The effects of diseases on drug
s
Several common disorders influence the way in which the body handles drugs and these must be considered
before pre- scribing. Gastro-intestinal, cardiac, renal, liver and thyroid disorders all influence drug
pharmacokinetics, and individu- alization of therapy is very important in such patients.
Gastro-intestinal disease
alters the absorption of orally administered drugs. This can cause therapeutic
failure, so alternative routes of administration are sometimes needed.
GASTRIC EMPTYING
Gastric emptying is an important determinant of the rate and sometimes also the extent
of drug absorption. Several pathological factors alter gastric emptying . Absorption of analgesics is delayed
in migraine, and a more rapid absorption can be achieved by
administering analgesics with metoclopramide, which increases gastric emptying.
SMALL INTESTINAL AND PANCREATIC DISEASE
The
very large absorptive surface of the small intestine provides a substantial functional reserve, so even
extensive involvement with, for example, coeliac disease may be present without causing a clinically
important reduction in drug absorption. Crohn’s disease typically affects the terminal ileum. Absorption of
several antibiotics actually increases in Crohn’s disease. Cystic fibrosis, because of its effects on
pancreatic secretions and bile flow, can impair the absorption of fat-soluble vitamins. Significant reductions
in the absorption of cefalexin occur in cystic fibrosis, necessitating increased doses in such patients. Patients
with small bowel resection may absorb lipophilic drugs poorly.
:
Pathological factors influencing the rate of gastric emptying
Decreased rate
Increased rate
Trauma Gastric ulcer
Duodenal ulcer
Pain (including myocardial infarction, Gastroenterostomy)
acute abdomen
Coeliac disease
Diabetic neuropathy
Drugs, e.g. metoclopramide
Labour Migraine Myxoedema
Raised intracranial pressure Intestinal obstruction
Anti-muscarinic drugs
=========================== ========================== ========.
Cardiac failure
affects pharmacokinetics in several ways and these are discussed below.
ABSORPTION
Absorption of some drugs (e.g. furosemide) is altered in cardiac failure because of mucosal oedema
and reduced gastro- intestinal blood flow. Splanchnic vasoconstriction accompanies cardiac failure as an
adaptive response redistributing blood to more vital organs.
DISTRIBUTION
Drug distribution is altered by cardiac failure. The apparent volume of distribution (Vd) of, for example,
quinidine and lidocaine in patients with congestive cardiac failure is markedly reduced because of:-
decreased tissue perfusion and altered partition between blood and tissue components. Usual doses can
therefore result in elevated plasma concentrations, producing toxicity.
ELIMINATION
Elimination of several drugs is diminished in heart failure. Decreased hepatic perfusion accompanies
reduced cardiac output. During lidocaine infusion:-
1-the steady-state concentrations are almost 50% higher in patients with cardiac failure than in healthy
volunteers.
2-The potential for lidocaine toxicity in heart failure is further increased by the accumulation of its polar
metabolites, which have cardiodepressant and proconvulsant properties. This occurs because renal blood
flow and glomerular filtration rate are reduced in heart failure.
Theophylline clearance is decreased and its half-life is doubled in patients with cardiac failure and pulmonary
oedema, increasing the potential for accumulation and toxicity.
=The metabolic capacity of the liver is reduced in heart failure both by tissue hypoxia and by hepatocellular
damage from hepatic congestion. Liver biopsy samples from patients with heart
failure have reduced
drug-metabolizing enzyme activity.
=
Heart failure reduces renal elimination of drugs because of
reducedglomerular filtration, predisposing to
toxicity from
drugs that are primarily cleared by the kidneys, e.g. aminoglycosides and digoxin
.
========================== ================== ==============.
Renal excretion is a major route of elimination for many drugs
and drugs and their metabolites that are
excreted
predominantly by the kidneys accumulate in renal failure. Renal disease also affects other
pharmacokinetic processes (i.e. drug absorption, distribution and metabolism) .
