5PY022 Musculoskeletal System Study Pack 2024

5PY022 Musculoskeletal System TBL Pack Musculoskeletal System (1) Student Study Guide Facilitators References Fatimah Abbas F.abbas4@wlv.ac.uk Required references: • British National Formulary (current edition). • Stovitz SD, Johnson RJ (2003) NSAIDs and musculoskeletal treatment: what is the clinical evidence? Phys Sportsmed.;31(1):35-52. • Van Wijck K, Lenaerts K, Van Bijnen AA, Boonen B, Van Loon LJ, Dejong CH, Buurman WA (2012) Aggravation of exercise-induced intestinal injury by Ibuprofen in athletes. Med Sci Sports Exerc.;44(12):2257-62. • Online links specified within this study pack. Additional reading: • Medical Pharmacology and Therapeutics, Section 6, Derek G. Waller and Anthony P. Sampson, Elsevier. ISBN: 9078-0-7020-5180-7 Dr Steve Anderson (Steve.Anderson@wlv.ac.uk) Dr Mark Hewitt (M.Hewitt@wlv.ac.uk) Zainab Yaseen (z.yaseen4@wlv.ac.uk) Shabana Chaudary (Shabana.Chaudary@wlv.ac.uk) Study pack based on material produced by Dr Mike and Jan Daly. Learning Outcomes This learning pack focuses on sports injuries, rheumatoid arthritis, osteoarthritis and gout. After studying this pack, you should be able to: • Understand the epidemiology, pathophysiology, clinical presentation of minor ailments and the above long-term musculoskeletal conditions. • Identify the pharmacological and non-pharmacological management of long-term musculoskeletal conditions and consider the associated adverse effects of treatments. • Consider treatment efficacy and drug compatibility. • Understand the principles of drug delivery (including routes of administration) and dosage form design including uniformity and stability. • Understand the specific formulation principles and packaging applying to capsules and pharmaceutical powders. 1 5PY022 Musculoskeletal System TBL Pack Contents Introduction ………………………………………………………………………………….. 3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) ………………………………...…… 5 Selective COX-2 inhibitors ………………..………………………………………. 9 Pharmacy and NSAIDS ……………………………………………………………. 10 Capsule Formulations ………………………………………………………..…………… 11 Hard Gelatine Capsules ………………………………………………………...…. 12 Soft Gelatine Capsules ……………………………………..………………..……. 15 Powder and Granule Based Products ..………………………………….………………. 17 Rheumatoid Arthritis …………………………………… ….……………………………… 20 Pharmacological Management of RA ……….…………………………………… 21 Diseases Affecting the Bone ……………………………………………………………… 28 Osteoarthritis ……..…………………………………………………………………. 29 Paracetamol ………………………………………………………………………… 31 Gout & Hyperuricaemia ……………………………………………………………………. 33 2 5PY022 Musculoskeletal System TBL Pack Introduction • • • The musculoskeletal system (MSK) consists of muscles and the skeleton which provide support and stability to the body so that we can carry out movements. It is made up of tendons, ligaments, muscle, skeleton, cartilage and connective tissue. The skeleton can be broadly split into two the axial skeleton, which is the central core of the body, and the appendicular bones, which form the extremities of the arms and the legs (see figure 1). Fig. 1: Diagram showing the appendicular and axial skeleton • • • • The skeleton provides various functions such as allowing movements to take place, protecting the organs, storing calcium and producing blood cells from bone marrow. Skeletal muscles and bones are interdependent in their function and development, e.g. regular exercise leads to skeletal muscle development, which places more stress on bones, so bones then increase their mass to cope with the added stress. The general working of the skeleton and muscles is covered in the neurological system TBL pack. The YouTube video below summarises the function of the musculoskeletal system. Some concepts mentioned e.g. synovial joints, osteoclasts/osteoblasts will be discussed in further detail in this study pack. https://www.youtube.com/watch?v=gSW2ryFmihk • • • The musculoskeletal system can be affected by several conditions, each of which commonly involves pain due to physical trauma, joint damage and tissue dysfunction. Several medical terms apply to any anatomical study of the skeleton, as shown in table 1. Pain is a protective sensation which can aid the healing process by causing an injured site to be rested, thereby preventing further damage from occurring. Condition porous bone tumour (composed) of muscle binding, fixation (of a bone or joint) rupture of muscle abnormal condition of being stiff, bent, or crooked weakness or debility of muscle softening of cartilage visual examination of a joint Terminology oste/o/porosis my/oma arthr/o/desis my/o/rrhexis ankyl/osis my/asthenia chondr/o/malacia arthr/o/scopy Table 1: some terminology used in conditions affecting the MSK 3 5PY022 Musculoskeletal System TBL Pack Sporting Injuries and Delayed Onset Muscle Soreness • Muscle pain that occurs during exercise is thought to be due to a combination of potassium ions, inorganic phosphate, lactic acid, hydrogen ions and nucleotides being released from fatiguing muscles, which recover on rest. • This pain is especially noticeable if muscles sustain a high-intensity contraction for several minutes. • Contractions compress and occlude supplying arterioles, so muscles experience ischaemia. • A less intense but more prolonged sustained contraction may compress and occlude draining venules, but not affect arterioles. • Blood flows into the affected area but cannot drain out, causing discomfort, swelling, underperformance of the affected muscles or limbs and a lack of accurate muscle control. This is known as chronic exertional compartment syndrome (CECS). • Most people experience muscular pain following heavy or unaccustomed exercise. Such discomfort tends to develop 6-12 hours after the exercise, so patients often feel mild discomfort at the end of the day, but awaken the following morning with severe pain. • At rest there may be no pain, until the muscle is moved or touched that symptoms are felt. • Symptoms include: o Muscle stiffness (sensation of a muscle becoming shorter, so that fully stretching or flexing a limb is difficult) o Muscle tenderness (pain experienced when pressure is applied to the affected muscle). This can be referred to as delayed onset muscle soreness or ‘DOMS’. o Eccentric exercise, where muscles are acting as brakes (e.g. when slowing down whilst running downhill or landing following a jump) is very good at inducing DOMS. Eccentric exercise involves muscles developing a lot of tension, but instead of them shortening (as in concentric exercise), they lengthen. o DOMS may be caused by muscle damage and spasm, connective tissue damage, lactic acid, inflammation and enzyme efflux from damaged tissues. • Pharmacological management of these injuries is discussed in further detail in this study pack. Non-pharmacological advice to prevent sporting injuries includes: o Ensuring adequate warm up before exercise o o o Avoiding over intensive training Completing dynamic stretches before and after physical activity Ensuring protective equipment is used where appropriate e.g. shin guards Inflammation To have a good understanding of musculoskeletal injuries, it is essential to understand the inflammation pathway. Refer to your MCS semester one notes on blood systems for a refresher. 4 5PY022 Musculoskeletal System TBL Pack Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Sporting injuries are common and can range from the trivial to serious problems requiring surgical intervention and specialist recovery programmes. In mild cases, individuals commonly treat themselves with non-steroidal anti-inflammatory drugs (NSAIDs), such as those shown below (Figure 1): Diclofenac Naproxen Ibuprofen Aspirin Fig. 2: Commonly used non-steroidal anti-inflammatory drugs (NSAIDs) • • • • • NSAIDs work by interfering with the production of autacoids, which are biological molecules formed by one set of cells that can then alter the functioning of other cells. [Greek, autos = self and akos = remedy]. Many autacoids induce pain and mediators include, examples include eicosanoids, histamine, 5-hydroxytryptamine and nitric oxide. The eicosanoids are derived from arachidonic acid (Figure 2) and the main types are: o Prostaglandins (PG) o Thromboxane A2 (TxA2) 1 o Leukotrienes (LT) Arachidonic acid is also known as 5, 8, 11, 14eicosatetraenoic acid (eicosa = 20 carbon atoms, 20 tetraenoic= 4 carbon to carbon double bonds). Eicosanoids are not stored, but are generated de novo “from the new”. The plasma half-life for most Fig. 3: Structure of arachidonic acid eicosanoids is less than 1 minute and arachidonic acid is liberated from phospholipids by the enzyme phospholipase A2, as shown below in Figure 3. 