CPE Dinner Lecture: NSAIDs and COXIBs in 2010: Where do we Go From here?

Date: 19th December 2009 (Saturday)
Time: 7.00 pm- 8.30 pm
Venue: Sultan 1, Le Meridien Hotel, Kuala Lumpur

Speaker: Prof. Gurkirpal Singh, MD
Adjunct Clinical Professor of Medicine, Stanford University School of Medicine
Chief Science Officer, Institute of Clinical Outcomes Research adn Education Palo Alto, California

Below are some of the issues that Dr. Singh will elucidate in his presentation:

• Does short-term use of NSAIDs increases risk of GI bleeds?
• How can you identify patietns who are at a greater risk of GI bleeds? Dr. Singh has developde as imple six-item questionnaire which can predict future GI risk with about 90% accuracy.
• Does COX-2 selectivity guarantees GI safety?
• Is COX-2 selectivity associated with cardiovascular risk?
• Is NSAID-induced hypertension clinically significant?
  

Agenda

Time	Program
7.00 pm-7.30 pm	Registration
7.30 pm-7.35 pm	Introduction by Chairperson
7.35 pm-8.15 pm	Lecture by Prof Gurkirpal Singh, MD
8.15 pm-8.30 pm	Q & A Session
8.30 pm	Dinner

RSVP by 16th December 2009 to Ms Hema at 03-5568 6688

Please indicate if Vegetarian food required.

1 CPE point will be awarded. For Healthecare Professional Only

Post Exposure Prophylaxis (PEP)

Scenario

A nurse walks in the outpatient pharmacy carrying a written prescription for Combivir® [lamivudine/zidovudine 150 mg/300 mg] 1/1 OD and Metoclopramide. Worry is etched across her face as she tells the pharmacist her fear of post-exposure HIV from a percutaneous injury in the ward. The pharmacist tells her that the average risk for HIV transmission after percutaneous exposure to HIV-infected blood is estimated at only 0.3% and that treatment will further decrease the risk of infection when started within 72 hours.She took her meds and walked away. Relieved? I know not.

The situation above is a good example behind the fact that healthcare workers are constantly exposed to needle stick injuries which occurs all too often. Some sources report that nearly 1 million healthcare workers suffer needle stick injuries each year, increasing the risk for diseases such as Hepatitis B, Hepatitis C or worse, HIV. For that reason, post-exposure prophylaxis (PEP) should be made accesible to all healthcare workers to decrease the incidence of sero-conversion and HIV infection (by 79%).

Risk. Chances of infection varies with a calculated risk related to blood quantity. Increased risk for HIV infection is associated with exposure to larger quantities of blood from the source as indicated by the 1) blood-contaminated device, 2) a procedure that involved the needle being placed directly in a vein or artery or 3) depth of injury. The risk increases when the source is a terminally ill patient, possibly reflecting either a higher titre of HIV in blood late in the course of AIDS or other factors (e.g. the presence of syncytia-inducing strains of HIV). So, be careful.

Moving on to treatment, it is common to prescribe Combivir® on a once daily basis or Zidovudine (AZT, ZVD, Retrovir®) 300mg BD and Lamivudine (3TC, Epivir®) 300mg OD separately for PEP. The advantage behind this regime is that it is supported in a CDC case-control study to decrease the risk of occupational HIV transmission, the side effects (e.g. diarrhea, nausea, vomiting) are predictable and managable and it is safe for pregnant women. The disadvantage is, well, the side effects commonly occur (poor compliance) as well as prior viral resistance to this regime.

There are alternatives to this regime. One of them is the well-tolerated combination of Lamivudine 300mg OD and Stavudine (d4T, Zerit®) 40mg BD and also, the combination of Didanosine (ddl, Videx®) 400mg OD and Stavudine 40mg BD. The course of treatment is around 4 weeks.

In cases where exposure constitues a higher risk of transmission (e.g. larger volume of blood/ higher virus blood titer), Indinavir (Crixivan®) 800mg TDS may be added to a basic regime. In cases of intolerance to Indinavir, Efavirenz (Stocrin®) 600mg ON or Nelfinavir (Viracept®) 1250mg BD or Lopinavir/ Ritonavir (Kaletra® 100mg/25mg) three capsules BD.

