Rational Drug Combinations

The combination of two or more drugs with near about identical plasma half-life, in the same pharmaceutical formulation is termed as 'fixed dose combination' (FDC). The formulation may be in the form of tablet, capsule, syrup, powder or injection. The ratio of dose depends on peak plasma concentration and body mass of the patient. Some of the fixed dose combinations (FDCs) discussed below are 'rational drug combinations' as these have been found advantageous in terms of better therapeutic efficiency, reduced adverse effects, convenience of dose and better patient compliance.

Some rational drug combinations as per WHO's essential drug list and other lists:

1. Amoxycillin + Clavulanic Acid

The combination is indicated in bacterial infections producing b-Lactamase. Amoxycillin is inactivated by b-Lactamase if given alone. Clavulanic acid is b-Lactamase inhibitor and thus restores the sensitivity of Amoxycillin against the b-Lactamase producing bacteria. Escherechia coli, Klebsiella, H. influenzae, N. gonorrhoe, Staphylococci, Proteus, M. catarrhalis and Bacteroid species are known b-Lactamase producing bacteria.

2. Cotrimoxazole (Sulfamethaxazole +Trimethoprim)

Cotrimoxazole is prescribed to treat bacterial infections. We know that a variety of bacteria survive and proliferate in our body by synthesis of folate. Sulfamethaxazole inhibits folate's synthesis while Trimethoprim inhibits dihydrofolate reductase which converts folate
to tetrahydrofolate. Thus the combination is synergistic and potent bactericidal and provides wider spectrum of antibacterial activity. The combinations is a rational drug combination in terms of drug action.

3. Imipenem + Cilastatin

This combination drug is an antibiotic and used to treat bacterial infection. The drugs we take orally or through injection, are exposed to the metabolic enzymes present in our stomach as well as other organs. Imipenem is a broad-spectrum antibiotic but the enzyme dehydropeptidase present in kidney destroys it. The Cilastatin present in the combination inhibits the dehydropeptidase present in kidneys and thus prevents the inactivation of Imipenem.

4. Neomycin + Bacitracin

This combination is used in powder, solution and ointment form to treat bacterial infections of skin, ulcers of mucous membranes, infected wounds and conjunctivitis. Infected dermatosis and infected corneal ulcers are also treated by this rational drug combination.

5. Benzoic Acid + Salicylic Acid

The Benzoic acid is an antifungal agent, very effective in acidic pH. The Salicylic acid is a keratolytic agent, and thus improves the penetration of Benzoic acid and provides additional acidic environment.

6. Sulfadoxine + Pyrimethamine

This FDC is indicated for the treatment of chloroquine resistant falciparum malaria (Plasmodium falciparum) along with quinine therapy or artemisinin therapy. The combination is justified as sulfadoxine inhibits folate synthesis by the malarial parasite while pyrimethamine inhibits the action of dihydrofolate reductase which converts folate to
tetrahydrofolate thus blocks the growth and survival of malarial parasite.

7. Artemether + Lumefantrine

This FDC is indicated for the treatment of chloroquine resistant falciparum malaria (Plasmodium falciparum). One tablet of this combination contains Artemether (20 mg) and Lumefantrine (120 mg). The combination drug is very effective against blood schizonts and prevents relapse of malaria. It has been reported that Lumefantrine is less cardio-toxic drug in
comparison to side effects of halofantrine.

8. Drug Combinations for Anti-Tuberculosis Therapy (ATT)

• INH + Rifampicin


• INH + Ethambutol


• INH + Rifampicin + Pyrazinamide


• INH + Rifampicin + Pyrazinamide + Ethambutol

The treatment of tuberculosis is very critical. Antitubercular drugs are used in combination for better efficacy, to shorten duration of therapy, to prevent emergence of resistant organisms and for better patient compliance.

Important Tips:

i.) During intensive care phase, 3-5 drugs are used for 2-3 months. These drugs reduce bacterial load, ameliorate the acute symptoms and make patient non-contagious.

ii.) During continuation phase, 2 or 3 drugs are used for 4-7 months. These drugs kill all the persisters and thus sterilize all the organ and tissues.

iii.) Complete cure of tuberculosis should be ensured to prevent relapse.

9. Drug Combinations for Anti-retroviral Therapy (ART)

• Zidovudine + Lamivudine


• Zidovudine + Lamivudine + Navirapine


• Stavudine + Lamivudine + Navirapine


• Emtricitabine + Tenofovir


• Efavirenz + Emtricitabine + Tenofovir


• Lopinavir + Ritonavir

These are highly active antiretroviral drugs used in the treatment of AIDS (HIV infection). Antiretroviral drugs are combined to prevent resistance, limit toxicity and for synergistic effect. There are four groups of antiretroviral drugs depending on their anti-viral actions as:

• Zidovudine, Lamivudine, Stavudine and Emtricitabine are nucleoside reverse transcriptase inhibitors (NRTIs).


