Pharmacodynamics—A Pharmacognosy Perspective

Chapter 26

Pharmacodynamics—A Pharmacognosy Perspective J.E. Campbell1 and D. Cohall2 1

The University of the West Indies, Mona, Jamaica, 2The University of the West Indies, Cave Hill, Barbados

Chapter Outline 26.1 Definitions 26.2 Drug Targets 26.2.1 Introduction to Drug Targets 26.2.2 Concluding Remarks—Drug Targets 26.3 Adverse Drug Reactions 26.3.1 The Impact of ADRs 26.3.2 Pharmacovigilance

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26.3.3 The Assessment of ADRs—Severity and Seriousness 26.3.4 Polypharmacy 26.3.5 Drug Interactions 26.4 Concluding Remarks 26.5 Questions References

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Objectives: Upon completion of this chapter, you should be able to: G G G G G G

Define drug targets. Describe the basic and molecular basis for drug and drug target interactions. Identify the mechanisms for cellular effects of the drug-receptor interaction. Define the terms adverse drug reaction, adverse drug event, polypharmacy. Discuss the impact of adverse drug reactions and the need for pharmacovigilance. Discuss the importance of drug drug and drug herb interactions.

26.1

DEFINITIONS

Pharmacodynamics is defined as the response of the body to the drug. It refers to the relationship between drug concentration at the site of action and any resulting effects namely, the intensity and time course of the effect and adverse effects. Pharmacodynamics is affected by receptor binding and sensitivity, postreceptor effects, and chemical interactions. Both pharmacodynamics and pharmacokinetics explain the drug’s effects, which is the relationship between the dose and response. The pharmacologic response depends on the drug binding to its target. The concentration of the drug at the receptor site influences the drug’s effect. A drug’s pharmacodynamics can be affected by physiologic changes due to disease, genetic mutations, aging, or other drugs. These changes occur because of the ability of the disorders to change receptor binding, alter the level of binding proteins, or decrease receptor sensitivity. Pharmacognosy is the study of drugs derived from natural sources. The content of this chapter emphasizes pharmacodynamics and mechanisms by which substances, primarily from natural sources, effect changes directly or indirectly on living systems.

Pharmacognosy. DOI: http://dx.doi.org/10.1016/B978-0-12-802104-0.00026-3 © 2017 Elsevier Inc. All rights reserved.

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26.2 26.2.1

DRUG TARGETS Introduction to Drug Targets

In the introductory chapter we discussed that drugs are characterized as substances which bring about changes in physiological systems [1]. Medicines were defined as one or more drugs given to produce a desirous effect [1]. We also addressed the concept that these characterized substances also can effect changes in biological systems in their natural states as observed in herbal and other natural forms of medicine as well as in their comodified and synthetic forms. In this chapter, we will discuss how drugs interact with specific targets in biological systems to bring about changes at the cellular level to effect changes. Drug targets are macromolecular components of cells and tissues which interact with drugs and, in some cases, endogenous substances, to effect physiological changes [2]. To bring about these changes, the introductory chapter on Pharmacokinetics mentioned that drugs and these endogenous substances are distributed after their point of origin, to facilitate interaction with the molecular targets. We also discussed that cellular transport mechanisms were integral in facilitating the movement and subsequent interaction of drugs with their respective molecular targets [3]. These molecular targets are mainly polypeptides in structure but there are other macromolecules, such as nucleic acids, primarily deoxyribonucleic acids, which are targeted by drugs for cancer, immunological, and antiinfective chemotherapy. Not much will be mentioned about nonpolypeptide targets but essentially these targets are explored for the disruption of cell division process which eventually effects cell death via apoptosis and other cell death mechanisms. The protein drug targets which will be discussed are classified below.

