**3. Systemic concentration and occurrence of adverse effects**

The key concept in explaining the effects of drugs is "plasma concentration" or the amount of drug that reaches the systematic circulation; it reflects the amount of drug that will be available to act and produce effects at the site of action. Classically, it is has been established that what is known as the effect of a drug is actually a combination of the action of a drug or drug action; its effect or drug effect and the body's response or drug response. This may be illustrated as follows: For example, for a penicillin antibiotic, the "action" consists of inhibiting bacterial protein synthesis, the "effect" corresponds to the killing rate or growth inhibition rate of bacteria, and the clinical "response" would be the cure of the body from the infection and its manifestations [6, 11, 12].

In order to achieve its effect, a drug must first be released from its pharmaceutical form from the site of administration; be absorbed and distributed through the body to reach its site of action where it will interact with its specific receptors and/or some other nonspecific receptors. Through its journey, the body acts on it by metabolizing it in order, primarily, to wear off and eliminate it. The result of metabolism may sometimes achieve the goal of inactivating or destroying the structure of the drug; or sometimes it may lead to the production of active metabolites that actually will interact with receptors and produce the expected therapeutic effects of the particular drug [11, 13, 14].

For drugs subject the first-pass effect that is drugs that are metabolized before they reach the systemic circulation; generally, this pre-systemic metabolism reduces their bioavailability except when and if the resulting metabolites are pharmacologically active. In the case of nitroglycerin, which is almost totally first metabolized, its di- and mononitrate metabolites produced have very much reduced activity, and hence this drug is considered to be inactive when taken orally [15].

When a drug successfully crosses the physical and biochemical barriers described above, it will reach the systemic circulation and its plasma concentration will continue to rise as for as it will be absorbed. If, the increase is beyond a certain threshold, toxic effects or adverse effects will be clinically observed. This is well established now that there is an optimum range of concentrations over which a drug has beneficial or expected useful effects, with no clinical toxicity, this is known as the "therapeutic range," sometimes referred to as the "therapeutic window" [6]. Moreover, it has been established also that there is a threshold concentration below which the drug is deemed ineffective, or not producing expected therapeutics effects, and a higher threshold above which adverse or unwanted toxic effects become apparent as shown in **Figure 3**.

The plasma concentration fluctuates based on the rates of absorption, the influence of the firstpass effect, and based on whether the drug is following a one compartment model of distribution or a multiple compartment model. For drugs using the multiple compartment model, which are drugs that accumulate in other compartments other than the systemic circulation, namely the liver, skeletal muscles, bones, adipose tissues; their absorption, distribution, and metabolism may be complex. For instance, thiopental, once absorbed, its liver concentrations rapidly equilibrate with those in plasma while the concentrations in skeletal muscle rise initially and then equilibrate later and their concentrations in adipose tissue will rise for at least the first 3.5 h following the bolus injection of thiopental; its duration of action will be short due to uptake of the drug into skeletal muscle and fat [16–18].

In order to understand the influence of multiple compartments, it is important to remember that typically the body is made of 11 chemical elements, namely carbon, calcium, chlorine, hydrogen, nitrogen, magnesium, oxygen, phosphorus, potassium, sodium, and sulfur; and 5 molecules such as water which comprises 60–62%; proteins 16–18%; fat 10–15%; minerals 6–7%; up to 1% of carbohydrates [19, 20] (**Figure 4**).

**Figure 3.** Drug levels in relation to elicited effects. Source: [6].

**3. Systemic concentration and occurrence of adverse effects**

and its manifestations [6, 11, 12].

**Figure 2.** Transport mechanisms of drugs. Source: [6].

4 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

effects of the particular drug [11, 13, 14].

when taken orally [15].

The key concept in explaining the effects of drugs is "plasma concentration" or the amount of drug that reaches the systematic circulation; it reflects the amount of drug that will be available to act and produce effects at the site of action. Classically, it is has been established that what is known as the effect of a drug is actually a combination of the action of a drug or drug action; its effect or drug effect and the body's response or drug response. This may be illustrated as follows: For example, for a penicillin antibiotic, the "action" consists of inhibiting bacterial protein synthesis, the "effect" corresponds to the killing rate or growth inhibition rate of bacteria, and the clinical "response" would be the cure of the body from the infection

In order to achieve its effect, a drug must first be released from its pharmaceutical form from the site of administration; be absorbed and distributed through the body to reach its site of action where it will interact with its specific receptors and/or some other nonspecific receptors. Through its journey, the body acts on it by metabolizing it in order, primarily, to wear off and eliminate it. The result of metabolism may sometimes achieve the goal of inactivating or destroying the structure of the drug; or sometimes it may lead to the production of active metabolites that actually will interact with receptors and produce the expected therapeutic

For drugs subject the first-pass effect that is drugs that are metabolized before they reach the systemic circulation; generally, this pre-systemic metabolism reduces their bioavailability except when and if the resulting metabolites are pharmacologically active. In the case of nitroglycerin, which is almost totally first metabolized, its di- and mononitrate metabolites produced have very much reduced activity, and hence this drug is considered to be inactive 6 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

disease state as well as their lifestyle as already explained. In case of overdose, drug metabolism is altered because enzymes responsible for metabolism become saturated; this leaves the excess drug free to force its way to nonspecific receptors by overcoming both inhibition or competition; consequently, it produces nontypical adverse effects while its clearance is

