Haemato- oncology and malignancy

Cancer is a common cause of morbidity and mortality in the United Kingdom (UK), affecting approximately two out of every five people during their lifetime. In 2015 there was an estimated 2.5 million people in the UK who had had a cancer diagnosis, an increase of almost half a million in the previous 5 years. The proportion of people living longer after cancer is increasing, and the number of people alive more than 5 years from initial diagnosis is predicted to more than double between 2010 and 2030 to 2.7 million. By the end of 2020, more than a thousand people would have been diagnosed with cancer every day in the UK. Cancer can affect all organs of the body with over 200 types identified. However, only a small number of cancer types account for most cases. Over half of all new diagnoses are due to four cancers (in order of frequency)— breast, pros­tate, lung, and bowel. In 2011 there were approximately 50 000 new diagnoses of breast cancer in the UK. The in­cidence of cancer diagnosis is increasing year on year, in part due to improving diagnostic skills, but also because of an increasing elderly population. Cancer of unknown primary origin accounts for about 3% of total cancers. Although UK statistics show a general improvement in the 5-year survival rates for the majority of common cancers, some have not shown any notable improvement. Survival is not only determined by the type of cancer, but also the age at diagnosis, stage, and co- morbidities such as heart, pulmonary, and renal disease, which can affect the treatment regimen. As well as this, certain cancers carry a significantly worse prognosis than others. For example, 10- year survival for pancreatic and lung cancer are 1% and 5%, respectively. In comparison, the 10- year survival for testicular cancer is over 98% and almost 90% in skin con­fined melanoma. Newer diagnostic strategies are expected to detect all cancers early, allowing prompt intervention, and improving both morbidity and mortality rates further. Cancer is a product of mutations in genes involved in controlling cell growth, differentiation, and death (apop­tosis).

Anaesthetics

Anaesthesia is a state of reversible unconsciousness that comprises some or all of the ‘triad of anaesthesia’— hypnosis, analgesia, and muscle relaxation. Safe and ef­fective anaesthesia requires information of the drug’s potency at effector sites and knowledge of administration concentrations, as well as an understanding of the degree of noxious stimulus and how a patient’s physiology may modulate drug actions. Historically, the first compounds used as anaesthetics were diethyl ether, nitrous oxide, and chloroform. Diethyl ether was demonstrated to the wider medical commu­nity in 1846 by William Morton in the removal of a jaw lump from Gilbert Abbot, and the introduction of chloro­form followed within the year. It was noted by James Simpson, Professor of Obstetrics in Edinburgh in 1847, that chloroform was much more potent, but had a ten­dency to precipitate death in the anxious and could cause severe liver damage. This tendency demonstrates clearly that the depth of anaesthesia is critical. Too much cir­culating drug can lead to respiratory depression, cardiac arrhythmias, and death, while too little permits persistent consciousness, pain, and muscular spasm. This is of particular concern with regards to laryngospasm, which when combined with an unsecured airway can rapidly lead to hypoxia and death. Nowadays, death is incredibly rare, with signs of hypotension, tachy- , or bradycardia detected early and easily reversed by controlling drug dosage. The risk of drug- induced side effects when using anaesthetic drugs means that the depth of anaesthesia must be closely monitored. This is achieved subjectively with experience and training, in combination with ob­jective clinical assessment, such as pulse, BP, and mean alveolar concentration. See Table 8.1 for ideal properties of anaesthetic agents. There are many approaches to the application of gen­eral anaesthesia, and these depend on clinical situation, depth, and length of anaesthesia required, the type of sur­gical or interventional procedure to be undertaken and as­sociated patient risk factors. The stages of anaesthesia (outlined in Table 8.2) was a concept introduced at a time when induction was rou­tinely achieved through the use of inhalational anaes­thetics. More recently the use of IV induction agents has meant that transition between these stages is smoother, resulting in a rapid induction with minimal excitation responses, compared with inhalation agents. Inhalation agents also carry the risk of airway irritation.

