PBL 13: Bone pain Flashcards
Discuss the presentation, initial investigation, red flags, key differential diagnosis & initial management of bone pain
Presentation
Tenderness, discomfort or deep pain
Constant pain, can be dull and deep-seated
Muscle weakness
Widespread bone pain
Bone deformities
Fractures (fragility)
Sharp pain could mean a neuropathic aetiology.
Initial investigation
Blood test: FBC, U&E, ESR, calcium, phosphate, alkaline phosphatase and LFT
If high alkaline phosphatase is detected, isoenzymes may be required to discover whether this is from a liver or a bone source.
Vitamin D level
PTH level
X-ray may be necessary if the pain is localised to a specific area
CXR may be required if bronchogenic carcinoma is suspected.
A DEXA scan to assess bone mineral density.
Red Flags
History of malignancy
Weight loss
Night sweat
Night pain
Pain that is progressive/persistent
Any history of recent trauma
Symmetrical joint swelling
Key differential diagnosis
Rickets
Bone cancer
Metastatic cancer
Infection
Osteoporosis
Osteomalacia
OA, RA etc
Pagets
Osteoporosis
Initial treatment
NSAIDs for pain relief
Nutrition supplements - for those with osteoporosis and vitamin D deficiency
Antibiotics - for bone infections
Cancer treatments like surgery radiation therapy or chemotherapy
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of bony metastasis
Primary bone tumours
Bone: Osteosarcoma
Cartilage: Chondrosarcoma
Fibrous tissue: fibrosarcoma
Bone marrow: Ewing’s sarcoma / myeloma
Osteosarcoma - most common usually under the age of 20. Long bones - growth plate
Chondrosarcoma - half as common, in 40s painful and progressively. May arise from underlying benign lesions
Ewing’s tumour - very aggressive
Epidemiology
Patients that are most likely to get bone metastasis are those with these tumours:
Myeloma - (Bone marrow cancer)
Bronchus
Breast
Prostate
Kidney
Thyroid
Or any other - 10% have no identifiable primary but the list above is most common
Pathophysiology
Bone metastasis is a secondary tumour and a metastatic process is usually complete in 3 phases:
Break away of cancer cells from the primary tumour
Malignant potential of cancer cells is dependent on their capability to pass over the basement membrane and extracellular matrix, to break away from the primary tumour and invade surrounding tissues, which results in entry to the lymphatic system. This will allow them to reach the bone.
Adhesion to, and invasion into a distant organ
Stromal cell-derived factor 1 alpha is found in tissues localised in areas with widespread metastatic lesions.
This ligand demonstrates its affinity to a chemokine receptor which is expressed in higher amounts in especially breast and prostate cancer.
This allows prostate cancer cells to migrate from bone marrow to endothelial cells.
Another adhesion molecule αvβ3 integrin incorporates RGD (Arg-Gly-Asp) peptide sequence found in various extracellular matrix proteins which is important for the arrival of tumour cells to the target, and potential invasion of endosteum of bone tissue
Settlement in bone microenvironment
Osteolytic Bone disease:
Essentially causes the progressive destruction of bone.
Parathyroid hormone-related protein (PTHrP) concentration is locally increased in the bone as it is released from breast cancer cells.
This causes RANKL expression to increase and therefore inhibits the secretion of osteoblasts.
As there are now less osteoblasts, activated osteoclasts break down more of the bone. This then releases a transforming growth factor –β.
This growth factor then stimulates breast cancer cells introducing a vicious cycle.
Osteoblastic bone disease:
Factors released by prostate cancer and some types of breast cancer stimulate osteoblasts, which results in abnormal bone tissue.
Presentation
Pain - Red flag symptoms
Pathological fractures
Spinal cord compressions
Pain is usually worse at night and can be partially relieved by activity
However, the pain does then become more constant and is exacerbated by movement
May also have symptoms from primary tumour
Investigation
Serum biochemistry - high levels of alkaline phosphatase
Most sensitive way of detecting bone metastases is by an isotope bone scan.
However, the preferred method is plain x-ray films as lytic lesions may not be detected by a bone scan, also shows bone structure
CT good for structure
MRI for soft tissues
In patients with a single lesion it is very important to perform a biopsy to obtain a tissue diagnosis. This is due to primary bone tumours potentially looking very similar to metastases on x-ray
Management and Prognosis
The main goals of management are:
Pain relief - Intravenous bisphosphonates (pamidronate, zoledronic acid or denosumab) are widely used for bone metastases and are effective at improving pain and in reducing further skeletal related events, such as fractures and hypercalcaemia.
