(Diclofenac Sodium)

1.   What Voltarol Tablets are, and what they are used for

Diclofenac sodium, the active ingredient in Voltarol Tablets, is one of a group of medicines called non-steroidal anti-inflammatory drugs (NSAIDs).  NSAIDs reduce pain and inflammation.

•     Voltarol Tablets relieve pain, reduce swelling and ease inflammation in conditions affecting the joints, muscles and tendons including:

Rheumatoid arthritis, osteoarthritis, acute gout, ankylosing spondylitis Backache, sprains and strains, soft tissue sports injuries, frozen shoulder, dislocations and fractures Tendonitis, tenosynovitis, bursitis.

•     They are also used to treat pain and inflammation associated with dental and minor surgery.

•     In children Voltarol Tablets are used to treat juvenile chronic arthritis.

2.    Things to consider before you start to take Voltarol Tablets

Some people MUST NOT take Voltarol Tablets. Talk to your doctor if:

•   you think you may be allergic to diclofenac sodium, aspirin, ibuprofen or any other

NSAID, or to any of the other ingredients of Voltarol Tablets.  (These are listed at the end of the leaflet.)  Signs of a hypersensitivity reaction include swelling of the face and mouth (angioedema), breathing problems, runny nose, skin rash or any other allergic type reaction

•   you have now, or have ever had, a stomach (gastric) or duodenal (peptic) ulcer, or

bleeding in the digestive tract (this can include blood in vomit, bleeding when emptying bowels, fresh blood in faeces or black, tarry faeces)

•   you have had stomach or bowel problems after you have taken other NSAIDs

•   you have severe heart, kidney or liver failure

•   you are more than six months pregnant.

You should also ask yourself these questions before taking Voltarol Tablets:

•     Do you suffer from any stomach or bowel disorders including ulcerative colitis or Crohn’s disease?

•     Do you have kidney or liver problems, or are you elderly?

•     Do you have a condition called porphyria?

•     Do you suffer from any blood or bleeding disorder? If you do, your doctor may ask you to go for regular check-ups while you are taking these tablets.

•     Have you ever had asthma?

•     Are you breast-feeding?

•     Do you have heart problems, or have you had a stroke, or do you think you might be at risk of these conditions (for example, if you have high blood pressure, diabetes or high cholesterol or are a smoker)?

•     Do you have Lupus (SLE) or any similar condition?

•     Do you have an inherited intolerance to some sugars such as lactose?   (Voltarol Tablets contain a small amount of lactose.)

If the answer to any of these questions is YES, discuss your treatment with your doctor or pharmacist because Voltarol Tablets might not be the right medicine for you.

Are you taking other medicines?

Some medicines can interfere with your treatment. Tell your doctor or pharmacist if you are taking any of the following:

•     Medicines to treat diabetes

•     Anticoagulants (blood thinning tablets like warfarin)

•     Diuretics (water tablets)

•     Lithium (used to treat some mental problems)

•     Methotrexate (for some inflammatory diseases and some cancers)

•     Ciclosporin and tacrolimus (used to treat some inflammatory diseases and after transplants)

•     Quinolone antibiotics (for infections)

•     Any other NSAID or COX-2 (cyclo-oxgenase-2) inhibitor, for example aspirin or ibuprofen

•     Mifepristone (a medicine used to terminate pregnancy)

•     Cardiac glycosides (for example digoxin), used to treat heart problems

•     Medicines known as SSRIs used to treat depression

•     Oral steroids (an anti-inflammatory drug)

•     Medicines used to treat heart conditions or high blood pressure, for example beta-blockers or ACE inhibitors.

•     Sulfinpyrazone (a medicine used to treat gout) or voriconazole (a medicine used to treat fungal infections).

•     Phenytoin (a medicine used to treat seizures).

Always tell your doctor or pharmacist about all the medicines you are taking.  This means medicines you have bought yourself as well as medicines on prescription from your doctor.

Pregnancy

•     Are you pregnant or planning to become pregnant? Although not common, abnormalities have been reported in babies whose mothers have taken NSAIDs during pregnancy. You should not take Voltarol Tablets during the last 3 months of pregnancy as it may affect the baby’s circulation.

•     Are you trying for a baby? Taking Voltarol Tablets may make it more difficult to conceive.  You should talk to your doctor if you are planning to become pregnant, or if you have problems getting pregnant.

Will there be any problems with driving or using machinery?

Very occasionally people have reported that Voltarol Tablets have made them feel dizzy, tired or sleepy. Problems with eyesight have also been reported. If you are affected in this way, you should not drive or operate machinery.

