Drugs that affect the Musculoskeletal System

Question 1

What are NSAIDs?

Answer 1

Anti-inflammatory - Non-steroidal anti-inflammatory drugs (e.g. aspirin, ibuprofen, voltaren)

a) They are not steroids
b) They reduce pain associated with inflammation
1. Indications:
a) Headache (non-migraine)
b) Muscle aches and pain
c) Dysmenorrhea
d) Joint pain of osteoarthritis
2. Pharmacodynamics:
a) Inhibits inflammation by reducing pain - performed by blocking COX-1 and COX-2 enzymes to prevent synthesis of prostaglandins and thromboxanes
b) Also stabilise cell membranes to prevent further leakage of substances - reducing oedema
3. Adverse effects:
a) Nausea
b) Gastrointestinal distress, ulceration, bleeding
c) Vomiting
d) CNS stimulation
e) Headache
f) Vertigo
g) Mental confusion
h) Hypersensitivity reactions (rash, fever)
i) Hepatic damage (elevated serum enzymes)
j) Lowers GFR in kidneys
4. Drug interactions:
a) NSAIDs are highly bound to albumin and will displace other drugs from these binding sites causing increased concentrations of active drugs in blood such as oral anticoagulants (e.g. warfarin) and antibiotics, anticonvulsants, and methotrexate
b) Alcohols and barbiturates

Question 2

What are analgesics, anti-inflammatories, and anti-gout agents?

Answer 2

Non-narcotics

1. Comprised of drugs that reduce mild to moderate pain

Question 3

What are non-narcotic analgesics?

Answer 3

Anti-inflammatory drugs that reduce mild to moderate pain

1. Indications:
   a) Prevent or interrupt mild to moderate pain associated with inflammatory conditions without altering consciousness
   b) Treat joint pain (osteoarthritis, gout), muscle pain (myalgia), and headache (non-migraine)
   c) Elevated body temperature (fever)
2. Pharmacodynamics:
   a) Irreversible inhibition of COX 1 and COX 2 enzymes making them unable to bind arachidonic acid
   b) The enzymes can no longer convert arachidonic acid to prostaglandins and thromboxanes
   c) Inhibiting one or both of these relieves pain and inflammation
3. Types of non-narcotic analgesics:
   a) Paracetamol
   b) Salicylates (aspirin)
   c) Nonsteroidal anti-inflammatory drugs (NSAIDs)

Question 4

What is aspirin (salicylates)?

Answer 4

Non-narcotic analgesics

1. Pharmacological effects:
   a) Analgesic - reduce pain
   b) Antipyretic - reduces fever
   b) Increase peripheral blood flow (vasodilation)
   c) Anticoagulant - prophylactically inhibit clotting (anti-thrombotic)
   d) Anti-inflammatory
   2a. Pharmacodynamics at high dosage:
   a) Acetylates serine-529 active site preventing COX-1 and COX-2 from binding (causes a steric block)
   b) This prevents arachidonic acid from binding to its substrate and thus inhibits synthesis of prostaglandins (at high dosages)
   c) Aspirin also mediates anti-platelet effects via irreversible inhibition of platelet COX-1 and causes subsequent blockade of thromboxane A2

Question 5

Why is aspirin not used as an anti-inflammatory?

Answer 5

1. 3000-6000 mg is needed to obtain anti-inflammatory effect
   a) This is a very dangerously high dose
   b) 325 mg aspirin equates to 12-18 aspirin per day = very high
2. High dose aspirin leads to decreased prostaglandin production which decreases inflammation and oedema but still too risky
3. Creates very high risk of adverse effects including:
   a) Gastric upset, bleeding, and ulceration
   b) Nausea due to erosion of stomach lining
   c) Decrease prostaglandin cytoprotective effect
   d) Hepatoxicity (elevated serum levels)
   e) Hypersensitivity - rash, laryngeal oedema, asthma
4. Effects are caused because it is a secretalogue:
   a) Acetylsalicylic acid secreted inhibits goblet cells from producing mucous in stomach
   b) Leads to increase in gastric acid secretion from parietal cells
   c) Additionally, there is release of histamine, opening of calcium channels, inhibition of prostaglandins

Question 6

How do COX-2 specific inhibitors work?