Preservation and restoration of function
Skeletal stabilisation - surgical intervention where there is evidence of skeletal instability (e.g. anterior or posterior spinal column fracture) or an impending fracture (e.g. a large lytic lesion on a weight-bearing bone with more than 50% cortical involvement).
Local tumour control - for prostate and breast hormonal therapy may help. Radiotherapy may also be useful for some patients. In some settings (breast carcinoma) chemotherapy can be used in the management of bone metastasis.
Orthopaedic treatment:
Intramedullary nails
Joint replacement
Plate / Screw constructs
Cement augmentation
This is for movement purposes only and they are unable to remove cancer from bone
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of pathological fractures
Pathological fractures → a broken bone that’s caused by a disease, rather than an injury.
Epidemiology
Osteoporosis causes more than 8.9 million fractures annually
Pathologic fractures occur in 8% to 30% of patients with bone metastases
Pathophysiology
Some diseases weaken bones which causes breaking
Presentation
Normally they share the same symptoms as an injury-related fracture
These can include:
Mild to severe pain near the broken bone
bruising, tenderness, and swelling near the broken bone
localised pain
tender on palpitation
inability to put weight on the injured area
Investigation
The clue to a pathological fracture is in the history and the radiograph.
history → frequently one of minimal trauma.
past medical history e.g. PMH of Adenocarcinoma (cancer in the glands that line your organs )may lead to the suspicion of bony metastases
Physical exam
X-RAY, MRI, CT, or nuclear bone scan
Blood count
Calcium, Vitamin D levels (osteomalacia)
Biopsies to check for tumours and/or infection
Management
Depends on the underlying cause
Pin, plate, or screw- depending on location
Rest
Surgery may be required if your ability to heal is affected
If the disease doesn’t affect the ability of the bone to heal then: cast or splint
Prognosis
Recovery can take anywhere from a couple of weeks to several months, depending on the affected body part
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of osteomalacia
Most common in people with vitamin D deficiency
Patients with malabsorption disorders (such as inflammatory bowel disease)
People who have a lack of exposure to sunlight without vitamin D supplementation
Pathophysiology
Osteomalacia occurs as a result of chronic secondary hyperparathyroidism, which is also accompanied by a long term vitamin D deficiency.
Sustained high PTH levels maintain normal levels of serum calcium by increasing bone resorption - this leads to progressive demineralisation of the skeleton.
Phosphate released in the resorption process is lost through increased renal excretion. The raised PTH levels stimulate osteoblast activity.
This causes new bone formation, but the matrix is not mineralised properly due to the lack of calcium and phosphate.
Therefore, the bone is soft and mechanically weak which can make fractures more common.
Presentation
Vitamin D deficiency in children
In adults:
Fractures
Low bone mineral density (BMD)
Bone pain
General malaise (General ill feeling)
Proximal muscle weakness
Walking with a waddling gait
Struggling to walk upstairs or stand up from a chair
Bone and muscle tenderness on pressure
Investigation
Measurement of serum 25(OH)D - this is the primary circulating form of vitamin D, PTH, Calcium, Phosphate and ALP.
ALP is raised
25(OH)D levels are undetectable
PTH is markedly elevated
Serum phosphate levels tend to be low
Serum calcium is usually normal unless the disease is advanced
X-rays often show osteopenia or vertebral crush fractures
In children there is thickening and widening of the epiphyseal plate
A radionuclide bone scan may show multiple hot spots in the ribs and pelvis at the site of fractures and the appearance may be mistaken for metastases
The diagnosis can be confirmed by bone biopsy, which shows the pathognomonic features of increased thickness and extent of osteoid seams
Management and Prognosis
Osteomalacia responds promptly to treatment with vitamin D.
Treatment between 10,000 and 25,000 IU daily for 2-4 weeks is associated with rapid clinical improvement, an elevation in 25(OH)D and a reduction in PTH.
Serum ALP levels may rise initially but eventually fall to within the reference range as the bone disease heals.