Keep in mind that regimes may vary between physicians. In the event of exposure dear pharmacists, approach the nearest doctor or HIV specialist as soon as possible for treatment and evaluation. HIV-antibody testing should be performed for a least 6 months post exposure (6 weeks, 12 weeks then 6 months) along with drug-toxicity assessements (e.g. FBC, LFT and hyperglycemia when using a protease inhibtor).

Do your best to prevent secondary transmissions during the first 6-12 week period after exposure. This means abstain from sex, pregnancy and organ/ blood donations. Breastfeeding is not encouraged either. Remember, compliance towards the prescribed regime is important if you want to be HIV-free.

With reference to Consensus of Antiretroviral Treatment (Second Edition). Ministry of Health. Year 2001.

Warfarin

Despite warfarin's use in clinical practice for over 50 years, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK still receives a substantial number of case reports on adverse reactions with warfarin. As such, the the Summaries of Product Characteristics (SPCs) for all warfarin products are to be amended to give clearer and up-to-date advice to healthcare professionals.

A quick overview of warfarin before we look at the update in the MHRA Public Assessment Report of Dec 2009:

Indication & Duration
Warfarin is an anticoagulant used to treat stroke patients, patients who develop deep vein thrombosis/ are at risk of embolism, and to prevent stroke in patients with atrial fibrillation.

Patients who suffer from atrial fibrillation or have undergone surgery for insertion of mechanical prosthetic heart valves need lifelong therapy with warfarin, while patients with a single episode of deep vein thrombosis require treatment for only 6 months.

Patients are told to take warfarin at 6 p.m. every day to enable blood test to be done the following morning.


Moving on to the updates in the MHRA Public Assessment Report of Dec 2009:
Contraindications
• Known hypersensitivity to warfarin or to any of the excipients
• Haemorrhagic stroke
• Clinically significant bleeding
• Within 72 hours of major surgery with risk of severe bleeding
• Within 48 hours postpartum
• Pregnancy (first and third trimesters)
• Patients on fibrinolytic drugs such as streptokinase and alteplase


Special Warnings & Precautions of Use
1) Commencement of Therapy
INR should be monitored more frequently in patients at an increased risk of over coagulation e.g. patients with severe hypertension, liver or renal disease.

Patients with protein C deficiency are at risk of developing skin necrosis when starting warfarin treatment. In patients with protein C deficiency, therapy should be introduced without a loading dose of warfarin even if heparin is given.


2) Risk of Haemorrhage
Warfarin should be given with caution to patients where there is a risk of serious haemorrhage (e.g. concomitant NSAID use, recent ischaemic stroke, bacterial endocarditis, previous gastrointestinal bleeding).

Risk Factors for Bleeding:

• high intensity of anticoagulation (INR >4.0)
• age ≥65,
• highly variable INRs
• history of gastrointestinal bleeding
• uncontrolled hypertension
• cerebrovascular disease
• serious heart disease
• risk of falling
• anaemia
• malignancy
• trauma
• renal insufficiency
• concomitant drugs (refer to 'drug interactions' below)
  

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed on measures to minimise risk of bleeding and to report signs and symptoms of bleeding to doctors/pharmacists.


3) Ischaemic Stroke
Anticoagulation following an ischaemic stroke increases the risk of secondary haemorrhage into the infarcted brain.

Warfarin treatment should be re-started 2–14 days following ischaemic stroke, depending on the size of the infarct and blood pressure. In patients with large embolic strokes, or uncontrolled hypertension, warfarin treatment should be stopped for 14 days.


4) Surgery
Surgery with no risk of severe bleeding: surgery can be performed with an INR of <2.5

Sugery with risk of severe bleeding: warfarin should be stopped 3 days prior to surgery

Where it is necessary to continue anticoagulation e.g. risk of life-threatening thromboembolism, the INR should be reduced to <2.5> re-instating warfarin therapy depends on the risk of post-operative haemorrhage. In most instances warfarin treatment can be re-started as soon as the patient has an oral intake.


