Musculoskeletal conditions Flashcards
what does the Musculoskeletal system consists of?
- Bones
- Joints (Junction between 2 or more bones).
- Muscles
- Tendons (attach muscle to bone)
- Ligaments (attach bone to bone, and help stabilise joints)
- Cartilage and other connective tissues
what do NICE guidelines on low back pain and sciatica recommend?
1st line: exercise, e.g. stretching, strengthening, aerobics or yoga
then: NSAIDs: ibuprofen, aspirin (lowest dose).
Move on to weak opioids e.g. codeine.
surgery (prolapsed disks)
how does physiological Ageing affect the Musculoskeletal System in terms of bones, joints and muscle?
Bones: Loss of bone mass occurs >30 years in both men and women.
Loss accelerates post-menopause in women (oestrogen levels drop).
Joints: Joints stiffen with age as ligaments and tendons become more rigid.
Cartilage thins leading to increased friction/wear and tear (–> arthritis).
Muscle: Progressively lost from ~30yrs (sarcopenia), reduced mass and strength increases risk of injury.
what is the main symptom of most musculoskeletal conditions?
other symptoms?
Bone pain (trauma, infection, cancer): deep, penetrating or dull pain.
Muscle pain (trauma, inflammation, cramp/spasm etc): often less intense than bone pain but unpleasant.
Other joint and tendon/ligament pain (trauma, sprains, arthritis and so on): stiff, dull ache, less intense than bone pain; worse when moved and/or stretched.
swelling, bruising, inflammation, loss of movement
Musculoskeletal conditions- how is a patient diagnosed?
Observation of gait/movement of the patient.
Questions: pain with movement, at rest, at night, any trauma?
Physical examination (swelling, bruising, tenderness, heat).
Blood tests (biomarkers, inflammatory markers), computed tomography (CT) scans, X-ray
what are the functions of bone?
Support: provides a framework for attachment of muscles; gives us our ‘human shape’
Protection: protects internal organs from injury (i.e. rib cage, vertebrae and skull).
Movement: enables body movement by acting as levers and points of attachment for muscles.
Mineral storage: reservoir for calcium (99% of body’s calcium) and phosphorus (85% of body’s phosphorus).
Haematopoiesis: certain bones house bone marrow which is essential for production of blood cells (red and white, also platelets).
Energy storage: certain bones contain fats/lipids (yellow bone marrow).
what are the two types of bones?
Compact/Cortical bone: Hard, dense outer layer of bone (~80% of human skeleton) consisting of:
- Proteins (primarily type I collagen (95%) make up ~1/3 of bone mass.
- Hydroxyapatite (mostly calcium phosphate) makes up ~2/3 of bone mass.
Spongy/Cancellous/Trabeculae Bone:
- Porous and highly vascularised.
- Storage of bone marrow.
- Low density and strength (lattice-like, ‘honeycomb’ structure: i.e. trabeculae).
spongy bone structure
Less organized than compact bone.
Trabeculae align along positions of stress and exhibit extensive cross-bracing (important for providing bone reinforcement/strength).
(forms a lattice like structure within the layer of compact bone. The trabeculae align in a pattern that provides cross-bracing against the stresses that are placed on the bone. This cross-bracing structure is vital to provide bone strength. A loss of bone density is observed as we age and it is the loss of spongy bone in osteoporosis that leads to increased risk of fragility fractures. Someone with osteoporosis may break a bone doing something normal, like falling from a seated position in a chair onto the floor.)
define Bone remodelling
when does it occur?
the formation of new bone to replace old bone.
Occurs constantly in growing children to allow lengthening and thickening of bones.
Occurs in adults in response to: Trauma (fractures), Stress (i.e. weight bearing exercise), Metabolic changes (use or replenishment of e.g. calcium stores).
name 3 types of bone cells and their roles
Osteoblasts: bone formation.
Osteocytes: maintain and repair bone tissue: act as mechanosensors and orchestrators of the bone remodelling process.
Osteoclasts: bone resorption (breakdown).
what happens if there is an imbalance between bone resorption and formation?
can result in bone diseases
When osteoclast activity leads to greater breakdown of bone than new bone formation, you get conditions such as osteoporosis.
when osteoblasts lay down too much bone, you get conditions such as pagets disease/ osteomalacia
what are osteoblasts and how do they form new bones?
cuboidal cells located along the bone surface comprising 4–6% of the total resident bone cells
synthesis of bone matrix: osteoblasts secrete collagen proteins (mainly type I collagen) and proteoglycan.
Initiate calcification (sulphated proteoglycans immobilise calcium ions stored within matrix vesicles).
role of osteocytes?
location?
what happens if Osteocyte dies?
Comprise 90–95% of the total resident bone cells (derived from mesenchymal stem cell lineage through osteoblast differentiation).
Located within lacunae surrounded by mineralized bone matrix:
At end of a bone formation cycle, osteoblast subpopulation become osteocytes in the matrix.
Connected to other osteocytes (via their cytoplasmic processes) and bone surface via canaliculi.
Role to maintain bone by regulating mineral ion exchange.
Osteocyte dies, surrounding bone dies.
what are osteoclasts?
role?
how do they work?
Large multi-nucleated cells (originate from bone marrow).
Bone resorption: remove deteriorating bone or unnecessary new bone.
Secrete hydrogen ions to dissolve mineral matrix (i.e. hydroxyapatite crystals) and hydrolytic enzymes (e.g. collagenase) to degrade other components of bone
origins of bone cells?
Osteoblasts and osteocytes are differentiated from mescenchymal stem cells in the bone marrow
osteoclasts are differentiated from haematopoietic stem cells in the bone marrow.
define fracture
A break in a bone, commonly associated with injury surrounding tissues
what is the most common cause of fractures?
other causes?
trauma
underlying conditions such as osteoporosis, infections or bone tumours can weaken bones and make fractures more likely to occur.
symptoms of fractures
Pain.
Loss of function.
Deformity.
Crepitus (grating, popping, cracking sound and/or sensation).
Bleeding can occur from bone or surrounding tissues.
treatment of fractures
Immediate emergency treatment required:
- Immobilise and support limb, elevate, ice.
- Pain relief: not NSAIDs for frail or older adults (reports of delayed healing). Pain management in adults (16 years+): paracetamol, then move on to codeine.
- Open fractures need immediate treatment or surgery to clean and close wound. (a fracture when the bone has broken through the skin)
- Closed fractures less urgent but, until treated, patient experiences pain and loss of function. (Sometimes, swelling can make it difficult to see hairline or greenstick fractures so the limb might be supported and treatment delayed until swelling has subsided and a clear x-ray of the fracture can be taken)
Further treatment required:
- Immobilisation with casts or being placed in traction.
- Surgical fixation of fracture (using rods, plates, hip replacement).
tips for Living with a cast
Keep it dry. You can now get fiberglass casts with waterproof liners.
Never relieve itch with sharp or pointed objects. (could injure themselves and get an infection)
Check skin visible edge of cast for smell, redness or sores.
Rest with care to prevent cast chaffing or digging into skin; pad rough edges.
Elevate cast regularly to reduce risk of swelling.
Contact doctor if cast feels excessively tight or causes persistent pain.
name two complications that can arise with fractures
explain what they are, how they occur, symptoms and treatments.
Compartment Syndrome: serious limb-threatening condition caused by excessive swelling of injured muscles:
- Fibrous membrane surrounding muscle prevents expansion of swollen muscle and pressure builds within muscle.
- Pressure in muscle restricts blood flow and this leads to hypoxia, further injury of muscle and potentially death of muscle fibres.
- Symptoms: increasing pain in immobilised limb after fracture- Emergency medical treatment required!
- Surgery to relieve pressure in constricted tissue. If muscle/nerves have died, amputation might be necessary.
Pulmonary embolism: sudden blockage of an artery in the lung by a blood clot (usually travels from leg vein):
- Common fatal complication after serious hip and pelvic fractures, less common in lower leg fractures; very rare in fractures of upper body.
- Risk increased due to combination of trauma to leg, forced immobility and reduced blood flow in veins due to swelling
- Symptoms: chest pain, cough, shortness of breath- Emergency medical treatment required!