ABSORPTION
Gastric pH increases in chronic renal failure because urea is cleaved, yielding ammonia which buffers acid
in the stomach. This reduces the absorption of ferrous iron and possibly also of other drugs.
DISTRIBUTION
Renal impairment causes accumulation of several acidic substances that compete with drugs for binding
sites on albumin
and other plasma proteins. This alters the pharmacokinetics of many drugs, but is seldom
clinically important.
= Phenytoin is an exception, because therapy is guided by plasma concentration . In renal impairment,
phenytoin protein binding is reduced by competition with accumulated molecules normally cleared by the
kidney and which bind to the same albumin drug-binding site as phenytoin. Thus, for any measured
phenytoin concentration, free (active) drug is increased compared to a subject with normal renal function
and the same measured total concentration. The therapeutic range therefore has to be adjusted to lower
values in patients with renal impairment, as otherwise doses will be selected that
cause toxicity.
=Tissue binding of digoxin is reduced in patients with
impaired renal function, resulting in a lower
volume of distribution than in healthy subjects. A reduced loading dose of
digoxin is therefore
appropriate in such patients, although the
effect of reduced glomerular filtration on digoxin clearance is
even more important, necessitating a reduced maintenance
dose.
=The blood–brain barrier is more permeable to drugs in central nervous system, an effect that is
believed to contribute to the increased incidence of confusion caused by cimetidine, ranitidine and
famotidine in patients with renal failure.
METABOLISM
Metabolism of several drugs is reduced in renal failure. These
include drugs that undergo phase I
metabolism by CYP3A4.
Drugs that are mainly metabolized by phase II drug metabolism are less affected,
although conversion of sulindac to its
active sulphide metabolite is impaired in renal failure.
RENAL EXCRETION
Glomerular filtration and tubular secretion of drugs usually fall in step with one another in patients with
renal impairment. Drug excretion is directly related to glomerular filtration rate (GFR). Some estimate of
GFR (eGFR) is therefore essential when deciding on an appropriate dose regimen.
=Serum creatinine concentration adjusted for age permits calculation of an estimate of GFR per 1.73 m2
body surface area. This is now provided by most chemical pathology laboratories, and is useful in many
situations. The main limitation of such estimates is that they are misleading if GFR is changing rapidly as in
acute renal failure. (Imagine that a patient with normal serum creatinine undergoes bilateral nephrectomy: an
hour later, his serum creatinine would still be normal, but his GFR would be zero. Creatinine would rise
gradually over the next few days as it continued to be produced in his body but was not cleared.) A normal
creatinine level therefore does not mean that usual doses can be assumed to be safe in a patient who is
acutely unwell.
= eGFR is used to adjust the dose regimen in patients with some degree of chronic renal impairment for
drugs with a low therapeutic index that are eliminated mainly by renal excretion. Dose adjustment must be
considered for drugs for which there is >50% elimination by renal excretion.
Examples of drugs to be used with particular caution or avoided in renal failure
Angiotensin-converting enzyme
Angiotensin receptor
inhibitorsa blockersa
Aldosterone antagonists
Aminoglycosides
Amphotericin
Atenolol
Ciprofloxacin
Cytotoxics
Digoxin
Lithium
Low molecular weight heparin
Metformin
NSAIDs
Methotrexate
aACEI and ARB must be used with caution,but can slow progressive renal impairment .
=There are two ways of reducing the total dose to compensate for impaired renal function. Either each dose can
be reduced, or the interval between each dose can be lengthened. The latter method is useful when a drug must
achieve some threshold concentration to produce its desired effect, but does not need to remain at this level
RENAL IMPAIRMENT
RENAL HAEMODYNAMICS
Patients with mild renal impairment depend on vasodilator prostaglandin biosynthesis to preserve renal
blood flow and GFR. The same is true of patients with heart failure, nephrotic syndrome, cirrhosis or ascites.