The dose of vitamin D can then be reduced to a maintenance level of 800-1600 IU daily, except in patients with malabsorption who require a higher dose.
Discuss the basic epidemiology, presentation, investigation, management and prognosis of osteomyelitis
Overview
· Refers to infection of the bone
· May occur for reasons such as: open fractures, skin ulcers, surgery, haematogenous spread of bacteria
· Staphylococcus aureus is the most commonly identified organism that causes the infection
Epidemiology
· More commonly affects people younger than 20 and adults over 50
Risk factors
· Immunosuppression
· HIV
· IV drug user
· Open fracture
· Surgery
· Diabetes
· Peripheral vascular disease
Causative Organisms
· Staphylococcus aureus => gram-positive cocci – incl. MRSA (Methicillin Resistant Staphylococcus Aureus) = penicillin resistant organism
· Pseudomonas aeruginosa => gram-negative rod – more commonly seen in IV drug users
· Salmonella => gram-negative rods – more commonly seen in patients with sickle cell anaemia
· Neisseria gonorrhoeae => gram-negative diplococci – seen in people sexually active
· Mycobacterium tuberculosis => acid fast bacilli – may cause osteomyelitis – characteristically in Pott’s disease (TB affecting the spine)
Presentation
· Deep bone pain
· Fever
· Erythema
· Swelling
· Signs of local inflammation
Investigations
· Blood tests normally show a non-specific rise in inflammatory markers
· Bedside => vital signs, blood sugar, urine dip
· Bloods => FBC, U&E, CRP, LFT, ESR, HbA1c
· Microbiology => urine MSU, blood cultures, wound swab, bone culture
Imaging
· Osteomyelitis normally diagnosed on MRI scans
· Terms used to refer to radiological evidence of underlying pathological findings:
o Sequestrum = refers to dead piece of devitalised bone that has been separated due to necrosis from the surrounding bone
o Involucrum = new growth of periosteal bone around a sequestrum
o Cloaca = opening in an involucrum that allows the internal necrotic bone and pus to discharge out
· X-ray:
o X-ray of suspected area should be taken in long bones including adjacent joints
o Not the most sensitive for osteomyelitis
o Bone may show:
- Local osteopenia
- Areas of bone lysis
- Cortical loss
- Periosteal reaction
o Sequestrum and involucrum may be seen in more advanced cases
· CT scan:
o Good at defining bone, small sequestrum, involucrum
o Significantly less sensitive than MRI for osteomyelitis
o More readily available + can be used to aid surgical planning but MRI usually preferred
· MRI scan:
o Good visualisation of both bone and surrounding soft tissue
o Bone marrow oedema may be seen very early on
o Nearby metalwork (possibly from prosthesis) can have an impact on the quality of the images
Management
· Two main methods: intravenous antibiotics + surgical debridement
· Antibiotics:
o When possible, should be held until bone cultures (or blood cultures + relevant tissue swabs) have been taken
o Courses tend to be a minimum of 4-6 weeks
o Treatment usually guided by microbiology based on suspected organism – updated if there are positive culture results
o E.g., once-daily ceftriaxone and vancomycin (vancomycin active against MRSA)
o Length of course dependent on many factors
o Patients require regular blood tests to monitor inflammatory markers + may need repeat imaging
· Surgery:
o Surgical debridement mostly used in non-haematogenous spread osteomyelitis
o Thoroughly cleaning wound + removing dead/infected tissue
o If there is surgical metalwork present in the body, it should be considered for removal which is decided by the senior orthopaedic/plastic surgeon
Prognosis
· In acute cases, there is usually a good outcome and majority of patients make a full recovery
· In chronic cases, surgical procedures are often need and sometimes can result in amputations
Discuss the basic epidemiology, pathophysiology, presentation, investigation, management and prognosis of osteopenia & osteoporosis
Osteoporosis
Definition
Systemic skeletal disease, low bone mass, deterioration of bone tissue. Increased bone fragility and susceptibility to fracture
Epidemiology and Risk Factors
Women, post menopause
Age/ previous fracture/ High BMI/ Smoking/ Low Bone Density/ family history
Co-morbities; Diabetes
Glucocorticoids, anticonvulsants
Presentation
None until fracture (spine, NOF, wrist common)
DXA T score < -2.5
Pathophysiology
Imbalance of osetoclastic and osteoblastic activity
Investigations
plain radiograph/ DXA scan/ blood tests (alkaline phosphatase, thyroid function, bone turnover markers (blood and urine))
Treatment
Diet (Vit D, Calcium)
Lifestyle - exercise to load bones/ reduce alcohol and smoking
Falls prevention interventions
Drugs: Bisohosphonates (Alendronate, Zolendronic acid)
calcium and Vit D supplements
Prognosis
no cure, just maintaining bone density to reduce risk of fractures
Osteopenia:
All the same. It is the stage before osteoperosis.
