Musculoskeletal system

• Muscle pain in 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.
• In contraction, arterioles are being compressed, reducing the supply of blood and resulting in ischaemia.
  • A less intense but more prolonged sustained contracting may compress and block draining venules, but not affect arterioles.
    • Blood can flow to the affected area, but not drain out, causing swelling, discomfort, underperformance and a potential lack of muscle control. (Chronic exertional compartment syndrome CECS)
• Delayed onset muscle soreness (DOMS)
  • Muscle stiffness, pain, tenderness.
  • Eccentric exercise, when muscles develop a lot of tension, but instead of them shortening, they lengthen.
  • Can be caused by muscle damage and spasm, connective tissue damage, lactic acid, inflammation and enzyme efflux from damaged tissues.

• Work by interfering with the production of autacoids
  • Autacoids include eicosanoids, histamine, serotonin and nitric oxide.
  • Eicosanoids are not stored, they are generated.

Phospholipid

Phospholipase A2

Arachidonic acid           Lipoxygenase           Leukotrienes

Cyclo-oxygenase

Endoperoxides

               Prostaglandin isomerase        Thromoxane synthase   Prostacyclin synthase

Prostaglandins                                          Thromboxane A2                                     Prostacyclin

• Prostaglandins mediate the following effectsNSAIDs inhibit the COX enzymes, reducing the production of prostaglandins, meaning NSAIDs possess anti-inflammatory, anti-pyretic and analgesic properties.
  • Inflammation
    • PGE₂ and PGI₂ are generated locally and are both vasodilators, this increases blood flow to the affected area, resulting in increased redness and warmth.
  • Increase the action of histamine
    • increasing postcapillary venule permeability, enhancing swelling and oedema.
  • Pain
    • Sensitize afferent C nerve fibres to molecules such as bradykinin, increasing the pain felt.
  • Fever
    • Stimulate the thermoregulatory centre in the hypothalamus to mediate fever.
    • Endotoxins cause macrophages to release IL-1, stimulating E-type prostaglandin generation
• Some NSAIDs are selective inhibitors of the two different COX enzymes, giving them different profiles of therapeutic activity and side effects.

• Non-selective NSAIDs
  • Aspirin
  • Ibuprofen
  • Naproxen
  • Diclofenac
  • Indomethacin
• Inhibition of COX 1 can result in negative side effects such as the loss of the mucosal protective layer of the stomach
• Not generally effective in reducing visceral pain
• Do not halt the progression of chronic disease states
  • Pro-inflammatory leukotriene mediators are still being produced
• Most NSAIDs bind reversibly to the site in COX enzymes that accepts arachidonic acid
  • Except aspirin, which irreversibly inactivates the enzyme
  • Platelets are unable to produce thromboxane A2, and so thromboxane A2 receptors aren't stimulated, phospholipase C isn't stimulated and so no InsP3 is produced
  • Calcium ion levels do not rise and platelets remain inactive, reducing the viscosity of blood.

• Aspirin is very useful as an antiplatelet drug in sub-analgesic doses
  • As aspirin irreversibly inhibits COX1, normal platelet function only returns by producing new platelets
    • Platelet turnover is 7-10 days
    • Platelets are affected more than endothelial cells as platelets have no nucleus so cannot produce more COX1.
  • Aspirin has a considerabel first pass metabolism
    • Affects intestinal and hepatic blood but distribution around the rest of the body is limited
• Arterial thrombosis 
  • Anticoagulants aren't very effective
  • Antiplatelet drugs work better

• COX1 inhibition results in common GI disturbances
  • Gastric discomfort
  • Dyspepsia
  • Nausea
  • Vomiting
  • GI bleeding 
  • Ulceration
  • GI preforation
  • All effects are mediated by a reduction in prostaglandin formation 
    • Increased gastric acid production 
    • Reduction in gastric mucus secretion 
    • Vasodilation 
• Renal function reduced as PGE2 and PGI2 are involved with maintaining renal blood flow by dilating the renal artery 
  • Inhibition means blood flow is reduced, potentially leading to renal failure

