Rational Use of Medicine: A Pressing Need

RATIONAL PHARMACOTHERAPEUTICS Rational Use of Medicine: A Pressing Need Priyanka Singh, Vijay Thawani* Abstract Increasing incidents of overprescribing, multi-medicine prescribing, use of unnecessary expensive medicines, self medication and overuse of antimicrobials and injections is a big concern today.increasing use of Fixed dose combinations (FDCs)by prescribers and introduction by pharmaceutical houses is a big concern in the filed of rational pharmacotherapeutics.the current review highlights this very important aspect in detail. Key Words Rational Medicine, Fixed dose combinations (FDCs), Essential Medicines Received - 16.1.13 Revised -Nil Accepted-29.1.13 From the Department of Pharmacology, VCSGGIMSR, Srikot, Srinagar. Pauri- Garhwal and *Senior Program Officer & Prof. of Pharmacology, Lata Medical Research Foundation. Vasant Nagar. Nagpur- India Correspondence to : Dr Priyanka Singh, Junior Resident, Department of Pharmacology, VCSGGIMSR, Srikot, Srinagar. Pauri- Garhwal E mail: priyankadec08@gmail.com Introduction The Alma-Ata declaration, during the International Conference on Primary Health Care in 1978, reaffirmed that health is a fundamental human right and the attainment of the highest possible level of health is an important worldwide social goal. [1] The conference of experts on the rational use of medicines, convened by the World Health Organization (WHO) in Nairobi 1985, stated that rational use of medicines requires that patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements for an adequate period of time, at the lowest cost to them and their community. Irrational use is the use of medicines in a way that is not compliant with rational use as defined above. The use of too many medicines per patient known as polypharmacy is one of the common types of irrational medicine use. [2, 3] Medicines are integral part of the health care system and modern health care is unthinkable without the availability of necessary medicines. Accessibility to medication is a fundamental right of every person. [4] Ever since the accessibility of modern medicine increased all over the world, increasing incidents of its misuse in the form of overprescribing, multi-medicine prescribing, use of unnecessary expensive medicines, self medication and overuse of antimicrobials and injections started. Fixed dose combinations (FDCs), are combinations of two or more active medicines in a single dosage form. The Food and Drug Administration, USA defines a combination product as 'a product composed of any combination of a medicine and a device or a biological product and a device or a medicine and a biological product or a medicine, device, and a biological product'. [5] Advantages of Fixed Dose Combinations [6] - The FDCs have the advantage of combination therapy as well as advantage related to reducing the number of pills to be taken. - Reducing the number of pills diminishes the complexity of the regimen and therefore leads to improved patient adherence. - Reduced administration costs stem from simplified packaging, fewer prescriptions, and lesser dispensing time and cost. 10 Vol. 1 No.1, January - March 2013

- The FDCs can improve compliance in the treatment of chronic infectious disease; where as partial adherence can lead to the development of medicine resistant strains, treatment failure, and a threat to public health e.g. treatment of TB and HIV. - The side effects of one medicine can be reduced by combining it with another medicine in a FDC e.g. levodopa + carbidopa. - The efficacy of one medicine can be synergistically increased by combining it with another e.g. estrogen + progesterone, sulfamethoxazole + trimethoprim. Disadvantages of Fixed Dose Combinations [6] - Titration of dose of medicine to suit individual is not possible e.g. atorvastatin 10 mg + amlodipine 5 mg. - FDCs increase the price of the medication if unnecessary medicines are included e.g. ibuprofen + paracetamol + caffeine. - One of the medicines in the FDC may be superfluous or wasteful e.g. vitamins + iron. - The incidence of adverse drug reactions (ADRs) increases due to FDC e.g. nimesulide + paracetamol. - In FDCs there is always a chance that medicines may not be present in adequate amount e.g. multivitamins. - Incompatible pharmacodynamics e.g. combination of an antihistaminic with an antidiarrhoeal is dangerous as the antihistaminic action may mask other symptoms and make accurate diagnosis and treatment difficult. The 16 th essential medicines list (EML) of WHO has 351 essential medicines (EM), including 26 FDCs [7] [Table 1], whereas