All the same barring: DXA T score < -1.0 to -2.5
Discuss the mechanisms of action of analgesics, their indications and contraindications and different routes of administration
Analgesics: painkillers
two types:
opioids - a class of drugs that derive from, or mimic, natural substances found in the opium poppy plant - morphine and codeine
Non-opioids - (acetaminophen (paracetamol) and NSAIDs, COX-2 inhibitors) - all work by blocking COX enzyme
Routes of administration:
- oral, sublingual, buccal, intranasal, inhaled, subcutaneous, intravenous, intramuscular, rectal, intramedullary, intrathecal, transdermal and topical
Mechanism of action of non-opioid analgesics
COX-1 enzyme produces prostaglandins (hormones that induce pain, inflammation etc) that help regulate normal physiological processes, such as maintaining gastric mucosal integrity and kidney function, therefore inhibition of COX-1 is thought to be responsible for the adverse effects of NSAIDs
COX-2 produces prostaglandins that mediate pain and inflammatory responses, therefore inhibition of COX-2 is thought to be responsible for some of the analgesic, anti-inflammatory, and antipyretic properties of NSAIDs
NSAIDs vary in how selective they are for COX-1 and COX-2 pathways. The degree of selectivity for COX-1 relative to COX-2 can be used to classify NSAIDs as:
Nonselective NSAIDs (includes most NSAIDs, such as diclofenac, ibuprofen, indomethacin, and naproxen). These act on both COX-1 and COX-2 enzymes.
Coxibs (for example celecoxib and etoricoxib). These are highly selective for COX-2 enzymes but can interact with COX-1 in certain circumstances.
Acetaminophen - mechanism of action isn’t completely understood, thought to inhibit the COX enzymes in the CNS - offers both analgesic and antipyretic (fever relieving) effects but does not treat inflammation.
NSAIDs (eg/ ibuprofen) selectively inhibit the COX-1 and COX-2 enzymes in the CNS and other parts of the body - analgesic, anti-inflammatory, and antipyretic effects - however can reduce some of the positive benefits of the COX enzyme on the GI tract, therefore can lead to side effects of indigestion, nausea and ulcers
With the exception of aspirin, NSAIDs can also significantly increase the risk of heart attack and stroke in people with a history of cardiac disease
COX-2 inhibitors (celebrex) - suppress only the COX-2 enzyme - educing pain and inflammation without triggering gastrointestinal side effects. However, as a class of drug, they are known to increase the risk of heart attack by 40%
Mechanism of action of opioid analgesics:
Bind to opioid receptors throughout the nervous system and GI tract
Opioid analgesics may be given orally, by injection or intrathecally to produce analgesia.
Regulate pain and trigger some psychoactive effects
Can be natural opioid alkaloids (morphine/codeine), semi-synthetic opioids (oxycodone, hydrocodone, hydromorphone, and oxymorphone), or fully synthetic opioids (pethidine , fentanyl , methadone , buprenorphine)
3 main opioid receptors - m,d,k (mu, delta, kappa)
Mu – analgesia, euphoria (but also constipation, respiratory depression)
Kappa – analgesic at periphery ( but dysphoria, hallucinations)
Delta –analgesia at spine?
