Management of Tuberculosis: Therapeutic Approach

Pulmonary tuberculosis (Tuberculosis of lungs) or Extra-pulmonary tuberculosis (Tuberculosis of organs other than lungs) in humans is caused by Mycobacterium tuberculosis, a human tubercle bacillus. Mycobacterium tuberculosis is an obligate anaerobic bacterium, whose natural reservoir is human beings. Mycobacterium tuberculosis (MTB) is non-motile and does not produce spores. The generation time of MTB is 15 to 20 hours, so it is also called slow growing bacterium.

Tuberculosis (TB) of any type remains a challenging clinical problem and important public health issue the world over. In the recent past the World Health Organization (WHO) has documented an annual incidence of 9.27 million new cases of TB with a prevalence of 13.7 million cases. Majority of TB cases exist in Africa and South East Asia. The annual incidence rate in Africa and South East Asia has been reported as 356 and 182 cases per 100,000 population respectively that is much higher than the global incidence rate.

The ‘gold standard’ in the diagnosis of TB has been the detection of Mycobacterium tuberculosis in the sputum smear or in the pathological lesions (by histopathological methods). The rapid diagnosis of TB is fundamental to clinical outcome. On general physical examination careful attention should be given to the presence of lymphadenopathy (swollen/enlarged lymphnodes), draining sinuses, non-healing ulcers, spinal or joint lesions etc.

Extensive research has been going on in the field of management of TB through anti-tubercular treatment (ATT) ever since the discovery of rifampicin in 1960s. The major objectives of research in anti-tubercular treatment (ATT) include the shortening of duration of therapy, preventing the emergency of drug resistance, avoiding toxicity and shortening the period of infectivity. Direct Observation Therapy-Short Course (DOTS) is the most effective strategy propagated for the management of tuberculosis. Several new drugs and non-pharmacological therapeutic modalities are under extensive study for the effective management of tuberculosis.

A)  Pharmacological Approach to Management of TB:

Pharmacological drugs can be classified as

Ø  Drugs susceptible for MTB.

Ø  Drugs susceptible for conventional ‘drug-resistant bacilli’, which include the followings:

·         Re-purposed drugs (e.g. Fluoroquinolones)

·         New dosages of already available drugs (e.g. Rifampicin rifamycin or high dose isoniazid)

·         New drugs (e.g. Bedaquiline for ‘multi drug resistant-TB).

B)  Preventive Approach to Management of TB:

Ø  Vaccination: The use of BCG vaccination is recommended. Recombinant BCGs are also under clinical trials.

Ø  Chemoprophylaxis for Latent-TB: Chemoprophylaxis is recommended for new born babies born to ‘sputum smear positive’ mothers. Chemoprophylaxis should also be recommended for the cases having ‘Latent-TB’. Interferon gamma release assay test (IGRAs) and Mantoux Test (a Skin Test) are useful tests for establishing a diagnosis of Latent-TB. However, these tests do not necessarily indicate the presence of active tuberculosis and requirement of ATT.

C)  Non-pharmacological Approach to Management of TB:

Ø  Non-pharmacological advances are based on immunomodulation and immunotherapy. Use of protective cytokines, anti-cytokine agents (such as thalidomide pentoxiphylline) and immune-enhancement with ‘heat killed Mycobacterium vaccine’ and other recombinant BCGs have been under clinical trials. These modalities have not been recommended for standard clinical practice.

Ø  Strategies for Airborne Infection Control:  ‘International Guidelines on Airborne Infection Control in Healthcare Settings’ should be adopted. These guidelines are very important in the isolation wards, multi-drug resistant-TB (MDR-TB) wards and the Medical Laboratories conducting TB tests, for prevention of spread of infection among health workers in hospitals.

 

 

Jaundice: Should the Drugs be Used ?

Jaundice is a symptom of a liver disease wherein the level of a yellow colored pigment called bilirubin increases in blood. The cause of jaundice may be infectious, pathological, obstructive or therapeutic. However, the most prevalent cause of jaundice is due to viral infection. Till 1940 this disease was considered catarrhal (catarrhal jaundice), due to catarrh of bile passages responsible for transporting bile from the liver to the intestine. It was during World War-II (1939-1945), the attending physicians discovered that the disease is due to some infection; and it was labeled as 'infectious hepatitis'. Many soldiers died due to infectious hepatitis during the World War-II. It was also observed during the period of war that there are two viruses infecting the soldiers with relatively shorter and longer incubation periods.