the national list of essential medicines of India (NEML) has 354 essential medicines, including 14 medicine combinations. [8] [Table 2]. Unfortunately, many FDCs being introduced in India are irrational. The most pressing concern with irrational FDCs is that they expose patients to unnecessary risk of ADRs, for instance, paediatric formulations of nimesulide + paracetamol. Nimesulide alone is more antipyretic than paracetamol, more anti-inflammatory than aspirin, and equivalent in analgesia to any of the NSAIDs alone [9], so efficacy gains are unlikely with added paracetamol. However, the patients may be subject to increased hepatotoxic ADRs from the combination. The FDCs of diclofenac + serratopeptidase do not offer any particular advantage over the individual medicines despite the claim that serratopeptidase promotes more rapid resolution of inflammation [10]. On the other hand, the patient is exposed to greater risk of gastrointestinal (GI) irritation and serious bleeding from unsuspected peptic ulceration. The FDCs of quinolones and nitroimidazoles (e.g. norfloxacin + metronidazole, ciprofloxacin + tinidazole, ofloxacin + ornidazole) have not been recommended in any standard book [4,11] but continue to be heavily prescribed medicines in GI infections, pelvic inflammatory disease, dental infection to cover up for diagnostic imprecision and the lack of access to laboratory facilities. Such injudicious use of FDCs can rapidly give rise to resistant strains of organisms, which is a matter of serious concern for any resource poor country. A glaring example is the emergence of ciprofloxacin-resistant Salmonella typhi strains which have made treatment of typhoid fever a difficult and expensive proposition in India today. [10] [12, 2] Problems with Irrational Use - Overuse of medicines and injections: It is consequence of overprescribing as well as overconsumption. It concerns particularly use and Table 1. Fixed Dose Combinations Included in 16 th WHO Model List of EM Amoxicilin + Clavulanic Acid Efavirenz + Emtricitabine + Tenofovir Emtricitabine + Tenofovir Lamivudine + Nevirapine + Stavudine Lamivudine + Nevirapine + Zidovudine Lopinavir + Ritonavir Lamivudine + Zidovudine Lopinavir + Ritonavir Ethambutol + Isoniazid Ethambutol + Isoniazid + Pyrazinamide + Rifampicin Ethambutol + Isoniazid + Rifampicin Isoniazid + Rifampicin Artemether + Lumefantrine Sulfadoxine + Pyrimethamine Sulfamethoxazole + Trimethoprim (Oral) Sulfamethoxazole + Trimethoprim (injection) Neomycin sulphate + Bacitracin Imipenem + Cilastatin Ethinylestradiol + Levonorgestrel Ethinylestradiol + Norethisterone Estradiol cypionate + Medroxyprogestrone acetate Levodopa + Carbidopa Ferrous salt + Folic acid Lidocaine + Epinephrine (Adrenaline) Benzoic acid + Salicylic acid Oral rehydration salts (Sodium chloride, trisodium citrate dehydrate, potassium chloride, glucose) Vol. 1 No. 1, January - March 2013 11

Table 2. Fixed Dose Combinations Included in National Essential Medicine List of India Co-trimoxazole ( Trimethoprim + Sulfamethoxazole) Lamivudine + Nevirapine + Stavudine Lamivudine + Zidovudine Sulfadoxine + Pyrimethamine Neomycin + Bacitracin Ethinylestradiol + Levonorgesterol Ethinylestradiol + Norethisterone Levodopa + Carbidopa Lignocaine hydrochloride + adrenaline Acriflavin + Glycerin Benzoic acid + Salicyclic acid Aluminium hydroxide + Magnesium hydroxide Oral rehydration salts ( sodium chloride, trisodium citrate dehydrate, potassium chloride, glucose) prescription of antimicrobials, antidiarrhoeals, painkillers, injections and cough - cold preparations. Injections have long had a special connotation as particularly powerful and fast acting medicines. - Multi-medicine use or polypharmacy: The number of medicines per prescription is often more than needed, with an average of 2.4 up to 10 medicines, while generally one or two medicines would have sufficed. Multi-medicine use is also common among consumers who purchase their medicines over the counter medicines (OTC). - Incorrect medicine use: It involves wrong medicine for a specific condition (e.g. antibiotics or antidiarrhoeals Fig 1. Drug Categories of FDCs Prescribed in India (Kastury N et al.) [9] for childhood diarrhoea), medicines of doubtful efficacy (e.g. antimotility agents for diarrhoea), or use of medicines in the wrong dosage (which is often the case with antimicrobials, ORS and antimalarials). Incorrect medicine use occurs due to inappropriate prescribing as well as wrong use by consumer. [13, 2] Reason for Irrational Use - Lack of information: Unlike developed economies we do not have regular facilities, to