Opioid receptors are G-protein coupled —> (3 subunits a, b and g - when opioid binds to receptor, the a subunit uncouples and produces a cellular effect)
They decrease Ca2+ entry by inhibiting Ca2+ entry and increase movement of K+ out of neurones by opening K+ channels
They also couple to adenylate cyclase then inhibit the breakdown of ATP into cAMP
These actions mean opioids inhibit neurotransmitter release:
Presynaptic action - inhibits neurotransmitter release at excitatory neurones and inhibitory neurones
This means they are also excitatory at post-synaptic neurones if the pre - synaptic neurone was inhibitory —> normally the release of neurotransmitter by the pre-synaptic nerve inhibits neurotransmitter release, so by the opiate inhibiting the pre-synaptic neurone the post-synaptic neurone would become excitatory
Pharmacological effects of morphine (all opioids contain or mimic the action of morphine) in practice:
CNS
Analgesia
Euphoria – particularly with iv adminstration
Sedation
Pupillary Constriction – stimulation of oculomotor nucleus brainstem
Gastrointestinal
Nausea and vomiting – chemoreceptor trigger zone in medulla
Constipation – from reduced motility and muscle tightening
Respiratory Depression – inhibits respiratory centres in brainstem
Suppress cough reflex
Safety problems:
Acutely – sedation, respiratory depression, vomiting
Chronic – constipation.
Tolerance with recurrent use:
Desensitisation of mu receptors
Increasing doses needed to achieve sufficient analgesia
Dependence causes problems with opioid withdrawal
Physical – restlessness, aggression, runny nose, diarrhoea, shivering
Psychological – cravings may persist months or years
Opioid receptor antagonists
Naloxone is most important drug
Reverses opioid actions on mu receptor.
Given iv/sc in acute opioid toxicity e.g. drowsy patient with small pupils and poor respiration.
However, can trigger acute physical withdrawal.
Other antagonists related to naloxone:
Methylnaltrexone, naloxegol – peripheral action to prevent GI problems with morphine
Naltrexone – aids detox in opioid and alcohol withdrawal programmes
Indications of analgesics:
Pain or inflammation
Acetaminophen:
Mild to moderate pain (eg/ acute sudden pain such as headaches or menstrual cramps)
Moderate to severe pain (alongside opioids)
Antipyretics
NSAIDs:
Mild to moderate pain associated with inflammation
Antipyretics
Opioids:
Moderate to severe pain (acute and chronic)
Contraindications of analgesics:
Acetaminophen:
Hypersensitivity
NSAIDs:
History of GI problems
Renal disease
Pregnancy
History of stroke and heart failure (excluding aspirin)
Opioids:
Respiratory problems
Mental instability/suicide risk
History of substance abuse
Intolerance to opioids
Renal or hepatic impairment
Neuropathic pain
Migraines or tension headaches
Discuss the basic epidemiology, presentation, investigation, management and prognosis of spinal fracture
Epidemiology:
Two Types - Acute Traumatic and Pathological
Most common is fragility crush fracture in osteoporotic bone (usually lumbar spine)
59.2% of cases are males
Commonly aged between 19-64
Most fractures occurred in the thoracic spine
Most common cause of injury was falling from height, then traffic accidents
Spinal cord injuries reported in 73% of patients
Presentation (of Thoracic Spine Fractures):
Pain
Shrinking and Becoming Round Shouldered
Kyphotic Deformity - Exaggerated, Forward Rounding of Back
Paraplegia - Paralysis of Legs and Lower Body Caused By Injuries to T6-T12
Spinal Shock - Period of Altered Distal Function resulting from Inadequate Tissue Perfusion due to Spinal Injury (Leads to Bradycardia and Hypotension)
Investigation:
Blood Tests
FBC & CRP - Test to Exclude Malignancy or Infection
Bone Profile - excludes metabolic causes of fracture
Serum Ca
Albumin
PTH
Phosphate
Alkaline Phosphatase
Mg
Serum 25(OH)D
Thyroid Screen
LFTs & U&Es e.g. Creatinine
Myeloma Screen
Imaging
CT Scan - Shows Bones & Soft Tissues e.g. Nerves. Allows doctors to look at cross-sections of the spine.
MRI Scan - Shows Soft Tissues like Discs and Nerves. Helps to distinguish between osteoporotic causes and tumour or infection causes.
