Clinical indications and therapeutic actions
NSAID's are a group of drugs that are used for their analgesic and anti-pyretic effect, to relieve stiffness and for inflammation against rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders. In this assignment three drugs, which are Ibuprofen, Diclofenac and Etoricoxib, will be compared together. The three drugs chosen are: Ibuprofen which is a propionic acid derivative, Diclofenac which is a phenylacetic acid derivative and Etoricoxib which is a coxib.
The three drugs, like all the other NSAID'S, helps in relieving symptoms of the painful conditions the patient is suffering from but they do not cure the disease. Indications include:
Inflammatory diseases and rheumatoid disorders including juvenile rheumatoid arthritis, mild-to-moderate pain, fever, dysmenorrhea, osteoarthritis
Ankylosing spondylitis, primary dysmenorrhea, acute and chronic treatment of rheumatoid arthritis, osteoarthritis, postoperative pain
Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis and acute pain
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Table 1 Clinical indications that are relieved by ibuprofen, diclofenac and etoricoxib.
They are all considered as effective against pain when prescribing the appropriate dosage regimen. But some are more potent than others. Example Diclofenac is more potent than Ibuprofen.
Ibuprofen, paracetamol, aspirin
Diclofenac, co-codamol, co-dydramol
Table 2 showing ibuprofen and diclofenac graded in terms of potency according to http://www.nmhct.nhs.uk/pharmacy/protocol-analgesia.html
During a study in patients suffering from osteoarthritis, it was evaluated that when giving etoricoxib 30mg daily, it was observed that it will have similar efficacy in treating pain to ibuprofen 2400mg given daily. Etoricoxib 60mg daily have similar efficacy in treating pain to diclofenac 150mg given daily. Merck &Co. announced results in 2006 of the MEDAL programme showing that Etoricoxib have similar efficacy to Diclofenac with similar risk of cardiovascular events while etoricoxib shows less risk of gastrointestinal side effects when compared to diclofenac.
The following table shows case studies from forums over the internet about patients taking one of ibuprofen, diclofenac and etoricoxib and asking if they can take another drug since no therapeutic action was observed or due to undesirable side effects.
Patient taking ibuprofen for about 8 years was experiencing acid indigestion and heartburn
Patient was suggested Voltarol patches (diclofenac) or etoricoxib
Patient was complaining that ibuprofen didn't have any effect on her bad headache
Diclofenac was suggested to the individual.
Patient complaining that ibuprofen "didn't really have much of an effect" and diclofenac "seems to be the only thing that works well"
Another patient responded him saying that he "had been on diclofenac for 10 years and works well" and telling him to return to the GP for the prescription instead of buying over-the-counter medicines.
Patient was taking ibuprofen for sciatica for 6 weeks but no therapeutic action was observed.
The patient's GP prescribed him diclofenac with omeprazole which relieved him from pain without any side effects.
Table 3 Showing case four case studies about patients taking an NSAID over the internet from www.pharmacyreviewer.com, www.arthritiscare.org.uk.
Therefore we come to a conclusion that Ibuprofen is prescribed for mild to moderate pain and from the 3 drugs, ibuprofen is the preferred choice in children.
Diclofenac is more stronger than Ibuprofen so it is prescribed where pain maybe stronger or where the patient is not happy with the therapeutic action of Ibuprofen.
Etoricoxib maybe preferred to diclofenac when the patient might be at risk of developing a stomach ulcer while diclofenac is preferred to etoricoxib when the patient might be at risk of a heart attack. Although recently there has been some studies on the potential of cardiovascular effects that can arise due to ibuprofen and diclofenac, long term use of diclofenac must be discussed as well in order to establish that the beneficial therapeutic actions of diclofenac are superior to its side effects. The FDA, in its non-approval letter to Merck, had asked to be shown that the therapeutic actions of etoricoxib must be good enough to eliminate its cardiovascular risk.
Mode of action of these 3 drugs at molecular level
The 3 drugs act by inhibiting the cyclooxygenase (COX) enzyme, the enzyme that converts arachidonic acid into prostaglandin H2. The enzymes involved are COX-1 and COX-2. By inhibiting the prostaglandin production, the analgesic, anti-inflammatory and anti-pyretic effects are achieved. It is believed that inhibition of the COX-1 leads to the gastrointestinal side effects and that the therapeutic actions are achieved through the inhibition of the COX-2.
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The traditional NSAID's, ibuprofen and diclofenac, inhibit both COX-1 and COX-2 reversibly. Ibuprofen and diclofenac competes with arachidonic acid for the active binding site in the COX enzyme. The difference between diclofenac and ibuprofen is that diclofenac is time dependent.
Weakly COX-1 selective
Weakly COX-2 selective
Very COX-2 selective
Table 4 showing the selectivity of the three drugs towards the COX enzymes
Figure 1 showing the COX1/COX2 selectivity ratio of the three drugs
Etoricoxib is different from ibuprofen and diclofenac as it selectively inhibits the COX-2, the enzyme that is less responsible for damaging the gastrointestinal lining. Diclofenac may have a low preference towards COX-2 than COX-1. This shows why diclofenac at high doses taken for a long period of time may have the same risks at causing cardiovascular side effects as etoricoxib.