Such patients develop acute reversible renal impairment, often accompanied by salt and water retention and
hypertension if treated with non-steroidal anti-inflammatory drugs , because these inhibit cyclo-oxygenase
and hence the synthesis of vasodilator prostaglandins, notably prostaglandin I2 (prosta- cyclin) and
prostaglandin E2. Sulindac is a partial exception because it inhibits cyclo-oxygenase less in kidneys than in
other tissues, although this specificity is incomplete and dose dependent.
Angiotensin converting enzyme inhibitors (e.g. ramipril) can also cause reversible renal failure due to altered
renal haemodynamics. This occurs predictably in patients with bilateral renal artery stenosis .
NEPHROTIC SYNDROME
Plasma albumin in patients with nephrotic syndrome is low, resulting in increased fluctuations of free drug
concentration
in practice this is seldom clinically important. The high albumin concentration in
tubular fluid contributes to the resistance to diuretics that accompanies nephrotic syndrome. This
is because both loop diuretics and thiazides act on ion-transport processes in the luminal
membranes of tubular cells . Protein binding of such diuretics within the tubular lumen therefore
reduces the concentration of free (active) drug in tubular fluid in contact with the ion
transporters on which they act.
PRESCRIBING FOR PATIENTS WITH RENAL DISEASE:-
1. Consider the possibility of renal impairment before drugs are prescribed and use
available data to estimate GFR.
2. Check how drugs are eliminated before prescribing them. If renal elimination accounts for more than
50% of total elimination, then dose reduction will probably be necessary after the first dose, i.e. for
maintenance doses.
3. Monitor therapeutic and adverse effects and, where appropriate, plasma drug concentrations.
4. If possible avoid potentially nephrotoxic drugs (e.g. aminoglycosides, NSAIDs); if such drugs are
essential use them with great care.
Liver diseases
The liver is the main site of drug metabolism . Liver disease has major but unpredictable effects on drug
handling. Pharmacokinetic factors that are affected include absorption and distribution, as well as the
metabolism of drugs.
Attempts to correlate changes in the pharmacokinetics of drugs with biochemical
tests of liver function have been unsuccessful (in contrast to the use of plasma creatinine in chronic renal
impairment described above). In chronic liver disease, serum albumin is the most useful index of hepatic
drug-metabolizing activity, possibly because a low albumin level reflects depressed synthesis of hepatic
proteins, including those involved in drug metabolism. Prothrombin time also shows a moderate correlation
with drug clearance by the liver. If possible, drugs that are eliminated by routes other than the liver should
be employed.
EFFECTS OF LIVER DISEASE ON DRUG ABSORPTION Absorption of drugs is altered in liver disease
because of portal hypertension, and because hypoalbuminaemia causes mucosal oedema. Portal/systemic
anastomoses allow the passage of orally administered drug directly into the systemic circulation, bypassing
hepatic presystemic metabolism and markedly increasing the bioavailability of drugs with high presystemic
metabolism such as propranolol, morphine, verapamil and cyclosporin, which must therefore be started in
low doses in such patients and titrated according to effect
DISTRIBUTION OF DRUGS IN PATIENTS WITH LIVER DISEASE
Drug distribution is altered in liver disease. Reduced plasma albumin reduces plasma protein binding. This
is also influenced by bilirubin and other endogenous substances that accumulate in liver disease and may
displace drugs from binding sites. The free fraction of tolbutamide is increased by 115% in cirrhosis, and that
of phenytoin is increased by up to 40%.
Reduced plasma protein binding increases the apparent Vd if other factors remain unchanged. Increased Vd
of several drugs (e.g. theophylline) is indeed observed in patients with liver disease.
DRUG METABOLISM IN LIVER DISEASE
CYP450-mediated phase I drug metabolism is generally reduced in patients with very severe liver disease,
but drug
metabolism is surprisingly little impaired in patients with moderate to severe disease.
