoring.


Dr: Ahmed Refat &



within the clinical laboratory. Although each is considered a sub-discipline within laboratory medicine,

the two fields overlap significantly. In this course, we will provide an overview of

disciplines and discuss the utility, rationale, and practice of each one.


Therapeutic Drug Monitoring (TDM) is a branch of clinical chemistry that specializes

measurement of medication levels in serum. TDM requires that the laboratory make quantitative

measurements of drugs and/or their metabolites. These measurements are almost always made on

patient serum samples. TDM can be contrasted with urine drug testing. Urine drug testing is usually


Determining actual concentrations are less important for urine drugs of

Providing accurate concentrations for TDM, on the other hand, is essential. Serum

concentrations provided with TDM allow clinicians to adjust medication dosages as well as

patient's drug metabolism response and their compliance or dosing regimen.

Pharmacogenomics Definition Pharmacogenomics (usually abbreviated PGx) is the study of how variations in the human

genome affect a given individual's response to medications. It refers to how administered drugs will be

handled by a specific person given specific genetic mutations and polymorphisms they may have.

In order to discuss TDM and PGx we need to also introduce the concept of pharmacokinetics.

Pharmacokinetics is the study of drug disposition in the body: It concerns how and when drugs enter

remain in the blood, and how they are ultimately eliminated from the

TDM is the clinical assessment of a drug's pharmacokinetic properties. Physicians and

ists often need to establish that a drug is present at a clinically

concentration yet does not reach a toxic concentration. The next few pages will describe some of the

factors that determine a drug's disposition in the body. These factors ultimately decide the




clinical toxicology -related areas

discipline within laboratory medicine,

ill provide an overview of each of these

disciplines and discuss the utility, rationale, and practice of each one.

Therapeutic Drug Monitoring (TDM) is a branch of clinical chemistry that specializes in the

serum. TDM requires that the laboratory make quantitative

almost always made on

testing. Urine drug testing is usually


Determining actual concentrations are less important for urine drugs of

on the other hand, is essential. Serum

concentrations provided with TDM allow clinicians to adjust medication dosages as well as assess a

Pharmacogenomics (usually abbreviated PGx) is the study of how variations in the human

to medications. It refers to how administered drugs will be

polymorphisms they may have.

In order to discuss TDM and PGx we need to also introduce the concept of pharmacokinetics.

concerns how and when drugs enter

remain in the blood, and how they are ultimately eliminated from the

TDM is the clinical assessment of a drug's pharmacokinetic properties. Physicians and clinical

drug is present at a clinically-effective

The next few pages will describe some of the

tely decide the need for


4


When a drug enters the body, it reaches a peak concentration

eliminated. The figure on the right shows a typical drug kinetic when a dr

Drug Metabolism

The liver plays a major role in converting lipophilic, nonpolar molecules (including drugs) to

more polar, water-soluble forms through a

modified by either phase I or phase ll reactions. These reactions are carried

classes of enzymes.

- Phase I reactions alter chemical structure by oxidation, reduction, or hydrolysis.

- Phase ll reactions conjugate drugs to create p

Drug Elimination

Most water-soluble drugs are eliminated from the b

filtration, or a combination of the two. It

soluble. When a small molecular

by simple filtration through the kidneys and it will then enter the urine. Since fatty, nonpolar

molecules do not dissolve in water they tend to accumulate in tissues or bi

Until the body can render these molecules

An alteration in renal function will have a major effect on the clearance of the drug or its active

metabolite(s). Decreased renal function

Half-life

The amount of time it takes for a drug concentration in the body to decrease by 50% is called

the drug's half-life (abbreviated t1/2).

body. Most drugs are eliminated from the body in 1 to 3 days, but some

can still be detected in the body weeks after the initial dose.

kinetic pattern for an oral drug.


Dr: Ahmed Refat &



When a drug enters the body, it reaches a peak concentration that starts to fall as the drug is

right shows a typical drug kinetic when a drug is given


soluble forms through a series of enzymatic reactions. Drug molecules can be

modified by either phase I or phase ll reactions. These reactions are carried out by several important

Phase I reactions alter chemical structure by oxidation, reduction, or hydrolysis.

Phase ll reactions conjugate drugs to create products that are water-soluble.

soluble drugs are eliminated from the body through hepatic metabolism,

filtration, or a combination of the two. It makes sense that the body would aim to make a drug water

small molecular-weight compound is water soluble, it can be excreted from the blood


do not dissolve in water they tend to accumulate in tissues or bind strongly to proteins.

Until the body can render these molecules water-soluble, they are much less likely to be excreted.


unction results in elevated serum drug concentrations.


life (abbreviated t1/2). The longer a drug's half-life, the slower it is remov

body. Most drugs are eliminated from the body in 1 to 3 days, but some drugs with longer half

can still be detected in the body weeks after the initial dose. The figure below illustrates a typical




that starts to fall as the drug is

ug is given intravenously (IV).


series of enzymatic reactions. Drug molecules can be

out by several important

Phase I reactions alter chemical structure by oxidation, reduction, or hydrolysis.

soluble.

ody through hepatic metabolism, renal

makes sense that the body would aim to make a drug water

can be excreted from the blood


nd strongly to proteins.

soluble, they are much less likely to be excreted.


results in elevated serum drug concentrations.


life, the slower it is removed from the

drugs with longer half-lives

The figure below illustrates a typical


5

Bioavailability

Bioavailability refers to the amount of drug that actually reaches

by comparing (in the same subjects) the area of the curve (AUC) that is found under the

concentration kinetic graph. This is done u

form. Then the two areas are compared. This is illustrated in the diagram on

oral drug that makes it to the circulatory system is the bioavailability of that drug.

bioavailability is 100%.

For oral medications, the bioavailability will be less than 100%,

reasons: 1- Oral drugs have slower absorption and distribution than IV

that is absorbed can depend on the status

integrity/health of the intestines, speed of the GI tract, etc.)

enzymes that are present anywhere along the GI tract.

If bioavailability is low then the

achieves the appropriate serum

IV drug and the drug takes longer to enter the circulation, clearing the drug will also

longer time.

Protein Binding

Most drugs are bound to proteins when they

considering general solubility rules of

lithium, it will easily dissolve into the aqueous environment of the

the circulation. However most drugs are complex

For drugs that are not highly soluble in

to solubilize that drug into blood. Serum contains a myriad of proteins.

Although these proteins themselves are water

they often contain lipophilic regions on them, which

drugs through the circulation.


Dr: Ahmed Refat &


Bioavailability refers to the amount of drug that actually reaches the circulation. It is calculated

subjects) the area of the curve (AUC) that is found under the

concentration kinetic graph. This is done using an equivalent dose of the intravenous form and oral

two areas are compared. This is illustrated in the diagram on the right. The fraction of

circulatory system is the bioavailability of that drug.

For oral medications, the bioavailability will be less than 100%, due in part to any of these

Oral drugs have slower absorption and distribution than IV drugs. 2

depend on the status of the GI tract (stomach pH, presence of food,

the intestines, speed of the GI tract, etc.). Oral drugs may be broken down by

anywhere along the GI tract.

If bioavailability is low then the oral dose needed has to be increased so that a given dose

achieves the appropriate serum concentration. Since the absorption of an oral drug is slower than an

IV drug and the drug takes longer to enter the circulation, clearing the drug will also

Most drugs are bound to proteins when they circulate in the body. This makes sense when

considering general solubility rules of chemistry. If a drug is simple, eg, an elemental salt such as

dissolve into the aqueous environment of the blood and widely distribute through

circulation. However most drugs are complex organic molecules with variable solubility in

For drugs that are not highly soluble in an aqueous environment, some carrier protein

blood. Serum contains a myriad of proteins.

Although these proteins themselves are water soluble (since they are found dissolved in

they often contain lipophilic regions on them, which can bind non-polar drugs and thus carry these




the circulation. It is calculated

subjects) the area of the curve (AUC) that is found under the serum

equivalent dose of the intravenous form and oral

the right. The fraction of

circulatory system is the bioavailability of that drug. For IV drugs, the

due in part to any of these

2- The amount of drug

of the GI tract (stomach pH, presence of food,

Oral drugs may be broken down by

oral dose needed has to be increased so that a given dose

Since the absorption of an oral drug is slower than an

IV drug and the drug takes longer to enter the circulation, clearing the drug will also most likely take a

circulate in the body. This makes sense when

elemental salt such as

blood and widely distribute through

organic molecules with variable solubility in water.

ome carrier protein will be needed

soluble (since they are found dissolved in blood)

polar drugs and thus carry these


6

Albumin is a major drug-binding protein in serum.

neutral drugs primarily bind to it.

can bind to lipoproteins. Alkaline drugs tend to bind to globulins, particularly to a globulin called alpha

1 acid glycoprotein. Only free, unbound drugs are able to bind protein drug receptors on cells and

have therapeutic effects.

An equilibrium exists in the systemic circulation between a free and protein

between a free and receptor-bound drug. This


Drug-binding proteins in serum can fluctuate in disease states.

fall, as can occur in liver failure or

If this happens a new dose of drug may produce a toxic concentration of f

now lower. The image on the right illustrates the loss of equilibrium between a protein

and a free drug when drug-binding proteins are diminished.

bound may need to be adjusted in

common drugs that are highly protein

imipramine and phenytoin.

Conclusion: So far we have learned that many factors (proteinbioavailability, elimination, etc.) affect a drug's disposition in the body. Because we usually cannot safely

predict how a drug will be tolerated in a person, we use therapeutic drug monitoring (TDM) to verify that

a drug is present at an appropriate


In addition to protein availability, other factors may affect drug absorption and distribution in

the body as a whole or within specific

other factors.


Dr: Ahmed Refat &


binding protein in serum. Albumin is an alkaline protein, so acidic and

neutral drugs primarily bind to it. If albumin binding sites become saturated, acidic and neutral drugs

Alkaline drugs tend to bind to globulins, particularly to a globulin called alpha

Only free, unbound drugs are able to bind protein drug receptors on cells and

An equilibrium exists in the systemic circulation between a free and protein

bound drug. This is illustrated in the image to the right.


in serum can fluctuate in disease states. For example, if albumin levels

fall, as can occur in liver failure or nephritic syndrome, less albumin will be available for drug binding.

dose of drug may produce a toxic concentration of free drug since albumin is

The image on the right illustrates the loss of equilibrium between a protein

binding proteins are diminished. Doses of drugs that are highly protein

bound may need to be adjusted in patients with lower drug-binding protein levels.

common drugs that are highly protein-bound include thyroxine, warfarin, diazepam, heparin,

So far we have learned that many factors (protein

bioavailability, elimination, etc.) affect a drug's disposition in the body. Because we usually cannot safely


nt at an appropriate.



the body as a whole or within specific sites of the body. The following table highlights some of these




Albumin is an alkaline protein, so acidic and

saturated, acidic and neutral drugs

Alkaline drugs tend to bind to globulins, particularly to a globulin called alpha-

Only free, unbound drugs are able to bind protein drug receptors on cells and

An equilibrium exists in the systemic circulation between a free and protein-bound drug and

is illustrated in the image to the right.

For example, if albumin levels

albumin will be available for drug binding.

ree drug since albumin is

The image on the right illustrates the loss of equilibrium between a protein-bound drug

Doses of drugs that are highly protein-

binding protein levels. Examples of some

thyroxine, warfarin, diazepam, heparin,

binding, lipophilicity,

bioavailability, elimination, etc.) affect a drug's disposition in the body. Because we usually cannot safely



following table highlights some of these


7

Factor Discussion

Regional blood flow

Reduced area blood flow can be seen in diabetics and enhanced blood flow can be

seen in tumors. Reduced blood flow means reduced exposure to drug.

Lipid solubility of the drug

The more lipophilic a drug is, the more likely it will enter the central nervous

system. The brain itself is a very lipid

normal web of epithelial cells in the CNS blood vessels.

blood-brain-barrier. Lipophilic drugs can cross cell membranes of this barrier more

easily than polar drugs.

The integrity of the GI tract

In a diseased gut, an orally

Age

Drug kinetics and dispositions change throughout life. In general,

drugs is reduced in the elderly.

Genetics

Mutations or deletions in drug metabolizing enzymes can greatly affect a drug's

disposition.

Steady State

Most drugs are not given as a single dose but are part of a multi

physician's responsibility to prescribe a drug such that the concentration of that drug reaches a

and effective level as quickly as possible without inducing toxicity. The

clinician, if multiple doses of a drug will be given, is for both the peak and the trough

consistently within the therapeutic range.

life, it will take about 5 half-lives to

Steady State Example

If the drug Gentamicin has an elimination half

drug should reach steady state

dosing results in a 'sawtooth' pattern. Peaks correspond to the times right after the drug is taken;

troughs correspond to the times right before the

Of course a physician may want to get a patient into the therapeutic range mor

these cases a higher loading dose of drug can be prescribed initially with instructions that after the

first couple of doses, the dose should be reduced.


Dr: Ahmed Refat &




solubility of the drug


system. The brain itself is a very lipid rich organ but there also exists a tighter

normal web of epithelial cells in the CNS blood vessels. This leads to the so called

barrier. Lipophilic drugs can cross cell membranes of this barrier more

easily than polar drugs.

The integrity of the GI tract

In a diseased gut, an orally-administered drug may not be absorbed as expected.

Drug kinetics and dispositions change throughout life. In general,

drugs is reduced in the elderly.


given as a single dose but are part of a multi dose regimen. It is the

physician's responsibility to prescribe a drug such that the concentration of that drug reaches a

and effective level as quickly as possible without inducing toxicity. The dosing-goal for the

clinician, if multiple doses of a drug will be given, is for both the peak and the trough

consistently within the therapeutic range. If a drug is given at intervals that are the same as its half

lives to reach steady state.

If the drug Gentamicin has an elimination half-life of 12 hours and is given every 12 hours, the

after 5 half-lives (60 hours). Notice in the diagram th


troughs correspond to the times right before the next dose.

Of course a physician may want to get a patient into the therapeutic range mor

dose of drug can be prescribed initially with instructions that after the

first couple of doses, the dose should be reduced.







rich organ but there also exists a tighter-than

This leads to the so called

barrier. Lipophilic drugs can cross cell membranes of this barrier more

administered drug may not be absorbed as expected.

Drug kinetics and dispositions change throughout life. In general, metabolism of


dose regimen. It is the

physician's responsibility to prescribe a drug such that the concentration of that drug reaches a safe

goal for the prescribing

clinician, if multiple doses of a drug will be given, is for both the peak and the trough drug levels to be

If a drug is given at intervals that are the same as its half-

life of 12 hours and is given every 12 hours, the

lives (60 hours). Notice in the diagram that this kind of


Of course a physician may want to get a patient into the therapeutic range more quickly. In

dose of drug can be prescribed initially with instructions that after the


8

Sampling

Ideally, a drug level would be monitored frequently and

a detailed pharmacokinetic profile over time.

relatively infrequent clinic visits,

concentration 'snap-shot' is taken. This then requires us to ask: 'when should we collect blood in order

to best measure the serum concentration of the drug in question?'


A trough refers to the valley or bottom 'spike' of the

drug is taken orally the trough will be the low point of the serum concentration. It will be

period immediately before the next dose. Thus, when we want to draw a trough

before the patient is supposed to take their next dose.

concentration) the time for drawing depends

kinetics of the drug.

For oral medications One hour after drug is taken is usuall

> two hours). For IV medications: sample 15

(IM) injections: sample 30 minutes to one hour after injection


Dr: Ahmed Refat &


Ideally, a drug level would be monitored frequently and consistently, providing the clinician

a detailed pharmacokinetic profile over time. In reality, serum samples are often measured only during

relatively infrequent clinic visits, meaning that many days or weeks may pass before a drug

taken. This then requires us to ask: 'when should we collect blood in order

the serum concentration of the drug in question?'


A trough refers to the valley or bottom 'spike' of the sawtooth pattern we saw earlier. When

drug is taken orally the trough will be the low point of the serum concentration. It will be

period immediately before the next dose. Thus, when we want to draw a trough

is supposed to take their next dose. To assess peak levels (the time of maximum

concentration) the time for drawing depends on the route of administration and the absorption

For oral medications One hour after drug is taken is usually adequate (this assumes

For IV medications: sample 15-30 minutes after injection/infusion

(IM) injections: sample 30 minutes to one hour after injection




consistently, providing the clinician with

In reality, serum samples are often measured only during

meaning that many days or weeks may pass before a drug

taken. This then requires us to ask: 'when should we collect blood in order

sawtooth pattern we saw earlier. When a

drug is taken orally the trough will be the low point of the serum concentration. It will be the time

period immediately before the next dose. Thus, when we want to draw a trough level we draw just

To assess peak levels (the time of maximum

on the route of administration and the absorption

y adequate (this assumes a half-life of

30 minutes after injection/infusion. For Intramuscular


9

Why Therapeutic Drug Monitoring TDM?

Pharmacologists determine a drug's pharmacokinetic characteristics empirically during clinical

drug trials. From these studies, they are able to determine the solubility and distribution, the average

half-life, the levels of protein binding, and the

However, every patient is unique. Changes in the gut (if the drug is taken orally), genetic

variations in the liver's metabolizing

liver) all affect how a drug will be handled by an individual. Given

important to take a measurement of the drug in serum so that we can be sure the dose given is

leading to an appropriate concentration in the body.

appropriate for a given patient.

