Module 1.2.1 (Pharmacology of drugs for OA) Flashcards
For paracetamol;
A) Why is it used in OA?
B) What is the dose of osteo formulations? What is the max dose a day?
C) What is the half-life?
D) What happens in an overdose?
E) How to correct toxicity?
A)
- Preferred drug for pain relief
- Better tolerated than true NSAIDs
> may be placebo for pain relief
B)
- Osteo formulations 665mg
- A max of 4 g per day for this drug due to toxic intermediate build up needing glutathione conjugation for removal
C)
- 2-4 hour plasma ½ life
- 4-8 hours for very high doses
D)
- Saturation of normal conjugating enzymes
- mixed-function oxidase instead:
> N-acetyl p-benzoquinone imine –> toxic = cell death
E)
- Increase glutathione in cells to overcome toxicity
> acetylcysteine i.v. or methionine orally
For NSAIDs;
A) Should it be used with paracetamol for OA, is it better than paracetamol?
B) What are the types? Provide examples, divide answer into short-acting and long-acting plasma 1/2 lives.
C) What are examples of topical forms?
A)
- Can be used with paracetamol or on its own
- WILL CAUSE MORE HARM THAN PARACETAMOL
B)
non-selective COX1+2 inhibitor
- Diclofenac, Ibuprofen, Ketoprofen (short acting – plasma ½ life <6 h)
- Piroxicam, Naproxen, Meloxicam, (long acting – plasma ½ life >10h)
selective COX-2 (still has cox-1 related adverse effects)
- Celecoxib and Etoricoxib (both classed as longer plasma ½ life drugs)
C)
Topical forms include Diclofenac, Ketoprofen and Piroxicam
- topical on joints may have less systemic adverse effects (eg stomach)
Provide FIVE side effects of current NSAIDs, should you use ore than 1 NSAID at a time?
> Gastrointestinal ulceration - bleeding = most common
- Indomethacin (very high)
- COX-2 inhibitors (lower)
> Skin reaction - topical NSAIDS = mild rashes
> Do not use more than ONE NSAID at a time –> increase adverse effects with no increase in benefits
> Blockade of platelet aggregation
> Inhibition of uterine motility
> Renal function
- Decreased blood flow
- CHF if renal disease present
- Increase sodium and water retention, increased potassium reabsorption = hypertension
> hypersensitivity reactions
- Aspirin most pronounced –> bronchospasms
What are some examples of Arylpropionic acids (NSAID)? How is their half-life different? Discuss the properties of some of them.
Ketoprofen, ibuprofen, tiaprofenic acid, naproxen
- 99% plasma protein-bound
- All alter platelet function & prolong bleeding time
- Ibuprofen – liver metabolised –> renal cleared
- Naproxen – renal cleared of parent drug
What is an example of a heteroaryl acetic acid? What is it used for and what are some unique properties that differentiate it from other NSAIDs?
Diclofenac (Voltaren)
- RA, OA, AS
- 50% first pass – CYP 2C group
- Short plasma half life (1-2 h)
- 20% side effects –> G.I. tract mostly
Accumulates in synovial fluid compared to other NSAIDs
- Few patients increase transaminase 3 fold
Give an example of a non-selective and selective enolic acid (NSAID). What is it used for? What are some unique properties?
Non-selective: piroxicam (feldene)
COX2 selective at high doses: meloxicam (mobic)
- Used for RA, OA, AS
- Equivalent to aspirin
- Long half-life –> 35-50h enterohepatic cycling of piroxicam
- Single daily dose
- Max effects in 2 weeks
- Effects on neutrophil activation, COX & collagenase
- Greater Na+ & H2O retention
What is an example of a diaryl substituted pyrazole? What are some contraindicationsContr and what is it used for? Discuss its metabolism.