Answer 6

NSAIDs

1. Pharmacological effects:
   a) Primarily induced at sites of inflammation and block production of pro-inflammatory prostaglandins
   b) Do not interfere with gastric mucosa (no associated GIT ulcers)
   c) Do not have anti-platelet activity (no GIT associated bleeding)
2. Limitations:
   a) More expensive
   b) Associated with significant increase in heart attacks and strokes with long term use

Question 7

What is the difference in COX1 and COX2 inhibtion? DIAGRAM

Answer 7

1. COX1 inhibition prevents clotting, reduces gastric mucosa, and reduces renal blood flow resulting in:
   a) Increased bleeding
   b) GIT ulcers
   c) Increase sodium retention
2. COX2 inhibition reduces temperature regulation, inflammatory cells, and pain sensitivity leading to:
   a) Decreased fever
   b) Decreased inflammation
   c) Decrease pain
3. However, long term use of COX2 increases risk of heart attack and stroke

Question 8

What is Ibuprofen?

Answer 8

NSAID

1. Pharmacokinetics:
   a) Longer duration of action than paracetamol
   b) Peak plasma levels achieved in 15-30 minutes of ingestion
   c) Rapid onset of action - beneficial for quick relief of pain
   d) Half-life of about 2 hours - must be taken every 6-8 hours to maintain effect
   e) Anti-inflammatory regimen requires 2400-3200 mg daily - sufficient analgesia achieved by daily dosage of less than 2400 mg daily
   f) Taken in 3 separate doses at meal times - decreased likelihood of gastric irritation
2. Adverse effects:
   a) 10-15% of individuals discontinue due to gastrointestinal symptoms (chronic use)

Question 9

What is Celecoxib?

Answer 9

NSAID - COX-2 inhibitor

1. Indications:
   a) Treatment of Barrett’s Oesophagus
2. Pharmacokinetics:
   a) 200 mg tablets
   b) Peak plasma levels = 3 hours
   c) Half-life approx. 11 hours
3. Adverse effects:
   a) Liver and kidney conditions
   b) Increased risk of CV events

Question 10

What are clinical indications of Anti-gout drugs?

Answer 10

1. Indications:
   a) Treatment of gout
   i) Special inflammatory condition in which uric acid deposits in the joint fluid of the toes, knees, or kidneys because uric acid is overproduced or not efficiently excreted
   ii) Phagocytes attempt to digest the uric acid crystals and set up a cycle of localised inflammation
2. Types of anti-gout drugs:
   a) Acute treatment - colchicine, aspirin, voltaren, indomethacin
   b) Prophylaxis
   i) Allopurinol blocks uric acid production
   ii) Probenecid for uric acid excretion
   iii) Sulfinpyrazone for uric acid secretion

Question 11

What is Indomethacin?

Answer 11

Anti-gout drug - Selectivity COX-1

1. Indication:
   a) Effective in rheumatoid arthritis, ankylosing spondylitis, and gout
   b) Not recommended for use as simple analgesic or antipyretic due to potentially severe adverse effects
2. Adverse effects:
   a) Bleeding
   b) Nausea and vomiting
3. Pharmacokinetics:
   a) 90% protein bound
   b) Absorbed well orally
   c) Metabolised by liver, excreted by kidney
   d) Plasma half-life of 2-5 hours
   e) Dosages of 25-75 mg
4. Pharmacodynamics:
   a) Highly potent inhibitor of PG synthesis - decrease in neutrophils

Question 12

What are immunomodulatory agents?

Answer 12

1. Two types:
   a) Immunosuppressive drugs - reduce activity of the immune system
   b) Immunostimulant drugs - increase ability of the body to resist infection and growth of abnormal cancer cells

Question 13

What are antihistamines?

