The use of medicines in the management of disease is becoming increasingly complex. Advances in medical technologies, and the increasing incidence of co‐morbidity and polypharmacy associated with an ageing population, present significant challenges to all healthcare professionals. The increased emphasis on medicines management in existing roles, alongside the proliferation of advanced practice roles, adds to the need for proficiency in this area.

In line with the need for effective medicines management, there is a vast and ever‐expanding volume of published literature and treatment guidelines to inform decision making. However, these resources may be presented in an inaccessible way, particularly for those less familiar with the subject. The aim of this book is to introduce students and healthcare professionals who may be less well versed in this area to some of the key principles of pharmacology and medicines management. This book is not intended to replace, but instead to sit alongside and add context to other standard reference sources (such as the British National Formulary). In addition, the book does not replace guidelines, protocols, and other evidence‐based texts. Professional judgement and up‐to‐date knowledge should always be applied in making clinical decisions directly affecting the health and well‐being of patients.

We have divided the book into four broad sections. Whilst the sections have been organised into a logical sequence, the book is not necessarily intended to be read in any particular order. Most chapters can be read as stand‐alone entities to obtain information on a given subject or drug. The first section introduces the reader to some fundamental principles of pharmacology, as well as to the terminology/vocabulary that is used in later sections to describe the properties of different drugs. For example, the term ‘antagonist’ is explained in Chapter 6 and used in later chapters where the mechanism of action of a specific drug or drug group is described. The second section considers the ways in which drugs are administered and how their actions can be affected when they are used for specific patient groups. In addition, this section includes chapters on adverse drug reactions and the mechanisms resulting in drug interactions.

Section III describes the actions, therapeutic effects, and adverse effects of some specific drugs or drug groups that are commonly used in practice in the UK. Each chapter is intended to provide a summary of key points and not an exhaustive account. These chapters use a common template, which is explained in more detail in Chapter 32. At the end of Section III you will find some blank templates that you may wish to complete yourself for drugs that are relevant to your area of practice but are not included. The final section of the book includes some practical considerations for the management of medicines, such as public health perspectives, legal aspects, and evidence‐based medicine.

We have also included a glossary to give you easy access to explanations of certain pharmacological concepts and terminology that did not necessarily warrant chapters to themselves.

During our time teaching medicines management and pharmacology to pre‐registration and post‐registration students, many of them have told us how daunting this subject can be. This book was written for those students and practitioners who, like the ones we have spoken to, wanted some additional support in this area. We hope you find it informative and helpful.

Pharmacodynamics is often described as ‘what the drug does to the body’. It is the study of how the drug interacts with a particular body system, and how it affects this system to bring about a therapeutic effect. The pharmacodynamic properties of a drug can help us to predict what side effects, adverse effects, and drug interactions we might expect to see when a drug (or combination of drugs) is used in practice.

Sites of drug action

The site of drug action within the body can be broadly divided into receptors, enzymes, and transmembrane transporters and channels. Many drugs will have an effect at more than one site, one of which may be the intended target to mediate the therapeutic effect. However, the other could be a different site, or a similar site located in a different part of the body, and which mediates a completely different effect from that intended. This forms the basis for some of the side effects that patients may experience. Competition between two or more drugs for a particular target may result in an increased or decreased effect, and is the basis for pharmacodynamic drug interactions.

Receptors

Receptors are specific sites, typically located on cell membranes, which are bound to by the body's endogenous signalling molecules (such as hormones and neurotransmitters). When these signalling molecules bind to the receptor, they bring about or mediate an effect. Drugs have been discovered which, due to their chemical structure, will also bind to these receptors within the body. Once bound, the drug may mimic the effect of the endogenous signalling molecule and bring about a physiological response. Alternatively, it may have no effect and prevent the action of the endogenous signalling molecule, blocking the normal response. Examples include salbutamol (which mimics the effect of endogenous adrenaline) and atenolol (which blocks the effect of endogenous adrenaline), used in the treatment of asthma and hypertension, respectively.

Enzymes

Enzymes are proteins that catalyse (facilitate) chemical reactions occurring in the body through an interaction with molecules at specific parts of their structures. Some drugs are able to interact with the enzyme either at its binding site (or sometimes elsewhere on its structure) and can interrupt this action. As a result, the physiological process that is mediated by the enzyme will be prevented. This might include inhibition of the normal breakdown of a neurotransmitter, prolonging its effect (e.g. the inhibition of acetylcholine metabolism by donepezil). Alternatively, it could be the inhibition of the formation of a clotting factor, resulting in impaired blood clotting and an anticoagulant effect (e.g. the factor Xa inhibitor rivaroxaban).

Transport proteins and channels

The movement of many molecules and ions across cell membranes is facilitated by transport proteins and channels. These membrane‐spanning proteins allow water‐soluble substances to move across the lipid membranes responsible for maintaining cellular homeostasis. Preventing or in some cases facilitating the movement of these substances with drugs can result in a therapeutic effect. An example is the calcium channel blocker group of drugs, which prevent the movement of calcium ions into (and within) nerve cells and muscle cells, and which are used in the treatment of angina and hypertension.