THYROID DISEASES
Thyroid dysfunction affects drug disposition partly as a result of effects on drug metabolism and partly via
changes in renal elimination.
DIGOXIN:-Myxoedematous
patients are extremely sensitive to digoxin, whereas unusually high doses are
required in thyrotoxicosis.1- In general, hyperthyroid patients have lower plasma digoxin concentrations
and hypothyroid patients have higher plasma concentrations than euthyroid patients on the same dose, a
difference in Vd has been postulated to explain the alteration of plasma concentration with thyroid activity.
2-GFR is increased in thyrotoxicosis and decreased in myxoedema. These changes in renal function
influence elimination, and the reduced plasma levels of digoxin correlate closely with the increased creatinine
clearance in thyrotoxicosis. 3-Other factors including enhanced biliary clearance, digoxin malabsorption due
to intestinal hurry and increased hepatic metabolism, have all been postulated as factors contributing to the
insensitivity of thyrotoxic patients to cardiac glycosides.
ANTICOAGULANTS:-Oral anticoagulants produce an exaggerated prolongation of prothrombin time in
hyperthyroid patients. This is due to increased metabolic breakdown of vitamin K-dependent clotting
factors , rather than to changes in drug pharmacokinetics.
GLUCOCORTICOIDS:-Glucocorticoids are metabolized by hepatic mixed-function oxidases (CYP3A4)
which are influenced by thyroid status. In hyperthyroidism, there is increased cortisol production and a
reduced cortisol half-life, the converse being true in myxoedema.
THYROXINE:-The normal half-life of thyroxine (six to seven days) is reduced to three to four days by
hyperthyroidism and prolonged to nine to ten days by hypothyroidism.
ANTITHYROID DRUGS:-The half-life of propylthiouracil and methimazole is prolonged in
hypothyroidism and shortened in hyperthyroidism because of altered hepatic metabolism.
OPIATES:-Patients with hypothyroidism are exceptionally sensitive to opioid analgesics, which cause
profound respiratory depression in this setting. This is probably due to reduced metabolism and increased
sensitivity
Summarly
•
Gastro-intestinal disease:
(a) diseases that alter gastric emptying influence
the response to oral drugs (e.g. migraine reduces
gastric emptying, limiting the effectiveness of analgesics);
•
Heart failure:
(a) absorption of drugs (e.g. furosemide) is reduced as a result of splanchnic hypoperfusion;
(b) elimination of drugs that are removed very efficiently by the liver (e.g. lidocaine) is reduced as
a result of reduced hepatic blood flow, predisposing
to toxicity;
(c) tissue hypoperfusion increases the risk of lactic acidosis with metforin (cor pulmonale
especially predisposes to this because of hypoxia).
Prescribing for patients with liver disease
1. Weigh risks against hoped for benefit, and minimize non- essential drug use.
2. If possible, use drugs that are eliminated by routes other than the liver ( renally cleared drugs).
3. Monitor response, including adverse effects (and occasionally drug concentrations), and adjust
therapy accordingly.
4. Avoid sedatives and analgesics if possible: they are common precipitants of hepatic coma.
5. Predictable hepatotoxins (e.g. cytotoxic drugs) should only be used for the strongest of indications,
and then only with close clinical and biochemical monitoring.
6. Drugs that are known to cause idiosyncratic liver disease (e.g. isoniazid, phenytoin, methyldopa) are
not necessarily contraindicated in stable chronic disease, as there is no evidence of increased susceptibility.
Oral contraceptives are not advisable if there is active liver disease or a history of jaundice of pregnancy.
7. Constipation favours bacterial production of false neurotransmitter amines in the bowel: avoid drugs
that cause constipation (e.g. verapamil, tricyclic antidepressants) if possible.
8. Drugs that inhibit catabolism of amines (e.g. monoamine oxidase inhibitors) also provoke coma and
should be avoided.