The three drugs also have the potential to inhibit thromboxane A2 to a certain extent that may hinder platelet aggregation. Hence such interactions with warfarin can be dangerous by increasing their anticoagulant effect.
The pharmacokinetic parameters involve the ADME properties of the drug i.e. absorption, distribution, metabolism and excretion.
Ibuprofen is rapidly absorbed following an oral administration with peak plasma concentration levels occurring after approximately 2 hours or less. Peak plasma concentration levels for diclofenac and etoricoxib appears after approximately 1 to 6 hrs and approximately 1 to 3 hours respectively. Tmax depends on the form of tablet and if the patient is fasting or taking the drug after meal.
Volume of Distribution
Table 5 showing some of the pharmacokinetic parameters of ibuprofen, diclofenac and etoricoxib
The mean oral bioavailability of etoricoxib at steady state is approximately 100% while the bioavailability of diclofenac and ibuprofen are approximately 55% and between 49 and 73% respectively . The volume of distribution of ibuprofen is very low compared to that of diclofenac and etoricoxib. The three drugs are highly protein bound in the human plasma.
All of the three drugs are extensively metabolised in the liver mainly by oxidation and by conjugation with glucuronic acid to form metabolites with very weak or mostly no activity.
The half lives of the three drugs are:
Table 6 showing the half life of ibuprofen, diclofenac and etoricoxib
This shows that etoricoxib can be given once daily in a single dose while for ibuprofen and diclofenac you need to give repeated doses in order to maintain the plasma concentration levels within the therapeutic window. The duration of action of ibuprofen is approximately 10 hours compared with approximately 24 hours of etoricoxib when admistered in a 120mg dose.
The plasma clearance of diclofenac is approximately 260mls/minute compared to that of etoricoxib which is 50mls/minute. Elimination of the three drugs occurs mainly by renal excretion. Approximately 10% of unchanged ibuprofen is excreted while for diclofenac, only less than 1% is excreted unchanged. Less than 2% etoricoxib was excreted unchanged as well.
Pharmacokinetic studies on how the drugs would affect special populations were done as well. Patients with hepatic impairment metabolised ibuprofen, diclofenac and etoricoxib with no any significant difference from those with a 'normal' liver. Patients with renal impairment also did not have any significant difference in eliminating the drug compared to other patients with proper renal function although the elimination of metabolites of diclofenac may be reduced in patients with renal impairment, even if the small percentage of the unchanged diclofenac is excreted at the normal rate. Also the three drugs have similar pharmacokinetic properties in geriatrics compared to a healthy adult.
Increase risk of bleeding and GI ulcers
Decrease the effects of these drugs
Increase drug concentration in the plasma
Increase kidney toxicity
Enhance antiplatelet effect
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Table 7 showing the drug interactions of ibuprofen, diclofenac and etoricoxib in which all the interactions are the same for the three drugs.
Side effect profile
These three drugs can give rise to serious side effects. The most famous are the gastrointestinal side effects for the traditional ibuprofen and diclofenac and the serious cardiovascular side effects that can be due to the COX-2 selective inhibitor etoricoxib. Ibuprofen has a lower risk at producing gastrointestinal sideffects than diclofenac while etoricoxib has lower risk than ibuprofen. Etoricoxib, being a COX-2 selective, can result in serious cardiovascular effects but long term usage of high dose diclofenac can have the same risks as etoricoxib to cause these serious effects. Ibuprofen has a lower risk than etoricoxib and diclofenac but still can cause these events if used for a long period with high doses. The cause of the cardiovascular side effects is due to the drug blocking the COX 2 enzyme which is responsible for the fatty acids that protect the heart.
Other side effects that can happen in the three drugs include:
Headache, hypersensitivity reactions, dizziness, nervousness, depression, insomnia, depression, vertigo, hearing disturbances, hypertension and exacerbation of asthma and with etoricoxib fatigue, dry mouth and chest pains can occur less commonly.
Table 8 showing side effects of ibuprofen, diclofenac and etoricoxib.
Some reported side effects over the internet were:
"I take 100mg of Diclofenac Sodium once a day. I now have a numbing sensation in my arm and it makes me rather light headed. It does get rid of the pain but I worry about the long term affects."
"I was recently prescribed Diclofenac following surgery to alleviate inflammation. I have suffered extreme diarrhoea and pain in my upper left abdominal area. This pain and diarrhoea lingered for 2 days after discontinuing the medication. It was so severe that I had blood in my stools. Please be aware that these side affects can be very serious."
"Within about 30 minutes my stomach was gurgling and I had heartburn, just praying it goes away and nothing serious is going on like bleeding"
Female patient, 78 years of age, was diagnosed with back pain, osteoporosisÂ and was treated with Etoricoxib. After drug was administered, patient experienced the following side effects: transient ischaemic attack.
Table 9 showing side effects reported over the internet from www.rsdalert.co.uk, www.askapatient.com, www.patientsville.com.