Introduction
The aim of drug therapy is to provide a stable, predictable pharmacological effect that can be adjusted to the needs of the individual patient for as long is deemed clinically necessary. The physician may start drug therapy at a dosage that is decided on the basis of previous clinical experience and standard recommendations. At some point, the dosage might be increased if the desired effects were not forthcoming, or reduced if side effects are intolerable to the patient. This adjustment of dosage can be much easier in drugs that have a directly measurable response, such as a change in clotting time. However, in some drugs, this adjustment process can take longer to achieve than others, as the pharmacological effect, once attained, is gradually lost over a period of days. The dosage must be escalated to regain the original effect, sometimes several times, until the patient is stable on the dosage. In some cases, after some weeks of taking the drug, the initial pharmacological effect seen in the first few days now requires up to eight times the initial dosage to reproduce. It thus takes a significant period of time to create a stable pharmacological effect on a constant dose. In the same patients, if another drug is added to the regimen, it may not have any effect at all. In other patients, sudden withdrawal of perhaps only one drug in a regimen might lead to a gradual but serious intensification of the other drug ’ s side effects. These effects are shown by some illustrative histories, as detailed below.
History 1
After suffering a head trauma in a motorcycle accident, a 22-year-old male was subject to recurrent grand-mal convulsions that were treated with carbamazepine. After starting on 200 mg daily, this dose had to be gradually increased stepwise over four weeks to maintain plasma levels within the therapeutic window to 1200 mg daily.
Analysis
Plasma levels were not maintained within the therapeutic window at each dose level for more than a week or so, as carbamazepine clearance appeared to gradually increase, until a dosage was reached where clearance stabilized so that drug levels remained within the therapeutic window.
History 2
A 23-year-old male epileptic was prescribed phenytoin (300mg/day) and carbamazepine (800 mg/day). The laboratory assays showed that phenytoin was in the therapeutic range, while carbamazepine was undetectable in the plasma. A 50 per cent reduction of the phenytoin dosage allowed the carbamazapine plasma concentrations to rise to therapeutically effective levels.
Analysis
The lack of carbamazepine in the plasma at a dosage which is known to exert a reasonable therapeutic effect in other patients implied that the drug’s clearance was much higher than normal, to the point where bioavailability was almost zero. Cutting the phenytoin dosage slowed the high rate of clearance of carbamazepine, allowing plasma levels to ascend to the therapeutic window.
History 3
A 49-year-old male epileptic was prescribed phenytoin at 600 mg/day and carbamazepine at 2000 mg/day. The patient’s condition was controlled with minimal side effects for three months. The phenytoin was then abruptly discontinued; within four days, the patient became gradually more lethargic and confused, until one week later hospitalization was necessary. The carbamazepine dosage was reduced to 1200 mg/day and the confusion and sedation gradually disappeared.
Analysis
A stable co-administration of two drugs implies that despite the high dose of carbamazepine, blood levels for both drugs were initially in the therapeutic window. The removal of the phenytoin led to gradual increase in the symptoms of carbamazepine overdose, without any change in the dose. This indicates that carbamazepine blood levels climbed way above the therapeutic window into toxicity. This was caused by a marked, but gradual, fall in carbamazepine clearance when the phenytoin was withdrawn.
History 4
A 64-year-old obese male was prescribed simvastatin 10 mg daily. Over the next three months, lack of clinical response led to a fivefold increase in dosage. He was then admitted to hospital with rhabdomyolysis. On his own initiative he had self-administered.
Analysis
The statin was not effective unless considerably higher doses than normal were used, indicating that the drug was being cleared at a higher rate than normal.The patient abruptly stopped taking the herbal extract and the clearance of the statin gradually fell while the dose did not, so the drug accumulated and exerted toxicity.
History 5
A 47-year-old female was stabilized on phenobarbitone and warfarin and her prothrombin time was optimized by substantial increase over the normal dosage of anticoagualant, although blood levels were within normal limits. Within 10 days of the abrupt withdrawal of phenobarbitone the patient suffered a mild haemorrhage.