• Skin rashes are common
• Can cause Stevens-Johnson syndrome and angioedema
  • Potentially fatal allergic reactions
• In asthma patients with reduced sensitivity to sympathomimetic agents, they can rely on prostaglandins to induce smooth muscle relaxation
  • Taking an NSAID inhibits prostaglandin production, potentially causing an asthma attack.
• Bone marrow disturbances
• Liver disorders
• Blood abnormalities

• Analgesic 
• Anti-inflammatory 
• Anti-pyretic
• NSAID use could inhibit the beneficial inflammation during recovery, delaying the healing of minor injuries
  • NSAIDs are only reccomended for a few days after surgery to enable natural healing of the body
• Can be used pre-emptively to allow athletes to train harder for longer
  • Use in this way can increase the risk of GI disturbances as well as other side effects
• Non-selective NSAIDs can have a higher selectivity for the inhibition of one COX ezyme over another.
  • COX1
    • Aspirin
    • Ibuprofen
    • Naproxen
    • Flurbiprofen
  • COX2
    • Diclofenac
    • Celecoxib

• The chemical structure of selective COX 2 inhibitors is larger than non-selective NSAIDs
  • COX2 binding sites contain a 'side pocket' that can accomodate larger molecules
  • COX1 has a narrower binding site, excluding selective COX2 inhibitors
  • Non-selective NSAIDs are small enough to fit into both binding sites. 
• COX2 inhibitors were mostly removed from the market as they were associated with a small increased risk of thrombotic events 
  • COX1 normally produces PGI2, which acts against any TxA2 released, preventing clot formation
  • During haemostasis, TxA2 production will overcome PGI2, forming a platelet plug
  • Following cardiac insult, it seems that COX2 is important in PGI2 formation
    • Inhibiting COX2 enzymes will cause PGI2 to fall, leaving more room for a clot to form
      • COX1 continues to produce TxA2

• Is not an NSAID as it has very little inhibitory effect on the COX enzymes in peripheral tissues
• Has an indirect inhibitory effect on COX2 in the CNS by reducing to availability of essential co-enzymes
• Has some COX3 activity
  • Is not thought to be phamacologically important
  • Insinuates that COX3 does not have a role in inflammation
• Has anti-pyretic and analgesic effects but no anti-inflammatory effects
  • Appears to be able to inhibit prostaglandin synthesis in some situations but not others
• Toxicity is a big issue (10g-15g)
  • Metabolism pathways become saturated in overdose, leading to metabolism by CYP450 enzymes
    • Leads to the production of a toxic substance which can be inactivated by glutathione
    • Once glutathione is depleated, this leads to liver and kidney necrosis
    • No symptoms will occur for 24 hours following OD
    • Irreversible liver damage reaches it's peak by 72-96 hours.
    • Ideally N-acetylcysteine must be administered within 8-10 hours of indegestionOnce liver damage becomes too sever a transplant is the only option to save the patient
      • Speeds up the production of glutathione

• Bone balances between bone reabsorption and bone formation
  • Osteoclasts reabsorb bones by 'digging' pits
  • Osteoblasts secrete osteoid into the pits which is mineralised, resulting in calcium phosphate crystals being deposited.
• Compromised of calcium, phosphate and a protein meshwork
• Serium calcium ion concentration is controlled by parathyroid hormone (PTH)
  • Secreted from the parathyroid glands beind the thyroid gland in the neck
  • PTH is secreted in response to low serum calcium ion levels
    • Acts on the kidneys to reabsorb calcium ions and stimulate the activation of vitamin D
      • VD is a fat soluble vitamin but is biologically inert so must undergo 2 hydroxylations for activation
      • Activated VD promotes the absorbtion of dietary calcium ions
    • PTH acts directly on bone to mobilize calcium ions
• Calcitonin sevreted from C cells in the thyroid gland inhibits calium mobility and decreases reabsorbtion from the renal tubule 