5 5PY022 Musculoskeletal System TBL Pack Phospholipid phospholipase A2 lipoxygenase Arachidonic acid cyclo-oxygenase Leukotrienes LTB4, LTC4, LTD4 Endoperoxides prostacyclin prostaglandin synthase isomerase TxA2 Prostaglandins PGD2, PGE2, PGF2 Prostacyclin thromboxane (PGI2) synthase ‘Prostanoids’ Fig. 4: The biosynthetic pathway of eicosanoid production. Substrates are represented in BLACK, enzymes in BLUE and products in RED. Cyclo-oxygenase (COX): a derivative of Arachidonic acid has TWO isomers: • COX-1, a widely distributed constitutive enzyme producing prostanoids involved with homeostatic regulation (housekeeping role). • COX-2, an inducible enzyme that may only be expressed in low level ordinarily, but whose expression is up-regulated during inflammation. • The different eicosanoids means that the inflammatory mediators can have very different properties and effects on the body. For example: o PGD2: Acts as a vasodilator and inhibits platelet aggregation. o PGE2: Causes uterine smooth muscle contraction, vasodilation, inhibition of gastric acid secretion, increased gastric mucus secretion and is hyperalgesic. o PGF2 : Causes bronchoconstriction and uterine contractions. o TxA2: Vasoconstrictor and thrombotic. o PGI2: Vasodilator, hyperalgesic, inhibits platelet aggregation. o LTB4: chemotaxin (a substance released by bacteria, injured tissue, and white blood cells that stimulates the movement of neutrophils and other white blood cells to the injured area). o LTC4 and LTD4: bronchoconstrictors, increase vascular permeability. Prostaglandins are activated by trauma, and they then mediate the following effects: ➢ Inflammation - as PGE2 and PGI2 are generated locally in tissues and will cause vasodilation. This causes more blood to flow through the affected area, causing increased redness and warmth. Prostaglandins also potentiate the effects of molecules such as histamine to increase postcapillary venule permeability, so enhancing swelling and oedema. 6 5PY022 Musculoskeletal System TBL Pack ➢ Pain - prostaglandins do not cause much pain themselves, but instead they sensitize afferent C nerve fibres to molecules such as bradykinin, which potentiates the pain felt. ➢ Fever - as prostaglandins (mostly PGE2) are pyrogenic, they can stimulate the thermoregulatory centre in the hypothalamus to mediate fever. Endotoxins cause macrophages to release IL-1, thereby stimulating E-type prostaglandin generation. • • • • • • NSAIDs inhibit the COX enzymes and thereby reduce the production of prostaglandins, which means that NSAIDs possess anti-inflammatory, anti-pyretic and analgesic effects. The two COX enzymes are important therapeutically, as some NSAIDs are selective inhibitors of the different enzymes giving them different profiles of therapeutic activity and side effects, for example: o They can suppress PGE2 – which means this eicosanoid cannot protect the stomach mucosa, and so gut ulceration is a side effect of NSAIDs. o Similarly, PGD2 is a vasodilator, so NSAIDs can cause vasoconstriction, which means that blood pressure can increase (leading to hypertension) in patients on NSAIDs. Drugs such as aspirin (acetylsalicylic acid), ibuprofen and naproxen (propionic acid derivatives), diclofenac (a phenylacetic acid derivative) and indomethacin (an indoleacetic acid derivative) are examples of non-selective NSAIDs (inhibiting both COX-I and -2). o The reduction in prostanoid synthesis by inhibiting COX-2 produces the therapeutic effect, but inhibition of COX-I leads to side effects as the ‘housekeeping’ role, such as maintaining the mucosal protection of the stomach, will be lost and GI ulcers can form during treatment. Most NSAIDs bind reversibly to the site in the COX enzymes that accepts arachidonic acid (except aspirin which irreversibly inactivates the enzyme by acetylation of a serine residue), so the platelets are unable to produce TxA2. Therefore, platelet TxA2 receptors are not stimulated, phospholipase C is not stimulated, and no inositol trisphosphate is produced. This means that Ca2+ levels do not rise, platelets remain quiescent, and this reduces the viscosity of the blood. This mechanism means that aspirin is also useful as an antiplatelet drug (but at a lower dose than for mild to moderate pain control). Platelets require COX-1 to synthesise thromboxane A2 (a potent platelet-aggregating agent) and irreversible inhibition of COX-1 by aspirin means that platelet function only returns by producing new platelets (platelet turnover 7-10 days). Low dose aspirin affects platelets more than endothelial cells because platelets have no nucleus (so they cannot produce more COX-1) and aspirin has a considerable first-pass metabolism, so it affects intestinal and hepatic blood, but its distribution around the rest of the body is limited. Anticoagulants are not very effective in arterial thrombosis, however antiplatelet drugs are much more useful. Adverse effects of NSAIDs GI disturbances are common with NSAIDs, predominantly due to COX1 inhibition. Adverse effects include: o Gastric discomfort o Dyspepsia o Nausea o Vomiting o GI bleeding o Ulceration & GI perforation 7 5PY022 • • • • • • Musculoskeletal System TBL Pack These adverse effects are mediated by the reduction in prostaglandin formation, leading to increased gastric acid production, a reduction in gastric mucus secretion and vasodilatation. This can lead to ulceration, bleeding and possible haemorrhage from the gastric mucosa. Therefore in practice patients who are at high risk of bleeding are prescribed PPI’s alongside NSAID’s. You will learn more about PPI’s in your Gatroenterology TBL cycle. Skin rashes commonly occur with NSAIDs and range from mild erythema, urticaria and increased photosensitivity. They also cause serious adverse reactions such as StevensJohnson syndrome and angioedema. These are potentially fatal allergic reactions. Other adverse effects include bone marrow disturbances, liver disorders and blood dyscrasias. NSAIDs should be used with caution in patients with cardiac disease, renal impairment, and in elderly patients. NSAIDs and Asthma • Smooth muscle relaxation caused by prostaglandins is important in asthmatic patients, especially if they have reduced sensitivity to sympathomimetic agents such as adrenaline. • In some cases, the patient relies on their normal prostaglandin production to keep their airways open and dilated. However, if they take an NSAID, the prostaglandin inhibition means lung alveoli constrict and they can experience a severe and potentially fatal asthmatic attack (status asthmaticus). • For this reason, it is essential when selling an NSAID to a patient to ensure that they do not suffer from asthma. Renal function and NSAIDs • PGE2 and PGI2 are normally involved with maintaining renal blood flow by dilating the renal artery. Inhibition of these prostaglandins by NSAIDS reduces blood flow through the kidneys because the renal artery contracts, causing reduced renal function and potentially leading to acute renal failure. This is widely known as nephrotoxicity. • Therefore, NSAIDs are stopped in patients who are in AKI (Acute Kidney Injury). Uses of NSAIDs • Used for their analgesic, anti-inflammatory and antipyretic properties. • Often available in multiple formulations e.g. tablets, suspensions or topical gels and are commonly available ‘over the counter’ (OTC) from pharmacies and retail outlets. • Provide symptomatic relief ranging from minor aches and pains, but are also effective for severe pain such as: o Acute conditions e.g., sporting injuries, sprains and soft tissue injuries. o Dental pain, menstrual pain, headaches and migraines o Chronic joint disease e.g. osteo- and rheumatoid arthritis. o Postoperative pain. o Severe pains e.g. bone cancer. • NSAIDS are NOT generally effective in reducing visceral pain. • In degenerative conditions, such as osteoarthritis, NSAIDs do not reduce joint destruction. This is because lipoxygenase is not inhibited by NSAIDs and arachidonic acid can be ‘shunted’ through this pathway, thereby resulting in more leukotriene (pro-inflammatory) production. Therefore, NSAIDs do not halt the progression of chronic disease states. 