26.2.1.1 Membrane Carrier Proteins Membrane carrier proteins are important transmembrane polypeptide molecules which facilitate the movement of charged and polar molecules and ions across the lipid bilayer structure of the cell membranes [4]. Carrier proteins are usually found in tissues which function extensively in the absorption and excretion of molecules. Therefore, these can be found extensively in the digestive tract and the kidneys [5 7]. Carrier proteins are also important structural and functional protein molecules which play an important role in facilitated diffusion and active transport processes. These processes are two of the mechanisms introduced in the chapter on Pharmacokinetics which facilitate the distribution of drugs and other molecules to their respective drug targets (Fig. 26.1). Transmembrane carrier proteins undergo conformation changes upon the binding of polar molecules and ions at their respective binding sites on the carrier protein which results in the facilitated movement of the molecules and ions across the cell membrane. Drugs interact with carrier proteins by occupying the binding sites of the polar molecules and ions or by affixing themselves to allosteric sites to modulate the movement of the polar molecules and ions across the cell membrane which will result in an effect [7]. Reserpine, an indole alkaloid derived from the roots of Rauwolfia serpentine, is known to block the vesicular monoamine transporter carrier protein and prevents the storage of catecholamine neurotransmitters.

Transmembrane protein

Lipid bilayer

FIGURE 26.1 Transmembrane protein spanning the lipid bilayer of the cell membrane. The macromolecule can be both structural and functional.

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Some carrier proteins can also function in the dual movement of molecules and ions across the cell membrane especially for the movement of organic molecules. These carrier proteins are categorized as symport and antiport carriers [4]. The pairing and binding of these molecules and ions are integral to the function of the carrier proteins (Fig. 26.2). 26.2.1.1.1

Symport Carriers

Symport carrier proteins facilitate the movement of polar molecules and/or ions on the extracellular or intracellular side of the cell membrane [8]. The Na-K-2Cl carrier protein is a notable example of a symport cotransporter. It plays a vital role in salt secretion in the secretory epithelia cells along with renal salt reabsorption. Another notable example is the Na1-dependent glucose transporter which is active in the gastric mucosa and in the renal tubules. 26.2.1.1.2

Antiport Carriers

Antiport carrier proteins facilitate the movement of polar molecules and/or ions in opposite directions across the cell membrane [8]. The antiporter carrier protein can be illustrated with the Na1/Ca21 exchanger. This system is used by many cells to remove cytoplasmic calcium by the exchange of a Ca21 ion for three Na1 ions for the regulation of the cytosolic Ca21 level.

26.2.1.2 Ion Channels Conceptually, ion channels are quite similar to carrier proteins by the facilitation of the movement of polar ions across the cell membrane [8,9]. These drug targets are more predominantly associated with excitable cells and tissues in contrast to the carrier proteins. Ion channels have been shown to facilitate or modulate the transmission of nerve impulses in the nervous and neuroendocrine systems as well as generate other stimuli effecting smooth and striated muscle contraction [8,9] (Fig. 26.3). Ion channels are categorized into main categories: voltage-gated ion channels and ligand-gated ion channels. Quite notably, substances such as tubucararine, an alkaloid of plant origin, produces its muscle relaxant effect by antagonizing the binding of the neurotransmitter acetylcholine (Ach) on the ligand-gated receptor, nicotinic Ach receptor, thus inhibiting the influx of sodium ions through the receptor’s associated ion channel. Transport protein

Drugs can block the movement of molecules and ions across the transporters by binding at the respective binding sites and at allosteric sites.

Antiport cotransporter protein

FIGURE 26.2 Carrier proteins can also function as cotransport proteins. Antiport and symport carriers are characterized. Drugs interact with these carrier proteins by binding to the binding sites of the polar molecules and ions and also by binding at allosteric sites.

Symport cotransporter protein

Drugs can block ion channels or they can bind allosterically and modulate the permeability of the channel.

FIGURE 26.3 Ion channels open upon electrical stimuli or via a ligand-gated mechanism. Drugs can inhibit the permeability of ions through these channels by blocking the channel or binding at allosteric sites on the protein.

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26.2.1.2.1

Voltage-Gated Ion Channel

These are protein channels which open when the cell membrane is polarized. They play an active role in generation and transmission of electrical excitability [9]. There are two main types of voltage-gated channels which have shown physiological and pharmacological relevance in biomedical studies. 26.2.1.2.2

