Monday, May 9, 2011

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 5th 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.

Thursday, May 5, 2011

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.

Sunday, May 1, 2011

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 100oF. 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 (>100oF) 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.