8 5PY022 • • • • Musculoskeletal System TBL Pack The usefulness of the anti-inflammatory action of NSAIDs in muscle injury has been questioned. During a tissue injury, the body initially uses inflammation and inflammatory cells to promote healing and deal with tissue debris. Theoretically NSAID use could delay the healing of musculoskeletal injuries, and therefore for the first 48 hours the use of NSAIDs is not recommended. Although an analgesic effect may occur around one week, full anti-inflammatory effects are not usually achieved until after approximately three weeks of treatment, therefore it is important to counsel patients to continue taking their medicines regularly. Some athletes use NSAIDs to reduce or prevent anticipated musculoskeletal pain, enabling them to train harder for longer. Different NSAIDs inhibit the two main isoenzymes COX1/2 to varying effects, as shown in table 1 below. Table 2: NSAID selectivity for COX-1 and COX-2 Drug Class Flurbiprofen Propionic acid Aspirin Salicylate Ibuprofen Propionic acid Naproxen Propionic acid Diclofenac Phenyl acetic acid Increasing selectivity for inhibition of COX-1 compared with COX-2 Approximately equal inhibition of COX1 and COX-2 Increasing selectivity for inhibition of COX-2 compared with COX-1 Celecoxib Coxibs Selective COX-2 Inhibitors • • • • • Highly selective COX-2 inhibitors were developed to remove unwanted adverse effects associated with COX-1 inhibition. Both COX-1 and -2 isoforms have a long channel that forms their active sites. In comparison, the chemical structure/molecular size of selective COX-2 inhibitors is larger than non-selective NSAIDs. The drug binding site for COX-2 contains a ‘side pocket’ that can accommodate the bulkier size of selective COX-2 inhibitors. COX-1 has a narrower binding site, which excludes selective COX-2 inhibitors. Non-selective NSAIDs are small enough to fit into both COX-1 and COX-2 binding sites. Selective COX-2 inhibitors (such as celecoxib and etoricoxib) should in theory be effective NSAIDs with reduced side effects, as they do not inhibit COX-1, but unfortunately several COX-2 inhibitors were withdrawn from the market as their use was associated with a small increased risk of thrombotic events (e.g. myocardial infarction and stroke). For this reason, selective COX-2 inhibitors are contraindicated in patients with established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. 9 5PY022 • • Musculoskeletal System TBL Pack The mechanism is thought to be related to the COX-1 enzyme normally producing vascular PGI2, which acts against any TxA2 released by platelets, and this prevents clot formation. So, normally PGI2 and TxA2 balance with each other. During haemostasis, however, TxA2 production will swamp the effects of PGI2 and a platelet plug will form and potentially occlude blood vessels in the heart. Following a cardiovascular insult, it seems that COX-2 may become important in PGI2 formation. So, if a selective COX-2 inhibitor is now administered PGI2 formation will fall, but TxA2 is still synthesized by platelet COX-1. Therefore the balance has shifted towards unopposed TxA2, which increases the risk of developing a thrombosis and potential heart attack (myocardial infarction). The adverse effects of selective COX-2 inhibitors • Refecoxib, a COX-2 specific NSAID (marketed by Merck under the tradename VIOXX®) was used to treat arthritis for five years before a clinical trial indicated that it was associated with an increased risk of heart attacks and strokes. • Lumiracoxib (also a selective COX-2 inhibitor) was introduced in 2006 and withdrawn within a year due to causing severe liver toxicity. A genetic biomarker has now been identified to indicate which patients are at risk of these side effects, which means that the drug could potentially be reintroduced in a limited capacity. Pharmacy and NSAIDs • • Due to the adverse effect profile of NSAIDs, they are often only available as prescription-only medicines (POMs) and caution must be exercised before giving any NSAID to a patient with any history of allergic reactions, asthma, dermatological problems, gastro-intestinal problems, cardiac problems and liver or kidney disease. Attempts to limit or control side effects have been made by altering formulations for NSAIDs, such as: o Enteric coating: NSAIDs such as diclofenac and ibuprofen can be enclosed in a tablet or capsule with an enteric coating which dissolves in a more alkaline environment. This is to reduce stomach ulceration by ensuring that drug absorption does not occur in the acid environment of the stomach. However, the mechanism of GI ulceration (mediated by the reduction in prostaglandin formation, leading to increased gastric acid production and a reduction in gastric mucus secretion) is a systemic effect and GI injury can still occur. o Soluble preparations: To avoid a concentrated amount of NSAID in one area of the stomach when taken as a tablet, for example, NSAIDs can be formulated as soluble products to be taken dispersed in water (see dispersible or effervescent formulations). However, as with enteric coating, this does not necessarily remove the potential for side effects. o Suppositories: The rectal mucosa provides an alternative absorption route and some NSAIDs are also available as suppositories. The same systemic side effects still occur, however. You will learn more about suppositories in the gastrointestinal system TBL cycle. Task 1: Identify which NSAIDS are available over the counter in community pharmacies, including formulation and strength. 10 5PY022 Musculoskeletal System TBL Pack Capsule Formulations What is a capsule? • From the Latin “capsula”, which means small box. • Capsules are dosages forms in which a unit dose (either a powder, semisolid or liquid) is enclosed within a shell. • The shell is commonly made from gelatine, but other shells are available made from polymers such as hydroxypropylmethylcellulose (HMPC) or polyvinyl alcohol (PVA). Depending on the makeup of the capsule shell, capsules are classified generally either as hard or soft gelatine capsules. • Most capsules are intended to be administered orally and taken whole. However, some soft gelatine capsules are intended for rectal or vaginal insertion. • Bioavailability from capsule formulations is usually high and comparable with that of immediate release tablet formulations. The capsule shell is designed to dissolve rapidly when it encounters gastrointestinal fluids releasing the capsule’s contents. • Sustained release capsules formulations are available whereby the capsule shell or contents are coated with an appropriate polymer to control the rate of capsule/drug dissolution. This will be covered in greater detail next year. Why gelatine? • Gelatine is obtained from partial hydrolysis of collagen sourced from animal skin and bones. • It is colourless, translucent and is almost tasteless. • It is brittle when dry and has elastic properties when exposed to moisture, forming a semisolid gel. It is also readily soluble in biological fluids at body temperature. • Therefore gelatine is the ideal choice of material for capsule shells since it is cheap to produce, in plentiful supply and can be worked easily. • Several gelatine-free capsules are available. CapsuGel® developed hard shell capsules from starch. Task 2: What are the potential problems with using gelatine and why have gelatine-free capsule shells been developed? 