Voltage-Gated Calcium Channels

Voltage-gated calcium channels have been characterized in nerve terminals, cardiac muscle, and also vascular smooth muscle, where they play important roles in nerve transmission, automaticity, and vascular smooth muscle contraction [10]. Upon opening, there is an influx in calcium ions which further polarizes the tissue and can lead to the development of electrical excitability and other secondary processes. 26.2.1.2.3 Voltage-Gated Sodium Channels Voltage-gated sodium channels have been characterized in nerve and cardiac tissue and play an important role in neurotransmission, especially relating to the induction of local anesthesia and automaticity of the cardiac myocytes [11]. Upon opening, there is an influx of sodium ions which further polarizes the tissue and can lead to the development of electrical excitability. 26.2.1.2.4 Ligand-Gated Ion Channels Ligand-gated ion channels incorporate a receptor which has to be bound by a ligand for the channel to open [9]. The nicotinic Ach receptor and gamma-aminobutyric acid (GABA) receptors are two popular types of ligand-gated ion channels characterized and play an active role neurotransmission. The nicotinic Ach receptor is known to produce excitatory effects while GABA receptor is known to produce inhibitory effects.

26.2.1.3 Enzymes Enzymes are important drug targets and have been found to be quite effective for the screening of natural inhibitors from plants and other sources for novel drug compounds [12]. These are functional proteins which have catalytic activity within cells and tissues. Inhibitors of enzymes are molecules which have similar structure and stereochemistry to the enzyme’s known substrate; however, they are not catalyzed to form products from the enzymatic reactions. These inhibitors can be categorized as reversible or irreversible based on the strength of their chemical interaction at the binding sites of the enzyme. Drugs can also modulate enzyme activity allosterically. Cholinesterases, extracellular membrane enzymes, facilitate the recycling of the nerve transmitter, Ach, and also enable the continuous transmission of nerve impulses across the neuromuscular junction [13]. Inhibitors of this enzyme have been used clinically as muscle relaxants and also have been shown to manifest as toxic chemicals which can lead to paralysis and other symptoms associated to Ach crisis. A useful and clinically relevant example of an enzyme inhibitor derived from natural sources is the cardiac glycoside digoxin, similar to digitoxin from the foxglove plant, which inhibits sodium/potassium adenosine triphosphatase (Na/K ATPase) and is used in heart failure and to treat cardiac arrhythmias (Fig. 26.4).

26.2.1.4 Receptors Receptors can be described as protein targets which can be bound and activated by endogenous substances [14]. These endogenous substances can be but are not limited to hormones, neurotransmitters, signal transduction

Enzyme Substrate

Enzyme and substrate complex

Enzyme and drug (false substrate) complex

Drug binding at an allosteric site on the enzyme.

FIGURE 26.4 Inhibitors of enzymes can bind at the respective binding sites of the substrates and also at allosteric sites.

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intermediates, and cytokines [14]. These drug targets are usually transmembrane proteins, notwithstanding that intracellular receptors also exist and have important roles as drug targets. Receptors tend to have an extensive signal transduction pathway associated with them to elicit their cellular effects. Before we delve into the specific types of receptors, there are some basic concepts which should be known about receptors and their respective ligands. It is generally understood that receptors have to be bound to elicit any response [15]. The binding of drugs to their respective receptors depend on the activated and inactivated states of receptors. There are drugs or substances which can lead to receptor activation upon binding and there are also drugs or substances which can prevent receptors from activation. The former substances are known as receptor agonists and the latter are termed as receptor antagonists [16]. Both classes of drugs bind differentially to the two state activation model of receptors. Agonists have a greater affinity to the activated state of the receptor, while antagonists tend to bind more readily to inactivated receptors. Drugs or substances must be selective to receptors to enable binding to form a receptor ligand complex. Selectivity is governed by the affinity of the drug or substance to the receptor. The greater the affinity of the drug or substance to the receptor, the greater the binding of the two molecules [15].

26.2.1.4.1

Receptor Agonists

Agonist will bind to receptors and cause receptor activation. This activation is governed by efficacy. Efficacy is the ability of the drug or substance to bring about a response from the binding of the receptor and is usually between 0 and 1. Full receptor agonists can bring about maximal tissue response upon 100% occupancy of their respective receptors except in the case of spare receptors dealt with in Section 26.2.1.4.3. However, partial receptor agonists cannot bring about maximal tissue response even when there is 100% receptor occupancy of their respective receptors [16]. There are also inverse agonists which are known to decrease the intrinsic activation which is an attribute of some receptors such as cannabinoid receptors and GABA receptors [17]. The potency of an agonist drug is a function of the drug’s efficacy and its affinity to the receptor [16].

