Inflammation Clincal Workshop-1 Flashcards
Learning objectives
Describe and apply the therapeutics of paracetamol, aspirin, NSAIDs both non-selective and COX-II selective.
Paracetamol
Aspirin
NSAIDs
GI side effects
CV events
Renal side effects
Therapeutics of Paracetamol
Paracetamol is mainly used as an analgesic and as an antipyretic when thinking therapeutically paracetemol would not normally be described as an NSAIDs as it has none of the traditional effects on peripheral Cox inhibition
P does not have significant anti-inflammatory effects although some of its mechanism of action appears to be related to central Cox inhibition (COX-3)
Paracetamol has completely separate drug profile in terms of its cautions contraindications side effects to the other NSAIDs paracetamol is generally well tolerated at standard doses when patient considerations are taken into account and appropriate dose adjustments made
Considerable issues in terms of overdose of paracetamol This is why there are limited legal requirements for sales so for example tablets and capsules cannot be sold in packs of greater than 32 however a pharmacist can sell up to 100 tablets in justifiable situations this is to reduce the risk of overdose situations
Another risk of overdose is inadvertent overdose and this is a major risk and it’s a relatively common problem so it’s important to make sure that when checking patients medications for example that we’re checking for duplicate prescribing in terms of a patient using regular paracetamol and then using top up as and when required paracetemol and when a patient is using compound products so the product doesn’t clearly say paracetamol in its name special patient groups
children fall into this category care needs to be taken to ensure that the correct strength of preparation is supplied and that the appropriate dosing schedule is being used please refer to the BNF for direction on this
patients with low body weight that’s less than 50 kilos
patients with liver impaired impairment or with risk factors for hepatotoxicity these patients may be at more risk of toxicity from paracetemol BNF guidance states clinical judgement should be used to adjust the dose of both the oral and the IV preparations generally in practise we may see doses such as 500 milligrammes three times a day
15mg/kg four times a day in lower weight patients and in patients with hepatic impairment
Paracetamol can have a similar analgesic effect to single doses of NSAIDs.
Paracetamol is preferred over the use of NSAIDs in elderly patients as older people are more risk of the side effects associated with NSAIDs so paracetomol is preferred
Paracetamol is also preferred for patients with hypertension cardiovascular disease renal impairment and GI issues because all of these factors can be further compounded by the potential adverse effects of NSAIDs
Paracetamol is also preferred in patients taking other medicines that may interact with NSAIDs for example warfarin so it is acceptable for a patient on warfarin to take paracetamol as analgesia
Available preparations paracetamol comes as tablets capsules orodispersible tablets suspension suppository can be used as an infusion in secondary care when patients are nil by mouth for example and compound preparations so things such as cocodamol containing paracetamol and codeine
Co-dydramol and OTC products such as lemsip so patients may not consider these as medications that contain paracetemol and want to use them alongside a regular dose of paracetemol we need to make sure that this doesn’t happen to prevent inadvertent overdoses in patients
Therapeutics of Aspirin
Aspirin can be used both as an analgesic and an antiplatelet, as an antiplatelet aspirin is used to inhibit thrombus formation in the arterial system, in these fast flowing vessels thrombi are composed mainly of platelets with little fibrin therefore you see the use of antiplatelet aspirin used for the primary and secondary prevention of cardiovascular disease and events
The standard dose of antiplatelet therapy is 75 milligrammes however you do sometimes see it increase to 300 milligrammes daily and sometimes there is a loading dose that goes alongside this at these doses it has no anti-inflammatory or analgesic effect
Aspirin as an analgesic it’s standard oral doses 300 to 900 milligrammes every 4-6 hours when required for pain up to a maximum of 4grams a day you rarely see aspirin being used to treat inflammation in inflammatory diseases anymore due to its risk of side effects
Special patient groups:
aspirin is contraindicated in children under 16 years this is due to the risk of Reyes disease a condition causing swelling in the liver and brain it is however seen for the treatment of a specific syndrome called Kawasaki syndrome and this is extremely specialist use
Aspirin is also contraindicated in patients with previous or active peptic ulceration, bleeding disorders, severe cardiac failure, previous high hypersensitivity to aspirin or NSAIDs the reasons for this are that aspirin can increase the risk of bleeding and GI irritation it has the potential to cause bleeding issues due to its antiplatelet effect and can exacerbate cardiac failure older patients are also more at risk of the potential side effects so GI irritation increase risking of bleeding increased, risk of kidney side effects
Aspirin should also be used with caution in patients with asthma due to the risk of bronchospasm so an increase in their symptoms.