Answer 13

1. Pharmacodynamics:
   a) Compete with histamines for the receptor sites on H1 receptors
   b) Antihistamine binds to H1 receptor and eliminate histamine action - H1 antagonist
2. Pharmacological effect:
   a) Antihistaminic - selectively block histamine at Histamine-1 receptor sites leading to decreased cellular response
   b) Anticholinergic - relax smooth muscle, decrease secretion
   c) Sedative

Question 14

What are the indications of immunosuppressants?

Answer 14

1. Organ transplantion (allografts) to prevent rejection
2. Dampen inappropriate or over activation of immune system
3. Control autoimmune diseases (e.g. Rheumatoid arthritis)
4. Control Chronic inflammatory disease (e.g. IBD)

Question 15

What are corticosteroid drugs?

Answer 15

Anti-inflammatory and immunomodulatory agent (immunosuppressant) - e.g. Prednisone, Prednisolone, Dexamethasone, Methylprednisolone

1. Indication:
   a) Used to suppress immune system in severe allergy
   b) Inflammation
   c) Prevent rejection following organ transplantation
2. Pharmacodynamics:
   a) Bind to glucocorticoid receptors
   b) Complex interacts with DNA to inhibit gene transcription of inflammatory genes
   c) This stimulates migration of T cells to intravascular tissue to lymph nodes
   d) Inhibits mitosis of lymphocytes which reduces size and lymphoid content of the lymph node and spleen
   e) Inhibit production of inflammatory mediators including leukotrienes, prostaglandins, histamine, and bradykinin
   f) Ultimately reduces production of Th1 cytokines (IL-2, interferon, and TNF)

Question 16

What is methotrexate (MTX)?

Answer 16

DMARDS (Disease Modifying Anti-Rheumatic Drugs) - Immunomodulatory

1. Indications:
   a) Rheumatoid arthritis
   b) Cancer
   2a. Pharmacodynamics DMARDs in general:
   2b. Pharmacodynamics methotrexate:
   a) Results in T cell deactivation - used at higher doses to suppress bone marrow in cancer
   b) Increases intracellular adenosine which helps stimulate alpha-2 receptors
2. Drug interactions:
   a) Patient must be supplemented with folic acid with MTX use - this is because MTX has effect on this pathway
   b) Certain drugs such as NSAIDs compete for serum albumin and push methotrexate off - risk of toxicity
   c) Oral antibiotics may decrease intestinal absorption of drug and metabolism of drug
   d) Penicillin decreases renal clearance of methotrexate - increase serum concentrations (higher risk of toxicity)
   e) Increased hepatotoxicity when administered with other hepatotoxic agents
   f) Severe bone marrow suppression, anaemia, and GIT toxicity when combined with some NSAIDs
3. Contraindications:
   a) Pregnant women or women of childbearing potential
   b) Individuals with impaired renal or liver function
4. Early diagnosis and treatment is key to relieve pain, reduce inflammation, and help limit damage
   a) Because irreversible damage takes place in the first 2 years of RA - early intervention crucial
5. Pharmacokinetics:
   a) Partially bound to serum albumin
6. Adverse effects:
   a) Mouth sores - may be reduced with folate supplementation
   b) Hepatoxicity, fibrosis, and cirrhosis after prolonged use
   c) Methotrexate-induced lung disease may occur acutely at any time at doses as low as 7.5 mg/week
   d) Occasionally fatal skin reactions
   e) Fatal opportunistic infections

Question 17

What are some immuno-stimulant agents?