Now, these hepatitis viruses are called hepatitis virus-A and hepatitis virus-B. We can accurately diagnose the cause of jaundice and classify the causative virus. Hepatitis-B is severer of the two. Disease is transmitted not only through transfusion of infected blood or blood products but also through saliva, tears, breast milk, and seminal fluid and rarely by feces and urine of the patient.

Fatigue, loss of appetite, nausea, vomiting, joint and muscle pains, cough, coryza and headache may precede for one to two weeks preceding the onset of jaundice. Dark colored urine and light colored stools are other visible signs in addition to yellow coloration of eyes. There may be pain in the upper right quadrant of tummy along with discomfort in the tummy. Progress of recovery is very encouraging in cases of Hepatitis-A.


The medical management in cases of viral hepatitis/jaundice is just symptomatic and maintenance of nutrition is taken care of in these patients. There is no specific treatment for viral hepatitis/jaundice. Restriction of physical activity is advisable. A high calorie diet is generally recommended but special care is required in diabetics. Drugs should be avoided to avoid adverse effect on the liver. Patient should be isolated to a room (and a bathroom too) and routine hygiene measures should be observed. Serious patients should be hospitalized.

Inimical Interaction of Tobacco with Drugs

Consumption of tobacco in any form is bad as it has inimical interaction with a majority of drugs/medicines in addition to its other bad effects and health hazards. There are thousands of chemical substances in the tobacco and the smoke of its products like cigarette and bidi. Nicotine, tar and carbon monoxide are three most damaging chemical substances present in the smoke of cigarette and bidi. Smoking and chewing of tobacco would affect your metabolism and physiology. Like cocaine and morphine; nicotine causes addiction to tobacco. Cigarette smoking speeds up your heart beat and increases blood pressure. It is major cause of emphysema (chronic obstructive lung disease leading to damage of alveoli), chronic bronchitis, coronary heart disease (CHD) and lung cancer. Carbon monoxide along with nicotine increases the prevalence of heart attack in smokers.

The tar present in the smoke of cigarette or bidi damages the delicate epithelial lining of lungs. The brown and sticky deposit produced by the tar is a cause of lung cancer in smokers. The nicotine content per cigarette has been estimated to 20-30 mg. The carbon monoxide remains in the blood of a smoker for 5-6 hours after he finishes a cigarette and keeps interacting with body metabolites and drugs. The tobacco that is chewed, kept in the mouth or snuffed has equally bad effects. The consumption of tobacco is like ‘slow motion suicide’ due to its bad effects and inimical interaction with large number of drugs taken for various health ailments:


Tobacco has been found to reduce the effectiveness of pain killers (analgesics), anti-asthma drugs, anti-coagulants and drugs used to treat heart ailments. The risk of cardiovascular diseases increases in women taking oral contraceptives.

Toxic Effects of Antiworm or Antihelminthic Drugs

There are a variety of antiworm/antihelminthic drugs used to treat worm infestations/infections. Though the effects and side effects of antiworm/ antihelminthic drugs are well evaluated before the clinical trials but the real time toxic effects with respect to age, sex and associated medication of patients should always be kept in mind. For your benefit, toxic effects of some commonly used antiworm/antihelminthic drugs are summarized below.