Interactions with aspirin important ones to consider are interactions with drugs that can increase the risk of GI irritation or bleeding so things such as steroids, NSAIDs, selective serotonin reuptake inhibitors SSRI’s and anticoagulants also drugs that may increase the risk of renal side effects such as Bisphosphonates.
Aspirin is known to reduce the clearance of methotrexate so to increase the toxicity potential of methotrexate.
available preparations our tablets and enteric coated tablets and dispersible tablets suppositories and again there are some compound preparations that are available.
NSAIDs therapeutics
In regular full dosage, NSAIDs have a lasting analgesic and anti-inflammatory effect.
1- Analgesic effects start after administration and full effects are obtained within a week.
2- Anti-inflammatory effect may not be achieved for up to 3 weeks.
The difference in anti-inflammatory effect of the NSAIDs is small and there considerable variations in individual response and tolerance.
Details of this can be found in the BNF it is known that for example diclofenac and naproxen have a slightly increased efficacy to say ibuprofen but the Diclofenac and naproxen do also have increase side effect risk profiles. Celecoxib interocoxib so your Cox 2 inhibitors have a similar efficacy to the naproxen and the Diclofenac have less upper GI issues associated with them but do have some other issues associated with cardiovascular disease so there is this small difference in their anti-inflammatory profiles but each drug has its specific profile related to its side effects as well which needs to be considered.
Selection of an NSAID should be based on the characteristics of the drug and individual patient risk factors for adverse effects;
There is quite a large variation in individual responses to NSAIDs and individual patients tolerances to NSAIDs so the selection should be based on the characteristics of the drug so it’s actual drug profile it’s cautions contraindications side effects and also the characteristics of your patient so the risk factors that they have for adverse effects so the key differences are the effects of these drugs on the gastrointestinal mucosa the kidneys and the cardiovascular system.
Selection of an NSAID should be based on the characteristics of the drug and individual patient risk factors for adverse effects
Key side effects:
-GI mucosa
-Kidney
-Cardiovascular system
Ranking of cyclo-oxygenase selectivity
If an NSAID is indicated for treatment is important that we use the lowest effective dose and use it for the shortest duration possible to reduce risks of the adverse events
GI side effects are thought to be due to the inhibition of the constitutive housekeeping Cox 1 enzyme and its production of its prostaglandins we need to consider the selectivity of the drugs for the different Cox enzymes
NSAIDs and COX-2 inhibitors not all of the drugs on this slide are used so for example rofecoxib has actually been removed from the market however it does show you quite well the different selectivity profiles of the different drugs.
NSAIDs are split into really 3 different groups;
1-Standard NSAIDs; non selective such as ibuprofen indometacin mefenamic acid and naproxen
2- Standard NSAIDs non selective but has more of Cox-2 preference: Diclofenac etodolac and meloxicam
Coxibs so these are selective for your Cox 2: celecoxib & etoricoxib
COX-2 selective NSAIDs were designed to select for COX-2 enzyme with the hope that would lead to less GI side effects, their risk of upper GI side effects is less in comparison to traditional NSAIDs however they still do cause some GI side effects and some of these can be severe.
GI side effects of NSAIDs
NSAIDs are known to cause epithelial damage within the gut, ulceration and bleeding this is caused by suppression of the physiological homeostatic prostanoid inhibition through inhibition of the COX-1 enzyme this causes reduced mucus production in the gut reduced bicarbonate production and reduced mucosal blood flow which increases the risk of damage ulceration and bleeding.
There is also a topical effect these drugs can actually cause direct irritation and damage to the epithelium of the gut.
All NSAIDs associated with GI issues and it’s important for us to consider the drug with the lowest risk when we’re giving it to a patient again the highest instance of GI side effects is in the elderly population they are the most at risk and it’s important that whenever we’re considering NSAIDs for any patient that we’re thinking about their cautions and contraindications of the individual drugs and that we make sure to monitor patients once they are started on therapy.
Selective COX-2 agents-Coxibs-designed to inhibit those prostanoids of COX-2 isoform (involved with inflammation and less important in GI homeostatic roles.
Lower risk of upper GI s/e than non-selective NSAIDs.
What NSAIDs cause serious upper GI s/e? What precautions can be taken to minimise patient risk of GI s/e?
There are differences risk of serious upper GI s/e between the non-selective NSAIDs
NSAIDs are stratified in terms of their risk of GI side effects:
1-Highest risk group Piroxicam
ketoprofen and Ketorolac
2-Intermediate group indometacin Diclofenac and naproxen.
