Drugs

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Allopurinol
Allopurinol lowers the levels of uric acid in the body. It is available as tablets containing 100 or 300mg of drug. A maximum daily dose of 600 mg is permissible so as to maintain the blood uric acid levels below 6 mg/dl. Liquid intake should be more than 2 litres a day. Avoid all forms of alcohol. Allopurinol may sometimes cause hypersensitivity (allergic) reactions such as itchy skin rashes. The risk of hypersensitivity reactions is further increased on concurrent administration of antibiotics such as Ampicillin and Amoxycillin. This adverse effect may be serious and sometimes life-threatening. Allopurinol is therefore started in small doses and the dose is gradually increased over time. Other adverse effects of Allopurinol include gastrointestinal disturbances, itching of eyes, burning urination and dizziness. Antacids impair the absorption of Allopurinol. The risk of adverse effects is increased by concurrent administration of anti-hypertensives such as Enalapril and diuretics. The doses of anti-diabetic drug Chlorpropamide and anti-coagulant Warfarin need to be adjusted as Allopurinol increases their efficacy.

Azathioprine
Azathioprine is available commercially in the form of 50mg tablets. The usual dose is one 50 mg tablet taken twice a day (for a patient of 50kg body weight). The dose is initially small and is gradually increased over next few months. Gastrointestinal disturbances, malaise, fatigue, dizziness and allergic skin rashes are occasional adverse effects of Azathioprine. It may also cause liver dysfunction, reduction in blood cells and ecchymoses (bleeding under skin). Regular blood tests are advisable while on this drug. This drug does not have any adverse effects on male or female fertility or on fetus. Though secreted in breast milk for 2-8 hours after administration, Azathioprine is not reported to have any adverse effects on the breast-fed infant.

Bisphosphonates

Alendronate (70mg) and Risedronate (35mg) are administered on empty stomach, once a week. It is advisable to drink plenty of water (one glass – 200 ml) along with the tablet so that it reaches well into stomach and does not hold up in food pipe (oesophagus). These tablets should never be broken or chewed to avoid contact of drug with food pipe. Further, it is not advisable to eat or lie down at least for half an hour after taking these drugs; instead one should sit upright or stand up straight and carry out routine chores if required. These precautions must be followed meticulously; lest these drugs can cause severe swelling of food pipe. Contact your doctor immediately in case of symptoms such as chest pain, heartburn, difficulty in swallowing and blood in vomit or blackening of stools. These drugs may sometimes cause generalized body pain or unusual fractures of the femur bone. Thus, in case of pain in the groin or thighs, one must contact the doctor immediately. In view of their adverse effects on teeth, dental hygiene (brushing twice daily) and regular dental check up are essential. In case one has to undergo dental surgeries while on Bisphosphonate therapy, the dentist must be fully informed about the same. Moreover, one should contact their dentist immediately in case of heaviness, pain or swelling of jaw or loosening of teeth.

Another drug belonging to the class of Bisphosphonates namely, Ibandronate, is administered orally (5mg once a month) or intravenously (once in three months). Zolendronate is administered intravenously once a year. Intravenous route is preferred in case of patients with gastrointestinal disorders in view of a possibility of compromised absorption.

Biologic drugs

The new biologic drugs such as Etanercept, Infliximab, Rituximab, though expensive, are extremely effective in patients nonresponsive to conventional drugs. These drugs control rheumatoid arthritis by different mechanisms of action such as suppressing chemical mediators of inflammation (TNF, Interleukin), modifying B type of lymphocyte cells. Detailed recommendations on their indications and usage have been published by American College of Rheumatology, European League Against Rheumatism, Indian Rheumatology Association and other international organizations. These drugs need to be prescribed by rheumatologist only.

Etanercept is administered like insulin injection once or twice a week. Hospitalization is required for a 2-6 hour intravenous infusion of other drugs. Infection and cancer are important adverse effects of these biologic drugs. It is essential to investigate for hidden tuberculosis even in absence of symptoms in view of high prevalence of this disease in our country. One should contact doctor immediately even if minor symptoms (fever, sore throat, night sweats, burning micturition) appear. These drugs can cause local or generalized allergic reactions. Other adverse effects include loss of appetite, abdominal pain, weight loss and appearance of nodes in neck, axilla or groins. Occasional adverse effects on nervous system can lead to significant disability.