• Navirapine and Efavirenz are non nucleoside reverse transcriptase inhibitors (NNRTIs).


• Tenofovir is very effective nucleotide reverse transcriptase inhibitor.


• Lopinavir and Ritonavir are protease inhibitors (PIs).

10. Ethinyl estradiol + Norethisterone

Used for female contraception as FDC pill from 5^th day of menstrual cycle for 21 days.

Justified role of ingredients in combination:

Estrogen (Ethinyl estradiol) and progesterone (Norethisterone) by exerting negative feedback over the pituitary gland, reduce the secretion of Follicle Stimulating Hormone (FSH)
and Luetinizing Hormone (LH). In the absence of LH, the ovulation does not occur and the ovulatory cycle becomes an anovulatory cycle. Estrogen with progesterone make endometrium unfit for implantation of ovum. Progesterone ensures withdrawal bleeding after stoppage of medication. Progesterone also prevents risk of endometrial carcinoma due to estrogen (if used alone as contraceptive).

11. Lignocaine + Adrenaline

This is used as local anesthetic in the ratio of 1:50,000 - 1:200,000. The combination drug is administered for infiltration anesthesia, nerve block, spinal anesthesia and epidural anesthesia.

Justification for the combination:

i.) Adrenalin is a vasoconstrictor, so it reduces the absorption of Lignocaine and prevents its early clearance.

ii.) Adrenalin prolongs duration of action of local anesthetic, reduces its toxicity and provides almost blood less zone for the surgery.

Limitations:

This combination is not indicated for anesthetizing organs and tissues supplied by end arteries. So, ear lobes, finger tips, toes, nose tip and penis should not be anesthetized with this combination anesthesia.

12. Glucose (5%) with Saline (0.9%)

This glucose saline fluid is used as intra-venous maintenance fluid for dehydration. Dextrose provides energy and saline covers the deficiency of sodiumand chloride in extracellular compartments.

13. Acriflavin + Glycerin

Acriflavin in glycerin is used as anti-infective agents for dressing the wounds, cuts, ulcers, burns and umbilical cord.

14. Aluminium Hydroxide + Magnesium Hydroxide

This rational drug combination is used in hyperaciditym peptic ulcer, upper GI bleeding and gastro-esophageal reflux disease (GERD) to neutralize gastric acid.

Advantage: Aluminium hydroxide causes constipation but Magnesium hydroxide causes diarrhoea if used alone. So, the combination would not cause any intestinal upset.

15. Metronidazole + Diloxanide Furoate

Metronidazole is a pan-amoebicidal drug to which Diloxanide Furoate is added to make it effective to kill the cysts also. The combination drug is used in the management of amoebiasis.

16. b₂-Agonist + Inhaled Corticosteroid

• Salbutamol + Beclomethasone


• Formeterol + Budesonide

Salbutamol and Formeterol are b₂ -agonists and cause bronchodilation. Inhaled corticosteroid (Beclomethasone or Budesonide) helps to control the bronchial asthma by its anti-inflammatory and immunosuppressive action.

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.

Common and Serious Side Effects of Vaccines !

Vaccines are for preventing disease but any vaccine can cause side effects. The risks of use of immunization are adjudged to be acceptable in relation to the benefits and safety during the life. Majority of the vaccines have minor side effects like low grade fever, pain at the site of administration and sore arm, but sometimes there can be severe and life threatening anaphylactic reactions. Almost half of the persons experience fever after the administration of vaccines. The fever may be around 100^oF. Pain, redness, swelling and itching around the site of administration are common with injectable-vaccines. Muscle pain and tiredness are also commonly seen. The minor and common side effects usually subside within a few days and respond well to common antipyretics and analgesics. Cooling the injection site and topical application of lignocaine emulsion is generally recommended for decreasing pain. Some less common side effects like headache, nausea, vomiting and mild rash are also seen with most of the vaccines. The rota virus vaccine may cause self limiting diarrhoea.