Other special warnings

•     You should take the lowest dose of Voltarol for the shortest possible time, particularly if you are underweight or elderly.

•     There is a small increased risk of heart attack or stroke when you are taking any medicine like Voltarol. The risk is higher if you are taking high doses for a long time. Always follow the doctor’s instructions on how much to take and how long to take it for.

•     Whilst you are taking these medicines your doctor may want to give you a check-up from time to time.

•     If you have a history of stomach problems when you are taking NSAIDs, particularly if you are elderly, you must tell your doctor straight away if you notice any unusual symptoms.

•     Because it is an anti-inflammatory medicine, Voltarol may reduce the symptoms of infection, for example, headache and high temperature. If you feel unwell and need to see a doctor, remember to tell him or her that you are taking Voltarol.

•     The 50 mg tablets are not suitable for children aged under 12.

3.   How to take Voltarol Tablets

The doctor will tell you how many Voltarol Tablets to take and when to take them. Always follow his/her instructions carefully. The dose will be on the pharmacist’s label.  Check the label carefully. If you are not sure, ask your doctor or pharmacist. Keep taking your tablets for as long as you have been told, unless you have any problems.  In that case, check with your doctor.

Take the tablets before or with food.

Swallow the tablets whole with a drink of water. Do not crush or chew the tablets.

The usual doses are: Adults and children over 12 75 mg to 150 mg daily divided into two or three doses. The number of tablets which you take

will depend on the strength the doctor has given you.

Elderly

Your doctor may advise you to take a dose that is lower than the usual adult dose if you are elderly. Your doctor may also want to check closely that the Voltarol Tablets are not affecting your stomach.

Children aged 1-12 years

Doses vary with the age and weight of the child. The usual dose is 1 mg to 3 mg per kilogram of body weight a day. This is usually divided into two or three separate doses.

The doctor may also prescribe another drug to protect the stomach to be taken at the same time, particularly if you have had stomach problems before, or if you are elderly, or taking certain other drugs as well.

What if you forget to take a dose?

If you forget to take a dose, take one as soon as you remember. If it is nearly time for your next dose, though, just take the next dose and forget about the one you missed.  Do not double up on the next dose to make up for the one missed. Do not take more than 150 mg (three 50 mg tablets or six 25 mg tablets) in 24 hours.

What if you take too many tablets?

If you, or anyone else, accidentally takes too much, tell your doctor or your nearest hospital casualty department. Take your medicine pack with you so that people can see what you have taken.

4.   Possible side effects

Voltarol Tablets are suitable for most people, but, like all medicines, they can sometimes cause side effects.

Some side effects can be serious

Stop taking Voltarol Tablets and tell your doctor straight away if you notice:

•     Stomach pain, indigestion, heartburn, wind, nausea (feeling sick) or vomiting (being sick)

•     Any sign of bleeding in the stomach or intestine, for example, when emptying your bowels, blood in vomit or black, tarry faeces

•     Allergic reactions which can include skin rash, itching, bruising, painful red areas, peeling or blistering

•     Wheezing or shortness of breath (bronchospasm)

•     Swollen face, lips, hands or fingers

•     Yellowing of your skin or the whites of your eyes

•     Persistent sore throat or high temperature

•     An unexpected change in the amount of urine produced and/or its appearance.

If you notice that you are bruising more easily than usual or have frequent sore throats or infections, tell your doctor.

The side effects listed below have also been reported.

Up to 1 in 10 people have experienced:

•     Stomach pain, heartburn, nausea, vomiting, diarrhoea, indigestion, wind, loss of appetite

•     Headache, dizziness, vertigo

•     Skin rash or spots

•     Raised levels of liver enzymes in the blood.

Between 1 in 100,000 and 1 in 100 people have experienced:

•     Stomach ulcers or bleeding (there have been very rare reported cases resulting in death, particularly in the elderly)

•     Drowsiness, tiredness

•     Hypotension (low blood pressure, symptoms of which may include faintness, giddiness or light headedness)

•     Skin rash and itching

•     Fluid retention, symptoms of which include swollen ankles

•     Liver function disorders, including hepatitis and jaundice.

Isolated side-effects, reported in less than 1 in 100,000 people include:

Effects on the nervous system:

Tingling or numbness in the fingers, tremor, blurred or double vision, hearing loss or impairment, tinnitus (ringing in the ears), sleeplessness, nightmares, mood changes, depression, anxiety, mental disorders, confusion, hallucinations, malaise, disorientation and loss of memory, fits, headaches together with a dislike of bright lights, fever and a stiff neck, disturbances in sensation.