Analysis
As a higher than normal dosage of warfarin was necessary to maintain its plasma levels in the therapeutic window in the presence of the phenobarbitone, it suggests that the latter drug was accelerating the clearance of warfarin. Once the phenobarbitone was stopped, this accelerating effect was lost too, leading to accumulation of the warfarin to the point that blood levels rose above the therapeutic window leading to toxicity, in this case an exaggerated therapeutic effect.
History 6
A 55-year-old male being treated for tuberculosis was taking rifampicin (600mg daily), isoniazid (400 mg daily), ethambutol (200 mg daily) and pyrazinamide (400 mg daily), was also epileptic and was taking carbamazepine (2000 mg daily). The patient decided to stop all medication over the Christmas period to enter his annual seasonal alcohol binge, where he drank heavily for several days. After approximately 13 days, he resumed his drug regimen and before the end of the first day, he was drowsy, lethargic, confused and eventually difficult to wake and was hospitalized. Some of the symptoms of the tuberculosis resumed, such as fever, chills and cough.
Analysis
The patient was suffering from carbamazepine toxicity and very high plasma levels were found on blood analysis. This indicates that the cessation of all drug intakes over the Christmas period of 13 days had led to a marked reduction in the clearance of car-bamazepine, and the resumption of his previous high dosage caused drug accumulation and significant CNS toxicity. The absence of pressure of the anti-tuberculosis drugs had also allowed the disease to partially re-establish itself and may well have led to selection of partly drug-resistant forms of the bacteria.
History 7
A terminally ill cancer patient stabilized on methadone (250mg/day) for pain relief contracted an infection soon after another patient arrived from a major hospital. The infection was determined to be MRSA (methicillin-resistant Staphylococcus aureus) and rifampicin (600 mg/daily) was started for a projected period of 14 days. At day two, the patient complained of severe breakthrough pain and the methadone dose was increased. By day 14 the infection had been cleared and the patient was taking methadone at 600mg/day to control their pain. After rifampicin was stopped, the methadone dose was tapered to its original level over 21 days with minimal toxicity or pain breakthrough.
Analysis
The rifampicin accelerated the clearance of methadone to the point that analgesia was lost extremely rapidly and had to be restored with more than a doubling of the dose. The reversal of the induction effect appeared to take somewhat longer than the onset of the initial effect, which may have been related to the highly variable nature of methadone’s half-life and the pathology of the terminal patient.
Summary
In all five cases, there are a number of common features:
• Some of the drugs’ clearances were not stable until a relatively high dose was employed.
• One drug (or herbal preparation) was able to grossly accelerate the clearance of another agent (s).
• The changes in plasma levels were sufficiently great to either lead to toxicity or total loss of efficacy.
• The toxic effects occurred gradually over days, rather than hours.
• The increase in drug clearance caused by other drugs was fully reversible.
A number of explanations could be put forward for the effects seen above. There could be a reduction in drug absorption in the presence of another agent, possibly linked to inhibition of intestinal drug uptake transporters,although this is relatively rare and would happen within hours rather than days of the regimen change. Perhaps the renal clearance of the drug could be accelerated in some way, although this too is unlikely. To enter the circulation from an oral dose, the drugs must pass through the gut, the portal circulation and then into the liver itself. In Histories 1 and 2, the clearance of carbamazepine was initially unstable and in the presence of phenytoin, virtually 100 per cent cleared before it reached the circulation.
Since the liver’s blood flow is not likely to undergo a sustained increase, then the only way such a large effect on drug levels can occur is that the liver is extracting much more of the drug than usual in the presence of the other drug. This acceleration of drug metabolism as a response to the presence of certain drugs is known as ‘enzyme induction’ and drugs which cause it are often referred to as ‘inducers’ of drug metabolism. The process can be defined as: ‘An adaptive increase in the metabolizing capacity of a tissuethis means that a drug or chemical is capable of inducing an increase in the transcription and translation of specific CYP isoforms, which are often (although not always) the most efficient metabolizers of that chemical. Usually, hepatic induction has the most significant clinical impact, although other tissues are also involved, such as the lung, intestine and the kidneys.