provide us with up to date, unbiased information on the currently used medicines. The majority of our practitioners rely for medicine information on medical representatives. There are differences between pharmaceutical concern and medicine regulatory authorities in the interpretation of the data related to indications and safety of medicines. - Faulty, inadequate training and education of medical graduates: Lack of proper clinical training regarding writing a good prescription during training period, over dependency on diagnostic aids, rather than clinical diagnosis acumen development is on the increase. - Poor communication between health professional and patient: Medical practitioners and other health professionals giving less time to the patient and not explaining basic information about the use of medicines. Prescription is delivered to patient to terminate the conversation with the patient. - Lack of diagnostic facilities / uncertainty of diagnosis: 12 Vol. 1 No.1, January - March 2013

Correct diagnosis is an important step toward rational medicine therapy. Doctors posted in remote areas have to face a lot of difficulty in reaching to a precise diagnosis due to non availability of diagnostic facilities. This promotes poly-pharmacy. - Demand from the patient: To satisfy the patient expectations and demand of quick relief, clinicians prescribe medicines for every single complaint thus leading to symptomatic treatment. Also, there is a belief that "every ill has a pill". All these increase the tendency of polypharmacy. - Defective medicine supply system and ineffective medicine regulation: Absence of well organized medicine regulatory authority and presence of large numbers of medicines in the market leads to irrational use of medicines. - Medicine promotion: The lucrative promotional programmes of the various pharmaceutical industries influence medicine prescription. [14, 2] Consequences of Irrational Use - Adverse, possibly lethal effects e.g. due to antimicrobial misuse or inappropriate use of medicines in self-medication. - Limited efficacy e.g. in the case of under-therapeutic dosage of antimicrobials, tuberculosis or leprosy medicines. - Antimicrobial resistance due to widespread overuse of antimicrobials as well as their use in under-therapeutic dosage. - Medicine dependence e.g. due to daily use of painkillers and tranquilizers. - Risk of infections due to improper use of injections like injection abscess, polio, hepatitis and AIDS. - Waste of resources: Reduced availability of other vital medicines and increased cost. Medicine Categories of FDCs Prescribed in India It has been reported that out of total 300 prescriptions collected, 225 contained FDC formulations 9. On analysis these were found to contain one, two, three and four FDCs. These were 90 (30%), 93 (31%), 39 (13%), 3(1%), respectively. Out of these 225 prescriptions only 45 (20%) contained FDCs as recommended by WHO list of FDCs. In 10.2% of the FDC containing prescription, one ingredient was present at least two times both as a part of FDC formulation and as a single medicine. Out of these 45 (11%) FDCs were in accordance with recommended WHO list of FDCs. The most commonly prescribed were antimicrobials (15.55%), analgesics (15.8%), multivitamins (13.8%), antihypertensive (8.88%), and cough and cold remedies (8.64%), antidiarrhoeal (6.175), antiasthmatics (3.70%) and others (16.3%) [15] (Fig 1). Stakeholders The various stakeholders for medicines are producers of medicines, retailers, regulators and patients. The patients are ignorant consumers of the medicines, deprived of medicine information, in developing economies. In the mix it has become difficult to identify as to who decides about treatment with medicines. Under these circumstances it is difficult to blame doctor, pharmaceutical industry, trader, Government or patient for this malady most. [16] Market The FDCs are available for the treatment of diseases of cardiovascular, central nervous system, diabetes, infectious diseases, Helicobacter pylori, gastrointestinal infections, HIV infection, cough and cold, respiratory diseases. The FDCs cover therapeutic groups like antipyretic and anti-inflammatory, dermatologicals, oral contraceptives and combination vaccine products. The FDCs also exist in the market for OTC availability. Thus FDCs are there in almost all the major therapeutic groups and hence of interest to common cause of the patients. [16] Strategies Suggested in WHO Policy Perspective for Rational Use of Medicine (RUM) [17] - Evidence-based standard treatment guidelines (STG); - EML based on treatments of choice; - Drugs and therapeutic committees in hospitals; - Problem-based training in pharmacotherapy in undergraduate (UG) medical teaching; - Continuing medical education as a licensure requirement; - Independent medicine information; - Supervision, audit and feedback; - Public education; - Avoidance of financial incentives; - Appropriate and enforced drug regulation. Vol. 1 No. 1, January - March 2013 13