Large scale high quality research is ongoing for development of new drugs in rheumatoid arthritis. Various new drugs, though expensive, are now available in market. Biosimilars, less expensive alternatives to biologic drugs, are also available. These drugs are certainly a boon for patients with rheumatoid arthritis who do not respond adequately to standard therapy.

Calcium
We require about 600-800 mg Calcium every day. Post-menopausal women require around 1000mg Calcium per day. Regular vegetarian diet along with two cups of milk contains 500 mg of elemental Calcium. A tablet containing 500 mg of elemental Calcium is therefore sufficient to fulfill our everyday Calcium requirement. Excessive calcium intake leads to accumulation of Calcium in the blood vessels and increases the risk of heart attacks and stroke. Drugs suppressing gastric acid (Omeprazole, Panteprazole) hamper the breakdown and absorption of Calcium by decreasing acid in stomach. Diuretics (drugs increasing urine output) increase the calcium levels in our body. Calcium impairs absorption of certain antibiotics (such as Ciprofloxacin, Tetracycline etc), Thyroxine and iron from gut. Calcium tablet should be taken along with food at night. Excessive intake of fibrous foods, such as green leafy vegetables in the diet decreases Calcium absorption. Various Calcium salts are available in market. Of these, Calcium Carbonate is the least expensive and equally effective. Other Calcium compounds such as Citrate, Maleate (possibly less chances of kidney stones), Borate etc. are costlier and do not have any significant advantages over Calcium Carbonate. The adverse effects of Calcium supplements include gastrointestinal disturbances and constipation. Iron supplements also cause constipation. Some patients do not tolerate simultaneous administration of Calcium and iron as they develop severe constipation with this combination. Calcium impairs absorption of iron. Hence, it is not advisable to take Calcium and Iron simultaneously – an interval of at least two hours must be maintained between their administrations.

Chloroquin
Quinine, earlier used in malaria, was obtained from the Cinchona bark. Chloroquin and Hydroxychloroquin are presently used to reduce the inflammation in arthritis. It has beneficial effects on blood vessels by reducing blood lipids. Chloroquin is most inexpensive drug. To avoid pigmentation (darkening) of skin these drugs should be taken at night and prolonged exposure to sunlight be avoided. To avoid hyperacidity they need to be taken after food. Patients with G6PD enzyme deficiency have a possible risk of haemolysis (destruction of red blood cells) due to Chloroquin. Greying of hair, ringing in ears, weakness in the thigh muscles (myopathy) etc are frequent adverse effects in the patients using Chloroquin for long period. Prolonged use can affect eyes in the form of irritation of eyes, blurring of vision, altered vision, difficulty in focusing eyes, double vision, halos around lights, inability to see a part of an object, inability to move eyes etc. It is therefore necessary for patients on Chloroquin and Hydroxychloroquin to visit an Ophthalmologist for field of vision and other tests every 6 and 12 months respectively. It was observed in animal experiments that efficacy of Chloroquin increases if consumed along with juice of neem leaves.

Chloroquin tablet: 250 mg; Hydroxychloroquin tablet: 200 /300/ 400 mg

Colchicine
Colchicine is the first line drug used for treatment of inflammation due to deposition of uric acid and other crystals in joints or other areas of the body. One tablet of Colchicine (0.5mg) should be taken immediately at the onset of pain. One more tablet can be taken after an hour or so. A maximum of eight tablets can be taken in a day. Some patients may experience diarrhea due to Colchicine. If used with other anti-inflammatory painkillers, just two tablets a day may suffice. Colchicine needs to be continued in the dose of 2 tablets a days for 4-6 months after control of inflammation to avoid recurrence. Colchicine acts as an anti-inflammatory agent; it does not decrease the levels of uric acid. In case one misses a dose, that dose should be taken as soon as remembered. Colchicine has various adverse effects such as gastrointestinal disturbances, diarrhea, fatigue, numbness of limbs and muscle pains (rare). Special precautions should be taken while administering Colchicine along with antibiotics such as Azithromycin and Fluconazole as well as cholesterol-lowering drugs such as Atorvastatin.