- In those at risk of pulmonary embolism, anticoagulants, i.e. heparin (often given together with warfarin), can be given to reduce the occurrence of blood clots.
what do joints consist of?
Consist of components that ensure stability and reduce risk of damage:
- Articular cartilage.
- Synovial membrane and fluid.
- Stabilising ligaments.
what additional features does a knee joint have?
Meniscus: a cushion of fibrous cartilage which ensures an even distribution of body weight on the joint.
Bursa(e): a fluid-filled sac (lined by synovial membrane) that provides a cushion between bone and tendons, or muscles around a joint.
Patella (knee cap): protects the knee joint.
Ligaments: connective tissue (collagen and elastin fibres) which provide stability (bone to bone), while allowing a range of movement.
what are tendons and what is their function?
Tough bands of connective tissue (made up mostly of collagen).
Attach muscle to bone.
Contained within a sheath and lubricated to allow movement without friction.
name the 3 types of muscle
skeletal, cardiac and smooth muscle.
Skeletal (Striated) Muscle:
Bundles of contractile fibres that are responsible for our movement and posture.
Attached to bones and arranged in opposing groups:
Biceps bend elbow, triceps straighten it.
Opposing arrangement ensures smoothness of movement and limits risk of damage.
Size and strength of muscle can increase/decrease with workload.
what are Satellite cells?
myogenic stem cells responsible for the post-natal growth, repair and maintenance of skeletal muscle.
Sporting injuries
- Strains:
- Sprains:
- Tendinitis:
- Shin splints:
Strains: Damaged/torn muscle, i.e. Hamstring.
Sprains: Damaged/torn ligaments, i.e. anterior cruciate ligament (ACL) injury.
Tendinitis: Inflammation of tendon.
Shin splints: Fractures of shin bone.
Sporting injuries: treatment
Self-care technique that helps reduce swelling, pain, and speed up healing.
Rest- Minimises internal bleeding and swelling, prevents further injury.
Ice- Cold reduces pain, inflammation and swelling. Ice (wrap in towel) 10 minutes, remove 10 minutes, ice 10 minutes, repeat for 60-90 minutes to prevent cold injury.
Compression- Reduce swelling and the risk of further injury.
Elevation- Reduce swelling (keep the area at or above the level of your heart).
give examples of Inflammatory arthritis diseases
cause?
symptoms?
inflammatory markers?
RA, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis
autoimmune disorders.
typically characterised by joint pain (and joint swelling) and joint stiffness in the morning and also after inactivity, lasting more than 30 min.
Synovial inflammation i.e. synovitis is a predominant feature.
Normochromic and normocytic anaemia: reduced numbers of normal-sized erythrocytes (red blood cells) with normal haemoglobin content which is associated with chronic disease.
Raised inflammatory markers: erythrocyte sedimentation rate (ESR) and also C reactive protein (CRP).
what is Rheumatoid arthritis?
symptoms?
mechanism that causes RA?
a chronic, disabling autoimmune disorder Characterised by synovitis (synovial inflammation) of small and large joints, destruction of cartilage and bone.
Gradual onset of symptoms most common; joint pain and swelling: flares, may alternate with periods of remission.
cause:
- Generalised, non-specific inflammatory response, localised tissue damage and release of neo-autoantigens leading to T cell activation (initiating event).
- B cells activated and produce autoantibodies (e.g. rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP)) which form immune complexes, bind to complement, stimulating neutrophils to produce pro-inflammatory cytokines (e.g. IL-1, TNF-alpha) and chemokines.
- Chronic inflammation seen in RA is maintained by e.g. rheumatoid factor and by continuous stimulation of macrophages which release pro-inflammatory cytokines and chemokines.
- In response to proinflammatory mediators, leukocytes and vascular cells are activated; T cells and other immune cells eventually extravasate from blood vessels into the synovium (the ‘inflammation zone’), where they are retained. New blood vessels formed.
- Synovial hyperplasia, tissue grows out over cartilage surface, and forms a pannus.
- Pannus destroys articular cartilage and subchondral bone, producing bony erosions.
- Subcutaneous rheumatoid nodules may form.
what are the clinical features of RA?
Insidious (gradual) onset of pain.
Early-morning stiffness (lasting more than 30 minutes).
Swelling in small joints of hands and feet (symmetrical).
Joint capsules are weakened leading to instability, subluxation (partial dislocation) and deformity.
Multiple joints may become involved: Wrists, elbows, shoulders, cervical spine, knees, ankles, feet.
Joint effusions (increased fluid in tissue surrounding the joint) and muscle wasting
RA: Non-articular features (tendons, ligaments, fascia):
Extra-articular features (beyond joints):
- Bursitis (inflammation/swelling of bursa).
- Tenosynovitis (inflammation of the lining of the tendon sheath around a tendon).
2
- Fever.
- Fatigue.
- Anaemia.
- Nodules (present in <30% of cases).
- Muscle wasting.
- Sjögren’s syndrome (dry eyes and mouth due to destruction of epithelial exocrine glands; can also affect joints- autoimmune disease).
- Carpal tunnel syndrome (median nerve compression: wrist).
urgent referral for RA
Small joints of hands or feet are affected.
one joint is affected.
Been a delay of > 3 months between onset of symptoms and seeking medical advice.
(even if normal acute-phase response, negative anti-CCP antibodies or rheumatoid factor, RF)
what investigations for diagnosis for RA should be carried out?
- investigations following diagnosis?
Offer blood test for rheumatoid factor in adults with suspected RA: have synovitis on clinical examination.
if negative for RF: Consider anti-cyclic citrullinated peptide (CCP) antibody measurement
X-ray the hands and feet (early in disease course) in adults with suspected RA and persistent synovitis: look for reduced joint space, erosion, deformities.
2.
If anti-CCP antibodies present, or bone erosions are seen on X-ray, emphasise the importance for individual to monitor their condition, and seek quick access to specialist care, if: Disease worsens or They have a flare.
what are Disease activity scores (DAS)?
target DAS in RA?
a measure used to assess response to treatment in RA: value is based on clinical assessment (e.g. number of swollen joints) and inflammation biomarkers (e.g. ESR, CRP). DAS28, remission: score of <2.6; low disease activity: score of ≤3.2.
Treat active RA in adults (or those at risk of developing RA) with the aim of achieving a target of remission, or low disease activity if remission is not achieved.
non-pharmacological management for RA
Adults with RA should have access to:
Specialist physiotherapy:
- Improve general fitness, encourage regular exercise.
- Learn exercises to enhance joint flexibility, muscle strength.
- Learn about short-term pain relief methods: transcutaneous electrical nerve stimulators (TENS) and wax baths.
Specialist Occupational therapy, if: Have issues with everyday activities or hand function.
Hand exercise programmes (delivered by practitioner), if:
- Not on a drug regimen.
- Have been on stable RA drug regimen for >3 months.
Podiatrist, if have foot problems (discuss e.g. insoles).
Psychological interventions, i.e. stress management.
Diet and complementary therapies, i.e. Mediterranean diet
Pharmacological treatments available for RA
Analgesics: non-steroidal anti-inflammatory drugs (NSAIDs).
Glucocorticoids (corticosteroids): e.g. prednisolone.
Disease-modifying anti-rheumatic drugs (DMARDs):
- ‘Traditional’ conventional synthetic DMARDs (cDMARDs and/or csDMARDs): methotrexate, sulfasalazine, leflunomide, gold salts, antimalarials (hydroxychloroquine), D-penicillamine.
- Biological DMARDs (bDMARDs): sarilumab, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab, abatacept, etc.
- Targeted synthetic DMARDs (tsDMARDs): tofacitinib (first Janus Kinase [JAK] inhibitor, ‘jakinibs’, approved for treatment of RA), fostamatinib, baricitinib, apremilast, etc.
what effect do NSAIDs/COX-2 inhibitors have in RA?
use?
Relieve pain and stiffness (i.e. used only for symptom control); they do not slow RA disease progression (i.e. are not DMARDs).
NSAIDs should be used at the lowest dose and for the shortest time possible (e.g. ibuprofen 200-400mg tbs).
Gastric protection is recommended: proton pump inhibitors e.g. lansoprazole.
Pain relief is rapid (full effect obtained within 1 week) but anti-inflammatory effect of NSAID(s) may take up to 3 weeks.
