MSK Information Flashcards
How do NSAIDS work?
NSAIDs work by interfering with the production of autacoids, which are biological molecules formed by one set of cells that can then alter the functioning of other cells.
What is cycle-oxygenase?
a derivative of Arachidonic acid has TWO isomers
* COX-1, a widely distributed constitutive enzyme producing prostanoids involved with homeostatic regulation (housekeeping role).
* COX-2, an inducible enzyme that may only be expressed in low level ordinarily, but whose expression is up-regulated during inflammation.
What do NSAIDS inhibit?
They act to inhibit or suppress COX They can suppress PGE2 – which means this eicosanoid cannot protect the stomach mucosa, and so gut ulceration is a side effect of NSAIDs. Similarly, PGD2 is a vasodilator, so NSAIDs can cause vasoconstriction, which means that blood pressure can increase (leading to hypertension)
Therapeutics and side effects of COX inhibition
The reduction in prostanoid synthesis by inhibiting COX-2 produces the therapeutic effect, but inhibition of COX-I leads to side effects.
NSAIDS and Asthma
Smooth muscle relaxation caused by prostaglandins can be particularly important in patients with severe asthma, the person concerned relies on their normal prostaglandin production to keep their airways open and dilated. If they take an NSAID, this inhibits prostaglandin production, which means their lung alveoli constrict and they can experience a severe and potentially fatal asthmatic attack.
NSAIDS and Kidneys
Renal function is reduced during NSAID treatment because PGE2 and PGI2 are normally involved with maintaining renal blood flow by dilating the renal artery. Inhibition of these prostaglandins with a NSAID means that blood flow through the kidney is reduced because the renal artery contracts, potentially leading to renal failure. NSAIDs are stopped in patients who are in AKI
Selective COX-2 inhibitors and the heart
Selective COX-2 inhibitors have been withdrawn from the market as their use was associated with a small increased risk of thrombotic events (e.g. myocardial infarction and stroke).
Selective COX-2 Inhibitors and the heart (2)
Selective COX-2 inhibitors are contraindicated in patients with established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease
Selective COX-2 Inhibitors and the heart (3)
Following a cardiovascular insult, it seems that COX-2 may become important in PGI2 formation. So, if a selective COX-2 inhibitor is now administered PGI2 formation will fall, but TxA2 is still synthesized by platelet COX-1. Therefore the balance has shifted towards unopposed TxA2, which increases the risk of developing a thrombosis and potential heart attack (myocardial infaction).
NSAID cautions
Caution must be exercised before giving any NSAID to a patient with any history of allergic reactions, asthma, dermatological problems, gastro-intestinal problems, cardiac problems and liver or kidney disease
Rheumatoid arthritis (1)
Proliferation of the synovium and destruction of joint cartilage and bone by osteoclasts occurs, and inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor- (TNFa) play an important pathogenic role.
Rheumatoid arthritis (2)
Rheumatoid arthritis can cause joint deformity and affect different organs of the body, such as the heart, lungs, and eyes; therefore early diagnosis
DMARDS (RA)
DMARDs can produce long-term suppression of inflammatory responses, so they can:
Reduce joint swelling and tenderness
Retard progression rates of joint erosion and destruction
Improve pain and disability scores
Cause falls in plasma acute-phase proteins and rheumatoid factor
Corticosteroid bridging (RA)
Short-term ‘bridging’ treatment with a corticosteroid by oral, intramuscular, or intra-articular administration may be useful when starting treatment with a new DMARD to provide rapid symptomatic control, while waiting for the DMARD to take effect.
DMARD categories (RA)
➢ Drugs that suppress the rheumatic disease process (including drugs that affect the immune response)
➢ Cytokine modulators, which are often described as ‘biologics’
Methotrexate (1)(RA)
Methotrexate is an analogue of folic acid, it inhibits dihydrofolate reductase to prevent the conversion of dihydrofolic acid to tetrahydrofolic acid for nucleic acid synthesis.
