Therapeutic drug monitoring deals with
the measurement of drug and its metabolites during therapy with pharmaceutical
agents at a particular time. The world therapeutic is an
adjective that describes the drug. A therapeutic drug produces a
healing or curative effect when an undesirable physiological or psychological
condition is present.
A drug can be defined as
a chemical used to selectively perturb specific tissues or specific functions
of these tissues in an organism. A chemical is considered a drug only if it has
the following characteristics:
1. Selectivity
to its site of action or target
2. Reversibility
in its action.
3. Production
of a beneficial or therapeutic effect
Monitoring implies a
constant process of determining the quantity of drug required to produce a
predetermined desirable effect. Monitoring or analyzing a tissue or fluid to
determine the concentration of drug in the body is of utmost importance,
especially when trying to maintain the fine line between productions of
therapeutic versus toxic effects.
Therapeutic drug monitoring is
sometimes incorrectly classified under the subject heading toxicology. Toxicology
and therapeutic drug monitoring shares the same feature of drug monitoring. The
clinical toxicology laboratory, however, monitors substances that have no
curative effects, either by nature of the chemical itself or by the higher than
normal level of exposure of the individual to the chemical. Thus, toxicology
may be considered non–therapeutic drug monitoring. The status of patient in
toxicology is confused, disoriented or unconscious and therefore unreliable in
providing a complete history. In contrast, patients being monitored for
therapeutic drugs are more likely to be amenable to treatment, have a known history
and be on a carefully controlled drug regimen.
Purposes of Therapeutic Drug
Monitoring
1. To
determine when changes in the therapeutic regimen to be made because of either
failure to respond to treatment or symptoms of toxicity. Prime candidates for
this:
a. Neonates
and geriatrics
b. Patients
with mitigating medical conditions
c. Patients
undergoing multiple drug therapy
2. To
determine if the patient is actually taking the prescribed drug in the
prescribed dosage
Terms used to describe a
therapeutic drug
1. Dose
is the amount of drug administered.
2. Dose–response
curve is a plot of the intensity of drug response as a function of the dose of
drug.
3. Minimum
effective concentration (MEC) is the lowest concentration of drug in the blood
that will produce the desired response.
4. Minimum
toxic concentration (MTC) is the lowest concentration of drug in the blood that
will produce an adverse response.
5. Multiple
dosing administrations of a set amount of drug at regular intervals but the
individual doses will produce the expected rise and fall in the blood level but
the cumulative effect is a gradual increase in the concentration of drug in the
system.
6. Peak
is the highest concentration of drug measured in blood.
7. Therapeutic
index is the ratio of the MTC to the MEC and varies from drug to drug and even
from patient to patient.
8. Therapeutic
range is the level of concentration in the bloodstream which provides the
optimum amount of medication for treatment of the clinical disorder.
9. Trough
is the lowest concentration of drug measured in blood. The trough should be
reached immediately before the next dose of drug and should not fall below the
MEC.
Different processes undergone
by drug
1.
Absorption
Absorption is
the process whereby a drug taken into the body enters the blood. Drugs maybe
formulated to be available for absorption at sites different from the site of
administration
Sites of
administration:
a.
Oral, rectal
or sublingual
Drugs administered
by this method are absorbed via the small intestine and pass through the
intestinal wall to reach the circulation.
After
absorption in the bloodstream, the drug then passes through the circulatory
system of the liver via the hepatic portal vein, a process known as first
past route. A number of liver enzymes convert the drug to other forms,
both active and inactive.
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For some drugs
that undergo a first –pass effect, the blood concentration of active drug is
decreased because of the production of many inactive metabolites. However,
other drugs are metabolized to compounds that themselves have pharmacologic
activity, causing an increase therapeutic response in the patient.
b.
Parenteral
administration
(1) Intravenous
– injection of drugs into veins
(2) Intramuscular
– injection of drugs into muscles
(3) Intradermal
– injection of drugs into the skin
(4) Intrathecal
– injection of drugs into the spinal fluid
c.
Other routes
of administration
(1) Inhalation
of gaseous drugs
2.
Distribution
or transport
Blood is the
vehicle by which drugs are translocated to all organs and fluid compartments.
Depending upon the pH of the physiologic environment, drugs may exist in ionized
and non–ionized forms.