• Osteopenia
  • Reduction in the mineral content of bone
• Osteoporosis 
  • Reduction in actual bone mass
  • Main causes
    • Postmenopausal oestrogen deficiency
    • Age related deterioration in bone homeostasis
    • Long term levothyroxine use
      • Doses should be titrated to the lowest possible effective dose.
    • Prolonged glucocorticoid therapy
    • Myeloma 
• Estimated that 1 in 2 women and 1 in 5 men over 50 will suffer an osteroporosis related fracture

• HRT
  • Effective but not selective so can affect all body systems.
• Selecting estrogen receptor modulators (SERMs)
  • Have agonistic actions on some tissue and antagonistic action on others
  • Raloxifene has agonist action on bone and the CV system, antagonist action on mammary tissue
    • Increased osteoblast activity
    • Reduced osteoclast activity 
    • Extensive first pass metabolism so has a low bioavailability (2%)
    • Well distributed 
• PTH/PTH fragments (teriparatide)
  • Increase bone mass
  • Stimulate osteoblast numbers and decrease osteoblast apoptosis
  • Act on PTH1 receptors, activating adenylyl cyclase, PLA2, PLC and raised calcium ion levels
  • Given subcutaneously

• Bisphosphonates (alendronate and risedronate)
  • Act on osteoclasts to promote apoptosis
  • Given orally
  • Accumulate at the side of bone mineralisation
• Absorbtion can be impared by foods such as milk
  • bisphosphates can cause severe GI disturbances
  • Patients usually instructed to remain upright for 30 mins after taking the drug
    • Ensure the drug has passed into the stoamch to minimise ulceration of trachea

• Softening of the bones occurs
  • Causes the bones to bend if they are weight-bearing
• Absence of vitamin D leads to poor dietary calcium absorption
  • Results in hypocalcaemia
  • Can lead to skeletal and dental deformities
• In areas where vitamin D absobtion from sunlight is limited, these conditions are prevelent 
• Problems can be caused by overuse of suncream
• Prevention methods:
  • Increase dietary consumption of vitamin D
  • Increase exposure to sunlight 
• Vitamin D
  • Calcitriol (active form)
  • Ergocalciferol (inactive form)
  • Main unwanted effect is hypercalcaemia

• Joint pain accompanied by varying degrees of functional limitation
• Joint degeneration 
  • Results from loss of articular cartilage 
  • More common with increasing age
• Usually develops in people over 45
• Almost any joint can be affected
  • Most often found in knees, hips and hands
• Pain, reduced function and an effect on carrying out daily activities are consequences 
• Not caused by ageing and doesn't always deteriorate 
• Characterised by localised loss of cartilage, remodelling of adjacent bone and associated inflammation

• Can be diagnosed without investigation
  • 45 and over
  • Activity related joint pain AND no morning related stiffness or stiffness that lasts no longer than 30 mins
• Non-pharmacological management 
  • Activity and exercise to strengthen muscles 
  • Efforts towards weightloss if necessary
  • Advice on footwear and assistive devices
  • Transcutaneous electrical nerve stimulation (TENS) can be used as an adjunct to core pain relief treatments.
• Pharmacological management
  • Current NICE reccomendation is paracetamol and/or a topical NSAID
    • Should be considered ahead of oral NSAIDs, COX2 inhibitors or stronger analgesics (opioids)
    • Topical capsaicin in combination with core treatmenrs for knee or hand osteoarthritis 
  • If first line treatments are ineffective, oral NSAIDs/COX2 inhibitors can be considered Intra-articular corticosteroid injections for the relief of moderate to severe pain
    • A proton pump inhibitor must be co-prescribed
  • Joint surgery for people with joint pain that has a substatioal impact on quality of life and can't be managed non-surgically