Introductory Chapter: Linkages between Pharmacokinetics and Adverse Effects of Drugs

http://dx.doi.org/10.5772/intechopen.76511

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Once a drug is metabolized and reduced to hydrosoluble entities, it is ready to be excreted through the kidneys and eliminated in the urine. However, some changes may impact negatively to this process. An important pharmacokinetic change in the elderly, for instance, is the decrease in renal drug elimination due to the fact that as someone ages, his/her renal mass as well as glomerular filtration and tubular secretion capacities decrease. It should be noted that after age 40, there is a decrease in the number of functional glomeruli, and the renal blood flow is estimated to decline by approximately 1% yearly. The clinical effect of decreased renal clearance includes prolonged drug half-life, increased serum drug level to toxic level which

At the core, genetic factors play a major role because of the genetic polymorphism or difference in drug responses between individuals. The drug response is genetically determined by the type, quality, and quantity of genes, proteins, enzymes that one has. A well-known example suffices here, the case of the enzyme, N-acetyltransferase which differs between individuals such that the population may be divided into slow and fast acetylators. People who are slow acetylators may experience more adverse effects unless doses of drugs requiring acetylation for metabolism are reduced. Other inherited variations in pharmacokinetics include deficiency of one or more hepatic cytochrome-P450 isozymes or plasma cholinesterase enzymes. The metabolic conversion of drugs into metabolites is established as a source of

As stated above, lifestyle factors such as diet and exercise affect bodyweight which is used as the basis for determining the dose administered. In case of chronic diseases, an increase or a drop of 10–20% in bodyweight should normally be noted and followed by a dose adjustment. Tuberculosis treatment is an example whereby patients normally increase their bodyweights sometimes up to 30% of their initial weights within 2–4 months. Clearly based on the treatment algorithms as defined by WHO, the doses or number of tablets for these patients should increase following the increase in their bodyweights; however, often this is not usually done [39, 40]. Moreover, diet, smoking, and alcohol may affect enzyme activity and lead to unexpected drug interactions. Cigarette smoking affects drug therapy by pharmacokinetic. The polycyclic aromatic hydrocarbons in tobacco smoke are believed to be responsible for the induction of cytochrome P450 (CYP) 1A1 and CYP1A2 which are responsible for the metabolism

decreased and its half-life is prolonged [27–30].

several idiosyncratic drug reactions [32–38].

**4. Elimination or excretion of drugs and adverse effects**

obviously leads to increased potential for adverse drug reactions [6, 31].

**5. Pharmacokinetics related risk factors of adverse effects**

**Figure 4.** Body composition. Source: Fomon et al. [19]; Chumlea et al. [20].

It should be noted that there are variations in the concentration of the elements and molecules making up the body. These variations are rhythmic, cyclic, and dependent on the age, sex, and health status of the individuals. It is known that, in each disease state, and in case of multi-morbidity, the composition of these elements and molecules vary in relation to the lifestyle of an individual, namely his/her water and food intake, smoking and alcohol consumption, exercise and sleeping patterns in terms of quantity, quality, and variety or diversity [21–24]. This situation largely explains why a same dose of a drug may not always produce similar effects (beneficial or adverse) on a group of individuals even if they have same bodyweights, are of same ethnicity or sex. This observation explains why standard doses cannot be prescribed indiscriminately to each individual patient; hence the new concept of individualized treatment regimen.

The need for individualized regimen can be more understood when one considers the "halflife" concept. Half-life is a very useful parameter in pharmacokinetics; it is defined as the time it takes for the concentration of a drug to halve from its initial peak concentration in plasma or urine. It is important to note that even drugs from the same class have different half-lives because they have different volumes of distribution and/or systemic clearance. This is so because the apparent volume of distribution depends, as said earlier, upon the nature of the drug and the makeup of individuals. For instance, lipophilic drugs tend to have large apparent volumes of distribution and to be widely distributed in someone who is obese, due to the availability of more adipose tissue. Hence, the lipophilic drugs will have a longer elimination half-life in obese people; their longer stay may mean also longer lingering affects both beneficial and unwanted [23, 25, 26].

When drugs accumulating in other compartments continue to be taken, there will be a saturation of the receptors or even storage spaces in these compartments, resulting in much more concentrations in the interstitial liquids, and overwhelming of related receptors, thus the advent of adverse and side effects not typical of drug class. Such side effects may and should become a subject of pharmacovigilance investigation. It should be said here that atypical or new side effects may occur even with normal doses in certain individuals because of their uniqueness with regard to the receptors, enzymes, or proteins, they may have in abundance or absence thereof as a matter of their genetic makeup or as a result of a subclinical or clinical disease state as well as their lifestyle as already explained. In case of overdose, drug metabolism is altered because enzymes responsible for metabolism become saturated; this leaves the excess drug free to force its way to nonspecific receptors by overcoming both inhibition or competition; consequently, it produces nontypical adverse effects while its clearance is decreased and its half-life is prolonged [27–30].