11 5PY022 Musculoskeletal System TBL Pack Hard Gelatine Capsules Formulation components of hard gelatine capsules: • Gelatine • Water • Colourants • Preservatives • Processing excipients • • • • E.g. Diclomax SR® (diclofenac controlled release capsule) Hard gelatine capsules consist of two U-shaped halves. One half is known as the cap and the other the body – the cap fits over the body to form a sealed compartment. As such the cap is of a slightly higher diameter allowing it to fit over body counterpart. The design of the capsule shell can be modified to include features such as notched bodies to interlock with the cap. The image (taken from Aulton’s) and video below give you some idea of how hard gelatine shells are made: Fig. 5: Hard gelatine capsule production [Aulton’s Pharmaceutics] 12 5PY022 Musculoskeletal System TBL Pack https://www.youtube.com/watch?v=NVqN-Dinh48 • • Capsules are available in a range of sizes and powder holding capacities. A single modern high-speed capsule filling machine is capable of filling approximately 2.4 million capsules in a 24-hour period. Most hard gelatine capsules contain the API in the form of powder, granules or pellets. Multiple other forms are available including microtablets, capsules, liquids or semisolids. The latter two options are becoming increasing popular. Once the capsule comes into contact with an aqueous environment it takes on water, softens, swells and dissolves releasing the API. Hard gelatine capsules are often intended for oral administration, but are also used to deliver dry powder drug formulations for inhalation into the lung, e.g. Spiriva® (Boehringer Ingelheim) – tiotropium (a antimuscarinic bronchodilator packaged into a hard gelatine capsule for use with the HandiHaler®). • • • Table 3: Advantages and disadvantages of hard gelatine capsules Advantages Disadvantages • • • • • • Useful for challenging drugs e.g. drugs which are liquid or semisolid at room temperature and unsuitable for production as tablets (especially at high doses) Very low dose (ųg) can have dose uniformity issues. Formulation as a liquid or semisolid hard gelatine capsule can resolve this Generally require fewer excipients and are less dependent on powder flow properties Flexibility of capsules for filling with powder, granules, etc. Allow for better oral bioavailability than tablets • • • 13 Often a tedious and difficult to optimise manufacturing process Until the development of high-speed capsules filling equipment, capsule production was slower than tablet formation More costly to develop than tablets Certain drugs cannot be encapsulated (e.g. highly soluble iodide and chloride salts) 5PY022 Musculoskeletal System TBL Pack Diclomax SR® is an example of a hard gelatine capsule relating to the musculoskeletal system: Diclomax SR® (Galen Limited) (https://www.medicines.org.uk/emc/medicine/19831) 1. Name of the medicinal product Diclomax SR 2. Qualitative and quantitative composition Each Diclomax SR capsule contains diclofenac sodium 75mg. 3. Pharmaceutical form Modified release capsules for oral use. Pharmaceutical particulars: List of excipients Sucrose Maize starch Polyethylene glycol 6000 Ammonio methacrylate copolymer type A Talc Lactose Polysorbate 80 Purified water Ethanol 96% Acetone Capsule Shell Constituents: Gelatin Yellow iron oxide (E172) Titanium dioxide (E171) Overprint Ink Constituents: Shellac glaze Propylene glycol Black iron oxide (E172) 14 Can you determine why each of these excipients is present? 5PY022 Musculoskeletal System TBL Pack Soft Gelatine Capsules Formulation components of soft gelatine capsules: • Gelatine • Water • Colourants • Preservatives • Processing excipients • • • • • • • • • E.g. Nurofen 200 mg liquid capsule (Reckitt Benckiser Healthcare UK Ltd). Soft gelatine capsules (often called GelCaps) consist of a hermetically sealed shell that is filled with an oily solution/suspension or semi-solid. Unlike hard gelatine capsules, soft gelatine capsules are completely sealed and cannot be opened without destroying the capsule itself. The use of soft gelatine capsules has gained popularity in recent years and today several drugs are formulated in this manner (including cyclosporine, digoxin and vitamins A and E). By formulating drugs such as ibuprofen in soft gelatine capsules (dissolved in polyethylene glycol (PEG)), bioavailability can be increased. Soft gelatine capsules are a one-piece construct that can be either oval or oblong in shape Administration is generally via the oral route. Karvol® decongestant capsules [Reckitt Benckiser Healthcare UK Ltd] are an exception as they consist of a twist-off teat that releases a combination of aromatic oils intended for inhalation to relieve congestion and make breathing easier. Soft gelatine capsules can be enteric coated (gastro-resistant) or surrounded with a delayed release matrix to achieve delayed release of the contents. Table 4: Advantages and disadvantages of soft gelatine capsules Advantages • Solution for non-palatable solutions/suspensions and/or oily liquids • Ability to deliver low-dose lipid soluble drugs allows for greater dose uniformity over tablets dosage forms • Ability to develop immediate, slow or sustained release formulation or to add an enteric coat Disadvantages • Limited formulations that can be encapsulated (only liquids or semisolids) • Optimisation of the manufacturing process if difficult • The breakage of just one capsule during manufacture (or in storage) can coat several others with the formulation leading to increased waste • Greater moisture content of soft gelatine capsules means moisture-sensitive drugs are incompatible due to chemical instability • Soft gelatine shells are temperature sensitive. Temperature of capsule contents cannot exceed 35oC (70oC for hard gelatine capsules) 15 5PY022 Musculoskeletal System TBL Pack Nurofen 200mg liquid capsules soft gelatine capsule relevant to the musculoskeletal system: Nurofen 200mg liquid capsules (Reckitt Benckiser Healthcare (UK) Ltd) (https://www.medicines.org.uk/emc/medicine/25272) 1. Name of the medicinal product Ibuprofen 200mg Liquicaps Nurofen Express 200mg Liquid Capsules Nurofen 200mg Liquid Capsules 2. Qualitative and quantitative composition Each capsule, soft contains Ibuprofen 200 mg. Excipients: Potassium hydroxide Sorbitol 3. Pharmaceutical form Capsule, soft. A clear red oval soft gelatin capsule printed with an identifying logo in white. Pharmaceutical particulars: List of excipients Macrogol 600 Potassium hydroxide 50% solution (E525) Gelatin Sorbitol Liquid, Partially Dehydrated (E420) Purified Water Ponceau 4R (E124) Lecithin (E322) or Phosphatidylcholine in Medium Chain Triglycerides Triglycerides , medium chain Ethanol White ink* The ink contains the following residual materials after application: Titanium Dioxide (E171), Polyvinyl Acetate Phthalate, Macrogol 400, ammonium hydroxide (E527), propylene glycol. 16 5PY022 Musculoskeletal System TBL Pack Powder and Granule-based Products • • Almost all pharmaceutical dosage forms involve a powder at some stage. The powder may be compressed into a tablet, used to fill a capsule or formulated as a powder for oral solution or suspension, which require reconstitution with water before administration. Powders offer extended shelf-life over their liquid equivalents owing to increased chemical stability. What is a pharmaceutical powder? • Most APIs are crystalline solids (as opposed to amorphous) that can be made into finely divided solids (a powder). The characterisation of pharmaceutical powders if a critical step in development of a successful drug formulation. These properties include: o Particle size and shape – critical for effective dissolution, absorption etc. o Surface area – important for dissolution o Density and porosity – critical in powder flow and mixing o Flow – critical in mixing, tablet manufacture, capsule filling, transfer of powders between equipment, etc. o Compactability – important in the production of both tablets and capsules where powders (or granules) are compacted into a solid mass. o Content uniformity – CRITICAL – most pharmaceutical powders are a mixture of API and one or more excipients. Uniform distribution (mixing) of each component is desired to ensure each tablet or capsule contains the same ratio of API (and other excipients). So, what is a granule? • Often the physical characteristics of a powder may not be favourable due to small particle sizes etc. Granulation may then be performed to produce granules (physical aggregates of powder particles) to increase particle size and resulting characteristics (flow, Compactability etc.). • Gravy granules are an example of this; the powder is more difficult to handle, especially when exposed to moisture, so granules are produced. • Adhesion of powder particles to form granules can be classified as either dry or wet: o Dry granulation: compaction of a powder followed by braking of the compacts. This does not involve the use of water. Of course, compactability is a characteristic of the powder(s) in question. o Wet granulation: involves the addition of water to a powder, followed by mixing and the removal of water. • You all should have come across examples of powders and granules before. They fall into two classes, bulk and divided: o Bulk powders are dispensed in large containers and a dose is measured, reconstituted and administered by the patient, for example, laxatives. o Divided powders are individually packaged, pre-measured doses allowing for simple reconstitution by the patient, for example, Fybogel® or Lemsip® sachets. Further information on the presentation and characteristics of bulk and divided powders and granules is provided in the table below: 17 5PY022 Musculoskeletal System TBL Pack Table 5: Powders