Every drug has a sub-clinical concentration (a

achieved) and a toxic concentration (a concentration at

For some drugs, the range between the minimum

concentration is large. These drugs are thus relatively safe. Other drugs

therapeutic window and need closer

therapeutic windows, like the anticonvulsant carbamazepine (Tegretol), should be

since elevated doses can cause serious conditions such as agranulocytosis.


Dr: Ahmed Refat &


Why Therapeutic Drug Monitoring TDM?



life, the levels of protein binding, and the effective concentrations needed for treatment.


variations in the liver's metabolizing enzymes, and the functional status of organs (like the kidneys and

affect how a drug will be handled by an individual. Given these variables, it becomes


an appropriate concentration in the body. TDM helps to ensure that a dosing regimen is

clinical concentration (a concentration at which effective therapy won't be

achieved) and a toxic concentration (a concentration at which the drug will be harmful to the

For some drugs, the range between the minimum effective concentration and the toxic

large. These drugs are thus relatively safe. Other drugs

therapeutic window and need closer monitoring. This is the role of TDM. Medications with narrow

anticonvulsant carbamazepine (Tegretol), should be

serious conditions such as agranulocytosis.






effective concentrations needed for treatment.


enzymes, and the functional status of organs (like the kidneys and

these variables, it becomes


at a dosing regimen is

concentration at which effective therapy won't be

which the drug will be harmful to the patient.)

effective concentration and the toxic

have a very narrow

Medications with narrow

anticonvulsant carbamazepine (Tegretol), should be closely monitored


10

Unexpected ConcentrationsTDM provides a quantitative measure of the circulating concentration of a drug. The physician

determines if the dosage of the drug

If a drug concentration is determined to be outside the therapeutic range, it

the reasons listed in the table below

Factor Discussion

Noncompliance

Patients may (intentionally or unintentionally) not take the drug as prescribed. TDM

can thus help monitor

Dosing errors

The dose may have been

Malabsorption

The TDM result will reveal if the drug cannot be absorbed well through the gut and

an alternative route of

Drug interactions

Many drugs interfere

interactions will be revealed

Kidney or liver disease

Any pathology that affects elimination will cause an elevation in a drug level that

will be unmasked by TDM.

Altered protein binding


disposition.

Variations in the genetics of drug

the body. This is the field of pharmacogenomics that will be

Conclusion: The drug should be measured at a time corresponding to the peak concentration (not the trough). One to 2 hours after an oral dose is

should correspond to peak concentration.

injection of the drug will not represent the peak value. A drug that is given via IV

immediately, and the peak concentration of the drug would be measured

injection. A measurement that is taken just before the next dose is given represents the trough value of the

drug.


Dr: Ahmed Refat &


Unexpected Concentrations: TDM provides a quantitative measure of the circulating concentration of a drug. The physician

determines if the dosage of the drug needs to be adjusted based on this information.

If a drug concentration is determined to be outside the therapeutic range, it

the reasons listed in the table below.


can thus help monitor compliance.

The dose may have been erroneous or inappropriate given the patient's condition.


an alternative route of administration will be needed.

Many drugs interfere with the absorption or metabolism of other drugs. These

interactions will be revealed by TDM.


will be unmasked by TDM.


Variations in the genetics of drug-metabolizing enzymes can also affect drug concentrations in

pharmacogenomics that will be discussed later in the course.

The drug should be measured at a time corresponding to the peak concentration (not

the trough). One to 2 hours after an oral dose is usually sufficient time for a drug to be absorbed and

peak concentration. A drug measurement that is taken 2 to 4 hours after an IV

injection of the drug will not represent the peak value. A drug that is given via IV

immediately, and the peak concentration of the drug would be measured 15 to 30 minutes after the IV

A measurement that is taken just before the next dose is given represents the trough value of the




TDM provides a quantitative measure of the circulating concentration of a drug. The physician

needs to be adjusted based on this information.

If a drug concentration is determined to be outside the therapeutic range, it may be for one of


erroneous or inappropriate given the patient's condition.


with the absorption or metabolism of other drugs. These



metabolizing enzymes can also affect drug concentrations in

discussed later in the course.

The drug should be measured at a time corresponding to the peak concentration (not

usually sufficient time for a drug to be absorbed and

A drug measurement that is taken 2 to 4 hours after an IV

injection of the drug will not represent the peak value. A drug that is given via IV enters the circulation

15 to 30 minutes after the IV

A measurement that is taken just before the next dose is given represents the trough value of the


11

TDM For All Drugs? Can all drugs benefit from TDM? Not really. For TDM to be effective and useful, one or

the following should apply:

� The effective concentration and toxic concentrations must be well

� The pharmacokinetics of the drug are known to be variable.

� The drug is given chronically.

� There is the potential for drug

� The drug exhibits high protein binding.

� The toxicity will mimic the indication for the drug; toxicity may not be visible during an exam

but will only be revealed with TDM.

� The patient is pregnant, very young, or elderly.

� Compliance or history with the drug

Unless criteria like these exist, it doesn't make much sense to perform TDM testing. Penicillin,

for example is never measured in the

chronically, it has minimal toxicity, etc.

When is TDM Not Useful?

TDM is not useful in these specific situations:

� For drugs which act intracellularly, or that need to be converted to active forms (like AZT)

� For drugs in which the effects last much longer than the serum concentrations of the drugs;

examples include Antineoplastics

� Narcotic pain medications where continued use can lead to tolerance such that the levels

needed for pain relief in one person

Alternative to TDM Some drugs are more efficiently monitored by determining their effects rather than by

measuring the serum drug level. Warfarin dosing, for example, is better monitored by

prothrombin time (PT) and International Normalized Ratio (INR). We monitor

the physiologic effect since the effects of warfarin will outlast its


Dr: Ahmed Refat &


Can all drugs benefit from TDM? Not really. For TDM to be effective and useful, one or

The effective concentration and toxic concentrations must be well-defined.

The pharmacokinetics of the drug are known to be variable.

The drug is given chronically.

There is the potential for drug-to-drug interactions.

The drug exhibits high protein binding.

The toxicity will mimic the indication for the drug; toxicity may not be visible during an exam

but will only be revealed with TDM.

The patient is pregnant, very young, or elderly.

Compliance or history with the drug is poor.


for example is never measured in the serum. It has a wide therapeutic window, it is not given

chronically, it has minimal toxicity, etc.

TDM is not useful in these specific situations:

For drugs which act intracellularly, or that need to be converted to active forms (like AZT)

For drugs in which the effects last much longer than the serum concentrations of the drugs;

Antineoplastics (cancer chemotherapies) and warfarin.

Narcotic pain medications where continued use can lead to tolerance such that the levels

needed for pain relief in one person would be toxic to another person.

are more efficiently monitored by determining their effects rather than by

measuring the serum drug level. Warfarin dosing, for example, is better monitored by

prothrombin time (PT) and International Normalized Ratio (INR). We monitor

the physiologic effect since the effects of warfarin will outlast its presence in the blood.




Can all drugs benefit from TDM? Not really. For TDM to be effective and useful, one or more of

defined.

The toxicity will mimic the indication for the drug; toxicity may not be visible during an exam


serum. It has a wide therapeutic window, it is not given

For drugs which act intracellularly, or that need to be converted to active forms (like AZT)

For drugs in which the effects last much longer than the serum concentrations of the drugs;

(cancer chemotherapies) and warfarin.

Narcotic pain medications where continued use can lead to tolerance such that the levels

are more efficiently monitored by determining their effects rather than by

measuring the serum drug level. Warfarin dosing, for example, is better monitored by measuring the

warfarin by looking at

presence in the blood.


12

Examples of Drugs That are Monitored by TDMFour major classes of drugs are frequently monitored by TDM:

1. Antibiotics

2. Anticonvulsants

3. Immunosuppressants

4. Cardiac medications

There are other drugs that are monitored by TDM that are not included in any of the above

classifications, but the majority of TDM testing

four categories.

TDM for Antibiotics Infection is obviously a very serious indication, and effective antibiotic levels must be achieved

as soon as possible. However, many

concentrations of these antibiotics need to be monitored. Having serum

high are both situations which must be avoided.

Examples of antibiotics that are monitored by TDM include:

Amikacin

Gentamicin

Tobramycin

Vancomycin

Antibiotics such as ampicillin that are readily cleared and have a wide therapeutic window are

not usually monitored by TDM.

TDM for Anticonvulsants Anticonvulsants (also known as anti

therapeutic windows. When lev

are too high can depress the central nervous system and may even lead

Examples of anticonvulsants that are monitored by TDM include:

Carbamazepine (Tegretol)

Valproic acid (Depakene)

Phenytoin (Dilantin)

Phenobarbital

Primidone (Mysoline)

TDM for ImmunosuppressantsDrugs used to inhibit the immune system are part of standard treatment after transplant

surgeries. Unfortunately, these life

high concentrations. The reason drug monitoring is used for

concentrations are adequate to suppress the immune response and prevent rejection yet not

enough to cause liver failure or severe

Examples of immunosuppressants that are monitored by TDM include:

Cyclosporine

Methotrexate (this drug is also used as an anti

Tacrolimus

Sirolimus


Dr: Ahmed Refat &


Examples of Drugs That are Monitored by TDM Four major classes of drugs are frequently monitored by TDM:


classifications, but the majority of TDM testing is performed for drugs that are included in one of thes

Infection is obviously a very serious indication, and effective antibiotic levels must be achieved

as soon as possible. However, many antibiotics also have nephrotoxic or ototoxic effects; the

antibiotics need to be monitored. Having serum concentrations too low or too

high are both situations which must be avoided.

Examples of antibiotics that are monitored by TDM include:

ampicillin that are readily cleared and have a wide therapeutic window are

Anticonvulsants (also known as anti-epileptic or anti-seizure medications) typically have narrow

therapeutic windows. When levels are too low, the risk for seizure remains present. Drug levels that

are too high can depress the central nervous system and may even lead to coma.

Examples of anticonvulsants that are monitored by TDM include:

Carbamazepine (Tegretol)

epakene)

Phenytoin (Dilantin)

Primidone (Mysoline)

TDM for Immunosuppressants Drugs used to inhibit the immune system are part of standard treatment after transplant

surgeries. Unfortunately, these life-saving drugs also cause hepatotoxicity and nephrotoxicity with

high concentrations. The reason drug monitoring is used for immunosuppressants is to ensure that

concentrations are adequate to suppress the immune response and prevent rejection yet not

enough to cause liver failure or severe immunodeficiency.

Examples of immunosuppressants that are monitored by TDM include:

Methotrexate (this drug is also used as an anti-neoplastic drug)





is performed for drugs that are included in one of these

Infection is obviously a very serious indication, and effective antibiotic levels must be achieved

antibiotics also have nephrotoxic or ototoxic effects; the

concentrations too low or too

ampicillin that are readily cleared and have a wide therapeutic window are

seizure medications) typically have narrow

too low, the risk for seizure remains present. Drug levels that

to coma.

Drugs used to inhibit the immune system are part of standard treatment after transplant

and nephrotoxicity with

immunosuppressants is to ensure that

concentrations are adequate to suppress the immune response and prevent rejection yet not high


13


Inotropics (drugs used to increase the

need TDM. The cardiac glycoside

Overdose can cause vomiting, diarrhea, confusion, visual

difficulty with these medications is that overdose produces the same symptoms that the

to treat. For example, procainamide is used for arrythmyia, but an overdose of procainamide can

produce an arrythmia. Thus, without TDM the physician will not kno

less, since both states can lead to the same

Examples of cardiac medications that are monitored by TDM include:

Digoxin

Digitoxin

Procainamide

N-Acetylprocainamide (NAPA)

Quinidine

TDM for Theophylline Theophylline is used as a bronchodilator for the treatment of moderate to severe asthma and

chronic obstructive pulmonary disease

TDM is needed for theophylline because the kinetics of the drug are highly variable. It has a

narrow therapeutic window, and overdose

excitability.

Clearance of the drug is increased in children, smokers, persons with cystic fibrosis, and persons

with hyperthyroidism. Elimination is

Laboratory Methods Immunoassays are the most common technique used by clinical laboratories for therapeutic

drug monitoring. Antibodies that recognize specific drugs have been developed. Although most drugs

are much too small to evoke an immune

proteins to produce antibodies that recognize drug

There are several methods that utilize the principals of immunoassay for detection and

quantification of therapeutic drugs in serum.

Some of these methods are:

• Particle-enhanced turbidimetric inhibition immunoassay (PETINIA)

• Cloned enzyme donor immunoasssay (CEDIA)

• Fluorescence Polarization Immunoassay (FPIA)

• Chemiluminescent assays

PETINIA Particle-enhanced turbidimetric inhibition immunoassay (PETINIA) is a homogeneous

competitive immunoassay.

Antibody fragments and drug

turbidity of the solution. Free drug from the

decreasing the rate of particle aggregation.

The rate of aggregation is inversely proportional to the concentration of drug in the sample.


Dr: Ahmed Refat &



Inotropics (drugs used to increase the pumping ability of the heart) and antiarrhythmics may

need TDM. The cardiac glycoside inotropics digoxin and digitoxin have narrow therapeutic windows.

Overdose can cause vomiting, diarrhea, confusion, visual disturbances, and cardiac arryhthmias. A

ulty with these medications is that overdose produces the same symptoms that the


Thus, without TDM the physician will not know whether to give more drug or

less, since both states can lead to the same presentation.

Examples of cardiac medications that are monitored by TDM include:

Acetylprocainamide (NAPA) -the metabolite of procainamide

Theophylline is used as a bronchodilator for the treatment of moderate to severe asthma and

chronic obstructive pulmonary disease (COPD).


narrow therapeutic window, and overdose can result in elevated heart rate, arrhythmia, and CNS


with hyperthyroidism. Elimination is slowed in congestive heart failure and in the elderly.

Immunoassays are the most common technique used by clinical laboratories for therapeutic

Antibodies that recognize specific drugs have been developed. Although most drugs

much too small to evoke an immune response, scientists can conjugate drugs to immunogenic

proteins to produce antibodies that recognize drug-specific epitopes.


cation of therapeutic drugs in serum.

Some of these methods are:

enhanced turbidimetric inhibition immunoassay (PETINIA)

Cloned enzyme donor immunoasssay (CEDIA)

Fluorescence Polarization Immunoassay (FPIA)

Chemiluminescent assays

enhanced turbidimetric inhibition immunoassay (PETINIA) is a homogeneous

Antibody fragments and drug-latex particles will bind to form aggregates that increase the

turbidity of the solution. Free drug from the sample competes for the antibody fragment, thereby

decreasing the rate of particle aggregation.





pumping ability of the heart) and antiarrhythmics may

inotropics digoxin and digitoxin have narrow therapeutic windows.

disturbances, and cardiac arryhthmias. A

ulty with these medications is that overdose produces the same symptoms that the drug is used


w whether to give more drug or

Theophylline is used as a bronchodilator for the treatment of moderate to severe asthma and


can result in elevated heart rate, arrhythmia, and CNS


congestive heart failure and in the elderly.

Immunoassays are the most common technique used by clinical laboratories for therapeutic

Antibodies that recognize specific drugs have been developed. Although most drugs

response, scientists can conjugate drugs to immunogenic


enhanced turbidimetric inhibition immunoassay (PETINIA)

enhanced turbidimetric inhibition immunoassay (PETINIA) is a homogeneous

latex particles will bind to form aggregates that increase the

the antibody fragment, thereby



14

FPIA • Fluoresence polarization immunoassay (FPIA) is also a homogenous competitive

this system, fluorescein-labeled drug competes with unlabeled drug from the patient's serum

sample for binding sites on an antibody reagent.

• The patient's sample, presumably containing the therapeutic drug that is being monitored, and

the fluorescein-labeled drug are added to a chamber containing antibody for that drug.

• The labeled and unlabeled drug will compete for binding sites on the antibody. The greater the

amount of drug in the sample, the fewer the number of binding sites that are a

labeled analyte, leaving a greater number of small, free fluorescein

solution.

• When the chamber is excited with plane polarized light, fluorescein will absorb the light and emit

it at a higher wavelength as fluores

• A small, free fluorescein-labeled drug rotates randomly and faster than it would if it were bound

to antibody, interrupting the light and leading to less emission of light.

• The larger antibody-drug-

measured plane.

• A lower level of drug in the patient's sample results in greater emission of polarized light because

there are more antibody-drug

plane. A higher level of drug

This inverse relationship between the concentration of the drug and the polarization units (signal)

is illustrated in the image below.

• FPIA assays are rapidly being replaced by higher

now rarely used.

Chemiluminescence Chemiluminescent assays use antibodies that are conjugated to enzymes, such as peroxidase or

alkaline phosphatase. These enzymes, when mixed with chemiluminescent

the visible spectrum.

A direct relationship exists between the amount of drug that is present in the sample and the

light units that are produced and

chemiluminescence are more sensitive than immunoassays that

product.


Dr: Ahmed Refat &


Fluoresence polarization immunoassay (FPIA) is also a homogenous competitive

labeled drug competes with unlabeled drug from the patient's serum

sample for binding sites on an antibody reagent.