Musculoskeletal medicine

Osteoarthritis (OA) is best described as a chronic pain syndrome affecting one, or more frequently, multiple joints. It most commonly affects the knees, hips, hands, neck and lower back, although any joint can be affected. Defining OA by pathological changes is no longer con­sidered best practice, as the correlation between path­ology and symptoms is frequently discordant, i.e. patients with severe structural changes may present with min­imum symptoms and vice versa. For this reason, patients should be assessed using a biopsychosocial model, which takes into consideration impact on social and psycho­logical well- being, alongside pathological changes. OA can create substantial mobility problems and is the most common cause of disability in elderly people in the devel­oped world. Prevalence rises with age such that approxi­mately one- third of people in the UK over 45 have sought treatment for OA compared with 40– 50% of people over the age of 75. In the pathological conditions of OA, there are specific hallmarks of damage that affect load- bearing articular cartilage, the formation of new bone at the joint mar­gins (osteophytosis), subchondral bone changes (scler­osis), thickening of the joint capsule, loss of cartilage, and joint space narrowing (Figure 7.1B). In general, struc­tural changes seen on X- ray or CT do not correlate with the pain of OA, but an association does occur between the presence of synovitis, subchondral bone oedema and osteophytes. In OA the vasculature of the osteochondral junction also expresses higher levels of nerve growth fac­tors (NGF) so pain sensitization associated with inflam­mation is likely to occur. OA is considered by some to be the result of physio­logical processes originally targeted at joint repair that, over time, cause tissue damage resulting in symptomatic OA. In many cases, severe trauma or pathological repair processes may be contributory factors. Other risk factors for OA include genetic and patient factors, such as age and obesity (see Box 7.1). Anti- NGF drugs may be of benefit, primarily via pain modulation, but OA is not considered to be a disease of inflammation and the mainstay of treatment relies on effective analgesia. The presence of synovitis in late disease is controversial and the presence of joint crys­tals may confound inflammation in OA. It is clear that wear, tear, and damage is associated with the break­down of collagen and increased presence of proteo­lytic enzymes called matrix metalloproteinases (MMPs).

Infectious disease

Antibiotics include an extensive range of agents able to kill or prevent reproduction of bacteria in the body, without being overly toxic to the patient. Traditionally derived from living organisms, most are now chemically synthesized and act to disrupt the integrity of the bacterial cell wall, or penetrate the cell and disrupt protein synthesis or nucleic acid replication. Typically, bacteria are identified according to their ap­pearance under the microscope depending on shape and response to the Gram stain test. Further identification is obtained by growth characteristics on various types of culture media, based on broth or agar, biochemical and immunological profiles. Further testing on broth or agar determines antibiotic sensitivity to guide on anti­biotic therapy in individual patients. This process can take 24– 48 hours to culture and a further 24– 48 hours to measure sensitivities. Increasingly, new technology, e.g. Matrix Assisted Laser Desorption Ionization— Time of Flight (MALDI- TOF) and nucleic acid amplification as­says, are being used to provide more rapid identification. The Gram classification, however, is still widely referred to as it differentiates bacteria by the presence or absence of the outer lipid membrane (see Figure 11.1), a fundamental characteristic that influences antibiotic management. Antimicrobial agents rely on selective action exploiting genetic differences between bacterial and eukaryotic cells. They target bacterial cell wall synthesis, bacterial protein synthesis, microbial DNA or RNA synthesis, by acting on bacterial cell metabolic pathways or by inhibiting the ac­tion of a bacterial toxin (see Table 11.1). Both Gram- positive and Gram- negative bacteria possess a rigid cell wall able to protect the bacteria from varying osmotic pressures (Figure 11.1). Peptidoglycan gives the cell wall its rigidity and is composed of a glycan chain of complex alternating carbohydrates, N- acetylglucosamide (N- ATG), and N- acetylmurcarinic acid (N- ATM), that are cross- linked by peptide (or glycine) chains. In Gram-positive bacteria, the cell wall contains multiple peptido­glycan layers, interspersed with teichoic acids, whereas Gram- negative bacteria contain only one or two peptido­glycan layers that are surrounded by an outer membrane attached by lipoproteins. The outer membrane contains porins (which regulate transport of substances into and out of the cell), lipopolysaccharides, and outer proteins in a phospholipid bilayer. For both Gram- negative and Gram-positive bacteria, peptidoglycan synthesis involves about 30 bacterial enzymes acting over three stages. Since the cell wall is unique to bacteria, it makes a suitable target for antibiotic therapy.