Rare and serious side effects of vaccines:

Vaccines like MMR, MMRV, Hib and HPV can cause high grade fever (>100^oF) in some cases. The fever has to be controlled quickly and effectively by antipyretics and cold sponging to prevent febrile seizures. In some adolescents, fainting episodes have been reported after administration of HPV, H1N1-inactivated influenza vaccine and MCV_4 (meningococcal vaccine). Arthralgia and Arthritis have been reported in young women after administration of MMR vaccine. Rabies vaccine may also cause arthralgia and arthritis in around 6% cases. Thrombocytopenia (low count of platelets in blood) has also been reported with MMR, varicella vaccine and Yellow fever vaccine. The most serous side effect of Yellow fever vaccine is multi-organ failure or viscerotropic reaction. The varicella vaccine may also cause pneumonia. The BCG vaccine has been reported to cause disseminated tuberculosis and regional adenitis in immnocompromised people. Oral Polio Vaccine (OPV) can cause paralytic polio if administered to already ailing infant/child. The BCG vaccine has also been reported to be associated with the development of Type-1 and Type-2 diabetes mellitus with metabolic syndrome. Life threatening, anaphylactic reactions have been reported with anti-viral vaccines probably due to egg protein of embryonated eggs used to grow various viruses.

Important tips:

• Live vaccines should not be given to pregnant women as there are chances of risk of active disease to the fetus.


• Live vaccines are also contraindicated in patients on immunosuppressive therapy as the risk of developing active disease is there.


• Breast feeding mothers should also not be administered live vaccines and small pox vaccine.


• General health status of infants and children should be assessed before administration of a vaccine.

Why vaccination is necessary ?

The World Health Organization (WHO) is concerned for the world's health and always put emphasis on the availability and supply of clean drinking water and immunization or vaccination. The word vaccine is of Latin origin. The word vacca in Latin means cow. The word vaccine was coined from vacca because Edward Jenner first used fluid from the cowpox to prevent smallpox. Though the word vaccination and immunization are interchangeable but don't mean exactly the same. The administration of vaccines could be called vaccination but the immunization is the induction or acquiring of immunity by using pharmacological agents other than vaccines too. Immunization may be active (production of antibodies after administration of antigen or vaccine) or passive (administration of readymade/preformed antibodies). Vaccination is the active immunization. Vaccination may not provide active immunity to all the individuals. Under the Universal Immunization Programme (UIP) launched by WHO in 1985, free vaccination is available for tuberculosis, diphtheria, pertussis (whooping cough), tetanus, poliomyelitis and measles. The vaccines for these six vaccine-preventable diseases should be administered as per WHO schedule for UIP. The vaccination is necessary for healthy human race all over the world. By timely vaccination we can save our younger generations from major disabling and fatal diseases. Vaccines are considered safe when the side-effects of use are judged to be acceptable in relation to the benefits.

Risks for a Pregnant Smoker !

The period of gestation, number of pregnancy and general health of a pregnant woman with smoking habit are the important factors which could influence the effect of smoking on the unborn baby. When a pregnant woman smokes, her unborn baby does the same. The carbon monoxide and nicotine are passed onto unborn baby through blood stream. The maternal blood laced with nicotine and enriched with carbon monoxide lessens the oxygen supply and accelerate the heart beat of unborn baby. The child is likely to be premature or under weight. The growth of the toddler would be affected and the child may be more susceptible to infectious diseases. The chances of spontaneous abortions and still-births are three times more in pregnant smoker as compared to non smoker pregnant. The risks are more pronounced in pregnant smokers with anemia and poor nutrition.

A non-smoker pregnant woman, whose husband smokes, would be having identical risks for her unborn baby. In fact a non-smoking wife of a smoker husband thus becomes a non-smoking smoker or passive smoker. Pregnant smokers and the husbands of non-smoker pregnant women should quit smoking for the better outcome of pregnancy and the health of their baby. Excessive smoking during first trimester of pregnancy may lead to abortion. Primigravida women ( women with first pregnancy) would be at more risk as compared to multigravida due to pregnancy associated physiological and metabolic changes as well as psychological and emotional factors.

Tobacco – An addiction forming drug and its implications

A doctor who smokes today must be a fool. There are many medical men who have not made much effort to give up smoking habit though they full knowledge of harmful effects and consequences of smoking. The role of tobacco in producing morbidity and mortality is well known. It is we proved that cigarette smoking is related with higher risk of lung cancer, ischemic heart disease, emphysema and chronic bronchitis. The risk of young one suffering from pneumonia and bronchitis is much higher if the parents smoke. The children of smoking parents also develop the habit of smoking.

Cigarette smoking carries special risks for women. Smoking during pregnancy has been observed to retard fetal growth. The habit may also lead to genetic disorders in babies born to smoker mothers. Spontaneous abortion rate is higher in women who smoke. However, outcome of pregnancy is not affected if smoking is given up as early as possible after conception. Smokers are more susceptible to infectious diseases also. There are many chemical substances in the smoke of cigarette and biri, but nicotine, carbon monoxide and tar are most harmful and hazardous for health. The tobacco that is not smoked but chewed or left in the mouth or snuffed is called smokeless tobacco. Smokeless tobacco is no alternative to smoking and is equally harmful. Chewable tobacco leads to tooth decay and mouth cancer.