Methotrexate (2)(RA)
Methotrexate decreases the production of IL-1 and TNF-a cytokines, but increases the production of IL-10, which is inhibitory, and adenosine production may also be increased, which then acts as an anti-inflammatory paracrine. Methotrexate treatment can improve symptoms in RA within a period of around 1 month
Methotrexate (3)(RA)
When used as a DMARD methotrexate is given ONLY ONCE A WEEK
NSAIDs and Methotrexate
NSAIDs reduce the renal clearance of methotrexate therefore increasing the risk of toxicit
Trimethoprim and methotrexate
Very serious drug interaction with trimethoprim, which also acts on dihydrofolate reductase – if taken together, both drugs may actively suppress the bone marrow leading to agranulocytosis or neutropenia
Folic acid and methotrexate
Folic acid reduces the toxicity of methotrexate treatment and improves continuation of therapy and compliance. Folic acid is usually also prescribed ONCE weekly, but SHOULD NOT be taken on the same day as the methotrexate as it will antagonise the effectiveness of the latter.
Azathioprine (RA)
Azathioprine inhibits the production of purines and is immunosuppressive and cytotoxic.
Azathioprine inhibits the proliferation of B- and T-lymphocytes by a cytotoxic action on dividing cells, and has been used as an immunosuppressant to stop transplanted organ rejection. Azathioprine inhibits both cell-mediated and antibody-mediated immune reactions.
Pencillamine (RA)
Penicillamine may reduce T-lymphocyte activity and inhibit rheumatoid factor from binding to immunoglobulin, so preventing the formation of immune complexes
in RA
Sulfasalazine (RA)
Sulfasalazine is relatively effective, cheap, orally administered and has fewer side effects when compared to other DMARDs. Once administered sulfapyridine is released, which may reduce lymphocyte proliferation by interfering with folate metabolism and reducing cytokine production
Mineralocorticoids
Mineralocorticoids’ (such as aldosterone), which regulate salt and water balance.
Glucocorticoids
Glucocorticoids’ (such as hydrocortisone) which regulate the use of carbohydrate, fat and protein in the conventional stress response. In addition to maintaining normal homeostatic mechanisms, natural and synthetic corticosteroids act as powerful anti-inflammatory and immunosuppressant agents
Glucocorticoids
Glucocorticoids can induce the production of annexin-1 (lipocortin-1). This inhibits phospholipase A2 and so can produce some very powerful anti-inflammatory responses, as all eicosanoid production (prostaglandins and leukotrienes) is affected and reduced amounts of arachidonic acid will be liberated
* Glucocorticoids can suppress the expression of phospholipase A2, COX-2 and the interleukin-2 receptor
* Glucocorticoids can reduce the number of leukocytes in the circulation
Steroids and Infections
There is an increased risk of developing infections with steroids, owing to suppression of immune responses. This means, for example, oral candidiasis (thrush) can be a common complaint when administering glucocorticoids by inhalation, so they should rinse their mouth
Cushings syndrome and glucocorticoids
Cushing’s syndrome is the condition caused by an excess amount of released corticosteroid hormones, which may be due to over stimulation of the adrenal glands by excess ACTH being secreted from a pituitary tumour or by a tumour of the adrenal glands. High doses of glucocorticoids can also produce Cushing’s syndrome.
Osteopenia & osteoporosis
Osteopenia is a reduction in the mineral content of bone, whereas osteoporosis is a reduction in actual bone mass. The onset of both of these conditions is often age-related and they can cause bones to fracture easily
The main causes of osteoporosis
- Postmenopausal oestrogen deficiency
- Age-related deterioration in bone homeostasis
- Long term levothyroxine use. To minimise the risk of osteoporosis, dosage of levothyroxine sodium should be titrated to the lowest possible effective level.
-Prolonged glucocorticoid therapy, with associated bone loss - Myeloma (a type of cancer that develops from cells in the bone marrow)
Treatment for osteoporosis
Hormone Replacement Therapy (HRT)
- Selective oestrogen receptor modulators (SERMs) have agonist actions on some tissues and antagonist actions on others. For example, raloxifene has agonist actions on bone and the cardiovascular system, but antagonist actions on mammary tissue
Raloxifene’s mechanisms (SERMS for Osteoporosis)
- Increased osteoblast activity in a dose-dependent manner,
- Reduced activity of osteoclasts.
- It undergoes extensive first-pass metabolism, so its bioavailability is low (2%), but
it is well distributed around the body.
PTH and PTH fragments (teriparatide for osteoporosis)
These increase bone mass by paradoxically stimulating osteoblast numbers and decreasing osteoblast apoptosis. They act on PTH-1 receptors (GPCR), activating adenylate cyclase, PLA2, PLC and raise intracellular Ca2+ levels. These are given subcutaneously and are generally well tolerated.
