**2. Rates of absorption influence on the occurrence of adverse effects**

For the majority of drugs that are administered by other routes than intravenous injection, they need to overcome several hurdles before they reach the systemic circulation. These include the layers of the outer skin of the body or veins in case of subcutaneous and intramuscular routes or the walls of the digestive system. For drugs administered orally, the active substances must first be released from the dosage from, namely tablets, capsules, and other forms. There will be a reduction of therapeutic effects if there is little absorption, or destruction of the drug by

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

digestive system enzymes, or if the active substance was not released from its dosage form [1, 2]. Sometimes the absorption may be impaired by the presence of foods or other drugs or substances that react with the active substance and make it not absorbable. On the contrary, the presence of physical lesions in the digestive tract, or substances that increases the liposolubility of the active substance may actually increase its absorption [3].

As depicted in **Figure 1**, largely unionized substances such as, aspirin when in acidic environment, it is absorbed from the stomach but most of the absorption occurs in the small intestine where the large surface area compensates for the less favorable degree of ionization. On the contrary, weak bases, which are highly ionized in gastric acid, cannot be absorbed until they have left the stomach, so delayed gastric emptying (when foods is in the stomach) can delay

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On the other hand, it is often recommended that drugs should be taken at meal times. This is to aid adherence to treatment and in some circumstances, to reduce gastric irritation (a local adverse effect), as, for example, with aspirin, which may cause gastric bleeding. It is noted here that the effect of food is not always predictable, although, generally, food delays gastric emptying and increases the secretion of gastric acid while reducing the overall gastric pH. Hence, the presence of foods may reduce the absorption of drugs such as ketoconazole that are more soluble in acid; yet on the contrary, the absorption of griseofulvin, an antifungal drug, as well as that of saquinavir, an antiretroviral drug, is increased when taken with a

As depicted in **Figure 2**, several transportation mechanisms have been envisaged from the site of absorption. It should be noted that the preponderance of each transport mechanism is different for each individual patient due to their genetic and constitutional

the effect of such drugs [6, 8].

"fatty" meal [6, 9, 10].

**Figure 1.** Absorption throughout the gastrointestinal tract. Source: [6].

makeup.

Several factors affect the journey of the drug that result in increased or decreased absorption or volume of distribution as well as the metabolism thereof. The physicochemical characteristics of the drug itself, the pharmaceutical dosage form it is in and its intrinsic quality, the state of the first layers of skin or membranes through which the drug is to be absorbed through, the composition of the environment such as the presence or absence of foods or other chemicals in the digestive system as well as the type of foods or the other chemicals, the type and number of carriers subunits of enzymes or proteins complex available at the site of absorption, all influence the absorption rates [4].

For medicines administered orally, whether tablets, capsules, solution, suspension, syrup, or elixir, it should be noted that the gastrointestinal tract is a harsh environment. With its low pH, acid-labile drugs such as benzylpenicillin (penicillin G) and methicillin, they become inactivated as a result of the catalysis that takes place due to beta-lactamase enzymes [4–6]. Similarly, the presence of proteases makes the oral route unsuitable for many proteins and peptides such as insulin and oxytocin [1–3]. When taken orally, the absorption of drugs occurs chiefly by passive diffusion of lipophilic molecules and by carrier-mediated transport for drugs that are structurally similar to endogenous compounds such as levodopa and 5 fluorouracil. With passive diffusion, the rate of absorption is proportional to the concentration or the amount of drug to be absorbed and the fraction or percentage absorbed in a given interval remains constant.

With carrier-mediated mechanisms, be it active transport or facilitated diffusion, there is a limited capacity and the transporter can be saturated, hence limiting the amount of drug reaching the systemic circulation. In this instance, increasing the dose will result in local adverse effects [6]. Clinicians ought to understand the particularity of a particular drug before deciding to indiscriminately increase the dose when a subtherapeutic effect is observed. Indeed, this remark is true even for drugs absorbed by passive diffusion like aspirin (salicylic acid) as the percentage absorbed is independent of the continuous concentration but proportional to the initial drug concentration.

Nowadays, the proliferation of substandard and falsified drugs particularly in Africa makes it difficult to predict the beneficial effects of these drugs [7]. This is because the intrinsic pharmaceutical quality of these drugs is not optimal leading to several consequences with regard to the absorption and elicited effects of these drugs. Several examples have been encountered in clinical practice; for instance, cotrimoxazole tablets badly compressed have been taken by patients just to be excreted intact in their feces! This example means that no dissolution took place, so little or nothing of the drug was absorbed, consequently, the therapeutic effects expected from the drug could not be elicited rather than the placebo effect.

