THERAPEUTIC DRUG MONITORING 2023.pdf [email protected]
EMMANUELAKPABLI1
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Jul 23, 2024
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Slide Content
THERAPEUTIC DRUG
MONITORING/MANAGEMENT
(TDM)
DR MRS SANDRA A N A CRABBE
MGCP, MBChB
MONITORING/MANAGEMENT
(TDM)
DR MRS SANDRA A N A CRABBE
MGCP, MBChB
Objectives
•Students should be able
•To define certain terms related to action of drugs in humans
•To discuss factors that affect pharmacokinetics and
pharmacodynamics of drugs
•Discuss the rationale for monitoring therapeutic drug concentrations
•Discuss the methods of drug analysis available for TDM
•Discuss the role of TDM in some specific drugs
•Students should be able
•To define certain terms related to action of drugs in humans
•To discuss factors that affect pharmacokinetics and
pharmacodynamics of drugs
•Discuss the rationale for monitoring therapeutic drug concentrations
•Discuss the methods of drug analysis available for TDM
•Discuss the role of TDM in some specific drugs
Some definitions
•Pharmacology: The body of knowledge surrounding chemical agents and
their effects on living processes.
•Pharmacotherapeutics: That part of pharmacology concerned primarily
with the application or administration of drugs to patients for the purpose
of prevention and treatment of disease.
•Toxicology: Subdiscipline of pharmacology concerned with adverse effects
of chemicals on living systems
•Pharmacogenomics: The relationships and correlations between genetic
variation and response or toxicity associated with drug therapy
•Pharmacogenetics: The study of the influence of genetic variation on drug
response in patients by correlating gene expression or single-nucleotide
polymorphisms with a drug's efficacy or toxicity.
•Pharmacology: The body of knowledge surrounding chemical agents and
their effects on living processes.
•Pharmacotherapeutics: That part of pharmacology concerned primarily
with the application or administration of drugs to patients for the purpose
of prevention and treatment of disease.
•Toxicology: Subdiscipline of pharmacology concerned with adverse effects
of chemicals on living systems
•Pharmacogenomics: The relationships and correlations between genetic
variation and response or toxicity associated with drug therapy
•Pharmacogenetics: The study of the influence of genetic variation on drug
response in patients by correlating gene expression or single-nucleotide
polymorphisms with a drug's efficacy or toxicity.
Some definitions
•Pharmacodynamics: Describes response to drugs and encompasses
the processes of interaction of pharmacologically active substances
with target sites, and the biochemical and physiologic consequences
that lead to therapeutic or adverse effects.
•Pharmacokinetics: Describes how drugs are received and handled by
the body and includes the processes of uptake of drugs by the body,
the biotransformations they undergo, the distribution of the drugs
and their metabolites in tissue, and the elimination of the drugs and
their metabolites from the body.
•Pharmacodynamics: Describes response to drugs and encompasses
the processes of interaction of pharmacologically active substances
with target sites, and the biochemical and physiologic consequences
that lead to therapeutic or adverse effects.
•Pharmacokinetics: Describes how drugs are received and handled by
the body and includes the processes of uptake of drugs by the body,
the biotransformations they undergo, the distribution of the drugs
and their metabolites in tissue, and the elimination of the drugs and
their metabolites from the body.
INTRODUCTION
•Medicines as we know, can heal as well as hurt
•“All things are poison and nothing is without poison, only the dose
makes that a thing is not a poison.” (Paracelsus, over 500 years ago)
•Challenge therefore is what dose of medicine is optimal (help patient
with limited associated harm)
•In the USA studies in the 1990s revealed that adverse events
associated with drug therapy rank within top 10 causes of death
•More than a 3
rd
of these appear to be preventable
•Significant economic impact
•Medicines as we know, can heal as well as hurt
•“All things are poison and nothing is without poison, only the dose
makes that a thing is not a poison.” (Paracelsus, over 500 years ago)
•Challenge therefore is what dose of medicine is optimal (help patient
with limited associated harm)
•In the USA studies in the 1990s revealed that adverse events
associated with drug therapy rank within top 10 causes of death
•More than a 3
rd
of these appear to be preventable
•Significant economic impact
Introduction
•There are many causes of preventable drug-related adverse events
•Inadequate monitoring of therapy is a major source contributing as
much as 40%
•Thus improving monitoring strategies is likely to have an impact on
health and the costs associated.
•There are several products authorized for use by the Food and Drugs
Authority in Ghana including prescription and non-prescription drugs
for clinical use.
•Many people are on various prescription medications in some cases,
more than one, especially in the older age groups
•There are many causes of preventable drug-related adverse events
•Inadequate monitoring of therapy is a major source contributing as
much as 40%
•Thus improving monitoring strategies is likely to have an impact on
health and the costs associated.
•There are several products authorized for use by the Food and Drugs
Authority in Ghana including prescription and non-prescription drugs
for clinical use.
•Many people are on various prescription medications in some cases,
more than one, especially in the older age groups
Introduction
•Non-prescription medications do not require therapeutic drug
monitoring except for acetaminophen and salicylates in situations of
overdose
•Even among the prescription drugs, many do not require routine TDM
•Non-prescription medications do not require therapeutic drug
monitoring except for acetaminophen and salicylates in situations of
overdose
•Even among the prescription drugs, many do not require routine TDM
Definition of TDM (International association of
therapeutic drug monitoring and clinical
toxicology)
•A multi-disciplinary clinical specialty aimed at improving patient care
by individually adjusting the dose of drugs for which clinical
experience or clinical trials have shown it improved outcome in the
general or special populations.
•It can be based on pharmacogenetic, demographic and clinical
information alone (a priori TDM), but is normally supplemented with
measurement of drug or metabolite concentrations in blood or
markers of clinical effect (a posteriori TDM).
therapeutic drug monitoring and clinical
toxicology)
•A multi-disciplinary clinical specialty aimed at improving patient care
by individually adjusting the dose of drugs for which clinical
experience or clinical trials have shown it improved outcome in the
general or special populations.
•It can be based on pharmacogenetic, demographic and clinical
information alone (a priori TDM), but is normally supplemented with
measurement of drug or metabolite concentrations in blood or
markers of clinical effect (a posteriori TDM).
Drug therapy can be monitored in several ways
•Clinical signs and symptoms of toxicity or treatment failure e.g
measuring blood pressure or heart rate in a patient on β-blocker.
These can be easily measured hence no need for monitoring beyond
this
•Laboratory measurement of biomarkers of drug efficacy or toxicity
e.g. blood glucose for insulin therapy. These are highly desirable but
not always available
•Measuring the drug itself
•Clinical signs and symptoms of toxicity or treatment failure e.g
measuring blood pressure or heart rate in a patient on β-blocker.
These can be easily measured hence no need for monitoring beyond
this
•Laboratory measurement of biomarkers of drug efficacy or toxicity
e.g. blood glucose for insulin therapy. These are highly desirable but
not always available
•Measuring the drug itself
•TDM is traditionally used to describe the activity of measuring drug
concentrations to tailor the dose of medication to an individual.
•It implies that there is a relationship between the drug concentration
and its efficacy or toxicity outcomes
•TDM involves several members of the healthcare team including
pharmacists, laboratory professionals, physicians etc
concentrations to tailor the dose of medication to an individual.
•It implies that there is a relationship between the drug concentration
and its efficacy or toxicity outcomes
•TDM involves several members of the healthcare team including
pharmacists, laboratory professionals, physicians etc
So how are drugs supposed to work?
•The way an individual responds to a particular drug is dependent on
many factors broadly categorized under pharmacokinetic (effect of
body on drug) and pharmacodynamic (action of drug on body)factors
•The way an individual responds to a particular drug is dependent on
many factors broadly categorized under pharmacokinetic (effect of
body on drug) and pharmacodynamic (action of drug on body)factors
PHARMACOKINETICS
Pharmacokinetics (ADME)
Pharmacokinetics is concerned with
the absorption, distribution in body
compartments, metabolism and
excretion of the drugs after
administration
Pharmacokinetics is concerned with
the absorption, distribution in body
compartments, metabolism and
excretion of the drugs after
administration
The gastrointestinal system
ADME
•Absorption depends on whether the drug is taken orally, by
intravenous or intramuscular injection, sublingually or rectally. Drug
absorption from the site of administration permits entry of the
therapeutic agent (either directly or indirectly) into plasma
•Distribution: The drug may then reversibly leave the bloodstream and
distribute into the interstitial and intracellular fluids
•Metabolism: The drug may be biotransformed by metabolism by the
liver, or other tissues
•Elimination: The drug and its metabolites are eliminated from the
body in urine, bile, or faeces
•Absorption depends on whether the drug is taken orally, by
intravenous or intramuscular injection, sublingually or rectally. Drug
absorption from the site of administration permits entry of the
therapeutic agent (either directly or indirectly) into plasma
•Distribution: The drug may then reversibly leave the bloodstream and
distribute into the interstitial and intracellular fluids
•Metabolism: The drug may be biotransformed by metabolism by the
liver, or other tissues
•Elimination: The drug and its metabolites are eliminated from the
body in urine, bile, or faeces
Routes of drug Administration
•The route of administration is determined primarily by the properties
of the drug (for example, water or lipid solubility, ionization) and by
the therapeutic objectives (for example, the desirability of a rapid
onset of action, the need for long-term treatment, or restriction of
delivery to a local site). Major routes of drug administration include
enteral, parenteral, and topical among others.
•Enteral administration, or administering a drug by mouth, is the
safest and most common, convenient, and economical method of
drug administration. When the drug is given in the mouth, it may be
swallowed, allowing oral delivery, or it may be placed under the
tongue (sublingual), facilitating direct absorption into the
bloodstream.
•The route of administration is determined primarily by the properties
of the drug (for example, water or lipid solubility, ionization) and by
the therapeutic objectives (for example, the desirability of a rapid
onset of action, the need for long-term treatment, or restriction of
delivery to a local site). Major routes of drug administration include
enteral, parenteral, and topical among others.
•Enteral administration, or administering a drug by mouth, is the
safest and most common, convenient, and economical method of
drug administration. When the drug is given in the mouth, it may be
swallowed, allowing oral delivery, or it may be placed under the
tongue (sublingual), facilitating direct absorption into the
bloodstream.
Routes of administration
•The parenteral route introduces drugs directly across the body’s barrier
defenses into the systemic circulation. Parenteral administration is used for
drugs that are poorly absorbed from the GI tract (for example, heparin) and
for agents that are unstable in the GI tract (for example, insulin). Parenteral
administration is also used for treatment of unconscious patients and
under circumstances that require a rapid onset of action. In addition, these
routes have the highest bioavailability and are not subject to first-pass
metabolism or harsh GI environments. Parenteral administration provides
the most control over the actual dose of drug delivered to the body.
However, these administrations are irreversible and may cause pain, fear,
local tissue damage, and infections. The three major parenteral routes are
intravascular (intravenous or intra-arterial), intramuscular, and
subcutaneous. Each route has advantages and drawbacks
•The parenteral route introduces drugs directly across the body’s barrier
defenses into the systemic circulation. Parenteral administration is used for
drugs that are poorly absorbed from the GI tract (for example, heparin) and
for agents that are unstable in the GI tract (for example, insulin). Parenteral
administration is also used for treatment of unconscious patients and
under circumstances that require a rapid onset of action. In addition, these
routes have the highest bioavailability and are not subject to first-pass
metabolism or harsh GI environments. Parenteral administration provides
the most control over the actual dose of drug delivered to the body.
However, these administrations are irreversible and may cause pain, fear,
local tissue damage, and infections. The three major parenteral routes are
intravascular (intravenous or intra-arterial), intramuscular, and
subcutaneous. Each route has advantages and drawbacks
Other routes of administration
•Inhalational (oral/nasal)
•Intrathecal, intraventricular
•Topical
•Transdermal
•Rectal
•Inhalational (oral/nasal)
•Intrathecal, intraventricular
•Topical
•Transdermal
•Rectal
Absorption of drugs
•Absorption is the transfer of a drug from its site of administration to
the bloodstream via one of several mechanisms. The rate and
efficiency of absorption depend on both factors in the environment
where the drug is absorbed and the drug’s chemical characteristics
and route of administration (which influence its bioavailability). For IV
delivery, absorption is complete. That is, the total dose of drug
administered reaches the systemic circulation (100% bioavailability).