Dental Surgery: Warfarin need not be stopped before routine dental surgery, eg, tooth extraction.


5) Active Peptic Ulceration
Due to a high risk of bleeding, patients with active peptic ulcers should be treated with caution. Such patients should be reviewed regularly and informed of how to recognise bleeding and what to do in the event of bleeding occurring.


6) Thyroid Disorders
The rate of warfarin metabolism depends on thyroid status. Therefore patients with hyper- or hypo-thyroidism should be closely monitored on starting warfarin therapy.


7) Additional Circumstances where Changes in Dose may be required
The following also may exaggerate the effect of warfarin tablets, and necessitate a reduction of dosage:
• Loss of weight
• Acute illness
• Cessation of smoking


The following may reduce the effect of warfarin tablets, and require the dosage to be increased:
• Weight gain
• Diarrhoea
• Vomiting


Drug Interactions
Drugs which should be avoided if possible:
(or administered with caution with increased clinical and laboratory monitoring)
• Clopidogrel
• NSAIDs (including aspirin and cox-2 specific NSAIDS)
• Sulfinpyrazone
• Thrombin inhibitors such as bivalirudin, dabigatran
• Dipyridamole
• Unfractionated heparins and heparin derivatives, low molecular weight heparins
• Fondaparinux, rivaroxaban
• Glycoprotein IIb/IIIa receptor antagonists such as eptifibatide, tirofiban and abciximab
• Prostacyclin
• SSRI and SNRI antidepressants
• Other drugs which inhibit haemostasis, clotting or platelet action

Warfarin is a mixture of enantiomers which are metabolised by different CYPP450 cytochromes. R-warfarin is metabolised primarily by CYP1A2 and CYP3A4. S-warfarin is metabolised primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.


Drugs which Potentiate the Effects of Warfarin

• allopurinol
• amiodarone
• azole antifungals (ketoconazole, fluconazole etc)
• capecitabine
• disulfiram
• erlotinib
• erythromycin
• fibrates
• methylphenidate
• metronidazole
• omeprazole
• paracetamol (prolonged regular use)
• propafenone
• statins (not pravastatin; predominantly associated with fluvastatin)
• sulfamethoxazole
• tamoxifen
• zafirlukast

Drugs which Antagonise the Effect of Warfarin

• azathioprine
• barbiturates
• carbamazepine
• griseofulvin
• oral contraceptives
• phenytoin
• primidone
• rifampicin

Drugs with Variable Effect

• corticosteroids
• nevirapine
• ritonavir

Other Drug Interactions
Broad spectrum antibiotics may potentiate the effect of warfarin by reducing the gut flora which produce vitamin K. Similarly, orlistat may reduce absorption of vitamin K. Cholestyramine and sucralfate potentially decrease absorption of warfarin.



Interactions with Herbal Products
These products are best avoided when patient is on warfarin (according to “Stockley’s herbal medicines interactions”):

Coenzyme Q10(ubidecarenone)
(A controlled study found no interaction. Reduced warfarin effects have been reported in four cases and increased effects have been reported in others.)

Danshen (Salvia miltiorrhiza)
(There have been three cases of markedly increased INRs and bleeding, and one animal study suggests increased warfarin bioavailability. Danshen may have some antiplatelet effects.)

Dong quai (Chinese angelica; Angelica sinensis)
(There have been two cases of markedly increased INRs and two experimental studies suggesting a modest increase in prothrombin times with dong quai.)

Feverfew (Tanacetum parthenium)
Fenugreek together with boldo (Peumus boldus)

Fish oil supplements containing eicosapentaenoic acid and docosahexaenoic acid
(Two studies in patients found no interaction (increase in INR or bleeding time), but one study found an increased bleeding time. There is an isolated and unexplained case of raised INR but no bleeding

High doses of these products increase the risk of bleeding, so some caution is appropriate.)