and Granules: Bulk versus Divided Presentations Powders Granules • Mixed ingredients (powdered drug and excipients) are packaged into a bulk container, e.g. plastic or laminated cardboard jar Toxic and/or potent medicaments are not available as bulk powders due to the issues with dose variability Inclusion of hygroscopic ingredients can be an issue for product stability and visual presentation Individual particle sizes need to be as monodisperse as possible to prevent dose segregation within the container Can be stability issues for bulk powder products and their packaging: o Ingress of water can cause caking and ultimately issues with solubility E.g. Andrew’s Liver Salts (GSK) • • Individual doses of product are packaged separately Packaging: o Foil and laminate o Protects hygroscopic products o Can be used on high-speed packing lines Effervescent powders: o Sodium bicarbonate o Citric acid Storage in a cool dry place is often required to prevent article adhesion and cake formation E.g. Beecham’s Powders (GSK) • • • • Bulk • • • • • Divided • • 18 • • • • Granulated powder-based formulation Prevents segregation of bulk powders (which is a major issue in powder formulations with a polydisperse size profile) and resultant dose variability In common with bulk powders, granulated products feature: o Low toxicity o High dose o Drug powder Compared to bulk powder formulations, granulated products require an additional granulation step to be included into the production process Dose uniformity per granule and hence within a given dose is of vital importance E.g. Fybogel® (Reckitt Benckiser) o Methylcellulose granules o Bulk-forming laxative Same considerations as for divided powders: o Individual doses of product are packaged separately o Packaging: ▪ Foil / plastic laminate ▪ Protects hygroscopic products ▪ Can be used on highspeed packing lines o E.g. effervescent granules: ▪ Sodium bicarbonate o Storage in a cool dry place is often required to prevent article adhesion and cake formation o E.g. Fybogel® sachet (Reckitt Benckiser) 5PY022 Musculoskeletal System TBL Pack Table 6: Advantages and Disadvantages of Powder and Granule Formulations Advantages Disadvantages • • • • • Increased chemical stability versus liquid formulations Easier to dispense into a large dose Relatively fast dissolution and absorption rates (versus tablets, capsules, etc.) Advances in packaging technology are making divided doses easier to separate and carry (e.g. laminated sachets) • • • Bulk products are not as convenient as small containers of tablets (e.g. blister pack strips) Taste masking is more difficult but can be overcome by formulating the product into a taste-masked effervescent form Administration of low doses from a bulk product is difficult. Dose variability can result from: o Measuring inaccuracies (i.e. heaped tsp versus level 5 mL spoon) o Bulk density variations Cannot be used for oral administration of drugs which are inactivated in the stomach This is a snapshot of a very complex field. For further learning and insight on the formulations covered, refer to ‘Aulton’s Pharmaceutics’. 19 5PY022 Musculoskeletal System TBL Pack Rheumatoid Arthritis (RA) • • • • • • • • Rheumatoid arthritis (RA) is a chronic condition of autoimmune origin which is usually progressive and can be severely debilitating, impacting a patient’s quality of life. It typically affects synovial joints (such as those in the hands and feet), causing swelling, stiffness, pain and progressive irreversible joint destruction and deformity. Proliferation of the synovium and destruction of joint cartilage and bone by osteoclasts occurs, and inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-α (TNFα) play an important pathogenic role. Acute-phase proteins are plasma proteins that show a dramatic increase in concentration (up to 1000-fold) in response to ‘alarm’ mediators such as macrophage derived IL-1, IL-6 etc., which is released following infection or tissue injury. Acute-phase proteins can act as soluble pattern recognition molecules that are capable of binding to infectious agents to function as opsonins, to enhance the uptake by macrophages and neutrophils. This process is referred to as ‘opsonisation’. Examples include C-reactive protein, mannose-binding lectin and serum amyloid P component. Immunoglobulin G (IgG) or IgM rheumatoid factors are found in almost all RA patients and are autoantibodies. IgG can function as both antigen and antibody, with IgG aggregates being detected in synovial tissue and fluid, causing acute inflammatory reactions. As the disease progresses, it may cause complications including joint deformity, and affect different organs of the body, such as the heart, lungs, and eyes; therefore, early diagnosis and treatment of rheumatoid arthritis is essential to reduce the impact of the disease. The following video outlines the main symptoms of rheumatoid arthritis: https://www.youtube.com/watch?v=0uwx64YaxSk The following video describes the differences in pathophysiology between RA and OA: https://www.youtube.com/watch?v=VIfQh71XwMM NICE has produced a Clinical Knowledge Summary on the management of rheumatoid arthritis, which can be accessed using the following link: https://cks.nice.org.uk/topics/rheumatoid-arthritis/ 20 5PY022 Musculoskeletal System TBL Pack Pharmacological Management of Rheumatoid Arthritis • • • • • • • • • • • The aims of treatment are to relieve the symptoms of rheumatoid arthritis, achieve disease remission or low disease activity if remission cannot be achieved, and to improve the patient's ability to perform daily activities. Progressive joint damage is a common feature of RA and other inflammatory arthritis, and there is substantial evidence that treatment which achieves disease remission or low disease activity leads to a better long-term outcome. NSAIDs provide symptomatic relief in RA, but they do not alter the long-term progression of the condition. Symptoms are reduced, but joint destruction will continue. Disease-modifying anti-rheumatic drugs (DMARDs) are a diverse group of drugs with unrelated chemical structures that have different mechanisms of action. DMARDs can produce long-term suppression of inflammatory responses, so they can: o Reduce joint swelling and tenderness o Retard progression rates of joint erosion and destruction o Improve pain and disability scores o Cause falls in plasma acute-phase proteins and rheumatoid factor o DMARDs can lead to an improvement in symptoms and in the clinical markers of rheumatoid arthritis. DMARDs should be started soon after a confirmed diagnosis, as they have a slow onset of action with improvements beginning approximately three months after starting treatment. NSAIDs may be used to reduce symptoms during this period, but NSAID therapy can normally be reduced once DMARD actions take effect. Short-term ‘bridging’ treatment with a corticosteroid [see later under glucocorticoids] by oral, intramuscular, or intra-articular administration may be useful when starting treatment with a new DMARD to provide rapid symptomatic control, while waiting for the DMARD to take effect. Bridging treatment is therapy intended to serve as a ‘bridge’ to another stage of therapy, carrying the patient past a challenging period of some kind. Short-term corticosteroids may also be given to rapidly decrease inflammation during flare-ups. However, long-term treatment with glucocorticoids is not recommended due to the adverse effects associated with prolonged use (as outlined later). DMARDs can be divided into two main categories: o Drugs that suppress the rheumatic disease process (including drugs that affect the immune response) o Cytokine modulators, which are often described as ‘biologics’, as they are derived from biological sources such as antibodies- you will cover these in detail next year (stage 3) These DMARDs suppress or modify immune responses, and while can slow the progression of RA, it also means that they increase the risk of serious infections due to interfering with the normal immunological responses against infections. 