A smoker who can not quit smoking is essentially an addict. Youngsters develop tobacco addiction during pre-teen years as they are not aware of its harmful effects and consequences. Youngsters fall prey to seductive advertising and sales promotion drives. More than one billion kilograms of tobacco is produced and consumed world wide every year. Around 40% of males above the age of 15 years smoke cigarettes or chew or eat tobacco. Around 3 million people die of tobacco-related diseases, worldwide yearly. The incidence of cancer of mouth, esophagus and the pharynx is 10 times higher in smokers as compared to non-smokers. Biri smoking carries a higher risk of lung cancer than cigarette smoking due to higher amount of tar sucked by the smokers.

Tobacco reduces the effectiveness/efficiency of a wide range of drugs used for the treatment of various ailments. The efficiency of analgesics, anti-asthmatic and anti-coagulants has been found to be reduced. Cigarette smoking increases the risk of cardiovascular diseases in women taking oral contraceptives. Female smokers are at higher risk if their blood pressure and cholesterol levels are high. Be determined to quit smoking for the sake of your own health and for the health of your family. Smoking is a slow-motion suicide attempt. If you are not able to quit smoking through determined will power, consult your physician and take de-addiction therapy and counseling.

Can we eradicate smoking ?

The smoking habit is not natural but acquired one as one has to learn smoking. How does one get initiated to smoking ? Social influence such as parental example, sibling, friends' pressure and motivation by industrial promoters, initiate youth to smoking. Seductive tobacco advertisements by the cigarette manufacturers play a vital role in the initiation of new smokers. The tobacco industry is very powerful the world over. Tobacco industries spend US$ 25-30 billion every year to promote smoking as they need to add 2-3 million new smokers every year to run their business successfully. The smoking is an addictive habit and the danger posed by use of tobacco is not recognized by most of smokers as well as governments the world over. Non-smokers also suffer because of contaminated atmosphere.

Nicotine is the active agent behind the drug dependence of tobacco. A smoker experiences withdrawal symptoms after considerable time and gets stimulation through smoking. Habits can not be checked by force but through determination and medical and psychological counseling. Can we eradicate smoking ? Yes, probably we can eradicate smoking with political determination, public participation and community counseling. Tobacco perhaps is the more abused drug than alcohol but less dependence inducing. The cultural, commercial and economical factors are involved in addiction to cigarette (or biri) smoking. There is a need for strong governance and policies to bring social transformation to eradicate smoking.

Lithotripters, Stones and Lithotripsy

Stones in kidneys, urinary tract, urinary bladder and gall bladder could be treated with open surgery, percutaneous laproscopic surgery or lithotripsy. Treatment of stones in organs with drugs is of limited scope. A lithotripter is an instrument which breaks up stones in situ by shockwaves, which are focused on them. There are a variety of lithotripters available worldwide. Kidney stones or renal calculi are effectively treated with extracorporeal shockwave lithotripsy (ESWL), though sometimes percutaneous nephrolithotomy (PCNL) or open surgery is also required to remove renal stones. The lithotripsy treatment is said to be successful if stones are eliminated or reduced to <2 mm size. Comparative total cost of treatment by lithotripsy is almost half than by open surgery. ESWL has its own advantages as there is no blood loss and very little morbidity. Extracorporeal shockwave lithotripsy (ESWL) is the cheapest and quickest way of returning patient to normal life.

Extracorporeal shockwave lithotripsy is the best option as a mono-therapy for a medium-size stone (1-2 cm). However, for larger and stag-horn type stones, the best results could only be achieved by multi model approach. After nephrolithotripsy, the fragments of stones are expected to be passed in the urine within about 3 months time. The success rate varies with the size of stones but is always above 80% with ESWL and >90% for percutaneous nephrolithotomy (PCNL). Depending on the location, volume and composition, ureteral and kidney stones need endoscopic treatment via uretero-renoscopy (URS) and/or percutaneous nephrolithotomy.

Childcare and Hospitals for Children

Children constitute around 40% of the world population. Pediatric medicine is a broad specialty embodying all the organ specialties of adult medicine such as cardiology, dermatology, endocrinology, gastroenterology, hepatology, neurology, pulmonology, rheumatology etc. Pediatric surgery and its specialties also make a list as long as in the case of adults' specialties. All hospitals worldwide do have pediatric departments but special hospitals for sick children could provide better care of children by child specialists or pediatricians. The childcare begins at birth with mandatory vaccination planning which could be handled well by specialized vaccinologists. Vaccination and preventive medicine should be allocated special funds, as that would be an investment for the children's welfare and community health. All the countries and states on this earth should have special hospitals for children since childcare is the foundation of a healthy nation.