Ginkgo biloba
(Studies in patients and healthy subjects found no interaction, but there is an isolated and unexplained case of bleeding, and a few cases of bleeding with ginkgo alone.)

Ginseng
(A controlled study using P ginseng found no interaction, whereas two case reports describe reduced anticoagulation. Another controlled study using P quinquefolius found a small reduction in warfarin effects.)

Glucosamine with or without chondroitin
(increased INR has been reported in patients taking glucosamine and warfarin)

St John’s wort (Hypericum perforatum)
(controlled studies and case reports describe a small reduction in warfarin effects)

Vitamin K
(Vitamin K is an antidote to warfarin. Small doses (10 to 50µg) in multivitamin supplements are probably unimportant in those with normal vitamin K status, but good monitoring is advisable when starting or stopping the supplement.)

Wintergreen (topical methyl salicylate)
(Some reports of increased warfarin effects (raised INRs, bleeding) with topical methylsalicylate. )


Alcohol
Acute ingestion of a large amount of alcohol may inhibit the metabolism of warfarin and increase INR. Conversely, chronic heavy alcohol intake may induce the metabolism of warfarin. Moderate alcohol intake can be permitted.


Interactions with food
Patients should be advised to avoid cranberry products as individual case reports suggest a possible interaction between warfarin and cranberry juice, in most cases leading to an increase in INR or bleeding event.

Certain foods such as liver, broccoli, Brussels sprouts and green leafy vegetables contain large amounts of vitamin K. Sudden changes in diet can potentially affect control of anticoagulation. Patients should be informed of the need to seek medical advice before undertaking any major changes in diet.


Pregnancy & Lactation
Warfarin is contraindicated in pregnancy in the 1st and 3rd trimester. (Warfarin causes congenital malformations and foetal death when administered during pregnancy.)

Women of child-bearing age who are taking warfarin tablets should use effective contraception during treatment.

Warfarin can be used during breast-feeding.
Although warfarin is excreted in breast milk in small amounts, at therapeutic does of warfarin no effects on the breast-feeding child are anticipated.


Management of Warfarin Overdose

Condition	Management
Pt presents within 1 hour of ingestion of > 0.25 mg/kg or > pt’s therapeutic dose	activated charcoal (50 g for adults; 1 g/kg for children)
Life-threatening haemorrhage	Stop warfarin treatment Give prothrombin complex concentrate (factors II, VII, IX, and X) 30–50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg, or both.
Non-life threatening haemorrhage where anticoagulation can be suspended where rapid re-anticoagulation is desirable	Give slow intravenous injection of phytomenadione (vitamin K1) 10–20 mg for adults (250 micrograms/kg for a child) Give prothrombin complex concentrate (factors II, VII, IX, and X) 30–50 units/kg or (if no concentrate available) fresh frozen plasma 15 mL/kg. [Monitor INR to determine when to restart normal therapy. Monitor INR for at least 48 hours post overdose.]
Pt on long-term warfarin therapy without major haemorrhage INR >8·0, no bleeding or minor bleeding INR 6·0–8·0, no bleeding or minor bleeding INR <6·0 but > 0·5 units above target value	Stop warfarin. Give phytomenadione (vitamin K1) 0·5–1 mg for adults, 0·015–0·030 mg/kg for children by slow intravenous injection or 5 mg by mouth. (for partial reversal of anticoagulation give smaller oral doses of phytomenadione eg, 0·5–2·5 mg using the intravenous preparation orally) Repeat dose of phytomenadione if INR still too high after 24 hours. [Large doses of phytomenadione may completely reverse the effects of warfarin and make re-establishment of anticoagulation difficult.] Stop warfarin, restart when INR <5·0 Reduce dose or stop warfarin, restart when INR <5·0
Pt NOT on long-term anticoagulants without major haemorrhage	Measure the INR (prothrombin time) at presentation and sequentially every 24–48 hours after ingestion depending on the initial dose and initial INR. If the INR remains normal for 24–48 hours and there is no evidence of bleeding, there should be no further monitoring necessary. Give vitamin K1 (phytomenadione) if: a) there is no active bleeding and the patient has ingested more than 0·25 mg/kg; OR b) the prothrombin time is already significantly prolonged (INR >4·0).