Effects on the stomach and digestive system:

Constipation, inflammation of the tongue, mouth ulcers, taste changes, lower gut disorders (including inflammation of the colon).

Effects on the heart, chest or blood:

Palpitations (fast or irregular heart beat),    chest pain, hypertension (high blood pressure), inflammation of blood vessels (vasculitis), inflammation of the lung (pneumonitis), congestive heart failure, blood disorders (including anaemia).

Effects on the liver or kidneys:

Kidney or liver disorders, presence of blood or protein in the urine.

Effects on skin or hair:

Serious skin rashes including Stevens-Johnson syndrome and Lyell’s syndrome and other skin rashes which may be made worse by exposure to sunlight.

Hair loss.

Other effects:

Inflammation of the pancreas, impotence.

Medicines such as diclofenac may be associated with a small increased risk of heart attack or stroke.

Do not be alarmed by this list – most people take Voltarol Tablets without any problems.

If any of the symptoms become troublesome, or if you notice anything else not mentioned here, please go and see your doctor. He/she may want to give you a different medicine.

5.    How to store Voltarol Tablets

Store in a dry place, below 30°C. Keep the tablets in their original pack.

Keep out of the reach and sight of children.

Do not take Voltarol Tablets after the expiry date which is printed on the outside of the pack.

If your doctor tells you to stop taking the tablets, please take any unused tablets back to your pharmacist to be destroyed.   Do not throw them away with your normal household water or waste. This will help to protect the environment.

6.     Further information

The tablets come in two strengths containing either 25 mg or 50 mg of the active ingredient, diclofenac sodium. The tablets are enteric-coated. This special coating prevents absorption of diclofenac sodium in the stomach, reducing the risk of stomach irritation.  It is absorbed when it reaches the intestine.

The tablets also contain the inactive ingredients silicon dioxide, lactose, maize starch, sodium starch glycollate, povidone, microcrystalline cellulose, magnesium stearate, hydroxypropylmethylcellulose, polyethoxylated castor oil, talc, titanium dioxide, methacrylic acid copolymer, polyethylene glycol, silicone, yellow iron oxide, red iron oxide (50mg tablets only).

The 25 mg tablets come in blister packs containing 84 tablets. The 50 mg tablets come in blister packs containing 14 or 84 tablets.

The launch of highly effective biological therapies in the late 1990s — in particular, the tumor necrosis factor-alpha (tumor necrosis factor-alpha) inhibitors — has dramatically improved the therapeutic options available for the treatment of rheumatoid arthritis (rheumatoid arthritis). The availability of these effective, albeit expensive, agents has significantly raised the bar for emerging therapies in the rheumatoid arthritis market. Despite the steep competition in developing therapies for this market, a vast number of agents, many of them biologies, are under development for the treatment of rheumatoid arthritis.

This discussion focuses on emerging therapies that have mLed comparatively late-stage development for rheumatoid arthritis (i.e., Phase II or later trials, for which clinical results are available). TABLE . Emerging Therapies in Development for Rheumatoid Arthritis summarizes emerging therapies in late-stage development for rheumatoid arthritis. The discussion of emerging therapies is organized in this section according to their mechanisms of action.

Tumor Necrosis Factor-a Inhibitors

Overview

Inhibitors of tumor necrosis factor-alpha represent the most recent and significant advance in the treatment of rheumatoid arthritis. The first anti-tumor necrosis factor-alpha agent approved for rheumatoid arthritis, etanercept (Amgen/Wyeth/Takeda’s Enbrel), was launched in the United States in 1998. Since then, two other agents have entered the market — infliximab (Centocor [a Johnson&Johnson subsidiary]/Schering-Plough/Tanabe Seiyaku’s Remicade) and adalimumab (Abbott/Eisai’s Humira). Because of the relatively high cost and risk of immunomodulatory side effects associated with these agents, researchers have directed their attention toward the development of improved anti-tumor necrosis factor-alpha therapies for the treatment of rheumatoid arthritis. Different approaches to targeting and blocking tumor necrosis factor-alpha include monoclonal antibodies, tumor necrosis factor-alpha receptors, TNF-binding proteins, and antisense technology. Two new tumor necrosis factor-alpha inhibitors that have progressed into Phase II clinical trials or beyond are discussed here.

Currently available products are administered parenterally, and various companies have sought to develop orally active agents as a means of reducing cost and broadening the market scope for anti-tumor necrosis factor-alpha therapy. Oral delivery of tumor necrosis factor-alpha inhibition is seen as a particularly desirable goal by many rheumatologists. In practice, however, the development of orally active agents has proven difficult. Work on a number of apparently promising oral agents, such as AtheroGenics’ AGIX-4207, Bristol-Myers Squibb’s BMS-561392, and Isis’s ISIS-104838, has been discontinued. The most promising oral tumor necrosis factor-alpha inhibitor remaining in the pipeline is apratastat. This agent, however, is in early Phase II development and is not discussed because of a lack of clinical trial data.