9. Low plasma potassium provokes encephalopathy: avoid drugs that cause this if possible. Potassium-
sparing drugs, such as spironolactone, are useful.
10. Avoid drugs that cause fluid overload or renal failure (e.g. NSAID) and beware those containing
sodium (e.g. sodium-containing antacids and high-dose carbenicillin).
11. Avoid drugs that interfere with haemostasis (e.g. aspirin, anticoagulants and fibrinolytics) whenever
possible, because of the increased risk of bleeding (especially in the presence of varices!).
•
Renal disease:
(a) chronic renal failure as well as reduced excretion, drug absorption, distribution and metabolism
may also be altered. Estimates of creatinine clearance or GFR based on serum creatinine
concentration/ weight/age/sex/ ethnicity provide a useful index of the need for maintenance dose
adjustment in chronic renal failure;
(b) nephrotic syndrome leads to altered drug distribution because of altered binding to albumin
and altered therapeutic range of concentrations for drugs that are extensively bound to albumin
(e.g. some anticonvulsants). Albumin in tubular fluid binds diuretics and causes diuretic resistance.
Glomerular filtration rate is preserved in nephrotic syndrome by compensatory increased
prostaglandin synthesis, so NSAIDs can precipitate renal failure.
•
Liver disease – as well as effects on drug metabolism, absorption and distribution may also be
altered because of portal systemic shunting, hypoalbuminaemia and ascites. There is no widely
measured biochemical marker (analogous to serum creatinine in chronic renal failure) to guide dose
adjustment in liver disease, and a cautious dose titration approach should be used.
•
Thyroid disease:
(a) hypothyroidism increases sensitivity to digoxin and opioids;
(b) hyperthyroidism increases sensitivity to warfarin and reduces sensitivity to digoxin.
THERAPEUTIC
DRUG MONITORING
monitoring the treatment enables you to determine whether it has been successful or whether additional
action is needed. and this can be done in
two ways.
Passive monitoring means that you explain to the patient what to do if the treatment is not effective, is
inconvenient or if too many side effects occur. In this case monitoring is done by the patient.
Active monitoring means that you make an appointment to determine yourself whether the treatment has
been effective. You will need to determine a monitoring interval, which depends on the type of illness, the
duration of treatment, and the maximum quantity of drugs to prescribe. At the start of treatment the interval
is usually short; it may gradually become longer, if needed. Three months should be the maximum for any
patient on long-term drug therapy. Even with active monitoring the patient will still need the information.
The purpose of monitoring is to check whether the treatment has solved the patient's problem. You chose
the treatment on the basis of efficacy, safety, suitability and cost. You should use the same criteria for
monitoring the effect, but in practice they can be condensed into two questions: is the treatment effective?
Are there any side effects? History taking, physical examination and laboratory tests will usually provide
the information you need to determine the effectiveness of treatment. In some cases more investigations
may be needed.
Treatment is effective
If the disease is cured, the treatment can be stopped.4 If the disease is not yet cured or chronic, and the
treatment is effective and without side effects, it can be continued. If serious side effects have occurred you
should reconsider your selected drug and dosage schedule, and check whether the patient was correctly
instructed. Many side effects are dose dependent, so you may try to lower the dose before changing to
another drug.
Treatment is not effective
If the treatment is not effective, with or without side effects, you should reconsider the diagnosis, the
treatment
which was prescribed, whether the dose was too low, whether the patient was correctly instructed, whether
the patient actually took the drug, and whether your monitoring is correct. When you have determined the
reason for the treatment failure you should look for solutions. So the best advice is to go again through the
process of diagnosis, definition of therapeutic objective, verification of the suitability of the drug for this
patient, instructions and warnings, and monitoring. Sometimes you will find that there is no real alternative
to a treatment that has not been effective or has serious side effects. You should discuss this with the
patient. When you cannot determine why the treatment was not effective you should seriously consider
stopping it.
