Therapeutic drug monitoring _TDM_

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Therapeutic drug monitoring (TDM).

Pharmacodynamic measures of response include clinical or laboratory
measurements such arterial blood pressure in patients with hypertension, peak
expiratory flow rate in patients with asthma, INR in patients treated with oral
Pharmacokinetic measures (measurement of drug concentrations in the
blood or plasma TDM) facilitates adjustment of dosage to produce a
desired response when:
1. clinical end point is quantal (a grand mal seizure), and there is no satisfactory
   intermediate end point which is a continuous variable (such as blood
2. interindividual variability in plasma concentrations from the same dose is
   large and unpredictable (phenytoin with zero-order kinetics)
3. a low therapeutic index
4. a narrow therapeutic window
5. noncompliance with therapy
6. intoxication

Drugs for which therapeutic drug monitoring is used:
     Digoxin (therapeutic range 0.8-2 g/ml) and other cardiac glycosides. TDM can be
useful as a guide to individualize therapy (suspected toxicity, poor compliance).
Cardiotoxicity of digoxin is increased by hypokalemia and concomitant use chinidin.

       Lithium plasma concentrations in samples obtained 12 hr after dosing of 0.75-1.25
mmol/l are usually regarded as therapeutic.

       Aminoglycosides. Cmax measured 30 min after dosing of 7-10 mg/L are usually
effective against sensitive organisms. Gentamicin .Trough levels taken immediately before a
dose, of 1 to not  2 mg/L reduce the risk of otoxicity. Amikacin, netilmycin : the resirable
peak concentration is 4-12 mg/L, with a trough value not  4 mg/L. Tobramycin peak 4-5
mg/L, trough not  2 mg/L.

       Phenytoin (usual therapeutic range 10-20 mg/L) and some other anticonvulsants
including carbamazepine (approximate therapeutic range 5-10 mg/L).
When using the steady-state plasma concentration of phenytoin as a guide to dose
adjustment, it is important to be aware of the non-linear nature of its pharmacokinetis, and
of possible effects on concurrent renal and hepatic disease or of pregnancy on its distribution.

       Methotrexate (MTX).
MTX is the only cytostatics whose toxicity can be prevented by an antagonist (folinic acid).
Plasma concentration is an important predictor of MTX toxicity. Concentrations  5 mol/L
24 hours after stopping an IV infusion with HDMTX ( 1g/m2/24 hr) usually require high-
dose folinic acid (leucovorin) to prevent severe toxicity of MTX.

       Theophylline is an effective drug (a bronchodilator) with a narrow therapeutic
window. Many factors influence its clearance: cigarette smoking, cardiac and hepatic failure,
enzyme inhibitors (cimetidine, erythomycin). Measurement of            plasma theophylline
concentrations can help     minimize toxicity (cardiac arrhythmias, seizures if drug
concentrations  40 mg/L).Therapeutic range is 5-15 mg/L in adults and 5-10 mg/L in

        Cyclosporin (an immunosuppressant). Careful TDM is uniquely valuable. Trough
plasma concentrations in the range 50-200 g/L are usually recomended during maintenance
treatment. Compliance is a particular problem in children, and deterioration in renal function
can reflect either graft rejection due to inadequate cyclosporin concentration or toxicity from
excessive concentrations.

Drugs at Extremes of age

I.Drugs in infants and children.

Children are not miniature adults in term of drug handling because of differences in body
constitution, kinetics and sensitivity to drugs. Infants skin is thin and percutaneous
absorption is increased relative to adults. Systemic absorption of corticoids from local
preparations may be increased and cause toxicity if used extensively. Kernicterus caused by
displacement of bilirubin from albumin by sulfonamides is well recognized. At birth the
hepatic microsomal enzymes system is relatively immature but after the first 4 weeks it
matures rapidly. Chloramphenicol can produce „gray baby syndrome“ in neonates due to high
plasma levels secondary to inefficient glucuronidation. All renal mechanisms (filtration,
secretion and reabsorption) are reduced in newborn. T1/2 of aminoglycosides in premature
newborn during the first week of the postnatal life is significantly prolonged.

Breast feeding can lead to toxicity in the infants if the drug enters the milk in
pharmacological quantities. However, drugs in breast milk may cause hypersensitivity
reactions even in very low dose. All drugs that reach the maternal systemic circulation will
enter breast milk, especiallly lipid- soluble unionized low molecular weight drugs. Milk is
weakly acidic, so drugs that are weak bases are concentrated in brest milk.Some drugs are
contraindicated and breast feeding should cease during treatment if there is no safer
thiazide diuretics
The infants should be monitored if betalytics, corticosteroids and lithium are prescribed.
Betalytics rarely cause significant bradycardia. In high doses corticosteroids can influence the
infant´s adrenal function. Lithium can cause intoxication. Bromocriptine and diuretics
suppress lactation. Metronidazole gives milk an unpleasant taste.

Adverse effects:
Of particular significance is the potential of chronic corticosteroid use including high-dose
inhaled corticosteroids to inhibit growth. Aspirin is avoided in those under 12 years due to
association with Reye´s syndrome, a rare but often fatal illness of unknown etiology
consisting of hepatic necrosis and encefalopathy, often in the aftermath of a viral illness.
Tetracyclines are deposited in growing bone and teeth causing staining and occasionally
dental hypoplasia, and should not be given to children under 8 years.