Mechanism Of Action

The role of tumor necrosis factor-alpha in rheumatoid arthritis has been demonstrated in transgenic mouse models in which tumor necrosis factor-alpha overexpression led to joint destruction and aggressive synovitis. Among rheumatoid arthritis patients, the degree of synovial tumor necrosis factor-alpha expression correlates with the degree of synovitis and bone erosion. Further investigations have shown increased expression of tumor necrosis factor-alpha receptors in synovial tissues of patients with rheumatoid arthritis but not in some other forms of arthritis.

Receptors for tumor necrosis factor-alpha are found on the surface of most cells, including mononuclear cells and cells in the synovium. Cleavage of membrane-bound tumor necrosis factor-alpha receptors yields soluble tumor necrosis factor-alpha receptors that retain ligand-binding ability but cannot activate cells. Two distinct types of tumor necrosis factor-alpha receptors have been identified: type I (p55) and type II (p75). tumor necrosis factor-alpha inhibitors reduce free, bioactive tumor necrosis factor-alpha by emulating the physiological role played by soluble tumor necrosis factor-alpha receptors.

TABLE . Emerging Therapies in Development for Rheumatoid Arthritis

COX-2 = Cyclooxygenase-2; Disease-modifying antirheumatic drugs = Disease-modifying antirheumatic drugs; IL = Interleukin; MAP = Mitogen-activated protein; PR = Preregistered; tumor necrosis factor-alpha = TNF-α.

This action modulates the amount of circulating, bioactive tumor necrosis factor-alpha by binding to the cytokine before it can activate cell-surface receptors on mononuclear cells. Because tumor necrosis factor-alpha plays an important role in the eradication of neoplastic cells, its suppression is not without hazard — particularly as a long-term therapeutic strategy. Concerns have been raised as to whether chronic immunosuppression leads to opportunistic infection, malignancies, or other complications.

CDP-870

UCB is developing CDP-870, a pegylated anti-tumor necrosis factor-alpha antibody fragment, for the treatment of rheumatoid arthritis and other inflammatory disorders such as Crohn’s disease in the United States and Europe. The agent was originally under development with Celltech, which was acquired by UCB in mid 2004, and is currently in Phase III trials. Celltech had previously been developing the agent in collaboration with Pfizer under an agreement terminated in December 2003. Regulatory filings are expected in 2006. No development has been reported in Japan.

CDP-870 binds tumor necrosis factor-alpha with high affinity, thereby blocking its ability to activate the inflammatory cascade. Unlike infliximab, which is a chimeric monoclonal antibody (mAb) composed of 75% human and 25% mouse protein, CDP-870 is a humanized anti-tumor necrosis factor-alpha mAb fragment conjugated to two polyethylene glycol (PEG) subunits. The agent is being developed as an injectable formulation with a once-monthly subcutaneous (SC) dosing regimen. UCB can manufacture CDP-870 in Escherichia coli at very low cost using proprietary technology. The production cost may be as little as 10% of that for creating an antibody or receptor fusion product using mammalian cell culture.

In a Phase II, double-blind, placebo-controlled study involving 203 patients, CDP-870 significantly reduced the signs and symptoms of rheumatoid arthritis (Keystone E, 2001). In the study, patients were randomized to receive CDP-870 (50, 100, 200, or 400 mg) once monthly as an SC injection or placebo for 12 weeks. Clinical response was assessed using American College of Rheumatology (ACR) criteria. The percentages of patients achieving an ACR 20, ACR 50, or ACR 70 response

at week 12 after treatment with the most-effective dose (400 mg) of CDP-870 were 72%, 48%, and 32%, respectively, compared with 15%, 0%, and 0% for placebo. The most common adverse events reported in this trial were headache, nausea, and upper respiratory tract infection.

In October 2002, Celltech presented data from a Phase II clinical trial involving approximately 600 rheumatoid arthritis patients. Of the patients receiving CDP-870 (400 mg once monthly), 75% achieved an ACR 20 response seven days after initial administration. The company reported no significant differences in adverse events between CDP-870 (400 mg or 800 mg once monthly) and placebo, and no significant occurrences of injection-site reaction or urinary tract infection. In 2004 press releases, Celltech announced preliminary results from two Phase III studies in rheumatoid arthritis, in which CDP-870 was used both in combination with methotrexate (Stada’s Rheumatrex, generics) and as monotherapy. Again, the agent met the primary end point: a significant ACR 20 response at 24 weeks. A further trial required for registration, designed to assess the impact of CDP-870 on disease progression, was scheduled to commence in the second half of 2004. Additional information on the drug’s safety or efficacy were not announced in the press releases, but UCB stated that full results will be released after conclusion of the entire Phase III program in rheumatoid arthritis.