• Progressive and severely debilitatingCan begin at any age
  • Rapid onset
• Painful swollen joints
• Is symmetrical and can affect small and large joints
• Morning stiffness lasts longer than an hour
• Patients are often fatigued and have a general ill feeling
• Proliferation of the synovium and destruction of joint cartilage and bone by osteoclasts
  • Inflammatory cytokines (interleukin 1 and tumour necrosis factor alpha) play an important pathogenic role
  • Acute-phase proteins 
    • Show a dramatic increase in concentration in response to alarm mediators released as a result of infection or tissue injury
    • Can act as pattern recognition molecules (recognise molecules found in pathogens) that are capable of binding to infectious agents and act as opsonins
• IgG or IgM rheumatoid factors are found in almost all RA patientsAs it progresses, can cause joint deformity and affect different organs of the body
  • They are autoantibodies
  • IgG can be an antigen and antibody 

• NSAIDs can provide symptomatic relief but do not alter the long term progression of the condition
• Diease modifying anti-rheumatic drugs (DMARDs) can produce long term suppression of inflammatory responses
  • Reduce joint swelling and tenderness
  • Slow progression rates of joint erosion and destruction
  • Improve levels of pain and disability 
  • Cause falls in plasma acute phase proteins and rheumatoid factor
  • Should be started soon after confirmed diagnosis
    • How a slow onset of action of about 3 months
    • NSAIDs can be used in the meantime to help with symptoms
    • NSAIDs can be stopped after 3 months
  • Briding treatment with a corticosteriod can be used instead of an NSAID
    • Oral, intramuscular, intra-articular
    • May also be given to rapidly decrease inflammation during flare ups
    • Long term corticosteroids are not reccomended due to long term adverse effects

• Suppress or modify immune responses
  • Means the patient is at risk of serious infection
• Methotrexate
  • Decreases the production of IL1 and TNF alpha cytokines
  • Increases the production of IL10 (inhibitory)
  • May also increase adenosine production
    • Acts as an anti-inflammatory paracrine
  • Can improve symptoms within a period of about 1 month
  • Treatment can be long term with appropriate monitoring
  • When used as a DMARD it is one dose per week
    • Accumulates intracellularly 
    • Potential fatal and severe adverse effects can occur
    • Comes with a methotrexate treatment booklet
      • What dose to take and what monitoring is required
    • Side effects
      • Nausea, stomatitis, blood dyscrasias, liver cirrhosis and pneumonitits.
    • Patients that develop breathing difficulties must be urged to seek urgent medical attention

• NSAIDs can reduce the renal clearence 
  • May also intefere with serum binding
  • These effects can result in toxicity
  • Patients should be carefully monitored when taking both
• Trimethoprim
  • When taken together, both drugs may suppress the bone marrow
    • Leading to agranulocytosis or neutrophenia which is life threatening
  • Should never be taken together
• Folic acid
  • Reduces the toxicity of treatment 
  • Improves continuation of therapy and compliance
  • Usually prescribed once weekly but shouldn't be taken on the same day as methotrexate
    • It antagonises the effectiveness of methotrexate

• Azathroprine
  • Prodrug that inhibits the productio of purines
  • Immunosuppresive and cytotoxic
  • Inhibits the proliferation of B and T lymphocytes
  • Has been used to stop transplant rejection
  • Inhibits both cell-mediated and antibody-mediated immune reactions
  • Side effects
    • Nausea, vomiting, diarrhoea, bone marrow suppression, liver toxicity and increased risk of infections/fever
    • Signs of marrow suppression
      • Unusual bleeding and bruising
      • Sore throat
• Sulfasalazine
  • Cheap and orally adminsitered 
  • Few side effects
  • Sulfapyridine is released which reduces lymphocyte proliferation 
    • By interfering with folate metabolism and reducing cytokine production
  • GI disturbances can occur, can be reduced by taking with food and an enteric coating
  • Can cause blood dyscrasias and allergic reaction