Other sites of drug action

In addition to the above, drugs may also mediate their therapeutic effects through other actions within the body. Monoclonal antibody based therapies (such as adalimumab) bind to specific inflammatory proteins to prevent them from exerting their normal physiological effect. Osmotic laxatives (such as lactulose), maintain water in the colon by increasing the osmolarity when they are present in the gastrointestinal tract. Replacement therapies (such as fluids, electrolytes, and oxygen) are sometimes considered a separate group of medicines and could be considered less pharmacologically active in this regard. However, the molecule that is being replaced may have an action at one of the pharmacological sites of action mentioned above (examples include levothyroxine or insulin).

Many physiological processes occurring within the body are regulated by the nerve cells of the autonomic nervous system, or through the action of other neuronal pathways. Conduction of a signal or message (action potential) through an individual nerve cell utilises the properties of the neuronal membrane and its ability to conduct an electrical impulse. However, the arrangement of neurons in the autonomic nervous system results in junctions (synapses) between nerve cells or between nerve cells and their target tissue. These synapses (or ‘synaptic clefts’) are spaces through which the electrical conduction of an action potential cannot be transmitted. Consequently, an alternative means of conducting the signal from one cell to another must be used.

Synaptic transmission forms the basis through which signals are conducted from one nerve cell to another or from a nerve cell to its target tissue. The mechanism through which this is achieved is via a chemical signalling molecule. The chemical signalling molecule that allows transfer of a signal across the synapse is termed a neurotransmitter. The cell from which the neurotransmitter is released is termed ‘presynaptic’ and the second cell that receives the signal from the neurotransmitter is termed ‘postsynaptic’.

The process through which a presynaptic neuron utilises a neurotransmitter to transmit a signal can be divided into five steps:

• neurotransmitter synthesis and storage
• neurotransmitter release
• receptor interaction
• neurotransmitter reuptake
• neurotransmitter metabolism.

Each of these steps provides a potential target for drug action and, as such, a way in which to manipulate physiological processes and treat symptoms of disease.

Neurotransmitter synthesis and storage

There are a number of different neurotransmitters in the body, each with their own chemical structure. Before a neurotransmitter can be released from the presynaptic neuron and exert an effect, it must first be synthesised. This process is typically facilitated by enzymes located in the presynaptic neuron, which convert a precursor chemical into the active neurotransmitter. Once synthesised, the neurotransmitter is typically stored in the presynaptic neuron (in a structure known as a vesicle) prior to its release in response to an action potential.

Medicines may promote the synthesis of neurotransmitters by providing additional amounts of the precursor chemical to the presynaptic neuron. Once converted to the neurotransmitter, there is a larger amount of neurotransmitter available to exert an effect. Examples of medicines that utilise this mechanism include levodopa (a precursor for the neurotransmitter dopamine), which is used in the management of Parkinson's disease.

Medicines may also interfere with the storage of neurotransmitters in vesicles. The medicine tetrabenazine reduces the transfer of the neurotransmitter dopamine into its storage vesicles, resulting in depletion of the neurotransmitter and a reduced effect. This forms the basis for the treatment of certain movement disorders associated with long‐term antipsychotic use and symptoms of Huntington's disease.

Neurotransmitter release

Neurotransmitter release occurs in response to an action potential and typically involves the movement of calcium ions in the presynaptic neuron. Medicines inhibiting the influx of calcium into the neuron have the potential to reduce the release of a neurotransmitter, thereby reducing its effect. An example of this in practice is the opioid group of medicines used in the management of pain. Alternatively, neurotransmitter release may occur independently of the action of calcium. Drugs such as amfetamine can displace the neurotransmitter from its storage vesicle and into the synapse, resulting in a stimulant effect.

Receptor interaction

Once released from the presynaptic neuron, the neurotransmitter is able to exert an effect. This is typically achieved through an interaction with a receptor site located on a neuronal membrane or target tissue. There is a vast diversity of receptor types in the body, each able to interact with a specific neurotransmitter and mediate a physiological effect. Each neurotransmitter typically has more than one receptor group or subtype through which its effects are mediated. For example, there are seven groups of receptor for the neurotransmitter serotonin, most with a number of subtypes, resulting in more than ten individual receptor types for that neurotransmitter.

Both the neurotransmitter and the type of receptor with which it interacts will determine the resulting physiological effect. Some receptors have a stimulatory effect on the cell on which they are located, whilst others inhibit the activity of that cell. As a result, some neurotransmitters may have either stimulatory or inhibitory actions depending on the type of receptor with which they interact. For example, noradrenaline can cause vasodilatation through an action at one of its receptor subtypes, but vasoconstriction through a different receptor subtype.