Cyclophosphamide

Cyclophosphamide is a highly effective drug administered intravenously every 2-4 weeks for a period of 3-6 months. It may be prescribed for a longer duration in some patients. The dose varies from patient to patient according to the intensity of the disease. Cyclophosphamide injections may have immediate adverse effects such as allergic rashes, redness of skin (especially face), nasal stuffiness, vomiting and diarrhea. Over time, loss of appetite, weight loss, darkening of nails and skin may be seen in some patients. Some of these adverse effects, however, are controllable. Hair loss may occur after 3-6 weeks of therapy. However, hair grow again once the drug is stopped. Suppression of bone marrow due to this drug leads to reduction in various types of circulating blood cells. Cell counts normalize within next two weeks. The next dose is reduced if cell counts do not normalize. Cyclophosphamide is excreted through the kidneys (urine). It is advisable to drink plenty of water (2-4 liters daily) and urinate every two hours at least for two days before and after Cyclophosphamide injection to ensure proper excretion of the drug. This prevents accumulation of drug in urinary bladder and averts risk of bladder cancer. MESNA (2-Mercaptoethane sulfonate sodium) is administered alongwith to prevent bladder cancer. Gonadal suppression occurs after 8 weeks of therapy. However it normalizes in 90% young patients on stopping the drug. Conception is contraindicated while on this drug and can be attempted 4 months after stopping the drugs. Breast feeding too is not allowed. High doses of Cyclophosphamide may cause bloody stools, various types of cancers, swelling and dysfunction of heart. Smoking is strictly prohibited as it further increases the risk of cancers due to Cyclophosphamide.

Cyclophosphamide is also available in the form of 50 mg tablets. Maximum dose of 9 gm (i.e. two tablets a day for 3 months) should not be exceeded as it increases the possibility of adverse effects. Intravenous administration is, therefore, preferable in view of rapid action and fewer adverse effects due to lower cumulative dose.

Cyclosporine
Cyclosporine and related drugs such as Tacrolimus are also expensive. Cyclosporine is available commercially in the form of 25, 50 and 100 mg capsules and is administered up to 125 mg or more per day. Fatty substances such as ghee, oil etc. enhance the absorption of Cyclosporine. Hypertension, an adverse effect seen in some cases, can be easily controlled by administration of anti-hypertensive drugs. Anemia, swelling of gums and unwanted hair-growth may be seen in some patients. Darkening of skin, headache, tremulousness, bone pains are other adverse effects of cyclosporine. It may also cause increased uric acid levels and kidney dysfunction. Hence, this drug should always be taken as prescribed by physician. Regular blood testing is mandatory.

Febuxostat

This drug has the same mechanism of action as Allopurinol. It is generally used in patients with compromised kidney function. The initial dose of Febuxostat is 40-80 mg which may be gradually increased up to 160mg as the need be. Though Febuxostat has relatively lesser adverse effects, regular blood check is advisable for liver function.

Both Allopurinol and Febuxostat only help in controlling uric acid levels; they do not cure the disease. Therefore, life-long treatment with these drugs is inevitable in order to maintain optimum blood uric acid levels.

Leflunomide
Leflunomide is another important drug used in rheumatoid arthritis. Tablet of Leflunomide is administered every day. The effects of the drug can be seen only after 3-5 months of continuous administration. Pregnancy is not allowed while taking this drug. The drug remains in our body for about 2 years after its discontinuation. Patients on Leflunomide desirous of conception can attempt so after an 11- day detoxification using Cholestyramine. Minor adverse effects of Leflunomide include hyperacidity and gastric upsets where as major adverse effects include weakness, weight loss, high blood pressure, tingling and numbness of limbs and vasculitis (inflammation of small blood vessels) rashes especially on legs. Consumption of alcohol must be avoided in view of adverse effects of Leflunomide on liver. Leflunomide therefore must be used under supervision of an expert physician.