Slow-release preparation at night can help morning symptoms (stiffness).
what are corticosteroids used for in RA?
Concerns over long-term use?
Bridging treatment: glucocorticoids are used for a short period of time when a person is starting a new DMARD: intention is to improve symptoms while waiting for the new DMARD to take effect (as it can take 2-3 months).
Managing flares: Offer short-term treatment in adults with recent or established disease to rapidly decrease inflammation.
Long-term use of glucocorticoids: Only for those with established RA when long-term complications have been discussed, and when all other treatment options have been offered.
Concerns over long-term safety: infections, diabetes, osteoporosis, gastrointestinal and cardiovascular events.
Methotrexate (MTX) for RA
how does it work?
monitoring & adverse effects?
dose?
Folic acid analogue: inhibits dihydrofolate reductase, the rate-limiting enzyme in tetrahydrofolate production, which is required for purine and pyrimidine synthesis. Inhibiting DNA synthesis, it reduces cell division in immune cells (suppressing cell-mediated immunity).
Response often seen in 4-6 weeks
Careful monitoring is required to detect/prevent occurrence of serious adverse effects such as, blood disorders (some fatal), renal impairment, liver fibrosis or cirrhosis, pulmonary fibrosis: Full blood count, renal and liver function tests prior to, and repeated weekly until therapy is stabilised; every 2-3 months thereafter.
reduce risk of some adverse effects (especially mucosal or GI side effects) with a once weekly folic acid supplement (oral: 5 mg, dose to be taken on a different day to MTX dose).
Adults with moderate to severe RA: 7.5mg (oral) once weekly. max weekly dose of 20mg.
Adults with severe active RA: SC or IM injection: 7.5mg once weekly, 2.5mg incremental steps according to response. max weekly dose of 25mg.
Sulfasalazine for RA
action?
dose?
side effects?
monitoring?
Immunosuppressant actions
Initially 500mg daily (oral), increased in 500mg intervals weekly; max of 2-3g daily in divided doses.
Common side effects: GI disturbances, fever, headache, rashes, blood disorders; frequency not known: yellow discolouration of body fluids (tears).
Blood counts and liver function tests required monthly for first 3-6 months.
Folic acid supplements (same as for methotrexate) may be required to counteract impaired folic acid absorption.
Leflunomide for RA
action?
Severe adverse effects?
monitoring?
Common side effects?
cDMARD with immunosuppressant effects: potent inhibitor of pyrimidine synthesis which affects T cell proliferation and, thus, is immunomodulatory.
Licensed for moderate to severe active RA; therapeutic effect after 4-6 weeks.
Active metabolite of leflunomide persists for a long time (long half-life) which can be a concern if serious adverse effects are experienced.
Severe adverse effects include bone marrow toxicity, hepatotoxicity, increased risk of infection and malignancy.
Patients must be monitored; Blood counts and liver function.
Common side effects: GI disturbance, decreased appetite, hypertension, headache, dizziness, accelerated hair loss.
Antimalarials for RA
action?
example and dose?
adverse effects?
monitoring?
Direct anti-inflammatory effect by stabilising lysosomes, inhibiting the release of lysosomal enzymes, hence, inhibiting their inflammatory effects.
Hydroxychloroquine is used to treat RA of moderate inflammatory activity: Well tolerated with effect observed within 1-3 months.
200-400mg daily (oral), max 6.5 mg/kg per day (very toxic in overdosage!)
Antimalarials may cause retinopathy: ocular toxicity (keep to recommended doses):
Adults who have taken hydroxychloroquine > 5 years are recommended to be annual screened for potential retinopathy.
when are these drug used to treat RA and why are they not commonly used?
Ciclosporin
D-Penicillamine, azathioprine and gold
Chloroquine
Ciclosporin (immunosuppressant effects; licensed for severe active RA when conventional second-line therapy is inappropriate or ineffective).
D-Penicillamine, azathioprine and gold i.e. sodium aurothiomalate (licensed for severe active RA and latter for active progressive RA).
Chloroquine (antimalarial; licensed for treating inflammatory disorders but reserved for use if other drugs have failed).
Not as well tolerated, some take longer to reach clinical effectiveness, and adverse effects are common and can be serious (careful monitoring is necessary).
when are Biological DMARDs (bDMARDs) used?
Common side effects?
Used for highly active RA if patient has failed to respond to at least 2 cDMARDs (including methotrexate unless it is contraindicated): SC or IV injection.
Often given in combination with methotrexate (unless it is contraindicated).
Common side effects: increased risk of infections (caution in those exposed to tuberculosis; hepatitis B reactivation, septicaemia), dyslipidaemia, nausea, vomiting, abdominal pain, worsening heart failure, hypersensitivity, fever, headache, depression, injection site reactions, blood disorders (anaemia).
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy.
Targeted synthetic DMARDs (tsDMARDs):
when are they used?
side effects?
moa?
Oral, monotherapy (baricitinib, tofacitinib), or in combination with methotrexate for treatment of moderate to severe active RA in patients who had an inadequate response to, or who are intolerant to, one or more DMARDs.
Side effects: increased incidence of infection, hypercholesterolaemia (lipids), reduce lymphocyte numbers, lower haemoglobin levels.
JAK inhibition by tsDMARDs –> downstream block of cytokine production.
What is medicinal inorganic chemistry?
area of research concerned with metal ions and metal complexes and their clinical applications
a relatively new research area grown from the discovery of the anticancer agent cisplatin.
What is a transition metal?
Elements in groups 3-12 in the Periodic Table.
Presence of d-orbitals. Also called d-block elements.
elements with an incomplete d subshell or elements that can form a cation with an incomplete d subshell.
Characteristic properties of d-block metals
hard,
malleable
ductile
conduct electricity and heat.
Group 11: Coinage metals charecteristics?
Relatively inert, corrosion-resistant metals.
Excellent conductors of electricity and heat.
what are Cuproenzymes?
Enzyme examples?
Copper–dependant enzymes
Cupric (Cu2+) dominant form in human body compared to cuprous form (Cu+)
Enzyme examples:
Lysyl oxidase: cross-linking collagen and elastin (formation of blood vessels and heart)
Ceruloplasim: oxidation of ferrous to ferric ion
Superoxide dismutase
what is Wilson’s Disease?
treatment options?
Inherited Genetic disorder caused by Excessive copper built up in the body. Stored in: Liver –> liver cirrhosis. Brain –> brain damage
Treatment options:
- Chelation therapy: BAL, D-penicillamine
- Zinc supplementation
- Liver transplant
how does copper aid in wound healing?
Glycyl-L-histidyl-L-lysine (GHK): a Tripeptide that Binds to Cu2. Involved in wound healing. Secreted by mast cells in the skin.
GHK-Cu(II): Anti-inflammatory: protects tissue from oxidative injury after damage. and Activator for wound healing as activates tissue remodelling
GHK not very stable under physiological conditions
uses of silver (Ag)
mode of action?
(anti-bacterial activity - Inhibit growth of microorganisms. toxicity to human cells is considerably lower than to bacteria.
- Water disinfectant
- Silver nitrate (AgNO3) – wart treatment: Silver nitrate destroys tissue
- Silver(I) sulfadiazine- antiseptic: primarily on second- and third-degree burns.
Ag+ damages irreversibly key enzymes (lactate dehydrogenase and glutathione peroxidase) in the cell membranes of pathogens. Enzymes precipitation / inactivation (bacteria but not viruses).
Mode of action of silver dressing
Silver ions bind to the DNA of bacteria and bacterial spores, thus reducing their ability to replicate
The various silver-containing dressings differ in the way the Ag+ ions are released.
Mostly, Ag+ ions are released from the dressing through oxidation when the silver atoms come into contact with fluid
side effect of colloidal silver
Argyria: Built up of colloidal silver in body.
a bluish-grey discoloration of the skin, which is usually permanent.
Colloidal silver can also cause poor absorption of some drugs, such as certain antibiotics and thyroxine
Chrysotherapy
examples of drugs
The treatment of certain diseases, especially rheumatoid arthritis, with gold compounds.
