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

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 several idiosyncratic drug reactions [32–38].

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 of a number of drugs. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis that results in enhanced heparin binding to antithrombin factor III [41, 42]. Moreover, cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Hence, the impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy; this why clinicians should regularly enquire of smoking and drinking habits of their patients [43, 44].

In the elderly, it is well known that the incidence of diseases increases with aging. A major consideration is the presence of comorbid conditions present in aging people that affect plasma concentrations of drugs through changes in the extent of absorption, in the rates of metabolism and/or excretion, and changes in tissue localization, for example, increased tissue binding leading to reduced plasma concentrations. In case of warfarin, age was found to have a significant effect on dosing; older patients require much lower doses than the young adults. Furthermore, it is well established that higher gastric pH, delayed gastric emptying, and decreased intestinal motility and blood flow are observed in elderly individuals. Consequently, even normal doses for health adults may become overdosage in the elderly patients who may experience more and severe adverse effects. Other factors that affect distribution of drugs in the body are changes in body fat and water and changes in protein binding. In the elderly, lean body mass can decrease by as much as 12–19% through the loss of skeletal muscle. Thus, blood levels of drugs primarily distributed in muscle such as digoxin will increase and become a risk for overdose when normal or standard dose are used. Moreover, due to a decrease in water concentration in older people, hydrosoluble drugs would reach higher concentrations because there is less water to dilute them while liposoluble drugs would accumulate more because there is relatively more fat tissue to store them. Furthermore, the kidney and liver functions perform less optimally; hence drugs are not readily metabolized and excreted into the urine to be eliminated. This leads to many drugs staying much longer than they do in a younger person's body, the net result would be the prolongation of

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With regard to disease states, there are pharmacodynamic differences in patients with liver disease. Effects have been observed with β-blockers and drugs that depress the CNS. In case of β-blockers, it is documented that there is a reduction in β-adrenoceptor density in mononuclear cells which results in a decrease in effect; this has been observed with propranolol. Similarly, patients with liver cirrhosis had been found to be particularly sensitive to opioids and anxiolytics. In case of kidney disease, a drug that is 100% metabolized may also be affected to some extent particularly its excretion if its metabolites accumulate in plasma, leading to an exaggerated response if the metabolites contribute to the pharmacological effect; or, atypical toxicity that is not seen when the metabolites are excreted normally. Additionally, renal impairment is likely to lead to varying degrees of water loading and this may lead to the changes in the concentrations of the drug in the fluid compartments of the body, including plasma. Children with cystic fibrosis present with greater renal clearance of drugs such as aminoglycosides when compared with children without the disease; this observation suggests that higher doses by weight and more frequent dosing intervals are required in these

With regard to drug-drug interactions, it should be said that patients commonly use two or more drugs concurrently; some prescribed by their health care providers, others bought by themselves or received from family and friends. Because patients are often unaware of the multiple drug interactions, they suffer from adverse drug reactions resulting from alterations of the pharmacokinetics parameters due to interacting substances; often with the end result being a decreased therapeutic efficacy, or an increased toxicity or occurrence of adverse effects. The binding of drugs to macromolecules such as receptors on plasma proteins is governed

pharmacodynamic effects and occurrence of side effects [2, 54–63].

children [64–72].

With regard to sex, differences between male and female will include differences in weight and weight distribution as well as hormonal differences particularly in relation to the menstrual cycle and its absence in prepubescent girls and postmenopausal women [45]. Moreover, physiological differences relating to body composition, gastric motility, liver metabolism, renal function, and glomerular filtration rates all affect differently the disposition of drugs with regard to gender. Simply put, drug absorption, distribution, metabolism, and elimination are not actually similar in men and women. Drug absorption in the lung may differ according to gender [46]. It has been demonstrated that there is a significant less deposition of an aerosolized drug in women than men which has been ascribed to differences in breathing patterns. Gastrointestinal transit time is longer in women (mean 91.7 h) than in men (44.8 h), as is gastric emptying time. This situation causes delays in the absorption of certain drugs. It has been shown for instance that following oral doses of levofloxacin and losartan, the areas under the curve (AUC) of these drugs were significantly greater in females than males. Moreover, relatively fast absorption of oral salicylates and that of ferrous sulfate has been shown in females and prepubertal girls than in boys. After intravenous infusion, the systemic clearance of verapamil was shown to be greater in women than in men. In case of propofol, women are said to be less sensitive to the effects of propofol and recover from anesthesia more quickly than men. This observation was demonstrated in a study that showed that the AUC values for the metabolites, 4-hydroxypropofol and propofol glucuronide, were significantly higher in women than in men and that this effect was 3.6 times higher in Hispanic females than in Caucasian females. On the contrary, protein binding is reportedly higher in males than females, for chlordiazepoxide and warfarin. Hepatic enzyme CYP3A4 is more active in females than males; drugs metabolized by this enzyme are thus affected more efficiently in females than males [47–50].

