(1994; 115 pages) [French] [Spanish]
Step 3B: Is the standard dosage schedule suitable for this patient?
The aim of a dosage schedule is to maintain the plasma level of the drug within the therapeutic window. As in the previous step, the dosage schedule should be effective and safe for the individual patient. There are two main reasons why a standard dosage schedule may have to be adapted. The window and/or plasma curve may have changed, or the dosage schedule is inconvenient to the patient. If you are not familiar with the concept of the therapeutic window and the plasma concentration-time curve, read Annex 1.
Exercise: patients 17-20
Review for each of the following cases whether the dosage schedule is suitable (effective, safe) for the patient. Adapt the schedule where necessary. The cases are discussed below.
Woman, 43 years. History of insulin dependent diabetes for 26 years. Stable on treatment with two daily doses of neutral insulin, 20 IU and 30 IU. Recently mild hypertension was diagnosed, and diet and general advice have not been sufficiently effective. You would like to treat this condition with a beta-blocker. Your P-drug is atenolol 50 mg once daily.Patient 18:
Man, 45 years. Terminal lung cancer. He has lost 3 kg during the last week. You have been treating his pain successfully with your P-drug, oral morphine solution, 10 mg twice daily. Now he complains that the pain is getting worse.Patient 19:
Woman, 50 years. Chronic rheumatic disease, treated with your P-drug, indometacin, 3 times 50 mg daily plus a 50 mg suppository at night. She complains of pain early in the morning.Patient 18 again, after one week:
He has lost another 6 kg, and looks very ill. He was on oral morphine solution, 15 mg twice daily, to which he had responded well. However, he has become very drowsy and has to be woken up to hear what you say. He has no pain.Patient 20:
Man, 73 years. Has suffered from depression for two years, after the death of his wife. You want to prescribe an antidepressant drug. Your P-drug is amitriptyline, 25 mg daily initially, followed by a slowly rising dose till the drug is effective (with a maximum of 150 mg per day).
Changes in therapeutic window
For a variety of reasons (e.g. age, pregnancy, disturbed organ functions) individual patients may differ from the standard. These differences may influence the pharmaco-dynamics or pharmacokinetics of your P-drug. A change in pharmacodynamics may affect the level (position) or width of the therapeutic window (Figure 1; see also Annex 1). The therapeutic window reflects the sensitivity of the patient to the action of the drug. Changes in the therapeutic window are sometimes expressed as the patient being ‘resistant’ or ‘hyper-sensitive’. The only way to determine the therapeutic window in the individual patient is by trial, careful monitoring and logical thinking.
Figure 1: Shift in therapeutic window
In Patient 17 (diabetes) it is important to note that b-blockers counteract the effect of insulin. This means that higher concentrations of insulin are needed for the same effect: the therapeutic window for insulin shifts upwards. The plasma curve no longer matches the window, and the daily dose of insulin must be raised. b-blockers may also mask any signs of hypoglycemia. For these two reasons you may decide to change to another drug group that does not affect glucose tolerance, e.g. calcium channel blockers.
Patient 18 (lung cancer) has probably become tolerant to morphine, as he responded well to the drug before. Tolerance to effect and also to side effects, is common in opiates. The therapeutic window is shifted upwards and the dose has to be raised, for example to 15 mg twice daily. In terminal patients drug absorption and metabolism may be so disturbed that even larger dosages (e.g. 10 times the normal dose) may be necessary.
Changes in plasma concentration-time curve
The plasma concentration-time curve may be lowered or raised, or the concentration may fluctuate outside the therapeutic window. This effect depends on the pharmacokinetics of the drug in that patient.
In Patient 19 (pain at night) the plasma concentration of indometacin probably falls below the therapeutic window early in the morning (see Figure 2). Any change in medication should therefore aim at increasing the plasma level in that period. You could advise her to take the evening dose later, or to set the alarm in the night to take an extra tablet. You could also increase the strength of the evening suppository to 100 mg, while decreasing her first morning tablet to 25 mg.
Figure 2: Slow fall in plasma concentration late at night in patient 19
The second visit of Patient 18 (lung cancer) presents a complicated problem. He has probably been overdosed, because his metabolism is impaired by the terminal cancer, decreasing the elimination of the drug and therefore lengthening its half-life. In addition, the distribution volume of his body is reduced because of emaciation. The curve therefore probably lies above the window, implying that the daily dose should be reduced. Remember that it takes about four half-lives to lower the plasma concentration to a new steady state. If you want to speed up this process you can stop the morphine for one day, after which you can start with the new dose. This is the reverse process of a loading dose.