1. Piperazine:  Piperazine is considered safe and cheap and widely used in large scale treatment programs for roundworm infestations/infections. It acts by producing a neuromuscular block in Ascaris (roundworm) through anticholinergic action at myoneural junction and decrease the succinic acid production by worm. Piperazine is easily absorbed from the gastrointestinal tract. Around 20% of it is metabolized and rest is excreted in the urine. Its mild side effects are: Intestinal discomfort, dizziness, nausea and vomiting may occur occasionally. Over dose can cause urticaria or allergic respiratory reaction. Severe toxic effects could be referable to the 'central nervous system' (CNS) leading to confusional states, inordination, dropping of objects, vertigo, muscular weakness and myoclonic contractions. Severe epileptic seizures have also been reported. Piperazine should not be prescribed to patients with history of epilepsy, renal or liver disease and neurological disease. Use of piperazine should be avoided during the first trimester of pregnancy.
2. Pyrantel pamoate:  Pyrantel pamoate is highly effective broad spectrum antihelminthic. Pyrantel pamoate induces paralysis of roundworms. It is very effective as single dose therapy with moderate side effects. Adverse reactions such as abdominal disturbance, headache and dizziness occur occasionally.
3. Tetramisole:  Tetramisole is very effective against nematodes especially Ascaris lumbricoides or roundworms. It acts by inhibiting the action of enzyme succinate dehydrogenate in the muscles of Ascaris lumbricoides or roundworms, inhibiting the conversion of fumerate to succinate, resulting in paralysis of muscles of worms. Nausea, vomiting, abdominal disturbance, headache and dizziness are minor side effects of tetramisole.
4. Mebendazole:  Mebendazole is extremely effective and well tolerated broad spectrum antihelminthic like pyrantel pamoate. Cure rates of 100% have been documented in the treatment of roundworm infections. Mebendazole inhibit the glucose intake by worms and thus kill them. Mebendazole also kills the ova of nematodes. Only 5-10% drug is absorbed from intestine and excreted in urine as metabolite. Around 90% of drug is utilized to kill the worms in the intestine. Mebendazole is embryotoxic and teratogenic. Its use should be avoided in children below 2 years of age and during pregnancy.

Irrational Drug Combinations !

When two or more drugs are combined in a fixed dose formulation like tablet, capsule, syrup, powder or injection, then their plasma half-life should approximately be same. The ratio of dose would depend on the volume of distribution and peak plasma concentration. If the combination of drugs is illogical in terms of plasma half-life and pharmacokinetics of the drug, the combination should be termed as irrational drug combination. Large number of such irrational drug combinations are available in the market which unnecessarily increase the cost of medication and add to the side effects of the therapy. Some of these combinations have been discussed below:

1. Ampicillin + Cloxacillin:

Ampicillin is effective against Gram negative bacilli but Cloxacillin is an Anti-staphylococcal penicillin and not effective against Gram negative bacilli. Mixed Gram negative and Staphylococcal (Gram positive) infection rarely coexists. So, in a patient with a single infection, one of the drug of the combination would be useless. In addition to the cost of therapy it would add to adverse side effects and resistance of bacteria to the drug. On the other hand the combination would reduce the dose of effective drug to the half and the patient would need longer course of therapy.

2. Antibacterial + Antiamoebic Combinations:

Ciprofloxacin + Metronidazole, Norfloxacin + Tinidazole and Ofloxacin + Ornidazole are such commonly available fixed dose drug combinations. In bacterial diarrhoea only anti bacterial drug is effective and antiamoebic drug is useless. Similarly, in intestinal amoebiasis only antiamoebic drug is effective while antibacterial drug is useless. Amoebiasis and bacterial diarrhoea rarely coexist. The therapy should be based on the diagnosis to reduce the cost of treatment since in a given case, only one drug of the combination would be effective and the other one would be useless.

3. NSAIDs Combinations

Nimesulide, diclofenec, ibuprofen and paracetamol are some non-steroidal anti-inflammatory drugs (NSAIDs). There is no justification in combining one NSAID (nimesulide, diclofenec, ibuprofen) with another NSAID (paracetamol) having same pharmacological actions. The increased risk of hepatotoxicity has been reported due to the use of combination of nimesulide with paracetamol. There is increased risk of nephrotoxicity with NSAIDs combinations.

4. H₂ Blocker + Domperidone

Ranitidine and Famotidine are H₂ blockers. H₂ blockers reduce gastric acid production in peptic diseases and give symptomatic relief. The combination of these drugs with antiemetic drug (Domperidone) is an irrational drug combination as peptic ulcer is not always associated with vomiting. Even in gastro-esophageal reflux disease (GERD), the domperidone is less effective as compared to metoclopramide, so combining H₂ blockers with domperidone seems to be an irrational choice.

5. Domperidone + Proton Pump Inhibitors

Omeprazole, Pantroprazole and Lansoprazole are proton pump inhibitors. Proton pump inhibitors reduce gastric acid production in peptic diseases and give symptomatic relief. The combination of these drugs with antiemetic drug (Domperidone) is an irrational drug combination as peptic ulcer is not always associated with vomiting. Even in gastro-esophageal reflux disease (GERD), the domperidone is less effective as compared to metoclopramide, so combining proton pump inhibitors with domperidone seems to be an irrational choice.