Each drug has
a particular dissociation constant (pK), which is defined as the pH at which
there is an equal concentration of ionized and non–ionized forms. Only the non–ionized
forms of drugs are lipid soluble and can penetrate the lipid cellular
component.
Base on Henderson–Hasselbach
equation, the following rules determines if the drug can penetrate the cell or
not:
a. An
acidic drug can be considered as
(1) Ionized
form if the pH of the environment exceeds the pK.
(2) Non
– ionized form if the pH of the environment is less than the pK.
Example:
Acetylsalicylic
acid is an acidic drug with a pK of 3.5, while the stomach has a pH of 1.0.
Thus, it can be absorbed.
pK = pH + log [non
– ionized form]
[ionized form]
3.5 =
1.0 + log [non–ionized form]
Ionized form
b. A
basic drug can be considered as:
(1) Ionized
form if the pH of the environment is less than the pK.
(2) Non
– ionized form if the pH of the environment exceeds the pK
Depending on
the individual drug and the concentration of serum proteins, a drug may
distribute in a protein–bound form. Albumin and alpha–1–acid glycoprotein are
the usual, although not the exclusive, drug binding protein. A protein–bound
drug is pharmacologically active. The extent of protein binding is a factor
unique to each drug and most drugs exist in equilibrium between bound and unbound
forms.
Conditions or
disease states that decrease the serum protein concentrations, such as hepatic
disease or hypoalbuminemic renal failure, may cause increased serum drug
concentration with concomitant toxicity. The toxicity results from less protein
available for binding and an increased concentration of the free,
pharmacologically active drug.
Complications
may also arise when a second drug is added to a patient’s treatment regimen. If
the first drug has an intermediate or low affinity for protein binding and the
second drug has a higher affinity for protein binding, the first drug can be
competitively displaced from protein–binding sites by the second drug. The
amount of the unbound, pharmacologically active form of the first drug then
increases and toxicity can result even though administered dose of the drug was
unchanged.
3.
Metabolism or
biotransformation
The major site
of drug metabolism or biotransformation, is the liver. Secondary sites include
lungs, kidneys, skin, brain and gastrointestinal tract. The unmetabolized drug
is often referred to as the parent compound and the products of
metabolism are referred to as metabolism.
a.
A drug may be
metabolize in one of the three ways:
(1) Activation
– increase in activity
(2) Inactivation
– decrease in activity
(3) No
effect
b.
Two major
metabolic pathways:
(1)
Phase I or
Cytochrome P–450 system
(a) Lipophilic
drugs are metabolized to more polar forms to facilitate renal excretion. This
is accompanied by oxidative or reproductive such as:
Hydroxylation
Deamination
Sulfoxidation
Dealkylation
(b) A
group enzyme of the smooth endoplasmic reticulum called monooxygenase or
mixed–function oxidases contributes in drug’s biotransformation. In a series of
electron–transfer reactions, an oxidized form of the drug is produced that more
polar than the parent compound
(c) Cytochrome
P–450, a heme–containing protein, is involved in the final reaction
(2)
Phase II
reaction
(a) These
reactions involve the conjugation of drugs with compounds such as glutathione,
sulfonic acid, glucuronic acid or amino acid (particularly glycine) to
facilitate their elimination.
(b) Specific
enzymes catalyze each conjugation reaction, depending on the substrate used.
The conjugates produced are water–soluble entities and can be readily excreted
by the kidneys.
c. For
a drug to produce an effect it must enter cells; drugs in the blood are, for
the most part, pharmacologically ineffective. Therefore, the measurement of the
concentration of drug in the blood is only an estimate of the concentration of
drug available at its target site. Many drugs enter cells via receptors.
Receptors are usually proteins, located on the cellular membrane of the
cytoplasm with which the drug binds. The interaction of drug receptor is
reversible; it is only desirable that the effect produced by the drug last for
a limited time.
4.
Excretion
a. The
major route of drug excretion is the kidney. Acidic urine facilitates
elimination of basic drugs and alkaline urine facilitates elimination of acidic
drugs by extraction from the plasma.
b. Drugs
and their metabolites may also be excreted in bile, feces, saliva, expired air
and breast milk but urine is most frequently assayed to indicate previous drug
exposure.