The adult dose of vitamin K1 is 10–20 mg orally (250 micrograms/kg body weight for a child). Delay oral vitamin K1 at least 4 hours after any activated charcoal has been given. Repeat INR at 24 hours and consider further vitamin K1.

References:
The Medicines and Healthcare products Regulatory Agency public assessment report. Dec 2009.
http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywar
ningsandmessagesformedicines/index.htm

Youssef S. Patients taking warfarin: problems revealed by medicines use reviews. http://www.pjonline.com/news/patients_taking_warfarin_problems_revealed_by_medicines_use_reviews

Stockley IV and Lee CR. Can I take herbal products or dietary supplements with my warfarin?
http://www.pjonline.com/cpd/can_i_take_herbal_products_or_dietary_supplements_with_my_warfarin

Dutasteride vs Finasteride

My hospital is currently running low for the stock of finasteride, and they changed finasteride 5mg to dutasteride 0.5mg.

Rationale :
1) Preliminary data from a 2-year study comparing dutasteride (0.5-milligram (mg) daily or greater) and finasteride indicated greater decreases in serum dihydrotestosterone with dutasteride after 24 weeks of treatment (at least 95% versus 70%)

Anon: FDC Reports: The Pink Sheet: GSK Dutasteride vs Merck Proscar data for BPH expected by mid-2002. November 26 2001a; 63(48):3

2) Patients with symptomatic BPH who receive dutasteride or finasteride, either as monotherapy or combination therapy with α-blockers, can expect to experience significant prostate gland size reduction, improved symptoms, and reduced risk of progression in terms of long-term adverse outcomes.

Nickel JC. Comparison of Clinical trials with finasteride and dutasteride. Rev Urol 2004; 6: S31-S39.

Paraquat Poisoning

Yesterday afternoon, I came across a case of paraquat poisoning by a 14-year old Indian boy in the ward. He was brought to A&E the previous night and on enquiry, claimed that he drank 1 gulp of weed killer after scolded by his mother. In the ward, he was given:

• activated charcoal 25 g 4 hourly
• fuller's earth 60 g hourly [consists of hydrated aluminium silicates]
  
• 3 pint normal saline & 2 pint dextrose 5% over 24 hours [to promote diuresis]
  

The patient's urine was tested postive for paraquat, hence he and his parents have been informed of his prognosis-Dead in List =(

I guess most of you are aware of the the recent tragedy that struck a Malaysian family (the mother gave drinks laced with paraquat to her 4 children before drinking it her herself). From conversations with other healthcare professionals, it is found out that paraquat poisoning is very common among the Indian community in the estate due to its availability and possibly, their ignorance of the serious implication (most suicidal attempts were impulsive, and they didn't really mean to end their lives). I have googled paraquat poisoning and here are some of my findings:


What is Paraquat
Paraquat is used to prepare land for planting or control weeds in major food crops. It is highly poisonous to humans, but becomes inactive upon adsorption with clay in soil or water.

In the United States, paraquat is classified as "restricted use," which means that it can be used only by licensed applicators. In the European Union, paraquat has been forbidden since July 2007. However, it is readily available in Malaysia and other developing countries.

Due to its toxicity, the form of it that is marketed in the United States has a blue dye to keep it from being confused with beverages such as coffee, a sharp odour to serve as a warning, and an added agent to cause vomiting if someone drinks it. If only the paraquats marketed in Malaysia have these safeguards added.


Clinical Manifestations of Paraquat Poisoning
Major acute effects- ulceration of skin, lips, tongue, pharynx and oesophagus
Acute systemic effects- pulmonary oedema, cardiac, renal or hepatic failure and convulsions

After a person ingests a large amount of paraquat, he or she is likely to immediately have pain and swelling of the mouth and throat. The next signs of illness following ingestion are gastrointestinal (digestive tract) symptoms, such as nausea, vomiting, abdominal pain, and diarrhoea (which may become bloody).

