Verify the suitability of your P-drug
A Active substance and dosage form
B Standard dosage schedule
For each of these, check:
Effectiveness (indication,
convenience)
Safety
(contraindications, interaction, high risk groups
Safety
The safety of a drug for the individual patient depends on
contraindications and interactions; these may occur more
frequently in certain high risk groups. Contraindications
are determined by the mechanism of action of the drug and the
characteristics of the individual patient. Drugs in the same group usually have
the same contraindications. Some patients will fall into certain high risk
groups (See Table 5) and any other illnesses should also be considered. Some
side effects are serious for categories of patients only, such as drowsiness
for drivers. Interactions can occur
between the drug and nearly every other substance taken by the patient. Best
known are interactions with other prescribed drugs, but you must also thing of
over-the-counter drugs the patient might be taking. Interactions may also occur
with food or drinks (especially alcohol). Some drugs interact chemically with
other substances and become ineffective (e.g. tetracycline and milk).
Fortunately, in practice only a few interactions are clinically relevant.
Table 5: Hight risk
factors/groups
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Pregnancy
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Lactation
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Children
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Elderly
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Renal Failure
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Hepatic failure
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History of drug allergy
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Other diseases
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Other medication
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Exercise: patients 13-16
Verify in each of these
cases whether the active substance and dosage form of your P-drug is suitable
(effective, safe) for this patient. Examples are discussed below.
Patient 13:
Man, 45 years. Suffers from asthma. Uses salbutamol inhaler. A few
weeks ago you diagnosed essential hypertension (145/100 on various occasions).
You advised a low-salt diet, but blood pressure remains high. You decide to add
a drug to your treatment. Your P-drug for hypertension in patients under 50 is
atenolol tablets, 50 mg a day.
Patient 14:
Girl, 3 years. Brought in with a severe acute ashmatic attack, probably
precipitated by a viral infection. She has great difficulty in breathing
(expiratory wheeze, no viscid sputum), little coughing and a slight
termperature (38,2°C). Further history and physical examination reveal nothing.
Apart from minor childhood infections she has never been ill before and she
takes no drugs. Your P-drug for such a case is a salbutamol inhaler.
Patient 15:
Woman, 22 years, 2 months pregnant. Large abscess on her right forearm.
You conclude that she will need surgery fast, but in the meantine you want to
relieve the pain. Your P-drug for common pain is acetylsalicylic acid (aspirin)
tablets.
Patient 16:
Boy, 4 years. Cough and fever of 39,5°C. Diagnosis: pneumonia. One of
your P-drugs for pneumonia is tetracycline tablets.
Patient 13 (hypertension)
Atenolol is a good P-drug for the treatment of essential hypertension
in patients below 50 years of age, and it is very convenient. However, like all
beta-blockers, it is relatively contraindicated in asthma. Despite the fact
that it is a selective beta-blocker, it can induce asthmatic problems,
especially in higher doses because selectivity the diminishes. If the asthma is
not very severe, atenolol can be prescribed in a low dose. In severe asthma you
should probably switch to diuretics; almost any thiazide is a
good choice.
Patient 14 (child with acute
asthma)
In this child a fast effect is needed, and tablets work too slowly for
that. Inhalers only work when the patient knows how to use them and can still
breathe enough to inhale. In the case of a severe asthma attack this is usually
not possible; moreover, some children below the age of five may
experience difficulties with an inhaler. Intravenous injection in young
children can be very difficult. If an
inhaler cannot be used, the best alternative is to give salbutamol by
subcutaneous or intramuscular injection, which is easy and only briefly
painful.
Patient 15 (abscess)
this patient is pregnant and will soon be operated on. In this case
acetylsalicylic acid is contraindicated as it affects the blood clotting
mechanism and also passes the placenta. You should switch to another drug that
does not interfere with clotting. Paracetamol is a good choice and there is no
evidence that it has any effect on the fetus when it is given for a short time.
Patient 16 (pneumonia)
Tetracycline is not a good drug for children below 12 years of age,
because it can cause discolouration of the teeth. The drug may interact with milk and the child may have
problems swallowing the large tablets. The drug and, if possible, the dosage
form, will therefore have to be changed. Good alternatives are cotrimoxazole
and amoxicillin. Tablets or parts of tablets could be crushed and dissolved in
water, which is cost-effective in you can clearly explain the procedure to the
parents.3 You could also prescribe a more convenient dosage form,
such as a syrup, although this is more expensive.
In all these patients your P-drug was not suitable, and in each case
you has to change either the active substance or the dosage form, or both.
Atenolol was contraindicated because of another disease (asthma); an inhaler was not
suitable because the child was too young to handle it; acetylsalicylic
acid was contraindicated because it affects the blood clotting mechanism and
because the patient is pregnant; and tetracycline tablets were contraindicated
because of serious side effects in young children, possible interactions with
milk, and inconvenience as a dosage form.
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.
Patient 17:
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 heart 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 pharmacodynamics 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.
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.
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.
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
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Plasma concentration curve will drop if:
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Absorption is low
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Distribution is high
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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 winsow 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 anti-depressant 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.
Convenience
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 medify 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).
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
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