Drug dose levels

Consequently, the best drugs are usually a compromise. They are neither too lipophilic nor too hydrophilic. In general, it is found that the most effective drugs have a pKa value in the range 6-8. In other words, they are drugs which are partially ionized at blood pH and can easily equilibrate between their ionized and non-ionized forms. This allows them to cross cell membranes in the non-ionized form and to bind to their receptor in the ionized form (Fig. 8.3). 

On the other hand, it is sometimes useful to have a fully ionized drug which is incapable of crossing cell membranes. For example, highly ionized sulfonamides are used against gastrointestinal infections. They are incapable of crossing the gut wall and are therefore directed efficiently against the infection. 

Estimating dose levels for certain drugs can be a problem with a further range of variables to be taken into account. 

Other complications include differences of age, sex, and race. Diet, environment, and altitude also have an influence. Body weight is an important factor to be taken into account. Obese people present a particular problem since it can prove very difficult to estimate how much of a drug will be stored in fat tissue and how much will be free drug. The precise time when drugs are taken may be important since metabolic reaction rates can vary throughout the day. 

Drugs can interact with other drugs. For example, some drugs used for diabetes are bound by plasma protein in the blood supply and are therefore not free to react with receptors. However, they can be displaced from the plasma protein by aspirin and this can lead to a drug overdose. A similar phenomenon is observed between anticoagulents and aspirin. 

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By the use of radioactively labelled precursor chemicals, the cell s ability to synthesize macromolecules such as DNA, RNA, and proteins, after treatment with the drug, can be measured. A typical result is shown in Fig. 5, for exposure of the cells to the equivalent level of drug found in tumor tissue of a treated animal. The synthesis of new total DNA is selectively and persistently inhibited. Total RNA and protein syntheses are not markedly affected until much higher drug-dose levels, which are frankly toxic to... 

To be more precise, the therapeutic index compares the drug dose levels which lead to toxic effects in 50 per cent of cases studied, with respect to the dose levels leading to maximum therapeutic effects in 50 per cent of cases studied. This is a more reliable method of measuring the index since it eliminates any peculiar individual results. 

Most drugs can be expected to have potentially lethal effects, as their usefulness depends on their ability to infiuence physiological processes. However, the dose level at which toxic effects manifest should be significantly higher than those required to produce a pharmaceutical response, so that a good safety margin exists between therapeutic and toxic levels. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

The law of mass action has been successfully applied to many drug dose-response relationships since the early work of Clark. The systematic relation between the dose of a drug and the magnitude of its response is based on three assumptions (1) response is proportional to the level of receptor occupancy (occupancy theory), (2) one drug molecule combines with one receptor site, and (3) a negligible fraction of total drug is combined with the receptors. These assumptions must also apply to Beidler s equation. 

Once the loading dose of the AED is administered, it is important to remember to initiate maintenance doses to ensure that therapeutic levels are sustained. Chronic and idiosyncratic side effects as well as potential drug interactions should be considered if the patient will continue AED therapy indefinitely. All drug therapy should be adjusted for any hepatic or renal disease states. Table 28-1 summarizes the drug doses used in SE, and Table 28-2 provides an example of an algorithm for the treatment of patients in SE. Published studies comparing these treatment strategies are summarized in Table 28-3. 

Dexamethasone therapy may reduce antibiotic penetration, so antimicrobial drug dosing may have to be increased (especially vancomycin) to achieve adequate CSF levels. Serum levels of vancomycin should be measured and doses titrated to ensure adequate CNS concentrations. Evaluate whether intraventricular or intrathecal antibiotics are indicated. 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

In summary, OTC toxicity either toward animal organs or as drugs appears in four broad target areas, namely neurotoxicity, hepatoxicity, immunotoxicity and cutaneous toxicity10. Although other effects occur in select species or at high dose levels, their importance is minor compared to the four areas listed above. 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

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