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Musculoskeletal Pharmacology - Coggle Diagram
Musculoskeletal Pharmacology
Paracetamol
Indications: first line analgesic for most forms of acute and chronic pain
At treatment doses, paracetamol is safe with few side effects, hence it is usually used as first-line treatment
MOA: exact mechanisms are poorly understood
Paracetamol is a weak inhibitor of cyclo-oxygenase (COX), the enzyme involved in prostaglandin metabolism. In the CNS, COX inhibition appears to increase the pain threshold and reduce prostaglandin (PGE2) concentrations in the thermoregulatory region of the hypothalamus, controlling fever. Paracetamol has specificity for COX-2, however, it is a weak anti-inflammatory as its actions are inhibited in inflammatory lesions by the presence of peroxides
Strong analgesic and antipyretic actions but rather weaker anti-inflammatory effects compared to NSAIDs
Paracetamol is metabolised in the liver and is well absorbed when given orally (peak plasma concentration reached in 30-60 mins). It has a half life of 2-4 hours
In overdose, it can cause liver failure
Non-steroidal anti-inflammatory drugs (NSAIDs)
Examples: ibuprofen and naproxen
MOA: NSAIDs inhibit synthesis of prostaglandins from arachidonic acid by inhibiting cyclo-oxygenase (COX)
COX exists as two main isoforms: COX-1 and COX-2
COX-1 is the constitutive form – it stimulates prostaglandin synthesis that is essential to preserve integrity of the gastric mucosa; maintain renal perfusion (by dilating afferent glomerular arterioles); and inhibit thrombus formation at the vascular endothelium
COX-2 is the inducible form, expressed in response to inflammatory stimuli. It stimulates production of prostaglandins that cause inflammation and pain
Indications: when needed for mild-moderate pain (either as an alternative or in addition to paracetamol) or regular treatment for pain related to inflammation (such as RA, OA, and gout)
Adverse Effects: GI toxicity; renal impairment and an increased risk of cardiovascular events (e.g. MI and stroke)
Gastroprotection should be considered (e.g. a PPI) for all patients prescribed an NSAID
Avoid NSAIDs in severe renal impairment; heart failure and liver failure
Use the safest NSAID at the lowest effective dose for the shortest time possible
NSAIDs increase the risk of bleeding with warfarin and reduce the therapeutic effects of antihypertensives and diuretics
Opioids
3 main types of opioid receptors: μ (mu), κ (kappa) and δ (delta)
μ (mu) receptors are responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression; constipation; euphoria)
Weak opioids
Examples: codeine and dihydrocodeine
Indications: mild-moderate pain, as second line, when simple analgesics such as paracetamol are insufficient
MOA: in unmodified form, codeine and dihydrocodeine are very weak opioids; they are metabolised in the liver to produce small amounts of morphine (from codeine) or diamorphine (from dihydrocodeine)
These metabolites, which are stronger agonists of opioid μ (mu) receptors probably account for most of the analgesic effect
Adverse Effects: nausea; constipation; dizziness; drowsiness etc
Lot of opioids rely on both the liver and the kidneys for their elimination so dose should be reduced in patients with renal impairment and hepatic impairment
Tramadol
Asynthetic analogue of codeine (sometimes classed as a ‘moderate strength opioid’)
Like codeine, tramadol and its active metabolite are mu receptor agonists
Unlike other opioids, tramadol also affects serotonergic and adrenergic pathways – this probably contributes to its analgesic effect
Compound preparation opioids
Examples: co-codamol and co-dydramol
Indication: mild-moderate pain, as second line, when simple analgesics such as paracetamol are insufficient
Adverse effects: mainly due to codeine and dihydrocodeine include nausea, constipation and drowsiness
MOA: see paracetamol and weak opioids
Combining two analgesics with different MOA may offer better pain control than can be achieved with either drug by itself
Contraindications: see weak opioids (hepatic and renal impairment)
Strong opioids
Examples: morphine and oxycodone
Indication: rapid relief of acute severe pain including post-operative pain, relief of chronic pain (when paracetamol, NSAIDs, and weak opioids are not sufficient)
Adverse effects: constipation (common) and in higher doses respiratory and neurological depression
MOA: opioids encompass naturally occurring opiates (e.g. morphine) and synthetic analogues (e.g. oxycodone)
Therapeutic action arises from activation of μ (mu) receptors in the CNS
Activation of these G-coupled receptors has several effects which reduce neuronal excitability and pain transmission
By relieving pain, opioids reduce sympathetic nervous system (fight or flight activity)
Continued use can lead to tolerance and dependence (dependence becomes apparent upon cessation, when a withdrawal reaction occurs)
Contraindications: see weak opioids (hepatic and renal impairment)
Should ideally not be used with other sedating drugs e.g. benzodiazepines
Can be given in different forms e.g. morphine may be given IV for rapid relief of acute severe pain
Analgesic ladder
Step 2: Add a weak opioid for mild to moderate pain (such as codeine, dihydrocodeine, and tramadol)
Step 1: paracetamol and/or NSAID
Step 3: Change to a strong opioid for moderate to severe pain (such as morphine, methadone, or fentanyl)
Methotrexate
Indication: disease-modifying treatment for RA
Referred to as a Disease-Modifying Anti-Rheumatic Drug (DMARD)
Adverse effects: mucosal damage (e.g. sore mouth; GI upset) and bone marrow suppression
MOA: inhibits dihydrofolate reductase, which converts dietary folic acid to tetrahydrofolate (FH4). FH4 is required for DNA and protein synthesis, so lack of FH4 prevents cellular replication. Actively dividing cells are particularly sensitive to the effects of methotrexate, accounting for its efficacy in cancer
Methotrexate also has anti-inflammatory and immunosuppressive effects
Usually administered once weekly; there is a risk of accidental overdose if patients take more frequently
Methotrexate is teratogenic and must be avoided in pregnancy
Renally excreted, hence contraindicated in patients with severe renal impairment . It should be avoided in patients with abnormal liver function as it can cause hepatotoxicity
Corticosteroids
Examples: prednisolone and hydrocortisone
Mainly prescribed to modify the immune response
MSK indications: used in suppression of autoimmune disease (such as inflammatory arthritis)
MOA: bind to cytosolic glucocorticoid receptors, which then translocate to the nucleus and bind to glucocorticoid-response elements, which regulate gene expression
Increase the risk of peptic ulceration and GI bleeding when used with NSAIDs
They enhance hypokalaemia in patients taking beta-agonists, theophylline, loop or thiazide diuretics