CDP-870 treatment was considered to be well tolerated in a Phase II study in 36 rheumatoid arthritis patients. The most common adverse event reported was headache, and there was a higher incidence of mild or moderate lower respiratory tract infections and urinary tract infections in the treatment group as compared with placebo. Overall, CDP-870 appears to have a similar safety profile to the other tumor necrosis factor-alpha inhibitors, with the most common side effects being headache, nausea, and respiratory and urinary tract infections.

Pegsunercept

Amgen has been evaluating the pegylated monomeric soluble TNF receptor type I inhibitor pegsunercept (PEG-sTNF-RI) in Phase II clinical trials in the United States. Although the product remains in the corporate portfolio, no clinical development has been reported since 2003, and Amgen appears to be pursuing other opportunities in rheumatoid arthritis. Despite the lack of recent development, pegsunercept is cited here as an emerging therapy because Amgen may decide to revive the product for use in combination regimens or as a defensive posture against market encroachment by CDP-870.

Pegsunercept is a second-generation TNF-binding protein (TNF-bp) that comprises a soluble TNF-receptor type I (TNF-RI) subunit joined by a pegylated (PEG) linker. Like other tumor necrosis factor-alpha inhibitors, pegsunercept binds tumor necrosis factor-alpha with high affinity, thereby blocking its ability to activate the inflammatory cascade. As with CDP-870, pegsunercept is manufactured in Escherichia coli at a very low cost.

At the 67th annual ACR meeting in October 2003, researchers presented results of a Phase II trial in which 309 patients with active rheumatoid arthritis were randomized to receive an SC injection of pegsunercept (400, 800, or 1,100 µg/kg) twice weekly or placebo for 24 weeks. All patients received concomitant methotrexate, and the primary end point was improvement in ACR response.

At the end of the study period, all doses of pegsunercept significantly improved ACR 20, ACR 50, and ACR 70 responses, but the most significant response was seen for pegsunercept at 800 µg/kg. The ACR 20, 50, and 70 responses for pegsunercept 800 µg/kg in combination with methotrexate were 68%, 35%, and 25%, respectively, compared with 26%, 10%, and 3% for placebo. The results indicate that pegsunercept may reduce disease activity when administered concomitantly with methotrexate. The overall incidence of adverse events was similar between treatment groups, but injection site reactions were more frequent in patients receiving pegsunercept (38%, 36%, and 50% for 400, 800, and 1,100 µg/kg) than in those given placebo (30%).

Pegsunercept has been evaluated in combination with other agents in clinical trials, suggesting that its efficacy as a monotherapy cannot compete with that of currently available drugs. Additionally, the ACR 20, 50, and 70 response rates for pegsunercept in combination with methotrexate are lower than those demonstrated by etanercept in combination with methotrexate in the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) study: 85%, 69%, and 43%, respectively.

Interleukin-Based Therapies

Lymphocyte Modulators

Conventional Disease-Modifying Antirheumatic Drugs

Selective Cyclooxgenase-2 Inhibitors

Immunosuppressants

MAP Kinase Inhibitors

Table: Drugs of abuse

Questions

[1] Alcohol is oxidized by which of the following enzymes?

A. Acetate oxidase

B. ADH

C. Aldehyde dehydrogenase

D. Monoamine oxidase

[2] Which of the following is the most common adverse effect resulting from chronic ethanol abuse?

A. Cirrhosis

B. Cutaneous vasodilation

C. Disinhibited j udgment

D. Respiratory depression

[3] Which of the following is a drug of abuse that blocks the dopamine uptake transporter?

A. Alcohol

B. Cocaine

C. Marijuana

D. Nicotine

Answers

[1] B. Alcohol is oxidized in the liver, stomach, and other organs to acetaldehyde by the cytosolic enzyme ADH and the hepatic microso-mal enzymes. Acetaldehyde is oxidized to acetate by mitochondrial hepatic aldehyde dehydrogenase.

[2] A. Liver cirrhosis is an effect of chronic alcohol use. Disinhibited judgment, respiratory depression, and cutaneous vasodilation are acute effects of alcohol.