The patient's sample, presumably containing the therapeutic drug that is being monitored, and

labeled drug are added to a chamber containing antibody for that drug.

The labeled and unlabeled drug will compete for binding sites on the antibody. The greater the

amount of drug in the sample, the fewer the number of binding sites that are a

labeled analyte, leaving a greater number of small, free fluorescein-labeled molecules in the

When the chamber is excited with plane polarized light, fluorescein will absorb the light and emit

it at a higher wavelength as fluorescent light.

labeled drug rotates randomly and faster than it would if it were bound

to antibody, interrupting the light and leading to less emission of light.

fluorescein complexes rotate slower and emit m

A lower level of drug in the patient's sample results in greater emission of polarized light because

drug-fluorescein complexes present to produce light in the measured

plane. A higher level of drug in the patient's sample results in a lower emission of polarized light.


is illustrated in the image below.

FPIA assays are rapidly being replaced by higher-throughput chemiluminescent assays. FPIA is

Chemiluminescent assays use antibodies that are conjugated to enzymes, such as peroxidase or

enzymes, when mixed with chemiluminescent substrates, produce light in


light units that are produced and measured by the luminometer in the instrument. Assays that use

nce are more sensitive than immunoassays that rely on the generation of a colored




Fluoresence polarization immunoassay (FPIA) is also a homogenous competitive immunoassay. In

labeled drug competes with unlabeled drug from the patient's serum

The patient's sample, presumably containing the therapeutic drug that is being monitored, and

labeled drug are added to a chamber containing antibody for that drug.

The labeled and unlabeled drug will compete for binding sites on the antibody. The greater the

amount of drug in the sample, the fewer the number of binding sites that are available for the

labeled molecules in the

When the chamber is excited with plane polarized light, fluorescein will absorb the light and emit

labeled drug rotates randomly and faster than it would if it were bound

fluorescein complexes rotate slower and emit more light in the

A lower level of drug in the patient's sample results in greater emission of polarized light because

fluorescein complexes present to produce light in the measured

in the patient's sample results in a lower emission of polarized light.


throughput chemiluminescent assays. FPIA is

Chemiluminescent assays use antibodies that are conjugated to enzymes, such as peroxidase or

substrates, produce light in


measured by the luminometer in the instrument. Assays that use

rely on the generation of a colored


15

Individualized Medicine It has been said that we live in a new era of "individualized medicine" or "personalized

medicine." One of the primary drivers for this

PGx is the study of how individual variations in the human genome affect

The term "pharmacogenetics" is also used for this discipline (people in the field use both terms;

however, the term 'pharmacogenomics' is more popular).

The primary reason that individuals metabolize and respond to drugs differently is the inter

individual differences in receptor proteins and

receptor proteins and enzymes can give rise to very different responses to drugs.

mutations are referred to as variants.

Polymorphism and CYP450To discuss PGx, we must first define two terms:

1. A polymorphism is a variation in a specific gene

population. It is essentially a mutation that

2. CYP450 refers to a family of enzymes found predominantly in the liver. CYP450 enzymes

work on a variety of substrates

facilitate excretion in the urine and feces.

There are many known polymorphisms which occur in the protein sequences of CYP450

enzymes.

CYP450s Many CYP450 enzymes have been characterized, and

recognize have been worked out to a

to-date, been associated with significant polymorphisms that affect drug

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2D6

There has been much research on CYP450 enzymes and many papers reporting polymorphisms

with clinical significance. We can't

• It is estimated that about 25% of common drugs are metabolized b

• CYP2D6 accounts for only about 1% of all CYP450 enzymes, but it is important in the metabolism

of about 100 drugs.

• There are more than 80 genetic variants that have been described in the CYP2D6 gene. The

normal, wild-type allele displays normal

have enhanced or diminished activity.

• The variants can be grouped generally according to the resulting alterations in protein function.

• The groupings correlate with four major enzyme metabolic capacities

intermediate, extensive (normal), or ultrarapid


Dr: Ahmed Refat &


It has been said that we live in a new era of "individualized medicine" or "personalized

medicine." One of the primary drivers for this idea is the emerging field of pharmacogenomics (PGx).

PGx is the study of how individual variations in the human genome affect responses to medications.


'pharmacogenomics' is more popular).

The primary reason that individuals metabolize and respond to drugs differently is the inter

individual differences in receptor proteins and enzymes that metabolize the drugs. Mutations in these

oteins and enzymes can give rise to very different responses to drugs.

mutations are referred to as variants.

Polymorphism and CYP450 To discuss PGx, we must first define two terms:

A polymorphism is a variation in a specific gene (allele) that affects at least 1% of the

population. It is essentially a mutation that occurs relatively frequently in the population.

CYP450 refers to a family of enzymes found predominantly in the liver. CYP450 enzymes

work on a variety of substrates (in this case, drugs), altering their chemical structures to

facilitate excretion in the urine and feces.


Many CYP450 enzymes have been characterized, and the substrates (drugs) that each can

recognize have been worked out to a large extent. The major subfamilies of CYP450 enzymes that have

date, been associated with significant polymorphisms that affect drug disposition are:


with clinical significance. We can't discuss all CYP450s but lets consider CYP2D6 as an example:

It is estimated that about 25% of common drugs are metabolized by CYP2D6.

CYP2D6 accounts for only about 1% of all CYP450 enzymes, but it is important in the metabolism

There are more than 80 genetic variants that have been described in the CYP2D6 gene. The

type allele displays normal metabolic activity whereas some of the variant forms

have enhanced or diminished activity.

The variants can be grouped generally according to the resulting alterations in protein function.

The groupings correlate with four major enzyme metabolic capacities

intermediate, extensive (normal), or ultrarapid metabolizers.




It has been said that we live in a new era of "individualized medicine" or "personalized

idea is the emerging field of pharmacogenomics (PGx).

responses to medications.


The primary reason that individuals metabolize and respond to drugs differently is the inter-

enzymes that metabolize the drugs. Mutations in these

oteins and enzymes can give rise to very different responses to drugs. In PGx, these

(allele) that affects at least 1% of the

occurs relatively frequently in the population.

CYP450 refers to a family of enzymes found predominantly in the liver. CYP450 enzymes

drugs), altering their chemical structures to


the substrates (drugs) that each can

The major subfamilies of CYP450 enzymes that have

disposition are:


discuss all CYP450s but lets consider CYP2D6 as an example:

y CYP2D6.

CYP2D6 accounts for only about 1% of all CYP450 enzymes, but it is important in the metabolism

There are more than 80 genetic variants that have been described in the CYP2D6 gene. The

metabolic activity whereas some of the variant forms

The variants can be grouped generally according to the resulting alterations in protein function.

The groupings correlate with four major enzyme metabolic capacities (phenotypes): poor,


16

Metabolizers When discussing PGx, we classify a person according to his/her phenotype (their metabolic

capacity for a given enzyme).

• A poor metabolizer (PM) is a person who lacks a fully

expression of the enzyme and therefore

would require lower doses of a drug that is metabolized by that enzyme. A PM

standard dose is more likely to experience unwanted side effects or toxicity. A PM can also

experience diminished effects with drugs that need to be metabolized to active compounds by

the enzyme in question.

• An ultrarapid metabolizer

polymorphism (mutation) that codes for a more

enzyme. They will eliminate the drug more quickly. A UM may be resistant to standard

treatments, and it may take some time to adjus

• An intermediate metabolizer

dysfunctional copy. The IM group is

• A person with normal enzyme activity is referred to as wild type or as an

(EM). This person should respond to

population in which most dosing regimens have been worked out


Not all PGx is concerned with CYP450 enzymes. There are other drug

show polymorphisms and can affect the way people respond to a drug. The following is a list of

enzymes for which known mutations have been associated with

Enzymes Acetylcholinesterase

Acetylcholinesterase

Alcohol dehydrogenase

Dihydropyrimidine dehydrogenase

CYP2C9

CYP2C19

CYP2D6

Glucose-6-phosphate dehydrogenase

N-acetyltransferase

Thioprine methyltransferase

UDP-glucuronosyl transferase

Clinical Utility • The ultimate goal in measuring CYP450 function or identifying polymorphisms is to predict

effective therapeutic doses and responses

• Polymorphisms are identified using molecular techniques (allele

sequencing, hybridization assays,


Dr: Ahmed Refat &


When discussing PGx, we classify a person according to his/her phenotype (their metabolic

(PM) is a person who lacks a fully-functional enzyme or has reduced

expression of the enzyme and therefore exhibits decreased metabolism of drugs. This person

would require lower doses of a drug that is metabolized by that enzyme. A PM

dard dose is more likely to experience unwanted side effects or toxicity. A PM can also

effects with drugs that need to be metabolized to active compounds by

ultrarapid metabolizer (UM) will require a higher dose than usual since he/she has a

polymorphism (mutation) that codes for a more efficient enzyme or more expression of an


treatments, and it may take some time to adjust the dosage before therapy is achieved.

intermediate metabolizer (IM) has one wild-type (normal) copy of the gene and one absent or

dysfunctional copy. The IM group is very heterogeneous.

A person with normal enzyme activity is referred to as wild type or as an extensive metabolizer

(EM). This person should respond to standard dosages of a drug. Most people are EM's. This is the

population in which most dosing regimens have been worked out in clinical


Not all PGx is concerned with CYP450 enzymes. There are other drug-metabolizing enzymes that

affect the way people respond to a drug. The following is a list of

which known mutations have been associated with clinical effects.

Substrates (Drugs)

Alcohol Succinylcholine

Alcohol Dihydropyrimidine dehydrogenase Fluorouracil

Warfarin, phenytoin, losartanDiazepam, omeprazole (Prilosec)Many antidepressants, opioids,

phosphate dehydrogenase Aspirin, quinidine Procainamide, isoniazid

Thioprine methyltransferase 6-mercaptopurine glucuronosyl transferase Acetaminophen, tolbutamide, irinotecan

The ultimate goal in measuring CYP450 function or identifying polymorphisms is to predict

effective therapeutic doses and responses in patients.

Polymorphisms are identified using molecular techniques (allele-specific PCR, restriction digests,

sequencing, hybridization assays, bead-based systems, microarrays, pyrosequencing, et al).




When discussing PGx, we classify a person according to his/her phenotype (their metabolic

functional enzyme or has reduced

exhibits decreased metabolism of drugs. This person

would require lower doses of a drug that is metabolized by that enzyme. A PM who receives a

dard dose is more likely to experience unwanted side effects or toxicity. A PM can also

effects with drugs that need to be metabolized to active compounds by

r dose than usual since he/she has a

efficient enzyme or more expression of an


t the dosage before therapy is achieved.

type (normal) copy of the gene and one absent or

extensive metabolizer

standard dosages of a drug. Most people are EM's. This is the

trials.

metabolizing enzymes that

affect the way people respond to a drug. The following is a list of

phenytoin, losartan Diazepam, omeprazole (Prilosec) Many antidepressants, opioids, antiarrhythmics

Acetaminophen, tolbutamide, irinotecan

The ultimate goal in measuring CYP450 function or identifying polymorphisms is to predict

specific PCR, restriction digests,

based systems, microarrays, pyrosequencing, et al).


17

• Although most clinical labs do not offer PGx testing, reference la

tests. For example, one reference

measures about one dozen of the most common and significant mutation sites on

This allows for detection of approximately

laboratory then generates a report

metabolizing status.

• Estimates show that 6-10% of the general population have a complete deficiency of CYP2D6, with

the prevalence of mutations varying from

Warfarin Metabolism • PGx testing for warfarin metabolism has received the most attention thus far.

• Recent studies have revealed that about half of the variations seen in

anticoagulant warfarin are due to PGx

obviously serious, with inadequate doses predisposing patients to

placing them at risk for hemorrhage.

• The United States' Food and Drug Administration (FDA) recently approved updated labeling for

Coumadin (warfarin sold by Bristol

incorporate PGx information into warfarin

warfarin products are now adding similar labeling.

• The genes involved in warfarin metabolism are CYP2C9 and vitamin K epoxide reductase complex

subunit 1 (VKOR).

• Warfarin owes its anticoagulant action to its inhibition of VKOR. This enzym

critical element for the clotting

metabolism of warfarin: CYP2C9 *2, *3, *4, *5, *6, and *11.

denoted with asterisks.)

• One-third of the patients that receive warfarin metabolize it differently than expected and

experience a higher risk of bleeding.

• Genetic testing for the two most common polymorphisms (CYP2C9*2 and *3) as well as for VKOR

may be able to reduce the variability

• Labs performing PGx testing can provide general warfarin dosing recommendations based on the

patient's genotype analysis. The lab

moderate, high, or very high sens

then help physicians calculate an appropriate starting and maintenance dose given the phenotype

of a particular person.

• For example, a patient who has one CYP2C9 normal wild

polymorphism (CYP2C9*3), and also a VKOR

sensitivity to warfarin. This patient should have frequent INR monitoring and possible

dose reduction.

• It is important to recognize that knowing a g

dose prediction; other drugs and/or

activity. Therefore, monitoring the INR is still very important.

Conclusion: A person classified as an ultrarapid m

activity of the enzyme. This means that a UM would need more of the drug to achieve a 'normal' level since he/she is

rapidly metabolizing the drug.


Dr: Ahmed Refat &


Although most clinical labs do not offer PGx testing, reference labs are beginning to market these

tests. For example, one reference laboratory in the Midwest that offers CYP2D6 profiling

measures about one dozen of the most common and significant mutation sites on

This allows for detection of approximately 98% of the known CYP2D6 polymorphisms. The

laboratory then generates a report which will advise the physician on the patient's drug

10% of the general population have a complete deficiency of CYP2D6, with

alence of mutations varying from <1% to as much as 21% within a given population.

PGx testing for warfarin metabolism has received the most attention thus far.

Recent studies have revealed that about half of the variations seen in

anticoagulant warfarin are due to PGx factors. The consequences of incorrect warfarin dosing are

obviously serious, with inadequate doses predisposing patients to thrombosis and higher doses

placing them at risk for hemorrhage.

ed States' Food and Drug Administration (FDA) recently approved updated labeling for

Coumadin (warfarin sold by Bristol-Myers Squibb). The new labeling suggests that physicians

incorporate PGx information into warfarin-dosing regimens for patients. Manufac

warfarin products are now adding similar labeling.

The genes involved in warfarin metabolism are CYP2C9 and vitamin K epoxide reductase complex

Warfarin owes its anticoagulant action to its inhibition of VKOR. This enzym

critical element for the clotting. There are six CYP2C9 alleles that are known to cause prolonged

metabolism of warfarin: CYP2C9 *2, *3, *4, *5, *6, and *11. (Polymorphisms in CYP450 genes are

the patients that receive warfarin metabolize it differently than expected and

experience a higher risk of bleeding.

Genetic testing for the two most common polymorphisms (CYP2C9*2 and *3) as well as for VKOR

may be able to reduce the variability associated with warfarin dosing response.

Labs performing PGx testing can provide general warfarin dosing recommendations based on the

patient's genotype analysis. The lab report will indicate whether a patient has a normal, mild,

moderate, high, or very high sensitivity to warfarin. Online calculators or handy


For example, a patient who has one CYP2C9 normal wild-type allele (CYP

polymorphism (CYP2C9*3), and also a VKOR polymorphism is predicted to have a moderate

sensitivity to warfarin. This patient should have frequent INR monitoring and possible

It is important to recognize that knowing a genotype does not necessarily guarantee accurate

dose prediction; other drugs and/or environmental or disease factors can also alter CYP2C9

activity. Therefore, monitoring the INR is still very important.

Conclusion: A person classified as an ultrarapid metabolizer (UM) has a polymorphism that enhances the catabolic





bs are beginning to market these

laboratory in the Midwest that offers CYP2D6 profiling

measures about one dozen of the most common and significant mutation sites on this enzyme.

98% of the known CYP2D6 polymorphisms. The

which will advise the physician on the patient's drug-

10% of the general population have a complete deficiency of CYP2D6, with

<1% to as much as 21% within a given population.

PGx testing for warfarin metabolism has received the most attention thus far.

Recent studies have revealed that about half of the variations seen in patients taking the

factors. The consequences of incorrect warfarin dosing are

thrombosis and higher doses

ed States' Food and Drug Administration (FDA) recently approved updated labeling for

Squibb). The new labeling suggests that physicians

dosing regimens for patients. Manufacturers of generic

The genes involved in warfarin metabolism are CYP2C9 and vitamin K epoxide reductase complex

Warfarin owes its anticoagulant action to its inhibition of VKOR. This enzyme recycles vitamin K, a

There are six CYP2C9 alleles that are known to cause prolonged

(Polymorphisms in CYP450 genes are

the patients that receive warfarin metabolize it differently than expected and

Genetic testing for the two most common polymorphisms (CYP2C9*2 and *3) as well as for VKOR

ed with warfarin dosing response.

Labs performing PGx testing can provide general warfarin dosing recommendations based on the

report will indicate whether a patient has a normal, mild,

itivity to warfarin. Online calculators or handy paper charts can


type allele (CYP2C9 *1), one

polymorphism is predicted to have a moderate

sensitivity to warfarin. This patient should have frequent INR monitoring and possible warfarin

enotype does not necessarily guarantee accurate

environmental or disease factors can also alter CYP2C9

etabolizer (UM) has a polymorphism that enhances the catabolic



18


• PGx is not the only factor to consider when thinking about variation in drug responses among

different people. Although

are other big players that influence drug metabolism.