26.2.1.4.2

Receptor Antagonists

In the classical description, a receptor antagonist will bind to the receptor and prevent the binding of the agonist to the receptor and thus prevent the activation of the receptor [16]. This classic description can be described as competitive antagonism and can be further categorized to irreversible or reversible competitive antagonism. As the name suggests, reversible competitive antagonism is surmountable with an increase in the concentration of the agonist; however, this is not the case with the irreversible competitive antagonism [14]. Atropine, an alkaloid, is a prototypic reversible competitive cholinergic antagonist from the plant Atropa belladonna, which is selective for muscarinic cholinergic receptors. In understanding drug interactions, we have expanded our understanding of antagonism to identifying other forms of antagonism [14,18]. These other forms are described below: Chemical antagonism—a chemical interaction of the agonist and the antagonist which affects the ability of the agonist from binding to its pharmacological target. Pharmacokinetic antagonism—the ability of the antagonist to affect any of the pharmacokinetic processes which results in a reduction in the concentration of the agonist at its respective pharmacological targets. Physiological antagonism—occurs when two agonists acts independently to bring about opposite effects which oppose each other. Noncompetitive antagonism—the binding of the antagonist at an allosteric site on the receptor or at a specific location of the signal transduction pathway associated with the receptor rendering cellular effects of the receptor’s activation. Thus, a noncompetitive antagonist maintains receptors in the inactivate state.

26.2.1.4.3 Concept of Spare Receptors Spare receptors addresses specific types of receptors which can bring about maximal tissue response when activated by an agonist without having 100% receptor occupancy. In some instances the percentage of receptors that needs to be bound is less than 1% [18]. Interestingly, noncompetitive and irreversible antagonism can affect the potency of an agonist interacting with spare receptors, unlike other receptors without this reserve capacity. This phenomenon of spare receptors is observed more frequently among drugs which elicit smooth muscle contractions.

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Emax or 100% response

Full agonist

Emax or 100% response Full agonist in the absence of an antagonist

Potency (EC 50)

Full agonist in the presence of a reversible competitive antagonist

50% Partial agonist

Full agonist in the presence of a non competitive or an irreversible competitive antagonist

Log [Agonist]

Log [Agonist]

FIGURE 26.5 Drug dose response curves for receptor agonists in the presence and absence of competitive and noncompetitive antagonists.

Therapeutic Effect

Toxic Effect

Lethal Effect

100%

Participants Responding % 50%

ED50

TD50

LD50

Log [Drug]

FIGURE 26.6 Quantal dose response curves outlining the ED50, TD50, and LD50 doses by extrapolation.

26.2.1.4.4

Drug Dose Response Relationships

Drug dose response relationships are important in assessing the efficacy and potency of drugs. They are also useful for the interpretation of drug and receptor interactions. There are two types of drug dose response relationships, namely, the graded dose response and the quantal dose response relationships. In the graded dose response relationship, the tissue will respond to the administered drug until it reaches maximal response as the drug concentration is increased. The occupancy of the receptors by the drugs also plays a critical role in determining the response and is stated to be proportional. A drug’s potency can be derived from a graded dose response curve [19]. The EC50 is the concentration which brings about 50% of the maximal tissue response and is used to determine the potency of drugs (Fig. 26.5). Quantal dose response curves describe responses in a noncontinuous way and are usually used for the determination of toxic, therapeutic, and lethal doses of drugs during development, specifically, TD50, ED50, and LD50 values [18,20]. The concept is to generalize a result to a population, rather than to examine the graded effect of different drug doses on a single individual or experimental specimen. TD50 is the dose which 50% of the participants showed a toxic response. ED50 is the effective dose which 50% of the participants received the therapeutic effect and is also used to determine the potency of drugs. LD50 is the dose which causes death in 50% of the participants. The ratio of the TD50 and ED50 is used to determine the therapeutic index of a drug, which is a numerical index of the drug’s safety and, generally, is $ 1. Drugs or substances with a therapeutic index of 1 are considered to be toxic [18]. That is, the dose which will brings about the therapeutic effect in 50% of participants may also elicit a toxic effect. Drugs such as warfarin, an anticoagulant, and a coumarin derivative of the sweet clover plant are known to have low therapeutic index in comparison to aspirin, a salicylate also of plant origin which has a high index (Fig. 26.6).

