WEEK 3: Drugs in management of MSK disorders Flashcards
A 55-year-old female presents to the clinic for routine examination. X-ray outline absorptiometry
studies demonstrate abnormally decreased bone density in the lumbar vertebrae.
What is your tentative diagnosis?
Osteoporosis
A 55-year-old female presents to the clinic for routine examination. X-ray absorptiometry
studies demonstrate abnormally decreased bone
density in the lumbar vertebrae.
Name some examples of hormonal drugs used for tx her condition.
Hormonal agents
Parathyroid hormone (Teriparatide)
Calcitonin (Salcatonin)
Estrogen (Raloxifen)
Vitamin
PARATHYROID HORMONE
What is the trigger for PTH release?
Name the cells in the parathyroid gland that secrete PTH.
Describe the effect of PTH on bone.
A Recombinant form of parathyroid hormone. Administered subcutaneously once a day. Increased risk of osteosarcoma in rats.
State the drug name.
Synthesized and secreted by the chief cells of the parathyroid glands in response to decreased serum calcium.
Dual effect on the bone (Bone remodeling)
Continuous secretion (i.e. Hyperparathyroidism) = Bone resorption
Intermittent or pulsatile exposure+ Bone formation
Teriparatide
Name cells that secrete calcitonin in the thyroid in response to increased serum calcium.
State the function of calcitonin in bone.
Name synthetic salmon calcitonin which is more potent and longer acting than human calcitonin.
Calcitonin secreted by the parafollicular cells of the thyroid in response to increased serum calcium.
The major action of calcitonin is to inhibit osteoclastic bone resorption, which decreases the plasma Ca2+ concentration.
Salcatonin
Vitamin D2 and D3 are inactive.
What are their other names?
What are they activated into and where?
What is the function of Vitamin D?
State the main vitamin D preparation used clinically.
What other preparations are also available?
Otten prescribed with calcium supplements
State the effects of excessive chronic intake of vitamin D.
Vitamin D2 (ergocalciferol) and D3 (cholecalciferol) are inactive.
Activated to Calcifediol and calcitriol in the liver and the kidneys.
Vitamin D facilitates intestinal absorption of calcium.
The main vitamin D preparation used clinically is ergocalciferol.
Other preparations are alfacalcidol and calcitriol are also available.
Otten prescribed with calcium supplements
Excessive chronic intake may lead to hypercalcemia and calnosis
NB: Calnosis is deposits of calcium salt crystals in the skin and subcutaneous tissue.
SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM)
State the MOA of SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERM).
Raloxifene
Raloxifene is a selective estrogen receptor modulator (SERM) that exhibits both estrogenic and antiestrogenic effects in different tissues of the body. Its actions can vary depending on the tissue and type of receptor it interacts with.
Estrogenic effects in the bone.
Antiestrogenic effects in breast and endometrium
Increased risk of venous thromboembolism
Estrogen replacement ↑ risk of thrombotic events, endometrial and breast cancers
A 55-year-old female presents to the clinic for Routine examination.
The patient has a long history of rheumatoid arthritis and reports that she has been taking many medications for several years.
X-ray absorptiometry studies demonstrate abnormally decreased bone density in the lumbar vertebrae.
Which of the following is most likely
to have contributed to her
condition (osteoporosis)?
a) Aspirin
b) Paracetamol
c) Methotrexate
d) Prednisone
D
Describe the MOA of glucocorticoids.
What is the effect of long term therapy?
GLUCOCORTICOIDS
* Suppress the synthesis of Osteoprotegerin (osteoclastogenesis inhibitory factor)
- Stimulate Receptor activator of nuclear factor κ B (RANK)
- ↑ apoptosis of osteoblasts
Long term therapy predisposes to osteoporosis and fractures.
A 55-year-old female presents to the clinic for routine examination. X-ray absorptiometry
studies demonstrate abnormally decreased bone density in the lumbar vertebrae.
Name some examples of non-hormonal drugs used for treatment of osteoporosis.
Calcium supplements
Bisphosphonates
RANK ligand inhibitors
BISPHOSHONATES
State examples of bisphosphonates.
Describe their MOA.
State reasons for the following indication when using bisphosphonates.
*Take on an empty stomach.
*Take the drug with a glass full of water and remain upright for 30 minutes.
Pyrophosphate analogues (Etidronate, Ibandronate, Alendronate, Tiludronate, Risedronate, Zoledronate)
Bind to the hydroxyapatite crystals.
Suppress osteoclastic bone resorption.
Take on an empty stomach: As mentioned, bisphosphonates are best taken on an empty stomach to improve absorption. Food and certain medications can interfere with the absorption of bisphosphonates.
Take with a glass of water and remain upright: To minimize the risk of esophageal irritation, individuals taking bisphosphonates are advised to take the medication with a full glass of water and remain upright (sitting or standing) for at least 30 minutes after ingestion.
This helps prevent the drug from staying in the esophagus for an extended period, reducing the potential for irritation.
RANK LIGAND (RANKL) INHIBITOR
Describe the MOA of RANKL inhibitors.
Name a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand (RANKL) and blocks osteoclast activation.
State the effects of RANKL inhibitors.
RANK (Receptor Activator for NFKB)
RANK is activated by RANK ligand.