Concept of pharmacokinetics
Pharmacokinetics measures the
rates of absorption, distribution, biotransformation and excretion and is
necessary component of therapeutic drug monitoring.
The half life (t½)
of a drug indicates the time required for elimination. It is defined as the
time required for the concentration of a drug to be decreased by one half.
Information of drug half–life is important to determine if therapeutic levels
have been achieved and maintained and also to schedule optimal dosing
intervals.
Half–life can be
determined by plotting concentrations versus time on semi logarithmic paper and
drawing a straight line through the points. The time required for any
concentration to decrease by one half can be easily determined and is the
half–life of the drug.
The apparent volume of
distribution (Vd) relates the absolute amount of drug in the body to a
relative amount (in volume). It is a parameter used to contrast the degrees to
which different types of drugs distribute.
Total plasma clearance (ClT) is the sum of
all processes by which a drug is cleared from the body per unit time. It
indicated the volume of plasma that must be completely cleared of drug,
frequently expressed in liters per hour, to account for drug elimination. ClT provide a measurement of the body’s
ability to eliminated a drug and to convert a pharmacologically active drug to
a pharmacologically inactive drug.
Variables affecting drug
disposition
1.
Physiologic
factors
a. Age
b. Gender
c. Body
size and composition
d. Pregnancy
e. Nutritional
status
f.
Activity
g. Emotional
mood
h. Body
temperature
2.
Genetic
heterogeneity
3.
Pathologic
conditions
4.
Drug interaction
a. Drug
against drug
b. Drug
against diet
c. Drug
against disease
Classification of Therapeutic
Drugs
1.
Antiarrythmics
and cardioactive drugs
Propranolol
Digoxin
Digitoxin
Lidocaine
Quinidine
Disopyramide
Procainamide
2.
Anticonvulsants
and antiepileptic drugs
Phenobarbital
Phenytoin
Valproic acid
Primidone
Carbamazepine
Ethosuximide
3.
Bronchodilator
Theophylline
4.
Antimicrobial
drugs
Streptomycin
Gentamicin
Kanamycin
Tobramycin
Neomycin
Chlorampenicol
Vancomycin
5.
Pyschotropic
drugs
Imipramine
Desipramine
Amitriptyline
Nortriptyline
Doxepine
Maprotiline
Lithium
6.
Antispsychotic
drugs
Chlorpromazine
Triflupromazine
Promethazine
Haloperidol
7.
Antineoplastic
drugs
Methotrexate
Cisplatin
Cyclophosphamide
****** ANTIARRYTHMIC AND CARDIOACTIVE DRUGS ******
1.
Propranolol
Propranolol is
a non–selective β–adrenergic blocker that acts as β1–receptors in
the myocardium and β2–receptors in the lungs, vascular smooth muscle
and kidney. Within the myocardium, it depresses heart rate, conduction
velocity, myocardial contractility and automaticity. For toxicologic
emergencies, it is usually administered by IV route. After IV injection, the
onset of action is nearly immediate and the duration of effect is 10 minutes to
2 hours, depending on the cumulative dose. The drug is eliminated by hepatic
metabolism, with a half–life of about 2–3 hours
a.
Indications
(1) To
control excessive sinus tachycardia or ventricular arrhythmias caused by
catecholamine excess (e.g. theophylline, caffeine) or sympathomimetic drug
intoxication (e.g. amphetamines, ephedrine, cocaine)
(2) To
control hypertension in patients with excessive β1–mediated increase
in heart rate and contractility used in conjunction with a vasodilator (e.g.
phentolamine) in patients with mixed alpha and β–adrenergic hyperstimulation
(3) To
raise the diastolic blood pressure in patients with hypotension due to
excessive β2–mediated vasodilation (e.g. theophylline or caffeine
intoxication)
b.
Contraindication
(1) Use
with extreme caution in patient with asthma, congestive heart failure, sinus
node dysfunction or other cardiac conduction disease and in those receiving
cardiac–depressant drugs.
(2) Do
not use as single therapy for hypertension due to sympathomimetic overdose; it
produces peripheral vascular beta–blockade, abolishing β2–mediated
vasodilation and leaving unopposed α–mediated vasoconstriction, resulting in
paradoxic worsening of hypertension.
c.