With regard to age, in children, their low gastric acid secretion can result in increased serum concentrations of weak bases and acid-labile medications, such as penicillin, and decreased serum concentrations of weak acid medications, such as phenobarbital, due to increased ionization. Additionally, gastric emptying time and intestinal transit time are delayed in premature infants; this increases drug contact time with the GI mucosa, hereby increasing drug absorption. In neonates, infants, and young children, there is increased risk of ADRs because of their incapacity to metabolize most drugs due to lack of appropriate enzymes and related functions. For instance, in neonates of less than 2 months old, because of their immature renal tubular function, it is recommended to avoid digoxin, aminoglycosides, ACE inhibitors, and NSAIDs [11, 51–53].

In the elderly, it is well known that the incidence of diseases increases with aging. A major consideration is the presence of comorbid conditions present in aging people that affect plasma concentrations of drugs through changes in the extent of absorption, in the rates of metabolism and/or excretion, and changes in tissue localization, for example, increased tissue binding leading to reduced plasma concentrations. In case of warfarin, age was found to have a significant effect on dosing; older patients require much lower doses than the young adults. Furthermore, it is well established that higher gastric pH, delayed gastric emptying, and decreased intestinal motility and blood flow are observed in elderly individuals. Consequently, even normal doses for health adults may become overdosage in the elderly patients who may experience more and severe adverse effects. Other factors that affect distribution of drugs in the body are changes in body fat and water and changes in protein binding. In the elderly, lean body mass can decrease by as much as 12–19% through the loss of skeletal muscle. Thus, blood levels of drugs primarily distributed in muscle such as digoxin will increase and become a risk for overdose when normal or standard dose are used. Moreover, due to a decrease in water concentration in older people, hydrosoluble drugs would reach higher concentrations because there is less water to dilute them while liposoluble drugs would accumulate more because there is relatively more fat tissue to store them. Furthermore, the kidney and liver functions perform less optimally; hence drugs are not readily metabolized and excreted into the urine to be eliminated. This leads to many drugs staying much longer than they do in a younger person's body, the net result would be the prolongation of pharmacodynamic effects and occurrence of side effects [2, 54–63].

of a number of drugs. Drugs for which induced metabolism because of cigarette smoking may have clinical consequence include theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, and estradiol. Cigarette smoking results in faster clearance of heparin, possibly related to smoking-related activation of thrombosis that results in enhanced heparin binding to antithrombin factor III [41, 42]. Moreover, cutaneous vasoconstriction by nicotine may slow the rate of insulin absorption after subcutaneous administration. Hence, the impact of cigarette smoking needs to be considered in planning and assessing responses to drug therapy; this why clinicians should regularly enquire of smoking

With regard to sex, differences between male and female will include differences in weight and weight distribution as well as hormonal differences particularly in relation to the menstrual cycle and its absence in prepubescent girls and postmenopausal women [45]. Moreover, physiological differences relating to body composition, gastric motility, liver metabolism, renal function, and glomerular filtration rates all affect differently the disposition of drugs with regard to gender. Simply put, drug absorption, distribution, metabolism, and elimination are not actually similar in men and women. Drug absorption in the lung may differ according to gender [46]. It has been demonstrated that there is a significant less deposition of an aerosolized drug in women than men which has been ascribed to differences in breathing patterns. Gastrointestinal transit time is longer in women (mean 91.7 h) than in men (44.8 h), as is gastric emptying time. This situation causes delays in the absorption of certain drugs. It has been shown for instance that following oral doses of levofloxacin and losartan, the areas under the curve (AUC) of these drugs were significantly greater in females than males. Moreover, relatively fast absorption of oral salicylates and that of ferrous sulfate has been shown in females and prepubertal girls than in boys. After intravenous infusion, the systemic clearance of verapamil was shown to be greater in women than in men. In case of propofol, women are said to be less sensitive to the effects of propofol and recover from anesthesia more quickly than men. This observation was demonstrated in a study that showed that the AUC values for the metabolites, 4-hydroxypropofol and propofol glucuronide, were significantly higher in women than in men and that this effect was 3.6 times higher in Hispanic females than in Caucasian females. On the contrary, protein binding is reportedly higher in males than females, for chlordiazepoxide and warfarin. Hepatic enzyme CYP3A4 is more active in females than males; drugs metabolized by this enzyme are thus affected more efficiently in

