A. Before You Read the Text, Can You Tell

Unit 1 - Introduction

Pre-reading task

A. Before you read the text, can you tell …

1. What factors delay/prevent the discovery of drugs that could cure diseases that are so far incurable?

………………………………………………………………………………………………..…………………………………………………………………………………………………..…

2. What features of a substance does a researcher look into when considering the development of a new drug?

1. The term ‘lead compound’ is an important one in the process of drug discovery. Can you scan the text to find what it is?

2. The questions of the pre-reading activity are answered by the information contained in the text. You can skim the text to verify or enhance your answers.

A1. …………………………………………………………………………………………………..

…………………………………………………………………………………………………..

A2. …………………………………………………………………………………………………..

…………………………………………………………………………………………………..

What have you noticed about the answers? Where are they to be found? How does that help you locate the main ideas of a text?

Introduction

P. N. Kourounakis and E. A. Rekka

Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 540 06, Greece

The discovery of drugs and drug molecules has always been the aim of pharmaceutical sciences and, in particular, of medicinal chemistry, which evolved from pharmaceutical chemistry. Half a century ago, pharmacochemistry, the modern expression of pharmaceutical chemistry, as a science whose main interest is the design and development of new pharmacomolecules, was at the beginning of its evolution. Drug design in its broad sense and structure-activity relationship studies are essential and at the heart of medicinal chemistry, and it is the progress and development of this field of research that has made medicinal chemistry the modern and enormously productive science it has become in recent decades. Today, studies on structure-activity relationships and their influence on the design of new drugs have rendered them one of the most useful and thus important activities of pharmacochemistry, a modern component science in the group of pharmaceutical sciences.

Despite the advances in medical and pharmaceutical sciences, there are still many diseases which are incurable or can only be treated symptomatically, and at a great economic and social cost owing to only moderately effective or even to the lack of appropriate therapeutic agents. Of the 30 000 or so diseases or disorders currently known, only one third can somehow be treated with drugs. Furthermore, there are incurable maladies, like viral diseases (influenza, AIDS), CNS disorders (Alzheimer’s disease), cancer and autoimmune disorders, which can be fatal or cause great suffering and disability. Therefore, there is still a great need for more and better drugs – more active and selective, drugs with fewer undesired or toxic side-effects, agents useful in prophylaxis and drugs which will cause as little as possible harmful contamination in the already polluted environment.

In a systematically planned program of drug discovery, several questions have to be answered:

-Is the research for the discovery of a certain drug justified by the medical expectation?

-How will the expected drug contribute to health?

-What would be the economic or other, more noble benefit that is expected from the drug?

-Is the state of the art of medicinal chemistry at a satisfactory level so that the risk of investing in the project should be taken? That is, have the coordinated attempts a favorable possibility for solving the problem in a reasonable time period?

-Does the specific disease affect sufficient people for the economic attempt to be justified? It is tragic that serious diseases, mainly in developing countries, are sometimes uncontrolled because of a lack of effective therapeutic agents due to the non-existent financial profit.

Because of the strict prerequisites of national drug authorities, which are becoming even more demanding, the cost of drug discovery is steadily increasing. Thus, rational drug design becomes the main objective of medicinal chemistry today. Based on rational design, new structures can be developed with a high probability of possessing the required properties. The setting of clear rules to help in the access to information hidden in accumulated experimental data is necessary, and this requires studies on the quantitative relationships between (physicochemical) properties and (biological) activity.

We are thus led to the selection of a subsystem of compounds originating from an initial structure, the lead compound, the discovery of which is the most decisive step in the process of drug discovery. Methods used in lead compound discovery include: folk/ethno-pharmacy and therapeutics; massive pharmacological screening; fortuitous discovery; modification of bioactive natural products; exploitation of secondary or side-effects of drugs; study of the basic processes of life; body biochemistry and the use of metabolic analogues; study and exploitation of differences in molecular biology, differential cytology, biochemistry and endocrinology; study of the biochemistry of diseases; an approach through the molecular mechanism of drug action; analysis of the mechanism of action and multipotent compounds; drug metabolism (hard, soft, pro- drugs); and chemical delivery systems.