Maturation of pre-osteoclasts into osteoclasts.
Denosumab
Predisposes to infections!
Immunomodulation: RANKL and its receptor, RANK, are not only involved in bone remodeling but also play a role in the immune system. The inhibition of RANKL may affect the immune response, potentially leading to alterations in the immune system’s ability to combat infections.
Osteoclasts in Immune Surveillance: Osteoclasts, which are inhibited by RANKL inhibitors, are not only involved in bone resorption but may also play a role in immune surveillance. Suppression of osteoclast activity might impact the ability of the immune system to detect and respond to pathogens.
Mucosal and Skin Barriers: The integrity of mucosal and skin barriers is crucial for preventing infections. Bone remodeling, including the action of osteoclasts, can influence the maintenance of these barriers. Inhibition of osteoclasts by RANKL inhibitors may indirectly affect barrier functions, potentially making individuals more susceptible to infections.
A thin 55-year-old female presents to the clinic for routine examination. The patient has a long
history of rheumatoid arthritis and reports that
she has been taking many medications for
several years.
What triggers rheumatoid arthritis?
Genetic Factors:
There is a genetic component to rheumatoid arthritis, and individuals with a family history of the disease may be at a higher risk. Certain genetic markers, such as specific human leukocyte antigen (HLA) genes, have been associated with an increased susceptibility to RA.
Autoimmune Response:
Rheumatoid arthritis is considered an autoimmune disease, where the immune system mistakenly attacks healthy tissues, primarily the synovium (lining of the joints). The triggering event that sets off this autoimmune response is not well-defined, but it is believed to involve a combination of genetic predisposition and environmental factors.
Environmental Factors:
Various environmental factors may contribute to the development or exacerbation of rheumatoid arthritis. These can include infections (such as viral or bacterial infections), exposure to certain pollutants, smoking, and hormonal factors.
Infections:
Infections have been suggested as potential triggers for rheumatoid arthritis in some cases. Certain infections, such as those caused by viruses or bacteria, may contribute to the development of RA in individuals with a genetic predisposition.
Hormonal Factors:
Hormonal changes, particularly in women, have been associated with the onset or exacerbation of rheumatoid arthritis. The disease often starts or worsens in women around the time of menopause, suggesting a hormonal influence.
Describe the immunopathogenesis of rheumatoid arthritis.
Genetic Predisposition:
Genetic factors, particularly certain human leukocyte antigen (HLA) genes such as the HLA-DRB1 shared epitope, contribute to an increased susceptibility to rheumatoid arthritis. Individuals with specific genetic markers are more prone to developing RA in response to environmental triggers.
Environmental Triggers:
Various environmental factors, including infections and exposure to certain pollutants, are believed to act as triggers for the onset of rheumatoid arthritis. Infections may lead to an abnormal immune response, especially in genetically predisposed individuals.
Activation of Antigen-Presenting Cells (APCs):
Antigen-presenting cells, such as dendritic cells, phagocytize and process self-antigens or citrullinated proteins. These processed antigens are presented on the cell surface in association with HLA molecules.
CD4 T Cell Activation:
CD4+ T cells, also known as helper T cells, recognize the processed antigens presented by APCs. The interaction between the T cell receptor (TCR) on CD4 cells and the antigen-HLA complex activates CD4 T cells.
Release of Inflammatory Cytokines:
Activated CD4 T cells release pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). These cytokines play a central role in orchestrating the inflammatory response in RA.
B Cell Activation and Autoantibody Production:
In response to the pro-inflammatory cytokines, B cells are activated, leading to the production of autoantibodies. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are examples of autoantibodies commonly found in RA.
Immune Complex Formation:
Autoantibodies form immune complexes when they bind to self-antigens, including citrullinated proteins. These immune complexes circulate in the blood and deposit in the synovium, triggering inflammation.
Synovial Inflammation and Pannus Formation:
The immune complexes, along with activated immune cells (macrophages, neutrophils), contribute to persistent synovial inflammation. Pannus formation, an aggressive and invasive tissue, develops in the synovium and can lead to destruction of cartilage and bone.
Angiogenesis:
Chronic inflammation in the synovium induces angiogenesis, the formation of new blood vessels. This process is driven by pro-inflammatory cytokines and contributes to the supply of nutrients and oxygen to the inflamed synovium, sustaining the inflammatory response.
Osteoclast Activation:
The inflammatory environment, along with the presence of immune cells and pro-inflammatory cytokines, activates osteoclasts. Osteoclasts are responsible for bone resorption, contributing to the erosion of bone within the joint.
State the 3 main goals of treatment in rheumatoid arthritis.
State what is given for each goal.
To minimize pain.
Non-steroidal anti-inflammatory drugs (NSAIDs) Corticosteroids
To prevent progression of the disease.
Disease Modifying Antirheumatic Drugs
To help the patient remain as functional as possible.
Physical therapy
Occupational therapy
? Surgery
DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDs).
Describe the MOA of DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDs).
Heterologous group of agents defined by their use in rheumatoid arthritis to slow down disease progression.
Immunosuppressants or immunomodulators
They have slow onset of action, taking weeks-months to induce an effect.
Biologic and non-biologic agents