Gastroenterology

Nausea and vomiting can be defined, respectively, as the urge to or the actual act of expelling undigested food from the stomach. It is thought to be an evolutionary defence mechanism to protect against toxic insult (drugs or mi­crobes) and over- eating, while it can also be triggered during pregnancy, or by unpleasant sights or smells. In some instances, it may be the symptom of a more severe underlying pathology. Severity of nausea and vomiting varies considerably between individuals exposed to the same stimulus and symptoms can be highly detrimental to patient quality of life affecting not only their nutritional intake, but also mood and well- being. Although nausea itself is a subjective term, vomiting is a pathophysiological reflex triggered by the vomiting centre located in the medulla. The vomiting centre re­ceives signals from a number of afferent inputs, i.e. the chemoreceptor trigger zone (CTZ), vestibular nucleus, ab­dominal and cardiac vagal afferents, and cerebral cortex (Table 6.1). It may also be activated by hormonal triggers, which accounts for hyperemesis in pregnancy, and the increased incidence of nausea and vomiting associated with the female gender. As the vomiting centre is located close to centres responsible for salivation and breathing, vomiting is often associated with hypersalivation and hyperventilation. The CTZ is highly vascularized and lo­cated at the floor of the fourth ventricle, just outside the blood– brain barrier and, therefore, is itself directly sensi­tive to chemical stimuli. Afferent inputs activate the vomiting centre through several known neurotransmitter pathways; dopamine (D₂), serotonin (5- HT₃, 5- HT₄), acetylcholine (ACh), and substance P (neurokinin 1; NK₁). Each of which provides a potential pharmacological target in the management of nausea and vomiting, once the cause has been established. Efferent pathways from the vomiting centre induce autonomic changes, including vasoconstriction, pallor, tachycardia, salivation, sweating, and relaxation of the lower oesophagus and fundus of the stomach. In vomiting, oesophageal relaxation leads to contraction of the pyloric sphincter, thereby emptying the contents of the jejunum, duodenum, and pyloric stomach into the relaxed fundus. Coordination of muscle contraction occurs within the dia­phragm and abdomen, and retrograde contractions from the intestine then expel the contents of the fundus.

Principles of clinical pharmacology

Pharmacology is defined as the study of the effects of drugs on the function of a living organism. It is an inte­grative discipline that tackles drug/ compound behaviours in varied physiological systems and links these to cellular and molecular mechanisms of action. As a scientific endeavour, pharmacology evolved from the early identification of therapeutic properties of nat­ural compounds, with herbal medicines and relatively complex pharmacopoeias widely used in early cultures. Despite this, lack of understanding of the physio­logical, pathological, and chemical processes governing the human body prevented the early establishment of pharmacology as a scientific discipline. Since then, pharmacology has progressed to be considered a fully developed integrative science that employs techniques and theories from various disciplines, such as chemistry, biochemistry, genomics, medicinal chemistry, physi­ology, and cellular and molecular biology. Collectively, these are applied to study disease causality and the rele­vant mechanistic action of compounds, to establish new treatments. In the last 100 years, the importance of clinical pharmacology has increased in line with the scientific and technological advances in biomedical research. Benefits gained from molecular and cellular approaches have enabled a more comprehensive analysis of drugs and their actions in functional context. Now, clinical pharmacology and therapeutics encompass the dis­covery, development, regulation, and application of drugs in a process that integrates scientific research with clinical practice to better treat illness and preserve health. Within this textbook the principles of pharmacology are discussed by therapeutic area so that the reader can link disease pathophysiology, drug mechanism, and modern prescribing behaviours for conditions commonly seen in clinical practice. There are, however, fundamental concepts that are universal in understanding the interaction between drugs and their ‘targets’, including receptor pharmacology, genomic pharmacology, and pharmacokinetics. The pharmacological receptor models preceded by many years the knowledge of the receptor as an entity. It was not until the last 150 years that a series of contributions from many notable biologists and chemists established the principles that founded modern day pharmacology. They produced a significant paradigm shift in therapeutics, where empirical descriptors of the activities observed (heating, cooling, moistening, emetic, etc.) were replaced by the concept of a ‘target’. After more than a century, the basic receptor concept is still the foundation of biomed­ical research and drug discovery.

