i) where does it happen? what is converted to arachadonic acid?
ii) what are the two things that arach acid can be converted to? what are these two pathways called?
iii) which condition are leucotrienes important in? what do they mediate?
iv) what are prostaglandins acted on by? what three things can this produce and name an action of each
i) happens in the cell membrane
- phosoplipids converted to AA by phospholipases
ii) AA can be converted to leucotrienes or prostaglandin
- leucotrienes by lipoxygenases
- prostaglandin H2 by COX pathway
iii) leucotrienes important in ashthma > mediate broncoconstric
iv) tissue specific synthases act on prostaglandins
- produce thromboxane (plat agg ans vconstric)
- prod prostaglandins (bronch tone, vasc tone, pain)
- prod prostacyclins (vdilation)
EICOSANOID PATHWAY TARGETS
i) which area of the pathway do NSAIDs work on?
ii) what are NSAIDs known as in relation to their action?
i) NSAIDs work on the COX pathway (antagonise) AA > prostaglandin H2
ii) NSAIDs = non selective COX inhibitors
NSAID MECHANISM OF ACTION
i) what do they inhibit?
ii) what are the three isoforms of COX and where is each expressed?
iii) what does inhibition of a) COX 1 and b) COX 2 cause?
iv) in what case may COX1 inhibitors be used? (2)
i) inhibit cyclo oxygenase
ii) COX 1 - constituitively expressed in all tissues
COX 2 - induced in inflammation
COX 3 - CNS only
iii) inhib of COX 1 - anti plat activity but also side effects eg GI bleeding
inhib of COX 2 - analgesia and antinflammatory
iv) use COX 1 inhibitor in stroke and MI
INDICATIONS FOR NSAID THERAPY
i) what can they be used for short term management of? (2)
ii) give four things they can provide mild analgesic effects for? which two methods of admin are used?
iii) give two situations where they may be used as potent analgesics? which three methods of admin are used?
iv) what condition do they have good antiinflammatory effects in? which group of conditions are they not so good at anti inflam/disease mod?
v) how many prescriptions are written for NSAIDs per year? what % is there serious SEs in? how many deaths per year?
i) short term management of pain and fever
ii) analgesic effects for mech pain, minor trauma, headaches, dysmennorhea > given orally or topically
iii) potent analgesics in peri-op pain and urteric colic
- oral, parenteral, rectal
iv) good inflam effects in gout
- not so good in inflammatory arthritis eg ankylosing spon/RA
v) 25 million prescriptions per year
- 1-2% serious SEs
- 2600 deaths
i) what is it mainly used for?
ii) what is its use in pain and inflammation limited by? (3)
iii) what side effect is specifically seen in children? give one situation where aspirin may be used in children
iv) what effect does it have on platelets? give two situations it can be therefore used in
i) mainly used for CV protection
ii) use for pain/inflam limited by GI tox, tinnitus, Reyes syndrome (hepatic fail in children)
iii) see reyes syndrome in children
- may use in kawasaki disease
iv) anti plat effect
- primary and secondary prevention of MI and stroke
- treatment of acute MI and stroke (low dose)
NSAID GI TOXICITY
i) which two prostaglandins are protective in the GI tract? name three things that they do
ii) what effect do NSAIDs have in stomach and duodenum? give three things this causes
iii) what effect do they have in the colon? name one culprit of this
iv) what is the relative risk of GI bleeding? does this vary between drugs?
v) what is the biggest risk factor for a GI bleed with NSAIDs? give three other RFs
i) prostaglandin E2 and I2 are gastroprotective
- decrease acid produc, increase mucus produc, increase blood supply
ii) NSAIDs inhibit prostaglandins in the stomach and duodenum
- causes irritation, ulcers (gastric 15-30% and duodenal 10%) and bleeding
iii) colitis in colon espec local preps eg rectal diclofenac
iv) RR of upper GI bleed is 4.7 and this varies between drugs eg azapropazone is 23.4
v) biggest risk factor for GI bleed is a previous GI bleed
- as well as age, chronic dosease and steroid use
i) what is it primarily related to?
ii) name four things that are seen?
iii) what % have acute renal failure?
iv) how should NSAID tx be managed in renal failure? which patients should it be avoided in?
i) primarily relat to changes in glomerular blood flow
ii) see decreased GFR, sodium retention, hyperkalemia, papillary necrosis (whole papilla dies)
iii) 0.5-1% have acute renal failure
iv) avoid or dose adjust in renal failure
- avoid in patients likely to develop renal fail
ASTHMA AND ASPIRIN
i) what do 10% of asthmatics experience after taking aspirin?
ii) what is thought to mediate this?
iii) what are the two routes that can be taken after membrane phospholipids are converted to AA? which pathway is implicated in this reaction?
