Undesirable Side Effects

The side effect profile of many drugs is of concern in patients with liver disease. Pharmacodynamics can be altered, making effects and side effects more pronounced, e.g. heightened receptor sensitivity to anxiolytics, and the complications of liver disease, e.g. coagulopathy, may increase the risk of adverse events. This chapter discusses the types of drug that should be avoided or used with caution in patients with liver disease. A number of drugs are listed, but please note that this is not an exhaustive list and that other drugs may need to be considered (Table 6.1). 

Hepatotoxicity is not a particularly common form of adverse drug reaction and a patient with pre-existing liver disease does not have increased susceptibility to hepatic injury when taking drugs known to cause liver damage [1]. Therefore, drugs that are known to be hepato-toxic should not be contraindicated in this group of patients. There are 

It should be noted that after the administration of any drug, isolated increases in liver function tests are not proof of hepatotoxicity, and if the biochemical changes are only moderate (equivalent to an approximate increase of twice the upper limit of normal) this is unlikely to be significant [1] however, it would be sensible to monitor liver function tests closely for further increases and to withdraw the drug if necessary. See Chapter 3 for further information on drugs that cause liver disease. 

If a patient has cholestasis careful consideration must be given to the use of any drug that can cause biliary problems. Several drugs are known to cause cholestatic hepatitis, including the antibiotics flucloxacillin, erythromycin and co-amoxiclav (amoxicillin/clavulanic acid). Although a patient with cholestasis is no more likely to suffer from this idiosyncratic reaction than a patient without liver impairment, it will be of greater concern if it does occur. 

Biliary sludging has been documented in children receiving ceftriaxone. The formation of biliary sludge has been reported to lead to biliary obstruction, cholecystitis, choledocholithiasis and psendolithiasis. Most cases are asymptomatic, transient, reversible, and nsnally only necessitate conservative management. However, greater care is required in patients with pre-existing liver disease, and it is advised that abdominal ultrasound scans are performed when ceftriaxone is initiated [2]. It would seem sensible to consider alternative antibiotic therapy in these types of patient. 

Meperidine is in part demethylated in the body appearing as normeperidine in the urine. It is, however, for the most part hydrolyzed and excreted as free and conjugated meperidinic acid. The normeperidine is also partially hydrolyzed to normeperidinic acid, which is partly conjugated. Only a small part of the drug is excreted in an unchanged form. In humans, meperidine is metabolized at the rate of about 17% per hour, so that a single dose exerts its analgesic effect for 3 to 4 h. In the dog, on the other hand, its rapid metabolism (70 to 90% per hour) makes it difficult to induce tolerance or addiction. 

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Let us outline one of our approaches with the following simple example. Suppose we have a dataset of compounds and two experimental biological activities, of which one is a target activity (TA) and the other is an undesirable side effect (USE). Naturally, those with high TA and low USE form the first subclass, those with low TA and high USE the second, and the rest go into the third, intermediate subclass. 

An undesirable side-effect of an expansion that includes just a quadratic and a cubic term (as is employed in MM2) is that, far from the reference value, the cubic fimction passes through a maximum. This can lead to a catastrophic lengthening of bonds (Figure 4.6). One way to nci iimmodate this problem is to use the cubic contribution only when the structure is ,utficiently close to its equilibrium geometry and is well inside the true potential well. MM3 also includes a quartic term this eliminates the inversion problem and leads to an t". . 11 better description of the Morse curve. 

Second-Generation Receptor Antagonists. Because of undesirable side effects caused by classical H receptor antagonists, dmgs... 

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

Because of the widespread nature of adrenoceptors, nonselective P-agonists can produce many undesirable side effects. Therefore, before adrenergic agonists could become widely used in the treatment of asthma, some selectivity in action was needed. Whereas epinephrine and ephedrine have significant agonist activity at both a and P adrenoceptors, isoproterenol is a selective agonist at the P receptor (39). However, isoproterenol does not distinguish between the P and receptors and it is not active orally. 

Cross-linked finishes are not permanent in the tme sense of the word however, under optimum conditions the finish can last for the usehil life of the material. Wet abrasion during laundering is probably the principal cause of gradual removal of the finish. In order to retain antistatic protection for extended use, an excess of finish is often appHed The extent of chemical interaction between the durable antistatic agents and the fiber substrates to which they are appHed is not perfectiy understood. Certain oxidizing agents such as hypochlorite bleaches tend to depolymerize and remove some durable antistatic finishes. Some of the durable finishes have also produced undesirable side effects on textile materials, ie, harsh hand, discoloration, and loss of tensile properties. 

Advantages to Membrane Separation This subsertion covers the commercially important membrane applications. AU except electrodialysis are pressure driven. All except pervaporation involve no phase change. All tend to be inherently low-energy consumers in the-oiy if not in practice. They operate by a different mechanism than do other separation methods, so they have a unique profile of strengths and weaknesses. In some cases they provide unusual sharpness of separation, but in most cases they perform a separation at lower cost, provide more valuable products, and do so with fewer undesirable side effects than older separations methods. The membrane interposes a new phase between feed and product. It controls the transfer of mass between feed and product. It is a kinetic, not an equihbrium process. In a separation, a membrane will be selective because it passes some components much more rapidly than others. Many membranes are veiy selective. Membrane separations are often simpler than the alternatives. 

A commonly expressed definition is Thermal Comfort is that condition of mind that expresses satisfaction with the thermal environment. The definition implies that the judgment of comfort is a mental process that results from physical, physiological, and psychological factors and processes. Dissatisfac tion can lead to complaints and other undesirable side effects. 