Drug delivery by other routes may result in only partial absorption
and, thus, lower bioavailability.
•Mechanisms of absorption from the GIT include: passive diffusion,
facilitated diffusion, active transport, endocytosis and exocytosis
•Absorption is the transfer of a drug from its site of administration to
the bloodstream via one of several mechanisms. The rate and
efficiency of absorption depend on both factors in the environment
where the drug is absorbed and the drug’s chemical characteristics
and route of administration (which influence its bioavailability). For IV
delivery, absorption is complete. That is, the total dose of drug
administered reaches the systemic circulation (100% bioavailability).
Drug delivery by other routes may result in only partial absorption
and, thus, lower bioavailability.
•Mechanisms of absorption from the GIT include: passive diffusion,
facilitated diffusion, active transport, endocytosis and exocytosis
Factors influencing absorption
•Effect of pH on drug absorption: A drug passes through membranes more
readily if it is uncharged. Therefore, the effective concentration of the
permeable form of each drug at its absorption site is determined by the
relative concentrations of the charged and uncharged forms. Distribution
equilibrium is achieved when the permeable form of a drug achieves an
equal concentration in all body water spaces
•Blood flow to the absorption site
•Total surface area available for absorption
•Contact time at the absorption surface
•Expression of P-glycoprotein: is a multidrug transmembrane transporter
protein responsible for transporting various molecules, including drugs,
across cell membranes
•Effect of pH on drug absorption: A drug passes through membranes more
readily if it is uncharged. Therefore, the effective concentration of the
permeable form of each drug at its absorption site is determined by the
relative concentrations of the charged and uncharged forms. Distribution
equilibrium is achieved when the permeable form of a drug achieves an
equal concentration in all body water spaces
•Blood flow to the absorption site
•Total surface area available for absorption
•Contact time at the absorption surface
•Expression of P-glycoprotein: is a multidrug transmembrane transporter
protein responsible for transporting various molecules, including drugs,
across cell membranes
Absorption
Functions of P glycoprotein include
•In the liver: transporting drugs into bile for elimination
•In kidneys: pumping drugs into urine for excretion
•In the placenta: transporting drugs back into maternal blood, thereby
reducing foetal exposure to drugs
•In the intestines: transporting drugs into the intestinal lumen and reducing
drug absorption into the blood
•In the brain capillaries: pumping drugs back into blood, limiting drug
access to the brain
Therefore, in areas of high expression, P-glycoprotein reduces drug
absorption. In addition to transporting many drugs out of cells, it is also
associated with multi drug resistance
Functions of P glycoprotein include
•In the liver: transporting drugs into bile for elimination
•In kidneys: pumping drugs into urine for excretion
•In the placenta: transporting drugs back into maternal blood, thereby
reducing foetal exposure to drugs
•In the intestines: transporting drugs into the intestinal lumen and reducing
drug absorption into the blood
•In the brain capillaries: pumping drugs back into blood, limiting drug
access to the brain
Therefore, in areas of high expression, P-glycoprotein reduces drug
absorption. In addition to transporting many drugs out of cells, it is also
associated with multi drug resistance
Bioavailability
•Bioavailability is the fraction of administered drug that reaches the
systemic circulation. For example, if 100 mg of a drug are
administered orally, and 70 mg of this drug are absorbed unchanged,
the bioavailability is 0.7, or 70 percent.
• Determining bioavailability is important for calculating drug dosages
for non-intravenous routes of administration. The route by which a
drug is administered, as well as the chemical and physical properties
of the agent, affects its bioavailability
•Bioavailability is the fraction of administered drug that reaches the
systemic circulation. For example, if 100 mg of a drug are
administered orally, and 70 mg of this drug are absorbed unchanged,
the bioavailability is 0.7, or 70 percent.
• Determining bioavailability is important for calculating drug dosages
for non-intravenous routes of administration. The route by which a
drug is administered, as well as the chemical and physical properties
of the agent, affects its bioavailability
Factors that influence bioavailability include
•First-pass hepatic metabolism
•Solubility of the drug
•Chemical instability
•Nature of the drug formulation
•First-pass hepatic metabolism
•Solubility of the drug
•Chemical instability
•Nature of the drug formulation
Bioavailability
•First pass hepatic effect: When a drug is absorbed across the GI tract, it
first enters the portal circulation before entering the systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during this initial
passage, the amount of unchanged drug that gains access to the systemic
circulation is decreased. Drugs that exhibit high first-pass metabolism
should be given in sufficient quantities to ensure that enough of the active
drug reaches the target concentration.
•Solubility of drugs: Very hydrophilic drugs are poorly absorbed because of
their inability to cross the lipid-rich cell membranes. Paradoxically, drugs
that are extremely hydrophobic are also poorly absorbed, because they are
totally insoluble in aqueous body fluids and, therefore, cannot gain access
to the surface of cells. For a drug to be readily absorbed, it must be largely
hydrophobic, yet have some solubility in aqueous solutions. This is one
reason why many drugs are either weak acids or weak bases.
•First pass hepatic effect: When a drug is absorbed across the GI tract, it
first enters the portal circulation before entering the systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during this initial
passage, the amount of unchanged drug that gains access to the systemic
circulation is decreased. Drugs that exhibit high first-pass metabolism
should be given in sufficient quantities to ensure that enough of the active
drug reaches the target concentration.
•Solubility of drugs: Very hydrophilic drugs are poorly absorbed because of
their inability to cross the lipid-rich cell membranes. Paradoxically, drugs
that are extremely hydrophobic are also poorly absorbed, because they are
totally insoluble in aqueous body fluids and, therefore, cannot gain access
to the surface of cells. For a drug to be readily absorbed, it must be largely
hydrophobic, yet have some solubility in aqueous solutions. This is one
reason why many drugs are either weak acids or weak bases.
Bioavailability
•Chemical instability: Some drugs, such as penicillin G, are unstable in
the pH of the gastric contents. Others, such as insulin, are destroyed
in the GI tract by degradative enzymes
•Nature of drug formulation: Drug absorption may be altered by
factors unrelated to the chemistry of the drug. For example, particle
size, salt form, crystal polymorphism, enteric coatings, and the
presence of excipients (such as binders and dispersing agents) can
influence the ease of dissolution and, therefore, alter the rate of
absorption.
•Chemical instability: Some drugs, such as penicillin G, are unstable in
the pH of the gastric contents. Others, such as insulin, are destroyed
in the GI tract by degradative enzymes
•Nature of drug formulation: Drug absorption may be altered by
factors unrelated to the chemistry of the drug. For example, particle
size, salt form, crystal polymorphism, enteric coatings, and the
presence of excipients (such as binders and dispersing agents) can
influence the ease of dissolution and, therefore, alter the rate of
absorption.
Drug Distribution
•Drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and then
the cells of the tissues.
•For a drug administered IV, when absorption is not a factor, the initial
phase represents the distribution phase, during which a drug rapidly
disappears from the circulation and enters the tissues.
•This is followed by the elimination phase, when drug in the plasma is
in equilibrium with drug in the tissues.
•Drug distribution is the process by which a drug reversibly leaves the
bloodstream and enters the interstitium (extracellular fluid) and then
the cells of the tissues.
•For a drug administered IV, when absorption is not a factor, the initial
phase represents the distribution phase, during which a drug rapidly
disappears from the circulation and enters the tissues.
•This is followed by the elimination phase, when drug in the plasma is
in equilibrium with drug in the tissues.
Distribution
•The delivery of a drug from the plasma to the interstitium primarily
depends on
a.cardiac output
b.regional blood flow
c.capillary permeability
d.the tissue volume
e.the degree of binding of the drug to plasma and tissue proteins
f.the relative hydrophobicity of the drug
•The delivery of a drug from the plasma to the interstitium primarily
depends on
a.cardiac output
b.regional blood flow
c.capillary permeability
d.the tissue volume
e.the degree of binding of the drug to plasma and tissue proteins
f.the relative hydrophobicity of the drug
Distribution (factors affecting it)
•Blood flow: The rate of blood flow to the tissue capillaries varies
widely as a result of the unequal distribution of cardiac output to the
various organs. Blood flow to the brain, liver, and kidney is greater
than that to the skeletal muscles. Adipose tissue, skin, and viscera
have still lower rates of blood flow. High blood flow, together with the
high lipid solubility of thiopental, permits it to rapidly move into the
CNS and produce anaesthesia. A subsequent slower distribution to
skeletal muscle and adipose tissue lowers the plasma concentration
sufficiently so that the higher concentrations within the CNS
decrease, and, thus, consciousness is regained
•Blood flow: The rate of blood flow to the tissue capillaries varies
widely as a result of the unequal distribution of cardiac output to the
various organs. Blood flow to the brain, liver, and kidney is greater
than that to the skeletal muscles. Adipose tissue, skin, and viscera
have still lower rates of blood flow. High blood flow, together with the
high lipid solubility of thiopental, permits it to rapidly move into the
CNS and produce anaesthesia. A subsequent slower distribution to
skeletal muscle and adipose tissue lowers the plasma concentration
sufficiently so that the higher concentrations within the CNS
decrease, and, thus, consciousness is regained
Distribution (factors affecting it)
•Capillary permeability: determined by capillary structure and by the
chemical nature of the drug.
•Capillary structure varies widely in terms of the fraction of the basement
membrane that is exposed by slit junctions between endothelial cells.
•In the liver and spleen, a large part of the basement membrane is exposed
due to large, discontinuous capillaries through which large plasma proteins
can pass.
•This is in contrast to the brain, where the capillary structure is continuous,
and there are no slit junctions. To enter the brain, drugs must pass through
the endothelial cells of the capillaries of the CNS or be actively transported.
•Capillary permeability: determined by capillary structure and by the
chemical nature of the drug.
•Capillary structure varies widely in terms of the fraction of the basement
membrane that is exposed by slit junctions between endothelial cells.
•In the liver and spleen, a large part of the basement membrane is exposed
due to large, discontinuous capillaries through which large plasma proteins
can pass.
•This is in contrast to the brain, where the capillary structure is continuous,
and there are no slit junctions. To enter the brain, drugs must pass through
the endothelial cells of the capillaries of the CNS or be actively transported.
Distribution (capillary permeability)
•For example, a specific transporter for the large neutral amino acid
transporter carries levo dopa into the brain.
•By contrast, lipid-soluble drugs readily penetrate into the CNS
because they can dissolve in the membrane of the endothelial cells.
•Ionized, or polar drugs generally fail to enter the CNS because they
are unable to pass through the endothelial cells of the CNS, which
have no slit junctions. These tightly juxtaposed cells form tight
junctions that constitute the blood-brain barrier.
•For example, a specific transporter for the large neutral amino acid
transporter carries levo dopa into the brain.
•By contrast, lipid-soluble drugs readily penetrate into the CNS
because they can dissolve in the membrane of the endothelial cells.
•Ionized, or polar drugs generally fail to enter the CNS because they
are unable to pass through the endothelial cells of the CNS, which
have no slit junctions. These tightly juxtaposed cells form tight
junctions that constitute the blood-brain barrier.
Types of capillary
Distribution (Binding of drugs to plasma
proteins and tissue)
Binding to plasma proteins:
•Reversible binding to plasma proteins sequesters drugs in a non-diffusible
form and slows their transfer out of the vascular compartment.
•Binding is relatively nonselective regarding chemical structure and takes
place at sites on the protein to which endogenous compounds, such as
bilirubin, normally attach.