Psychiatry

Anxiety disorders fall mainly into the category of neurotic, stress, or somatoform disorders, as defined by the inter­national classification of disease system (ICD- 11, WHO, 2018). They refer to several disorders that include gener­alized anxiety disorder (GAD), phobic anxiety disorders, panic disorder (± agoraphobia), obsessive compul­sive disorder (OCD) and post- traumatic stress disorder (PTSD). Collectively, anxiety disorders affect almost 30% of people in the western world during their lifetime, with PTSD and GAD amongst the most prevalent. In general, anxiety disorders are associated with neurotransmitter dysregulation and amygdala hyperactivity. Insomnia is the unsatisfactory quantity and/ or quality of sleep, which persists for sufficient time to affect quality of life. It is often associated with other mental health (e.g. depression, anxiety, alcohol dependence) and physical (e.g. pain, neoplasms) pathologies, or iatrogenic effects (e.g. diuretic, β- blockers, statins, levodopa). It may require treatment if symptoms are troublesome. Chronic insomnia can last for years, and affects almost 10% of the popula­tion. Around 30% have symptoms that are occasionally worse, with higher prevalence in older age. Many factors interplay to generate a state of anxiety, but from a biological perspective one of the key central brain pathways involved in this process is the limbic system, which regulates an array of functions, including emo­tion, fear, behaviour, and memory. One vital brain area that processes fear reactions from the thalamus and cortex is the amygdala, with connections to the hypothal­amus, which can activate sympathetic reactions and the hypothalamic– pituitary axis (HPA). Activation/ inhibition within this pathway leads to altered neurotransmitter activity. Corticotrophin- releasing factor (CRF) is known to be released from the hypothalamus in response to stress, under the regulation of the amygdala. CRF acts to drive the HPA, promoting the release of ACTH from the pituitary and then cortisol from the adrenal gland. In effect, sus­tained CRF exposure may lead to limbic system up- regu­lation and the heightening of anxiety states. Moreover, dysregulation in this system and changes in central cor­tisol sensing systems (e.g. decreased receptor expression) may cause chronic anxiety. The locus coeruleus (LC), is another brain region partly responsible for regulating the sympathetic effects of stress, again under the control of CRF.

Neurology

Cerebrovascular disease encompasses all disorders that temporarily or permanently affect the way oxygen and glucose are delivered to the brain via cerebral blood ves­sels. Stroke is a sudden focal event that leads to neuro­logical deficit, because of disturbed circulation. Ischaemic strokes account for around 80% of total numbers and are caused by inadequate blood flow secondary to occlusion by an atheroma, embolus, or less commonly, severe local vasospasm. The remaining 20% are haemorrhagic strokes that occur because of a bleed through ruptured vessels and may be defined by their location. Historically, symptomatology in stroke exceeds 24 hours and where symptoms resolve before this, i.e. a tran­sient vessel occlusion, is termed a transient ischaemic at­tack (TIA). More recently, however, a TIA has been defined by the American Heart Association and American Stroke Association (AHA/ ASA) as a ‘transient episode of neuro­logic dysfunction caused by focal brain, spinal cord or ret­inal ischaemia without acute infarction’. TIAs occur more commonly in men, increasing with age and affecting 35 per 100 000 people. It is also associated with an increased risk of stroke. Stroke is a major health burden in the UK, with an an­nual incidence in excess of 150 000, accounting for ap­proximately 40 000 deaths/ year. Furthermore, there are approximately 1.2 million people in the UK living with the effects of a stroke. Modification of risk factors, rapid clinical diagnosis, and efficient early intervention is essential in re­ducing incidence and improving outcomes (see Figure 9.1). Ischaemic stroke, the most common form of cerebrovas­cular disease, results mainly from the enlargement or rup­ture of an atheromatous plaque, or from an embolus that travels from the systemic arterial system into the CNS vasculature. The subsequent reduction in oxygenated blood flow by 20– 30% deprives brain tissues, normally completely dependent on aerobic metabolism, of glucose and oxygen. At a cellular level the resultant anaerobic conditions trigger the ischaemic cascade, so that cells ultimately undergo apoptosis and die. Persistent ischaemia lasting more than 1 hour leads to local tissue necrosis, neuro-inflammation, and oedema. Prior to cellular apoptosis, the normally maintained electrochemical gradient across the cell membrane is disrupted, such that intracellular Ca²⁺, Na⁺, and Cl^- levels rise uncontrollably, bringing with it an inflow of water causing neurons and glia to swell.