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Ligand-gated ion channels

G-protein-coupled receptors

Kinase-linked receptors

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Nuclear receptors

Ions Ions Drug R

R/E

G –/+

–/+ Hyperpolarization or depolarization

Effector

R G

Change in excitability

Gene transcription Cellular effects, e.g., nicotinic, Ach, & GABA receptors

2+

Ca

release

Protein phosphorylation

Nucleus

Protein phosphorylation

Second messengers

R

Gene transcription

Other

Cellular effects, e.g., muscarinic receptors

Protein synthesis Gene transcription Cellular effects, e.g., cytokine receptors

Cellular effects, e.g., estrogen receptors

FIGURE 26.7 The four main types of receptors and their signal transduction mechanisms which lead to the cellular response after receptor activation. Abbreviations: R, receptor; R/E, receptor/enzyme; Ach, acetylcholine.

26.2.1.5 Receptor Categories and Signal Transduction Mechanisms (Fig. 26.7) 26.2.1.5.1

Ligand-Gated Ion Channel Receptors

Ligand-gated ion channel receptors were mentioned in Section 3.3 as ion channels coupled with ligand binding domains in the extracellular domain of the receptor. The structure is usually an oligomeric assembly of subunits surrounded by a central pore [14]. These receptors are usually implicated where neurotransmitters such as Ach and gamma aminobutyric acid act. For example, the nicotinic Ach receptor has a significant role in cholinergic transmission in the central and peripheral nervous system. Upon the binding of Ach to its binding sites, the channel becomes permeable to sodium and potassium ions with a net influx of sodium causing depolarization which leads to an electrical excitatory effect [21]. In contrast to the nicotinic Ach receptors, the gamma aminobutyric acid receptors in the central nervous system elicit inhibitory effects on nerve transmission. Upon the binding of the neurotransmitter to the receptor, the ion channel becomes permeable to chloride ions. The net influx of these ions causes hyperpolarization which leads to the inhibitory effects on nerve transmission [22]. 26.2.1.5.2 G-Protein Coupled Receptors The G protein receptors are membrane receptors comprised of seven spanning alpha helices and coupled with intracellular effector systems via the G protein. The G protein is described as a molecular switch which alternates between the inactive guanosine diphosphate and active guanosine triphosphate (GTP)-bound states. The switching of these states effects downstream cellular processes [14]. These receptors are the largest subset of receptors and include receptors for many hormones and slow neurotransmitters. Examples of these receptors are the muscarinic cholinergic and adrenergic receptors. The receptors have three subunits, namely, alpha, beta, and gamma, and the alpha subunit has been associated with the GTPase activity which is critical for the activated state of the receptor. There are five main classes of the alpha subunits, namely, Gαs, Gαi, Gαo, Gαq, and G12/13 [14,23]. These five classes of the alpha subunits interact with various effector molecules to generate second messengers which facilitate the signal transduction pathways. Gαs is known to activate Ca21 channels and also activates adenylyl cyclase. The ionotropic and chronotropic effects of the heart upon the binding of the Beta-1 adrenergic receptor by catecholamines are based on the activation of the adenylyl cyclase effector and cAMP, the second messenger molecule. Gαq is known to activate phospholipase C which cleaves membrane phospholipid phosphatidylinositol-4, 5-biphosphate (PIP2) into diacylglycerol and inositol-1, 4, 5-triphosphate (IP3). IP3, the second messenger molecule, leads to the release of Ca21 ions from the sarcoplasm reticulum. This effector mechanism is the primary cause of smooth muscle contraction. Gαi is known to activate K1 channels and inhibit adenylyl cyclase. Gαo is known to inhibit Ca21 channels. G12/13 is known to have diverse ion transporter interactions [14,24].