Adverse
effects
(1) Bradycardia,
sinus and atrioventricular block
(2) Hypotension,
congestive heart failure
(3) Bronchospasm
in patients with asthma or bronchospastic chronic obstructive pulmonary
disease.
d.
Drug
interaction
(1) Additive
hypotensive effect with other antihypertensive agents
(2) Potentiate
competitive neuromuscular blockers
(3) Additive
depressant effect on cardiac conduction and contractility when given with same
calcium antagonists (e.g., verapamil, diltiazem)
(4) Cimetidine
reduces hepatic clearance of propranolol
2.
Digoxin and
Digitoxin
Extracted from
the leaves of the foxglove plant (Digitalis lanata or Digitalis pupurea), both
are classified as cardiac glycosides.
a.
Indications
(1) Treatment
of congestive heart failure
(2) Increases
the force of heart’s contraction but decreases its rate, i.e., to slow and
strengthen the contraction
b.
Contraindication
(1) Affects
cellular potassium transport, and since decreased potassium levels potentiate
cardiac glycoside toxicity, potassium is monitored and is often supplemented
when patients are treated with these drugs.
(2) Both
drugs have a low therapeutic index and frequent monitoring of plasma levels is
required. These drugs concentrate in cardiac tissue at levels 15–30 times those
found in the blood. Therapeutic levels are determined 8 hours after dosing.
c.
Adverse
effects
(1) Bradycardia,
arrhythmia, coma and death
d.
Drug
interactions
(1) Glycoside
toxicity may result when used with quinidine
Comparison
between Digoxin and Digitoxin
Digoxin
Digitoxin
Use frequently
prescribed infrequently
prescribed
Plasma half
life 1 – 2 days 4 – 6 days
Protein
binding 25% 96%
Therapeutic
plasma
concentration 0.8 – 2 ng / ml 15
– 25 ng / ml
Oral
absorption 65 – 80% 90 – 100%
Hepatic
metabolism none or
glucuronide inactive
metabolites
conjugates
Patient
treated reduced
hepatic function reduced renal function
Excretion renal renal,
hepatic
3.
Lidocaine
a.
Indication
(1) Treatment
of cardiac dysrhythmias because of its anesthetic effect
(2) It
decreases local abnormal initiation of nerve impulses in the heart and is
widely used in the treatment of premature ventricular contraction (PVCs).
b.
Adverse
effects
(1) Dizziness,
excitement or drowsiness and disorientation followed by convulsion, coma and
respiratory arrest.
c.
Active
metabolites
(1) Monoethylglycinexylidide
(MEGX)
(2) Glycinexylidide
4.
Quinidine
a.
Indications
(1) Treatment
of rapid irregular heartbeats by blocking abnormal electrical impulses,
decreasing blood pressure and decreasing contraction force.
(2) Antimalarial,
antipyretic and oxytocic effects
b.
Adverse
effects
(1) Cinchornism,
a group of CNS symptom like headache, deafness, tinnitus, lightheadedness and
giddiness
(2) Hematologic
abnormalities such as leukopenia, thrombocytopenia and anemia
c.
Drug
interaction
(1) Toxicity
enhancement of cardiac glycosides
(2) Oral
administration is most common because intravenous administration may cause a
precipitous decrease in blood pressure
5.
Procainamide
a.
Indication
(1) Decreases
heart rate and blood pressure
(2) It
is metabolized by acetylation to the pharmacologically active compound
N–acetylprocainamide (NAPA)
b.
Adverse
effects
(1) Hypotension,
agranulocytosis, development of systemic lupus erythematosus (SLE).
6.
Disopyramide
a.
Indications
(1) Treatment
of premature ventricular contractions and in the prophylactic prevention of
sudden death after myocardial infarction
b.
Adverse
effects
(1) Because
of it anticholinergic (prevention of normal digestive function) property, it
causes dry mouth, urinary hesitance and constipation.
****** ANTICONVULSANTS AND ANTIEPILEPTIC DRUGS ******
1.
Phenobarbital
a.
Indication
(1) Treatment
of all seizures except absence seizures that is unresponsive to conventional
anticonvulsant therapy (e.g., diazepam, phenytoin)
b.
Contraindication
(1) Known
sensitivity to the drug
(2) Manifest
or latent porphyria
c.