•Plasma albumin is the major drug-binding protein and may act as a drug
reservoir (that is, as the concentration of the free drug decreases due to
elimination by metabolism or excretion, the bound drug dissociates from
the protein). This maintains the free-drug concentration as a constant
fraction of the total drug in the plasma.
proteins and tissue)
Binding to plasma proteins:
•Reversible binding to plasma proteins sequesters drugs in a non-diffusible
form and slows their transfer out of the vascular compartment.
•Binding is relatively nonselective regarding chemical structure and takes
place at sites on the protein to which endogenous compounds, such as
bilirubin, normally attach.
•Plasma albumin is the major drug-binding protein and may act as a drug
reservoir (that is, as the concentration of the free drug decreases due to
elimination by metabolism or excretion, the bound drug dissociates from
the protein). This maintains the free-drug concentration as a constant
fraction of the total drug in the plasma.
Distribution (binding)
Binding to tissue proteins:
•Numerous drugs accumulate in tissues, leading to higher
concentrations of the drug in tissues than in the extracellular fluids
and blood.
•Drugs may accumulate as a result of binding to lipids, proteins or
nucleic acids.
•Drugs may also be actively transported into tissues. These tissue
reservoirs may serve as a major source of the drug and prolong its
actions or, on the other hand, can cause local drug toxicity.
Binding to tissue proteins:
•Numerous drugs accumulate in tissues, leading to higher
concentrations of the drug in tissues than in the extracellular fluids
and blood.
•Drugs may accumulate as a result of binding to lipids, proteins or
nucleic acids.
•Drugs may also be actively transported into tissues. These tissue
reservoirs may serve as a major source of the drug and prolong its
actions or, on the other hand, can cause local drug toxicity.
Distribution (factors affecting it)
Hydrophobicity:
•The chemical nature of a drug strongly influences its ability to cross
cell membranes.
•Hydrophobic drugs readily move across most biologic membranes.
These drugs can dissolve in the lipid membranes and, therefore,
permeate the entire cell’s surface.
•The major factor influencing the hydrophobic drug’s distribution is
the blood flow to the area.
•By contrast, hydrophilic drugs do not readily penetrate cell
membranes and must pass through the slit junctions
Hydrophobicity:
•The chemical nature of a drug strongly influences its ability to cross
cell membranes.
•Hydrophobic drugs readily move across most biologic membranes.
These drugs can dissolve in the lipid membranes and, therefore,
permeate the entire cell’s surface.
•The major factor influencing the hydrophobic drug’s distribution is
the blood flow to the area.
•By contrast, hydrophilic drugs do not readily penetrate cell
membranes and must pass through the slit junctions
Distribution (factors affecting it)
•Volume of distribution: The apparent volume of distribution, Vd, can
be thought of as the fluid volume that is required to contain the
entire drug in the body at the same concentration measured in the
plasma. It is calculated by dividing the dose that ultimately gets into
the systemic circulation by the plasma concentration at time zero (C0).
Vd = Amount of drug in the body / C0
•Although Vd has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water
compartments in the body.
•Volume of distribution: The apparent volume of distribution, Vd, can
be thought of as the fluid volume that is required to contain the
entire drug in the body at the same concentration measured in the
plasma. It is calculated by dividing the dose that ultimately gets into
the systemic circulation by the plasma concentration at time zero (C0).
Vd = Amount of drug in the body / C0
•Although Vd has no physiologic or physical basis, it can be useful to
compare the distribution of a drug with the volumes of the water
compartments in the body.
Distribution (factors affecting it)
•Distribution into the water compartments in the body: Once a drug
enters the body, from whatever route of administration, it has the
potential to distribute into any one of three functionally distinct
compartments of body water or to become sequestered in a cellular
site.
a.Plasma compartment: If a drug has a very large molecular weight
or binds extensively to plasma proteins, it is too large to move out
through the endothelial slit junctions of the capillaries and, thus, is
effectively trapped within the plasma (vascular) compartment. As a
consequence, the drug distributes in a volume (the plasma) that is
about 6 percent of the body weight or, in a 70-kg individual, about
4L of body fluid. Heparin shows this type of distribution
•Distribution into the water compartments in the body: Once a drug
enters the body, from whatever route of administration, it has the
potential to distribute into any one of three functionally distinct
compartments of body water or to become sequestered in a cellular
site.
a.Plasma compartment: If a drug has a very large molecular weight
or binds extensively to plasma proteins, it is too large to move out
through the endothelial slit junctions of the capillaries and, thus, is
effectively trapped within the plasma (vascular) compartment. As a
consequence, the drug distributes in a volume (the plasma) that is
about 6 percent of the body weight or, in a 70-kg individual, about
4L of body fluid. Heparin shows this type of distribution
Distribution (factors affecting it)
a.Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it
can move through the endothelial slit junctions of the capillaries into the
interstitial fluid. However, hydrophilic drugs cannot move across the lipid
membranes of cells to enter the water phase inside the cell. Therefore, these
drugs distribute into a volume that is the sum of the plasma water and the
interstitial fluid, which together constitute the extracellular fluid. This is about
20 percent of the body weight, or about 14L in a 70kg individual.
Aminoglycoside antibiotics show this type of distribution.
b.Total body water: If a drug has a low molecular weight and is hydrophobic, not
only can it move into the interstitium through the slit junctions, but it can also
move through the cell membranes into the intracellular fluid. The drug,
therefore, distributes into a volume of about 60 percent of body weight, or
about 42L in a 70-kg individual. Ethanol exhibits this apparent volume of
distribution
a.Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it
can move through the endothelial slit junctions of the capillaries into the
interstitial fluid. However, hydrophilic drugs cannot move across the lipid
membranes of cells to enter the water phase inside the cell. Therefore, these
drugs distribute into a volume that is the sum of the plasma water and the
interstitial fluid, which together constitute the extracellular fluid. This is about
20 percent of the body weight, or about 14L in a 70kg individual.
Aminoglycoside antibiotics show this type of distribution.
b.Total body water: If a drug has a low molecular weight and is hydrophobic, not
only can it move into the interstitium through the slit junctions, but it can also
move through the cell membranes into the intracellular fluid. The drug,
therefore, distributes into a volume of about 60 percent of body weight, or
about 42L in a 70-kg individual. Ethanol exhibits this apparent volume of
distribution
Distribution (factors affecting it)
• Apparent volume of distribution: A drug rarely associates
exclusively with only one of the water compartments of the body.
Instead, the vast majority of drugs distribute into several
compartments, often avidly binding cellular components, such as,
lipids (abundant in adipocytes and cell membranes), proteins
(abundant in plasma and within cells), and nucleic acids (abundant in
the nuclei of cells). Therefore, the volume into which drugs distribute
is called the apparent volume of distribution, or Vd- . Vd is a useful
pharmacokinetic parameter for calculating a drug’s loading dose
• Apparent volume of distribution: A drug rarely associates
exclusively with only one of the water compartments of the body.
Instead, the vast majority of drugs distribute into several
compartments, often avidly binding cellular components, such as,
lipids (abundant in adipocytes and cell membranes), proteins
(abundant in plasma and within cells), and nucleic acids (abundant in
the nuclei of cells). Therefore, the volume into which drugs distribute
is called the apparent volume of distribution, or Vd- . Vd is a useful
pharmacokinetic parameter for calculating a drug’s loading dose
Distribution (factors affecting it)
•Determination of Vd: The fact that drug clearance is usually a first order
process allows calculation of Vd. First order means that a constant fraction
of the drug is eliminated per unit of time. This process can be most easily
analyzed by plotting the log of the plasma drug concentration (Cp) versus
time. The concentration of drug in the plasma can be extrapolated back to
time zero (the time of injection) on the Y axis to determine C0, which is the
concentration of drug that would have been achieved if the distribution
phase had occurred instantly. This allows calculation of Vd as
Vd = Dose / C0
For example, if 10 mg of drug are injected into a patient and the plasma
concentration is extrapolated back to time zero, the concentration is C0 = 1
mg/L , and then Vd = 10 mg/1 mg/L = 10 L.
•Determination of Vd: The fact that drug clearance is usually a first order
process allows calculation of Vd. First order means that a constant fraction
of the drug is eliminated per unit of time. This process can be most easily
analyzed by plotting the log of the plasma drug concentration (Cp) versus
time. The concentration of drug in the plasma can be extrapolated back to
time zero (the time of injection) on the Y axis to determine C0, which is the
concentration of drug that would have been achieved if the distribution
phase had occurred instantly. This allows calculation of Vd as
Vd = Dose / C0
For example, if 10 mg of drug are injected into a patient and the plasma
concentration is extrapolated back to time zero, the concentration is C0 = 1
mg/L , and then Vd = 10 mg/1 mg/L = 10 L.
•Effect of Vd on drug half-life: A large Vd has an important influence
on the half-life of a drug, because drug elimination depends on the
amount of drug delivered to the liver or kidney (or other organs
where metabolism occurs) per unit of time. Delivery of drug to the
organs of elimination depends not only on blood flow, but also on the
fraction of the drug in the plasma. If the Vd for a drug is large, most of
the drug is in the extraplasmic space and is unavailable to the
excretory organs. Therefore, any factor that increases Vd can lead to
an increase in the half-life and extend the duration of action of the
drug. [Note: An exceptionally large Vd indicates considerable
sequestration of the drug in some tissues or compartments.]
on the half-life of a drug, because drug elimination depends on the
amount of drug delivered to the liver or kidney (or other organs
where metabolism occurs) per unit of time. Delivery of drug to the
organs of elimination depends not only on blood flow, but also on the
fraction of the drug in the plasma. If the Vd for a drug is large, most of
the drug is in the extraplasmic space and is unavailable to the
excretory organs. Therefore, any factor that increases Vd can lead to
an increase in the half-life and extend the duration of action of the
drug. [Note: An exceptionally large Vd indicates considerable
sequestration of the drug in some tissues or compartments.]
Drug clearance through Metabolism
•Once a drug enters the body, the process of elimination begins. The three
major routes involved are:
1)hepatic metabolism,
2)elimination in bile, and
3)elimination in urine.
•Together, these elimination processes cause the plasma concentration of a
drug to decrease exponentially.
•Metabolism leads to products with increased polarity, which will allow the
drug to be eliminated.
•Clearance (CL) estimates the amount of drug cleared from the body per
unit of time
•Once a drug enters the body, the process of elimination begins. The three
major routes involved are:
1)hepatic metabolism,
2)elimination in bile, and
3)elimination in urine.
•Together, these elimination processes cause the plasma concentration of a
drug to decrease exponentially.
•Metabolism leads to products with increased polarity, which will allow the
drug to be eliminated.
•Clearance (CL) estimates the amount of drug cleared from the body per
unit of time
Kinetics of metabolism
•1. First-order kinetics: The metabolic transformation of drugs is
catalyzed by enzymes, and most of the reactions obey Michaelis-
Menten kinetics v = rate of drug metabolism = Vmax [C] / Km + [C]
•In most clinical situations, the concentration of the drug, [C], is much
less than the Michaelis constant, Km, and the Michaelis-Menten
equation reduces to: Vmax [C] / Km =v = rate of drug metabolism
•That is, the rate of drug metabolism and elimination is directly
proportional to the concentration of free drug, and first-order kinetics
are observed. This means that a constant fraction of drug is
metabolized per unit of time (that is, with every half-life the
concentration reduces by 50%).
•1. First-order kinetics: The metabolic transformation of drugs is
catalyzed by enzymes, and most of the reactions obey Michaelis-
Menten kinetics v = rate of drug metabolism = Vmax [C] / Km + [C]
•In most clinical situations, the concentration of the drug, [C], is much
less than the Michaelis constant, Km, and the Michaelis-Menten
equation reduces to: Vmax [C] / Km =v = rate of drug metabolism
•That is, the rate of drug metabolism and elimination is directly
proportional to the concentration of free drug, and first-order kinetics
are observed. This means that a constant fraction of drug is
metabolized per unit of time (that is, with every half-life the
concentration reduces by 50%).