The pharmacochemical manipulations following the discovery of the lead compound include: attempts aimed at the development of substitutes of existing biologically active molecules; attempts aimed at the alteration of the activity spectrum of biologically active molecules; attempts aimed at the modification of the pharmacokinetics of the compounds used as drugs or as lead compounds; structural changes in natural products; molecular transformations performed by microbes; and other chemical processes that follow the molecular manipulations on the lead compounds (for example, construction of homologous series, application of the rule of bioisosteric groups, resolution of stereoisomers).

It is evident that in the process of drug development the molecular structure is the main feature that determines the molecular properties, and thus whether the particular molecule finally reaches the patient.

Since, in the majority of drugs, action appears after the interaction of the pharmacomolecule with its receptor, it seems reasonable to study the drug structure in relation to its receptor site (the dynamic aspect). For a productive drug-receptor interaction a good fit, determined by physicochemical properties, is required. Besides solving the basic synthetic problems, studies on the geometry and shape, conformational analysis and investigation of the influence of electronic and hydrophobic effects on drug-receptor interaction are performed. In quantitative structure-activity relationship studies attempts have been made, with success, to correlate quantitatively biological activity with molecular properties (electronic, hydrophobic, steric). This relationship has been based on the assumption that the relative importance of physicochemical properties for biological activity can be described numerically, for an objective evaluation of drug-receptor interactions. Numerous methods have been invented for the quantification of electronic, hydrophobic and steric effects of functional groups. Statistical methods, mainly Hansch or extrathermodynamic analysis, as well as those of Free and Wilson, pattern recognition/principal components analysis and cluster analysis, can lead to the prediction and optimization of activity, and ultimately to the design of better drugs. The development of powerful, interactive computers and molecular graphics systems helps in the analysis and visualization of biologically active compounds and in a better understanding of drug-receptor interactions. Techniques have been developed for the determination and visual presentation of pharmacophores (receptor mapping), as well as techniques for drug design based on a knowledge of receptor structure (receptor fitting).

The pharmacomolecule, before interacting with its receptor (this interaction being direct or indirect, a simple binding –affinity- or a productive interaction yielding a biological effect –efficacy), must reach, intact and in satisfactory concentration, the immediate environment of the receptor site. Access to the receptor is also determined by the physicochemical properties of the molecule. Thus, structure plays a decisive role not only in the dynamics, but also in the kinetics of the drug molecule.

Molecular structure is usually altered by the body. Drug metabolism, basically an adaptive process, is a rather useful property of the (liver) cell, as a whole. Drug biotransformation usually leads to more polar compounds, and thus to faster elimination, and to substances with lower or no activity. Only rarely is an increase of activity observed after biotransformation. However, in certain cases, very dangerous highly (chemically) reactive metabolic intermediates are formed. During drug metabolism, and through the catalytic activity of enzymes like the cytochrome P-450 family, prostaglandin synthase and xanthine oxidase, free radicals may be formed, which participate in the initiation and propagation of chain reactions. Oxygen is activated, and the presence of active oxygen species (O2 - , H2O2, HO) may lead, via lipid peroxidation or other cellular structure damage, to cell injury and necrosis. Numerous pathophysiological conditions are probably due to radical attack and oxidative damage. A knowledge of the pathophysiology of diseases constitutes a decisive step towards the discovery of lead compounds. This could be conducted in various ways, for example by the study either of free radical scavenging activity or of free radical formation. Therefore, drug metabolism and, in particular, relationships between the structure of the drug molecule and the enzyme systems responsible for drug biotransformation, resulting in detoxification, but also in biotoxification, are currently subjects of active pharmacochemical investigation. The ever-increasing number of modern, improved drug molecules, the discovery of which is based upon a knowledge of drug biotransformations and oxygen activation, supports the argument for the prominent position held by drug metabolism and free radical pharmacochemistry in currently used rational drug design techniques.