[3] B. Cocaine is a drug of abuse that binds the dopamine reuptake transporter. Ethanol may nonspecifically disrupt cell membrane protein functions. Marijuana interacts with G-protein-coupled cannabinoid receptors. Nicotine mimics the action of acetylcholine.

Pharmacology pearls

Alcohol is the most widely used drug of abuse.

Delirium Tremens, a syndrome associated with the abrupt discontinuation of alcohol in a chronic abuser, carries a high mortality rate if not promptly identified and treated.

Withdrawal from other drugs of abuse may cause unpleasant symptoms for the patient, but is rarely life threatening.

In all hypotheses of addiction, increased concentrations of dopamine in the mesolimbic system is considered the neurochemical correlate of dependence and addiction.

What are the acute pharmacologic effects of ethanol?

What are the chronic pharmacologic effects of ethanol?

How is alcohol metabolized?

What is the pharmacologic basis for using benzodiazepines to manage alcohol withdrawal?

Answers to case: Drugs of abuse

Summary: A 50-year-old man is displaying symptoms and signs of acute alcohol withdrawal.

Symptoms of acute ethanol toxicity: Disinhibited behavior and judgment, slurred speech, impaired motor function, depressed and impaired mental function, respiratory depression, cutaneous vasodilation, diuresis, gastrointestinal side effects, and impaired myocardial contractility.

Symptoms of chronic ethanol toxicity: Alcoholic fatty liver, alcoholic hepatitis, cirrhosis, liver failure, peripheral neuropathy, alcohol amnesic syndrome, pancreatitis, gastritis, fetal alcohol syndrome, nutritional deficiencies, cardiomyopathy, cerebellar degeneration.

Metabolism of alcohol: Oxidized primarily in the liver but also in the stomach and other organs to acetaldehyde by the cytosolic enzyme alcohol dehydrogenase (ADH) and by hepatic microsomal enzymes; acetaldehyde is oxidized to acetate by hepatic mitochondrial aldehyde dehydrogenase.

Benzodiazepines in alcohol withdrawal: Both alcohol and the benzodiazepines enhance the effect of y-aminobutyric acid (GABA) on GABA_A neuroreceptors, resulting in decreased overall brain excitability. This cross-reactivity explains why relatively long-acting benzodiazepines (e.g., lorazepam, chlordiazepoxide) can be substituted for alcohol in a detoxification program.

Clinical correlation

Ethanol is the most widely used CNS depressant. It is rapidly absorbed from the stomach and small intestine and distributed in total body water. Its exact mechanism of action is not known, but may be related to its generally disruptive effects on cell membrane protein functions throughout the body, including effects on signaling pathways in the CNS. At low doses it is oxidized by cytoplasmic ADH. At higher doses it is also oxidized by liver microsomal enzymes, which may be induced by chronic use. These enzymes are rapidly saturated by the concentrations of alcohol achieved by even one or two alcoholic drinks so that its rate of metabolism becomes independent of plasma concentration. Tolerance to the intoxicating effects of alcohol can develop with chronic use. Cross-tolerance with barbiturates and benzodiazepines may also develop. Because of this cross-tolerance effect, benzodiazepines are the most commonly used agents for the treatment of alcohol withdrawal, a potentially life-threatening syndrome commonly seen 2-3 days after the abrupt cessation of alcohol use by a chronic abuser. A long-acting benzodiazepine can be taken, and gradually tapered, to mitigate this effect. Disulfiram is also used on occasion to manage alcoholism. It is a drug that inhibits aldehyde dehydrogenase that in the presence of alcohol causes an accumulation of acetaldehyde, which results in a highly aversive reaction consisting of flushing, severe headache, nausea and vomiting, and confusion. Naltrexone, an opioid antagonist, is yet another drug used to manage alcoholism.

Approach to pharmacology of ethanol

Objectives

1. Define drug abuse, drug tolerance, drug dependence, and drug addiction.

2. List the common drugs of abuse and their properties.

3. List the adverse effects of the common drugs of abuse.

Definitions

Drug abuse: Nonmedical use of a drug taken to alter consciousness or to change body image that is often regarded as unacceptable by society. Not to be confused with drug misuse.

Drug tolerance: Decreased response to a drug with its continued administration that can be overcome by increasing the dose. A cellular tolerance develops to certain drugs of abuse that act on the CNS because of a poorly understood biochemical or homeostatic adaptation of neurons to the continued presence of the drug. Also, in addition to a cellular tolerance, a metabolic tolerance can develop to the effects of some drugs because they increase the synthesis of enzymes responsible for their own metabolism (alcohol, barbiturates).

