This chapter discusses the effectiveness of a drug on the physiological processes within the body, which is determined by its ability to enter the body, reach its intended target, and remain in the body for as long as is necessary for it to achieve its desired effect. It refers to drugs that are xenobiotics, which prevents them from entering the body and removes them when they do get inside the body. The chapter examines a vital part of drug design and development which is dedicated to overcoming or exploiting these mechanisms, known as the science of pharmacokinetics. This is commonly divided into absorption, distribution, metabolism, and excretion. The chapter provides an overview of the science of pharmacokinetics in order to explain the basic concepts.
Chapter
Absorption, Distribution, Metabolism and Excretion
Chris Rostron
Chapter
Activities of Ions in Solution
Many pharmaceuticals are used in salt forms that behave as electrolytes in aqueous solutions. (Electrolytes are solutions in which the solutes are ionic and that can conduct electric current.) It is also very common that the pharmaceutically active forms of acidic or basic compounds are...
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Alcohols, Phenols, Ethers, Organic Halogen Compounds, and Amines
Chris Rostron
This chapter considers a number of functional groups, such as oxygen in the air and oxygen as a component of water. It is also found in many molecules. Functional groups are made, changed, and destroyed in chemical reactions. The chapter highlights oxygen's value as a component of functional groups that stems from its high electronegativity, which means that it strongly attracts electrons. The chapter describes the hydroxyl group as the most biologically significant functional group as it is one of the most widely occurring in nature, being present in carbohydrates, proteins, and nucleic acids. The properties of carbohydrates, for example, are essentially a combination of hydroxyl chemistry and the chemistry of aldehydes and ketones.
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Analogue synthesis in drug design
This chapter discusses analogue synthesis in drug design. It looks into at how active compounds can be found from the natural world or synthesized in a chemistry laboratory can be used as the starting point for developing a new drug. The chapter notes thediscusses analogues for SAR studies and pharmacophore identification. It explains that the synthesis of simpler structures that retain the pharmacophore of the lead compound may result in active compounds that are more easily synthesisedsynthesized. The chapter, additionally, looks intoIn addition, the chapter considers the process of drug optimisation optimization, which may aim atsuch as improving pharmacodynamic or pharmacokinetic properties or minimizing side effects or toxicity. It explores how the analogues can be synthesised synthesized from a lead compound or through a full synthesis depending on the synthetic steps and reagents involved. Reagents It is highlighted that the required reagents and building blockss should also be either commercially available or easily synthesizedsynthesised.
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Another histamine receptor: blockers of the histamine-1 receptor for the treatment of seasonal allergic rhinitis
This chapter discusses agents which selectively block H1 receptors and are therefore of benefit in histamine-related allergic responses. It begins by reviewing the major drawbacks of first-generation H1 blockers which appeared in clinical practice in the 1940s, before proceeding to explain today’s most prescribed drugs for seasonal rhinitis. The chapter describes the synthesis of terfenadine which is free from anticholinergic and CNS-related side effects. Then it takes a closer look at the original and alternative routes to loratadine-a potent antihistamine but has sedative activity quite like the first-generation compounds. Lastly, the chapter discusses the syntheses of cetirizine and astemizole.
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Antagonists of histamine receptors as anti-ulcer remedies
This chapter takes a closer look at antagonists of histamine receptors as remedies to ulcers. It includes in the background that while the prototypic H2 antagonist, metiamide, was effective in reducing gastric acid secretion in patients, it had undesirable side effects possibly associated with the thiourea group. Then, it discusses the discovery of the functionality of cimetidine and describes its synthesis which started with ethyl ester. The chapter also tackles the synthesis of ranitidine, which had emerged as a market leader. It highlights that the Mannich reaction on 2-hydroxymethylfuran generated the first intermediate key towards ranitidine. The chapter ends with a discussion on famotidine whose synthesis is characterized by a series of functional modifications.
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Anti-ulcer agents
This chapter looks at peptic ulcers, which are localized erosions of the mucous membranes and occur in the stomach and duodenum. It analyzes hydrochloric acid (HCl) present in gastric juices which results in increased irritation, noting how drugs that inhibit the release of HCl act as anti-ulcer agents. It also talks about chemical messengers, namely histamine, acetylcholine, and gastrinc, that stimulate the release of HCl from stomach parietal cells by acting on their respective receptors. The chapter examines the use of H2-antagonists, which are anti-ulcer drugs that act on H2 receptors present on parietal cells. These reduce the amount of acid released. It describes the alignment of dipole moments between a drug and its binding site and shows how this plays a role in the binding and activity of H2-antagonists.