This volume covers topics such as drug discovery and physicochemical properties, structure-activity relationships, structure-interaction with specific receptor subtypes, and in combating serious diseases that cause great financial and social problems, for example Alzheimer’s disease and gastric ulceration. Also discussed is the dependence of the biological properties of a compound on chemical structure, in terms of quantitative structure-activity relationships, the merits and shortcomings of computational chemistry and the techniques applied to gaining insight into the complex molecular phenomena in innovative drug research, the characterization and prediction of drug metabolism in humans and the importance of labeling of bioactive compounds in the study of the dynamics but mainly the kinetics of a prospective drug.

These topics are presented by contributors, each one a specialist in his or her own field within the greater subject of pharmacochemistry. We are certain that the following chapters, tackling the subject of drug design from different viewpoints, will stimulate the creativity of those involved or interested in innovative drug research. Young medicinal chemistry investigators could be helped and inspired in their attempts to find new and better drug molecules among the structures waiting to be discovered.

Kourounakis, P. N. and E. Rekka, 1994: 1-4

C. After having skimmed the text, you could try to assess the truth of the following statements.

1. National drug authorities place strict restrictions on drug discovery research.

2. Modification of the pharmacokinetics of a substance is a step towards the development of a new drug.

3. The molecular structure of a component of a drug is the sole feature that determines its efficacy.

4. Drug biotransformation results in the formation of substances with increased activity.

You can read the text to see if your answers are correct.

D. The text contains several words that may present difficulty in your effort to understand it. Using your knowledge of the field and the context in which these appear, do you know/can you guess what the following mean? (the number of the paragraph appears in the beginning)

1. (1) render: ……………………………………………………………………………………

2. (1) component science: ……………………………………………………………………...

3. (2) moderately: ………………………………………………………………………………

4. (2) CNS: ……………………………………………………………………………………..

5. (4) accumulated: ……………………………………………………………………………..

6. (5) fortuitous: ………………………………………………………………………………..

7. (5) modification: …………………………………………………………………………….

8. (7) feature: …………………………………………………………………………………...

9. (8) site: ………………………………………………………………………………………

10. (8) fit: ………………………………………………………………………………………

11. (8) conformational: ………………………………………………………………………...

12. (8) quantification: …………………………………………………………………………..

13. (8) optimization: ……………………………………………………………………………

14. (9) yield: ……………………………………………………………………………………

15. (10) intact: ………………………………………………………………………………….

16. (10) via: …………………………………………………………………………………….

17. (11) shortcomings: …………………………………………………………………………

E. Can you now guess which words mean the following?

(2) disorders or diseases of the body: ……………………………

(3) the latest and most sophisticated or advanced stage of a technology, art, or science: ………………………………………

(4) required beforehand: …………………………….

(5) act of selecting, rejecting, considering, or grouping by examining systematically: ……………………………….

(5) one of a group of chemical compounds similar in structure but different in respect to elemental composition: ……………………………

(5) the study of the microscopic appearance of cells, esp. for the diagnosis of abnormalities and malignancies: …………………………….

(5) having power to produce or influence several effects or results: ………………………..

(8) assignment of a set of observations into subsets so that observations in the same set are similar in some sense: ……………………………..

(9) act of uniting: ……………………………..

(10) multiplication by natural reproduction; transmission or dissemination: ……………………...

F. Can you match the terms on the right with their definitions on the left?

1. an atom or molecule that bears an unpaired electron and is extremely reactive, capable of engaging in rapid chain reactions that destabilize other molecules and generate many more / a. correlate
b. steric
c. affinity
d. peroxidation
e. radical
f. scavenge
2. the force by which atoms are held together in chemical compounds
3. act of converting into an oxide of an element that contains an unusually large amount of oxygen
4. bring into mutual or reciprocal relation
5. purify by introducing a substance that will combine chemically with impurities or undesired elements
6. pertaining to the spatial relationships of atoms in a molecule

Unit 2 - Routes of drug administration

Pre-reading task:

A. Which routes of drug administration do you know? Can you think of cases in which each one should be selected? Are you aware of how they affect the formulation of medicines?

......