21 5PY022 Musculoskeletal System TBL Pack Drugs that suppress the rheumatic disease process: Methotrexate • Methotrexate is an analogue of folic acid analogue, and has been used in cancer chemotherapy for many years as it inhibits dihydrofolate reductase to prevent the conversion of dihydrofolic acid to tetrahydrofolic acid for nucleic acid synthesis. • Methotrexate (figure 6) contains a diaminopteridine ring system which has the ability to form an intricate hydrogen bonding network with the binding site. There are also interactions with Trp21, Thr-11 and Leu-114 by hydrogen bonding through water as can be seen below. • Methotrexate decreases the production of IL-1 and TNF- cytokines, but increases the production of IL-10, which is inhibitory, and adenosine production may also be increased, which then acts as an anti-inflammatory paracrine. Methotrexate treatment can improve symptoms in RA within a period of around 1 month, and treatment can then be long-term with appropriate monitoring. Fig. 6: Methotrexate Refer back to your first year physicochemical properties of drugs pack for more information on hydrogen bonding. • • • Methotrexate is administered ONLY ONCE A WEEK, (usually orally), as it accumulates intracellularly and potentially severe (and fatal) side effects have occurred due to patients mistakenly taking the drug daily in error. Pharmacists must counsel patients carefully when they supply methotrexate and should ensure that a methotrexate treatment booklet has also been issued, which contains information about what dose to take and what special monitoring is required while the patient is taking the drug. Side effects include nausea, stomatitis (buccal lining inflammation), blood dyscrasias (which can be fatal), liver cirrhosis and pneumonitis (lung tissue inflammation). Patients who develop 22 5PY022 • • • Musculoskeletal System TBL Pack breathing difficulties while taking methotrexate must be urged to seek urgent medical attention. NSAIDs reduce the renal clearance of methotrexate, and may also interfere with serum binding, and this combination of effects may seriously increase the risk of toxicity. So, while occasionally used together, patients should be carefully monitored if receiving both NSAIDs and methotrexate. There is also a very serious drug interaction with trimethoprim, which also acts on dihydrofolate reductase – if taken together, both drugs may actively suppress the bone marrow leading to agranulocytosis or neutropenia, which is rapidly life threatening. These two drugs should never be taken together. Folic acid reduces the toxicity of methotrexate treatment and improves continuation of therapy and compliance. Folic acid is usually also prescribed ONCE WEEKLY, but SHOULD NOT be taken on the same day as the methotrexate as it will antagonise the effectiveness of the latter. Azathioprine • Azathioprine is a prodrug that is converted to 6-mercaptapurine and has been used as an immunosuppressant to stop transplanted organ rejection. • It inhibits the production of purines and is cytotoxic, as shown in figure 6 below. • It inhibits the proliferation of B- and T-lymphocytes by a cytotoxic action on dividing cells. • It inhibits both cell-mediated and antibody-mediated immune reactions. Fig. 7: Mechanism of action of azathioprine Glutathione Glutathione _ Glutathione 6-mercaptopurine Azathioprine • • Side effects include nausea, vomiting, diarrhoea, bone marrow suppression, liver toxicity and increased risk of infections/fever (due to over-suppression of lymphocytes). Patients should be warned to report signs of marrow suppression, such as unusual bleeding and bruising (due to decreased platelet numbers). Bone marrow suppression is often first presented by a patient developing a sore throat, so patients should be counselled to seek urgent medical attention if they develop a sore throat. 23 5PY022 Musculoskeletal System TBL Pack Leflunomide • • • Leflunomide inhibits dihydroorotate dehydrogenase, which is involved with pyrimidine production, and inhibits B- and T-lymphocyte proliferation. It is administered orally and activated by the liver. The activated metabolite has a half-life of 2-4 weeks. Liver damage is possible and it is also associated with Stevens-Johnson syndrome. Leflunomide Fig. 8: Leflunomide Sodium aurothiomalate • • • • Sodium aurothiomalate (intramuscular) and auranofin (oral) are salts made with gold that are used for the treatment of RA, but their mechanism is unclear. Their mechanisms of action possibly include: o Inhibiting prostaglandin synthesis o Deactivating complement o Disruption of MHC o Inhibition of IL-1, IL-2 and TNF-α production o Reducing T-lymphocyte activity o Reducing phagocyte activity o Inhibiting neutrophil migration Fig. 9: Sodium aurothiomalate Side effects include skin rashes, mouth ulcers, non-specific flu-like symptoms, proteinuria, thrombocytopenia and blood dyscrasias. Encephalopathy, peripheral neuropathy and hepatitis can also occur. Patients should be warned of such side effects, and treatment stopped if early symptoms develop which greatly reduces the risk of serious toxicity. Antimalarials • Antimalarial drugs such as chloroquine and hydroxychloroquine (figure 8) have long halflives, as they are stored in tissues, so it takes months to reach a steady state in the blood and therefore they have a slow onset of clinical action. • They are generally reserved only for mild RA, as they are not considered to be as effective as other DMARDs. • They can cause GI disturbances, and regular eye examinations are required to detect possible retinopathy which can occur. Patients may be counselled to wear sunglasses in sunlight to afford some protection. • The mechanisms of action of these drugs have not been fully elucidated, but may include: o Inhibiting lysosomes o Inhibiting neutrophils o Suppressing phospholipase A2 activity o Inhibiting IL-1 and TNF- production 24 5PY022 Musculoskeletal System TBL Pack Chloroquine Hydroxychloroquine Fig. 10: The antimalarial DMARDs Penicillamine • Penicillamine (D-penicillamine) is derived from the hydrolysis of penicillin. • Penicillamine may reduce T-lymphocyte activity and inhibit rheumatoid factor from binding to immunoglobulin, so preventing the formation of immune complexes in RA. • It’s enantiomer (L-penicillamine) is toxic as it inhibits the action of pyridoxine. • Side effects include GI disturbances, rashes, stomatitis and taste disturbances. • Penicillamine is also a metal chelator, so it can be used in cases of heavy metal (Hg and Pb) poisoning. Taste buds contain zinc ions, to which penicillamine may chelate, so it may also cause taste disturbances. Fig. 11: Penicillamine Sulfasalazine Administration Sulfapyridine Sulfasalazine urothiomalate • Sulfasalazine is relatively effective, cheap, orally administered and has fewer side effects when compared to other DMARDs. • Once administered sulfapyridine is released (figure 9), which may reduce lymphocyte proliferation by interfering with folate metabolism and reducing cytokine production. • GI disturbances can occur that may be reduced by administration with food and using enteric coated preparations. • Sulfapyridine can cause blood dyscrasias and allergic reactions (sulfa/sulpha/sulfur drug allergies e.g., sulfonamide antibiotics). Fig. 12: Sulfasalazine 25 5PY022 Musculoskeletal System TBL Pack Glucocorticoids • Corticosteroids, so called because they are all naturally derived from the adrenal gland cortex, exert several powerful, important functions throughout the body. • The two main types of corticosteroids are the ‘mineralocorticoids’ (such as aldosterone), which regulate salt and water balance and the ‘glucocorticoids’ (such as hydrocortisone) which regulate the use of carbohydrate, fat and protein in the conventional stress response. • In addition to maintaining normal homeostatic mechanisms, natural and synthetic corticosteroids act as potent anti-inflammatory and immunosuppressant agents. • Hydrocortisone and prednisolone (which has predominantly glucocorticoid activity), are widely used for a variety of conditions where anti-inflammatory and/or immunosuppressive treatments are required, including autoimmune conditions such as RA, asthma and trauma. • In practice, synthetic drugs tend to be used clinically because they have less mineralocorticoid activity compared to natural glucocorticoids. Fig. 13: Prednisolone HO HO H H3C O CH3 H H OH H O • • • • • • • Glucocorticoids are an example of gene activating drugs. Generally they are lipid soluble, so they can diffuse into cells, where they will bind to glucocorticoid receptors in the cytoplasm, and the activated receptor/glucocorticoid complex enters the cell’s nucleus to regulate gene expression. This affects the production of mRNA, which in turn affects peptide synthesis. Glucocorticoids can induce the production of annexin-1 (lipocortin-1). This inhibits phospholipase A2 to produce a potent anti-inflammatory response, as all eicosanoid production (prostaglandins and leukotrienes) is affected and reduced amounts of arachidonic acid are liberated. Glucocorticoids can suppress the expression of phospholipase A2, COX-2 and the interleukin-2 receptor Glucocorticoids can reduce the number of leukocytes in the circulation Due to the profound actions that corticosteroids have on the body (as listed below in table 2), many adverse effects can occur with their use, especially at high doses. There is an increased risk of developing infections due to immunosuppression. Consequently, oral candidiasis (thrush) may occur when administering glucocorticoids by inhalation, due to the local suppression of the immune system. For this reason, pharmacists should instruct patients to rinse their mouths with water after using a corticosteroid inhaler such as beclometasone. 