Figure 3: Plasma concentration rising above therapeutic window in patient 18
Four factors determine the course of the concentration curve, usually called ADME-factors: Absorption, Distribution, Metabolism and Excretion. You always have to check whether ADME-factors in your patient are different compared to average patients. If so, you have to determine what this will do to the plasma curve. Any change in ADME-factors influences plasma concentration (see Table 6).
Table 6: Relation between ADME factors and plasma concentration
Plasma concentration curve will drop if:
Absorption is low
Distribution is high
Metabolism is high
Excretion is high
Plasma concentration curve will rise if:
Absorption is high
Distribution is low
Metabolism is low
Excretion is low
How can you define the position of the plasma curve in an individual patient? The plasma concentration can be measured by laboratory investigations, but in many settings this is not possible and it may be expensive. More important, each measurement represents only one point of the curve and is difficult to interpret without special training and experience. More measurements are expensive and may be stressful to the patient, especially in an outpatient setting. It is simpler to look for clinical signs of toxic effects. These are often easy to detect by history taking and clinical investigation.
Changes in window and curve
Changes in both window and curve are also possible, as illustrated in Patient 20 (depression) (see Figure 4). Elderly people are one of several categories of high-risk patients. Dosage schedules for antidepressant drugs in the elderly usually recommend that the dose be reduced to half the adult dose, for two reasons. First, in the elderly the therapeutic window of antidepressant drugs shifts downwards (a lower plasma concentration will suffice). At a full adult dose the plasma curve may rise above the therapeutic window, leading to side effects, especially anticholinergic and cardiac effects. Secondly, metabolism and renal clearance of the drug and its active metabolites may be reduced in the elderly, also increasing the plasma curve. Thus, in prescribing the normal adult dosage your patient will be exposed to unnecessary and possibly harmful side effects.
Figure 4: Downward shifted window and upward shifted curve in patient 20
A dosage schedule should be convenient. The more complex the schedule, the less convenient it is. For example, two tablets once daily are much more convenient than half a tablet four times daily. Complex dosage schedules decrease patient adherence to treatment, especially when more than one drug is used, and thus decrease effectiveness. Try to adjust a dosage schedule to other schedules of the patient.
In patients 17-20 the standard dosage schedule of your P-drug was not suitable. If you had not adapted the schedule, the P-drug treatment would have been less effective, or unsafe. You can prevent this by carefully checking the suitability of the standard dosage schedule before writing the prescription. You may have to modify the schedule, or change to a completely different P-drug.
How to adapt a dosage schedule
There are three ways to restore the mismatch between curve and window: change the dose, change the frequency of administration, or both. Changing dose or frequency have different effects. The daily dose determines the mean plasma concentration, while the frequency of administration defines the fluctuations in the plasma curve. For example, twice daily 200 mg will give the same mean plasma concentration as four times daily 100 mg, but with more fluctuations in plasma level. The minimum fluctuation would be obtained by delivering 400 mg in 24 hours by means of a continuous infusion (Figure 5).
Figure 5: Relation between frequency and fluctuations in plasma concentration
Decreasing the daily dose is usually easy. You can reduce the number of tablets, or divide them into halves. Beware of antibiotics, because some may need high peaks in plasma concentration to be effective. In that case you should reduce the frequency, not the dose.
Increasing the daily dose is a little more complicated. Doubling the dose while maintaining the same frequency not only doubles the mean plasma level, but also increases the fluctuations on both sides of the curve. In drugs with a narrow safety margin the curve may now fluctuate outside the therapeutic window. The safest way to prevent this is to raise the frequency of dosage. However, few patients like taking drugs 12 times a day and a compromise has to be found to maintain adherence to treatment. After changing the daily dose it takes four times the half-life of the drug to reach the new steady state. Table 7 lists those drugs for which it is advisable to start treatment with a slowly rising dosage schedule.
Table 7: Drugs in which slowly raising the dose is advisable
• Tricyclic antidepressants (anticholinergic effects)
• Some anti-epileptics (carbamazepine, valproic acid)
• Dopa-based anti-Parkinson drugs
• ACE-inhibitors in patients using diuretics
• Alpha-receptor blocking agents in hypertension (orthostasis)
• Some hormonal drug therapies (corticosteroids, levothyroxin)
• Gold salts in rheumatism
• Mixtures for desensitization
• Opiates in cancer