Gold salts are believed to suppress cell-mediated immune reactions, reducing concentrations of Rheumatoid Factor and immunoglobulins
Given orally (auronofin) or intramuscularly (sodium aurothiomalate) for active progressive rheumatoid arthritis
Au(I)thiolates
- Solganol
- (Di)sodium aurothiomalate
- Aurothiopropanolsulphonate
- Sodium gold 4-amino-2-mercaptobenzoic acid
uranofin
Sodium aurothiomalate
Common side effects?
Main toxicity?
monitoring?
Counseling?
dose?
Common side effects include mouth ulcers, skin reactions, proteinuria, peripheral nephritis, pulmonary fibrosis, hepatotoxicity, alopecia
Main toxicity: Myelosuppression (bone marrow suppression)
Clinical monitoring required with full blood counts (FBC) and urine tests before each dose!
Discontinue gold therapy in case of presence of blood disorders (sudden and fatal), GI bleeding or proteinuria (>300mg/litre)
Counseling - tell patient to report any symptoms that might indicate side effect (breathlessness, cough, bruising/bleeding, rashes, sore throat, infection etc)
Start therapy with 10mg test dose to exclude hypersensitivity. Follow with 50mg IM weekly injections until response occurs. Benefit not expected until patient receives 300-500mg (6-10 weeks)
Once disease is controlled, interval between doses can be lengthened gradually to monthly injections and continue for up to 5 years of complete remission
If no response is observed after patient has received 1g, discontinue
Side effects of gold injections
Discoloration of skin.
Nausea and vomiting.
Metallic taste
Gold injections cause mouth sores in about a third of patients
Itching and rash (can be severe in some patients).
Kidney damage and decreased white blood cell count (rare) – bone marrow damage
Mode-of-action of Au-drugs
- In the blood stream, Au-drugs form a complex with albumin
- –> Au-drugs thiol groups exchanged with cystein-34 of albumin
- –> Au(I)-albumin complex formation
- Au(I)/albumin complex arrive at the site of action- synovial cavity
- Au(I) may enter the cell via thiol exchange reaction with membrane transport proteins.
- Once absorbed in the cell, Au(I) might interact with mitochondria inducing cell apoptosis.
Juvenile idiopathic arthritis
Treatment
Affects children under age of 16: autoimmune disease
NSAIDs to relieve pain and stiffness.
Methotrexate is effective. Sulfasalazine is an alternative
Corticosteroids may be required for systemic disease
Biologics (i.e. abatacept, adalimumab, etanercept and tocilizumab) dependent on age.
Crystal deposition diseases
Gout: monosodium urate monohydrate (MSU/MSUM) crystal deposition.
Pseudogout: calcium pyrophosphate dihydrate (CPPD) crystal deposition.
what is gout?
Risk factors?
Abnormality in either uric acid metabolism (excess) or excretion (hyperuricaemia), resulting in deposition of uric acid crystals, which cause intermittent attacks of acute joint pain.
Can result in tophi (white nodules) in skin and around joints.
Risk factors: family history, obesity, excess alcohol intake, high purine diet, diuretics, acute infection, ketosis, surgery. sustained hyperuricaemia.
causes of Hyperuricaemia
Impaired renal excretion: Idiopathic (unknown cause, spontaneous) primary gout, chronic renal disease, drug therapy (i.e. diuretics, low-dose aspirin, ciclosporin), hypertension, increased lactic acid production (intense exercise, alcohol, starvation), hyperparathyroidism, hypothyroidism, etc.
Increased production of uric acid: Increased purine turnover (i.e. myeloproliferative disorders, lymphoproliferative disorders i.e. leukaemia, other cancers, psoriasis), increased de novo purine synthesis (biochemical abnormalities).
Gout: diagnosis
Serum uric acid levels 408 μmol/L
monosodium urate crystals in synovial fluid (Definitive diagnosis)
Physical examination (joint pain and swelling, tophi), ultrasound, X-ray.
Gout management: pharmacological treatments
Naproxen
Drug class:
Mechanism of action:
Indication and dose:
Cautions and contra-indications:
Other drugs in the same class
Naproxen
Drug class: Non-steroidal anti-inflammatory drug (NSAID).
Mechanism of action: Irreversibly binds to cyclooxygenase (COX) enzymes in platelets, inactivating COX and preventing the production of prostaglandins (which normally promote the inflammatory response).
Indication and dose: acute gout; oral: initial dose of 750 mg, then 250 mg every 8 hours until attack has passed.
Cautions and contra-indications: Avoid if patient has history of hypersensitivity to aspirin and other NSAIDS.
- Avoid in patients with active GI ulceration or bleeding.
- Use with caution if patient has asthma.
- Use with caution with drugs that increase bleeding risk.
- Use with caution in elderly (i.e. use gastroprotective treatment).
- Increases risk of thrombotic events.
Other NSAIDs: ketoprofen, diclofenac sodium/potassium, etoricoxib,
Colchicine for gout
how does it work?
dose?
side effects?
An alkaloid extracted from autumn crocus. Prevents migration of neutrophils/phagocytes into gouty joints:
- Binds to tubulin resulting in depolymerisation of microtubules and reduced cell motility.
- Also, it prevents release of inflammatory mediators by preventing/limiting the phagocytosis of urate crystals.
Given orally, well tolerated: Acute gout attack (flares): 0.5mg, 2–4 times a day until symptoms relieved (e.g. pain is relieved), maximum 6mg per course. People with moderate renal impairment: lower starting dose, or longer duration between doses is recommended.
Avoid eating grapefruit or drinking grapefruit juice.
Side effects: largely GI disturbances (such as nausea, diarrhoea, vomiting, abdominal pain, etc), rhabdomyolysis (muscle damage).
Gout: prevention
Key aim in the treatment of gout is to reduce the plasma uric acid levels in order to prevent the recurrence of acute gouty attacks.
Withdraw diuretics and salicylates (e.g. do not use aspirin): Prescribe allopurinol
Lifestyle changes:
- Lose weight.
- Stop smoking.
- Reduce alcohol consumption.
- Do drink lots of water (unless otherwise advised).
- Dietary changes: Reduce total calorie and cholesterol intake. Avoid purine-rich foods (i.e. Offal, red meat, certain fish e.g. anchovies, sardines, shellfish, pulses such as lentils, peas and spinach).
who is Urate lowering therapy (ULT) recommended for in Gout: prevention/prophylaxis?
recommended for those with:
Recurrent attacks (>two a year).
Tophi.
Urate arthropathy (e.g. X-ray shows joint erosion), or
renal impairment.
(initial target of 360 μmol/L.)
which Drugs reduce serum uric acid levels are so are used to prevent gout attacks
Xanthine oxidase inhibitors: Allopurinol (first line therapy) and febuxostat (second line therapy) decrease uric acid production.
Uricosuric agents: (sulfinpyrazone) increases excretion of uric acid in urine. (Second line therapy)
Allopurinol, febuxostat and sulfinpyrazone should not be started during an acute attack; usually started 1–2 weeks after the attack has subsided:
Allopurinol
drug class:
Mechanism of action:
Indication and dose:
Cautions and contra-indications:
side effects:
Drug class: xanthine oxidase inhibitor.
Mechanism of action: analogue of hypoxanthine; a competitive inhibitor of xanthine oxidase, which decreases the conversion of naturally occurring hypoxanthine into uric acid.
Indication and dose: Prophylaxis of gout, oral: initial dose of 100 mg daily (preferably after food), for maintenance, dose adjusted according to plasma or urinary uric acid concentration (100 mg increments every four weeks, maximum 900 mg/day
Cautions and contra-indications:
Withdraw therapy immediately if get a rash (if mild, can retry with caution).
May precipitate an acute attack of gout.
Reverses tophi and renal stone formation, and can be used in patients with renal impairment.
Side effects: GI disturbance and allergic reactions (skin rashes and fever), fatal skin diseases (toxic epidermal necrolysis)!
what is pseudogout?
diagnosis?
treatment?
a type of inflammatory arthritis characterized by sudden attacks of pain and swelling in the joints (less common than gout). Most common in elderly people.
diagnosis:
Physical examination (joint pain and swelling, tophi)
Diagnosed is confirmed through presence of small ‘brick-shaped’ crystals in synovium; can also consider ultrasound, CT scans, MRI.