Renal medicine

The kidneys are of fundamental importance in the regu­lation of fluid and electrolytes, maintaining permissive extracellular fluid composition (salts and water), pH, and volume, while also mediating the removal of waste prod­ucts. Based on the anatomy of the nephron, three main processes occur in order to deliver this balance: glom­erular filtration, tubular secretion, and tubular resorption. Drugs can act at different sites within this system, so that functional equilibrium can be restored in various disease states (e.g. hypertension, heart failure, liver failure, neph­rotic syndrome). CKD is a long- term condition that lasts more than 3 months and affects the function of both kidneys. It results from any pathology that reduces renal functional capacity and produces a decrease in GFR to less than 60 mL/ min/ 1.73 m². Prevalence within the UK is high, particularly in the elderly and affects 6– 8% of the population. The most common cause of CKD is idiopathic (unknown, usually with small kidneys), then diabetes mellitus. In both, glom­erular damage and mesangial injury (causing metabolic and haemodynamic effects) occur. Mild- moderate essen­tial hypertension does not cause CKD. Knowledge of the functional anatomy of the proximal tubule and loop of Henle is essential in understanding therapeutic targets and treatment of pathologies, as each region and transporter system has a key role. In brief, the journey of solutes from the blood to the production of urine occurs at five main anatomical sites— the glom­erulus, the proximal tubule, the loop of Henle, the distal tubule (proximal part and distal part), and the collecting ducts (Figures 5.1 and 5.2). The glomerulus is a network of capillaries (like a ball of string), which merge with the nephron via Bowman’s cap­sule. It is the first site of filtration and the place where solutes, toxins, and small proteins are removed from the wider circulatory system, after delivery by the renal ar­teries (via an afferent arteriole). Blood and larger proteins remain in the arteriole and leave via an efferent branch, while the filtrate enters the proximal convoluted tubule. The afferent:efferent system ensures that a constant filtration pressure is maintained irrespective of variations in arterial pressure. The capillary bed is very large, so that permeability and filtration rates are high. A normal glomerular filtration rate (GFR) i.e. 90– 120 mL/ min/ 1.73 m², depends on hydrostatic pressure, the colloid osmotic pressure and hydraulic per¬meability.

Respiratory Medicine

Asthma is a reversible chronic airways condition character­ized by airway obstruction, bronchial hyperresponsiveness and chronic inflammation. Exposure to triggers causes an inflammatory cascade and symptoms, such as wheeze, dyspnoea, and cough. It is the most common medical condition in children, affecting 1 in 10 to varying degree. Peaks in prevalence occur at 10 and 59 years of age, with a tendency towards those of an atopic (hypersensitive al­lergic/ genetic predisposition) nature. In asthma, there is a swing in balance between two opposing T- helper (Th) cell populations towards persistent and excessive T- helper cell type 2 (Th2) dominated immune responses. Th1 cells are involved in response to infection, while Th2 cells are responsible for cytokine production (e.g. IL- 4, IL- 5, IL- 6, IL- 9, and IL- 13) that are involved in allergic reaction, which may explain the overproduction of IgE, the presence of eosinophils and airway hyperresponsiveness. In the case of inhaled allergens, lung- based dendritic antigen- presenting cells ultimately stimulate Th2 cell pro­duction from naive Th0 cells (Figure 3.1). Aspirin and other NSAIDs can also initiate asthma symptoms, although this appears to be non- IgE dependant. Other dominant cells seen in asthma include mast cells and eosinophils. Mast cells, when activated by inhaled antigen, release bronchoconstrictive factors like histamine, cysteinyl-leukotrienes, prostaglandin D², and eosinophil chemotactic factor. Mast cells in the airway may be sensitive to osmotic changes, thus account for exercise- induced asthma. The production of IL- 5 from activated Th2 and mast cells causes differentiation of eosinophils, which then migrate to the lung tissue, where they adhere to surface proteins like vascular- cell adhesion molecule 1 (VCAM- 1) and intercellular adhesion molecule 1 (ICAM- 1). Upon activation, these release pro- inflammatory cytokines like leukotrienes and granule proteins, which injure airway tissues. Additionally, eosinophil life is prolonged by the presence of IL- 4 and granulocyte- macrophage colony-stimulating factor (GM- CSF). Collectively, the persistence and presence of eosinophils may potentiate chronic in­flammatory changes and this correlates closely with the clinical severity of disease. The overall cellular balance shift (Th2 dominance, mast cells, and eosinophils) and presence of an in­flammatory stimulus results in bronchoconstriction (mainly via IgE- dependant release of mediators from mast cells constricting smooth muscle cells), airway oe­dema (through inflammation, mucus hypersecretion, and smooth muscle hypertrophy and hyperplasia), and airway hyperresponsiveness (through inflammation, dysfunc­tional neuroregulation, and structural changes).