• Sodium aurothiomalate (intramuscular)/Auranofin (oral)
  • Salts made with gold
  • Unclear mechanism (suggested)
    • Inhibiting prostaglandin synthesis 
    • Deactivating complement
    • Disruption of major histocompatability complex (MHC)
    • Inhibition of IL1, IL2 and TNF alpha production
    • Reducing T lympocyte activity
    • Reducing phagocyte activity
    • Inhibiting neutrophil migration
  • Side effects
    • Rashes
    • Mouth ulcers
    • Flu like symptoms
    • Proteinuria
    • Thrombocytopenia 
    • Blood dyscrasias
    • Encephalophathy
    • Peripheral neuropathy
    • Hepatitis

• Antimalarials
  • Chloroquine
  • Hydroxycholoquine
  • Long half-lives as they're stored in tissues
    • Takes months to reach a steady state in the blood
    • Have a slow onset of action
  • Reserved only for mild RA as are not considered to be as effective as other DMARDs
  • Mechanisms may include
    • Inhibiting lysosomes
    • Inhibiting neutrophils
    • Suppressing phospholipase A2 activity
    • Inhibiting IL1 and TNF alpha production
  • Side effects
    • GI disturbances
    • Regular eye examinations required to detect possibly retinopathy
      • Can be counselled to wear sunglasses in sunlight

• Penicillamine
  • Derived from the hydrolysis of penicillin 
  • Mechanism
    • Reduce T lymphocyte activity 
    • Inhibit rheumatoid factor from binding to Ig
      • Preventing the formation of immune complexes 
  • Toxic enantomer (inhibits pyridoxine (vit B6) action)
  • Side effects
    • GI disturbances
    • Rashes
    • Stomatitis
    • Taste disturbances
  • Can be used in scenarios of metal poisioning 
    • Is a metal chelator
    • Taste buds contain zinc ions to which it may chelate

• Produced in a number of tissue or cell types rather than specialised glands
• Act locally as paracrine or autocrine molecules
• Common side effect is immune supression, increasing the risk of infection
  • Patients must report any signs of infection and stop therapy if a serious infection develops
  • Should not be given live vaccines during treatment 
• Target cytokines
• Have a similar efficacy to methotrexate, but when used in combination patient outcomes can improve by up to 50%
• Can be used on many diseases caused by the autoimmune system
• Derived from DNA or human antibodies
  • Expensive
• Tightly regulated by NICE
  • Usually only availble via specialised services with strict monitoring and surveillance 

• Adalimumab 
  • Antibodies which attach to circulating TNF alpha and stop it binding to it's receptor
  • Full human monoclonal
• Etanercept 
  • 'Mops up' excess TNF alpha to dampen immune responses
• Inflicimab
  • Antibodies which attach to circulating TNF alpha and stop it binding to it's receptor 
  • Chimeric monoclonal (mix of murine and human components)
• Anakinra
  • IL1 competitive antagonist
  • Similar efficacy and side effects to those mentioned above
  • Has to be given daily subcutaneously 
  • Should not be combined with TNF alpha supression as serious immune supression can result

• Naturally derived from adrenal gland cortex
• Maintain normal homeostatic mechanisms
• Powerful immunosuppresant and anti-inflammatories 
• Mineralocorticoids
  • Regulate salt and water balance
• Glucocorticoids
  • Regulate the use of carbs, fat and protein in the conventional stress response
• Tend to be used because the patient has less mineralcorticoid activity
• Prednisolone had predominantly glucocorticoid activity
• Used for a range of conditions where anti-inflammatory or immunosupressing activity is required
• An example of gene activating drugs
• Lipid soluble so highly mobile
  • Bind to glucocoritcoid receptors in the cytoplasm of cells
  • Activated complex then enters the nucleus to regulate gene expression
  • Affects production of mRNA, therefore affecting peptide synthesis

• Can induce the production of annexin-1.
  • Inhibits phospholipase A2, giving an anti-inflammatory property
• Can suppress the expression of phospholipase A2, COX2 and the interleukin 2 receptor
• Can reduce the number of leukocytes in circulation