Adverse
effects
(1) CNS
depression, coma and respiratory arrest may occur especially with rapid bolus
or excessive doses
(2) Hypotension
may result, especially with rapid intravenous infusion
(3) Laryngospasm
and bronchospasm have been reported after rapid intravenous injection, although
the mechanism is unknown.
d.
Drug interaction
(1) Phenobarbital
has additive CNS and respiratory depression effects with other drugs.
2.
Phenytoin
a.
Indication
(1) Control
of generalized tonic–clonic seizures or status epilepticus caused by various
drugs and poisons.
(2) Control
of cardiac arrhythmias associated with digitalis intoxication
b.
Contraindication
Do not use if
the patient has a known hypersensitivity to phenytoin or other hydrantoins
c.
Adverse
effects
(1) Rapid
IV administration (less than 50 mg/min in adults or 1 mg/kg in children) may
produce hypotension, atrioventricular block and cardiovascular collapse,
probably owing to the propylene glycol diluent.
(2) Extravasation
may result in local tissue necrosis and sloughing
(3) Drowsiness,
ataxia, nystagmus and nausea
d.
Drug
interaction
The various drug
interactions associated with chronic phenytoin dosing (i.e., accelerated
metabolism of other drugs) are not applicable to its acute emergency use.
3.
Valproic acid
Valproic acid
is notable because it is structurally unlike the other anticonvulsant drugs,
being a simple 8–C, branched–chain fatty acid. Its therapeutic concentration is
50–100 ug / ml, its half-life is 15 hours and is highly protein bound (93%).
Valproic acid has metabolic effects opposite those produce by phenobarbital; it
inhibits the microsomal mixed function oxidase system, thereby decreasing
metabolism and increasing plasma levels of other drugs.
4.
Primidone
This is the
metabolized by oxidation to phenorbarbital; therefore, phenobarbital
concentrations must be assayed when therapeutic primidone concentrations are
assayed. Another metabolite is phenylethylmalomide, which also has
anticonvulsant activity. The therapeutic concentration of primidone is 8–10
ug/ml and its half-life is 8 hours. Side effects include ataxia and sedation.
5.
Carbamazepine
This drug is
rarely the first choice among anticonvulsant drugs and is usually prescribed
only for individuals who have not responded satisfactorily to treatment with
other drugs. Carbamazepine therapy requires frequent monitoring of hematologic,
hepatic and renal functions because its use is associated with aplastic anemia,
hepatic injury, hypertension and acute urinary retention.
6.
Ethosuximide
Used only in
the treatment of absence seizures, also called petit mal seizures. These
seizures begin in early childhood but usually do not persist after the age of
20. They are characterized by 5 to 30 seconds of “absence,” in which the
individual is not fully conscious but not unconscious and can keep from falling
but may exhibit minor motor movements.
****** BRONCHODILATORS ******
1.
Theophylline
a.
Indications
(1) CNS,
respiratory and cardiac stimulant
(2) Causes
smooth muscle relaxation and diuresis
(3) Treatment
of asthma, chronic obstructive pulmonary disease and apnea of the premature
newborn.
b.
Adverse
effects
(1) Nausea,
vomiting, diarrhea, irritability and insomnia
****** ANTIMICROBIAL AGENTS ******
1.
Aminoglycosides
a. Streptomycin,
gentamicin, kanamycin, tobramycin and neomycin are examples of this drug.
b.
Indication
(1) Treatment
of infection of gram–negative bacteria
c.
Adverse
effects
(1) Ototoxicity,
involving both auditory (hearing) and vestibular (balance) function maybe
permanent
2.
Chloramphenicol
a.
Indication: Treatment of infection caused by
gram–negative bacteria.
b.
Adverse
effects:
(1) Bone
marrow depression leading to pancytopenia. This condition may occur in patients
who are on prolonged chloramphenicol therapy of who have been treated with
repeated courses of the drug.
(2) Neonate
with this drug develops fatal toxicity because of problems in metabolism and
excretion. The first manifestations of this “gray baby” syndrome are vomiting,
irregular and rapid respiration, diarrhea and cyanosis, followed by development
of flaccidity, an ashen gray color and hypothermia
3.
Vancomycin
a.
Indication
(1) Treatment
of infection caused by gram positive bacteria by inhibiting the synthesis of
bacterial cell wall and cytoplasmic membrane
b.
