Immunity and Effect of Emotions

You would find that one is more disease-prone when under stress. Many of us tend to catch eye flu, colds, or viral fever when exposed to prolonged periods of emotional stress or tension. It has been proved experimentally that immunological functions of animals get altered if stressful environments are created. In humans too significant change in lymphocytes' count and function had been documented in subjects whose spouses were died within previous six to eight weeks. Lowered values of cellular and humoral immunity parameters have also been documented in students during examination periods. The science of 'psychoimmunology' has well established experimental models to demonstrate the effect of emotions on immunological parameters. Theoretically, the stress could affect the immune system in two ways; it may suppress the immune system or may make it hyperactive.


The suppressed immune system may invite more viral infections or may flare-up the autoimmune disorders like rheumatoid arthritis. Assessment of links between the emotions and immunity has gained a great clinical importance. Psychological support and counseling in addition to therapeutic measures have been helpful in improving the health of many with autoimmune diseases, allergic asthma, acquired immunodeficiency syndrome (AIDS) etc. You must have observed that many patients visiting overcrowded hospitals get upset seeing a different doctor or attitude of an over busy doctor. The emotional stress of patients in response to doctor’s attitude has been found altering the drug response of patients. The therapeutic treatment in totality needs a balance between the emotions and immunity of a patient for quick recovery.

Geriatric Medicine

Geriatric Medicine was recognized as separate discipline of medicine in the year 1950. When we become old is a big question with multiple answers? It is 65 years of age arbitrarily in majority of the countries of the world. Depending on the physical and emotional state of health, most people above the age of 75-80 years do fall in the category of old. Quality of healthcare measures has changed the global scenario and extended life span is a global feature now. Special efforts are needed to be mounted to ensure the independence of elderly for as long as possible in their family/home environment.

In many countries geriatric medicine has become one of the largest medical specialties in terms of number of consultants. Geriatricians believe that they are more efficient and better trained in the healthcare of elderly patients than the general physicians. You would find that average length of stay of a geriatric patient in a geriatric ward is less than in a general medical ward. The integration of geriatric medicine with other medical services is necessary to provide appropriate medical expertise to elderly patients.

The old age people suffer unduly from incapacitating illness. Many people suffer from a decline in their higher functions when they get old. Personal cleanliness and comfort is must for the old people. We do not yet have geriatric wards for the old in majority of our hospitals, leave aside the specialty of geriatric medicine. Significant age related financial facilities should be made available from the public exchequer for the healthcare of elderly people. The cultural traditions in many nations include the care and respect of elderly people of the family. In early eighties the then Director General of the World Health Organization (W.H.O.), Dr. Halfdon Mahler, quoted the fifth commandment "To honour thy father and mother". The specialty of geriatric medicine needs to be fully developed worldwide to overcome the crisis of old age.

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.

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.