• For example, many drugs ar

produce more of a particular

For example, CYP2D6 can be inhibited by the common

fluoxetine (Prozac). Substances in food can also affect CYP450 expression or may simply compete

with a drug for metabolism. An example is grapefruit. Several organic compounds found in

grapefruit have an inhibitory action on CYP3A4.

• Since many patients are on m

change, CYP450 expression levels

• Some CYP450 inducers and inhibitors are listed in the table on the following page.

CYP450

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1

CYP3A

Note: This is not an exhaustive listing of inducers and inhibitors.

Conclusion: Since cimetidine inhibits CYP2D6

to be metabolized as readily. Most drug interactions are like this: one drug inhibits or competes with the same

as another drug. The end result is that higher

toxicity.


Dr: Ahmed Refat &



the only factor to consider when thinking about variation in drug responses among

polymorphisms of drug-metabolizing enzymes are a big player, there

are other big players that influence drug metabolism.

For example, many drugs are able to induce the expression of CYP450 enzymes (cause cells to

produce more of a particular enzyme). Also, CYP450s can be inhibited by a variety of substances.

For example, CYP2D6 can be inhibited by the common medications cimetidine (Tagamet) and

etine (Prozac). Substances in food can also affect CYP450 expression or may simply compete


grapefruit have an inhibitory action on CYP3A4.

Since many patients are on multiple medications and since dietary and environmental factors can

change, CYP450 expression levels cannot be solely predicted based on their genotype.

Some CYP450 inducers and inhibitors are listed in the table on the following page.

Inhibitor Inducer

Amiodarone Cimetidine Ciprofloxacin

Tobacco

Amiodarone Fluvastatin Isoniazid Fluconazole

RifampinSecobarbital

Cimetidine Indomethacin Ketokonazole

Prednisone

Celecoxib Cimetidine Cocaine Methadone Pentazocine

ImipramineDesipramineAmitriptyline

Disulfiram Fluoxetine

Ethanol Isoniazid

Midazolam Erythromycin Methadone

PhenobarbitalDexamethasone

: This is not an exhaustive listing of inducers and inhibitors.

CYP2D6, less amphetamine will probably need to be given since it will not be able

Most drug interactions are like this: one drug inhibits or competes with the same

lt is that higher concentrations of one, or both, drugs are present, leading to potential




the only factor to consider when thinking about variation in drug responses among

metabolizing enzymes are a big player, there

e able to induce the expression of CYP450 enzymes (cause cells to

enzyme). Also, CYP450s can be inhibited by a variety of substances.

medications cimetidine (Tagamet) and

etine (Prozac). Substances in food can also affect CYP450 expression or may simply compete


ultiple medications and since dietary and environmental factors can

cannot be solely predicted based on their genotype.

Some CYP450 inducers and inhibitors are listed in the table on the following page.

Tobacco

Rifampin Secobarbital

Prednisone

Imipramine Desipramine Amitriptyline

Isoniazid Phenobarbital Dexamethasone

, less amphetamine will probably need to be given since it will not be able

Most drug interactions are like this: one drug inhibits or competes with the same CYP450

concentrations of one, or both, drugs are present, leading to potential


19

Genotype versus Phenotype• Genotyping can give us a definitive profile of a given CYP450 enzyme's mutations. But since there

are dozens of mutations usually

CYP450 is not always realistic.

• Without complete sequencing of the entire allele, it may not be possible to entirely rule out a

mutation in a patient who shows none of

• If we consider the number of possible mutations and the possible presence of inducing/inhibiting

substances, phenotyping for drug

• Phenotyping involves measuring the metabolism of a probe

dextromethorphan or debrisoquine can

metabolized. Both these drugs are safe and extensively metabolized by CYP2D6.

as 'probe drug testing'. By measuring t

capacity of a CYP450 enzyme can be estimated.

• Such testing is complex and tedious, however, and has not become routine in clinical laboratories.

Therefore, genotyping is likely to be the

TDM and PGx • Can we use therapeutic drug monitoring (TDM) to assess PGx?

• TDM of the drug in question can also tell us a good deal about a drug's metabolism and will also

take into account all the other

etc.) However, unlike genotyping and probe

performed during therapy, not before. So, in fact, TDM is not really used to predict therapy in PGx

but serves as a confirmation of PGx findings.

• TDM and genotyping should be considered complementary and can be used in tandem to, first,

predict and then verify appropriate serum

The Bottom Line

• In recent years PGx has not expanded and become

for this are many. One reason is

metabolism (diet, co-medications, age, organ function, etc.) to rely on a

so many variables the cost of obtaining a PGx genotype on a patient becomes hard to justify. As

genetic test prices continues to fall this will present less of a barrier in the future. Another

problem has been the lack of clinical studies that

for patients. That is, if PGx testing doesn't cause better outcomes, then it is hard for

patients to justify its cost. There are some studies which suggest, for example, that PGx testing

may reduce hospital admissions (for those

studies which clearly demonstrate that PGx testing provides

• The US Medicare/Medicaid system has also been slow to reimburse for PGx testing. Thus, it has

not been adopted by mainly labs or

• There are some drugs however for which PGx testing is becoming more popular. Some of these

drugs have such a high potential for

these drugs has become standard of

assessed before use include:

Irinotecan (where UDP

6-mercaptopurine (Thiopurine methyl transferase (TPMT) activity is assessed)


Dr: Ahmed Refat &


Genotype versus Phenotype Genotyping can give us a definitive profile of a given CYP450 enzyme's mutations. But since there

usually associated with each enzyme, a complete characterization of a

CYP450 is not always realistic.

Without complete sequencing of the entire allele, it may not be possible to entirely rule out a

mutation in a patient who shows none of the more common polymorphisms.

If we consider the number of possible mutations and the possible presence of inducing/inhibiting

substances, phenotyping for drug metabolism may sound more reasonable than genotyping.

Phenotyping involves measuring the metabolism of a probe drug. For example, with CYP2D6,

dextromethorphan or debrisoquine can be given to a patient to see how well the drug is

metabolized. Both these drugs are safe and extensively metabolized by CYP2D6.

as 'probe drug testing'. By measuring the parent drug and the metabolite in urine, the metabolic

capacity of a CYP450 enzyme can be estimated.

Such testing is complex and tedious, however, and has not become routine in clinical laboratories.

Therefore, genotyping is likely to be the main tool that is used for assessing the PGx of a patient.

Can we use therapeutic drug monitoring (TDM) to assess PGx?

TDM of the drug in question can also tell us a good deal about a drug's metabolism and will also

take into account all the other variables at play (co-medications, diet, impaired organ function,

etc.) However, unlike genotyping and probe-drug testing, therapeutic drug monitoring must be


as a confirmation of PGx findings.

TDM and genotyping should be considered complementary and can be used in tandem to, first,

predict and then verify appropriate serum drug levels.

In recent years PGx has not expanded and become as widespread as most predicted. The reasons

for this are many. One reason is that there are just too many variables at play with drug

medications, age, organ function, etc.) to rely on a simple PGx result. With

ost of obtaining a PGx genotype on a patient becomes hard to justify. As

test prices continues to fall this will present less of a barrier in the future. Another

problem has been the lack of clinical studies that show that PGx improves morbidity an

for patients. That is, if PGx testing doesn't cause better outcomes, then it is hard for


admissions (for those on warfarin) but to-date there are few large, powerful

studies which clearly demonstrate that PGx testing provides added benefit to patients.

The US Medicare/Medicaid system has also been slow to reimburse for PGx testing. Thus, it has

mainly labs or health systems.

There are some drugs however for which PGx testing is becoming more popular. Some of these

drugs have such a high potential for severe, lethal toxicity that PGx testing or enzyme testing for

these drugs has become standard of care. Some examples of these drugs

assessed before use include:

Irinotecan (where UDP-glucuronosyl transferase 1A1 (UGT1A1) is assessed)

mercaptopurine (Thiopurine methyl transferase (TPMT) activity is assessed)




Genotyping can give us a definitive profile of a given CYP450 enzyme's mutations. But since there

associated with each enzyme, a complete characterization of a

Without complete sequencing of the entire allele, it may not be possible to entirely rule out a

polymorphisms.

If we consider the number of possible mutations and the possible presence of inducing/inhibiting

metabolism may sound more reasonable than genotyping.

drug. For example, with CYP2D6,

be given to a patient to see how well the drug is

metabolized. Both these drugs are safe and extensively metabolized by CYP2D6. This is referred to

he parent drug and the metabolite in urine, the metabolic

Such testing is complex and tedious, however, and has not become routine in clinical laboratories.

hat is used for assessing the PGx of a patient.

TDM of the drug in question can also tell us a good deal about a drug's metabolism and will also

medications, diet, impaired organ function,

drug monitoring must be


TDM and genotyping should be considered complementary and can be used in tandem to, first,

as widespread as most predicted. The reasons

that there are just too many variables at play with drug

simple PGx result. With

ost of obtaining a PGx genotype on a patient becomes hard to justify. As

test prices continues to fall this will present less of a barrier in the future. Another

show that PGx improves morbidity and mortality

for patients. That is, if PGx testing doesn't cause better outcomes, then it is hard for clinicians and


date there are few large, powerful

added benefit to patients.

The US Medicare/Medicaid system has also been slow to reimburse for PGx testing. Thus, it has

There are some drugs however for which PGx testing is becoming more popular. Some of these

severe, lethal toxicity that PGx testing or enzyme testing for

and the enzymes that

glucuronosyl transferase 1A1 (UGT1A1) is assessed)

mercaptopurine (Thiopurine methyl transferase (TPMT) activity is assessed)


20

5-Fluorouricil (Dihydropyrimidine dehydrogenase (DPD) activity is assessed)

• Clopidogrel (Plavix) is another drug in which PGx testing is getting more attention. For this anti

platelet drug, CYP2C19 or platelet function

able to convert clopidogrel to its active metabolite to achieve the needed anti

• Clopidogrel (Plavix) (where CYP2C19 or platelet function is assessed)

• By knowing a patient's disposition to specific drugs, the physician should be able to sta

patient on an appropriate regimen rather

Drugs whose metabolism may prove to be problematic can be avoided, and

that are metabolized by different, unaffected enzymes can be ch

• Clinical chemists, pharmacologists, and physicians need to translate knowledge of CYP450

polymorphisms into clinically

• Dosing recommendations for PM, EM, IM and UM patients are beginning to appear in the

literature for various classes of drugs, and

pharmacogenomic testing in the development process for new drugs.


Dr: Ahmed Refat &


dropyrimidine dehydrogenase (DPD) activity is assessed)

Clopidogrel (Plavix) is another drug in which PGx testing is getting more attention. For this anti

platelet drug, CYP2C19 or platelet function is often directly assessed to ensure that the patient is

able to convert clopidogrel to its active metabolite to achieve the needed anti

Clopidogrel (Plavix) (where CYP2C19 or platelet function is assessed)

By knowing a patient's disposition to specific drugs, the physician should be able to sta

patient on an appropriate regimen rather than perfecting treatment based on trial and error.

Drugs whose metabolism may prove to be problematic can be avoided, and

that are metabolized by different, unaffected enzymes can be chosen.

Clinical chemists, pharmacologists, and physicians need to translate knowledge of CYP450

polymorphisms into clinically-validated treatment algorithms.

Dosing recommendations for PM, EM, IM and UM patients are beginning to appear in the

various classes of drugs, and the FDA is encouraging the incorporation of

pharmacogenomic testing in the development process for new drugs.




dropyrimidine dehydrogenase (DPD) activity is assessed)

Clopidogrel (Plavix) is another drug in which PGx testing is getting more attention. For this anti-

is often directly assessed to ensure that the patient is

able to convert clopidogrel to its active metabolite to achieve the needed anti-platelet effect.

By knowing a patient's disposition to specific drugs, the physician should be able to start the

than perfecting treatment based on trial and error.

Drugs whose metabolism may prove to be problematic can be avoided, and second-line therapies

Clinical chemists, pharmacologists, and physicians need to translate knowledge of CYP450

Dosing recommendations for PM, EM, IM and UM patients are beginning to appear in the

the FDA is encouraging the incorporation of


21

IVIVIVIV---- IIIIndividualized TDM Drugndividualized TDM Drugndividualized TDM Drugndividualized TDM Drug

Acetylsalicylic acid (Aspirin)

USUAL DOSAGE

- Adults (antiinflammatory): 45 to 60 mg/kg/day

- Children (antiinflammatory) 70 to 90 mg/kg/day

USUAL DOSING INTERVAl

- Daily dose given in four to six divided doses

TOXIC EFFECTS

- Tinnitus, headaches, vertigo, hearing loss

-Gastrointestinal, intolerance

-Bronchospasm.

-Severe chronic and acute lntoxication, central Hyperventilation, respiratory alkalosis, metabolic

acidosis ( ˃400 mg/l: ˃2.9 mmol/l),hyperglycemia (early),

TIME TO PEAK SERUM CONCENTRATION

-Salicylic acid :1 to 2 hours(formulation dependent)

TIME TO ACHIEVE STEADY STATE

- Salicylic acid: 5 to 7 days of chronic oral dosing

ELIMINATION HALF-LIFE

-Acetylsalicylic acid:15 to 30 min

-The serum half-life and volume of distribution of salisylic acid may increase with increasing dose

-Salicylic acid:-3 hours after single 250 mg dose

ROUTE OF ELIMINATION

-Acetylsalicylic acid is hydrolyzed to salicylic aci

-Salicylic acid is then metabolized to the following compounds which undergo renal elimination:

• Salicyluric acid (saturable metabollc pathway)

• Gentisic acid (first- order pathway)

• Salicyl acyl glucuronide (first

• Salicyl phenol glucuronide

PROTEIN BINDING

-50 to 90% (concentration dependent)

USUAl SAMPLING TIMES

- 1 to 3 hours after an oral dose (formulation dependent)

USUAl THERAPEUTIC RANGE

- SaLicylic acid: 150 to 300 mg/l; 1.1 t0 2.2 mmol/l (antlinflamma

SELECTED FACTORS AFFECTING SERUM CONCENTRATIONS

Disease:

• Hypoalbuminemia (decreased protein binding)

Drugs:

• Acetylsalicyilc acid can cause a conformational change in albumin's structure, resulting in

altered protein binding for other drugs

• Corticosteroids decrease steady state levels

0thers:

• Rate 0f absorptlon from stomach is pH and formulation dependent (i.e., high pH, slow

absorption)


Dr: Ahmed Refat &


ndividualized TDM Drugndividualized TDM Drugndividualized TDM Drugndividualized TDM Drug ProfilesProfilesProfilesProfiles

45 to 60 mg/kg/day

Children (antiinflammatory) 70 to 90 mg/kg/day

Daily dose given in four to six divided doses

Tinnitus, headaches, vertigo, hearing loss

Gastrointestinal, intolerance

Severe chronic and acute lntoxication, central Hyperventilation, respiratory alkalosis, metabolic

˃400 mg/l: ˃2.9 mmol/l),hyperglycemia (early), Hypoglycemia (late).

TIME TO PEAK SERUM CONCENTRATION

alicylic acid :1 to 2 hours(formulation dependent)

5 to 7 days of chronic oral dosing

30 min

life and volume of distribution of salisylic acid may increase with increasing dose

3 hours after single 250 mg dose -20 hours at higher doses

cetylsalicylic acid is hydrolyzed to salicylic acid

alicylic acid is then metabolized to the following compounds which undergo renal elimination:

Salicyluric acid (saturable metabollc pathway)

order pathway)

Salicyl acyl glucuronide (first- order pathway)

Salicyl phenol glucuronide (saturable metabolic pathway)

50 to 90% (concentration dependent)

1 to 3 hours after an oral dose (formulation dependent)

300 mg/l; 1.1 t0 2.2 mmol/l (antlinflammatory)

AFFECTING SERUM CONCENTRATIONS

Hypoalbuminemia (decreased protein binding)

Acetylsalicyilc acid can cause a conformational change in albumin's structure, resulting in

altered protein binding for other drugs

Corticosteroids decrease steady state levels of salicylates

ate 0f absorptlon from stomach is pH and formulation dependent (i.e., high pH, slow




Severe chronic and acute lntoxication, central Hyperventilation, respiratory alkalosis, metabolic

Hypoglycemia (late).

life and volume of distribution of salisylic acid may increase with increasing dose

alicylic acid is then metabolized to the following compounds which undergo renal elimination:

Acetylsalicyilc acid can cause a conformational change in albumin's structure, resulting in

ate 0f absorptlon from stomach is pH and formulation dependent (i.e., high pH, slow


22

• Systemic acildosis can cause increased tissue uptake reducing the validity of serum level

concentrations

• Urinary alkalinization increases renal elimination in overdose

NOTES:

1. Half-life is longer in newborns

2 Salicylic acid is excreted unchanged in the urine only 2to 14 %

3. Therapeutic range is usually lower if the drug is used for analgesia

4. To assess risk 0f acute toxicity refer to the nomogram of Done

1978).