Answer 17

1. Synthetic drugs (e.g. Levamisole and Thalidomide)
2. Immuno-stimulant vaccines (e.g. BCG vaccine)
3. Recombinant cytokines
4. Interferons
5. Immuno-stimulatory Monoclonal antibodies
6. Non-specific stimulation via adjuvants used with vaccine

Question 18

Describe Parathyroid Hormone:

Answer 18

1. Pharmacokinetics:
   a) Intact, active PTH
   b) PTH half life is less than 5 minutes
   c) Liver (2 thirds) and Kidney (1 third) are major sites of fragmentation)
2. Pharmacological effects:
   a) Fine tunes calcium levels in blood (increases calcium and decreases Pi)
   b) PTH acts directly on bone to stimulate reabsorption and release of calcium into the extracellular space
   c) PTH acts directly on kidney to increase calcium reabsorption and phosphate excretion (rapid)
   d) PTH stimulates transcription of 1-alpha hydroxylase for Vitamin D activation in kidney
3. Indications:
   a) Pulsatile PTH for Osteoporosis
4. Adverse effects of Continuous PTH:
   a) Increases osteoclast activity thus promoting osteoporosis

Question 19

What is pulsatile PTH?

Answer 19

Intermittent PTH administration of parathyroid hormone used for osteoporosis

1. Pharmacological effects:
   a) Anabolic effects on bone mass whereas normal continuous PTH administration increased plasma calcium via bone catabolism
   c) Increases osteoblast numbers
   d) Direct effect on osteoblast differentiation and inhibition of apoptosis
2. Pharmacodynamics:
   a) Pulsatile PTH promotes osteoblast proliferation leading to increased bone mass
   b) Stops Osteoprotegerin (OPG)
   c) Continuous PTH however increases osteoclasts and therefore loss of bone (hence use of pulsatile PTH)

Question 20

What is Teriparatide?

Answer 20

PTH Analogues

1. Pharmacokinetics:
   a) Daily SC injection 20 mcg
   b) Maximum of 18-24 months
2. Pharmacodynamics:
   a) Pulsatile PTH
3. Indications:
   a) Reserved only for severe osteoporosis that fails to respond to other therapies (this is because it is very expensive)

Question 21

What are Bisphosphonates?

Answer 21

Osteoporosis therapy

1. Types:
   a) Alendronate
   b) Etidronate
   c) Pamidronate
   d) Risedronate
2. Indications:
   a) Osteoporosis
   b) Other bone loss diseases such as Pagets disease
   e) Zoledronic Acid
3. Pharmacokinetics:
   a) Poorly absorbed in gut - advised to be taken on an empty stomach with a full glass of water with patient remaining upright for at least 30 minutes
   b) Alendronate, etidronate and risedronate are given orally
   c) Pamidronate and zoledronic acid are given intravenously
4. Pharmacodynamics:
   a) Bisphosphonates encourage osteoclasts to undergo apoptosis, thereby slowing the rate of bone loss
   b) Also inhibit osteoclast activity
5. Adverse effects:
   a) Pyrexia and flu-like symptoms tend to occur after first intravenous use

Question 22

What is Raloxidene Hydrochloride?

Answer 22

SERM - Benzothiophene

1. Indication:
   a) Osteoporosis and related bone diseases
2. Pharmacodynamics:
   a) Raloxifene produces a dose-dependent increase in osteoblast activity and reduction in osteoclast action
3. Pharmacokinetics:
   a) Well absorbed in GIT
   b) Undergoes extensive first pass metabolism - 60%
   c) Bioavailability is 2%
   d) Highly protein bound - circulates as glucuronide metabolites
   e) Half life is 28-32 hours
   f) Excreted mainly in faeces
4. Contraindications:
   a) Patients with liver disease due to increased risk of thromboembolism

Question 23

What is Strontium Ranelate?

Answer 23

Dual Action Bone Agent (DABA)

1. Indication:
   a) Osteoporosis
2. Pharmacodynamics:
   a) Stimulates calcium sensing receptors ands leads to differentiation of pre-osteoblast to osteoclast which increases bone formation
   b) Stimulates osteoblasts to secrete osteoprotegrin to inhibit osteoclasts (via RANKL system) to decrease bone reabsorption
3. Not the best drug due to too many contraindications and adverse effects - should be used only as last resort