II. Drugs in the elderly.
Two main problems: - many drugs
                     - noncompliance  60% (a failure of memory
                                              misunderstanding how the drug should be taken
Changes of pharmacokinetics:
Increased ratio of fat to muscle and body water. This enlarges the volume of distribution of
fat-soluble drugs (diazepam, lignocain), whereas the distribution of polar drugs such as
digoxin is reduced compared with younger adults. Malnutrition and chronic disease cause a
fall in albumin and a rise in gamma globulin concentration.
Changes in elimination (metabolism): reduced clearance of half-life benzodiazepines have
important clinical consequences as when these are prescribed for prolonged periods, low
accumulation of drug may lead to adverse effects (confusion, memory impairment). Probably
the most important cause of drug accumulation is declining renal function. In healthy
individuals aged over 80 glomerular filtration rate is  60-70 ml/min. Tubular function also
declines with age. Drugs that are mainly excreted via the kidney are likely to accumulated in
patients in their seventies and eighties if given in doses suitable for young adults.

Changes in pharmacodynamics

Increased incidence of postural hypotension from drugs such as phenothiazines, betalytics and
diuretics. Clotting factor synthesis by the liver is reduced and old people often require lower
warfarin doses for effective anticoagulation .

Examples of drugs requiring dose adjustment in elderly:
     aminoglycosides (gentamicin, amikacin, tobramycin, netilmicin)
     non-steroidal anti-inflammatory drugs
     oral antidiabetics

Drugs in pregnancy
The use of drugs in pregnancy is complicated by the potential for harmful effects on the
growing fetus and altered maternal physiology. The coincidence of serious congenital
anbormality is about 2% of all birth.
Drugs can cross the placenta by active transport or by passive difussion down the
concentration gradient, and it is the latter which is usually involved in drug transfer. Effects
on the fetus may take several years to become clinically manifest, an example being
diethylstilbestrol which was widely used in the late 1940s for preventing miscarriages and
preterm births. In 1971 an association was reported between adenocarcinoma on girls in their
late teens whose mothers had been given diethylstilbestrol during pregnancy.

The stage of gestation influences the effects of drugs on fetus. Is it convenient to divide
pregnancy into four stages:
fertilization and implantation ( 17 days)
the organogenesis (17-57 days)
the fetogenic stage

Animal studies suggest that interference with fetus before 17 days gestation causes
absorption, i.e. if pregnancy continues, the fetus is unharmed.

Organogenesis/embryonic stage.
At this stage the fetus is differentiating to form major organs and this is the critical period for
teratogenesis. Teratogens cause deviations or abnormalities in the development of the embryo
that are compatible with prenatal life and observable postnatally. Some drugs are confirmed
teratogens, but for many the evidence is inconclusive.

Some drugs that are definitely teratogenic in humans

thalidomide (phocomelia)             androgens
cytostatics                          progestogens
alcohol                              diethylstilbestrol
warfarin                             radioisotopes
most anticonvulsants                 lithium

Fetogenic stage
In this stage the fetus undergoes further development and maturation.

Adverse effects of drugs on fetal growth and development

drugs used to treat maternal hyperthyreoidism can cause fetal and neonatal hypothyroidism
tetracycline antiobiotics inhibit growth of fetal bones and stain teeth
aminoglycosides cause fetal VIIIth nerve damage

opioids and cocaine taken regularly during pregnancy can lead to fetal drug dependency

Some drugs given late in pregnancy or during delivery may cause particular problems.
Pethidine can cause fetal apnoea (depresses the fetal respiratory centre and can inhibit the start
of normal respiration). Anesthetic agents given during Cesarian section may transiently
depress neurological, respiratory and muscular functions. Warfarin given in late pregnancy
causes a hemostasis defect in the baby and predisposes to cerebral hemorrhage during

Because experience with many drugs is severely limited, it should be assumed that all drugs
are harmful until sufficient data exist to indicate otherwise.

refers to a state of diminished responsiveness to a drug as a consequence of prior
exposures. This phenomenon is called tolerance (acquired). Innate tolerance is independent
of prior exposure. In its simplest form, drug tolerance is reflected in a parallel shift of the
dose-response curve to the right. The degree of drug tolerance, i.e. extend to which the dose-
response curve is shifted, is quite variable and depends on the effect being measured and on
the specific drug. For example: the degree of tolerance to a drug such as ethanol (a factor of
about 2) is modest, whereas the dose-response curve in opiates may shift by a log unit or
more. The phenomenon in which tolerance to one drug confers tolerance to another is called
cross-tolerance (opiates)
The mechanisms of tolerance: metabolic tolerance (enzyme induction), drug induced increase
in the rate of its own metabolism (pharmacokinetic mech.)
                              adaptive changes (up regulation) that take place either at the
receptor or in systems closely connected with the drug´s action- cellular tolerance
(pharmacodynamic mech.).

develops rapidly - rapidly tolerance.Tyramin - infusions are first followed by a pronounced
pressor effect, which is then quickly decreased in magnitude. This tachyphylaxis is attributed
to rapid depletion by tyramin of presynaptic stores of norepinephrine. Acute tolerance is
manifested by many sedative-hypnotics - benzodiazepines.

Physical dependence          is defined in terms of the signs and symptoms that occur
following termination of the drug of dependence and that these signs and symptoms are
collectively termed the abstinence or withdrawal syndrome. Based on observation of their
respective withdrawal syndromes, several types of physical dependence are evident.

Depressant- type physical dependence also called ethanol-barbiturate type. Convulsions are
a prominent component of this type of physical dependence, and largely for this reason,
untreated withdrawal has a significant mortality.

Opiate-type physical dependence is also called dependence of the narcotic-analgesic type.
The classic reference drug for opiate dependence is morphine. The withdrawal syndrome is
characterized by autonomic hyperactivity. Cross-physical dependence as manifested by
suppression of the abstinence syndrom is exhibited by a large number of drugs that share
morphine´s pharmacological activities

Other forms of physical dependence.
Withdrawal of caffeine is associated with headache, nicotine with anxiety, cocaine with