Celecoxib –> more selective for COX-2
- Contra-indications: if hypersensitive to other NSAID or with allergies to sulfonamides
- Used in OA, RA dysmenorrhoea
- Metabolised by CYP 2C9
- Inhibits CYP 2D6 (SSRIs, Tricyclics, B1 spec blockers also inhibits this)
- Half life = variable 4-15 hours (average = 11 hours)
For intra-articular injections in OA (IA corticosteroids);
A) How long does it provide relief from symptoms for knee OA?
B) Onset of action?
C) How many times can it be done?
D) What are some examples?
A)
- Provide relief from symptoms from 4 to 12 weeks in knee OA
- Doesn’t change disease progression
B)
- Quick onset of action
- Useful for special occasions or to improve exercise tolerance
C)
- Can be repeated every 3 months (4 per year)
D)
- Betamethasone, Dexamethasone, Methylprednisolone and Triamcinolone available as IA
What is the MOA of glucocorticoids (IA cotricosteroid)?
- Decrease production of T & B lymphocytes, macrophages, eosinophils, monocytes & basophils
- Decrease function of these cells
> decrease in IL-1 though 6, IL-8, TNF-γ, cell adhesion factors, GM-CSF
> inhibits cascade of cell-mediated immunity
- Stabilises lysosomes
- Inhibit complement system
- Induces Annexin-1 (Lipocortin) –> effects seen in hours rather than days
> negative feedback on hypothalamus
> inhibits Phospholipase A2 = decreases prostaglandins, thromboxanes, leukotrines
- Blocks recruitment of neutrophils
> decrease transcription of genes for cell adhesion factors
- Decreases fibroblast function
> less collagen, less glycosaminoglycan
> these normally impact on chronic inflammation
> less ability to heal & repair
- Decrease gene expression COX2, NOS2, TNF-a, IL-1
- Increase gene expression anti-inflammatory factors = IL-10
What are some downsides to glucocorticoids (IA corticosteroid)? When is it contraindicated?
Susceptible to infection
- Re-activation of latent infections - herpes virus, tuberculosis
- Recent infections can preclude use
Contraindicated in patients with infective arthritis, or soft tissue infection near joint – or when prosthetic joint involved
For IA hyaluronic acid;
A) How is it given
B) How does it compare to IA corticosteroids?
C) What is the cost associated with
D) What are some side effects?
A)
- Single IA injection or given as a weekly injection for 3 to 5 weeks
B)
- May provide longer DOA than IA corticosteroids –> may cause temporary worsening of OA symptoms
C)
- High cost treatment compared to IA corticosteroids
D)
- Pain, swelling, joint effusion
What is the MOA of hyaluronic acid? What role does the MW play in its efficacy?
Binds to CD44 on the surface of chondrocytes, which activates Phosphatases that suppress MAP kinases which are related to the action of TNF-α activation mechanisms – this leads to downregulation of MMPs and aggrecanases (MMP degrades aggrecan)
- Free HA assists in the suppression of the degradation pathway of chondrocytes –> Must be high MW.
- Low MW Hyaluronic acid thought to INCREASE proinflammatory action in synovial joint
What determines the effectiveness of therapy (how often it is given as an injection) for hyaluronic acid?
Length of glycoaminoglycan/glycosaminoglycan and source (animal vs biofermentation – will influence effectiveness of therapy)
- animal: no more than a week
- biofermentation: lasts for a month
What is the MOA of Glucosamine and Chondroitin? Does it help with OA?
- Makes up parts of hyaluronan (acetylated form) – not the form consumed
- Also lots of Chondroitin sulfate off of the backbone
- MOA is orally absorbed to allow normal body enzymes to add it where it needs to go
- 90% glucosamine absorption from the gut –> 1/2 eliminated in 1st past effect
- Combining with chondroitin reduces glucosamine absorb
- Chondroitin in plasma Is <20 ug/mL
> Clinical meta-analysis concluded no statistically relevant benefit from glucosamine supplementation at 1500 mg/day