Blood tests may show raised white blood cell count, mineral imbalance, e.g. low levels of magnesium.
With X-ray may see crystals and calcification of articular cartilage (chondrocalcinosis).
treatment: rest, joint aspiration (relieve pressure), NSAIDs and colchicine
- Pseudogout does not require uric acid lowering meds like allopurinol!
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA)
what is it?
symptoms?
diagnosis?
treatment?
rare inflammatory rheumatological syndrome associated with abrupt onset of morning stiffness and pain in proximal muscles of neck, shoulder or pelvic girdle, stiffness is worse after rest. low-grade fever, weight loss, anorexia.
diagnosis:
blood tests indicating elevated inflammatory markers: erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP); creatinine kinase, calcium levels.
Temporal artery biopsy
Ultrasound; can consider MRI; emerging tests: interleukin (IL)-6 (for PMR).
treatment: glucocorticoids- Prednisolone (PMR 10-15mg daily). (GCA 40-60mg daily). rest and exercise.
Prednisolone
Drug class:
Mechanism of action:
Indication and dose:
Counselling and cautions:
Alternative?
Drug class: (systemic) corticosteroid; it is a glucocorticoid (GC).
Mechanism of action: Binds irreversibly to GC receptors, preventing them from binding to steroid response elements and modifying gene expression. The latter leads to systemic suppression of inflammation.
Indication and dose: PMR, initial dose of 10-15mg daily, oral, until remission of disease is achieved; then, reduce dose gradually to maintenance dose (usually 7.5-10mg daily).
Counselling and cautions:
Adrenal suppression can occur with long-term use, leading to inability of body to produce natural corticosteroids (i.e. cortisol).
Treatment should not be stopped abruptly!
Increase the risk of osteoporosis; consider prophylaxis.
Relapse is common if stop treatment for PMR prematurely (i.e. <2 years).
Alternative to oral prednisolone is intramuscular methylprednisolone:
what is Long-term steroid use associated with?
increased risk of osteoporosis/fracture, insomnia, muscle wasting, mood changes (euphoria, depression), growth suppression, infection (i.e. severe chicken pox), suppression of clinical symptoms of disease, diabetes, Cushing’s syndrome and adrenal atrophy, sodium and water retention, increased blood pressure, glaucoma
Corticosteroid/glucocorticoid- induced osteoporosis treatment?
consider bone-protective therapy for women and men aged >70 years, with a previous fragility fracture, or taking high glucocorticoids doses:
Bisphosphonates (alendronate and risedronate as first-line treatment).
Calcium/vitamin D supplementation (e.g. cholecalciferol/colecalciferol; if have severe/chronic kidney disease (CKD), consider calcitriol).
Hormone replacement therapy
what is Osteoarthritis characterised by?
Progressive destruction/loss of articular cartilage.
Changes in subchondral bone: accompanying periarticular bone response i.e. hardening (sclerosis) and refashioning of underlying bone and formation of osteophytes (bony projections).
Synovial inflammation (more aggressive in rheumatoid arthritis, RA).
Changes in periarticular muscle.
Pain (and stiffness).
Osteoarthritis disease progression:
Initial Repair
Early stage OA:
Intermediate stage OA:
Late stage OA:
Initial Repair: Proliferation of chondrocytes which synthesize the extracellular matrix (ECM) of bone.
Early stage OA: Degradation of ECM exceeds chondrocyte activity resulting in net breakdown and loss of articular cartilage in joint. Subchondral bone remodelling increases.
Intermediate stage OA: Failure of ECM synthesis and increased breakdown of cartilage.
Late stage OA:
Extreme or complete loss of articular cartilage, joint space narrowing.
Bony outgrowths (new bone) appear at joint margins (osteophytes).
Bone remodelling decreases, subchondral bone sclerosis increases and there is also weakness of periarticular muscles.
Pain and reduced joint movement.
OA versus RA
OA: Cartilage loss, eventually joint is ‘ground down’ due to injury/overuse.
RA: Overactive immune system, chronic inflammation (synovitis).
Osteoarthritis risk factors
Increasing age
Gender
Ethnicity
Genetic predisposition
Obesity
Physical (mechanical stress) and occupational factors (i.e. farmers).
Trauma (e.g. Joint injury; not giving enough time to heal).
Linked to other conditions (secondary arthritis).
Osteoarthritis symptoms
Joint pain (and stiffness):
- Commonly affects weight-bearing joints (hip, knee, spine), or hands (base of thumb).
- Asymmetry of joints affected is common.
- Pain is worse with movement (activity-related joint pain), no pain at rest.
- Morning stiffness in joint lasts for less than 30 minutes.
Synovial thickening (can lead to bone deformity).
Deformity of joint.
Bony swellings
- Heberden’s nodes: mostly occur on finger joints, near fingertip (also referred to as the distal interphalangeal joints).
- Bouchard’s nodes: on lower joints (proximal interphalangeal joints).
Joint Effusion (fluid around joint).
Muscle weakening or wasting (osteophytes may contribute via nerve compression).
Crepitus (sound/sensation i.e. crackling).
Limited joint movement.
Osteoarthritis diagnosis
if person:
- Is 45 or over.
- Has activity-related joint pain.
- Has either no morning joint-related stiffness, or has morning stiffness lasting no longer than 30 min.
If require further investigations (e.g. possible alternative diagnosis, like gout):
- X-ray: Narrowing of joint space. Bony protrusions (osteophytes). Bone sclerosis (abnormal bone density).
- Magnetic Resonance Imaging (MRI): Provides information about cartilage and peri-articular structures (tendons).
osteoarthritis treatment goals
OA management: advice on core treatments
Access to appropriate information (education): Increase understanding of OA and its management. Discuss footwear (if applicable).
Activity and exercise: Discuss benefit of local muscle strengthening, general aerobic fitness (builds up muscle strength and improves range of joint movement).
Interventions to achieve weight loss (if overweight/obese):
Assess lifestyle, offer advice on how to implement changes (explore eating patterns/diet and physical activity levels; helps protect affected weight-bearing joints).
Investigate environmental, social and family factors (i.e. family history of overweight/obesity) and if there are any comorbidities.
OA management: non-pharmacological treatments
Thermotherapy: use of local heat or cold.
Electrotherapy: use of TENS (transcutaneous electrical nerve stimulation) for pain relief.
Aids and devices (if required): bracing/joint supports/insoles; also, can consider walking sticks, tap turners.
Manual therapy: manipulation and stretching, particularly for OA of hip.
OA management: pharmacological treatments
Topical preparations of ibuprofen, ketoprofen, felbinac, piroxicam are available
Rubefacients can relieve pain in joints, tendons and muscles through mild counter-irritation of the skin: cause redness, dilate capillaries, thus, increasing blood flow to area.
Example: Capsaicin is licensed for the symptomatic relief of OA
what are Spondyloarthropathies?
Group of inflammatory rheumatic diseases, which include:
- Ankylosing spondylitis (AS).
- Psoriatic arthritis (PsA).
- Reactive arthritis.
- Enteropathic arthritis (associated with inflammatory bowel disease).
Ankylosing spondylitis
what is it?
diseases progression?
symptoms?
diagnosis?
chronic inflammation of the axial skeleton and large peripheral joints.
Insidious onset: presents as morning back stiffness/pain. Pain can improve with exercise, worse after rest.
Inflammation of sacroiliac joint (sacroiliitis) moves up the spine leading to symptoms.
Progression of disease leads to spinal fusion (ankylosis) that decreases spinal movement and can lead to spinal kyphosis, sacroiliac joint fusion, neck hyper-extension and rotation.
symptoms- Fatigue, Spinal pain, Joint pain/swelling, Areas of localized tenderness (i.e. enthesitis: inflammation of tendons/ligaments)., Morning stiffness.
diagnosis:
Refer to a rheumatologist if low back pain started before age of 45 years and has lasted for >3 months
sacroilitis on X-ray, back pain for >3 months, reduced spinal movement, limited chest expansion
AS management: pharmacological treatments
how is disease activity evaluated in Ankylosing Spondylitis?
- Bath Ankylosing Spondylitis Disease Activity Index (BASDAI):
- Score of ≥4 suggest suboptimal control and may require change in medical therapy.