Kinetics of metabolism
•2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol , and
phenytoin, the doses are very large. Therefore [C] is much greater
than Km, and the velocity equation becomes
Vmax [C] / [C] =v = rate of drug metabolism
•The enzyme is saturated by a high free-drug concentration, and the
rate of metabolism remains constant over time. This is called zero-
order kinetics (sometimes referred to clinically as nonlinear kinetics).
A constant amount of drug is metabolized per unit of time, and the
rate of elimination is constant and does not depend on the drug
concentration.
•2. Zero-order kinetics: With a few drugs, such as aspirin, ethanol , and
phenytoin, the doses are very large. Therefore [C] is much greater
than Km, and the velocity equation becomes
Vmax [C] / [C] =v = rate of drug metabolism
•The enzyme is saturated by a high free-drug concentration, and the
rate of metabolism remains constant over time. This is called zero-
order kinetics (sometimes referred to clinically as nonlinear kinetics).
A constant amount of drug is metabolized per unit of time, and the
rate of elimination is constant and does not depend on the drug
concentration.
Reactions of drug metabolism
•The kidney cannot efficiently eliminate lipophilic drugs that readily
cross cell membranes and are reabsorbed in the distal convoluted
tubules. Therefore, lipid-soluble agents must first be metabolized into
more polar (hydrophilic) substances in the liver using two general sets
of reactions, called Phase I and Phase II
•Phase I reactions convert lipophilic molecules into more polar
molecules by introducing or unmasking a polar functional group, such
as –OH or –NH2. Phase I metabolism may increase, decrease, or leave
unaltered the drug’s pharmacologic activity
•Phase II reactions: This phase consists of conjugation reactions
•The kidney cannot efficiently eliminate lipophilic drugs that readily
cross cell membranes and are reabsorbed in the distal convoluted
tubules. Therefore, lipid-soluble agents must first be metabolized into
more polar (hydrophilic) substances in the liver using two general sets
of reactions, called Phase I and Phase II
•Phase I reactions convert lipophilic molecules into more polar
molecules by introducing or unmasking a polar functional group, such
as –OH or –NH2. Phase I metabolism may increase, decrease, or leave
unaltered the drug’s pharmacologic activity
•Phase II reactions: This phase consists of conjugation reactions
Phase I reactions (using P450)
• The Phase I reactions most frequently involved in drug metabolism are catalyzed
by the cytochrome P450 system (also called microsomal mixed-function
oxidases)
• The P450 system is important for the metabolism of many endogenous
compounds (such as steroids, lipids, etc.) and for the biotransformation of
exogenous substances (xenobiotics).
•Cytochrome P450, designated as CYP, is a superfamily of haem-containing
isozymes that are located in most cells but are primarily found in the liver and GI
tract
•There are many different genes that encode multiple enzymes, and therefore
there are many different P450 isoforms. These enzymes have the capacity to
modify a large number of structurally diverse substrates. In addition, an individual
drug may be a substrate for more than one isozyme. Four isozymes are
responsible for the vast majority of P450catalyzed reactions. They are CYP3A4/5,
CYP2D6, CYP2C8/9, and CYP1A2
• The Phase I reactions most frequently involved in drug metabolism are catalyzed
by the cytochrome P450 system (also called microsomal mixed-function
oxidases)
• The P450 system is important for the metabolism of many endogenous
compounds (such as steroids, lipids, etc.) and for the biotransformation of
exogenous substances (xenobiotics).
•Cytochrome P450, designated as CYP, is a superfamily of haem-containing
isozymes that are located in most cells but are primarily found in the liver and GI
tract
•There are many different genes that encode multiple enzymes, and therefore
there are many different P450 isoforms. These enzymes have the capacity to
modify a large number of structurally diverse substrates. In addition, an individual
drug may be a substrate for more than one isozyme. Four isozymes are
responsible for the vast majority of P450catalyzed reactions. They are CYP3A4/5,
CYP2D6, CYP2C8/9, and CYP1A2
Phase I reactions (using P450)
•P450 enzymes exhibit considerable genetic variability among individuals
and racial groups. Variations in P450 activity may alter a drug’s efficacy and
the risk of adverse events.
•The CYP450–dependent enzymes are an important target for
pharmacokinetic drug interactions. One such interaction is the induction of
selected CYP isozymes. Xenobiotics may induce the activity of these
enzymes by inducing the expression of the genes encoding the enzyme or
by stabilizing the enzymes. Certain drugs (for example, phenobarbital,
rifampin, and carbamazepine) are capable of increasing the synthesis of
one or more CYP isozymes. This results in increased biotransformation of
drugs and can lead to significant decreases in plasma concentrations of
drugs metabolized by these CYP isozymes, with concurrent loss of
pharmacologic effect
•P450 enzymes exhibit considerable genetic variability among individuals
and racial groups. Variations in P450 activity may alter a drug’s efficacy and
the risk of adverse events.
•The CYP450–dependent enzymes are an important target for
pharmacokinetic drug interactions. One such interaction is the induction of
selected CYP isozymes. Xenobiotics may induce the activity of these
enzymes by inducing the expression of the genes encoding the enzyme or
by stabilizing the enzymes. Certain drugs (for example, phenobarbital,
rifampin, and carbamazepine) are capable of increasing the synthesis of
one or more CYP isozymes. This results in increased biotransformation of
drugs and can lead to significant decreases in plasma concentrations of
drugs metabolized by these CYP isozymes, with concurrent loss of
pharmacologic effect
Phase I reactions (using P450)
•Consequences of increased drug metabolism include:
1)decreased plasma drug concentrations,
2)decreased drug activity if the metabolite is inactive,
3)increased drug activity if the metabolite is active, and
4)decreased therapeutic drug effect
•Consequences of increased drug metabolism include:
1)decreased plasma drug concentrations,
2)decreased drug activity if the metabolite is inactive,
3)increased drug activity if the metabolite is active, and
4)decreased therapeutic drug effect
Phase 1 reactions (P450)
•Inhibition of CYP isozyme activity is an important source of drug
interactions that lead to serious adverse events.
•The most common form of inhibition is through competition for the
same isozyme.
•Some drugs, however, are capable of inhibiting reactions for which
they are not substrates (for example, ketoconazole), leading to drug
interactions.
•Numerous drugs have been shown to inhibit one or more of the CYP-
dependent biotransformation pathways of warfarin.
•Inhibition of CYP isozyme activity is an important source of drug
interactions that lead to serious adverse events.
•The most common form of inhibition is through competition for the
same isozyme.
•Some drugs, however, are capable of inhibiting reactions for which
they are not substrates (for example, ketoconazole), leading to drug
interactions.
•Numerous drugs have been shown to inhibit one or more of the CYP-
dependent biotransformation pathways of warfarin.
Phase 1 reactions
•For example, omeprazole is a potent inhibitor of three of the CYP
isozymes responsible for warfarin metabolism. If the two drugs are
taken together, plasma concentrations of warfarin increase, which
leads to greater inhibition of coagulation and risk of haemorrhage
and other serious bleeding reactions.
•Natural substances may also inhibit drug metabolism. For instance,
because grapefruit and its juice inhibits CYP3A4, drugs such as
nifedipine, clarithromycin, and simvastatin, which are metabolized by
this system, persist in greater amounts in the systemic circulation,
leading to higher blood levels and the potential to increase the drugs’
therapeutic and/or toxic effects
•For example, omeprazole is a potent inhibitor of three of the CYP
isozymes responsible for warfarin metabolism. If the two drugs are
taken together, plasma concentrations of warfarin increase, which
leads to greater inhibition of coagulation and risk of haemorrhage
and other serious bleeding reactions.
•Natural substances may also inhibit drug metabolism. For instance,
because grapefruit and its juice inhibits CYP3A4, drugs such as
nifedipine, clarithromycin, and simvastatin, which are metabolized by
this system, persist in greater amounts in the systemic circulation,
leading to higher blood levels and the potential to increase the drugs’
therapeutic and/or toxic effects
Examples of P450 Isoenzymes
Phase I reactions not involving P450
These include
•amine oxidation (for example, oxidation of catecholamines or
histamine),
•alcohol dehydrogenation (for example, ethanol oxidation),
•esterases (for example, metabolism of pravastatin in liver), and
•hydrolysis (for example, of procaine).
These include
•amine oxidation (for example, oxidation of catecholamines or
histamine),
•alcohol dehydrogenation (for example, ethanol oxidation),
•esterases (for example, metabolism of pravastatin in liver), and
•hydrolysis (for example, of procaine).
Phase II reactions
• If the metabolite from Phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many Phase I metabolites are too
lipophilic to be retained in the kidney tubules. A subsequent conjugation
reaction with an endogenous substrate, such as glucuronic acid, sulfuric
acid, acetic acid, or an amino acid, results in polar, usually more water-
soluble compounds that are most often therapeutically inactive.
•Glucuronidation is the most common and the most important conjugation
reaction. Neonates are deficient in this conjugating system, making them
particularly vulnerable to drugs such as chloramphenicol, which is
inactivated by the addition of glucuronic acid, resulting in gray baby
syndrome. [Note: Drugs already possessing an –OH, –NH2, or –COOH
group may enter Phase II directly and become conjugated without prior
Phase I metabolism.] The highly polar drug conjugates may then be
excreted by the kidney or in bile
• If the metabolite from Phase I metabolism is sufficiently polar, it can be
excreted by the kidneys. However, many Phase I metabolites are too
lipophilic to be retained in the kidney tubules. A subsequent conjugation
reaction with an endogenous substrate, such as glucuronic acid, sulfuric
acid, acetic acid, or an amino acid, results in polar, usually more water-
soluble compounds that are most often therapeutically inactive.
•Glucuronidation is the most common and the most important conjugation
reaction. Neonates are deficient in this conjugating system, making them
particularly vulnerable to drugs such as chloramphenicol, which is
inactivated by the addition of glucuronic acid, resulting in gray baby
syndrome. [Note: Drugs already possessing an –OH, –NH2, or –COOH
group may enter Phase II directly and become conjugated without prior
Phase I metabolism.] The highly polar drug conjugates may then be
excreted by the kidney or in bile
Reversal of order of the phases
•Not all drugs undergo Phase I and II reactions in that order. For
example, isoniazid is first acetylated (a Phase II reaction) and then
hydrolyzed to isonicotinic acid (a Phase I reaction).
•Not all drugs undergo Phase I and II reactions in that order. For
example, isoniazid is first acetylated (a Phase II reaction) and then
hydrolyzed to isonicotinic acid (a Phase I reaction).
Biotransformation of drugs
Drug clearance by the kidneys
•Elimination of drugs from the body requires the agents to be sufficiently
polar for efficient excretion. Removal of a drug from the body occurs via a
number of routes, the most important being through the kidney into the
urine
•Elimination of drugs via the kidneys into urine involves the three processes
of glomerular filtration, active tubular secretion, and passive tubular
reabsorption.
•During glomerular filtration, drugs are filtered at the glomerulus. Free drug
(not bound to albumin) flows through the capillary slits into Bowman’s
space as part of the glomerular filtrate. The glomerular filtration rate (125
mL/min) is normally about 20 percent of the renal plasma flow (600
mL/min). Lipid solubility and pH do not influence the passage of drugs into
the glomerular filtrate. However, varying the glomerular filtration rate
and plasma binding of the drugs may affect this process.
•Elimination of drugs from the body requires the agents to be sufficiently
polar for efficient excretion. Removal of a drug from the body occurs via a
number of routes, the most important being through the kidney into the
urine
•Elimination of drugs via the kidneys into urine involves the three processes
of glomerular filtration, active tubular secretion, and passive tubular
reabsorption.
•During glomerular filtration, drugs are filtered at the glomerulus. Free drug
(not bound to albumin) flows through the capillary slits into Bowman’s
space as part of the glomerular filtrate. The glomerular filtration rate (125
mL/min) is normally about 20 percent of the renal plasma flow (600
mL/min). Lipid solubility and pH do not influence the passage of drugs into
the glomerular filtrate. However, varying the glomerular filtration rate
and plasma binding of the drugs may affect this process.