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Antibacterial agents
This chapter looks at antibacterial agents, such as the sulphonamides, penicillins, and cephalosporins, which act by inhibiting enzymes and synthetic enzyme inhibitors. It explores the principle of chemotherapy. This involves the design of chemicals that show selective toxicity against bacterial cells, rather than mammalian cells. It also traces early antibacterial agents, such as salvarsan, prontosil, and the sulphonamides. It examines the discovery of penicillin and several classes of antibiotics that were isolated from fungal strains. The chapter discusses five main targets that antibacterial agents act on: cell metabolism, cell wall, plasma membrane, protein synthesis, and nucleic acid function. It mentions steric shields and looks at how these can be added to penicillins to protect them from bacterial β-lactamase enzymes.
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Antibodies and other biologics
This chapter considers the antigen as a foreign protein which is identified by the body's immune system, while antibodies are host proteins that identify and bind to antigens and promote the immune response. It discusses B-Cells and T-cells, which are lymphocytes which are integral to the immune response. It also details the complement system that is made up of bloodborne proteins. These are attracted by an antibody–antigen complex and create protein complexes that attract phagocytes and create pores in the target cell membrane. The chapter examines chimeric antibodies which are part human and part mouse in character and are less likely to promote the HAMA response. It describes antibodies that have been clinically approved for the treatment of various tumours and other antibodies that have proved useful in the treatment of a wide range of disorders.
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Anticancer agents
This chapter introduces cancer cells which have defects in the normal regulatory controls governing cell growth and division. These arise from mutations resulting in the activation of oncogenes and the inactivation of tumour suppression genes. The chapter describes defects in signalling pathways that are commonly found in cancer cells, stimulating cell growth and division that are a result of the overproduction of a crucial protein in the pathway or the production of an abnormal protein. It also shows how the production of regulatory proteins that suppress cell growth and division is suppressed in many cancers. The chapter talks about cancer cells which can have intrinsic or acquired resistance to anticancer drugs. It explains how resistance may be due to poor uptake of the drug, increased production of the target protein, mutations that prevent the drug binding to its target, alternative metabolic pathways, or efflux systems that expel drugs from the cell.
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Antiviral agents
This chapter provides a background on viruses that pose a serious health threat and require new antiviral agents. It looks into vaccination, which is effective against many viruses but is less effective against viruses that readily mutate. It also analyzes the research on antiviral drugs which increased during the 1980s as a result of the AIDS epidemic and the need to find drugs to combat HIV. The chapter reviews antiviral research which has been aided by advances in viral genomics and genetic engineering, as well as by the use of X-ray crystallography and molecular modelling. It highlights nucleoside analogues, which are prodrugs that are activated by phosphorylation to a triphosphate structure.
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Artemisinin and related antimalarial drugs
This chapter provides a background on the ancient disease malaria, which is caused by a protozoal parasite carried by mosquitoes and is transmitted between mosquitoes and humans by mosquito bites. It explains that the malarial parasite is a microorganism that belongs to the Plasmodium genus and includes four species: P. vivax, P. falciparum, P. ovale, and P. malariae. The chapter also considers P. falciparum as the most dangerous of malarial parasites which can result in death. The chapter discusses the Chinese plant Artemisia annua, which was recorded in 1596 as a treatment for chills and fever, symptoms of malaria. It details how Artemisia annua was isolated and identified as artemisinin in 1972 and was found to be effective against the particularly dangerous chloroquine-resistant P. falciparum.
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Biotechnology and Biopharmaceuticals
This chapter studies biotechnology and biopharmaceuticals. The rapid developments in biotechnology over the last 30 years have not only impacted on the biological assays of potential drug molecules but also have changed the nature of drug design and development. Whereas small molecules dominated the search for new drugs for many years and have been the focus of previous chapters, biopharmaceuticals now tend to dominate the search for and design of potential new drugs. These biopharmaceuticals are being produced by recombinant DNA (rDNA) technology. It should be remembered that rDNA largely gives rises to molecules that are protein in nature with all the difficulties associated with the production, delivery and use of such molecules as drugs. The chapter explains that the protein molecules currently used or being investigated as drugs include hormones, cytokines, and antibodies. In addition, advances in genomics has led to the development of gene therapy and antisense therapy, involving recombinant genes and oligonucleotides respectively as therapeutic agents.