As depicted in **Figure 1**, largely unionized substances such as, aspirin when in acidic environment, it is absorbed from the stomach but most of the absorption occurs in the small intestine where the large surface area compensates for the less favorable degree of ionization. On the contrary, weak bases, which are highly ionized in gastric acid, cannot be absorbed until they have left the stomach, so delayed gastric emptying (when foods is in the stomach) can delay the effect of such drugs [6, 8].

digestive system enzymes, or if the active substance was not released from its dosage form [1, 2]. Sometimes the absorption may be impaired by the presence of foods or other drugs or substances that react with the active substance and make it not absorbable. On the contrary, the presence of physical lesions in the digestive tract, or substances that increases the liposolu-

Several factors affect the journey of the drug that result in increased or decreased absorption or volume of distribution as well as the metabolism thereof. The physicochemical characteristics of the drug itself, the pharmaceutical dosage form it is in and its intrinsic quality, the state of the first layers of skin or membranes through which the drug is to be absorbed through, the composition of the environment such as the presence or absence of foods or other chemicals in the digestive system as well as the type of foods or the other chemicals, the type and number of carriers subunits of enzymes or proteins complex available at the site of absorption, all

For medicines administered orally, whether tablets, capsules, solution, suspension, syrup, or elixir, it should be noted that the gastrointestinal tract is a harsh environment. With its low pH, acid-labile drugs such as benzylpenicillin (penicillin G) and methicillin, they become inactivated as a result of the catalysis that takes place due to beta-lactamase enzymes [4–6]. Similarly, the presence of proteases makes the oral route unsuitable for many proteins and peptides such as insulin and oxytocin [1–3]. When taken orally, the absorption of drugs occurs chiefly by passive diffusion of lipophilic molecules and by carrier-mediated transport for drugs that are structurally similar to endogenous compounds such as levodopa and 5 fluorouracil. With passive diffusion, the rate of absorption is proportional to the concentration or the amount of drug to be absorbed and the fraction or percentage absorbed in a given

With carrier-mediated mechanisms, be it active transport or facilitated diffusion, there is a limited capacity and the transporter can be saturated, hence limiting the amount of drug reaching the systemic circulation. In this instance, increasing the dose will result in local adverse effects [6]. Clinicians ought to understand the particularity of a particular drug before deciding to indiscriminately increase the dose when a subtherapeutic effect is observed. Indeed, this remark is true even for drugs absorbed by passive diffusion like aspirin (salicylic acid) as the percentage absorbed is independent of the continuous concentration but proportional to

Nowadays, the proliferation of substandard and falsified drugs particularly in Africa makes it difficult to predict the beneficial effects of these drugs [7]. This is because the intrinsic pharmaceutical quality of these drugs is not optimal leading to several consequences with regard to the absorption and elicited effects of these drugs. Several examples have been encountered in clinical practice; for instance, cotrimoxazole tablets badly compressed have been taken by patients just to be excreted intact in their feces! This example means that no dissolution took place, so little or nothing of the drug was absorbed, consequently, the therapeutic effects

expected from the drug could not be elicited rather than the placebo effect.

bility of the active substance may actually increase its absorption [3].

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

influence the absorption rates [4].

interval remains constant.

the initial drug concentration.

On the other hand, it is often recommended that drugs should be taken at meal times. This is to aid adherence to treatment and in some circumstances, to reduce gastric irritation (a local adverse effect), as, for example, with aspirin, which may cause gastric bleeding. It is noted here that the effect of food is not always predictable, although, generally, food delays gastric emptying and increases the secretion of gastric acid while reducing the overall gastric pH. Hence, the presence of foods may reduce the absorption of drugs such as ketoconazole that are more soluble in acid; yet on the contrary, the absorption of griseofulvin, an antifungal drug, as well as that of saquinavir, an antiretroviral drug, is increased when taken with a "fatty" meal [6, 9, 10].

As depicted in **Figure 2**, several transportation mechanisms have been envisaged from the site of absorption. It should be noted that the preponderance of each transport mechanism is different for each individual patient due to their genetic and constitutional makeup.

**Figure 1.** Absorption throughout the gastrointestinal tract. Source: [6].

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

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

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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

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

due to uptake of the drug into skeletal muscle and fat [16–18].

6–7%; up to 1% of carbohydrates [19, 20] (**Figure 4**).

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

shown in **Figure 3**.

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