While some of the above may have received attention, others remain to be attended to. Three International Conferences on Improving Use of Medicines (ICIUM) have so far been held with WHO support. The WHO makes efforts to ensure that global experiences are widely shared and discussed during these meets. Conclusion The issue of RUM has been throbbing since decades and the EM concept has been pulsating since long. Most of the developed economies and some developing also have a medicine policy and their national EML is regularly updated. Publication of NEML by Govt. of India in 2003 was a major step towards implementation of RUM. As of now, India has adopted the policies of generics, teaching and training the EM concept at UG level, pharmacovigilance programs and prescription audits, all contributing to the greater goal attainment of RUM. Monitoring and using the collected information to develop, implement and evaluate strategies to change the behaviour of inappropriate medicine use are fundamental to the success of RUM. [17, 18] Change is certainly possible, resistance can be overcome with sustained effort, but the sustained 'will' to change is required. Let us just do it! References 1. Declaration of Alma Ata (1978). Available at: http:// www.who.int/hpr/nph/docs/declaration_almaata.pdf Assessed on : 1.1.13 2. Brahma D, Marak M, Wahlang J. Rational Use of Drugs and Irrational Drug Combinations. The Internet Journal of Pharmacology 2012; 10(1). DOI:10.5580/2b59 3. Jadav SP, Parmar DM. Critical appraisal of irrational drug combinations: A call for awareness in undergraduate medical students. J Pharmacol Pharmacother 2011;12: 45-48. Available at: http://www.jpharmacol.com/text.asp?2011/2/ 1/45/77117 Assessed on : 1.1.13 4. Tripathi KD. Aspects of Pharmacotherapy, Clinical pharmacology and Drug Development. Essentials of medical pharmacology. Jaypee brothers medical publishers (p) ltd, New Delhi. 6 th ed.pp. 68 5. Chandler SG, Lekha S. Fixed dose drug combinations (FDCs): rational or irrational: a view point. 2008 published online.doi: 10.1111/j.1365-2125.2007.03089. 6. Rational use of medicines. Good pharmacy practice - I.P.A. - C.D.S.C.O. - W.H.O. India country office. Available at: http://www.whoindia.org/linkfiles/ GPP_Rational_Use_of_Medicines.pdf. Assessed on : 1.1.13 7. WHO model list of essential medicines 16th list. Available at:http://www.who.int/medicines/publications/ essentialmedicines/updated_sixteenth_adult_list_en.pdf 8. National list of essential medicines 2003. Available from: http://www.searowho.int/linkfiles/ Essential_Drugs_and_Medicines_India.pdf. Assessed on : 1.1.13 9. Kastury N, Singh S, Ansari KU. An Audit of Prescription for Rational use of Fixed Dose Combinations. Indian Journal of Pharmacology.1999; 31: 367-69. 10. Gulhati CM. Irrational fixed-dose drug combinations: a sordid story of profits before patients. Issues Med Ethics 2003;11:5 11. Gautam CS, Aditya S. Irrational drug combination: need to sensitize undergraduates. Ind J Pharmacol 2006; 38: 167-70 12. Amitava S. Indian market's fixation with fixed dose combinations (Editorial) Rational Drug Bulletin.2002;12:1 13. Burke A, Smyth E, Gerald G Brunton LL, Lazo JS, Parker KL. Analgesic-antipyretic agents; pharmacotherapy of gout. Goodman and Gilman's the Pharmacological Basis of Therapeutics 2006;11: 685 14. Grand AL, Hogerzeil HV, Haaijer-Ruskamp FM. Intervention research in rational use of drugs: a review. Health Policy Planning 1999; 2 : 89-102 15. Shivhare SC, Kunjwani HK, Manikrao AM, Bondre AV. Drugs Hazards and Rational Use of Drugs: A Review. J. Chem Pharm Res 2010. 2(1): 106-112 16. Sujith JC. Consequences of irrational use of antibiotics.indian journal of medical ethics. nbec. The Pharma Research 2009; 01 : 158 17. Neetesh KJ, Akarte AB, Pradeep T, Deshmukh B, Kannojiac P, Garud NC, Yadav A et al. Fixed dose combinations. Rational drugs- an update on rational drug use. Issue 31-32 18. Thawani V. Rational use of medicines: Achievements and challenges. Indian J Pharmacol 2010; 42(2):63-64. Source of Support Nil Conflict of Interest Declared How to Cite This Article Singh P, Thawani V. Rational Use of Medicine: A Pressing Need. 2013; 1(1):10-14 14 Vol. 1 No.1, January - March 2013