Dr: Ahmed Refat &


Systemic acildosis can cause increased tissue uptake reducing the validity of serum level

Urinary alkalinization increases renal elimination in overdose

2 Salicylic acid is excreted unchanged in the urine only 2to 14 %

3. Therapeutic range is usually lower if the drug is used for analgesia

4. To assess risk 0f acute toxicity refer to the nomogram of Done (Done AK, Pediatrics (Suppl) 62: 890




Systemic acildosis can cause increased tissue uptake reducing the validity of serum level

(Done AK, Pediatrics (Suppl) 62: 890-897,


23

Gentamicin (Cepiophal, Garamycin, Genticin, Gentisone):

USUAL DOSAGE (lV, IM)

- Loading Dose

Adults: 1 to 2 mg/kg

Children: 1 to 2 mg/kg

Neonates: 2 to 2.5 mg/kg

- Maintenance Dose

Adults: 3 to 6 mg/kg/day

Children: 4 to 10 mg/kg/day

Neonates: 2 to 7.5 mg/kg/day

USUAl DOSING INTERVAl

- Adults: given in two to four divided doses/day

- Children: given in three to six divided doses/day

- Neonates: given in one to two divided doses/day

TOXIC ETFECTS

- Nephrotoxicity .

- Ototoxicity

- Neuromuscular blockade


- Adults: ˂30 years: 2.5 to 15 hours

- Children: 2.5 to 12.5 hours of chronic dosing

- Neonates: 10 to 45 hours of chronic dosing


- Adults: ˂ 30 years 0.5 to 3 hours

- Children: 0.5 to 2.5 hours

- Neonates: 2 to 9 hours


- Renal excretion 90 % unchang

- No known metabolites

PROTEIN BINDING

- ≤ 10 %


- Peak: 0.5 to 1 hours after the end of 30 minutes infusion {1 hour after IM dose}

- Trough: immediately before next dose


- Peak: 5 to 10 mg/l

- Trough: ˂2 mg/l

SELECTED FACTORSAFFECTING SERUM CONCENTRATIONS

Drugs:

• Other nephrotoxic drugs which might decrease renal function

• High concentrations of certain penicillins (e.g.,

either in vitro or in vivo especially in patients

0thers:

• Renal impairement: ↓clearance

• Dehydration: ↓volume of distribuRon

• Obesity : alters distribution

• Burn patients: ↑dosage requirement


Dr: Ahmed Refat &


Cepiophal, Garamycin, Genticin, Gentisone):

2 to 2.5 mg/kg

3 to 6 mg/kg/day

4 to 10 mg/kg/day

2 to 7.5 mg/kg/day

given in two to four divided doses/day

in three to six divided doses/day

given in one to two divided doses/day

2.5 to 15 hours of chronic dosing / ˃30years: 7.5 to 75 hours of chronic dosing

2.5 to 12.5 hours of chronic dosing

10 to 45 hours of chronic dosing

30 years 0.5 to 3 hours/ ˃30years 1.5 to 15 hours

Renal excretion 90 % unchanged

Peak: 0.5 to 1 hours after the end of 30 minutes infusion {1 hour after IM dose}

Trough: immediately before next dose


ther nephrotoxic drugs which might decrease renal function will cause decreased clearance.

High concentrations of certain penicillins (e.g., carbenicillin) may inactivate

either in vitro or in vivo especially in patients its severely compromised renal function.

↓clearance

↓volume of distribuRon

alters distribution

↑dosage requirement




to 75 hours of chronic dosing


cause decreased clearance.

inactivate aminoglycosides

compromised renal function.


24

• Hypermeatbolic surgical patients:

• Cystic fibrosis : ↑ dosage requirement

Notes:

1. These are starting dosages which may exceed manufacturers

opinions of usual dosages required

infections and normal renal function.

2. In neonates the dosages should be adjusted based on patient

function.

3. Higher dosages may be necessary in select patients.

4. Dosing intervals should be adjusted based on patient response, serum concentrations, and renal function

5. Once daily dosages have been recommended. At a dosage o

concentration 0f 0.2 mg/l was found (Prins et al. 1993, Lancet 341 , 335

and monitoring may vary.

6. Assuming normal renal function.

7. Peak delayed in patients who have co

8. Usual therapeutic range will be dependent on infection organism,

the patient, and Severity of infection. Increases in trough concentrations consistent

accumulation have been associated with toxicity.


Dr: Ahmed Refat &


bolic surgical patients: ↑clearance

↑ dosage requirement

These are starting dosages which may exceed manufacturers recommendations and reflect the authors

dosages required to achieve therapeutic serum concentrations

infections and normal renal function. These dosages require monitoring of serum concentrations.

In neonates the dosages should be adjusted based on patient response, serum concentrations, and renal

Higher dosages may be necessary in select patients.

Dosing intervals should be adjusted based on patient response, serum concentrations, and renal function

nce daily dosages have been recommended. At a dosage of 4 mg/kg/day once a day (q.d.) an average peak

0.2 mg/l was found (Prins et al. 1993, Lancet 341 , 335-39). Guidelines for dosage regimens

Assuming normal renal function.

Peak delayed in patients who have compromised renal function

Usual therapeutic range will be dependent on infection organism, site of infection, immunological status of

everity of infection. Increases in trough concentrations consistent

associated with toxicity.




recommendations and reflect the authors

in patients with serious

These dosages require monitoring of serum concentrations.

concentrations, and renal

Dosing intervals should be adjusted based on patient response, serum concentrations, and renal function

4 mg/kg/day once a day (q.d.) an average peak

Guidelines for dosage regimens

site of infection, immunological status of

everity of infection. Increases in trough concentrations consistent with tissue


25

NETILMICIN (Netillin, Netromycin

USUAL DOSAGE (lV, IM)

- Loading Dose

Adults: 1 to 2 mg/kg

Children: 1 to 2 mg/kg

Neonates: 2 to 2.5 mg/kg

- Maintenance Dose

Adults: 4 to 86 mg/kg/day

Children: 4 to 2 mg/kg/day

Neonates: 2 to 7.5 mg/kg/day



- Children: given in three to six divided doses/day

- Neonates: given in one to two divided doses/day

TOXIC ETFECTS

- Nephrotoxicity .

- Ototoxicity

- Neuromuscular blockade


- Adults: ˂30 years-2.5 to 15 hours

- Children: 2.5 to 12.5 hours of chronic dosing

- Neonates: 10 to 45 hours of chronic dosing


- Adults: ˂ 30 years-0.5 to 3 hours

- Children: 0.5 to 2.5 hours



- Renal excretion 90 % unchanged

- No known metabolites

PROTEIN BINDING

- ≤ 10 %


• Peak: 0.5 to 1 hours after the end of 30 minutes infusion {1 hour after IM dose}

• Trough: immediately before next dose


• Peak: 5 to 12 mg/l {11 to 25 umol/l}

• Trough: ˂3 mg/l { 6umol/l}

SELECTED FACTORSAFFECTING SERUM CONCENTRAT

Drugs:

• Other nephrotoxic drugs which might decrease renal function wlll cause decreased clearance.

• High concentrations of certain penicillins (e.g., carbenicillin)

either in vitro or in vivo especially in patients with

0thers:

• Renal impairement: ↓clearance

• Dehydration: ↓volume of distribuRon

• Obesity: alters distribution

• Burn patients: ↑dosage requirement


Dr: Ahmed Refat &


etromycin)

2 to 2.5 mg/kg

4 to 86 mg/kg/day

2 mg/kg/day

2 to 7.5 mg/kg/day


given in three to six divided doses/day

given in one to two divided doses/day

2.5 to 15 hours of chronic dosing / ˃30years- 7.5 to 75 hours of chronic dosing

2.5 to 12.5 hours of chronic dosing

10 to 45 hours of chronic dosing

0.5 to 3 hours/ ˃30years-1.5 to 15 hours

unchanged


Trough: immediately before next dose

Peak: 5 to 12 mg/l {11 to 25 umol/l}

˂3 mg/l { 6umol/l}


ther nephrotoxic drugs which might decrease renal function wlll cause decreased clearance.

High concentrations of certain penicillins (e.g., carbenicillin) may lnactivate aminoglycosides

either in vitro or in vivo especially in patients with severly compromised renal function.

↓clearance

↓volume of distribuRon

alters distribution

↑dosage requirement




7.5 to 75 hours of chronic dosing


ther nephrotoxic drugs which might decrease renal function wlll cause decreased clearance.

may lnactivate aminoglycosides

severly compromised renal function.


26

• Hypermeatbolic surgical patients

• Cystic fibrosis: ↑ dosage requirement

Notes:

1. These are starting dosages which may exceed manufacturers

opinions of usual dosages required to achieve therapeutic serum concentrations

infections and normal renal function.

2. In neonates the dosages should be adjusted based on patient

function.


4. Dosing intervals should be adjusted based on patient response, serum concentrations, and renal function

5. once daily dosages have been recommended. At a dosage of

peak concentration 0f 21.3 mg/l was found (see ref

monitoring may vary.


7. Peak delayed in patients who have compromised renal function

8. Usual therapeutic range will be dependent on infection organism,

the patient, and severity of infection. Increases in trough concentrations consistent



Dr: Ahmed Refat &


Hypermeatbolic surgical patients: ↑clearance

↑ dosage requirement

1. These are starting dosages which may exceed manufacturers recommendations and reflect the authors

dosages required to achieve therapeutic serum concentrations

normal renal function. These dosages require monitoring of serum concentrations.

2. In neonates the dosages should be adjusted based on patient response, serum concentrations, and renal


sing intervals should be adjusted based on patient response, serum concentrations, and renal function

5. once daily dosages have been recommended. At a dosage of 6.6 mg/kg/day once a day (q.d.) an average

21.3 mg/l was found (see ref. 20 page 16). Guidelines for dosage regimens and


7. Peak delayed in patients who have compromised renal function

8. Usual therapeutic range will be dependent on infection organism, site of infection,

severity of infection. Increases in trough concentrations consistent





recommendations and reflect the authors

in patients with serious

These dosages require monitoring of serum concentrations.

response, serum concentrations, and renal

sing intervals should be adjusted based on patient response, serum concentrations, and renal function.

6.6 mg/kg/day once a day (q.d.) an average

Guidelines for dosage regimens and

immunological status of

severity of infection. Increases in trough concentrations consistent with tissue


27

VANCOMYCIN :(Fibrantil, Vancocin

USUAL DOSAGE (lV)

- Adults: 20 to 40 mg/kg/day

- Children: 40 to 60 mg/kg/day

- Neonates: 30 mg/kg/day



- Children: given in two to four divided doses/day

- Neonates: given in two divided doses/day

TOXIC ETFECTS

- Hypersensitivity: skin rashes and anaphylaxis

- Ototoxicity

- Phlebitis and pain at site of injection

- Nephrotoxicity(rare)


- ~20 to 30 hours of chronic dosing


- Adults: 4 to 10 hours

- Children: 2 to 3 hours



- renal ˃90 % unchanged in urine

PROTEIN BINDING

- 30 to 55 %


- Peak: 1 hour after the end of intravenous infusion

- Trough: immediately prior to next dose


- Peak: 20 to 40 mg/l {14 to 28 umol/l}

- Trough: 5 to 10 mg/l { 3 to 7umol/l}


- Renal disease may increase serum concentration

Notes:

- Peak delayed in patients who have compromised renal fu


Dr: Ahmed Refat &


ancocin)

40 to 60 mg/kg/day



given in two divided doses/day

ypersensitivity: skin rashes and anaphylaxis/ "Red-neck” syndrome/ Chills and fever

Phlebitis and pain at site of injection

~20 to 30 hours of chronic dosing

˃90 % unchanged in urine

Peak: 1 hour after the end of intravenous infusion

Trough: immediately prior to next dose

Peak: 20 to 40 mg/l {14 to 28 umol/l}

Trough: 5 to 10 mg/l { 3 to 7umol/l}


Renal disease may increase serum concentration

Peak delayed in patients who have compromised renal function




Chills and fever


28

CARBAMAZEPINE (Tegretol):

USUAL DOSAGE (lV)

- Adults: 5 to 25 mg/kg/day orally

trigeminal neuralgia}

- Children: 5to 30 mg/kg/day orally


- given in two to four divided doses depending on patient tolerance

TOXIC ETFECTS

- Diplopia,blurred vision,nystagmus

- Headache,dizziness,ataxia,sedation

- Nausea,vomiting

- Hyponatremia,water intoxication

- Exacerbation of seizure frequency

- Disturbances of heart rhythm and conduction

- Hypersensitivity reaction

Time to peak serum concentration

- Quite variable .usually 4 to 8 after dosing with conventional formulations.usually more than 12

hours after a single dose with sustained release formulatins,in overdosing afte


- After 2 to 6 days of chronic oral dosing


- 6 to 25 hours {chronic dosing}


- ~99% by hepatic metabolism

- ~1%execreted unchanged in urine

- The active 10,11-epoxide metabolite may

PROTEIN BINDING

- 65 to 80 %


- Chronic oral dosing :trough immediately before next dose


- 4 to 11 mg/l{17 to 47 umol/l}


Disease

- Hepatic: ↓ clearance

Other

- Children: ↑ clearance / -

- Pregnancy: ↑ clearance

Drug interactions:

- Cimetidine, danazol, diltiazem,

- Fluoxeline, fluvoxamine ,

- Isoniazid,macrolide antibiotics,

- propoxyphene, verapamril,

- viloxazine

- Activated charcoaL (used in

- Barbiturates, felbamate,phenytoin

- Valproic acid, Valpromide:


Dr: Ahmed Refat &


5 to 25 mg/kg/day orally {anticonvulsant}/ 3 to 20 mg/kg/day orally

5to 30 mg/kg/day orally {anticonvulsant}

given in two to four divided doses depending on patient tolerance

Diplopia,blurred vision,nystagmus

Headache,dizziness,ataxia,sedation

Hyponatremia,water intoxication

Exacerbation of seizure frequency

rhythm and conduction

Quite variable .usually 4 to 8 after dosing with conventional formulations.usually more than 12

hours after a single dose with sustained release formulatins,in overdosing afte

After 2 to 6 days of chronic oral dosing

hours {chronic dosing}

~99% by hepatic metabolism

~1%execreted unchanged in urine

epoxide metabolite may contribute to therapeutic and toxic effects

Chronic oral dosing :trough immediately before next dose

4 to 11 mg/l{17 to 47 umol/l}


Old age: ↓clearance

Cimetidine, danazol, diltiazem,

Isoniazid,macrolide antibiotics, ↓clearance

propoxyphene, verapamril,

Activated charcoaL (used inncases of toxicity or overdose): ↑ clearance by

Barbiturates, felbamate,phenytoin : ↑ clearance

: ↑ level of 10,11-epoxide metabolite




3 to 20 mg/kg/day orally {treatment of

Quite variable .usually 4 to 8 after dosing with conventional formulations.usually more than 12

hours after a single dose with sustained release formulatins,in overdosing after 24 hours

contribute to therapeutic and toxic effects

by ↓absorpRon


29

Notes:

1. Patients receiving concurrent treatment with barbiturates or

compared to patients on monotherapy. Treatment should be initiated with a low

one -fourth of the maintenance

doses are achieved in approximately 3 to 4 weeks.

epilepticus.

2. Sustained release formulations may a low prolongation of

3. Skin rashes are common (about 10 %). rare hypersensitivity or

lymphadenopathy, blood dyscrasias, hepatotoxicity, pneumonitis. Taken during

may increase the rate of congenital

4. At initiation of treatment. Serum drug levels may decrease

necessitating follow-up levels to verify stabilization of serum concentration.

5. Half lives are much longer (15 t0 50 hours) after a single d

children than in adults.

6. Serum drug levels may fluctuate markedly. An additional sample at time of peak may provide useful

information in some patients.

7. Lower concentrations are usually adequate for

8. Carbamazepine is an enzyme inducer and may stimulate the

such as valproic acid, cyclosporin, glucocorticoids, oral anticoagulants and

likelihood that enzyme induction

necessitate eventual dosage reduction 0f these concurrent drugs.


Dr: Ahmed Refat &


Patients receiving concurrent treatment with barbiturates or phenytoin generally require larger dosages

n monotherapy. Treatment should be initiated with a low dose, usually one

fourth of the maintenance dose,and lncreased gradually by about 25 % on a weekly basis

doses are achieved in approximately 3 to 4 weeks. Abrupt discontinuation of treatment may result in status

2. Sustained release formulations may a low prolongation of dosing interval.

3. Skin rashes are common (about 10 %). rare hypersensitivity or idiosyncratic reactions may include fever,

blood dyscrasias, hepatotoxicity, pneumonitis. Taken during pregnancy,

may increase the rate of congenital malformations.

4. At initiation of treatment. Serum drug levels may decrease after 1 To 3 weeks due to autoinduction,

up levels to verify stabilization of serum concentration.