- and, Spinal pain visual analogue scale (VAS).
Diclofenac sodium
Drug class:
Mechanism of action:
Indication and dose:
Cautions and contra-indications:
Other NSAIDs for Ankylosing spondylitis
Drug class: Non-steroidal anti-inflammatory drug (NSAID).
Mechanism of action: non-selective cyclooxygenase (COX)-2 inhibitor; inhibits COX enzymes leading to inhibition of prostaglandin synthesis and anti-inflammatory actions.
Indication and dose: pain and inflammation in rheumatic disease and other musculoskeletal disorders, by mouth: 75mg-150mg daily in divided doses, (modified release for Ankylosing spondylitis)
Cautions and contra-indications:
- Lowest effective dose; reviewed regularly.
- 150mg daily dose increases risk of thrombotic events.
- Maximum dose 150mg
- Combined use of aspirin and NSAIDs increase risk of GI damage.
- Contra-indicated in ischaemic heart disease, cerebrovascular disease, peripheral artery disease and mild to severe heart failure.
Other NSAIDs for AS: ibuprofen, meloxicam, phenylbutazone, celecoxib, etoricoxib, etc.
Psoriatic arthritis (pSa)
X-ray/MRI to confirm diagnosis
Pain and swelling in more than one joint; morning stiffness lasting >30min (similar to RA).
Dactylitis: swollen sausage-shaped fingers and toes
Enthesitis: inflammation at sites where ligaments or tendons attach to bone
Psoriatic arthritis treatment
Non-progressive monoarthritis: consider as monotherapy local corticosteroid injections.
Offer cDMARDs:
If max dose for 3 months and have no symptomatic relief: consider switching to, or combining with another cDMARD.
Consider oral NSAIDs as an adjunct to cDMARDs or bDMARDs to manage symptoms: NSAIDs at lowest effective dose for shortest possible period of time. Consider GI protective treatment.
If no symptomatic relief with NSAIDs, consider steroid injections (local or IM), or short-term oral steroid therapy as an adjunct to cDMARDs or bDMARDs to manage symptoms.
Leflunomide
use:
adverse effects:
pregnancy?
monitoring
side effects
Licensed for active Spondyloarthropathies (as well as RA): specialist use only.
Potent inhibitor of pyrimidine synthesis that affects T cell proliferation and, thus, is immunomodulatory.
Severe adverse effects include bone marrow toxicity, life-threatening hepatotoxicity, infection and malignancy.
Pregnancy must be excluded before treatment and effective contraception must be used during, and for at least 2 years after treatment in women; or 3 months in men
Patients must be monitored; Blood counts and liver function.
Other side effects: GI disturbance, hypertension, headache, dizziness, eczema, dry skin, rash.
Reactive arthritis
what is it
treatment
Form of inflammatory arthritis (peripheral SpA), occurs following infection:
- Gastrointestinal infection (Shigella, Salmonella, Campylobacter etc).
- Sexually-acquired (genitourinary) infection (i.e. Chlamydia).
persistent bacterial antigens in inflamed (but sterile) synovium of affected joints drive inflammation reaction.
Presents as acute arthritis (knees, ankles, feet) occurring within 4 weeks of an enteric or venereal infection; skin lesions resembling psoriasis.
Treat infections with antibiotics (after initial treatment do not offer this long-term, i.e. 4 weeks+). NSAIDs (ibuprofen) to reduce inflammation; for pain relief.
Acute condition resolves within a few months, but 50% patients go on to develop recurrent arthritis.
For treatment of severe and/or chronic condition consider corticosteroid or cDMARDs (i.e. sulfasalazine) treatment.
Enteropathic arthritis
treatment?
Arthritis (peripheral SpA) linked to inflammatory bowel disease:
Very difficult to treat/manage (revisit peripheral SpA drug treatment): NSAIDs (first-line) improve joint pain but aggravate bowel condition.
Osteoporosis
Osteoporosis classification
a progressive disease characterised by low bone density and the deterioration of bone microarchitecture which increases fracture risk.
Main treatment: Medication to strengthen bones. falls prevention. fracture treatment.
Normal: T-score > -1.
Osteopenia (reduced BMD, i.e. bone is weaker): T-score between -1 and -2.5 SD from mean.
Osteoporosis (greater risk of low-impact fractures): T-score ≤ -2.5 SD from mean.
Severe osteoporosis: T-score ≤ -2.5 SD from mean, and a history of previous fracture(s).
Osteoporosis risk factors
Age
Sex- women
Low BMI (<18.5kg/m2)
Untreated premature menopause (< age of 45), prolonged amenorrhoea or male hypogonadism:
Alcohol: People who consume >2 alcoholic drinks/day are associated with higher risk of hip fracture.
Smoking
Corticosteroid use (oral/long-term).
Conditions associated with prolonged immobility.
Genetics/family history of fractures/osteoporosis.
Other conditions/common comorbidities independently associated with bone loss (include: renal failure, inflammatory bowel or coeliac disease, hyperthyroidism, diabetes, rheumatoid arthritis, etc).
Other risk factors: Low vitamin D and calcium levels. Previous fracture. Ethnicity (Caucasian have higher risk).
Osteoporosis: non-pharmacological advice
Non-modifiable risk factors: previous fragility fracture, family history, untreated early (premature) menopause, etc.
Modifiable risk factors: smoking, alcohol intake, low BMI. Offer lifestyle advice to all:
- Stop smoking.
- Reduce alcohol intake.
- Advice weight-bearing exercise (may slow bone density decline), balance training, stretching etc (may reduce risk of falls).
- Balanced diet: achieve BMI between 20-25.
- Maintain adequate dietary levels of calcium (aim for 700mg/day).
- If vitamin D low/deficiency, discuss relevant supplements (prevention: 400IU daily; if deficient likely require higher doses).
Osteoporosis
define Fragility fracture (or low-impact fracture):
Primary prevention:
Secondary prevention:
Initial investigations:
Fragility fracture (or low-impact fracture): fracture caused by injury that is insufficient to fracture a normal bone (e.g. fall from standing height or lower).
Primary prevention: detect those at risk of osteoporosis based on clinical risk factors; determine whether (1) DXA, and then (2) pharmacological treatment is required. Aim: identify modifiable risk factors, reduce future fracture risk.
Secondary prevention: those who have fragility fracture(s) history, and are diagnosed with osteoporosis.
Initial investigations may include:
Assessment of fracture probability (FRAX, Qfracture).
Blood test: check calcium and vitamin D levels; also parathyroid hormone levels.
Scan/imaging: ultrasound, X-ray/DXA.
Osteoporosis: drugs
Anti-resorptives: reduce bone turnover by inhibiting osteoclast activity:
- Bisphosphonates: zoledronate (most potent), alendronate, risedronate, ibandronate, etidronate (least potent).
- Monoclonal antibodies: denosumab (first biologic) is a human anti-RANKL Ab (stands for: receptor activator of the nuclear factor kappa-B ligand).
- Hormonal modulators/therapies: HRT, tibolone (class: oestrogens), raloxifene (latter is an oestrogen agonist/antagonists, EAAs).
- first line alendronic acid or risendronate. alternative: zolendronic acid.
Anabolics: stimulate new bone formation by mobilising calcium from skeleton and re-depositing it; anabolics are given intermittently at small doses: Parathyroid hormone (PTH): teriparatide (is a recombinant human PTH analogue).
Anti-resorptive & anabolic: stimulate osteoblasts and inhibit osteoclasts: Strontium salts.
Bisphosphonates: mechanism
side effects:
cautions:
bisphosphonates are adsorbed onto hydroxyapatite crystals in bone, slowing both rate of growth and dissolution, thus, reducing the rate of bone turnover (i.e. anti-resorptive)
Simple bisphosphonates accumulate and cause osteoclast apoptosis (etidronate).
Nitrogen-containing bisphosphonates (i.e. alendronic acid) also interfere with attachment of osteoclast to bone (i.e. do not allow osteoclast ruffled border to form).
side effects:
- gastrointestinal side effects
- Alendronic acid and risedronate are associated with severe oesophageal reactions, including stricture, ulcers.
- PPIs shown to blunt effect of bisphosphonates
cautions:
Patients should not take dose at bedtime and should stay upright for at least 30 mins after taking dose.