X-Ray - Shows Bones and Fractures
Neurological Exam - To Test Reflexes For Nerve Damage
Management:
Conservative
Can be treated with bracing for 6 to 12 weeks
By gradually increasing physical activity and doing rehabilitation exercises, most patients avoid post-injury problems
Pharmacological
Analgesia e.g. morphine
Bisphosphonates or denosumab - for fragility fractures
Surgical
Balloon Kyphoplasty - use a balloon to inflate a space around the fracture. Then fill the space with cement. Used only for pathological fractures
Laminectomy - procedure used to decompress the spine by removing the bony arch called the lamina
Spinal Fusion - involves pedicle screws - can hold a fracture together & provide stability
Prognosis:
Majority of spinal fractures are treated effectively with full function and mobility restored
Complications Associated With Spinal Fractures:
DVT - these may develop during long periods of bed rest or immobility
PE - a blood clot that breaks free and travels to the lungs
Pneumonia
Pressure Sores
Complications Associated With Spinal Surgery:
Bleeding
Infection
Spinal Fluid Leaks
Instrument Failure
Wound Complications
Describe the main ways in which health care systems around the world are organised and funded
PUBLIC SECTOR:
This system is designed to provide the most benefit to the most people, however it can be inefficient and slow to change for different demands. It is organised by the government of a country and funded by general tax or public insurance. Healthcare is free for everyone at point of contact. Some examples of countries with public healthcare are: UK, Sweden, canada and Denmark.
PRIVATE SECTOR:
Deliver care for profit. Patients pay out of pocket or with private health insurance, where the cost is determined on the estimation of the future cost of healthcare for the person eg those with chronic conditions pay more. Many patients are uninsured and have to either decline treatment or go into massive debt.
NONGOVERNMENTAL ORGANISATIONS
Usually charities, usually operate in lower income countries where health needs aren’t being met. Usually providing free or much cheaper health care. Some criticisms of NGOs are that sometimes funding may disproportionately favour treatment for some diseases e.g. HIV leaving others in need without treatment. An example of an NGO is The bill and melinda gates foundation.
PATIENT GROUPS
These are groups of patients that can support research, educate patients or advocate to change policies and provide support services to patients. Their role is bridging the gap between patients and the healthcare industry. Eg patient groups can help recruit patients for a clinical trial or give a voice to patients or even just provide resources to patients.
INTERACTIONS
Most countries have a mix of all of these parts of healthcare
Describe the principles of tumour classification and explain the concepts of tumour grading and staging with reference to patient treatment and prognosis
SEE JOE MURPHY SLIDES FOR MORE
BENIGN: Stays localised Slow growing, remain similar to tissue, usually encapsulated. Small nucleus, all nuclei the same size, chromatin is encapsulated and evenly distributed.
MALIGNANT: Invades tissues and may metastasize, Fast growing, look different to original tissue large nuclei, chromatin is disordered and does not have a consistent margin.
Nomenclature:
Tumours can be classified with the histogenic classification which includes what kind of cell the tumour originated from and whether the tumour is malignant or benign
Eg the cell origin could be epithelial, connective tissue, lymphocyitic or haematopoietic (blood stem cell)
If a connective tissue cancer ends with ‘oma’ it’s benign but if it ends with ‘sarcoma’ then it is malignant
Classification: A tumour can be further classified by either stage or grade.
STAGE: Tumours are classed with the TNM staging system.
T is the size of the tumour and how much the tumour has spread into neighbouring tissue
T ranges from 1-4 where 4 is large and 1 is small
N is if there are any cancer cells in the neighbouring lymph nodes
N can range from 0-3 where 0 is no cancer cells and 3 is many lymph nodes containing cancer cells.
(lymph node spread is checked because it can be a good indicator if the the cancer has started to spread to other parts of the body especially if it’s unclear)
M is if the cancer has spread to another part of the body
0 is cancer hasn’t spread and 1 is it has.
GRADE: How different or abnormal the cells look under a microscope as well as how likely they are to be aggressive
Grade: The grade of a tumour usually ranges from 1-4
1- tumour looks almost likely healthy tissue- almost all the cells are differentiated to be the same kind as the tissue - unlikely to be aggressive
4- Completely undifferentiated cells that looking nothing like the surrounding tissue - very likely to grow quickly and spread faster than other cancers.
Discuss the pharmacology, therapeutic uses and side effects of opiods
Important Opioids
Opioid agonist → Morphine & Codeine
Antidote: Opioid Antagonist → Naloxone
Combination tablets → Co-Codamol
Pharmacology
All opioids bind to opioid receptors in the brain, spinal cord and gastrointestinal brain.
Some are endogenous (naturally produced) like endorphin, short for endogenous morphine.
Some are exogenous (not naturally produced) like heroin and morphine (from a poppy) and fentanyl (from a laboratory).