3-Lowest risk group is ibuprofen however that’s only in doses up to 1.2 grams daily which is your standard dose
The lowest risk group are the coxib so your COX-2 selective inhibitors the lowest risk agent is preferred whenever we’re starting a patient on NSAIDs must start at the lowest dose and not use it with another NSAID all of these factors will help to reduce the patients risk of suffering with adverse GI side effects from the NSAIDs
Use NSAIDs for the shortest duration and make sure that we’re reviewing the need for that NSAID on a regular basis also advising that the medication should be taken with food to reduce that contact irritation although this is less related to the risk of GI side effects so even patients that do take their NSAIDS with food may suffer with GI side effects due to the systemic effect
If we can reduce the risk further by telling the patient to have it with food that’s going to help also could potentially help
In patients with the risk of GI effects that have NSAID indicated for use we might want to Co-prescribe them with some gastro protection like a proton pump inhibitor to help to protect their gastrointestinal tract we want to make sure that we are monitoring the patient for adverse effects and that the patients aware these adverse effects self monitor and refer for help if required and also that we’re reviewing the patients risk factors for adverse GI effects
Interactions with other drugs can also increase the risk of GI side effects so use of enzymes with aspirin with other NSAIDs with drugs that can increase the risk of GI ulceration such as steroids and bisphosphonates things that can increase the risk of bleeding such as your SSRI’s and anticoagulants could also increase the risk of GI effects
In terms of monitoring want to make sure that the patient is able to recognise and report signs and symptoms of dyspepsia or GI irritation or burning sensation in the sternum or pain we would also be monitoring a patient’s haemoglobin because that will tell us whether there are any bleeding events going on also that we’re looking out for signs of GI bleeding so they may involve hemoptysis or dark stools.
How do NSAIDs (COX-2) cause CV?
Cardiovascular events many mechanisms have been postulated with in relation to what increases patients risk of cardiovascular events with NSAIDs and it’s believed to be due to increased COX-2 inhibition over COX-1 inhibition of the vasculature the platelets and potential effects on the kidneys.
2004- Rofecoxib withdrawn from market due to fear relating to increased CV-risk.
2005- EMA identified increased risk of thrombotic events-myocardial infraction and stroke with COX-2 inhibitors.
2006- EMA identified that this may also be a problem for non-selective NDAIDs such as Diclofenac
2013- Diclofenac removed from P availability.
2015- EMA confirmed high dose ibuprofen 2.4g or more had increased CV risk compared to COX-2 inhibitors and Diclofenac
CV events
All NSAIDs use can to varying degrees be associated with increased risk of thrombotic events.
Independent of baseline or duration of the use of the NSAID (however the greatest risk is with higher doses over longer periods)
Highest risk groups: COX-2 inhibitors Diclofenac 150mg daily, ibuprofen 2.4g or more daily.
Lower thrombotic risk: Naproxen (1g daily)
No evidence for increased risk: ibuprofen (low dose, 1.2g or less)
To prevent CV use lowest effective dose, for shortest period and review long term use.
CV events contraindications
1- NSAID selection
2- Use lowest effective dose
3- Use for the shortest duration (review need for long term therapy)
4- Monitor for adverse events
5- Review patient for risk factors (irrespective of NSAID risk)
1- COX-2 inhibitors Diclofenac and high dose ibuprofen are contraindicated in ischaemic heart disease, cerebrovascular disease and in some stages of heart failure.
2- Non-selective NSAIDs are cautioned in patients with heart failure, cerebrovascular disease, ischaemic heart disease, risk factors for CVD.
With these two groups use drug with lowest risk, lowest dose and shortest duration of time.
In CV events interactions involve; Antihypertensives as NSAIDs are know to increase patient blood pressure.
Anti-platelet dose of Aspirin (75mg) is reduced with long term use of NSAIDs.
Monitoring for CV events:
*Increase occurrence or first occurrence of CV event
*monitor for Risk factor for increased CV risk- BP- medical history of diabetes/ hypercholesterolaemia.
NSAIDs renal side effects?
Mainly seen in patients where compensatory prostaglandins are playing a role to maintain renal function I.e. advanced age, renal impairment, heart failure, volume depletion, liver cirrhosis.
Prostaglandins have a limited effect in healthy patients.
If NSAID is used in these patient groups this could lead to reduced renal function and this might cause renal failure.
NSAID can cause a decrease in renal blood flow and an increase in acute kidney injury.
NSAIDs increase sodium and water retention which in turn lead to Oedema and hypertension.
NSAIDs should be avoided in those
Patients with the above risk factors or characteristics.
Avoid NSAIDs in severe impairment/avoid or use with caution on other renal impairment.
*use lowest effective dose for the shortest duration
*close monitoring of renal function
What drugs worsen renal function
Interacting drugs that can make the renal effects of NSAIDs worse include other nephrotoxic drugs; diuretics, ACE-inhibitors, Antihypertensive (opposite effect)
NSAIDs decrease Lithium and methotrexate elimination- decreased renal elimination causing toxicity.