Elimination by the kidneys
Clearance by kidneys
•Proximal tubular secretion, drugs that were not transferred into the
glomerular filtrate leave the glomeruli through efferent arterioles,
which divide to form a capillary plexus surrounding the proximal
tubule. Secretion primarily occurs in the proximal tubules by two
energy-requiring active transport (carrier requiring) systems: one for
anions (e.g. deprotonated forms of weak acids) and one for cations
(e.g. protonated forms of weak bases). Each of these transport
systems shows low specificity and can transport many compounds.
Thus, competition between drugs for these carriers can occur within
each transport system. [Note: Premature infants and neonates have
an incompletely developed tubular secretory mechanism and, thus,
may retain certain drugs in the glomerular filtrate.]
•Proximal tubular secretion, drugs that were not transferred into the
glomerular filtrate leave the glomeruli through efferent arterioles,
which divide to form a capillary plexus surrounding the proximal
tubule. Secretion primarily occurs in the proximal tubules by two
energy-requiring active transport (carrier requiring) systems: one for
anions (e.g. deprotonated forms of weak acids) and one for cations
(e.g. protonated forms of weak bases). Each of these transport
systems shows low specificity and can transport many compounds.
Thus, competition between drugs for these carriers can occur within
each transport system. [Note: Premature infants and neonates have
an incompletely developed tubular secretory mechanism and, thus,
may retain certain drugs in the glomerular filtrate.]
Clearance by kidneys
• Distal tubular reabsorption, as drug moves toward the distal convoluted
tubule, its concentration increases and exceeds that of the perivascular
space. The drug, if uncharged, may diffuse out of the tubule, back into the
systemic circulation. Manipulating the pH of the urine to increase the
ionized form of the drug in the lumen may be done to minimize the
amount of back-diffusion and, hence, increase the clearance of an
undesirable drug. As a general rule, weak acids can be eliminated by
alkalinization of the urine, whereas elimination of weak bases may be
increased by acidification of the urine. This process is called “ion trapping.”
For example, a patient presenting with phenobarbital (weak acid) overdose
can be given bicarbonate , which alkalinizes the urine and keeps the drug
ionized, thereby decreasing its reabsorption. If overdose is with a weak
base, such as amphetamine, acidification of the urine with NH4Cl leads to
protonation of the drug (that is, it becomes charged) and an enhancement
of its renal excretion
• Distal tubular reabsorption, as drug moves toward the distal convoluted
tubule, its concentration increases and exceeds that of the perivascular
space. The drug, if uncharged, may diffuse out of the tubule, back into the
systemic circulation. Manipulating the pH of the urine to increase the
ionized form of the drug in the lumen may be done to minimize the
amount of back-diffusion and, hence, increase the clearance of an
undesirable drug. As a general rule, weak acids can be eliminated by
alkalinization of the urine, whereas elimination of weak bases may be
increased by acidification of the urine. This process is called “ion trapping.”
For example, a patient presenting with phenobarbital (weak acid) overdose
can be given bicarbonate , which alkalinizes the urine and keeps the drug
ionized, thereby decreasing its reabsorption. If overdose is with a weak
base, such as amphetamine, acidification of the urine with NH4Cl leads to
protonation of the drug (that is, it becomes charged) and an enhancement
of its renal excretion
Clearance by kidneys
•Role of drug metabolism: Most drugs are lipid soluble and, without
chemical modification, would diffuse out of the kidney’s tubular
lumen when the drug concentration in the filtrate becomes greater
than that in the perivascular space. To minimize this reabsorption,
drugs are modified primarily in the liver into more polar substances
using two types of reactions: Phase I and Phase II reactions. The
conjugates are ionized, and the charged molecules cannot back-
diffuse out of the kidney lumen.
•Role of drug metabolism: Most drugs are lipid soluble and, without
chemical modification, would diffuse out of the kidney’s tubular
lumen when the drug concentration in the filtrate becomes greater
than that in the perivascular space. To minimize this reabsorption,
drugs are modified primarily in the liver into more polar substances
using two types of reactions: Phase I and Phase II reactions. The
conjugates are ionized, and the charged molecules cannot back-
diffuse out of the kidney lumen.
Other Routes of Drug Clearance
•These include via intestines, the bile, the lungs, and milk in nursing mothers,
among others .
•The faeces are primarily involved in elimination of unabsorbed orally ingested
drugs or drugs that are secreted directly into the intestines or in bile. While in the
intestinal tract, most compounds are not reabsorbed and are eliminated in the
faeces.
•The lungs are primarily involved in the elimination of anaesthetic gases (for
example, halothane and isoflurane).
•Elimination of drugs in breast milk is clinically relevant as a potential source of
undesirable side effects to the infant. A suckling baby will be exposed, to some
extent, to medications and/or its metabolites being taken by the mother.
•Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a
small extent. However, deposition of drugs in hair and skin has been used as a
forensic tool in many criminal cases.
•These include via intestines, the bile, the lungs, and milk in nursing mothers,
among others .
•The faeces are primarily involved in elimination of unabsorbed orally ingested
drugs or drugs that are secreted directly into the intestines or in bile. While in the
intestinal tract, most compounds are not reabsorbed and are eliminated in the
faeces.
•The lungs are primarily involved in the elimination of anaesthetic gases (for
example, halothane and isoflurane).
•Elimination of drugs in breast milk is clinically relevant as a potential source of
undesirable side effects to the infant. A suckling baby will be exposed, to some
extent, to medications and/or its metabolites being taken by the mother.
•Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a
small extent. However, deposition of drugs in hair and skin has been used as a
forensic tool in many criminal cases.
Other routes of clearance
• A patient in renal failure may sometimes benefit from a drug that is
excreted through the liver, into the intestine and faeces, rather than
via the kidneys
•Some drugs may also be reabsorbed through the enterohepatic
circulation, thus prolonging their half-lives
• A patient in renal failure may sometimes benefit from a drug that is
excreted through the liver, into the intestine and faeces, rather than
via the kidneys
•Some drugs may also be reabsorbed through the enterohepatic
circulation, thus prolonging their half-lives
Clearance
•When a patient has an abnormality that alters the half-life of a drug,
adjustment in dosage is required.
•The half-life of a drug is increased by
1)diminished renal plasma flow or hepatic blood flow, e.g., in
cardiogenic shock, heart failure, or hemorrhage;
2)decreased ability to extract drug from plasma, e.g., as seen in renal
disease; and
3)decreased metabolism, e.g., when another drug inhibits its
biotransformation or in hepatic insufficiency, as with cirrhosis.
•When a patient has an abnormality that alters the half-life of a drug,
adjustment in dosage is required.
•The half-life of a drug is increased by
1)diminished renal plasma flow or hepatic blood flow, e.g., in
cardiogenic shock, heart failure, or hemorrhage;
2)decreased ability to extract drug from plasma, e.g., as seen in renal
disease; and
3)decreased metabolism, e.g., when another drug inhibits its
biotransformation or in hepatic insufficiency, as with cirrhosis.
Clearance
•On the other hand, the half-life of a drug may decrease by
1)increased hepatic blood flow,
2)decreased protein binding, and
3)increased metabolism
•On the other hand, the half-life of a drug may decrease by
1)increased hepatic blood flow,
2)decreased protein binding, and
3)increased metabolism
•To initiate drug therapy, the clinician designs a dosage regimen
administered either
•by continuous infusion or
•in intervals of time and dose
•This is dependent on various patient and drug factors, including how
rapidly a steady state (rate of administration equals that of
elimination) must be achieved.
•The regimen can be further refined, or optimized, to achieve
maximum benefit with minimum adverse effects.
administered either
•by continuous infusion or
•in intervals of time and dose
•This is dependent on various patient and drug factors, including how
rapidly a steady state (rate of administration equals that of
elimination) must be achieved.
•The regimen can be further refined, or optimized, to achieve
maximum benefit with minimum adverse effects.
PHARMACODYNAMICS
Pharmacodynamics
•Pharmacodynamics describes the actions of a drug on the body and
the influence of drug concentrations on the magnitude of the
response.
•Most drugs exert their effects, both beneficial and harmful, by
interacting with receptors present on the cell surface or within the
cell.
•The drug–receptor complex initiates alterations in biochemical and/or
molecular activity of a cell by a process called signal transduction
•Pharmacodynamics describes the actions of a drug on the body and
the influence of drug concentrations on the magnitude of the
response.
•Most drugs exert their effects, both beneficial and harmful, by
interacting with receptors present on the cell surface or within the
cell.
•The drug–receptor complex initiates alterations in biochemical and/or
molecular activity of a cell by a process called signal transduction
Pharmacodynamics
•Signal Transduction: Drugs act as signals, and their receptors act as
signal detectors. Many receptors signal their recognition of a bound
ligand by initiating a series of reactions that ultimately result in a
specific intracellular response.
•“Second messenger” molecules (also called effector molecules) are
part of the cascade of events that translates ligand binding into a
cellular response
•Signal transduction has two important features: 1) the ability to
amplify small signals and 2) mechanisms to protect the cell from
excessive stimulation.
•Signal Transduction: Drugs act as signals, and their receptors act as
signal detectors. Many receptors signal their recognition of a bound
ligand by initiating a series of reactions that ultimately result in a
specific intracellular response.
•“Second messenger” molecules (also called effector molecules) are
part of the cascade of events that translates ligand binding into a
cellular response
•Signal transduction has two important features: 1) the ability to
amplify small signals and 2) mechanisms to protect the cell from
excessive stimulation.
The recognition of a drug by a receptor
triggers a biologic response
triggers a biologic response
Transmembrane
signalling mechanisms
A. Ligand binds to the extracellular domain
of a ligand-gated channel.
B. Ligand binds to a domain of a
transmembrane receptor, which is coupled to
a G protein.
C. Ligand binds to the extracellular domain of
a receptor that activates a kinase enzyme.
D. Lipid-soluble ligand diffuses across the
membrane to interact with its intracellular
receptor.
R = inactive protein.
signalling mechanisms
A. Ligand binds to the extracellular domain
of a ligand-gated channel.
B. Ligand binds to a domain of a
transmembrane receptor, which is coupled to
a G protein.
C. Ligand binds to the extracellular domain of
a receptor that activates a kinase enzyme.
D. Lipid-soluble ligand diffuses across the
membrane to interact with its intracellular
receptor.
R = inactive protein.
Dose-Response relationships
•An agonist is defined as an agent that can bind to a receptor and elicit
a biologic response.
•An agonist usually mimics the action of the original endogenous
ligand on the receptor such as norepinephrine on β1 receptors of the
heart.
•The magnitude of the drug effect depends on the drug concentration
at the receptor site, which, in turn, is determined by both the dose of
drug administered and by the drug’s pharmacokinetic profile, such as
rate of absorption, distribution, metabolism, and elimination
•An agonist is defined as an agent that can bind to a receptor and elicit
a biologic response.
•An agonist usually mimics the action of the original endogenous
ligand on the receptor such as norepinephrine on β1 receptors of the
heart.
•The magnitude of the drug effect depends on the drug concentration
at the receptor site, which, in turn, is determined by both the dose of
drug administered and by the drug’s pharmacokinetic profile, such as
rate of absorption, distribution, metabolism, and elimination
Dose-Response Relationship
•As the concentration of a drug increases, the magnitude of its
pharmacologic effect also increases.
•The response is a graded effect, meaning that the response is
continuous and gradual.
•Plotting the magnitude of the response against increasing doses of a
drug produces a curve which can be described as a rectangular
hyperbola, which is a familiar curve in biology because it can be
applied to diverse biological events, such as ligand binding, enzymatic
activity, and responses to pharmacologic agents.
•Two important properties of drugs, potency and efficacy, can be
determined by graded dose– response curves
•As the concentration of a drug increases, the magnitude of its
pharmacologic effect also increases.