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Blockade of angiotensin-II receptors
This chapter takes a closer look at losartan and valsartan which are used in reducing blood pressure. It gives a brief overview of the factors leading to the synthesis of losartan. Then it describes the two key components required for the convergent route leading to losartan: the preformed imidazole and a substituted biphenyl derivative. The chapter presents the pathways by which losartan has been prepared. It also reviews the synthesis of valsartan, which was first approved in 1996. The process involves the hydrolysis to the primary alcohol via acetate, Swern oxidation, amination with L-valine methyl ester, and acylation with valeric acid chloride, among others.
Chapter
Brief Review of Logarithms
Logarithms (or ‘logs’) are widely used in the pharmaceutical sciences, especially to make it easier to deal with very large or very small numbers.
If
y = a
x,
Then we define
loga
y = x.
We say that the logarithm of...
Chapter
Calcium channel blockers in the treatment of angina and hypertension
This chapter discusses calcium channel blockers-agents which address myocardial oxygen deficiency by reducing the heart rate without affecting the force of contraction and by providing vasodilatory effects on coronary arteries. The chapter reviews drugs that act predominantly on the voltage-gated ion channels. It describes the synthesis of nifedipine which involves the classical Hantzsch condensation, isolation of the intermediate Knoevenagel product, and Hantzsch reaction with ethyl 3-aminocrotonate. The chapter also explains the synthesis of amlodipine, which gained success from its longer duration of action in man to the extent that once daily dosing can effectively manage hypertension in most patients. Furthermore, it tackles the preparation of diltiazem. Lastly, the chapter discusses the synthesis of verapamil-the first calcium blocker to be approved in the USA.
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Carbohydrates and Carbohydrate Metabolism
Alex White and Helen Burrell
This chapter focuses on carbohydrates, which are molecules composed almost exclusively of carbon, hydrogen, and oxygen. Carbohydrate monomers are called monosaccharides and are found throughout nature. The chapter explains how carbohydrates are synthesized in plants during the process of photosynthesis, with their carbon atoms being obtained from atmospheric carbon dioxide. The chapter considers carbohydrates as the main fuel source in human bodies and they are divided into two groups: simple sugars and complex carbohydrates. Simple sugars like glucose are metabolized directly via glycolysis and the citric acid cycle, whereas complex carbohydrates like starch and glycogen are first broken down into simple sugars.
Chapter
The Carbonyl Group and its Chemistry
Matthew Ingram
This chapter discusses the nature of the carbonyl group and the chemistry it can undergo. The chemistry of the carbonyl group can be found in lots of situations: in the body, in the environment, in manufacturing, and in pharmaceutical applications. At the heart of the chemistry of the carbonyl group is the carbonyl bond, a double bond comprising one σ and one π bond, which joins carbon and oxygen. The chapter points out the difference in electronegativity between carbon and oxygen, citing a dipole moment that exists between the two atoms. The carbonyl group is central to pharmaceutical chemistry and is present in many drug molecules and is present in many different types of compound.
Chapter
Cardiovascular drugs
This chapter focuses on cardiovascular drugs, which are used to treat hypertension, cardiac problems, atherosclerosis, and thrombosis. It details how the renin-angiotensin-aldosterone system (RAAS) cascade produces angiotensin II, which is a potent vasoconstricting hormone. It also mentions renin and angiotensin-converting enzyme (ACE), which are key enzymes in the RAAS cascade and are important targets for antihypertensive agents. The chapter talks about angiotensin II, which produces its vasoconstrictive effects by activating the angiotensin II receptor (AT1), making this receptor an important target for antihypertensive agents. Finally, the chapter provides a background on vasodilators, which relieve hypertension by dilating blood vessels and reducing blood pressure.
Chapter
Chemical and process development
This chapter explores focuses onthe chemical and process developments. Process development aims to ensure the number of reactions in the synthetic route and integrate the individual stages, whileC chemical development is the large-scale synthesis of a drug candidate, and process development aims to ensure that the number of reactions used in the synthetic route is as small as possible and the individual stages in the process are integrated in a way that ensures maximum efficiency on a production scale. The chapter looks intoalso looks at green chemistry and its twelve principles of designing processes that are environmentally friendly, energy efficient, and economical with respect to solvents and raw materials. It explores the chemical and process developmental process in relation to temperature, pressure, reaction times, solvents, reagents, catalysts, promoters, and avoiding impurities. Moreover, the chapter notes theconsiders experimental procedures and operational procedures alongside on the large scale, as well as the process of crystallizationcrystallisation. The chapter concludes with a case study illustrating the development of a commercial synthesis of sildenafil.