With regard to age, in children, their low gastric acid secretion can result in increased serum concentrations of weak bases and acid-labile medications, such as penicillin, and decreased serum concentrations of weak acid medications, such as phenobarbital, due to increased ionization. Additionally, gastric emptying time and intestinal transit time are delayed in premature infants; this increases drug contact time with the GI mucosa, hereby increasing drug absorption. In neonates, infants, and young children, there is increased risk of ADRs because of their incapacity to metabolize most drugs due to lack of appropriate enzymes and related functions. For instance, in neonates of less than 2 months old, because of their immature renal tubular function, it is recommended to avoid digoxin, aminoglycosides, ACE inhibitors, and

and drinking habits of their patients [43, 44].

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

females than males [47–50].

NSAIDs [11, 51–53].

With regard to disease states, there are pharmacodynamic differences in patients with liver disease. Effects have been observed with β-blockers and drugs that depress the CNS. In case of β-blockers, it is documented that there is a reduction in β-adrenoceptor density in mononuclear cells which results in a decrease in effect; this has been observed with propranolol. Similarly, patients with liver cirrhosis had been found to be particularly sensitive to opioids and anxiolytics. In case of kidney disease, a drug that is 100% metabolized may also be affected to some extent particularly its excretion if its metabolites accumulate in plasma, leading to an exaggerated response if the metabolites contribute to the pharmacological effect; or, atypical toxicity that is not seen when the metabolites are excreted normally. Additionally, renal impairment is likely to lead to varying degrees of water loading and this may lead to the changes in the concentrations of the drug in the fluid compartments of the body, including plasma. Children with cystic fibrosis present with greater renal clearance of drugs such as aminoglycosides when compared with children without the disease; this observation suggests that higher doses by weight and more frequent dosing intervals are required in these children [64–72].

With regard to drug-drug interactions, it should be said that patients commonly use two or more drugs concurrently; some prescribed by their health care providers, others bought by themselves or received from family and friends. Because patients are often unaware of the multiple drug interactions, they suffer from adverse drug reactions resulting from alterations of the pharmacokinetics parameters due to interacting substances; often with the end result being a decreased therapeutic efficacy, or an increased toxicity or occurrence of adverse effects. The binding of drugs to macromolecules such as receptors on plasma proteins is governed by the law of mass action which states that "the rate at which a chemical reaction proceeds is proportional to the active masses (usually molar concentrations) of the reacting substances." Taken from chemistry point of view, this concept means that for the reaction to occur, collision between the reacting molecules must take place. It follows that the rate of reaction will be proportional to the number of collisions; while the number of collisions will be proportional to the molar concentrations of the reacting molecules. Hence, drugs-foods and drugs-drugs interactions will affect the rates of a drug disposition based on the quantities available of the doses taken and the synchronicity which implies the presence of both substances at the same time for them to interact directly or indirectly through competition or inhibition of relevant receptors. The above observations imply that the degree of drug interaction depends on the relative concentrations of each drug; hence, the dose and the time of administration are critical elements in the onset of adverse effects resulting from drug-drug interactions. These interactions may produce changes in absorption rate, competition for binding sites on plasma proteins, oral bioavailability, extent and volume of distribution in organs and tissues, and hepatic and renal clearance as well as the extent of elimination from the body. Indeed besides other medicines, drugs of abuse, herbal medicines, and foodstuffs have been reported to affect the pharmacokinetics of specific drugs [73–78].

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The above observations suggest the need for caution when prescribing more than one drug as well as the need to counsel patients about the dangers of taking nonprescribed drugs, drugs for entertainment including alcoholic drinks without seeking proper advice from health care professionals [79–84].