If you decide to stop drug treatment you should remember that not all drugs can be stopped at once. Some
drugs have to be tailed off, with a decreasing dosage schedule
Some examples of drugs in which a slow reduction in dose should be considered
Amphetamines , Antiepileptics ,Antidepressants ,Antipsychotics , Cardiovascular drugs
Clonidine ,methyldopa ,beta-blockers ,vasodilators , Corticosteroids ,Hypnotics/sedatives
Benzodiazepines ,barbiturates ,Opiates
Drug response differs greatly between individuals. This vari- ability results from two main sources:
1.
variation in absorption, distribution, metabolism or elimination (pharmacokinetic);
2.
variation at or beyond tissue receptors or other macromolecular drug targets (pharmacodynamic).
►Monitoring of drug therapy by biological response include both kinds of variability. There must be a
continuous variable that is readily measured and is closely linked to the desired clinical outcome. Such
responses are said to be good
‘surrogate markers’ because what the prescriber really wants to achieve is to
reduce the risk of a clinical event, such as a stroke, heart attack, pulmonary embolism, etc.) For example,
antihypertensive drugs are monitored by their effect on blood pressure , statins by their effect on serum
cholesterol .
In some circumstances, however, there is no good continuous variable to monitor, especially for
diseases with an unpredictable or fluctuating course. Measuring drug concentrations
in plasma or serum
identifies only pharmacokinetic variability, but can sometimes usefully guide dose adjustment, for
example in treating an epileptic patient with an anticonvulsant
drug. Measuring drug concentrations for use
in this way is
often referred to as ‘therapeutic drug monitoring’.
►Measurement of drug concentrations is sometimes a useful complement to clinical monitoring to assist in
selecting the best drug regimen for an individual patient. Accurate and
convenient assays are necessary.
►Measurements of drug concentrations in plasma are most useful when:
1. There is a direct relationship between plasma concentration and pharmacological or toxic effect, i.e. a
therapeutic range has been established. (Drugs that work via active metabolites, and drugs with irreversible
actions, are unsuited to this approach. Tolerance also restricts the usefulness of plasma concentrations.)
2. Effect cannot readily be assessed quantitatively by clinical observation.
3. Inter-individual variability in plasma drug concentrations from the same dose is large (e.g. phenytoin).
4. There is a low therapeutic index ( if the ratio of toxic concentration/effective concentration is <2) .
5. Several drugs are being given concurrently and serious interactions are anticipated.
6. Replacement treatment (for example, of thyroxine) is to be optimized.
7. Apparent‘resistance’to the action of a drug needs an explanation,when noncompliance is suspected.
Another indication, distinct from therapeutic drug monitoring, for measuring drug concentrations in plasma
is in clinical toxicology. Such measurements can guide management a poisoned patient (e.g. with
paracetamol or aspirin).
►Drug distribution and the location (tissue and cell) of the drug’s target influence the relationship between
plasma drug concentration and effect. A constant tissue to plasma drug concentration ratio only occurs
during the terminal β-phase of elimination.
►Earlier in the dose interval, the plasma concentration does not reflect the concentration in the
extracellular tissue space accurately. Measurements must be made when enough time has elapsed after a
dose for distribution to
have occurred.
►Usually during repeated dosing a sample is taken just before the next dose to assess the ‘trough’
concentration, and a sample may also be taken at some specified time after dosing (depending on the drug)
to determine the ‘peak’ concentration.
►Analytical techniques of high specificity (often relying on high-performance liquid chromatography
(HPLC), or HPLC- tandem mass spectroscopy or radioimmunoassay) avoid the risk of less specific methods
which may detect related compounds (e.g. drug metabolites).
lists those drugs which may be monitored therapeutically.