i) 10% of asthmatics get bronchospasm (wheezing) post aspirin
ii) may be mediated by increased leucotriene production
iii) two routes of AA are COX pway > prostaglandin
or 5 lipoxygenase > leucotriene
- thought that inhibiting the COX pway with aspirin sends the pathway down the leucotriene pathway which causes bronchoconstric and wheezing
PREVENTING NSAID TOXICITY
i) give three alternative treatments
ii) which three things should be considered before giving an NSAID
iii) what can it be co-administered with?
iv) how much increase in potency is there with stronger NSAIDs? how much increase is there in side effects?
i) paracetamol, COX2 inhib, opioids, non pharma
ii) risk factors eg age, renal impair and previous peptic ulcer
iii) co admin with proton pump inhibitor eg omeprazole
i) not much increased potency with stronger drugs but lots of increased side effects
i) is it a member of the NSAID group? what two things is it good for?
ii) is it well tolerated? does it have many contraindics?
iii) what may it inhibit? what is it a weak inhibitor of?
iv) in which situation is it dangerous
i) not classical NSAID
- good analgesic / anti pyretic
ii) well tolerated and no contraindications
iii) may inhibit COX 3 and is a weak inhibitor of prostaglandin
iv) dangerous in overdose
i) in what type of reaction is it removed at normal doses? what organ does this take place in? what intermediate is produced before its excreted? (2)
ii) what happens if that pathway is saturated? what intermediate is produced? what can this intermed cause?
iii) does this toxic reaction occur instantly? how may patients present
iv) what drug can be used to counteract paracetamol poisoning? what does this do?
i) phase II conjugation reaction in the liver
- produce paracetamol sulphate and glucuronide
ii) if pathway is saturated then goes into phase I oxidation reaction > produces NAPQI that can cause hepatic necrosis
- then to NAPQI glutathione and excreted
iii) hepatonecrosis can present later
iv) use N-acetylcysteiene
- overrides saturation of conjugation pathway and allows NAPQI to be removed
SELECTIVE COX 2 INHIBITORS
i) what effects do they have in humans? (2) do they have more or less SEs than COX1 inhibitors?
ii) what type of efficacy do they have in relation to non selective NSAIDs in acute pain, dysmennorhea and inflam joint disease?
iii) what is there potential increased risk of? what could this be a result of?
iv) who is it currently only reccomended for? (2)
v) what are the most common SEs seen in NSAIDs
i) anti inflam and analgesic effects
- less side effects than COX1 inhibs
ii) comparable efficacy to non selective NSAIDs
iii) potential inc risk of MI but may be a result of the anti plat effect of the group taking non selective cox inhibitor
iv) currently reccom for high risk patients and after CV risk assessment
v) GI SEs
i) what is the predominant endogenous glucocorticoid?
ii) name four metabolic effects of endog GCs?
iii) what what levels do they have effects on immunity?
iv) by what mechanism do they work? where do they bind their receptor? what does binding of CS to receptor cause dissociation of? what then happens?
v) is onset of action immediate or delayed? why? what cell types do they affect (2)
i) cortisol (hydrocortisone)
ii) carb/protein metab, fluid/electrolyte balance, lipid metab, bone metab, modulation of immune response
iii) effects on immunity at pharmacological levels (not physiological)
iv) work by altering gene transcription
- drugs are lipophilic so cross cell mem and bind steroid receptor in cytoplasm
- binding causes steroid receptor to dissoc from Hsp90
- steroid receptor complex then transloc to the nucleus and affect gene transcrip/translat
v) onset is delayed as affects gene transcript
- affect expression of T and B cells
IMMUNOMODULATION BY STEROIDS
i) what changes in cell trafficking may be observed? (4)
ii) what changes in cell function may be observed? (5)
iii) which two things do steroids not affect?
i) cell traffick = lymphopenia (reduced lymphos), monocytopenia, neutrophillia and impaired phago migration
ii) cell func - T cell hyporesponsive, inhibited B cell maturation, decreased IL and TNF produc, inhibition of COX, decrease in collagenase and elastase (impairs wound healing)
iii) doesnt affect Ig levels or complement
CLINICAL USE OF STEROIDS
i) what is it principally used to supress? in what type of disease? give four examples
ii) what other type of therapy can it be used in to keep a patient in remission from disease?
iii) what condition can it be used as replacement therapy in?
iv) name two systemic routes of admin, name three topical routes of admin
i) used to supress inflammation
- espec in acute disease
- asthma, crohns, eczema, MS, RA, SLE
ii) can be used as maintanence therapy
iii) replacement therapy in hypoadrenalism
iv) systemic > oral and parenteral
topical > skin, joint injec, inhaled, enteric, rectal
CORTICOSTEROIDS AS DRUGS
i) hydrocortisone - what is the potency? lipid sol? systemic use? topical use?
ii) prednisolone - how is it normally given? potency? lipid sol? systemic use? topical use?