How can we prevent modifications from producing unforeseen and undesirable side effects References I and 2 propose a three-pronged approach ... 

The final steps to a synthetic blood depend completely upon good chemistry tailored to meet the exact needs of the body Fluorocarbons, such as perfluorodecalin, recently have been found to induce hypennflated lungs when given either intravenously as an emulsion or mtratracheally as a neat liquid [18, 19] But this and other physiological side effects are now understood, and research is well advanced to prevent undesirable side effects in medical applications of fluorocarbon liquids... 

Perhaps one of the most exciting new applications stems from the discovery in 1949 that small daily doses (l-2g) of LI2C03 taken orally provide an effective treatment for manic-depressive psychoses. The mode of action is not well understood but there appear to be no undesirable side effects. The dosage maintains the level of Li in the blood at about I mmol l and its action may be related to the influence of Li on the Na/K balance and (or) the Mg/Ca balance since Li is related chemically to both pairs of elements. 

The separation of enantiomers is a very important topic to the pharmaceutical industry. It is well recognized that the biological activities and bioavailabilities of enantiomers often differ [1]. To further complicate matters, the pharmacokinetic profile of the racemate is often not just the sum of the profiles of the individual enantiomers. In many cases, one enantiomer has the desired pharmacological activity, whereas the other enantiomer may be responsible for undesirable side-effects. What often gets lost however is the fact that, in some cases, one enantiomer may be inert and, in many cases, both enantiomers may have therapeutic value, though not for the same disease state. It is also possible for one enantiomer to mediate the harmful effects of the other enantiomer. For instance, in the case of indacrinone, one enantiomer is a diuretic but causes uric acid retention, whereas the other enantiomer causes uric acid elimination. Thus, administration of a mixture of enantiomers, although not necessarily racemic, may have therapeutic value. 

The concept of drug development is based on the findings that retinoid receptors (RARs and RXRs) offer a new approach by targeting different genes depending on the activated retinoid receptor complexes. The multiplicity of these retinoid signaling pathways affords potential for therapeutic opportunity as well as retinoid therapy associated undesired side effects. It is possible that the indiscriminate activation of all pathways by nonspecific retinoid ligands could lead to unacceptable side effects so that any enhanced efficacy would be obtained at the cost of enhanced toxicity. 

As a general rule, clinical data are required as evidence to support conformity with the requirements of the Active Implantable Medical Devices (AIMD) and the Medical Device (MD) directives with regards to safety and effectiveness under the normal conditions of use, evaluation of undesirable side effects, and the acceptability of the benefit/risk ratio. Risk analysis should be used to establish key objectives that need to be addressed by clinical data, or alternatively to justify why clinical data are not required (mainly for Class I devices). The risk analysis process should help the manufacturer to identify known (or reasonably foreseeable) hazards associated with the use of the device, and decide how best to investigate and estimate the risks associated with each hazard. The clinical data should then be used to establish the safety and effectiveness of the device under the intended use conditions, and to demonstrate that any of the residual risks are acceptable, when weighed against the benefits derived from use of the device. 

A difiiculty with this mechanism is the small nucleation rate predicted (1). Surfaces of a crystal with low vapor pressure have very few clusters and two-dimensional nucleation is almost impossible. Indeed, dislocation-free crystals can often remain in a metastable equilibrium with a supersaturated vapor for long periods of time. Nucleation can be induced by resorting to a vapor with a very large supersaturation, but this often has undesirable side effects. Instabilities in the interface shape result in a degradation of the quality and uniformity of crystalline material. 

Human insulin Two peptide chains A, 21 amino acids long, and B, 30 amino acids long . coli Juvenile onset diabetes Approved for sale A and B chains made separately as fusion proteins and joined in vitro Compared with animal Insulins some undesirable side-effects have been noted... 

In contrast, iproniazid, introduced in 1951 for treatment of tuberculosis, induced euphoria and was described as a psychic energiser . In fact, these patients, when given iproniazid, could become quite disruptive and this action was regarded as an undesirable side-effect However, its beneficial effects in depression were soon recognised and it was regarded as the first effective antidepressant drug. Studies of peripheral sympathetic neurons, later extended to noradrenergic neurons in the brain, showed that iproniazid irreversibly inhibits the catalytic enzyme, monoamine oxidase (MAO). Because only cytoplasmic monoamines are accessible to MAO, inhibition of this enzyme first increases the concentration of the pool of soluble transmitter but this leads to a secondary increase in the stores of vesicle-bound transmitter i.e. the pool available for impulse-evoked release (Fillenz and Stanford 1981). 

Laser illumination, which allows for significantly fiigher photon flux, has become widespread lately. An undesirable side effect of high intensities is heating of the solution layer next to the electrode. This effect can be reduced when intermittent (pulsed) fight is used. Light pulses offer the additional possibility to examine after effects of the illumination the relaxation processes that occur when the system returns to its original condition. 

Another major trend in performance chemicals is towards the development of products, e.g. drugs, pesticides, food additives, etc., that are more targeted in their action, with less undesirable side-effects. 

The ultimate fate of drugs and their metabolites is a major concern. If they are not cleared in a reasonable time, they could promote undesirable side effects. Polymer drug carriers are usually nonbiodegradable, and if their size is greater than 40,000 daltons, they could accumulate in the host with the potential of future unwanted effects. 

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