Bisphosphonates (alendronate and risedronate for osteoporosis):
These act on osteoclasts to promote their apoptosis, thereby inhibiting bone reabsorption
Rickets
Rickets is a condition where “softening” of the bones occurs, causing the bones to bend if they are weight-bearing, such as the legs. Vitamin D is required for normal Ca2+ ion absorption from the gut, and an absence of vitamin D leads to poor dietary calcium absorption, resulting in hypocalcaemia. This in turn can lead to skeletal and dental deformities.
The usual way to prevent rickets is to increase dietary intake of Vitamin D, or to increase exposure to sunlight.
Osteoarthritis (1)
Osteoarthritis refers to a clinical syndrome of joint pain accompanied by varying degrees of functional limitation and reduced quality of life. It is the clinical manifestation of joint degeneration that results from loss of articular cartilage and becomes more common with increasing age. Articular cartilage is the smooth, white tissue that covers the ends of bones where they come together to form joints. OA is a long-term condition that usually develops in people over 45 years of age.
Osteoarthritis (2)
It is characterised pathologically by localised loss of cartilage, remodelling of adjacent bone and associated inflammation OA can be diagnosed clinically without investigations if a person:
* is 45 or over and
* has activity-related joint pain and
* has either no morning joint-related stiffness or morning stiffness that lasts no longer
than 30 minutes.
Osteoarthritis (3)
Where paracetamol or topical NSAIDs are ineffective, or provide insufficient pain relief in OA, then an oral NSAID/COX-2 inhibitor should be considered and a proton pump inhibitor (PPI) must be co-prescribed.
Gout (1)
Gout is a type of arthritis where crystals of sodium urate form inside and around joints. It usually presents as an acutely painful joint in the hands or feet, caused by the accumulation of uric acid crystals due to a defect in uric acid metabolism that causes excess uric acid and urates to accumulate in the bloodstream and joints. Uric acid is the end product of purine metabolism and normally two-thirds of the uric acid formed in the body each day is eliminated via the GI tract or the kidneys
Gout(2)
Attacks of gout are very painful. Acute gouty arthritis can occur suddenly when crystals of sodium urate (tophi) are deposited in synovial tissue, skin and cartilage. This leads to an inflammatory response, where mediators like kinins and LTB4 are generated and neutrophils begin to accumulate, which try to engulf the crystals but release toxic oxygen metabolites (superoxide) and proteolytic enzymes.
Certain medications can cause an increase in uric acid levels and therefore the risk of developing gout.
- diuretics
- other drugs used to treat hypertension, such as beta-blockers, ACE inhibitors and
calcium channel blockers - low dose aspirin
- niacin (used to treat high cholesterol)
Acute drug treatments for gout include
Naproxen or other NSAIDs (symptomatic relief)
Colchicine (Acute)
Allopurinol (chronic)
Colchicine (Gout)
Colchicine prevents the migration of neutrophils into joints, possibly by binding to tubulin, so microtubules depolymerise. It is useful in patients with heart failure as, unlike NSAIDs, it does not cause fluid retention. Typical doses for the treatment of acute gout are 500 micrograms 2-4 times a day until symptoms are relieved, up to a maximum of 6 mg per course. the course should not be repeated within 3 days.
Gout non-pharmacological treatment
Lifestyle choices to help prevent further attacks include avoiding excessive alcohol and foods high in purines; losing weight (if appropriate); taking regular exercise and maintaining adequate hydration.
Allopurinol for Gout (1)
The enzyme xanthine oxidase converts hypoxanthine to uric acid via xanthine. Allopurinol is converted into alloxanthine by xanthine oxidase. Alloxanthine then non-competitively inhibits xanthine oxidase, so uric acid production decreases. The uric acid concentration decreases, which reverses the deposition of crystals.
Allopurinol for Gout (2)
Allopurinol which is good for long-term treatment must not be initiated during an acute attack as it can exacerbate the acute, painful condition because the rapid reduction of uric acid levels to below the saturation point causes existing crystals in the joint cartilage to partially dissolve and become smaller. These smaller crystals can escape or ‘shed’ into the joint cavity and then inflame the synovium.