Food should be avoided for at least 30 mins- food impairs absorption. Antacids, calcium salts and iron reduce absorption. Must be avoided in patients with renal impairment.
Osteonecrosis of jaw has been reported following bisphosphonates (most commonly if given IV [second line]; rare with oral dose.
Adequate oral hygiene should be maintained during and after treatment; any remedial dental work should be carried out prior to treatment.
Alendronic acid (alendronate)
Drug class:
Mechanism of action:
Indication and dose:
Counselling:
Drug class: bisphosphonate; nitrogen-containing, second generation.
Mechanism of action: Accumulates in bone and prevents bone resorption by inhibiting osteoclast attachment and survival (i.e. induces apoptosis in actively resorbing osteoclasts).
Indication and dose:
- Post-menopausal osteoporosis (10mg daily or 70mg once weekly).
- Osteoporosis in men (10mg daily).
- Prevention and treatment of corticosteroid-induced osteoporosis in post-menopausal women not taking HRT (10mg daily).
Counselling:
- Swallow tablets whole with plenty of water while sitting or standing.
- Take on an empty stomach at least 30 mins before breakfast (or another oral medicine).
- Patient should stand or sit upright for at least 30 mins after taking tablet.
Denosumab
Drug class:
Mechanism of action:
Indication and dose:
Counselling:
Drug class: biologic, human anti-Receptor Activator of NFkB ligand (RANKL) monoclonal antibody
Mechanism of action: Inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption.
Indication and dose: Osteoporosis in post-menopausal women, men at risk of fractures and for bone loss associated with long-term systemic glucocorticoid therapy in those at risk of fracture (60 mg every 6 months).
Counselling:
- Patients should report any new or unusual thigh, hip, or groin pain during treatment as atypical femoral fractures have occurred in patients receiving denosumab for 2.5 or more years
- Osteonecrosis of the jaw is common. Must see dentist before treatment for preventative dentistry. Must report any oral symptoms, maintain good oral hygiene and regular dental check-ups
- Serious risk of hypocalcaemia so patients should report muscle spasms, twitches, cramps, numbness or tingling in the fingers, toes, or around the mouth.
Raloxifene
use:
Class:
Agonist activity:
Contra-indications:
Side effects:
Raloxifene is licensed for the treatment and the prevention of postmenopausal osteoporosis (alternative to biphosphonates)
Class: selective oestrogen receptor modulator (SERM)
Raloxifene has selective agonist activity on bone and cardiovascular system and antagonist activity on mammary and uterine tissue.
Agonist activity: Inhibits bone resorption and bone turnover by preventing osteoclast recruitment, thus increasing BMD.
Increased risk of venous thromboembolism (VTE; discontinue if immobilised), worsening of pre-existing hypertriglycaeridemia/heart disease.
Contra-indications: history of thromboembolism, uterine bleeding, endometrial cancer, liver or renal impairment, pregnancy, breast feeding.
Side effects: peripheral oedema, leg cramps; uncommon/rare: VTE, menopausal symptoms (headache, hot flushes), GI disturbances, hypertension.
How do corticosteroids induce osteoporosis?
Excessive/supraphysiological pharmacological concentrations of GCs will affect osteoblasts, osteocytes, and osteoclasts. Predominant feature is suppression of osteoblast activity: GCs inhibit bone formation. This is achieved by: (1) inhibiting osteoblast differentiation, and maybe by (2) stimulating osteoclast activity.
GC treatment is considered the most common cause of secondary osteoporosis
BMD rapidly declines within 3-6 months of starting glucocorticoid therapy.
treating Corticosteroid/glucocorticoid -induced osteoporosis
Consider bone-protective therapy for women and men aged >70 years, with a previous fragility fracture, or taking high glucocorticoids doses (>7.5mg prednisolone daily):
- Bisphosphonates (alendronate and risedronate as first-line treatment).
- Calcium/vitamin D supplementation (e.g. cholecalciferol/colecalciferol; if have severe/chronic kidney disease (CKD), consider calcitriol).
- Hormone replacement therapy
what leads to Osteomalacia and Rickets?
Rickets (children) or osteomalacia (adults) is caused by a vitamin D deficiency. Lack of sunlight exposure (Vitamin D3/ colecalciferol), Lack of vitamin D in diet (Vitamin D2/ ergocalciferol)
Deficiency of vitamin D leads to decreased plasma calcium and phosphate levels, which impacts on bone
To increase plasma [Ca2+] levels caused by vitamin D deficiency, PTH levels increase, which leads to depletion of calcium stores in bone (de-mineralisation), which leads to their softening/weakening.
Osteomalacia and Rickets Symptoms
Bone Pain/tenderness
Skeletal deformity (bow legs, pigeon chest, spinal deformity (kyphosis, scoliosis) etc)
Pathological Fx
Dental deformities (delayed formation of teeth, increased cavities)
Muscular problems (progressive weakness, decreased muscle tone, cramps)
Impaired growth
Low calcium leading to numbness of extremities, hand or feet spasms or arrhythmias
Osteomalacia and Rickets causes
treatment?
Dietary deficiency - Particularly children with dark-skin living in northern climes
Age-related deficiency- Vitamin D metabolism decreases with age and many patients >80yrs are deficient
Secondary Rickets/osteomalacia- Deficiency due to another condition (i.e. malabsorption, liver disease, renal failure)
Vitamin D dependent rickets- Rare disorder arising due to lack of enzyme requires for metabolism of Vitamin D
Hypophosphataemic rickets (Vitamin D resistant rickets)- Caused by decreased renal resorption of phosphate
Treatment: Calcium and Vitamin D supplements
Paget’s disease of bone
what is it?
symptoms
Chronic bone disorder where areas of bone undergo accelerated bone remodelling due to hyperactivity of osteoblasts and osteoclasts.
Bones affected (commonly pelvis, femur, skull, tibia, vertebrae, clavicle or humerus) enlarge, becoming structurally abnormal and weaker than normal.
symptoms:
Bone pain: Deep aching (dull and/or shooting) pain, often worse by weight bearing that remains at rest/night); also joint pain, stiffness, swelling (if OA).
Bone enlargement:
- If skull affected, might result in hearing loss, dizziness/vertigo, tinnitus and headaches.
- If spine affected, might result in buckled vertebrae, loss of height, back pain, compressed nerves, tingling, numbness, etc.
- If pelvis, might see buckled legs, abnormal gait.
Bone deformity:
- Changes in adjacent joint structures might lead to osteoarthritis (OA).
- Bowing of affected weight bearing bones, often asymmetric.
Other complications:
- In rare cases can lead to hypercalcaemia.
- Heart failure (heart works harder due to more blood vessels than normal in new bone)
- Bone cancer (sarcoma) occurs in >1% of people with the disease (can spread rapidly).
Paget’s disease of bone: diagnosis and treatment
Diagnosis
- Blood test: elevated serum alkaline phosphatase.
- X-ray: evidence of bone reabsorption, bone enlargement, other bone deformities e.g. bowing.
- Bone scan: radioactive material is injected; it travels to the areas/bones most affected.
- Bone biopsy is the only way to confirm diagnosis but is rarely performed.
Non-pharmacological treatment: Exercise, physiotherapy, occupational therapy, walking-related devices. Ensure diet includes adequate levels of calcium and vitamin D.
Pharmacological treatment:
- Bisphosphonates slow disease progression: zoledronic acid (5mg single dose, IV), pamidronate disodium (30mg weekly for 6 weeks, IV), Risedronate sodium (30mg daily for 2 months, oral).
- Calcitonin if cannot tolerate/contra-indicated for bisphosphonates (given SC or IM).
- pain relief (e.g. paracetamol and ibuprofen).
- Calcium and vitamin D supplements (esp. if on bisphosphonate treatment, e.g. zoledronic acid).
explain drug release in a first-order model
what are Extended release dosage forms governed by?
In first-order model, drug release is dependent on the amount of drug available for release and therefore the rate of release declines exponentially with time.
Extended release dosage forms are governed by zero-order kinetics in which the rate of release is independent of amount of drug remaining in the dosage form.