5. Half lives are much longer (15 t0 50 hours) after a single dose in non-induced state. Half


7. Lower concentrations are usually adequate for trigeminal neuralgia or other neuropathic syndromes.

. Carbamazepine is an enzyme inducer and may stimulate the metabolism of concurrently administered drugs

acid, cyclosporin, glucocorticoids, oral anticoagulants and steroid oral contra

likelihood that enzyme induction will gradually decrease following carbamazepine discontinuation

necessitate eventual dosage reduction 0f these concurrent drugs.




phenytoin generally require larger dosages

dose, usually one-third to

lncreased gradually by about 25 % on a weekly basis so that full

Abrupt discontinuation of treatment may result in status

idiosyncratic reactions may include fever,

pregnancy, carbamazepine

after 1 To 3 weeks due to autoinduction,

induced state. Half-lives are shorter in


trigeminal neuralgia or other neuropathic syndromes.

metabolism of concurrently administered drugs

steroid oral contraceptives. The

will gradually decrease following carbamazepine discontinuation may


30

PHENOBARBITAL (Phenobarbitone

USUAL DOSAGE


- Children: 2 to 5 mg/kg/day orally


- May be given as once daily dose at bedtime

TOXIC ETFECTS

- Sedation,tiredness,fatigue,confusion

- Cognitive impairment,depression

- Irritability,hyperactivity(in children)

- Vitamin D deficiency

- Ataxia,dysarthria

- Exacerbation of seizure frequency

- Decreased libido,impotence

- Dupuytren,s contraction,shoulder stiffness

- Hypersensitivity reactions


- Variable usually 1 to 3 hours after


- Adults and adolescents: 10 to 25 days of chronic oral dosing

- Infants and children: 8 to 20 days of chronic oral dosing


- Adults: ~100 hours(range 50 to 150)

- Infants and children: ~ 65 hours(range

- Newborns: 60 to 200 hours


- ~70% by hepatic metabolism

- 20 to 40%execreted unchanged in urine

- No active metabolites

PROTEIN BINDING

- ~50%


- Due to the long half life, fluctuations in serum drug concentration

negligible. However, when making comparative measurements, it is advisable that

time be consistent.


- 10 to 40 mg/l {43 to 172 umol/l}


Disease

- Hepatic impairment will decrease metabolism

- Moderate to severe renal impairment will decrease clearance of unchanged drug

Other

- Neonates: ↓ clearance

- Children: ↑ clearance


- Urine alkalinization: ↑clearance


Dr: Ahmed Refat &


henobarbitone):

1 to 4 mg/kg/day orally

to 5 mg/kg/day orally

May be given as once daily dose at bedtime

Sedation,tiredness,fatigue,confusion

Cognitive impairment,depression

y(in children)

Exacerbation of seizure frequency

Decreased libido,impotence

Dupuytren,s contraction,shoulder stiffness

Variable usually 1 to 3 hours after dosing



~100 hours(range 50 to 150)

~ 65 hours(range 40 to 130)

~70% by hepatic metabolism

20 to 40%execreted unchanged in urine

Due to the long half life, fluctuations in serum drug concentration at steady state are usually

when making comparative measurements, it is advisable that

{43 to 172 umol/l}


Hepatic impairment will decrease metabolism

Moderate to severe renal impairment will decrease clearance of unchanged drug

↑clearance




at steady state are usually

when making comparative measurements, it is advisable that the sampling

Moderate to severe renal impairment will decrease clearance of unchanged drug


31

Drug interactions:

- chloramphenicol,dextropro

- dicoumarol,furosemide,methsuximide,

- methylphenidate,phenytoin,

- sulthiame,valproic acid

- Activated charcoal: ↑ clearance by

Notes:

1. Phenobarbital may also be used intravenously for the treatment

scheme involves a loading dose at a rate not exceeding 100 mg/min until seizures stop

mg/kg is administered. lf seizures continue, infusion can be continued at a rate of 50 mg/min until a total

dose of 20 mg/kg is reached. Sedation and respiratory

and adequate support facilities should be readily available.

2. Hypersensitivity reactions are relatively rare and may include

pregnancy, Phenobarbital may increase the rate 0f congenital malformations.

3. Longer half-lives are observed in premature newborns.

4. Some patients may be controlled at lower concentrations.

phenobarbital, chronically treated patients may tolerate, without major adverse effects, serum drug

concentrations which would be very toxic upon acute exposure. To minimi

treatment should be started at a low dosage whenever

discontinuation of treatment may result in status epilepticus.

5. Phenobarbital is present in serum of patients treated with primidone, methylphenobarbital (mephobarbital)

and eterobarbital.

6. Phenobarbital is an enzyme inducer and may stimulate the

such as valproic acid, carbamazepine, cyc

contraceptives. The likelihood that enzyme induction will gradually decrease following Phenobarbital

discontinuation may necessitate eventual dosage reduc


Dr: Ahmed Refat &


- poxyphene ,

dicoumarol,furosemide,methsuximide, ↓clearnce

methylphenidate,phenytoin,

↑ clearance by ↓absorpRon

Phenobarbital may also be used intravenously for the treatment of status epilepticus. A possible dosing

dose at a rate not exceeding 100 mg/min until seizures stop


dose of 20 mg/kg is reached. Sedation and respiratory depression occur frequently with intravenous doses

facilities should be readily available.

2. Hypersensitivity reactions are relatively rare and may include rashes, fever and eosinophilia. Taken during

may increase the rate 0f congenital malformations.

rved in premature newborns.

4. Some patients may be controlled at lower concentrations. Since tolerance develops to the sedative effects 0f


hich would be very toxic upon acute exposure. To minimize

treatment should be started at a low dosage whenever possible and titrated upwards. Abrupt

may result in status epilepticus.

present in serum of patients treated with primidone, methylphenobarbital (mephobarbital)

6. Phenobarbital is an enzyme inducer and may stimulate the metabolism of concurrently administered drugs

such as valproic acid, carbamazepine, cyclosporine, glucocorticoids, oral anticoagulants, and steroid oral


cessitate eventual dosage reduction of these concurrent drugs.




of status epilepticus. A possible dosing

dose at a rate not exceeding 100 mg/min until seizures stop or a total dose of 10


depression occur frequently with intravenous doses

rashes, fever and eosinophilia. Taken during

Since tolerance develops to the sedative effects 0f


ze initial adverse effects,

possible and titrated upwards. Abrupt

present in serum of patients treated with primidone, methylphenobarbital (mephobarbital)

metabolism of concurrently administered drugs

losporine, glucocorticoids, oral anticoagulants, and steroid oral


tion of these concurrent drugs.


32

PHENYTOIN (Dilantin, Epanutin

USUAL DOSAGE




- Adults: 1 or 2 daily doses formulation

- Children: 2 to 3 divided oral doses

TOXIC EFFECTS

- Nystagmus. dysarthria. diplopia, ataxia

- Cognitive dysfunction , behavioural problems

- Exacerbation of seiuzure frequency

- Encephalopathy

- Folate and vitamin D deficiency

- Coarse features, hirsutism, acne, gum hypertrophy . Hypersensitivity reactions


- Usually 2 to 6 hours after oral dosing

- With sustained release formulations,peak may occur 3 to 9 hours(or even later) after dosi


- Phenytoin exhibits dose-dependent kinetics and the time to reach steady state increases with

increasing serum concentrations,

oral dosing

ELIMINATION CHARACTERISTICS

- The term half life is not a useful parameter with druqs that

pharmacokinetics. More useful terms

concentration at which rate of metabolism is half of its maximal rate (K

- Vmax 100 to 1000 mg/day

- Km 1 ro 15 mg/l (4 ro 59 umol/l)


- More than 95% by hepatic metabolism

- Less than 5%execreted unchanged in urine

- No active metabolites

PROTEIN BINDING

- ~92%


- Due to slow oral absorption and

state are usually relatively small;

advisable that sampling time be consistent (ideally: trough level)


- Adults, children, infants˃ 3months:

- Preterm,term neonates and


Disease

- Mononucleosis: ↑clearance

- Chronic liver disease: ↓ clearance

- Renal disease: see note 4

Other

- Neonates: ↓Clearance


Dr: Ahmed Refat &


panutin)


to 9 mg/kg/day orally

1 or 2 daily doses formulation

2 to 3 divided oral doses dependent

Nystagmus. dysarthria. diplopia, ataxia

Cognitive dysfunction , behavioural problems probably serum level related

Exacerbation of seiuzure frequency

n D deficiency

Coarse features, hirsutism, acne, gum hypertrophy . Hypersensitivity reactions

Usually 2 to 6 hours after oral dosing

With sustained release formulations,peak may occur 3 to 9 hours(or even later) after dosi

dependent kinetics and the time to reach steady state increases with

increasing serum concentrations, usually steady state is achieved after 4 to 24 days of chronic

The term half life is not a useful parameter with druqs that exhibit dose dependent

pharmacokinetics. More useful terms would be maximal rate of metabolism (V

at which rate of metabolism is half of its maximal rate (Km):

1 ro 15 mg/l (4 ro 59 umol/l)

More than 95% by hepatic metabolism

Less than 5%execreted unchanged in urine

Due to slow oral absorption and elimination ,fluctuation in serum drug concentration at steady

ually relatively small; however ,hen making comparative measurements,it is

advisable that sampling time be consistent (ideally: trough level)

3months: 10 to 20 mg/l (40 to 80 umol/l)

m,term neonates and Infants 2 weeks to 3months: 6 to 14 mg/l ( 24 to 55 umol/l)

AFFECTING SERUM CONCENTRATIONS

↑clearance

↓ clearance




level related

Coarse features, hirsutism, acne, gum hypertrophy . Hypersensitivity reactions

With sustained release formulations,peak may occur 3 to 9 hours(or even later) after dosing

dependent kinetics and the time to reach steady state increases with

usually steady state is achieved after 4 to 24 days of chronic

exhibit dose dependent

would be maximal rate of metabolism (Vmax) and

elimination ,fluctuation in serum drug concentration at steady

however ,hen making comparative measurements,it is

( 24 to 55 umol/l)


33



- Urine alkalinization: ↑clearance

Drug interactions:

- Some antacids,antineoplastics,nasogastric feeding formulas,activated charcoal,and

may reduce phenytoin absorption

- Some drugs may displace phenytoin from protein binding sites in serum,usually this results in a

decrease in total serum phenytoin concentration without change in free

concentration.relationship between total serum

- Phenylbutazone ,valproic acid,and sulfonamides may increase free phenytoin

concentration{these drugs displace phenytoin from serum binding sites and may inhibit

phenytoin metabolism}

- Vigabatrin,folic acid ,and rifampicin may decrease serum phenytoin levels

- Amiodarone,chloramphenicol,cimitidine,dextropropoxyphene,felbamate,isoniazid,methsuximid

e,methylphenidate,some phenothiazines,sulthiame,and several other drugs may increase serum

phenytoin concentration

- PhenobarbitaI may cause a transient increase d

decrease due to enzyme induction

Notes:

1. Phenytoin js usually started at a low dosage and increased

response is required loading doses may be given.

linear relationship between sodium salt and free acid(10% dosage difference),may cause

disproportionately large increase in serum drug concentration.

in status epilepticus. phennytoin may also be used intravenously for the treatment of status epilipticus.a

possible dosing scheme involves a loading dose of 18 mg/kg at a rate not exceeding 50mg/min.hypotention

and a systole may occur and adequate support facilities should be readily available.diazepam or lorazepam

are usually combined with phenytoin in the treatment of status epilepticus.intravenous maintainance doses

of phenytoin should be given in two to three divided daily dos

2. Hypersensitivity reactions are relatively rare and may include

Lymphadenopathy systemic lupus erythematosus,

pregnancy, phenytoin may increase the rate of congenita

3. For practical purposes, however,

cases,the longest values being recorded at high serum

range from 10 to 30 hours at concentration between 10 and 20 mg/l{shorter or higher values are recorded

at concentrations below or above this range respectively}

4.binding to serum proteins may decrease in conditions associated withy hypoalbuminemia

{malnutrition,nephritic syndrome

displacing agents {hyperbilirubinemia,uremia}.

salicylates, sulfonylureas and most notably,valproic acid may also displace phenytoin

and increase its free fraction.since only the unbound (free)drug is pharmacologically active,in the presence

of decreased binding the total serum phenytoin concentration may underestimate the amount of drug

which is active ,and therapeu

situations,it may be useful to measure the free concentration.a therapeutic range of 1 to 2 mg/l(4 to 8

umol/l)is suggested for free phenytoin

5. some patients may be controlled at low

6.Phenytoin is an enzyme inducer and may stimulate the metabolism of concurrently administered drugs such

as valproic acid,carbamazepines,

contraceptives


Dr: Ahmed Refat &


↑clearance

antacids,antineoplastics,nasogastric feeding formulas,activated charcoal,and

may reduce phenytoin absorption

Some drugs may displace phenytoin from protein binding sites in serum,usually this results in a


concentration.relationship between total serum concentration and response will be altered.

Phenylbutazone ,valproic acid,and sulfonamides may increase free phenytoin


rifampicin may decrease serum phenytoin levels

Amiodarone,chloramphenicol,cimitidine,dextropropoxyphene,felbamate,isoniazid,methsuximid


arbitaI may cause a transient increase due to competitive jnhibition of metabolism or a

decrease due to enzyme induction

1. Phenytoin js usually started at a low dosage and increased graduall y according to clinical response. if rapid

required loading doses may be given. dosage adjustment should be cautions due to the non


disproportionately large increase in serum drug concentration. abrupt withdrawal of treatment may result

phennytoin may also be used intravenously for the treatment of status epilipticus.a


occur and adequate support facilities should be readily available.diazepam or lorazepam


of phenytoin should be given in two to three divided daily doses

2. Hypersensitivity reactions are relatively rare and may include; Skin rashes, fever and eosinophilia.

systemic lupus erythematosus, hepatotoxicity, blood dyscrasias.

phenytoin may increase the rate of congenital malformations.

however, it can be estimated that half lives range from 20 to 100 hours in most

cases,the longest values being recorded at high serum concentrations. In infants and children,half

at concentration between 10 and 20 mg/l{shorter or higher values are recorded

at concentrations below or above this range respectively}


{malnutrition,nephritic syndrome,neonates,elderly patients,pregnancy,atc}or accumulation of endogenous

displacing agents {hyperbilirubinemia,uremia}. other drugs such many sulfonamides,

sulfonylureas and most notably,valproic acid may also displace phenytoin



which is active ,and therapeutic and toxic effects will appear at lower total concentration.in these


umol/l)is suggested for free phenytoin

5. some patients may be controlled at lower concentrations .see also note 4

henytoin is an enzyme inducer and may stimulate the metabolism of concurrently administered drugs such

as valproic acid,carbamazepines, cyclosporine, glucucorticoids, oral anticoagulants and steroid oral




antacids,antineoplastics,nasogastric feeding formulas,activated charcoal,and sucralfate

Some drugs may displace phenytoin from protein binding sites in serum,usually this results in a


concentration and response will be altered.

Phenylbutazone ,valproic acid,and sulfonamides may increase free phenytoin


Amiodarone,chloramphenicol,cimitidine,dextropropoxyphene,felbamate,isoniazid,methsuximid


ve jnhibition of metabolism or a

graduall y according to clinical response. if rapid

dosage adjustment should be cautions due to the non-


al of treatment may result

phennytoin may also be used intravenously for the treatment of status epilipticus.a


occur and adequate support facilities should be readily available.diazepam or lorazepam


Skin rashes, fever and eosinophilia.

blood dyscrasias. taken during

it can be estimated that half lives range from 20 to 100 hours in most

concentrations. In infants and children,half-lives

at concentration between 10 and 20 mg/l{shorter or higher values are recorded


,neonates,elderly patients,pregnancy,atc}or accumulation of endogenous

other drugs such many sulfonamides, phenylbutazone,

sulfonylureas and most notably,valproic acid may also displace phenytoin from serum proteins



tic and toxic effects will appear at lower total concentration.in these


henytoin is an enzyme inducer and may stimulate the metabolism of concurrently administered drugs such

oral anticoagulants and steroid oral


34

VALPROIC ACID (Convulex,Depakene,Epilim,O

USUAL DOSAGE




- Given in one to four divided doses

TOXIC EFFECTS

- Gastric irritation,nausea and vomiting

- Weight gain

- Sedation,stupor,tremor

- Thrombocytopenia

- Hepatotoxicity,pancreatitis

- Teratogenicity(neural tube defects)

- Hyperammonemia


- Syrup: 0.5 to1 hour after dosing

- Capsules or plain tablets: 0.5 to 2 hours after dosing

- Enteric coated tablets: 3 to 8 hours after dosing


- After 2 to 4 days of chronic oral dosing


- Adults: 6 to 17 hours

- Infants and children: 5 to 15

- Newborns( ≤ 2months): 15 to 60 hours


- About 95% by hepatic metabolism

- Less than 5%execreted unchanged in urine

- Reactive metabolites may contribute to hepatotoxicity and possibly teratogenicity

PROTEIN BINDING

- ~90%


- Chronic oral dosing: trough immediately before next dose


- 50 to 100 mg/l(347 to 693 umol/l)


Disease

- Hepatic disease: see note 4

- Renal disease: see note 4

- Hypoalbuminemia: see note 4

Other

- Neonates: ↓ clearance


- Pregnancy : ↑ clearance

- Old age: see note4

Drug interactions:

- Activated charcoal, some antacids

- Salicylates: see note 4 &9


Dr: Ahmed Refat &


(Convulex,Depakene,Epilim,Orfiril)



Given in one to four divided doses

astric irritation,nausea and vomiting

eratogenicity(neural tube defects)

dosing

0.5 to 2 hours after dosing

3 to 8 hours after dosing

fter 2 to 4 days of chronic oral dosing

5 to 15 hours

15 to 60 hours

bout 95% by hepatic metabolism

Less than 5%execreted unchanged in urine

Reactive metabolites may contribute to hepatotoxicity and possibly teratogenicity

trough immediately before next dose

50 to 100 mg/l(347 to 693 umol/l)

FACTORS AFFECTING SERUM CONCENTRATIONS

see note 4

some antacids and Some antineoplastics: ↓absorpRon




Reactive metabolites may contribute to hepatotoxicity and possibly teratogenicity


35

- Barbiturates, Phenytoin, Carbamazepine

- Some drugs displace valproic acid f

Notes:

1. Available in several dosage forms ,e.g.valproic acid,sodium valproate,magnesium valproate.treatment is

usually initiated with arelatively low dose and increased gradually.abrupt discontinuation of treatment may

result in status epilepticus

2. Sustained release formulations may allow prolongation of dosing interval.

3. Absorption from enteric coated tablets may be m

4. Protein binding decreases at high serum concentrations Binding mav decrease in conditions associated with

hypoalbuminemia (malnutrition, nephrotic syndrome, neonates,

accumulation of endogenous displacing agents(uremia), and concurrent treatment with displacing

such as salicylates and phenylbutazone . since only the unbound (free)drug is pharmacologically active,

the presence of decreased binding the total serum valproic acid concent

amount of drug high is active,

5. Serum drug levels may fluctuate markedly

information in some patients

6. Valproic acid is the active moiety in the serum of patients treated with divalproex sodium

valpromide (depamide)

7. Some patients with seizures that are difficult to control may benefit from concentration greater than

100mg/l without adverse effects

8. Valproic acid may inhibit the metabolic elimination of Phenobarbital,

epoxide,and lamotrigine. Valproic acid displaces phenytoin from serum protein binding sites. A favourable

(synergistic) pharmacodynamic interaction between ethosuximide and valproic acid may occur in patients

with certain types of absence seizures.