Normally, in the absence of endorphins, inhibitory neurons secrete a neurotransmitter that prevents nearby neurons from releasing the neurotransmitter dopamine.
During exercise, there is a release of endorphins which activate the three major opioid receptors located on the inhibitory neurons, called the mu, kappa, and delta receptors.
As endorphins bind to these receptors, they block the inhibitory neuron from releasing neurotransmitters, allowing the dopamine secreting neurons to freely unload dopamine.
The dopamine then gets picked up by a third neuron in the same area.
When dopamine release takes place in pain processing regions of the brain like the thalamus, brainstem, and spinal cord, the result is feeling less pain.
When dopamine release takes place in reward pathway regions like the ventral tegmental area, nucleus accumbens, and prefrontal cortex, the result is a calming effect that feels good.
Therapeutic uses
Pain (Acute and Chronic) such as Fractures and Heart Attacks
Opioid Use Disorder
Acute Diarrhoea (Codeine)
Dry and Painful Cough using Linctus
Given before a surgery
Side effects
Itching
Nausea and vomiting → Chemoreceptor Trigger zone in medulla
Constipation → From reduced motility and muscle tightening
Respiratory Depression → Inhibits brainstem respiratory centres
Drowsiness
Dry mouth
Paracetamol Overdose through the joint use of Co-Codamol and Paracetamol
Tolerance
Dependence
Discuss the role of vitamin D in bone metabolism
Vitamin D (in the form of dihydroxycholecalciferol) is a factor in controlling serum calcium levels.
Vitamin D is absorbed by sunlight predominantly, but can also be found in small quantities in some food, and can be taken as a supplement. This is in the form calciferol.
Then, it is converted to 25-dihydroxyvitamin D in the liver, then 1,25-dihydroxyvitamin D in the kidneys. The latter being the active component.
1,25-dihydroxyvitamin D is a stimulator of intestinal calcium and phosphate absorption, and is also a stimulator of bone resorption when at high concentrations. It is needed for proper bone mineralisation.
The action of 1,25-dihydroxyvitamin D leads to increased Ca2+ levels due to increased absorption. It can also stimulate the proliferation and activity of osteoblasts.
Therefore, Vit. D plays an integral role in calcium homeostasis, which involves the resorption and making of bone. Low vitamin D, means low Ca, which means more bone resorption to maintain [Ca], which means more bone resorption than building, meaning weaker bones.
Discuss the role of genetic changes in carcinogenesis
Carcinogenesis: The evolution of an invasive cancer from a normal cell.
How a normal cell evolves into an invasive cancer cell.
Therefore LO really is asking how genetic changes mean a normal cell becomes cancerous?
3 main changes that occur when a cell becomes tumorigenic:
Immortalization- leading to indefinite growth
Fails to follow normal growth constraints
Invasion- Invasion of normal tissue. Metastasis.
TP53 and MADR2 are two key tumour suppressor genes.
Normal cells have receptor proteins that enable them to respond to a corresponding set of signal molecules. Without these signals, most cells will undergo apoptosis, cancer cells won’t.
There are recessive genetic changes at the cellular level. This is in instances such as when the normal protein role of tumour suppressor genes loses function of both copies of these genes in cancer.
There are also dominant activations of oncogenes. Oncogene products play a role in pathways that regulate growth. With this, usually the change of function of only one allele is required to make a functional difference. Protein expressed usually has a lack of regulation, or increased activity.
There are also epigenetic changes. These do not alter the gene sequence but include DNA modifications such as methylation of the DNA. Heritable epigenetic changes in cancer lead to gene expression occurring in the wrong place at the wrong time.
The types of changes in a cancer genome:
Substitutions, deletion, insertion, copy number change, break points.
The first three do as the name suggests. Copy number change refers to a large number being deleted or copied. Break points refer to a genome being split and rearranged.
Mutations can occur due to environmental/lifestyle factors, or via the process of replication.
Vast majority are repaired. Some persist and have a functional effect, initiating cancer development. At each stage of development, a further mutation is required.
You get passenger and driver mutations.
Driver: Alteration in the genome of a cancer cell that gives it a fundamental growth advantage.
Passenger: No effect on the fitness of the cell. Happens to be in the same cell mutation as the driver gene. It is a ‘hitchhiker’.