Drug dependence: Continued need of the user to take a drug. Psychologic dependence is the compulsive behavior of a user to continue to use a drug no matter the personal or medical consequences. Inability to obtain the drug activates a “craving” that is very discomforting. Physical or physiologic dependence is a consequence of drug abstinence after chronic drug use that results in a constellation of signs and symptoms that are often opposite to the initial effects of the drug and to those sought by the user. Psychologic dependence generally precedes physical dependence but, depending on the drug, does not necessarily lead to it. The development of physical dependence, the degree of which varies considerably for different drugs of abuse, is always associated with the development of tolerance, although the exact relationship is unclear.

Drug addiction: A poorly defined, imprecise term with little clinical significance that indicates the presence of psychologic and physical dependence.

Continuation: Drugs of abuse. Class

Antioxidants in Nutrition, Health, and Disease

John M.C. Gutteridge, Barry Halliwell
Oxford University Press, 70 Wynford Dr, Don Mills, ON M3C 1J9
1994/143 pp

Strengths

Summarizes current thought on free radicals and antioxidants. A clear, pithy, scientific, informative text

Audience

Physicians, medical students, nurses, biologists, nutritionists, and chemists

The authors have written a short textbook introducing antioxidants to clinical practice. They also refresh readers with a review of the basic clinical sciences.

A short, informative preface asks succinct questions on using antioxidants for treating heart disease, cancer, and degenerative illnesses. The authors answer their questions with sufficient information on free radicals, cholesterol, and oxidative stress for readers to use in laboratories and practices.

A historical discussion of oxygen, oxidation-reduction definitions, and electron transport is followed by scientific information on the Krebs cycle, vitamins, and nutrients and a timely presentation of free radicals as contributing to cardiovascular and degenerative disease.

Later, epidemiologic and pathologic evidence on nutrient use is presented. This evidence allows us to understand information applicable to a scientific study of tissue damage and regeneration. Clearly, interest in the effects of nutrition and vitamins on health has increased. This short text will help practitioners upgrade current knowledge and share the information with patients.

The authors acknowledge the brevity of their text. They have challenged readers to examine modern concepts that might be discussed with our patients in the office. They also give us sufficient information to provide our patients and colleagues with current thinking on the activity of essential vitamins A, E, and C.

The style of this book flows well with diagrams, bold headings, illustrations, and informative tables. I enjoyed the quotations from The Beatles and Butch Cassidy and the Sundance Kid mixed with Paracelsus and Francis Bacon, which set the tone for the discussion in each of the seven chapters.

Appendices supplementing chapters 1, 4, and 5 provide further information on cholesterol, saturated and unsaturated fats, and their effect on the cardiovascular system. The authors raise questions not only for academics, but also for the less scientific. Skillfully, they then lead us through a historical discussion of the building blocks of life: carbon, hydrogen, oxygen, and nitrogen. Are antioxidants elixirs or media hype? Are human phagocytes useful? Does oxidative stress help or hinder our health? Should vitamins and minerals be used as supplements? What is the window of optimum activity of antioxidants?

Although the jury is still out on the results of antioxidant research, the authors present much food for thought. This book is valuable, and a few nights’ perusal should give readers sufficient vital information on antioxidant therapy to guide application.

Most general practitioners (GPs) will be familiar with the sometimes perplexing problem of trying to decide whether a patient’s symptom is owing to an adverse drug reaction, to a symptom of the presenting illness, or to an unrelated illness. There is a large quantity of literature on the subject of adverse reactions associated with individual drugs and about adverse drug reactions in hospital inpatients; however, there has been little recent information about adverse reactions to drugs in the community. In 1973 Mulroy reported that one in 40 general practice consultations was the result of iatrogenic disease and a few years later Martys, looking specifically at the incidence of adverse drug reactions, found that 41% of patients have some form of adverse reaction to a prescribed drug.

This small practice-based study aims to assess the impact of adverse drug reactions in general practitioner consultations.

Method

Dingwall Medical Group is a rural general practice in the Scottish Highlands with a practice population of 11 201. The Scottish Prescribing Analysis (SPA) figures for the six-month period of this study showed the average cost per patient to be 1% below the Scottish average.

During the six-month period between April and September 1999, all doctors working in the Dingwall practice were asked to record any suspected adverse drug reactions in patients in whom an adverse drug reaction was a presenting symptom, using a simple data collection form. The definition of an adverse drug reaction was that used by the World Health Organisation (WHO), i.e. ‘any noxious, unintended or undesired effect of a drug which occurs at doses used in humans for prophylaxis, diagnosis or therapy’. As well as meeting the WHO classification, suspected adverse drug reactions had also to be datasheet-listed as a possible side-effect of the drug to be included in the analysis.