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26.2.1.5.3

Kinase-Linked and Related Receptors

Kinase-linked receptors respond primarily to protein mediators. They are comprised of an extracellular ligand binding domain which is linked to an intracellular domain by a single transmembrane helix. The intracellular domain is sometimes enzymatic with protein kinase or guanylyl cyclase activity [25]. These receptors are known to have significant effects in cell division, growth, apoptosis, differentiation, inflammation, tissue repair, and immune responses [14,18]. Cyclosporine and Tacrolimus are immunophilin inhibitors derived from fungal sources and produce their immunosuppressive effects by inhibiting mechanisms associated with these types of receptors. The main types of receptors in the category are described below. Receptor Tyrosine Kinases These include receptors for hormones and growth factors. They can transduce signals by phosphorylating tyrosine residues on the cytoplasmic tail of the receptor. Examples of these receptors are the insulin and epidermal growth factor receptors. Tyrosine Phosphatase These receptors can be found on the immune cells where they regulate cell activation. As the phosphatases are known to dephosphorylate molecules, receptor tyrosine phosphatases remove phosphate groups from specific tyrosine residues. Cytokine Receptors These receptors lack the intrinsic tyrosine kinase activity but associate with a cytosolic kinase when bound by its respective ligand. The ligands for the receptor are cytokines, e.g., interferons, and colonystimulating factors involved in immunological responses. Serine/Threonine Kinases The members of this kinase related receptor are the transforming growth factor family. Upon activation, these receptors stimulate the growth of normal cells, especially endothelial cells and also cancer cells. Guanylyl Cyclase-Linked Receptor These are similar to the RTKs and they exert their effects by the production of cGMP. 26.2.1.5.4

Nuclear Receptors

The nuclear receptors are a family of receptors that regulate gene transcription and are otherwise considered ligand activated transcription factors [26]. These receptors respond to lipid and hormonal signals and may be categorized into two main classes. Class 1 comprises receptors for steroid hormones, e.g., estrogen and androgen receptors [14]. Class 2 receptors generally respond to lipid and hormonal stimuli. The receptors which respond to lipid stimuli can be exemplified with the proliferator activated receptor which recognizes fatty acids and the liver oxysterol receptor that functions as a cholesterol sensor in the cell [27]. Receptors which respond to hormonal stimuli are the thyroid hormone, vitamin D, and retinoic acid receptor [14].

26.2.1.6 Tolerance and Tachyphylaxis Section 5.5 introduced us to the types of receptors and their signal transduction mechanisms which bring about their cellular effects. Comprehending those mechanisms will provide insight to the concept of drug tolerance. Drug tolerance can be described as the gradual diminishing effects of drugs when given continuously over a specified period of time with durations lasting days to weeks. On the other hand, tachyphylaxis is a rapid developing tolerance which usually occurs within the course of minutes. Refractoriness is also used to describe this phenomenon, primarily as it relates to the loss of therapeutic efficacy [18]. Both of these effects are primarily due to receptor desensitization and can be illustrated primarily among the G protein coupled receptors. There are many mechanisms which contribute to desensitization which include but are not limited to receptor phosphorylation, receptor sequestration, exhaustion of signal transduction mediators, and receptor degradation [28]. As one would imagine, there are exceptions to the concept of desensitization. These are primarily drugs which bring about their effects by not binding to receptors such as osmotic diuretic agents or drugs which bind to cell adhesion receptors.

26.2.2

Concluding Remarks—Drug Targets

So far from the reading, we have been convinced that drug targets form the basis of our understanding of how chemical substances effect physiological changes. The intricacies of the interactions between drugs, in their natural states or

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modified forms, and their targets provide a deeper understanding of the successes and pitfalls of the drug discovery pipeline. Ultimately, the advances in medicine and, more specifically, in pharmacology have been bolstered by our understanding of the mechanisms of these molecular targets upon which drugs of various classes act and it sets the platform for the further discovery of safer and more efficacious drugs.

26.3

ADVERSE DRUG REACTIONS

According to the World Health Organization, an adverse drug reaction (ADR) is “a response to a drug which is noxious and unintended and occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function” [29]. Another definition of the term ADR has been proposed that is “An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product” [30]. An adverse event (ADE) is defined as an unfavorable outcome that occurs while a patient is taking a drug, but which may or may not be caused by the drug [29]. An ADR has been described as an ADE with a causal link to the drug [31].

26.3.1

The Impact of ADRs

ADRs are ranked as one of the top 10 causes of morbidity, mortality, and illness in the developed world [32,33]. ADRs are documented in the United States to claim 100,000 to 218,000 lives annually and are the third leading cause of death after heart disease and cancer [34 36]. However the burden of the problem may actually be underestimated, as in many instances, ADRs are not suspected, thereby leading to underreporting [37,38]. ADRs represent a vast economic burden in terms of health care costs and contribute to a significant percentage of hospital admissions; they are regarded as a major public health problem [39 41,31].