A number of drugs exert their therapeutic effects through interactions with neurotransmitter receptors. Drugs may mimic the action of the body's own (endogenous) neurotransmitter and stimulate a receptor, enhancing a physiological effect (e.g. morphine, which stimulates opioid receptors, resulting in analgesia). Conversely, drugs may block receptors, preventing the endogenous neurotransmitter from binding and reducing the normal physiological effect (e.g. haloperidol, which blocks dopamine receptors and is used in the treatment of psychosis).

Neurotransmitter reuptake

In order to prevent continued stimulation of a receptor (and therefore stimulation of the tissue or organ on which it is located), which could be potentially harmful, the body has a mechanism for removing the neurotransmitter from the synaptic cleft. The cell membrane of the presynaptic neuron has a number of transport proteins (sometimes known as re‐uptake transporters), which bind to the neurotransmitter and return it to the presynaptic neuron.

Certain drugs can inhibit reuptake transporter proteins, and in doing so enhance or prolong the effect of the neurotransmitter. By reducing re‐uptake, the availability of the neurotransmitter in the synapse is increased, thereby increasing its ability to bind to receptors and exert an effect. Examples of drugs inhibiting serotonin reuptake include the antidepressants citalopram and fluoxetine (termed selective serotonin reuptake inhibitors).

Neurotransmitters are signalling molecules released from neurons. They are released in small amounts with the intention of travelling the small distance from one neuron to another, or from a neuron onto a specific target organ or tissue. This is different to a hormone, which is released into the bloodstream and dispersed throughout the whole body. The difference between a hormone and a neurotransmitter is defined by how it is used by the body rather than anything inherent to its nature. For example, both adrenaline and noradrenaline can be released from the adrenal gland as hormones and can also be released from neurons as neurotransmitters.

Neurotransmitters are invariably agonists, eliciting a positive response when binding to their respective receptors. However, this response may have an inhibitory effect on the associated tissue or organ. For example, acetylcholine acts as an agonist on receptors on the heart, but the effect is to slow the heart down.

Autonomic nervous system

The autonomic nervous system (ANS) is an integral part of the body's homeostatic control system, regulating physiological factors such as blood pressure, pulse rate, vasoconstriction, bronchodilation, digestive function, and salivary secretions. As such, by stimulating or blocking the action of the associated neurotransmitters it is possible to exert control over this wide variety of processes. The ANS can be divided into the sympathetic and parasympathetic nervous systems, each with its own neurotransmitters and receptors.

Noradrenaline

Noradrenaline is described as a catecholamine, which describes a feature of its molecular structure, the catechol ring with an amine group attached. Noradrenaline is similar in structure to other signalling molecules used by the body, such as adrenaline and dopamine. Noradrenaline and adrenaline are both used throughout the body, but notably as part of the sympathetic nervous system and as such are often considered together.

As well as occurring naturally in the body, noradrenaline and adrenaline can also be administered to patients as medicines. Whilst they are commonly known as noradrenaline and adrenaline within the UK, they are known internationally (based upon the WHO International non‐proprietary name) as norepinephrine and epinephrine. Practitioners should be familiar with both names and be aware that the literature relating to these agents and the name of products may refer to the international rather than the British names. A clear example of this is the adrenaline autoinjector used for the treatment of anaphylaxis, the best‐known brand of which is the Epipen^®.

Noradrenaline can sometimes be thought of as being the little brother of the better‐known adrenaline. Both are the key agents through which the sympathetic nervous system stimulates the organs and tissues of the body. The sympathetic nervous system has an impact on many organs and systems throughout the body, stimulating processes associated with increased physical activity (often referred to as ‘fight or flight’) and inhibiting activities associated with lower physical activity. Whilst adrenaline is released from the adrenal gland into the blood supply (and thereby affects every part of the body) noradrenaline is predominantly released from sympathetic nerve fibres directly onto tissues and organs. This allows noradrenaline to achieve selective, on‐demand activation of specific systems and processes rather than the system‐wide, all or nothing impact seen with adrenaline.

Noradrenaline can bind to adrenergic receptors on a variety of tissues around the body, although the action it has on different tissues can be radically different. For example, noradrenaline can cause smooth muscle contraction on the neck of the bladder, but smooth muscle relaxation in walls of the arteries supplying the muscles. These differences in action are mediated via different adrenergic receptor subtypes. These were initially grouped into two major types, alpha (α) and beta (β), but are now further divided into a number of subtypes including α₁, α₂, β₁, and β₂.

Acetylcholine

Acetylcholine is used as a neurotransmitter throughout the body. It is the principal neurotransmitter of the parasympathetic nervous system, promoting activities associated with lower physical activity and reduced state of mental arousal (often described as “rest and digest”). The parasympathetic nervous system typically works in opposition to the sympathetic nervous system, creating the opposite response in a given system. Acetylcholine is also used in other distinct systems, most notably at the neuromuscular junction. When a signal is sent from a patient's brain to a muscle in order to stimulate a contraction of the muscle, it is acetylcholine that is released from the motor‐neuron and binds to the receptors on the muscle cell membrane to achieve a response.