•The response is a graded effect, meaning that the response is
continuous and gradual.
•Plotting the magnitude of the response against increasing doses of a
drug produces a curve which can be described as a rectangular
hyperbola, which is a familiar curve in biology because it can be
applied to diverse biological events, such as ligand binding, enzymatic
activity, and responses to pharmacologic agents.
•Two important properties of drugs, potency and efficacy, can be
determined by graded dose– response curves
Graded dose response
curve
As the concentration of a drug increases, the
magnitude of its pharmacologic effect also
increases. The response is a graded effect,
meaning that the response is continuous and
gradual. Plotting the magnitude of the
response against increasing doses of a drug
produces a curve which can be described as a
rectangular hyperbola, which is a familiar
curve in biology because it can be applied to
diverse biological events, such as ligand
binding, enzymatic activity, and responses to
pharmacologic agents. Two important
properties of drugs, potency and efficacy, can
be determined by graded dose– response
curves
B is a semi-logarithmic plot of same data
curve
As the concentration of a drug increases, the
magnitude of its pharmacologic effect also
increases. The response is a graded effect,
meaning that the response is continuous and
gradual. Plotting the magnitude of the
response against increasing doses of a drug
produces a curve which can be described as a
rectangular hyperbola, which is a familiar
curve in biology because it can be applied to
diverse biological events, such as ligand
binding, enzymatic activity, and responses to
pharmacologic agents. Two important
properties of drugs, potency and efficacy, can
be determined by graded dose– response
curves
B is a semi-logarithmic plot of same data
•An agonist binds to a receptor and produces a biologic response. An
agonist may mimic the response of the endogenous ligand on the
receptor, or it may elicit a different response from the receptor and its
transduction mechanism
•Antagonists are drugs that decrease or oppose the actions of another
drug or endogenous ligand. An antagonist has no effect if an agonist is
not present. Antagonism may occur in several ways. Many antagonists
act on the identical receptor macromolecule as the agonist.
Antagonists, however, have no intrinsic activity and, therefore,
produce no effect by themselves. Although antagonists have no
intrinsic activity, they are able to bind avidly to target receptors
because they possess strong affinity
agonist may mimic the response of the endogenous ligand on the
receptor, or it may elicit a different response from the receptor and its
transduction mechanism
•Antagonists are drugs that decrease or oppose the actions of another
drug or endogenous ligand. An antagonist has no effect if an agonist is
not present. Antagonism may occur in several ways. Many antagonists
act on the identical receptor macromolecule as the agonist.
Antagonists, however, have no intrinsic activity and, therefore,
produce no effect by themselves. Although antagonists have no
intrinsic activity, they are able to bind avidly to target receptors
because they possess strong affinity
•If both the antagonist and the agonist bind to the same site on the
receptor, they are said to be “competitive.” The competitive
antagonist will prevent an agonist from binding to its receptor and
maintain the receptor in its inactive conformational state. For
example, the antihypertensive drug terazosin competes with the
endogenous ligand, norepinephrine, at α1-adrenoceptors, thus
decreasing vascular smooth muscle tone and reducing blood pressure
•The effects of competitive antagonists can be overcome by adding
more agonist.
•Irreversible antagonists, by contrast, cannot be overcome by adding
more agonist
receptor, they are said to be “competitive.” The competitive
antagonist will prevent an agonist from binding to its receptor and
maintain the receptor in its inactive conformational state. For
example, the antihypertensive drug terazosin competes with the
endogenous ligand, norepinephrine, at α1-adrenoceptors, thus
decreasing vascular smooth muscle tone and reducing blood pressure
•The effects of competitive antagonists can be overcome by adding
more agonist.
•Irreversible antagonists, by contrast, cannot be overcome by adding
more agonist
•Irreversible antagonists can act either via binding covalently or with very
high affinity to the active site of the receptor thus less receptor available
for agonist or binding to a site ("allosteric site") other than the agonist
binding site. This allosteric antagonist prevents the receptor from being
activated even when the agonist is attached to the active site
•An antagonist may act at a completely separate receptor, initiating effects
that are functionally opposite those of the agonist. A classic example is the
functional antagonism by epinephrine to histamine-induced
bronchoconstriction. Histamine binds to H1 histamine receptors on
bronchial smooth muscle, causing contraction and narrowing of the
bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial
smooth muscle, which causes the muscles to actively relax. This functional
antagonism is also known as “physiologic antagonism.”
high affinity to the active site of the receptor thus less receptor available
for agonist or binding to a site ("allosteric site") other than the agonist
binding site. This allosteric antagonist prevents the receptor from being
activated even when the agonist is attached to the active site
•An antagonist may act at a completely separate receptor, initiating effects
that are functionally opposite those of the agonist. A classic example is the
functional antagonism by epinephrine to histamine-induced
bronchoconstriction. Histamine binds to H1 histamine receptors on
bronchial smooth muscle, causing contraction and narrowing of the
bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial
smooth muscle, which causes the muscles to actively relax. This functional
antagonism is also known as “physiologic antagonism.”
Therapeutic index
It is the ratio of the dose that produces
toxicity to the dose that produces a clinically
desired or effective response in a population
of individuals:
Therapeutic index = TD50/ED50
where TD50 = the drug dose that produces a
toxic effect in half the population, and ED50
= the drug dose that produces a therapeutic
or desired response in half the population.
The therapeutic index is a measure of a
drug’s safety, because a larger value
indicates a wide margin between doses that
are effective and doses that are toxic
It is the ratio of the dose that produces
toxicity to the dose that produces a clinically
desired or effective response in a population
of individuals:
Therapeutic index = TD50/ED50
where TD50 = the drug dose that produces a
toxic effect in half the population, and ED50
= the drug dose that produces a therapeutic
or desired response in half the population.
The therapeutic index is a measure of a
drug’s safety, because a larger value
indicates a wide margin between doses that
are effective and doses that are toxic
Therapeutic index
•The therapeutic index is determined by measuring the frequency of desired
response and toxic response at various doses of drug.
•By convention, the doses that produce the therapeutic effect (ED50) and
the toxic effect (TD50) in 50 percent of the population are used.
•In humans, the therapeutic index of a drug is determined using drug trials
and accumulated clinical experience. These usually reveal a range of
effective doses and a different (sometimes overlapping) range of toxic
doses. Although some drugs have narrow therapeutic indices, they are
routinely used to treat certain diseases. Several lethal diseases, such as
Hodgkin lymphoma, are treated with narrow therapeutic index drugs, but
treatment of a simple headache with a narrow therapeutic index drug, for
example, would be unacceptable. Figure on the previous page shows the
responses to warfarin, an oral anticoagulant with a narrow therapeutic
index, and penicillin, an antimicrobial drug with a large therapeutic index
•The therapeutic index is determined by measuring the frequency of desired
response and toxic response at various doses of drug.
•By convention, the doses that produce the therapeutic effect (ED50) and
the toxic effect (TD50) in 50 percent of the population are used.
•In humans, the therapeutic index of a drug is determined using drug trials
and accumulated clinical experience. These usually reveal a range of
effective doses and a different (sometimes overlapping) range of toxic
doses. Although some drugs have narrow therapeutic indices, they are
routinely used to treat certain diseases. Several lethal diseases, such as
Hodgkin lymphoma, are treated with narrow therapeutic index drugs, but
treatment of a simple headache with a narrow therapeutic index drug, for
example, would be unacceptable. Figure on the previous page shows the
responses to warfarin, an oral anticoagulant with a narrow therapeutic
index, and penicillin, an antimicrobial drug with a large therapeutic index
MONITORING DRUG TREATMENT
Indications for measuring drug concentration
in various body fluids
•Check that the patient is taking the drug as prescribed (compliance)
•Ensure that the dose is sufficient to produce the required effect but
not so high as to be likely to cause toxic effects
•Help diagnose drug side effects and drug interactions
•Determine the type of drug(s) taken in cases of suspected overdose
and to assess the need for treatment
in various body fluids
•Check that the patient is taking the drug as prescribed (compliance)
•Ensure that the dose is sufficient to produce the required effect but
not so high as to be likely to cause toxic effects
•Help diagnose drug side effects and drug interactions
•Determine the type of drug(s) taken in cases of suspected overdose
and to assess the need for treatment
Questions to be considered when prescribing
a drug
•What effect is it hoped to achieve?
•Is the drug chosen capable of producing the desired effect?
•What are the side effects of the drug, and if they are predictable, do
the likely benefits outweigh the disadvantages?
•Are there any special factors in the patient that increase likelihood of
an abnormal response to the drug?
•How should the effect of the drug be monitored?
•If the drug is not effective, or produces undesirable effects, why does
this happen?
a drug
•What effect is it hoped to achieve?
•Is the drug chosen capable of producing the desired effect?
•What are the side effects of the drug, and if they are predictable, do
the likely benefits outweigh the disadvantages?
•Are there any special factors in the patient that increase likelihood of
an abnormal response to the drug?
•How should the effect of the drug be monitored?
•If the drug is not effective, or produces undesirable effects, why does
this happen?
•Assessing whether the dose of a drug is optimal can be done clinically
or by laboratory assays
•Most drugs can be assessed clinically e.g. measuring blood pressure
for antihypertensive drugs
•In most cases, the optimum dosage can be arrived at by starting with
a standard dose and modifying it as necessary in the light of the
observed response
•In some cases too, the laboratory biochemical effects of the drug can
be measured, such as;
or by laboratory assays
•Most drugs can be assessed clinically e.g. measuring blood pressure
for antihypertensive drugs
•In most cases, the optimum dosage can be arrived at by starting with
a standard dose and modifying it as necessary in the light of the
observed response
•In some cases too, the laboratory biochemical effects of the drug can
be measured, such as;
Some laboratory biochemical effects of drugs
•Plasma potassium concentration during potassium supplementation
•Thyroid stimulating hormone (TSH) concentrations while on thyroxine
therapy
•Plasma calcium concentration and alkaline phosphatase activity during
vitamin D treatment for hypocalcaemia or Osteomalacia
•Plasma cholesterol after hyroxy-malonyl-glutaryl coenzyme A reductase
inhibitor (statin) therapy
•Clotting status as judged by prothrombin time (PT) and the international
normalized ratio (INR) for determining warfarin overdose.
•Blood glucose concentration in a patient with diabetes mellitus treated
with insulin or oral hypoglycaemics
•Plasma potassium concentration during potassium supplementation
•Thyroid stimulating hormone (TSH) concentrations while on thyroxine
therapy
•Plasma calcium concentration and alkaline phosphatase activity during
vitamin D treatment for hypocalcaemia or Osteomalacia
•Plasma cholesterol after hyroxy-malonyl-glutaryl coenzyme A reductase
inhibitor (statin) therapy
•Clotting status as judged by prothrombin time (PT) and the international
normalized ratio (INR) for determining warfarin overdose.
•Blood glucose concentration in a patient with diabetes mellitus treated
with insulin or oral hypoglycaemics
Monitor for possible toxic effects of the drugs
•Proteinuria in patients treated with penicillamine
•Abnormal thyroid function in patients treated with iodine-containing
antiarrhythmic drug amiodarone
•Proteinuria in patients treated with penicillamine
•Abnormal thyroid function in patients treated with iodine-containing
antiarrhythmic drug amiodarone
TDM
•In TDM however, the physician usually asks for laboratory
quantification of drug or metabolite concentration in a body fluid for
the purposes of
a)assessing therapeutic compliance,
b)assessing efficacy, or
c)elucidating the cause of drug- induced toxicity.
•Note that the levels in biological fluids may not parallel tissue level
•In TDM however, the physician usually asks for laboratory
quantification of drug or metabolite concentration in a body fluid for
the purposes of
a)assessing therapeutic compliance,
b)assessing efficacy, or
c)elucidating the cause of drug- induced toxicity.