26.3.2

Pharmacovigilance

Prior to approval, most drugs will only have been tested for short-term safety and efficacy on a limited number of carefully selected individuals [42]. In some cases as few as 500 subjects and seldom more than 5000 will have received the drug prior to its release [43]. To identify an ADR that occurs in 1 in 10,000 patients, at least 30,000 patients need to be treated with the drug [44]. Consequently, the limited numbers of persons involved in premarketing clinical trials do not facilitate good estimation of the ADR profile of a drug. Additionally, the controlled environment of premarketing clinical trials bears very little resemblance to how the drug is used in larger populations. It is after release, when the drug is used in more patients having a variety of concurrent diseases and who may be taking other drugs, that limitations to its use become evident. These limitations result from a paucity of long-term safety data, underrepresentation of certain populations in clinical trials, and inadequate information regarding off label use.1 Furthermore the regular use of surrogate endpoints can give misleading information about the effects of drugs in comparison to usage in actual patients [46,47]. It is also during the postapproval phase that, previously unidentified ADRs (many manifesting years after the release of a drug) may occur [48]. This can be illustrated by two examples. Rhabdomyolysis is a serious but uncommon adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). However there have been reports of rhabdomyolysis occurring as a result of the interaction between azithromycin and various statins [49].

26.3.3

The Assessment of ADRs—Severity and Seriousness

The International Committee on Harmonization has distinguished serious from severe ADRs. A definition of severe is related to a grading of the degree of the reaction; a definition of serious is related to the outcome of the reaction [29]. Severity of reaction is defined as severe (potentially life-threatening, causes permanent damage, or requires intensive medical care); moderate (requires a change in drug therapy or specific treatment to prevent a further adverse outcome, symptoms resolved in more 24 h, caused a hospital admission to a nonintensive medical care unit); or minor (requires no therapy or antidote to event, symptoms resolve in less than 24 h, does not contribute to prolonging length of stay) [50]. 1. The use of a drug in a manner different from that approved [45].

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The WHO has defined a serious ADE or reaction as any untoward medical occurrence that at any dose: results in death; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is life-threatening. Using the WHO definition of serious, Lazarou et al. [32] estimated the incidence of serious ADRs to be 6.7%. In one of the few prospective studies that have measured the incidence of serious ADRs in a general practice setting, Lacoste-Roussillon et al. [51] reported 13 validated serious ADRs resulting in an incidence density of 10.2 per 1000 days of practice. In a retrospective chart review of 437 ADRs occurring in a university hospital, 24% of the reactions were considered severe to life-threatening [52]. These studies have highlighted the fact that serious and severe ADRs are of significant public health concern.

26.3.4

Polypharmacy

There is an increased risk of the development of ADRs with the number of drugs ingested [53 55]. Polypharmacy has been described “as the long-term2 simultaneous use of two or more drugs” [55]. Polypharmacy is considered minor (2 3 drugs), moderate (4 5 drugs), or major ( . 5 drugs) [54]. However this definition does not account for the appropriate or inappropriate use of drugs. That is, it does not account for the inclusion of “as-needed medications” (e.g., a short course of antibiotics), over-the-counter medications, topical drugs, ophthalmic drops, vitamin supplements, and herbal preparations [56]. Polypharmacy is prevalent in the elderly and has a significant impact on their health [56,57]. The practice of polypharmacy adds to the overall costs of drugs and increases the risk of development of adverse reactions to not only a single drug, but also as a result of interactions with other drugs, herbs, and food.