9. Salicylates may inhibit the metabolism of valproic acid in addi

these two mechanisms have opposing effects on total clearance of valproic acid


Dr: Ahmed Refat &


Carbamazepine: ↑clearance

splace valproic acid from serum protein binding sites: see note4

vailable in several dosage forms ,e.g.valproic acid,sodium valproate,magnesium valproate.treatment is

initiated with arelatively low dose and increased gradually.abrupt discontinuation of treatment may

ustained release formulations may allow prolongation of dosing interval.

bsorption from enteric coated tablets may be markedly delayed by food.

rotein binding decreases at high serum concentrations Binding mav decrease in conditions associated with

(malnutrition, nephrotic syndrome, neonates, elderly patients,

us displacing agents(uremia), and concurrent treatment with displacing

such as salicylates and phenylbutazone . since only the unbound (free)drug is pharmacologically active,

the presence of decreased binding the total serum valproic acid concentration may underestimate the

and therapeutic and toxic effects will appear at lower total concentration

g levels may fluctuate markedly an additional sample at time of peak may provide useful

alproic acid is the active moiety in the serum of patients treated with divalproex sodium

ome patients with seizures that are difficult to control may benefit from concentration greater than

out adverse effects.

alproic acid may inhibit the metabolic elimination of Phenobarbital, phenytoin,

alproic acid displaces phenytoin from serum protein binding sites. A favourable

pharmacodynamic interaction between ethosuximide and valproic acid may occur in patients

with certain types of absence seizures. valproic acid may increase serum ethosuximide concentrations

alicylates may inhibit the metabolism of valproic acid in addition to displacing it from protein binding sites.

these two mechanisms have opposing effects on total clearance of valproic acid




see note4

vailable in several dosage forms ,e.g.valproic acid,sodium valproate,magnesium valproate.treatment is

initiated with arelatively low dose and increased gradually.abrupt discontinuation of treatment may

rotein binding decreases at high serum concentrations Binding mav decrease in conditions associated with

elderly patients, Pregnancy, etc.).

us displacing agents(uremia), and concurrent treatment with displacing drugs,

such as salicylates and phenylbutazone . since only the unbound (free)drug is pharmacologically active, in

ration may underestimate the

and therapeutic and toxic effects will appear at lower total concentration

an additional sample at time of peak may provide useful

alproic acid is the active moiety in the serum of patients treated with divalproex sodium (depakote) and

ome patients with seizures that are difficult to control may benefit from concentration greater than

phenytoin, carbamazepine-10,11-

alproic acid displaces phenytoin from serum protein binding sites. A favourable

pharmacodynamic interaction between ethosuximide and valproic acid may occur in patients

valproic acid may increase serum ethosuximide concentrations

tion to displacing it from protein binding sites.


36

METHOTREXATE (Methotrexate LPD,

USUAL DOSAGE

- The dosage for methotrexate is widely varied,

to high dose lV therapy (1

must follow a specific treatment


- Consult specific treatment protocol(see above)

TOXIC EFFECTS

- Nausea and vomiting

- Myelosuppression

- Mucositis

- Renal dysfunction

- Hepatic dysfunction

- Leukoencephalopathy

- Rash


- Approximately 12 to 24 hours of chronic dosing


- 2 to 4 hours,initial half-life

- 8 to 15 hours,terminal half-


- Renal excretion 70- 90 % unchanged

- Renal excretion of methotrexate and 7

- Metabolism up to ~ 30%; major extracellular metabolite

activity; poor solubility in acidic

PROTEIN BINDING

- 50 to 60%


- The sampling times for methotrexate will depend on dose,

0f the patient (consult specific treatment protocol)

of leucovorin rescue doses

USUAl TOXIC RANGE

- A usual therapeutic range for methotrexate has not been defined. The minimum cytotoxic

concentration is ~ 0.01 µmol/l.

- Serum concentrations which have been assoc

high-dose (~ 5 g/m2) infusion. when only low

24 hours ˃5 µmol/l give higher dose of

48 hours ˃ 0.5 µmol/l leucovorin or extend rescue

72 hours˃0.05 µmol/l beyond planned endpoint


Disease

• Renal disease

• Aciduria {urine PH˂6.5} ↓clearance

• Decreased urine flow

• Ascites, pleural effusion,

• GI obstruction


Dr: Ahmed Refat &


Methotrexate LPD, Mexate):

The dosage for methotrexate is widely varied, ranging from low dose oral therapy (~ 20 mg/m

(1-12 g/m2) with leucovorin rescue. Thus, the dosage of

treatment protocol.

Consult specific treatment protocol(see above)

ausea and vomiting

pproximately 12 to 24 hours of chronic dosing

-life

90 % unchanged

enal excretion of methotrexate and 7-hydroxymethotrexate .

etabolism up to ~ 30%; major extracellular metabolite 7-hydroxy methotrexate (lit

vity; poor solubility in acidic urine)

The sampling times for methotrexate will depend on dose, duration of lnfusion and clinical status

specific treatment protocol). These are generally used to

A usual therapeutic range for methotrexate has not been defined. The minimum cytotoxic

µmol/l.

Serum concentrations which have been associated with increased risk of toxicity after a six

infusion. when only low-dose leucovorin rescue is given:

5 µmol/l give higher dose of

0.5 µmol/l leucovorin or extend rescue

0.05 µmol/l beyond planned endpoint


enal disease

˂6.5} ↓clearance

pleural effusion, 3rd

space fluid collection

Prolong serum half




low dose oral therapy (~ 20 mg/m2)

) with leucovorin rescue. Thus, the dosage of Methotrexate

hydroxy methotrexate (little cytotoxic

duration of lnfusion and clinical status

used to guide adjustment

A usual therapeutic range for methotrexate has not been defined. The minimum cytotoxic

toxicity after a six-hour

dose leucovorin rescue is given:

rolong serum half-life


37

• Drugs:

• Nonabsorbable antibiotics

• Concurrent or previous therap w

• Probenecid,salicylates

• NSAIDS.sulfonamides

Notes:

1.”toxicity”assignment is dependent on duration of exposure,

influenced by intensity 0f cumulative exposure prior

leucovorin dosage guidelines based on methotrexate serum concentration see

MethotrexateSerum concentration more than 24 hrs from

beginning of infusion

20 to 50 µmol/l

10 to 20 µmol/l

5 to 10 µmol/l

1 to 5 µmol/l

0.5 to 1 µmol/l

0.1 to 0.5 pmol/l

0.01 to 0.1 µmol/l

2.Methotrexate (MTX) concentrations should be monitored and leucovorin

in”high_risk” patients until serum MTX concentrations are < 0.05 µmol/l. Leucovorin

reduced, as indicated, as MTX serum concentrations decrease


Dr: Ahmed Refat &


Nonabsorbable antibiotics ↓absorpRon

or previous therap with neoplastic drugs

benecid,salicylates ↓clearance

NSAIDS.sulfonamides

1.”toxicity”assignment is dependent on duration of exposure, as well as serum concentration. and is probably

intensity 0f cumulative exposure prior to measured points and beyond measured points. For

based on methotrexate serum concentration see next table.

Methotrexate erum concentration more than 24 hrs from

beginning of infusion

LeucovorinApproximate dose required

20 to 50 µmol/l 500 mg/m2 lV Q 6 hours



1 to 5 µmol/l 30 mg/m2 lV or PO Q 6 hours

to 1 µmol/l 15 mg/m2 PO Q 6 hours

pmol/l 15 mg/m2 PO Q 12 hours

µmol/l 5to 10 mg/m2 PO Q 12 hours

Methotrexate (MTX) concentrations should be monitored and leucovorin administration should be continued

until serum MTX concentrations are < 0.05 µmol/l. Leucovorin

MTX serum concentrations decrease




↓absorpRon

ith neoplastic drugs

as well as serum concentration. and is probably

beyond measured points. For

next table.

Leucovorin

pproximate dose required

lV or PO Q 6 hours

PO Q 12 hours

administration should be continued

until serum MTX concentrations are < 0.05 µmol/l. Leucovorin dosages may be


38

THEOPHYLLINE (Aminophylline,T

USUAL DOSAGE

Loading dosage

• No prior theophylline administration

• Prior theophylline administration,

in an Emergency without symptoms of Intoxication

Maintenance dosage

• Adults(healthy nonsmokers)

• Adults(smokers)

• Adults(cardiac decompensation a

• Children(˃9 years;healthy)

• Children(1 to 9 years)

• Infants(4 to 52 weeks)

• Neonates

Chronic dosage

• Adults(healthy nonsmokers)

• Adults(smokers)

• Adults(cardiac decompensation a

• Adolescents(12 to 16 years)



• Infants(6 to 51 weeks)

• Neonates(premature or normal)


- Intravenous

- Loading doses 0f theophylline should be infused over 30 min .

- Maintenance doses of theophylline should be calculated for a

adriinistered as a continous intravenous

- Oral therapy

- Dosing intervals will vary dependent upon product formulation,

elimination rate. ln case of chronic

- However, the following will provide guidelines for dosage intervals

Total daily dosage

Rapid Release

Sustained Release: Children

Adults

TOXIC EFFECTS

- Nausea , vomiting ,diarrhea,insomnia,headache

- Irritability,nervousness


Dr: Ahmed Refat &


(Aminophylline,Theo-dur,theo 24):

oading dosage Theophylline dosage

administration In previous 24 hours 5 mg/kg IV over 30 min

Prior theophylline administration, Obtain serum concentration;

Emergency without symptoms of Intoxication.

2mg/kg IV over 30 min

dosage Theophylline

Infusion Rate (mg/kg/hour)

Adults(healthy nonsmokers) 0.4

Adults(smokers) 0.6

(cardiac decompensation and/or liver dysfunction 0.2

0.7

0.8

0.008

Neonates 0.13

dosage Theophylline dosage

Adults(healthy nonsmokers) 10

Adults(smokers) 15

(cardiac decompensation and/or liver dysfunction 4

Adolescents(12 to 16 years) 18

Children(9 to 12 years) 20

Children(1 to 9 years) 24

Infants(6 to 51 weeks) 0.3

Neonates(premature or normal) 3.0

0f theophylline should be infused over 30 min .

of theophylline should be calculated for a 24 hour period and then

adriinistered as a continous intravenous infusion starting 30 to 60 min after loading dose

Dosing intervals will vary dependent upon product formulation, age of patient, and

elimination rate. ln case of chronic dosage sustained release formulations are commonly used.

, the following will provide guidelines for dosage intervals

Given in divided Doses

elease 3 to 4

Adults

2 to 3

1 to 2

ausea , vomiting ,diarrhea,insomnia,headache

rritability,nervousness




Theophylline dosage

5 mg/kg IV over 30 min

2mg/kg IV over 30 min

Theophylline Infusion Rate (mg/kg/hour)

0.4

0.6

0.2

0.7

0.8

0.008 (age in weeks+0.021)

0.13

Theophylline dosage

10-15

15-18

4-8

18

20

24

0.3 (age in weeks+8)

3.0

24 hour period and then

infusion starting 30 to 60 min after loading dose

age of patient, and patients

dosage sustained release formulations are commonly used.

Given in divided Doses


39

- Seizures,sinus tachycardia,


- This is dependent upon product formulation, since sustained

prolonged time to "peak", compared to conventional products (about 3 to 8 hours longer)


- Adults: ~2 to 3 days of chronic oral dosing

- Children: ~1 to 2 days of chronic oral dosing

- Infants: ~1 to 5 days of chronic oral dosing

- Newborn: ~120 hours of chronic oral dosing

- Premature neonates: ~150 hours of chronic oral dosing

RATE OF ELIMINATION

- Adults(healthy ,nonsmokers)

- Adults(healthy,smokers)

- Adults(liver cirrhosis): 10 to 56 hours

- Children: 4 hours(range 2 to 10)

- Infants(4 to 52 weeks):

- Neonates:

• Premature: 30 hours

• Normal newborn

RATE OF ELIMINATION

- Hepatic metabolism th

metabolite in newborn

- Renal excretion of less than 10% unchanged drug (greater in newborn)

PROTEIN BINDING

- 55 to 66% (healthy adults)

- ~36%(neonates,adults with liver


- Intravenous

• Prior to intravenous infusion .

• 30 min after completion of loading dose to measure adequacy of dose .

• 4 to 6 hours after beginning continous infusion therapy (presteady state but used

to establish trend) or befor

- Oral, Peak

• 2 hours after administration of a product with rapid release properties

• 4 to 8 hours after administration of a product with sustained release properties

- Oral, Trough

• Immediately


- Asthma (bronchodilator)8 to 20 mg/l

- Neonatal apnea 6 to 11 mg/l


• Disease

• Fever associated with upper

• Cor pulmonale

• Acute pulmonary edema

• Hepatic cirrhosis

• Cardiac decompensation


Dr: Ahmed Refat &


,sinus tachycardia, cardiac arrhythmias, cerebral hypoxia, cardiorespiratory collapse

This is dependent upon product formulation, since sustained release products have a very


~2 to 3 days of chronic oral dosing



~120 hours of chronic oral dosing

~150 hours of chronic oral dosing

,nonsmokers): 9hours(range 3 to 12)

Adults(healthy,smokers): 4 hours

10 to 56 hours

4 hours(range 2 to 10)

: 3 to 14 hours

30 hours

ormal newborn: 24 hours

the renal execresion of relatively inactive metabolites,

metabolite in newborn

of less than 10% unchanged drug (greater in newborn)

55 to 66% (healthy adults)

~36%(neonates,adults with liver cirrhosis)

Prior to intravenous infusion .

30 min after completion of loading dose to measure adequacy of dose .

6 hours after beginning continous infusion therapy (presteady state but used

to establish trend) or before next infusion

hours after administration of a product with rapid release properties

to 8 hours after administration of a product with sustained release properties

before next oral dose

(bronchodilator)8 to 20 mg/l: (44 to 111 µmol/l)

apnea 6 to 11 mg/l: (33 to 61 µmol/l)


ever associated with upper respiratory illness

pulmonale

Acute pulmonary edema ↓clearance

Cardiac decompensation




cardiorespiratory collapse

release products have a very


relatively inactive metabolites, caffeine is a

30 min after completion of loading dose to measure adequacy of dose .

6 hours after beginning continous infusion therapy (presteady state but used

hours after administration of a product with rapid release properties

to 8 hours after administration of a product with sustained release properties


40

• Drugs:

• Erythromycin .

• Cimetidine

• Ciprofloxacin

• Enoxacin .

• Verapamil

• Allopurinol .

• Aminoglutethimide

• Carbamazepine .

• Phenobarbital

• phenytoin

• Rifampicin

• Other

• Smoking: ↑clearance

• Age (Neonates): ↓clearance

• Age (> 60 years): ↓clearance

Notes:

1. Aminophylline contains ~ 80 % theophylline.

2. At a relative constant Vd 0f 0.5 l/kg lean body weight or moderate

mg/kg -2 mg/l

3. maintenance dosage should be al

loading dose. Lf additional loading dose is required, administer necessary dose and redraw serum sample.

Further dosage adjustment (maintenance or chronic dosages) should be made with se

results as a guide. Clearance of theophylline in an adult, healthy nonsmoker is 0.04 l/kg/hour. To achieve a

concentration of 10 mg/|, dosage of 0.4 mg/kg/hour is reasonable.

4. This dosage of theophylline is intended only as a guide.

based upon theophylline serum concentration data. A dosage not

immediately discontinued.