Leflunomide tablet: 10, 20 mg

Methotrexate

Methotrexate, the main drug in rheumatoid arthritis, shows its effects after about 2-3 months. Methotrexate is used in large doses in cancer treatment. A small weekly dose of 7.5 to 25 mg is sufficient in management of rheumatoid arthritis. Methotrexate should never be taken every day. One should select any weekday and take the drug on that particular day without fail. Folic acid needs to be taken along with (at least 24 hours apart) Methotrexate to avoid its adverse effects. Multivitamin tablets should also be avoided on methotrexate-day as most of them contain folic acid. Injection of Methotrexate causes less gastric upset and has an advantage of being effective in lesser dose. Some antibiotics, theophylline (used in asthma) and a few other drugs need supervision if administered along with Methotrexate. Methotrexate sometimes causes loss of appetite, swelling of gums, glossitis, reduction of white cells in blood and liver dysfunction. It is therefore mandatory to check blood repeatedly as advised by doctor. These adverse effects can be easily reverted by stopping the drug and giving additional dose of folic acid. Once stabilized, Methotrexate can be restarted in a lower dose. Adverse effects on lungs manifest as cough and breathlessness. The drug should be stopped and medical advice obtained immediately. Methotrexate suppresses immunity and increases the risk of infections such as herpes zoster and tuberculosis as also risk of cancer to a small extent. Consumption of alcohol must be avoided in view of adverse effects of Methotrexate on liver.

Methotrexate tablet: 2.5, 5, 7.5, 10, 12.5, 15 mg.
Injection: 15 mg/ml ampoule, 25 mg/ml vial 2ml (50 mg)

Methotrexate – weekly injection
Methotrexate injection is administered with an insulin syringe on thigh or abdomen.1 ml of liquid contains 25 mg of Methotrexate. The 1 ml insulin syringe is calibrated for 40 units which means that every 4 units of fluid contains 2.5 mg of Methotrexate. Fill the insulin syringe according to prescribed dose. Clean the skin with spirit or iodine. Hold your skin between your thumb & index finger (as if pinching).Insert the needle in an oblique direction and pull back the piston to confirm that the needle is not in any blood vessel. Inject the drug and remove the needle. Press for a while with the swab to stop bleeding if any. This injection is almost painless as the needle is extremely fine. The injection is to be taken just once a week where as patients of diabetes take the injection one or more times every day.

Mycophenolate
Mycophenolate mofetil is available as 500 mg tablet and is administered in two divided doses upto a maximum of 3 grams a day. It should ideally be taken on empty stomach. Conception is not advisable while taking Mycophenolate. The drug must be stopped at least 3 months before conception. However breast feeding is safe. Adverse effects include gastrointestinal disturbances such as diarrhea, head ache and generalized body pain, allergic rashes and disturbed sleep. Progressive multifocal leucoencephalopathy is a serious adverse effect of this drug. The intensity of adverse reactions is directly proportional to the dose of this drug. Regular blood tests are a must while on Mycophenolate therapy.

Paracetamol
Aspirin and Paracetamol (Crocin) are the drugs that reduce pain though they do not reduce inflammation in arthritis. Use of aspirin is less common due to its side effects such as hyperacidity. Paracetamol is much safer and is available worldwide without prescription. Paracetamol can be consumed up to 2-3 grams a day in 3-4 divided doses since its effect lasts for about 6-8 hours. Controlled release preparation is also available which can be consumed twice daily. Paracetamol is a constituent of cough-cold remedies. Hence simultaneous use of these drugs can lead to over dosage of Paracetamol. Paracetamol can occasionally cause hyperacidity. Overdose can lead to liver toxicity manifesting as jaundice.

Paracetamol Tablet: 500, 650 mg; Controlled release tablet: 650, 1000 mg

Sulfasalazine
This drug is from sulfa-group and may cause skin hypersensitivity in the form of itching, redness and rashes. It is therefore started in a low dose which is gradually increased over few weeks. Yellowish orange discoloration of urine and tears is a typical feature which need not be worried about. Use of contact lenses should be avoided as they too may get discolored. The drug may cause stomach upset, loss of appetite and sometimes affect liver and white blood cells. It is necessary to take folic acid along with sulfa drugs.