Drug
Therapeutic range
Digoxin
0.8–2 mg/L (1–2.6 nmol/L)
Lithium
0.4–1.4 mmol/La
Phenytoin 10–20 mg/L (40–80 μmol/L)
Theophylline 5–20 mg/L (28–110 μmol/L
Cyclosporin 50–200 μg/L
1. Digoxin: measuring the plasma concentration can help optimize therapy, especially for patients in
sinus rhythm where there is no easy pharmacodynamic surrogate marker of efficacy, and is also useful in
suspected toxicity or poor compliance.
2. Lithium: plasma concentrations are measured 12 hours after dosing.
3. Aminoglycoside antibiotics – for gentamicin, peak concentrations measured 30 minutes after
dosing of 7–10 mg/L are usually effective against sensitive organisms, and trough levels, measured
immediately before a dose, of 1–2 mg/L reduce the risk of toxicity; for amikacin, the desirable peak
concentration is 4–12 mg/L, with a trough value of <4 mg/L.
4. Phenytoin: it is important to be aware of its non-linear pharmacokinetics , and of the possible effects of
concurrent renal or hepatic disease or of pregnancy on its distribution. Therapeutic drug monitoring
is also widely used for some other anticonvulsants, such as carbamazepine and sodium valproate.
5. Methotrexate: plasma concentration is an important predictor of toxicity, and concentrations of >5
μmol/L 24 hours after a dose or 100 nmol/L 48 hours after dosing usually require folinic acid
administration to prevent severe toxicity.
6. Theophylline: has a narrow therapeutic index and many factors influence its clearance . Measurement
of plasma theophylline concentration can help to minimize toxicity (e.g. cardiac dysrhythmias or
seizures). A therapeutic range of 5–20 mg/L is quoted. (Plasma concentrations >15 mg/L are, however,
associated with severe toxicity in neonates due to decreased protein binding and accumulation of caffeine,
to which theophylline is methylated in neonates, but not in older children.)
7. The therapeutic ranges of plasma concentrations of several anti-dysrhythmic drugs (e.g. lidocaine) have
been established with reasonable confidence. The therapeutic range of plasma amiodarone concentrations
for ventricular dysrhythmias (1.0–2.5 mg/L) is higher than that needed for atrial dysrhythmias (0.5–1.5
mg/L).
8. Immunosuppressants: Cyclosporin compliance is a particular problem in children, and deterioration in
r
enal function can reflect either graft rejection due to inadequate ciclosporin concentration or toxicity from
excessive concentrations. Sirolimus use should be monitored, especially when used with ciclosporin or
when there is hepatic impairment or during or after treatment with inducers or inhibitors of drug
metabolism.
Kesumerryy points
sumarry
•
Determining the plasma concentrations of drugs in order to adjust therapy is referred to as
therapeutic
drug monitoring. It has distinct but limited applications.
•
Therapeutic drug monitoring permits dose individualization and is useful when there is a
clear relationship between plasma concentration and pharmacodynamic effects.
•
The timing of blood samples in relation to dosing is crucial. For aminoglycosides, samples are
obtained for measurement of peak and trough concentrations. To guide chronic therapy (e.g. with
anticonvulsants), sufficient time must elapse after starting treatment or changing dose for the
steady state to have been achieved, before sampling.
•
Drugs which may usefully be monitored in this way include digoxin, lithium,
aminoglycosides, several anticonvulsants, methotrexate, theophylline, several anti-dysrhythmic
drugs (including amiodarone) and ciclosporin.
•
Individualization of dosage using therapeutic drug monitoring permits the effectiveness of these
drugs to be maximized, while minimizing their potential toxicity.
►►For theophyllin metabolism :-
Increased Smoking Marijuana Age 1–20 years High protein diet Phenobarbitone
Shortened half-life
Decrease
Cirrhosis, Heart failure,
Age >50 years
Neonates
,
Obesity,
Severe renal failure
,
Cimetidine
,
Erythromycin, Ciprofloxacin
Prolonged half-life