26 5PY022 Musculoskeletal System TBL Pack Table 7: The effects and adverse effects of corticosteroids ↑ = increases, ↓ = decreases in the effects and adverse effects seen • • • • • Corticosteroids Glucocorticoids Effects ↓ adrenocorticotropic hormone (ACTH) Adverse effects adrenal suppression ↑ infection susceptibility Mineralocorticoids ↓ immunological responses ↑ liver glycogen deposition ↑ gluconeogenesis ↑ glucose output from liver ↓ glucose utilization ↑ protein catabolism ↓ bone catabolism altered mood ↑ gastric acid and pepsin ↑ Na+ reabsorption diabetes muscle wasting osteoporosis psychosis peptic ulceration Na+ and H2O retention, hypokalaemia, hypertension, muscle weakness Adrenal suppression results from glucocorticoids having a negative feedback on the adrenal glands (as glucocorticoid levels rise in the blood, this is detected by the hypothalamus, which then causes the pituitary gland to secrete less adrenocorticotrophic hormone (ACTH) which then means that natural glucocorticoid synthesis in the adrenal cortex is reduced and blood levels fall). Sudden withdrawal following prolonged therapy should be avoided, and natural levels do not always rise back to normal levels until some considerable time after the steroid is stopped. Patients are therefore advised to carry a Steroid Card (see BNF). To avoid this problem, at the end of a prolonged treatment period, the dose is gradually tapered off, allowing the adrenal glands to start functioning again. Fluid retention can be a problem but is mostly associated with drugs having some mineralocorticoid activity. These drugs may also result in hypertension and hypokalaemia. Cushing’s syndrome is caused by an excess amount of released corticosteroid hormones, which may be due to over stimulation of the adrenal glands by excess ACTH being secreted from a pituitary tumour or by a tumour of the adrenal glands. High doses of glucocorticoids can also produce Cushing’s syndrome. Symptoms include: o Redistribution of body fat causing a rounded moon face, buffalo hump on the back and a pendulous abdomen o Plethoric (excess of any bodily fluid, especially blood) facial cheeks and catabolism of skeletal muscle causing spindly arms and legs o Thin skin resulting in poor wound healing, easy bruising and abdominal stria (stretch marks) o Osteoporosis Given the importance of these treatments, the corticosteroids will also be considered in the Respiratory System TBL pack and in much more detail in the Endocrine Systems TBL pack. 27 5PY022 Musculoskeletal System TBL Pack Diseases affecting Bone • Bone is constantly remodelled throughout life and a balance exists between bone reabsorption and bone formation, which run in cycles with each other (Figure 5): 1. 2. 3. 4. 5. 6. Fig. 14: Bone turnover • • • • • • • • • • Bone is comprised of calcium, phosphate and a protein meshwork. Serum Ca2+ ion concentration is controlled by parathyroid hormone (PTH) secreted from the parathyroid glands found behind the thyroid gland in the neck. PTH is secreted in response to low serum Ca2+ ion levels. It acts on the kidneys to reabsorb Ca2+ ions and to stimulate the activation of vitamin D. This fat-soluble vitamin is obtained from exposure to the sun, certain foods, and supplements but is biologically inert and must undergo two hydroxylations in the body for activation. Activated vitamin D (1,25-dihydoxycholecalciferol) promotes the absorption of dietary Ca2+ ions. PTH also acts directly on bone to mobilize Ca2+ ions (transfer Ca2+ from bone to the blood). Calcitonin, secreted from parafollicular cells (also known as C cells) in the thyroid gland, inhibits calcium mobilisation from bone and decreases reabsorption from the renal tubule. Osteoclasts are cells that reabsorb bone by “digging” pits, while osteoblasts secrete bone matrix into these pits, called osteoid. Osteoid is then mineralised, resulting in calcium phosphate crystals being deposited. Osteopenia is a reduction in the mineral content of bone, whereas osteoporosis is a reduction in actual bone mass. The onset of both of these conditions is often age-related and they can cause bones to fracture easily. The main causes of osteoporosis include: o Postmenopausal oestrogen deficiency o Age-related deterioration in bone homeostasis o Long term levothyroxine use. Subclinical hyperthyroidism may be associated with bone loss. To minimise the risk of osteoporosis, dosage of levothyroxine sodium should be titrated to the lowest possible effective level. You will learn more about thyroid disorders in the endocrine study pack. o Prolonged glucocorticoid therapy, with associated bone loss o Myeloma (a type of cancer that develops from cells in the bone marrow) 28 5PY022 Musculoskeletal System TBL Pack Osteoarthritis (OA) • • • • • • • Osteoarthritis refers to a clinical syndrome of synovial joint pain accompanied by varying degrees of functional limitation and reduced quality of life. It is the clinical manifestation of joint degeneration that results from loss of articular cartilage, remodelling of underlying bone, the formation of osteophytes [new bone at joint margins] and mild synovitis (inflammation) (see video below). Articular cartilage is the smooth, white tissue that covers the ends of bones where they come together to form joints. The severity of OA symptoms can vary greatly from person to person, and between different affected joints. Almost any joint can be affected but the condition most often causes problems in the knees, hips, and small joints of the hands. Pain, reduced function and effects on a person's ability to carry out their day-to-day activities can be important consequences of OA. Osteoarthritis is associated with increasing age although it not directly caused by ageing and does not necessarily deteriorate with time. There are multiple management and treatment options (both pharmacological and nonpharmacological), which represent effective interventions for controlling symptoms and improving function. OA can be diagnosed clinically without investigations if a person: o is 45 or over and o has activity-related joint pain and o has either no morning joint-related stiffness or morning stiffness that lasts no longer than 30 minutes. The National Institute for Health and Care Excellence (NICE) has produced a Clinical Knowledge Summary on the management of osteoarthritis, which can be accessed using the following link: https://cks.nice.org.uk/topics/osteoarthritis/ An overview of the management of osteoarthritis can be found on the NICE website using the following link: https://www.nice.org.uk/guidance/ng226 Make sure you know the main differences in pathophysiology between the two types of arthritis - it is important to appreciate the different characteristics of RA and OA. The following video describes the differences in symptoms between RA and OA: https://www.youtube.com/watch?v=H-OoyU8Gb_Q 29 5PY022 Musculoskeletal System TBL Pack Non-pharmacological management The following core treatments should be offered to all people with clinical osteoarthritis: • • • • Activity and exercise: people with OA should undertake exercise to strengthen muscles and improve general aerobic fitness irrespective of age, comorbidity, pain severity or disability Interventions to achieve weight loss if the person is overweight or obese Advice on appropriate footwear and assistive devices such as walking sticks and tap turners. The use of transcutaneous electrical nerve stimulation (TENS) can also be considered as an adjunct to core treatments for pain relief. Joint surgery should be considered for people with OA who experience joint symptoms (pain, stiffness and reduced function) that have a substantial impact