•Note that the levels in biological fluids may not parallel tissue level
Indications for TDM
•If the desired result cannot be measured precisely: e.g. the incidence of
epileptic fits is a poor indicator of the optimal dosage of anticonvulsants
•If the range of plasma levels that is most effective in producing the desired
result without toxic side effects (therapeutic range) has been defined: this
is particularly true if there is a narrow margin between therapeutic and
toxic drug concentrations, such as in the case of digoxin or lithium. This is
of particular value when the relation between dose and plasma
concentrations of a drug is unpredictable.
•If the prescribed drug is the main active compound and is not metabolized
significantly to an active metabolite: otherwise the active metabolite may
be measured, e.g. phenobarbital in primidone treatment
•If the desired result cannot be measured precisely: e.g. the incidence of
epileptic fits is a poor indicator of the optimal dosage of anticonvulsants
•If the range of plasma levels that is most effective in producing the desired
result without toxic side effects (therapeutic range) has been defined: this
is particularly true if there is a narrow margin between therapeutic and
toxic drug concentrations, such as in the case of digoxin or lithium. This is
of particular value when the relation between dose and plasma
concentrations of a drug is unpredictable.
•If the prescribed drug is the main active compound and is not metabolized
significantly to an active metabolite: otherwise the active metabolite may
be measured, e.g. phenobarbital in primidone treatment
Factors that affect drug plasma
concentrations
•Timing of sample: Samples must be taken at a standard time after
ingestion of the drug, the exact time varying with the known
differences in the rate of absorption, metabolism and excretion of
different drugs
•Patient compliance: Not all patients take drugs exactly as prescribed
e.g. not take at all, take more than prescribed dose, take
intermittently, confused about timing and dose especially if taking
more than one drug. Can lead to poor clinical response or cause
toxicity. Plasma assay of concentration is a crude method of
assessment of compliance and useful for the situation at the time
sample is taken
concentrations
•Timing of sample: Samples must be taken at a standard time after
ingestion of the drug, the exact time varying with the known
differences in the rate of absorption, metabolism and excretion of
different drugs
•Patient compliance: Not all patients take drugs exactly as prescribed
e.g. not take at all, take more than prescribed dose, take
intermittently, confused about timing and dose especially if taking
more than one drug. Can lead to poor clinical response or cause
toxicity. Plasma assay of concentration is a crude method of
assessment of compliance and useful for the situation at the time
sample is taken
Factors that affect drug plasma
concentrations
•Entry of the drug into and distribution through the ECF, thus the rate of
absorption in each patient may be affected by
a)Timing of ingestion with respect to meals
b)Rate of gastric emptying
c)Vomiting, diarrhoea or malabsorption syndromes
d)Administration of other compounds which may bind certain drugs in the
intestinal lumen
•The final plasma concentration of drug reached after a standard amount is
absorbed depends on the volume through which it is distributed, thus
they may be a difficulty in prediction when a patient is oedematous or
obese (larger than normal volume of distribution),likelihood of
unexpectedly low plasma concentrations, contrasted to risk overdosage in
small children with low volume of distribution
concentrations
•Entry of the drug into and distribution through the ECF, thus the rate of
absorption in each patient may be affected by
a)Timing of ingestion with respect to meals
b)Rate of gastric emptying
c)Vomiting, diarrhoea or malabsorption syndromes
d)Administration of other compounds which may bind certain drugs in the
intestinal lumen
•The final plasma concentration of drug reached after a standard amount is
absorbed depends on the volume through which it is distributed, thus
they may be a difficulty in prediction when a patient is oedematous or
obese (larger than normal volume of distribution),likelihood of
unexpectedly low plasma concentrations, contrasted to risk overdosage in
small children with low volume of distribution
Factors that affect drug plasma
concentrations
•Binding to plasma albumin: many drugs are partially inactivated by protein
binding usually albumin. Most drug assays measure the total concentration of
free and protein-bound drug. Changes in concentration of binding proteins can
thus affect concentration of the free form of drug which is the active form and
thus it’s effects and yet may not affect the measured plasma concentration of the
drug.
•When it comes to metabolism and excretion of drugs, the plasma concentration is
dependent on normal hepatic and renal function as well as acid-base and
electrolyte balance. To maintain a reasonably steady plasma concentration, drugs
with a short half-life should be taken more frequently than those with a long half-
life. Steady state is usually reached after about five times the half-life has elapsed
and thus first specimen for monitoring should not be taken earlier. In some cases,
a small increase in the dose of drugs may exceed the capacity of the metabolic
and excretory pathways leading to a disproportionate increase in plasma levels
concentrations
•Binding to plasma albumin: many drugs are partially inactivated by protein
binding usually albumin. Most drug assays measure the total concentration of
free and protein-bound drug. Changes in concentration of binding proteins can
thus affect concentration of the free form of drug which is the active form and
thus it’s effects and yet may not affect the measured plasma concentration of the
drug.
•When it comes to metabolism and excretion of drugs, the plasma concentration is
dependent on normal hepatic and renal function as well as acid-base and
electrolyte balance. To maintain a reasonably steady plasma concentration, drugs
with a short half-life should be taken more frequently than those with a long half-
life. Steady state is usually reached after about five times the half-life has elapsed
and thus first specimen for monitoring should not be taken earlier. In some cases,
a small increase in the dose of drugs may exceed the capacity of the metabolic
and excretory pathways leading to a disproportionate increase in plasma levels
Factors that affect drug plasma
concentrations
•Metabolic conversion may lead to active or inactive metabolites. Ideally a
drug assay should measure all the active forms and none of the inactive
forms
•Drug-drug interactions may occur when different drugs are being
prescribed with one affecting the plasma concentration of the other by
altering its binding to plasma proteins, rate of metabolism or excretion. E.g.
sodium valproate displaces phenytoin from its protein-binding sites and
reduces its rate of metabolism
•Some drugs may also induce the synthesis of enzymes that inactivate
them, and thus higher doses than usual will be needed to produce desired
effect. Also sometimes, reduced receptor sensitivity may require higher
doses than normal in order to increase the plasma concentration and to
achieve the desired effect
concentrations
•Metabolic conversion may lead to active or inactive metabolites. Ideally a
drug assay should measure all the active forms and none of the inactive
forms
•Drug-drug interactions may occur when different drugs are being
prescribed with one affecting the plasma concentration of the other by
altering its binding to plasma proteins, rate of metabolism or excretion. E.g.
sodium valproate displaces phenytoin from its protein-binding sites and
reduces its rate of metabolism
•Some drugs may also induce the synthesis of enzymes that inactivate
them, and thus higher doses than usual will be needed to produce desired
effect. Also sometimes, reduced receptor sensitivity may require higher
doses than normal in order to increase the plasma concentration and to
achieve the desired effect
Factors that affect drug plasma
concentrations
•Another important factor is patient variations affecting rate of metabolism of
drugs
•Age: premature infants with immature detoxifying mechanisms, metabolize and
excrete some drugs more slowly; children with higher metabolic rate than adults
may eliminate some drugs more rapidly; elderly may metabolize drugs slowly
•Genetic or racial factors: various enzymes are responsible for the metabolism of
drugs. Genetic variants of the CYPs have been associated with changes in enzyme
activity, stability and or substrate affinity that can lead to clinically significant
phenotypes. In addition to the genetic variability, many CYP isoenzymes are
susceptible to dramatic differences in expression (>1000-fold) and drug-drug
interactions that can change the phenotype from what might be predicted based
on genetics alone. Debrisoquine hydroxylase activity can be used as a guide to
cytochrome P450 phenotype. It reflects cytochrome (CY) 2D6 status which is
involved in the metabolism of a number of drugs including antiarrhythmics and
antidepressants.
concentrations
•Another important factor is patient variations affecting rate of metabolism of
drugs
•Age: premature infants with immature detoxifying mechanisms, metabolize and
excrete some drugs more slowly; children with higher metabolic rate than adults
may eliminate some drugs more rapidly; elderly may metabolize drugs slowly
•Genetic or racial factors: various enzymes are responsible for the metabolism of
drugs. Genetic variants of the CYPs have been associated with changes in enzyme
activity, stability and or substrate affinity that can lead to clinically significant
phenotypes. In addition to the genetic variability, many CYP isoenzymes are
susceptible to dramatic differences in expression (>1000-fold) and drug-drug
interactions that can change the phenotype from what might be predicted based
on genetics alone. Debrisoquine hydroxylase activity can be used as a guide to
cytochrome P450 phenotype. It reflects cytochrome (CY) 2D6 status which is
involved in the metabolism of a number of drugs including antiarrhythmics and
antidepressants.
Factors that affect drug plasma
concentrations (e.g. of genetic variation)
•Typical example , the inactivation of isoniazid by acetylation depends on
whether the patient is genetically capable of carrying out this process at a
normal rate. Toxicity is likely to set in at lower plasma concentrations in
“slow acetylators” than in “fast acetylators” [N-acetyltransferase (NAT)
polymorphisms]
•Thiopurine methyltransferase (TPMT) is involved in the metabolism of
azathioprine (cytotoxic, immunosuppressant). It shows pharmacogentic
variation and in about 90% of the UK population they have high enzyme
levels. However about 10% are heterozygotic for TPMT deficiency and 0.3%
are homozygotic for no functional activity. These latter 2 groups are more
susceptible to azathioprine toxicity and determination of red cell TPMT
activity prior to azathioprine administration may give a guide as to whom
the drug should be avoided or given at lower doses
concentrations (e.g. of genetic variation)
•Typical example , the inactivation of isoniazid by acetylation depends on
whether the patient is genetically capable of carrying out this process at a
normal rate. Toxicity is likely to set in at lower plasma concentrations in
“slow acetylators” than in “fast acetylators” [N-acetyltransferase (NAT)
polymorphisms]
•Thiopurine methyltransferase (TPMT) is involved in the metabolism of
azathioprine (cytotoxic, immunosuppressant). It shows pharmacogentic
variation and in about 90% of the UK population they have high enzyme
levels. However about 10% are heterozygotic for TPMT deficiency and 0.3%
are homozygotic for no functional activity. These latter 2 groups are more
susceptible to azathioprine toxicity and determination of red cell TPMT
activity prior to azathioprine administration may give a guide as to whom
the drug should be avoided or given at lower doses
Clinical and analytical considerations
•A robust TDM program offers clinicians the means to better manage
patients and has the potential to improve patient quality of life
through optimizing dose, supporting compliance and minimizing
toxicity
•The practice of TDM has been expanded and enhanced by
advancements in rapid, sensitive and specific analytical techniques for
a wide variety of therapeutic agents.
•A robust TDM program offers clinicians the means to better manage
patients and has the potential to improve patient quality of life
through optimizing dose, supporting compliance and minimizing
toxicity
•The practice of TDM has been expanded and enhanced by
advancements in rapid, sensitive and specific analytical techniques for
a wide variety of therapeutic agents.