iii) beclomethasone - potency? lipid sol? systemic use? topical use?
iv) dexamethasone - potency? how is it usually given? lipid sol? systemic use? topical use?
v) triaminiclone - potency? lipid sol? is it used systemically? is it used topically?
i) hydrocortisone - low potency, good lipid sol, systemically used in replacement treatment eg hypoadrenalism
- topical use in skin and joints
ii) prenisolone - given orally
- medium potency and good lipid sol
- systemic use as anti inflammatory eg acute asthma attach
- topical use as an enema eg in IBD
iii) beclamethasone - medium potency, poor lipid sol
- not used systemically but topical in asthma (brown inhaler) and in crohns
iv) dexamethasone - high potency - given IV or oral
- good lipid sol, used systemically in cerebral oedema and not topically
v) triaminiclone - high potency, poor lipid sol
- not used systemically but topical skin and joints
SIDE EFFECTS OF STEROID THERAPY
i) name four early effects
ii) late effects - how are muscles affected? how are bones affected?
iii) name four other changes seen later on?
iv) what type of phenotype may a person on long term steroid use resemble?
i) weight gain, glucose intol, mood change, supression of ACTH release (takes time)
ii) late effects - proximal muscle weakness
- osteoporosis espec in women
iii) skin changes, body shape change (central adipose), hypertension, cataracts, adrenal suppress
ADRENAL SUPPRESSION DURING CORTICOSTEROID THERAPY
i) what effect does high dose exogenous corticosteroid admin have on endogenous production? how long does this take to happen?
ii) what happens to the adrenal cortex after prolonged therapy?
iii) how long does endog production take to recover after therapy cessation?
iv) what does abrupt treatment withdrawal to below replacement dose cause? what may this lead to?
v) name three things that should be given/done in long term therapy
i) high dose exog CS admin supresses endogenous production within one week
ii) adrenal cortex can atrophy after prolonged therapy
iii) takes a while to recover and may not ever recover
iv) abrupt treatment withdrawal can reduce the ability to deal with physiol stress eg infection
- can lead to adrenal crisis (not enough cortisol)
v) give steroid warning card, tail doses slowly to prevent adrenal crisis, increase dose during acute illness and prior to surgery (in a stressful situation so there is enough cortisol to deal with it)
RISK OF INFECTION WITH CSTEROIDS
i) what is the risk of infection related to?
ii) what type of defects are seen earlier? what types of infection does this involve? give an eg of each
iii) which type of defecrs are seen later? what can this be attributed to? give three causative agents
iv) what infection can result from use of steroid inhaler? how can this be mitigated? (2)
i) related to cumulative use of corticosteroids
ii) early defects = phagocytic defects
- involves bacterial infection (s. aureus) and fungal infection (candida)
iiii) later effects = cell mediated defects
- attrib to intracell pathogens eg TB, varicella and listeria
iv) steroid inhaler can cause candida albicans at site of use (oropharynx)
- mitigate with good inhaler technique and washing mouth after use
DISEASE MODIFYING ANTI RHEUMATIC DRUGS (DMARDS)
i) what do they target? name another condition they can be used in apart from RA?
ii) what may they be used for in higher doses?
iii) how are they different to NSAIDs? steroids?
i) target the immune system
- can be used in transplantation
ii) higher doses in cancer chemotherapy
iii) NSAIDs are not disease modifying
- steroids have more toxicity than DMARDs
i) what is it a competitive inhibitor of? what action does it therefore have?
ii) how does this affect DNA synthesis? what two other things can it reduce?
iii) name the three main conditions its used in?
iv) name four main toxicities
v) how often is it given?
i) competitive inhibitor of dihydrofolate reductase (DHR) therefore has anti folate action
ii) folate is needed for purine synthesis in DNA therefore inhibits DNA synthesis
- can also reduce T cell activity and tumour synth in higher doses
iii) used in RA, psoriasis and crohns disease
iv) toxicities - hepatotox, leucopenia, pulm fibrosis, teratogenic
v) given one weekly > dosing error = major toxicity
i) what does it inhibit? what does this lead to?
ii) what is it more widely used in compared to methotrexate?
iii) what side effect is very common when starting? how can this be managed?
i) inhibits thiopurine S methyltransferase (TPMT) inhibits purine and therefore DNA synthesis
ii) more widely used in transplantation
iii) common SE when starting is GI upset > start at low dose then build up
i) what does it inhibit? what does this consequently cause?
ii) what is it used more in compared to aza/metho
iii) name four main toxicities
iv) how is it excreted? what must therefore be monitored?
v) what is a newer formula to this? how is it given?
i) inhibits calcineurin and reduced T cell activity
ii) used more in dermatology and transplantation
iii) nephrotoxic, hepatotoxic, gym hyperplasia, hirsutism
iv) renal excretion therefore look at renal function
v) tacrolimus > easier to take and given topically