6. Ondensetron + Proton Pump Inhibitor or H₂ Blocker

Such combination drugs are prescribed for the acid peptic disease, but the disease is not always associated with vomiting. So, the combination of Ondensetron, an antiemetic drug with antisecretary drugs like H₂ blocker (Ranitidine) or proton pump inhibitor (Omeprazole, Pantoprazole or Lansoprazole) seems to be an irrational drug combination.

7. H₂ Blocker (Ranitidine) + Antispasmodic Drug (Dicyclomine)

The pain of peptic ulcer is due to high level of gastric acid but not due to spasm of smooth muscles and will subside only with reduction in gastric acid in stomach by use of H₂ blocker (Ranitidine) or proton pump inhibitor drugs (Omeprazole, Pantoprazole or Lansoprazole). So there is no justification in combining H₂ blocker (Ranitidine) with antispasmodic drug (Dicyclomine).

8. Antacid + Antianxiety Drug

The acid peptic disease is rarely associated with psychosomatic basis. So, there is no justification of combining antianxiety drug like diazepam with antacids. The simultaneous use of antacids with antianxiety drugs should always be avoided as antacids reduce the absorption of antianxiety drugs.

9. Antacid + Antispasmodic Drug (Dicyclomine)

There is no justification in combining antacids with antispasmodic drug like Dicyclomine, because the pain of peptic ulcer is not due to the spasm of the smooth muscles.

10. Mucolytic Agent + Antibacterial

Ambroxol + Ciprofloxacin or Cefadroxil or Roxithromycin. Ambroxol is a mucolytic agent used to liquefy thick respiratory secretions. There is no justification in combining mucolytic agent with antibacterial, as thick secretions in respiratory tract are always not due to respiratory infections. Also the antibacterial therapy always does not require an associated dose of mucolytic agent

11. Mebendazole + Pyrantel-pamoate or Levamisole

Dosages' schedule of both the drugs mismatch so the combination of such two anthelminthic drugs is irrational. The Mebendazole is required to be administered twice a day for three days whereas Pyrantel-pamoate or Levamisole should be administered as a single dose.

12. Leukotrine Antagonist (Montelukast) + Bambuterol or Levocetirizine

Montelukast, the leukotrine antagonist is used as alternative to inhaled steroid in the management of mild persistent asthma. Levocetirizine is an antihistaminic drug and has limited role in the control of asthma as it is not only histamine that triggers the asthma attack. Bambuterol is a long acting beta-2 agonist having role in the management of moderate persistent asthma as well as severe persistent asthma. There is no justification in combining of Montelukast with Bambuterol or Levocetirizine.

13. Metformin + Glimeperide + Pioglitazone

Metformin is indicated drug in obese type -2 diabetes mellitus whereas Sulfonylurea (Glimeperide) is indicated drug in non-obese type-2 diabetes mellitus. As per pharmacological principle, other drug should be added only when monotherapy fails. Metmorfin (biguanide) is to be administered after meal whereas Glimeperide (sulfonylurea) drug is to be administered before meal, therefore even when both the drugs are required, it would be better to administer them separately. Pioglitazone is indicated in suspected cases of insulin resistance. So, the combination of all these drugs in one formulation is an irrational drug combination.

Neurostimulators or Fashion drugs: Worrisome Scenario

The neurostimulator materials have been known to mankind in the one form or the other, from the time immemorial. The alcohol in the form of wine has been known for ages. Now, synthetic chemicals are the core source of majority of drugs for various ailments. The stimulatory action of most of the drugs is being exploited by many to earn a quick buck. The scenario is worrisome the world over. The diversion of pharmaceutical products like ephedrine, pseudoephedrine and morphine for the production of amphetamine type stimulants (ATS)is a matter of grave concern and should be checked effectively by the governments of various countries. Pharmaceutical preparations like pethidine, codeine-based cough syrups, ephedrine and pseudoephedrine should be sold on the production of valid prescription only to avoid misuse as neurostimulators or fashion drugs. The Internet Pharmacies should be issued strict guidelines on narcotics. The manufacture of synthetic drugs like methamphetamine should be done in the government owned drug houses only. It is our duty to educate our siblings, children, students and friends, about the health hazards of narcotics. Effective policing and administrative measures at the National and International Level are the needs of the hour to check the smuggling of traditional narcotics like heroin. Avoid experimentation with fashion drugs for health and longevity.