26.3.5

Drug Interactions

26.3.5.1 Drug Drug Interactions Drug drug interactions (DDIs) occur when one drug interferes with the pharmacological activity of another [58]. These interactions can result in decreased effectiveness and/or increased toxicity. Additionally they may result in the development of ADRs, morbidity, hospitalizations and death [59]. DDIs constitute only a small proportion of ADRs; however, they are important because they are often predictable and therefore avoidable or manageable [58,60,61]. The frequency of DDI is related to the age of the patient and polypharmacy. As the number of medications taken by a patient increases, the risk of DDIs in that patient increases. In fact the risk of DDIs can increase from 6% in patients taking two drugs to 50% in those taking five drugs and 100% in those taking 10 drugs [62]. Although DDIs occur frequently in normal drug therapy, there is variation in the clinical significance of the interactions [59]. Additionally many of the DDIs that are potentially harmful only occur in a small number of patients with the severity of the interaction varying from one patient to another [61]. The classification of potential DDIs (pDDIs) on the basis of severity is important in the assessment of the possible impact of the DDI. The severity of pDDIs can be classified into different types as follows: Contraindicated: The drug-combination is contraindicated for concurrent use. Major: If there is risk of death and/or medical intervention is required to prevent or minimize serious negative outcome. Moderate: The effect of interaction can deteriorate a patient’s condition and require alteration of therapy. Minor: Little effects are produced that do not impair therapeutic outcome and there is no need of any major change in therapy [60].

26.3.5.2 Drug Herb Interactions Many herbs and prescription drugs are therapeutic at one dose and toxic at another. The concurrent use of herbs may mimic, magnify, or oppose the effect of drugs [63]. The use of herbal and dietary supplements is extremely common. In the Caribbean use of natural products is extensive with a survey indicating that 100% of households use herbs in both rural and urban settings in Jamaica. [64]. In a survey of adults in the United States, who regularly take prescription 2. Long term is defined as 480 days or more in 2 years.

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medication, 18.4% reported the concurrent use of at least one herbal product or high-dose vitamin. The majority of those persons (61.5%) did not disclose such use to their physicians. [65]. Of interest are the findings of a survey by Barnes et al. of 515 users of herbal remedies in the United Kingdom. The results demonstrated that 26% of those surveyed would consult their doctor for a serious ADR associated with a conventional over-the-counter medicine, but not for a similar reaction to an herbal remedy [66]. Research has revealed that a large proportion of persons on prescription medicines for diabetes, hypertension, and gastrointestinal disorders were comedicating with medicinal herbs [67]. Delgoda et al. [68] in a study of 306 adults and 60 children found that 80.6% of the adults and 75.6% of the children were engaged in the concomitant use of herbs and drugs. Among persons indicating such practices, the most commonly cited reasons for the concurrent use of prescription medications and herbal preparations was the belief that there was no harm in taking both and the belief that prescription medicine alone was not an adequate cure. The trend of not informing the physician of the practice of combining prescription and herbal medications persists with only 18% of respondents who practiced such comedication indicating that their doctors knew of their use of herbal preparations. As more persons engage in the concomitant use of herbs and drugs, there has been increased reporting of drug herb interactions—a reflection of the increasing world consumption of herbal remedies as medications [69]. Research has demonstrated that the concomitant use of red yeast rice and drugs can potentially cause undesirable herb drug interactions [70]. Common examples of drug herb interactions include the interactions between the HMG CoA reductase inhibitors and Red Yeast Rice resulting in rhabdomyolysis [71] and Azithromycin and Red Yeast Rice resulting in rhabdomyolysis [72]. Other reports include the interaction between warfarin and garlic (Allium sativum) resulting in increased international normalized ratio, INR [73]; warfarin and Dong quai (resulting in increased INR [73]; grapefruit and amiodarone resulting in ventricular tachycardia [74].

26.4

CONCLUDING REMARKS

Drugs have changed the way in which diseases are treated. Despite all the advantages of pharmacotherapy, evidence continues to mount that adverse reactions are a recognized hazard of drug therapy. ADRs are a common, frequently preventable, cause of illness, disability, and death. There is an increased risk of the development of ADRs with the number of drugs ingested. Many herbs and prescription drugs are therapeutic at one dose and toxic at another. The concurrent use of herbs may mimic, magnify, or oppose the effect of drugs.

26.5

QUESTIONS

1. Define the term “drug target.” Outline the four polypeptide drug targets with examples of each. 2. Identify the four main types of receptors and describe the signal transduction mechanisms which effect responses upon the receptors’ activation. 3. Differentiate between graded drug dose responses versus the quantal dose responses. 4. Define tachyphylaxis. 5. Define the terms adverse drug reaction and adverse drug event. 6. Give two definitions of the term "polypharmacy." 7. What is the difference between severe and serious adverse drug reactions? 8. Give three examples of drug herb interactions.

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