Advantages of modified release formulations
Reduced dosing frequency-night dosing
Dose reduction- safety and cost
Improved patient compliance
A constant level of drug concentration in blood plasma
Reduced toxicity due to overdose
Reduces the fluctuation of peak-value
Disadvantages of modified release formulations
Possibility of dose dumping
Reduced potential for dose adjustment
Cost of single unit higher than conventional dosage forms
Increased potential for first-pass metabolism
Decreased systemic availability in comparison to immediate release conventional dosage forms
Poor in vitro and in vivo correlations
Physicochemical factors affecting extent/rate of drug release
Aqueous solubility: low solubility –> longer time to dissolve
Partition coefficient: High Log P –> may diffuse slower from device
Drug pKa and ionization at physiological pH –> May affect solubility/ diffusion
Drug stability –> hydrolysis, e.g. penicillin
Molecular weight and diffusivity: Large MW –> low diffusion
when is a drug not suitable for Sustained release drug delivery?
Characteristics that makes a drug unsuitable?
A drug which is extensively metabolized
A drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site of absorption or first-pass effect is poor candidate for SR delivery, as it could be difficult to maintain constant blood level.
unsuitable:
- Long elimination half-life, i.e., t1/2 >8 hrs
- Narrow therapeutic index
- Large dose
- Poor absorption
- Low or slow solubility
- Extensive first-pass clearance
Formulation methods used to manipulate the drug release profiles
Physical (Diffusion, Dissolution, Osmotic pump, Hydrodynamically balanced system)
Chemical (ion-exchange resin)
explain these Formulation methods used to manipulate the drug release…
Diffusion matrix reservoir
Dissolution matrix reservoir
Ion-exchange resins:
Osmotic drug delivery systems
Hydrodynamically balanced system
- Diffusion matrix reservoir: a water insoluble polymer is used to form a reservoir.
- Dissolution matrix reservoir: Eudragit polyerms (methacrylic acid derivatives) and soluble cellulose based polymers are used to coat the drug.
- Ion-exchange resins:
- Ion-exchange can be defined as an electrostatic interaction of ions between ions in solution and ion-exchange resins
- The ionic interactions are strongly dependent on the pH and the competing ions in the reaction medium
- The interaction can be exploited in oral drug delivery since the resin can carry the drug and release it in the gastrointestinal (GI) tract due to the pH change or the presence of competing ions.
- Drug molecules can attach onto the ionic groups with opposite charge through electrostatic interaction.
- Osmotic drug delivery systems: release drug at a rate that is independent of the pH and hydrodynamics of the external dissolution medium.
cellulose acetate and selectively permeable poly(glycolic acid), poly(lactic acid) derivatives, and Eudragits can be used as semipermeable film-forming materials.
- Hydrodynamically balanced system: use a dosage form with lower density pellets able to float on gastric contents and take longer to dissolve
* Single-unit dosage forms, containing one or more gel-forming hydrophilic polymers. HPMC, hydroxethyl cellulose (HEC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (NaCMC), polycarbophil, polyacrylate or alginic acid are commonly used excipients to develop these systems.
Can you crush the tablet?
What makes mAbs Monoclonal Antibodies special?
mAbs are proteins- therefore unstable (structural, chemical) BUT the antibody molecule is more stable than other therapeutic proteins.
Serum half-life far higher than most other therapeutic proteins-
Molecular weight higher than most other therapeutic proteins – bioavailibilty very limited except by i.v.
Factors that affect immunogenicity:
Type of biologics (proteins especially likely target)
Sequence origin (human safer)
Origin of protein (mammalian cells best)
Delivery e.g. Erythropoetin: subcutaneous = high risk
Formulation- (Aggregation driven by denaturation, surfaces, silicone oil, incorrect storage)
What is a biosimilar?
What is a generic drug?
biological function similar to ‘original approved drug’. Have to prove functionally equivalent by clinical evaluation.
- The manufacture, formulation and delivery of biosimilars has to achieve the same function and performance as the original approved medicine
Generic is chemically identical to branded drug
why are biologics Complex to manufacture?
Fragility of biological macromolecules
Sensitivity of the living cells that produce biologics
Therefore complex manufacturing requirements for: fermentation, aseptic processing, storage, testing.
what are the Three challenges for all biologics/ macromoleules?
Complexity of biologics higher than typical drugs
- Molecular complexity
- Functional complexity
- Complex composition
- More to go wrong, more expensive to manufacture
Instability of biomacromolecules inherent due to biological origin
- Conditions must be compatible with biological molecules
- BUT this means they are good food for microbes – or at least in a good environment
- Also, many reactions of biological molecules are thermodynamically favourable in these conditions
- Finally, almost all Biologics contain proteins- and proteins are relatively unstable
Availability often limited by large molecular size
Formulation methods of biomacromolecules and how they work
Sterilisation- Prevents microbial growth
Preservatives- Prevents microbial growth
Stabilisers- Reduces chemical and physical instabilities of proteins
Fridge- Reduces rate of chemical and microbial spoilage
Freezer- Reduces rate of chemical and microbial spoilage
Lyophilisation- Prevents aqueous phase degradation (hydrolysis etc.) and microbial growth
excipients used in the Formulation of biomacromolecules
Solubility-enhancers – not needed for many proteins.
Detergents – e.g. polysorbate 20 or 80, albumin. Prevent interface-induced unfolding
Buffers – phosphates, citrates
Preservatives – e.g. phenol, benylalcohol
Antioxidants – e.g. ascorbic acid, sulphites, cysteine
Lyprotectants – Non-reducing sugar added during removal of water to protect structure of protein.
Osmotic compounds: ensure isotonicity (sugars, NaCl)
problems with the delivery of biologics
Availability often limited by large molecular size
- Permeability through epithelia- won’t pass through epithelia or membranes.
- Access to tissues from blood vessels
- Cell membranes (although drug target usually not within cells)
Common problem- oral delivery unsuitable
Delivery of monoclonal antibodies
typically:
High dose needed- blocking or killing
High injection volume- can be too high for subcutaneous
Serum half life very long
Typically intravenous or [in some cases, if dose can be achieved] subcutaneous
biologic- Adalimumab
Rationale
How the drug works
Contrast
How the mAb was discovered/engineered/created
Rationale
- RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
- Target inflammation
How the drug works
- Neutralising very specific pro-inflammatory signalling molecule called TNF
- By creating an antibody that binds to TNF and clears it from circulation
Contrast
- Infliximab
- Both TNF inhibitor antibodies BUT differ in origin and sequence:
How the mAb was discovered/engineered/created
- Infliximab was a mouse antibody, engineered into human IgG sequence to avoid immunogenicity– CHIMERA - XI in name
- Adalimumab is a human antibody, selected using phage display
biologic- Etanercept
Rationale
How the drug works
Rationale
- RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
- Target inflammation
How the drug works
- Neutralising very specific pro-inflammatory TNF signal
- By taking RECEPTOR for TNF, and cutting the binding domain- to produce soluble high-affinity binding molecule that “mops up” TNF very specifically
biologic- Certolizumab pegol (Cimzia)
Rationale
How the drug works
How the drug differs
Rationale- Same as other TNF inhibitors
How the drug works- Neutralising TNF inflammation
How the drug differs
- Fragment of antibody that binds to TNF thereby blocking inflammatory signllaing
- However fragment alone loses the long half-life provided by the full IgG molecule (Fc portion)
- PEG chains added to antibody fragment to prolong serum stability
biologic- Toxilizumab
Rationale
How the drug works
Rationale
- RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
- TARGET INFLAMMATION but TNF is not the only inflammatory signalling molecule
- Target IL-6 – inhibit another protein involved in inflammatory signalling
How the drug works
- Neutralising/blocking signalling by very specific pro-inflammatory molecule called IL-6
- By creating antibody that binds to and blocks IL-6 receptor (tocilizumab) (AlSO others which block by binding IL-6 directly siltuximab (Sylvant)
biologic- Rituximab
Rationale
How the drug works
Rationale
- RA pathology – pain, joint damage, immobility all caused by inflammation driven by autoimmune response
- Target autoimmune disease process
How the drug works
- Killing B lymphocytes which are involved in autoimmune response
- By binding the CD20 molecule only found on surface of B cells, therapeutic mAb targets killing