Moonitor patient:
Renal function- GFR, urine output, urea
BP
Electrolytes-sodium and potassium
Oedema (weight, visual signs)
What other considerations must be made with NSAIDs?
10-40% of patients can suffer of Bronchospasm due to NSAIDs, there can be cross sensitivities between NSAIDs. For this reason NSAIDs are cautioned in patients who are asthmatic.
Self medication and OTC usage of NSAIDs must be cautioned especially in asthmatic patients who have not used NSAIDs before is not recommended. If used patient is recommended to carry their reliever therapy and stop NSAID if they notice any deterioration of their symptoms.
Topical therapies available systemic absorption can occur especially if it is used over a larger area or if patient use heat therapy alongside their topical preparation this will increase the systemic absorption.
General interactions: consider drug-drug and drug-disease interactions.
*Anticoagulants: patients should not self medicate on NSAIDs as it can increase their risk of bleeding and close monitoring is required if NSAID is used.
Counselling points for patients:
Take the lowest effective dose for the shortest period.
Take with or after food.
Self monitor for signs of GI disturbances-report
Dork self medicate with NSAIDs.
Methotrexate therapeutics
Describe the therapeutics of key medicine used in the management of immune disease.
Methotrexate is used to treat a number of conditions, low dose is used to treat immune diseases, RA, cirrhosis and inflammatory bowl disease. At higher doses is used cancer chemotherapy regimes.
What are the key points on MTX prescribing and usage?
Prescribing of MTX must be done by a specialist or a healthcare professional aware of both risks and benefits of MTX and they must have a prescribing competence in the area to be able to prescribe to patients.
Low dose MTX can be taken orally it has a bioavailability of between 64 and 90% but at higher doses MTX bioavailability decreases due to saturation if it is carrier.
It can be administered via intramuscular route and subcutaneous, parenteral routes are not used first line but can be used to minimise GI side effects of MTX if not improved by increasing dose of folic acid.
Before starting patient on MTX, make sure patient understands it is risks and how to use MTX safely with the right dose.
There are slight differences in dosing for different immune diseases and when using different routes refer to BNF and summary of product characteristics.
Prior to therapy it is advisable for the patient to receive a test dose to rule out idiosyncratic adverse effects of MTX, dose is 2.5mg single one off dose, patient should monitor for any adverse effects associated with MTX.
the frequency of administration is once a week low dose MTX is taken once a week only should be taken on the same day of the week each week. The prescriber should document this on the prescription in full bold and it should say the day of week patient will take it. A prescription should never include the diet trio m as directed should have specified day and once a week with the right dose.
Patient should be appropriately educated about the dosing schedule and patient should be reminded at every opportunity.
Dose and frequency should be clear on the label in line with the prescription.
Alert card patient should complete and carry an alert card.
Guidance states MTX should be prescribed as a single strength of tablet so patient shouldn’t take two strengths to make up their dose.
And two strengths that should only be supplied is 2.5mg of patient dose is 10mg they would end up taking 4 of 2.5mg tablet to give them 10mg once a week. MTX is also available in 10mg tablets.
Time to effect- generally it will take time for MTX to start to have its effect and for that effect to be at maximum
I.e. for RA it can take 6-weeks to begin to work and 12 weeks to feel the maximum effect.
In RA, dose escalation is required to reach the optimal dose:
- 2.5mg to 5mg dose increase every 1-3 weeks
- aim for optimal dose in 4-6 weeks
Before starting therapy- baseline assessment this allows effects of MYX to be measured during therapy:
- Full blood count FBC; white cell count, neutrophil, platelets and Hb. This gives info on bone marrow.
- Liver function test LFT
- Urea and electrolytes U&E
*Renal function ( creatinine, Cr or estimated glomerular filtration rate, eGFR) because greater than 80% of MTX is excreted unchanged in the urine so we need to know how well patient kidney are functioning and how they are handling MTX.
- Chest X-ray baseline testing of chest X-ray to test for signs of pulmonary toxicity.
Patient must be monitored during their therapy- LFT, renal function, FBC- every 1-2 weeks until therapy is stabilised, once stabilised monitoring should be done every 2-3 months BNF guidance for RA but monitoring regimes vary for each condition and local guideline.
Patient and carers also have a responsibility for self monitoring:
Signs of an infection I.e. sore throat, bruising, bleeding- indicating blood disorders.
Nausea, vomiting, abdominal discomfort and dark urine- indicating liver toxicity.
Shortness of breath- indicating respiratory effects.