In an attempt to estimate the proportion of eligible cases that failed to be recorded by the participating doctors, two validation searches of patients’ notes were carried out by an independent, experienced research nurse. This validation exercise was carried out on two separate three-day periods at times unknown to the participating doctors. It showed a level of under-reporting of 27%.

Results

During the six-month period, 272 adverse drug reactions were recorded in a total of 16 253 routine and extra appointments, giving a consultation rate with this problem of 1.7%. One patient was admitted to hospital and two patients attended accident and emergency departments with suspected adverse drug reactions. One yellow card was completed. Fifty-two (19%) of the patients had a previously documented adverse drug reaction in their medical notes; in five cases the offending drug was contraindicated. One hundred and ninety-three (71%) drugs with suspected adverse reactions were stopped; in seven cases the symptoms persisted. Doctors reported adverse drug reactions as being probable (i.e. almost certainly a symptom caused by the drug rather than the illness) in 197 (72%) and possible (i.e. a symptom that might have been caused by the drug rather than the illness) in 75 (28%) cases.

Analysis of the reported adverse reactions showed that 50% were accounted for by three groups of drugs: antidepressants, antibiotics, and non-steroidal anti-inflammatory drug (NSAID)-containing agents. However, scrutiny of the practice’s SPA data showed that these three groups of drugs accounted for only 13.6% of the prescriptions written during the six-month study period.

Table 1 shows the top ten presenting drugs with adverse drug reactions as an event rate. Four of the top five presenting drugs are new serotonin selective reuptake inhibitors (SSRIs) or related antidepressant agents. Analysis of the practice’s total antidepressant prescribing pattern shows that during the study period 63% of the antidepressants prescribed belong to the SSRIs and related compounds and 37% were tricyclic antidepressant or related drugs.

Table 1. Top ten presenting drugs with adverse drug reactions as an event rate, i.e. number of adverse drug reactions divided by the total number of times the drug was prescribed, expressed as a percentage. The average daily dose for patients presenting with adverse reactions to these drugs is also listed.

Discussion

The results from this study suggest that presentation with an adverse drug reaction is a common reason for patients consulting their GR. The consultation rate of 1.7% is almost certainly an underestimate of the true rate. The validation exercise carried out during the study period would suggest that a rate greater than 2% is more likely. This is a rate similar to that expected for patients presenting with ‘dizzy spells’ or migraine.

The other main finding was that 50% of adverse drug reactions were accounted for by only three groups of drugs, i.e. antidepressants, antibiotics, and NSAIDs. Martys, in his survey of the incidence of drug-induced disease in general practice 20 years ago, also found high rates of adverse drug reactions with these drugs.

The current study suggests that there is a particular problem with SSRIs and related drugs, that have been introduced in this country in recent years and are being more frequently prescribed in general practice. One of the justifications for their use is a better side-effect profile and tolerability compared with tricyclic antidepressants. This was not borne out in the current study.

There were no reported difficulties in using the WHO definition of an adverse drug reaction but it was not possible to verify the accuracy of suspected adverse reactions, except to note that on follow-up only seven cases were still symptomatic after stopping the drug. Likewise, the distinction between a probable and possible adverse reaction is highly subjective but herein lies the dilemma that general practitioners are presented with every day. The adverse reaction is often mild or self-limiting but the offending drug is usually stopped. The decision to stop the drug is probably based on the GP’s assessment of the risks/benefits of continuing treatment and the patient’s wishes. We need to know more about how general practitioners approach this problem.

Breakthrough Drugs

Breakthrough medications and vaccines have had a tremendous impact on longevity in the past 65 years. First came the anti-infective drugs, such as sulfa in 1935, that set the stage for the development of penicillin. The years between 1938 and 1953 are heralded as the “Age of Antibiotics?because of the large number of anti-infective agents introduced. Vaccines then followed as the major force in eradicating deaths from diphtheria, syphilis, whooping cough, polio, and measles. Since 1920, the combined death rate from the flu and pneumonia has been reduced by 85%.

Recent Advances

New discoveries in genetics are leading to advances in therapies for cystic fibrosis, Parkinson’s disease, and cancer. In 1997, the death rate from AIDS dropped by nearly half, the biggest single-year decline in history for a major cause of death. These advances are coming in time to prevent a major “epidemic?in disease as the Baby Boom population ages. Demographic trends indicate that more than 50 million Americans past age 65 will be at risk for various degenerative diseases by 2050. But the fact is that today Americans can expect to live more than 76 years. In 1920 life expectancy at birth was 54 years. For every 5 years since 1965, an additional year has been added to life expect