on their quality of life and which cannot be managed by non-surgical treatment. Pharmacological management • There is emerging evidence that paracetamol may not be as effective at managing the pain of OA as alternative agents. • A Cochrane review on the evidence for the effectiveness of paracetamol in treating hip and knee OA was published in 2019. Cochrane is a British international charitable organisation formed to review medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. A link to the summary of the key results can be found using the following link: https://www.cochrane.org/CD013273/MUSKEL_paracetamol-treating-people-hip-or-kneeosteoarthritis • • Current guidance from NICE is that topical NSAIDs should be used first-line. Oral NSAIDS are recommended if treatment with a topical NSAID fails. o Consider risk of adverse effects o Co-prescribed gastro-protection with a PPI o Use the lowest effective dose for the shortest possible time PPIs will be covered in the gastrointestinal study pack • • • Paracetamol or a weak opioid may be used for short-term analgesia IF other pharmacological treatments are not clinically appropriate. Topical capsaicin may be used as an adjunct to core treatments for knee or hand osteoarthritis. Intra-articular corticosteroid injections may be considered for short term relief if other treatments are ineffective or not clinically appropriate. Herbal Remedies Herbal remedies such as glucosamine, turmeric and ginger are associated with a role in preventing degeneration. However, the evidence to support the use of herbal remedies is weak and further studies are required. Task 3: What would you advise a patient if they enquired about glucosamine supplements for osteoarthritis? Think about the language you would use. 30 5PY022 Musculoskeletal System TBL Pack Paracetamol • • • Paracetamol is often used as an analgesic and antipyretic, but it is not an NSAID and has very little inhibitory effect on COX-1 or COX-2 in peripheral tissues. It has an indirect inhibitory effect on COX-2 in the CNS by reducing the availability of essential co-substrates. It has some COX-3 activity, although this is not pharmacologically important. While it has good analgesic and antipyretic properties, paracetamol is not significantly antiinflammatory and it appears to be able to reduce prostaglandin synthesis in some situations, but not others. The COX-3 isoform appears to be more sensitive to paracetamol, indicating that COX-3 is not involved with inflammation. It is not certain, however, that COX-3 occurs in humans as it was originally discovered in canine brain tissue. Fig. 15: Paracetamol – Chemical structure and metabolic pathway in humans Paracetamol O 2 , CYP450 PAPS Sulfate UDPGA Glutathione Protein-SH Glucuronide Arylated protein Urinary Excretion DETOXIFICATION TOXIC Mercapturate 31 5PY022 • Musculoskeletal System TBL Pack Paracetamol is highly toxic to the liver in overdose which, combined with its ready availability, means pharmacists have a duty of care to manage the safe supply of paracetamol in healthcare settings. o Paracetamol is metabolised by the liver, where it undergoes conjugation with glucuronic acid and sulphate. o When toxic doses of paracetamol are taken (1015g), these pathways become saturated, leading to metabolism by cytochrome P450 enzymes (CYP2E1). o This leads to the production of toxic N-acetyl-pbenzoquinone, which can be inactivated by glutathione. However, once glutathione is depleted, N-acetyl-p-benzoquinone causes liver and kidney necrosis. o It is likely that no symptoms or nausea and vomiting will occur for 24 hours following the overdose, but irreversible liver damage usually reaches its peak by 72-96 hours. o Treatment depends on the time of patient presentation (to an Accident & Emergency department) and ideally N-acetylcysteine must be administered within 8-10 hours of ingestion. This speeds the replenishment of glutathione. o Once liver damage has become too severe, a liver transplant is the only realistic option to save the patient. Task 4: Complete the following table comparing RA and OA Characteristic Rheumatoid arthritis (RA) Age at which the condition starts Speed of onset Joint symptoms Pattern of joints that are affected Duration of morning stiffness Presence of symptoms affecting the whole body (systemic) 32 Osteoarthritis (OA) 5PY022 Musculoskeletal System TBL Pack Gout and Hyperuricaemia • • • • • Gout is a type of arthritis where crystals of sodium urate form inside and around joints. It usually presents as an acutely painful joint in the hands or feet, caused by the accumulation of uric acid crystals due to a defect in uric acid metabolism that causes excess uric acid and urates to accumulate in the bloodstream and joints. Uric acid is the end product of purine metabolism and normally two-thirds of the uric acid formed in the body each day is eliminated via the GI tract or the kidneys. Acute gouty arthritis can occur suddenly when crystals of sodium urate (tophi) are deposited in synovial tissue, skin and cartilage. This leads to an inflammatory response, where mediators like kinins and LTB4 are generated and neutrophils begin to accumulate, which try to engulf the crystals but release toxic oxygen metabolites (superoxide) and proteolytic enzymes. It is estimated that 1 in 45 people in the UK have gout, but it is more common in older adults affecting 1 in 7 older men and 1 in 6 older women. Gout symptoms usually occur after the age of 30 in men and in post-menopausal women (uric acid levels are generally lower in pre-menopausal women). The following video explains how gout affects the body, what treatments are available and why it is important to counsel patients with gout about lifestyle choices. https://www.youtube.com/watch?v=SH_ceFaKLA8 • • Raised urate concentration can result from consuming purine-rich food, a high alcohol intake, increased cell turnover and impaired uric acid excretion. Certain medications can cause an increase in uric acid levels and therefore the risk of developing gout. These include: o Thiazide-like diuretics o Other drugs used to treat hypertension, such as beta-blockers, ACE inhibitors and calcium channel blockers o Low dose aspirin (75mg) o Niacin (used to treat high cholesterol) (Most of these drugs will be covered in depth in the cardiovascular study pack) Acute drug treatments for gout include: • Naproxen or other NSAIDs (except for aspirin as it can inhibit nephron tubule excretion of uric acid in the urine, thereby making the situation worse). • Colchicine (figure 10) (Colchicum autumnale), derived from the autumn crocus plant) prevents the migration of neutrophils into joints, possibly by binding to tubulin, so microtubules depolymerise. Use of colchicine to treat an acute flare of gout is limited by the development of toxicity at higher doses (most commonly profuse diarrhoea, nausea and vomiting), but it is useful in patients with heart failure as, unlike NSAIDs, it does not cause fluid retention. Typical 33 5PY022 • Musculoskeletal System TBL Pack doses for the treatment of acute gout are 500 micrograms 2-4 times a day until symptoms are relieved, up to a maximum of 6 mg per course. The course should not be repeated within 3 days. Corticosteroids are also sometimes used to treat severe cases of gout in people who do not respond to other treatment or are unable to take or cannot tolerate an NSAID or colchicine. Prevention of further attacks of gout • Lifestyle choices to help prevent further attacks include avoiding excessive alcohol and foods high in purines; losing weight (if appropriate); taking regular exercise and maintaining adequate hydration. Drug treatments for established gout include: • Allopurinol: the enzyme xanthine oxidase converts hypoxanthine to uric acid via xanthine. Allopurinol (figure 11) is converted into alloxanthine by xanthine oxidase. Alloxanthine then non-competitively inhibits xanthine oxidase, so uric acid production decreases. The uric acid concentration decreases, which reverses the deposition of crystals. Allopurinol which is good for long-term treatment must not be initiated during an acute attack as it can exacerbate the acute, painful condition because the rapid reduction of uric acid levels to below the saturation point causes existing crystals in the joint cartilage to partially dissolve and become smaller. These smaller crystals can escape or ‘shed’ into the joint cavity and then inflame the synovium. Colc hicine 2 Allopurinol Fig. 17: Allopurinol Fig. 16: Colchicine 34