Sulphasalazine tablet (Sustained release): 500 and 1000 mg

Steroids

Steroids (Glucocorticoids) are produced naturally in our body. Hydrocortisone, Prednisolone, Methyl prednisolone, Betamethazone, Deflazacort are the various synthetic compounds belonging to the category of steroids. These drugs usually act for a long period of time; for instance, a single dose of Prednisolone acts for one full day (18-25 hours) whereas, Betamethazone acts for almost 2 days (36-54 hours). Betamethazone, if administered daily, keeps on accumulating in our body and hence use of Betamethazone tablets should be discouraged. Steroids in our body are secreted in a cyclical pattern – their levels being highest at 8 am leading to enthusiasm and freshness. Prednisolone should be administered at around 8 am after breakfast to coincide with this natural steroid cycle. The dose of Prednisolone can be small (up to 10 mg/day), medium (up to 30 mg/day) or more depending on the severity of the disease. Apart from arthritis, steroids are also used in the treatment of asthma, ulcerative colitis, skin diseases, allergies, kidney disorders, cancer, encephalitis and many other conditions. These drugs have proven saving in many critically ill patients.

Steroids rapidly control inflammation associated with rheumatic conditions thereby preventing joint damage. Pain also decreases due to control of inflammation. Guidelines for safe use of steroids can be found in various textbooks of Rheumatology as well as in recommendations of various national and international associations. Steroids are used only in small doses for controlling rheumatoid arthritis. Methotrexate, the mainstay of drug treatment in rheumatoid arthritis, is effective only after a period of 3-6 months. Risk of irreversible joint damage due to swelling is high during this period. Use of steroids, therefore, is inevitable during this period to prevent further joint damage. As the severity of the condition decreases, so does the dose of steroids and in certain cases, the use of steroids can be completely stopped once the disease is under control.

Proper care must be taken while using other drugs during steroid therapy. The doses of certain antibiotics, oral contraceptives, psychotherapeutic agents as well as drugs used in heart disease, blood pressure and diabetes need to be altered if they are to be administered concurrently with steroids. The powder for arthritis available in market appears to contain steroids and should not be taken alongwith drugs mentioned above. Limited use of salt in daily diet will prevent weight gain and rise in blood pressure due to water retention in the body. Steroids should not be suddenly stopped if taken for more than three weeks. The dose is gradually tapered in such cases. Abrupt stopping of steroid can lead to disease flare. Dose of steroids is required to be slightly increased in cases undergoing surgery in order to alleviate the stress of operation.

Prolonged use of steroids has various adverse effects (refer box). A long list of such effects can easily discourage a patient to use steroid drugs. However, use of steroids in small doses is not as dangerous as perceived by layman. In fact, non steroidal anti-inflammatory painkillers are more deleterious than steroids. It is just the stigma that people have with “steroids” that leads to all the misconceptions about their use. Steroid therapy-in proper doses for an optimum period of time- are, in fact a boon for arthritis patients.

Adverse effects of prolonged use of steroids
  1. Anorexia(lack of appetite), gastric disturbances, vomiting, hyperacidity, intestinal ulcers(rare)
  2. Thinning and dryness of skin, pimples (acne), reddish-purple discolored patches on skin, stretch marks on hands, abdomen, chest and thighs.
  3. Hair loss, unwanted hair
  4. Moon face (deposition of fat on face), fat deposition on shoulders, abdomen, thighs etc.
  5. Increase in blood levels of lipids (cholesterol and other fats), sugar and sodium, thus, increased risk of diabetes and hypertension
  6. Weakening of bones, thus, increased risk of fractures. Necrosis of thigh or other bones due to compromised blood supply and consequent loss of joint function
  7. Fatigue, muscle weakness – weakness of thigh muscles leading to inability to get up from sitting.
  8. Increased risk of clot formation in the blood vessels, which may cause complete blockade of vessel
  9. Masking of symptoms of infections leading to difficulty in early diagnosis. Delayed healing of wounds. Increased susceptibility to infections (Common cold, flu, fever etc. frequent) due to compromised immune system
  10. Eyes – cataract and glaucoma
  11. Irregular menses, lethargy, lack of enthusiasm, sleeplessness, disturbed sleep, restlessness, agitation, confusion, mood-swings, depression, suicidal tendency
  12. Growth retardation if used in large doses in children
  13. Dependence and addiction
Injections of steroids in joints:

Localized steroid injection in or around the joint is one of the important treatment for all kinds of arthritis. This is comparable simply to applying a cream over a skin rash, except that injection becomes necessary because inflammation is inside the joint. It may so happen that a single joint remains swollen despite good disease control. In such cases it is pragmatic to give a localized injection in such a joint instead of increasing dose of drugs or adding a new drug. These injections can be given in small or large joints alike. Inflammatory flares in osteoarthritis (disease of wear and tear) lead to inflammation and swelling due to fluid accumulation in the joint. Steroid injection in such cases is preceded by removal of fluid from the joint. This alleviates pain at least for a period of 3-4 months. Decrease in pain facilitates exercise which in turn strengthens muscles of the joint.

Fluid may accumulate in bursa (fluid filled sac) around a joint (bursitis) or in and around the tendons (fibers joining muscles to bones) near a joint (tendonitis). In these cases too, local steroid injections are useful. These injections may also help for diagnostic purposes, as in cases of gout or septic arthritis, where fluid needs to be withdrawn for testing the presence of uric acid crystals or organisms respectively.

Steroid injected in joints is not absorbed to a significant extent in our body so that the systemic adverse effects such as hyperacidity and diabetes can be averted. Joint injections are frequently used in children as there is no risk of growth retardation. The site of injection is sterilized to avoid risk of infection and anesthetized to reduce pain during injection.

Joint injections are not used in cases of unstable or deformed joints, septic arthritis, risk of fractures and clotting disorders of blood. Rarely (1 in 1500 cases) intra-articular injections may be followed by sepsis. Depigmentation may sometimes occur at site of injection. However this disappears with time and the skin becomes normal later. Sometimes thinning of skin may also occur. Steroid crystals can trigger a sudden swelling and severe pain immediately after injection. In these cases, a good pain-killer and ice-pack are useful. However, it is advisable to contact your doctor immediately if the joint becomes warm and reddish with intense pain and fever two-three days after injection.

Tramadol

Endorphins are opium-like chemicals present in our body. Opiate drugs can thus be effectively used for pain relief. Tramadol is a very mild opiate with unique mode of action. Combined use of Paracetamol and Tramadol is more effective and less harmful. Dizziness, nausea and headache are some of the side effects that can be more pronounced during initial days of usage of Tramadol. One should avoid driving during initial few days of Tramadol usage. These can be managed with symptomatic treatment. Alcohol should be avoided as it increases adverse effects of Tramadol.

Codein (a constituent of cough suppressant syrups), Oxycodone, Buprenorphine are other opiate painkillers. Some of these prescription drugs are very cheap. Constipation and possibility of addiction and tolerance (body becoming used to the drug necessitating increase of dose over a period of time) are important concerns about these drugs.

Tramadol tablet: 50 mg; Controlled release tablet: 100 mg

Vitamin D
The daily requirement of Cholecalciferol (Vitamin D3) is 800-1000IU. It is quite inexpensive and is available commercially as powder or granules (60000 IU) administered with water or milk. Fatty substances such as Ghee, cream, butter enhance the absorption of Vitamin D. Injections containing 6, 00,000 IU of vitamin D3 are also available. Calcitriol, an expensive form of Vitamin D, is needed only in patients with kidney or parathyroid diseases. Calcium supplements need to be administered along with Vitamin D. Hypervitaminosis D (excess Vitamin D in body) can cause head ache, excessive sweating, increased thirst, weakness, fatigue, diarrhea, increased urination (diuresis) and weight loss.
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