Following ingestion of greater than 50ml of the liquid concentrate, the patient may develop pulmonary oedema, cardiac failure, renal failure, liver failure and also convulsions caused by central nervous system involvement. Under these circumstances, death may occur within several hours to a few days as a result of multiple organ failure.

Ingestion of a smaller volume (10 ml to 20 ml) of the concentrate produces the same symptoms with the exception that the development of renal failure occurs within 2-6 days after ingestion.

Mechanism of Paraquat Poisoning
In the lungs, the paraquat ion undergoes a continuous redox process to form free radicals capable of reacting with oxygen. This reaction leads to the production of a reactive oxygen also known as superoxide anion and the regeneration of the paraquat ions. Subsequently, these ions may react to form the highly reactive hydroxyl radical, which is thought to be responsible for lipid peroxidation and cell death.

As oxygen exacerbates the destruction of lung tissues, supplemental oxygen should not be given as an initial measure. Oxygen is recommended only if fraction of inspired oxygen (FiO2) falls below 50%.


Management
Sadly, there is no clinically proven antidote for paraquat poisonining and treatment is generally supportive.

• Prevention of absorption

Gastric lavage should be performed immediately, if possible within 2 hours after ingesting paraquat (reduce further absorption of paraquat into the bloodstream.)

Following gastric emptying, the administration of mineral absorbents such as Fuller's Earth or activated charcoal is initiated to remove any unabsorbed paraquat remaining in the gastrointestinal tract.

In some cases, cathartics, for example magnesium sulphate, magnesium citrate or sorbitol, may be given every 4 hours either concurrently or separately with the absorbents.

• Enhancement of elimination

The recommended regimen for increased paraquat excretion from the blood is haemoperfusion, which has been shown to increase the chance of survival among poisoned patients. Using this approach, the haemoperfusion may be repeated until the paraquat level remains below a certain value, normally 0.01 mg/ml.



Interesting Facts (But Efficacy Not Proven)
In a study involving 375 patients, intensive antioxidant therapy (N-acetylcysteine, glutathione, vitamin C) was given in the hope that it may scavenge oxidants. Only 29.3% patients survived.

Some groups advocate routine use of antioxidants (Vitamin C 4000 mg/day and Vitamin E 250 mg/day) even though their efficacy is unproven.

Pulse therapy using steroids (methylprednisolone or dexamethasone) and cyclophosphamide has been shown to be effective in preventing pulmonary fibrosis by some authors and not so by others.

Food for thoughts:

There are actually some anti-paraquat lobby groups in overseas!

Perhaps our government should have tighter regulations on paraquat usage? (like in the States)

In view of the intentional suicidal attempts with paraquat, education to the public on paraquat is important as some people may not know that it is that fatal.

I wonder what the child was thinking when the doctor told him about his condition. When I saw him at the ward, he seemed fine emotionally, but I wouldn't know what was going through in his mind. Sad case indeed =(

Have you come across any paraquat poisoning at your hospital or klinik kesihatan? Do share with us the management practised there.

References:

Centers for Disease Control and Prevention; Available from: URL: http://www.bt.cdc.gov/agent/paraquat/basics/facts.asp

Dr. Mohd. Isa Abdul Majid. Know your pesticides: paraquat. Available from: URL: http://www.prn2.usm.my/mainsite/bulletin/sun/1997/sun13.html

BMJ Group Blogs. Louise Kenny on paraquat poisoning. Available from: URL: http://blogs.bmj.com/bmj/2009/11/12/louise-kenny-on-paraquat-poisoning

Sandhu JS et al. Outcome on paraquat poisoning-a five year study. Indian J Nephrol 2003;13: 64-68. Available from: URL: http://www.asiatox.org/6th%20APAMT%20pdf/Therapeutic%20approach%20to%20paraquat%20poisoning..pdf

Hong S-Y. Therapeutic approach to paraquat poisoning. Available from: URL: http://medind.nic.in/iav/t03/i2/iavt03i2p64.pdf