• Oral candidasis can be common when administered by inhalation due to local immune supression
  • Instruct to wash their mouth after use 

• adrenal suppression

• Increased infection susceptibility 
• diabetes
• muscle wasting
• osteoporosis
• psychosis
• peptic ulceration
• Na⁺ and H₂O retention, hypokalaemia, hypertension, muscle weakness

• Have a negative feedback on adrenal glands resulting in adrenal supression
  • Hypothalamus detects increasing glucocorticoid levels, causing pituitary glad to secrete less ACTH, so natural synthesis is reduced and blood levels fall
  • Sudden withdrawal should be avoided
  • Natural levels don't always go back to normal for some considerable time
  • Steriod card
  • Phased dosage reduction
• Fluid retention
  • Mostly associated with drugs having some mineralocorticoid activity
• Hypertension 
• Hypokalaemia
• Cushing's syndrome
  • Excess amount of released corticosteroids
  • Side effects
    • Redistribution of body fat, moon face, buffalo hump. pendulous abdomen
    • Plethoric facial cheeks and catabolism of skeletal muscle, small arms/legs
    • Thin skin (poor wound healing, easy bruising and stretch marks)
    • Osteoporosis

• Type of arthritis where crystals of sodium urate form in and around joints
• Presents
  • Acutely painful joint in hands or feet
• Cause by the defect in uric acid metabolism
• Uric acid is the end product of purine metabolism
  • Around 2/3 of uric acid formed is eliminated via the GI tract or kidneys each day
• Around 1 in 45 people in the UK have gout
  • Affects 1 in 7 older men
  • 1 in 6 older women 
  • Symptoms usually occur after 30 in men and 60 in women
    • Uric acid levels are generally lower in pre-menopausal women
• Rise in urine concentration
  • Consuming purine rich food
  • High alcohol intake
  • Increased cell turnover
  • Impaired uric acid excretion 

• Can occur suddenly when crystals of sodium urate are deposited in synovial tissue, skin and cartilage
  • Leads to an inflammatory response where mediators (kinins and LTB4) are generated and neutrophils begin to accumulate which try to engulf the crystals
    • This releases toxic ixygen metabolites and proteolytic enzymes
• Medications can cause an increase in uric acid levels
  • Diurets
  • Hypertension drugs (beta blockers, ACE inhibitors and calcium channel blockers)
  • Low dose aspirin 
  • Niacin

• Acute
  • Naproxen or other NSAIDs (not aspirin)
  • Colchicine 
    • Prevents the migration of neutrophils to joints
    • Possibly binds to tubulin so microtubules depolymerise 
    • Use is limited by the development of toxicity at higher doses
      • Profuse diarrhoea, vomiting and nausea
    • Useful in patients with heart failure as unlike NSAIDs it does not cause fluid retention
    • Typical doses for acute gout is 500micrograms tds/qds until symptoms are relieved
      • Maximum of 6mg per course which should not be repeated within 3 days
  • Corticosteroids
    • For people who do not respond to other treatment or cannot tolerate NSAIDs or colchicine
• Prevention
  • Lowered alcohol intake
  • Lower purine intake
  • Losing weight where appropriate 
  • Regular exercise 
  • Maintaining hydration

• Established
  • Allopurinol
    • Prodrug converted to alloxanthine by the same enzyme that converts hypoxanthine to uric acid
    • Non-competitively inhibits the enzyme (xanthine oxidase), so uric acid production decreases
    • Good for long term treatment 
    • Must not be initiated during an acute attack as it can exacerbate the condition
      • Rapid reduction of uric acid causes the crystals to partially dissolve and become smaller
      • The crystals can then escape into the joint cavity causing inflammation of the synovium

• Leflunomide
  • Inhibits dihydroorate dehydrogenase 
    • Involved with pyramidine production, inhibits B and T lymphocyte proliferation
  • Administered orally and is activated by the liver
  • Active mrtabolite has a half life of 2-4 weeks
  • Liver damage is possible and it is also associated with Stevens Johnson syndrome