Pre-reading task:

Oral route

A. Do you know what kind of medicinal formulations are administered orally? Can you think of any advantages or disadvantages in the choice of this route of administration?

......

B. Do you know or can you guess if the following statements are true or false?

1. The action of a drug in a tablet begins minutes after its administration.

2. A tablet is more suitable for pediatric use than other formulations administered orally.

3. Other medication that the patient may have taken affects the solubility of the drug administered in tablet form.

4. Enteric coating of tablets reduces the possibility of inactivation of the drug by the acidity of the stomach.

5. Tablets disintegrate faster than capsules in the body.

6. Emulsion formulations may take the form of capsules.

7. Suspensions are unsuitable for patients suffering from tonsillitis.

You can check your answers by reading the text.

Routes of drug administration

The absorption pattern of drugs varies considerably between individual drug substances as well as between the different administration routes. Dosage forms are designed to provide the drug in a suitable form for absorption from each selected route of administration. The following discussion considers briefly the routes of drug administration and whilst dosage forms are mentioned, this is intended only as an introduction since they will be dealt with in greater detail later in this book.

Oral route

The oral route is the most frequently used route for drug administration. Oral dosage forms are intended usually for systemic effects resulting from drug absorption through the various epithelia and mucosa of the gastrointestinal tract. A few drugs, however, are intended to dissolve in the mouth for rapid absorption or for local effect in the tract due to poor absorption by this route or low aqueous solubility. Compared with other routes, the oral route is the simplest, most convenient and safest means of drug administration. However, disadvantages include relatively slow onset of action, possibilities of irregular absorption and destruction of certain drugs by the enzymes and secretions of the gastrointestinal tract. For example, insulin-containing preparations are inactivated by the action of stomach fluids.

Table 1.2 Variation in time of onset of action for different dosage forms
Time of onset of action / Dosage forms
Seconds / i.v. injections
Minutes / i.m. and s.c. injections, buccal tablets, aerosols, gases
Minutes to hours / Short-term depot injections, solutions, suspensions, powders, granules, capsules, tablets, modified-release tablets
Several hours / Enteric-coated formulations
Days to weeks / Depot injections, implants
Varies / Topical preparations

Whilst drug absorption from the gastrointestinal tract follows the general principles described later in this book, several specific features should be emphasized. Changes in drug solubility can result from reactions with other materials present in the gastrointestinal tract, as for example the interference of absorption of tetracyclines through the formation of insoluble complexes with calcium, which can be available from foodstuffs or formulation additives. Gastric emptying time is an important factor for effective drug absorption from the intestine. Slow gastric emptying can be detrimental to drugs inactivated by the gastric juices and can delay absorption of drugs more effectively absorbed from the intestine. In addition, since environmental pH can influence the ionization and lipid solubility of drugs, the pH change occurring along the gastrointestinal tract, from a pH of about 1 in the stomach to approximately 7 or 8 in the large intestine, is important to both degree and site of drug absorption. Since membranes are more permeable to unionized rather than ionized forms and since most drugs are weak acids or bases, it can be shown that weak acids, being largely unionized, are well absorbed from the stomach. In the small intestine (pH about 6.5), with its extremely large absorbing surface, both weak acids and weak bases are well absorbed.

The most popular oral dosage forms are tablets, capsules, suspensions, solutions and emulsions. Tablets are prepared by compaction and contain drugs and formulation additives which are included for specific functions, such as disintegrants which promote tablet break-up into granules and powder particles in the gastrointestinal tract, facilitating drug dissolution and absorption. Tablets are often coated, either to provide a protective barrier to environmental factors for drug stability purposes or to mask unpleasant drug taste, as well as to protect drugs from the acid conditions of the stomach (enteric coating). Increasing use is being made of modified-release tablet products such as fast dissolving systems and controlled, delayed or sustained-release formulations. Benefits of controlled-release tablet formulations, achieved for example by the use of polymeric-based tablet cores or coating membranes, include reduced frequency of drug-related side-effects and maintaining steady drug-plasma levels for extended periods, important when medications are delivered for chronic conditions or where constant levels are required to achieve optimal efficacy, as in treating angina and hypertension.