5. Within the therapeutic range the probability of toxic effects is

probability and values > 35 mg/l have high probability of toxic effects.

6. This time is decreased in smokers and increased in patients

may be increased in children near upper end of ther

metabolism 0ccurs.

7. Morning trough levels may be greater than evening levels.


Dr: Ahmed Refat &


Ciprofloxacin ↓clearance

Phenobarbital ↑clearance

↓clearance

↓clearance

1. Aminophylline contains ~ 80 % theophylline.

2. At a relative constant Vd 0f 0.5 l/kg lean body weight or moderate obesity the following relation is valid: 1

3. maintenance dosage should be altered based on serum concentration data determined at the end of this


Further dosage adjustment (maintenance or chronic dosages) should be made with se


concentration of 10 mg/|, dosage of 0.4 mg/kg/hour is reasonable.

4. This dosage of theophylline is intended only as a guide. Increases or decreases in the dosage should be made

upon theophylline serum concentration data. A dosage not tolerated by any patient sh

5. Within the therapeutic range the probability of toxic effects is < 5 %. Values >

> 35 mg/l have high probability of toxic effects.

6. This time is decreased in smokers and increased in patients with cardiac decompensation of hepatic failure.

increased in children near upper end of therapeutic range (e.g., > 15 mg/l) if saturation of

7. Morning trough levels may be greater than evening levels.




obesity the following relation is valid: 1

data determined at the end of this


Further dosage adjustment (maintenance or chronic dosages) should be made with serum concentration


reases or decreases in the dosage should be made

tolerated by any patient should be

< 5 %. Values > 20 mg/l have higher

with cardiac decompensation of hepatic failure.

(e.g., > 15 mg/l) if saturation of


41

DOGOXIN (Lanoxin):

USUAL DOSAGE

- Loading dosage (rapid digitalizing)

Oral

• Adults and children > 10 years

• Children (2 to 10 years):

• infants (1 to 24 months):

• Neonates (0 to 4 weeks):

• Administer in 3 to 4 divided doses over 24 hours

- Intravenous

• Use approximately 0.8 x the oral loading dose.

30 minutes (at least 4 hour inter

the first or second dose; use the actual amount administered to calculate the maintenance

dose

- Maintenance dosage

• Adults

-Normal renal function

-Renal failure: see note 2 and table below


• Infants(1 to 24 months):

• Neonates(0 to 4 weeks):

• Adjust on the basis of the final loading dose and estimated renal

fibrillation, on the basis of heart rate.

clearance, are shown in the table below:

Creatinine clearance(ml/min)

100

50

25

10

0


• Once daily for adult patients receiving

0.25 mg/day. Divide the dose

• If there are gastrointestinal side effects, such as nausea, anorexia

• Divide the dose into 2 or 3 daily doses for paediatric patients

TOXIC EFFECTS

• Caraiac:

- Ventricular dysrhythmias, including multifocal PVC, ventricular tachycardia

- A V block, accelerated A

- Sinus bradycardia or complete SA block

- Atrial fibrillation with slow ventricular rate .

• Gastrointestinal:

- Anorexia, nausea, vomiting, diarrhea

• Neuroiogical:

- Headache, fatigue, malaise, disturbance of color vision


• Intravenous:


Dr: Ahmed Refat &


(rapid digitalizing)

Adults and children > 10 years: 12 to 20 µg/kg

o 10 years): 10 to 40 µg/kg

onths): 20 to 40 µg /kg

Neonates (0 to 4 weeks): 20 to 30 µg/kg

Administer in 3 to 4 divided doses over 24 hours

Use approximately 0.8 x the oral loading dose. Administer in 3 to 4 divided doses over 5 to

minutes (at least 4 hour intervals). 0mit doses if these are signs of digoxin toxicity after

first or second dose; use the actual amount administered to calculate the maintenance

ormal renal function: 125 to 500 µg/day PO

see note 2 and table below

Children(2 to 10 years): 8 to 10 µg/kg/day PO

Infants(1 to 24 months): 14 to 18 µg/kg/day PO

Neonates(0 to 4 weeks): 8 to 10 µg/kg/day PO

Adjust on the basis of the final loading dose and estimated renal function and, in atrial

fibrillation, on the basis of heart rate. Suggested maintenance doses, based on creatinine

are shown in the table below:

reatinine clearance(ml/min) Fraction of loading dose

0.33

0.25

0.20

0.16

0.14

nce daily for adult patients receiving < 0.2S mg/day and twice daily for patients receiving >

0.25 mg/day. Divide the dose

f there are gastrointestinal side effects, such as nausea, anorexia or dianhea.

the dose into 2 or 3 daily doses for paediatric patients

dysrhythmias, including multifocal PVC, ventricular tachycardia

A V block, accelerated A-V junctional rhythms.

Sinus bradycardia or complete SA block.

Atrial fibrillation with slow ventricular rate .

Anorexia, nausea, vomiting, diarrhea

, fatigue, malaise, disturbance of color vision




3 to 4 divided doses over 5 to

vals). 0mit doses if these are signs of digoxin toxicity after

first or second dose; use the actual amount administered to calculate the maintenance

function and, in atrial

doses, based on creatinine

raction of loading dose

daily for patients receiving >

or dianhea.

dysrhythmias, including multifocal PVC, ventricular tachycardia.


42

Peak concentration is usually reached immediately after

does not accurately reflect tissue digoxin concentration and thus pharmacological effect

(see usual sampling times).

• Oral:

Peak concentration following oral therapy is usually reached

ln 60 to 90 minutes after administration (see also above,


• Normal renal function: ~ 5 to 7 days of chronic dosing

• Reduced renal function: ~


• Adults mean 40 hours, range 20 to 50 hours

• Premature neonates 56 to 88 hours .

• Full term neonates 35 to 42 hours .

• lnfants 18 to 33 hours .

• Children ~ 12 to 24 hours


• Renal 75 to 80 % excreted unchanged .

• Hepatic ~ 30 % (may be increased substantially in patients

PROTEIN BINDING

• ~20%


• 8 to24 hours after dose administered(better correlation of serum and tissue concentrations)


• 0.8 to 2.0 µg/l (1.0 to 2.6 nmol/l)


Disease

• renal disease

• Sever,uncompensated heart failure

Drugs:

• Spironolactone

• Liquid antacids and kaolin

• Quinidine, amiodarone

Notes:

1. The preferred method of administering the loading dose is

loading dose by this route. lntravenous loading is generally reserved for patients

with life-threatening tachyarrhythmias responsive to the

patient and renal function. For patients with severe renal impairment

of the range to compensate for a reduction in the volume 0f distribution.

digitalizing is not necessary and treatment is started with the maintenance dose.

2. ln adults with renal failure, maintenance dose regimen should

3.The dosing intervals listed are only guidelines. Each patient

based on age, clinical response, and renal function.

4. For serum concentrations to best reflect cardiac activity, serum

equilibrium between serum and tissue. The time t

8 to 12 hours.

5. Depends on renal function e.g., up to 120 hours in renal failure.

6. There are other factors which do not affect digoxin serum concentrations,

effect of digoxin, for example hypokalemia, hypomagnesemia, hypercalcemia,

These may act by affecting myocardial

tablets. The user is referred to pharmacology tex

7. Acetyldigoxin is rapidly and totally converted to digoxin.

equivalent dose of diqoxin.

8. Bioavailability of digoxin products is highly variable (70 to


Dr: Ahmed Refat &


Peak concentration is usually reached immediately after administration. However, this

curately reflect tissue digoxin concentration and thus pharmacological effect

(see usual sampling times).

Peak concentration following oral therapy is usually reached

ln 60 to 90 minutes after administration (see also above, intravenous).

5 to 7 days of chronic dosing

~ Greater than 7 days,depending upon degree of reduction

Adults mean 40 hours, range 20 to 50 hours

Premature neonates 56 to 88 hours .

Full term neonates 35 to 42 hours .

Renal 75 to 80 % excreted unchanged .

Hepatic ~ 30 % (may be increased substantially in patients with renal impairment)

8 to24 hours after dose administered(better correlation of serum and tissue concentrations)

0.8 to 2.0 µg/l (1.0 to 2.6 nmol/l)


Sever,uncompensated heart failure

↓clearance

Spironolactone

Liquid antacids and kaolin-pectin preparations ↓absorpRon

uinidine, amiodarone: ↑serum concentraRon

method of administering the loading dose is orally, and the majority of patients receive their

by this route. lntravenous loading is generally reserved for patients

threatening tachyarrhythmias responsive to the drug. The dose varies, depending upon the age of the

and renal function. For patients with severe renal impairment chose a loading dose at the low end

for a reduction in the volume 0f distribution. ln most clinical situations rapid

and treatment is started with the maintenance dose.

2. ln adults with renal failure, maintenance dose regimen should be adjusted to individual patient requirments.

3.The dosing intervals listed are only guidelines. Each patient should have a dosing interval selected individually

age, clinical response, and renal function.

4. For serum concentrations to best reflect cardiac activity, serum samples should be taken when digoxin is in

serum and tissue. The time to equilibrium following either oral or lV digoxin is usually

5. Depends on renal function e.g., up to 120 hours in renal failure.

6. There are other factors which do not affect digoxin serum concentrations, but do affect the pharmacological

for example hypokalemia, hypomagnesemia, hypercalcemia, and acid

These may act by affecting myocardial sensitivity to digoxin or by affecting the oral absorption of digx

tablets. The user is referred to pharmacology texts for fulI lists of these factors.

7. Acetyldigoxin is rapidly and totally converted to digoxin. Methyldigoxin is converted to about 50 % of an

8. Bioavailability of digoxin products is highly variable (70 to 100 %) depending on the formulation.




administration. However, this

curately reflect tissue digoxin concentration and thus pharmacological effect

intravenous).

reater than 7 days,depending upon degree of reduction

with renal impairment)

8 to24 hours after dose administered(better correlation of serum and tissue concentrations)

↓clearance

orally, and the majority of patients receive their

, depending upon the age of the

chose a loading dose at the low end

ln most clinical situations rapid

be adjusted to individual patient requirments.

ave a dosing interval selected individually

samples should be taken when digoxin is in

oral or lV digoxin is usually

but do affect the pharmacological

and acid- base balance.

ting the oral absorption of digxxin

Methyldigoxin is converted to about 50 % of an

n the formulation.


43

CYCLOSPORIN A (Sandimmun):

USUAL DOSAGE

• Starting doses: (Monotherapy)10 to 15 mg/kg/day

• Chronic maintenance doses:~2 to 6mg/kg/day

• Autoimmune disease: 2.5 to 5 mg/kg/day


• Adults:once or twice daily

• Children:may require three times daily dosing

TOXIC EFFECTS

• Renal dysfunction/raised serum creatinine .

• Hepatic impairment, hypertension , hypomagnesaemia .

• Hypertrichosis, gum hyperplasia


• ~3 hours after oral adminstration


• 3 to 5 days of chronic dosing


• Adults: 15 hours(range 4 to 50).

• Children: 9 hours(range 3 to 20)


• Hepatic: ˃90% excreted in bile,

• Renal: ~ 6 % ˂0.1 % as unchanged drug

• Major metabolites: AM1,AM4N,AM9

PROTEIN BINDING

• 98 to 99 %


• Pre-dose,normally about 12 or 24 hours after the last dose


• induction therapy {approx.

• Maintenance therapy: 100 to 250 µg/l .

• Values refer to whole blood specific measurements.

• Therapeutic range varies dependent upon organ transplanted.


Disease

• Hepatic impairement reduces cyclosporin clearance and prolongs the elimination half

• Diarrhea and inflammatory bowel disorders reduce oral absorption.

Drugs:

• Ketoconazole .

• Erythromycin .

• Diltiazem . ↑

• Verapamil

• Nicardipine .

• rifampicin .

• isoniazlde .

• Phenytoin . ↓

• Phenobarbital .

• Carbamazepine

Notes:

1. Doses vary widely, depending upon the indication for cyclosporin,

co-prescription of other immunosuppressive drugs. lt is common practice for


Dr: Ahmed Refat &


onotherapy)10 to 15 mg/kg/day - (Compination therapy)7 to 10 mg/kg/day

hronic maintenance doses:~2 to 6mg/kg/day

2.5 to 5 mg/kg/day

Adults:once or twice daily

Children:may require three times daily dosing

enal dysfunction/raised serum creatinine .

Hepatic impairment, hypertension , hypomagnesaemia .

Hypertrichosis, gum hyperplasia

~3 hours after oral adminstration

3 to 5 days of chronic dosing

15 hours(range 4 to 50).

9 hours(range 3 to 20)

90% excreted in bile,˂1% as unchanged drug

˂0.1 % as unchanged drug

AM1,AM4N,AM9

dose,normally about 12 or 24 hours after the last dose

therapy {approx. < 3 months after transplantation) 150 to 350 µg/l .

100 to 250 µg/l .

refer to whole blood specific measurements.

range varies dependent upon organ transplanted.


Hepatic impairement reduces cyclosporin clearance and prolongs the elimination half

Diarrhea and inflammatory bowel disorders reduce oral absorption.

↑Cyclosporin concentrations

erapamil

↓Cyclosporin Concentration

Phenobarbital .

Doses vary widely, depending upon the indication for cyclosporin, the time following transplantation and the

of other immunosuppressive drugs. lt is common practice for cyclosporin dosage to be




ompination therapy)7 to 10 mg/kg/day

after transplantation) 150 to 350 µg/l .

Hepatic impairement reduces cyclosporin clearance and prolongs the elimination half-life

the time following transplantation and the

cyclosporin dosage to be


44

adjusted on the basis of blood concentration

cyclosporin measurements should be made in blood and the majority of centres follow

Concentrations in plasma or serum ar

blood sample.

2. A loading dose is not normally given. A variety of induction protocols

before transplantation, others only when adequate renal function ha

lntravenous doses are usually given in clinical settings in which

common. These include after liver transplantation, following bone marrow transplantation

with cystic fibrosis who have received a

between patients. lt may also be affected by bile acids and food. A new oral formulation

Neoral) is available, and appears to display more

current solution or gelatine capsules.

3. The dose is usually reduced on the basis of cyclosporin blood

signs of deteriorating renal function.

4. The intravenous preparation contains polyethoxylated castor oil

reactions, including anaphylaxis. lntravenous doses are approximately one

5. Patients with cystic fibrosis may require up

doses needed.

6. Blood monitoring prior to steady state may be useful to establish

7. The elimination half-life may be underestimated if blood samples

hour dosing lnterval.

8. Blood samples should not be collected via intravenous Iines

administered, as there is significant and reversible binding of the drug to the tubing.

9. Ranges apply primarily to kidney, liver and heart transplant recipients. Higher concentrations are common

using the doses associated with lung or heart

patients with triple or quadruple regimens and in patients with liver dy

variations in practice between different units.

10. High probability of toxicity at pre


Dr: Ahmed Refat &


adjusted on the basis of blood concentration measurements. The consensus recommendations are that

should be made in blood and the majority of centres follow

Concentrations in plasma or serum are lower and are affected by the temperature of separation of the

2. A loading dose is not normally given. A variety of induction protocols are used, some starting cyclosporin

others only when adequate renal function has been established,

lntravenous doses are usually given in clinical settings in which poor oral absorption is suspected or

after liver transplantation, following bone marrow transplantation

c fibrosis who have received a lung or heart/lung transplant. oral absorption varies substantially

also be affected by bile acids and food. A new oral formulation

Neoral) is available, and appears to display more consistent absorption characteristics than either the

solution or gelatine capsules.

3. The dose is usually reduced on the basis of cyclosporin blood concentration measurements and if there are

renal function.

paration contains polyethoxylated castor oil and has been associated with some adverse

anaphylaxis. lntravenous doses are approximately one third of the oral dose

5. Patients with cystic fibrosis may require up-to four times daily dosing because of the relatively large oral

6. Blood monitoring prior to steady state may be useful to establish that the patient is absorbing the drug.

life may be underestimated if blood samples are only collected durin

8. Blood samples should not be collected via intravenous Iines through which cyclosporin has been

significant and reversible binding of the drug to the tubing.

kidney, liver and heart transplant recipients. Higher concentrations are common

using the doses associated with lung or heart-lung transplantation. Lower concentrations are common in

patients with triple or quadruple regimens and in patients with liver dysfunction. However, there are wide

variations in practice between different units.

10. High probability of toxicity at pre-dose concentration > 400 µg/l during maintenance therapy.




The consensus recommendations are that

should be made in blood and the majority of centres follow this advice.

and are affected by the temperature of separation of the

are used, some starting cyclosporin

s been established, post-operatively.

poor oral absorption is suspected or

after liver transplantation, following bone marrow transplantation and in patients

oral absorption varies substantially

also be affected by bile acids and food. A new oral formulation (Sandimmun

ent absorption characteristics than either the

concentration measurements and if there are

and has been associated with some adverse

third of the oral dose

ng because of the relatively large oral

that the patient is absorbing the drug.

are only collected during a single 12 or 24

through which cyclosporin has been

significant and reversible binding of the drug to the tubing.

kidney, liver and heart transplant recipients. Higher concentrations are common

lung transplantation. Lower concentrations are common in

sfunction. However, there are wide

during maintenance therapy.


45

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