Adverse
effects
Ototoxicity
and nephrotoxicity
****** PSYCHOTROPIC DRUGS ******
1.
Tricyclic antidepressant
a. Imipramine
b. Desipramine
c. Amitriptyline
d. Nortriptyline
e. Doxepin
2.
Tetracycline
antidepressant
a. Maprotiline
3.
Adverse
effects of psychotropic drugs
a. Sedation,
anticholinergic effects (dry mouth, urinary retention, constipation) and
cardiac effects, including palpitations, tachycardia (abnormally rapid
heartbeat) and orthostatic hypotension.
b. Cardiac
dysrhythmias
4.
Lithium
a.
Indication
(1) Treatment
of bipolar disorder or manic–depressive illness.
(2) Substitute
for sodium and potassium ions in cellular transport and decrease catecholamine
activity
b.
Adverse
effects
(1) GI,
neuromuscular, CNS, mental and cardiovascular disorder
(2) Muscle
twitching and rigidity, a hyperactive deep tendon reflex and epileptic seizures.
****** ANTIPSYCHOTIC DRUGS ******
1.
Phenothiazine
group
Chlorpromazine
Trifluopromazine
Promethazine
a.
Indication
(1) Treatment
of psychiatric illness.
(2) Antiemetic
action, effects on central skeletal muscle mechanism, alteration of temperature
regulation, endocrine actions and peripheral nervous system effects.
b.
Adverse
effects
(1) Tachycardia,
hypothermia, lethargy, orthostatic hypotension and dryness of mouth.
2.
Butyrophenone
group
Haloperidol
Indication and
adverse effects are similar to phenothiazine group except for its chemical
structure.
****** ANTINEOPLASTIC DRUGS ******
1.
Methotrexate
a.
Indication
Inhibition of
proliferation of malignant cells and benign cells
b.
Mechanism of
action
(1) It
is cell cycle–specific drug (one that inhibits cell replication during a
specific phase of the cell cycle) that inhibits the synthesis of DNA.
(2) It
accomplishes this by inhibition of dihydrofolate reductase, an enzyme needed
for the formation of tetrahydrofolate, an essential compound in DNA, RNA and
amino acid synthesis
(3) Malignant
cells, which divide more rapidly and therefore synthesize more DNA than non–malignant
cells, are particularly susceptible to the drug’s effect.
c. Adverse
effect: hepatotoxicity
2.
Cisplatin and
cyclophosphamide (alkylating agents)
a.
Indication: same as
methotrexate
b.
Mechanism of
action
(1) Replacement
of normal atoms with alkyl groups.
(2) When
this replacement occurs in DNA, the alkylated DNA cannot undergo correct
replication or transcription, leading to cell death.
(3) Alkylating
agents are cell cycle – non–specific drugs and act on either actively dividing
or resting cells.
(4) Cyclophosphamide
requires hepatic biotransformation by the microsomal mixed–function oxidase
system to produce its active metabolites, 4–hydroxycyclophosphamide and
aldophosphamide, which in turn produce the alkylating cyclophosphamide mustard.
c.
Adverse
effects
(1) Hematologic
suppression, nausea, vomiting and reproductive dysfunction
(2) Cisplatin,
a platinum–containing compound, has additional nephrotoxic and ototoxic
effects.
Methods of quantitation
1. Spectrophotometric
a. Colorimetric
b. Fluorometric
2. Immunoassays
3. Chromatographic
Quantitation
of drugs using saliva in neonates
A number of
studies have shown that only free drug appears in saliva; material bound to
protein does not pass through membrane. Fairly good correlations have been
reported between saliva levels of a particular compound and the level of
unbound material in serum or plasma. This technique also has the advantage of
being non–invasive; no venipuncture necessary to obtain sample. One drawback is
the quite variable rate of saliva production.
Precaution in specimen
collection
1. Time
of specimen collection should always be noted to assure accuracy of results.
2. For
patients who are multi–dosing, list of drugs being received and the time of
administration should always be noted.
3. If
peak or trough drug levels is requires:
a. Peak
drug levels are drawn immediately upon attainment of steady–state levels.
b. Trough
drug levels are drawn immediately before administration of the subsequent dose.
4. Route
of administration should also be noted.
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