Clinical utility of TDM
•Best candidate drugs for TDM must have one or more of the
following criteria
a)Narrow therapeutic index
b)Used for long-term therapy
c)Correlation between serum concentration and clinical response
d)Wide interindividual variability in pharmacokinetics
e)Absence of biomarker associated with the therapeutic outcome
f)Administered with other potentially interacting compounds
•Best candidate drugs for TDM must have one or more of the
following criteria
a)Narrow therapeutic index
b)Used for long-term therapy
c)Correlation between serum concentration and clinical response
d)Wide interindividual variability in pharmacokinetics
e)Absence of biomarker associated with the therapeutic outcome
f)Administered with other potentially interacting compounds
Clinical utility
•Under ideal conditions, TDM allows determination of a baseline drug
concentration at a time when the patient is responding well clinically
and is known to be compliant
•Baseline therapeutic concentration can then be used over time to
assess compliance, address physiologic or pathologic changes and
maintain optimal dosing for each individual patient
•Single measurements of serum drug concentrations should always be
interpreted in the context of clinical presentation, length of therapy,
comedications and any other factors capable of influencing serum
concentrations
•Under ideal conditions, TDM allows determination of a baseline drug
concentration at a time when the patient is responding well clinically
and is known to be compliant
•Baseline therapeutic concentration can then be used over time to
assess compliance, address physiologic or pathologic changes and
maintain optimal dosing for each individual patient
•Single measurements of serum drug concentrations should always be
interpreted in the context of clinical presentation, length of therapy,
comedications and any other factors capable of influencing serum
concentrations
Clinical utility
•Some therapeutic agents have convenient biomarkers or clinical indicators
of their efficacy e.g. quantifying cholesterol in statin treatment or
measuring blood pressure in antihypertensive therapy
•For some drugs however, biomarkers and clinical indicators are absent or
not visible till after onset of therapeutic failure e.g. transplant rejection
from inadequate immunosuppression. These kinds of drugs are frequently
managed with TDM especially for conditions with potentially serious risks
to the patient such as such as anti-seizure medication
•Even in some situations with available biomarkers, use of TDM can assist
clinical decision making e.g. on antiarrhytmics fails to improve cardiac
rhythm, TDM may clarify whether the patient requires a different dose, is
refractory to that particular drug, or is simply non compliant
•Some therapeutic agents have convenient biomarkers or clinical indicators
of their efficacy e.g. quantifying cholesterol in statin treatment or
measuring blood pressure in antihypertensive therapy
•For some drugs however, biomarkers and clinical indicators are absent or
not visible till after onset of therapeutic failure e.g. transplant rejection
from inadequate immunosuppression. These kinds of drugs are frequently
managed with TDM especially for conditions with potentially serious risks
to the patient such as such as anti-seizure medication
•Even in some situations with available biomarkers, use of TDM can assist
clinical decision making e.g. on antiarrhytmics fails to improve cardiac
rhythm, TDM may clarify whether the patient requires a different dose, is
refractory to that particular drug, or is simply non compliant
Clinical utility
•The ability to detect non compliance by TDM is very useful without which it
may remain unnoticed until symptoms resume
•Interpatient variability in absorption, metabolism etc, presence of
comorbidities, comedication and their effects can result in poor responses,
and TDM helps to discern which patients are poor responders from those
not in the therapeutic range.
•Routine TDM is also helpful for detecting and managing changes in drug
disposition within an individual. Eg. physiologic processes like puberty,
pregnancy and aging, or reflect progression to pathologic state. Conditions
such as weight loss or severe illness can radically affect the disposition of a
drug within a single patient. Such acute or chronic shifts in
pharmacokinetic behaviour can be addressed more effectively with TDM
because dose adjustments can guide each patient’s drug concentrations
•The ability to detect non compliance by TDM is very useful without which it
may remain unnoticed until symptoms resume
•Interpatient variability in absorption, metabolism etc, presence of
comorbidities, comedication and their effects can result in poor responses,
and TDM helps to discern which patients are poor responders from those
not in the therapeutic range.
•Routine TDM is also helpful for detecting and managing changes in drug
disposition within an individual. Eg. physiologic processes like puberty,
pregnancy and aging, or reflect progression to pathologic state. Conditions
such as weight loss or severe illness can radically affect the disposition of a
drug within a single patient. Such acute or chronic shifts in
pharmacokinetic behaviour can be addressed more effectively with TDM
because dose adjustments can guide each patient’s drug concentrations
Analytical concerns
•Analytical techniques available include
a)Various immunoassays: rapid results and ready automation but
commercial immunoassays not available for most of the newer
generation drugs
b)Chromatographic techniques: improve specificity and limits of
detection but at a lower throughput. Progressively LC-MS/MS is
replacing other HPLC-based methods (greater selectivity, fewer
analytical interferences, allowing development of multianalyte
assays with higher throughput and less influence from metabolites
or other potentially coeluting compounds)
•Analytical techniques available include
a)Various immunoassays: rapid results and ready automation but
commercial immunoassays not available for most of the newer
generation drugs
b)Chromatographic techniques: improve specificity and limits of
detection but at a lower throughput. Progressively LC-MS/MS is
replacing other HPLC-based methods (greater selectivity, fewer
analytical interferences, allowing development of multianalyte
assays with higher throughput and less influence from metabolites
or other potentially coeluting compounds)
Analytical concerns
•Concerns similar to other areas of clinical chemistry such as: accurate
reproducible methods; quality assurance and proficiency testing programs;
established target ranges (therapeutic indices); critical values (toxic
concentrations)
•Some preanalytical/analytical issues e.g. some pharmaceuticals adsorb to
the gel matrix in serum /plasma separator tubes causing falsely low drug
concentrations, time of blood draw relative to administration of drug
important in interpreting results (many protocols require sampling at
trough especially if half–life is short)
•Also important is determination of which metabolites and which fractions
(free/protein-bound) are clinically relevant. Active metabolite should be
quantified (active parent plus active metabolite) concentration together
considered in interpreting.
•Concerns similar to other areas of clinical chemistry such as: accurate
reproducible methods; quality assurance and proficiency testing programs;
established target ranges (therapeutic indices); critical values (toxic
concentrations)
•Some preanalytical/analytical issues e.g. some pharmaceuticals adsorb to
the gel matrix in serum /plasma separator tubes causing falsely low drug
concentrations, time of blood draw relative to administration of drug
important in interpreting results (many protocols require sampling at
trough especially if half–life is short)
•Also important is determination of which metabolites and which fractions
(free/protein-bound) are clinically relevant. Active metabolite should be
quantified (active parent plus active metabolite) concentration together
considered in interpreting.
Analytical concerns
•Sometimes inactive metabolites are of interest too because it may be
associated with toxicity independent of drug’s intended activity as
with N-acetyl-p-benzoquinone imine a metabolite from
acetaminophen or may serve as a reservoir for conversion to active
drug.
•Sometimes inactive metabolites are of interest too because it may be
associated with toxicity independent of drug’s intended activity as
with N-acetyl-p-benzoquinone imine a metabolite from
acetaminophen or may serve as a reservoir for conversion to active
drug.
Specific drug groups
•Drugs routinely monitored are classified by type of therapy they support.
These include
•Anticonvulsants: examples are phenytoin, carbamazepine, valproate. Once
the dose that gives stable plasma concentration within therapeutic range
has been determined, monitoring becomes necessary in the following
cases
a)To assess compliance
b)If the frequency of fits increases in a previously well-controlled patient
c)If another drug is prescribed that may affect the plasma concentrations
•Plasma concentrations in children and pregnant women should be
monitored more frequently as these groups are more likely to develop
toxicity
•Drugs routinely monitored are classified by type of therapy they support.
These include
•Anticonvulsants: examples are phenytoin, carbamazepine, valproate. Once
the dose that gives stable plasma concentration within therapeutic range
has been determined, monitoring becomes necessary in the following
cases
a)To assess compliance
b)If the frequency of fits increases in a previously well-controlled patient
c)If another drug is prescribed that may affect the plasma concentrations
•Plasma concentrations in children and pregnant women should be
monitored more frequently as these groups are more likely to develop
toxicity
Specific drug groups
•Antimicrobial agents: these include a very wide range of compounds with very
different target organisms, mechanisms of activity and pharmacokinetics. Efficacy
of the therapy is dependent on both the drug and the infectious agent therefore
TDM for these requires knowledge of the pharmacological and toxicological
characteristics of the drug, as well as nature of the infection it is intended to
treat.
•Antibacterials: susceptibility of bacteria to antibiotics is commonly measured in
terms of the minimum inhibitory concentration (MIC) i.e. is concentration of drug
sufficient to inhibit growth of an organism. MIC varies widely for different strains
of the same species and therefore cultures must be obtained from each person to
ascertain the organism involved and the vulnerability to a panel of agents.
•TDM for antibiotics often involves relating some aspect of serum concentration of
drug (Area under the curve AUC, maximum serum concentration Cmax, or time
above a concentration) to the MIC
•Other antimicrobials include antifungals, antiretrovirals
•Antimicrobial agents: these include a very wide range of compounds with very
different target organisms, mechanisms of activity and pharmacokinetics. Efficacy
of the therapy is dependent on both the drug and the infectious agent therefore
TDM for these requires knowledge of the pharmacological and toxicological
characteristics of the drug, as well as nature of the infection it is intended to
treat.
•Antibacterials: susceptibility of bacteria to antibiotics is commonly measured in
terms of the minimum inhibitory concentration (MIC) i.e. is concentration of drug
sufficient to inhibit growth of an organism. MIC varies widely for different strains
of the same species and therefore cultures must be obtained from each person to
ascertain the organism involved and the vulnerability to a panel of agents.
•TDM for antibiotics often involves relating some aspect of serum concentration of
drug (Area under the curve AUC, maximum serum concentration Cmax, or time
above a concentration) to the MIC
•Other antimicrobials include antifungals, antiretrovirals
Aminoglycoside as an example
•Gentamicin is an example of aminoglycoside and is given IV or IM
•There are nephrotoxic and ototoxic, but considerably high concentrations are
needed for bactericidal effect. The half-life is also short.
•Toxicity is related to the trough concentration (found immediately before the next
dose) and bactericidal action requires sufficient peak concentration (achieved
shortly after a dose has been given)
•Thus trough level ensures levels are not already too high and further
administration not likely to cause toxicity or so low they are not effective. The
second sample is taken an hour after injection (expected peak) to ensure
adequate concentration achieved for bactericidal action
•Peak and trough concentrations can be manipulated independently to some
extent by altering the dose and frequency of dosage. Increasing dose will increase
both, but if peak is satisfactory and trough too low, the same dose can be given
but at more frequent intervals.
•Gentamicin is an example of aminoglycoside and is given IV or IM
•There are nephrotoxic and ototoxic, but considerably high concentrations are
needed for bactericidal effect. The half-life is also short.
•Toxicity is related to the trough concentration (found immediately before the next
dose) and bactericidal action requires sufficient peak concentration (achieved
shortly after a dose has been given)
•Thus trough level ensures levels are not already too high and further
administration not likely to cause toxicity or so low they are not effective. The
second sample is taken an hour after injection (expected peak) to ensure
adequate concentration achieved for bactericidal action
•Peak and trough concentrations can be manipulated independently to some
extent by altering the dose and frequency of dosage. Increasing dose will increase
both, but if peak is satisfactory and trough too low, the same dose can be given
but at more frequent intervals.
Other drugs
•Antineoplastics: e.g. methotrexate
•Cardioactive drugs: e.g. digoxin
•Immunosuppressants: e.g. azathioprine
•Antineoplastics: e.g. methotrexate
•Cardioactive drugs: e.g. digoxin
•Immunosuppressants: e.g. azathioprine
SUMMARY
•TDM is the measurement of the concentration of drugs, usually in plasma, to
provide a guide to the dose to prescribe
•It is valuable for drugs with low therapeutic ratio (the range of plasma
concentrations over which the maximum beneficial effect is seen is only a little
less than that at which it becomes toxic)
•Also valuable for drugs difficult to assess clinically
•It is not required for drugs whose effects can readily be assessed clinically or
laboratory measurements, or when drug of low toxicity has virtually guaranteed
effect when given in a standard dose
•It is of no value when the effect of a drug is due to a metabolite unless the
metabolite concentration can be measured
•Measurement of drug concentrations in body fluids are also valuable in the
investigation and management of patients who have taken overdoses of drugs or
been poisoned.
•TDM is the measurement of the concentration of drugs, usually in plasma, to
provide a guide to the dose to prescribe
•It is valuable for drugs with low therapeutic ratio (the range of plasma
concentrations over which the maximum beneficial effect is seen is only a little
less than that at which it becomes toxic)
•Also valuable for drugs difficult to assess clinically
•It is not required for drugs whose effects can readily be assessed clinically or
laboratory measurements, or when drug of low toxicity has virtually guaranteed
effect when given in a standard dose
•It is of no value when the effect of a drug is due to a metabolite unless the
metabolite concentration can be measured
•Measurement of drug concentrations in body fluids are also valuable in the
investigation and management of patients who have taken overdoses of drugs or
been poisoned.
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