03 September 2016

Lecture #13: THERAPEUTIC DRUG MONITORING




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.

Click here for Liver Function Test
Click here for Enzymology

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. Clprovide 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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