VANDANA BADAR, VIJAY THAWANI, HARSHAL VIKAS CHAUDHARItheantiseptic.in/uploads/medicine/Rationality.pdf · VANDANA BADAR, VIJAY THAWANI, HARSHAL VIKAS CHAUDHARI Dr. Vandana Badar (MD

September 201614 THE ANTISEPTIC

Rationality of anticough preparations in IndiaVANDANA BADAR, VIJAY THAWANI, HARSHAL VIKAS CHAUDHARI

Dr. Vandana Badar (MD Pharmacology)Asso.Prof. & Head, Dr. Vijay Thawani (MD Pharmacology)Asso.Prof. Dr. Harshal Vikas Chaudhari, (MD Pharmacology-Final year), Resident doctor,Department of Pharmacology,Indira Gandhi Government Medical College & Hospital, Nagpur.

Specially Contributed to "The Antiseptic" Vol. 113 No. 9 & P : 14 - 17

Introduction

Cough is a natural protective reflex meant for expelling respiratory secretions / foreign particles from respiratory system.1 Dry cough is troublesome, irritating, disturbing and calls for treatment whereas productive cough clears the airway hence is not suppressed but attempts are made to make it less viscous with mucolytic agents so that expectoration becomes easy. The formulations containing two or more drugs in combination in a fixed ratio are called fixed dose combinations (FDCs).2 More than one third of new drug products introduced globally during the last decade were FDCs. The WHO has listed 18 FDCs in Essential Medicine List (EML) which amongst others includes rational FDCs like antitubercular and anti HIV.3

The National Medicine List (NML) of India has 14 FDCs.4 However many more FDCs of vitamins, cough suppressants, anti-diarrhoeal, iron preparations, antacids, analgesics, tonics etc; are available in India, most of which are irrational. Usually the patients are prescribed more than one medicine. The concomitant use of two or more medicines adds to the complexity of individualization of drug therapy.5 Since the dose of each drug needs to be adjusted to attain optimal benefit and patient

compliance, to attain these, many FDCs are manufactured. In spite of the regulatory guidelines and WHO model EML.6 Many FDCs are marketed, sold and used. This study was planned to study the rationality of anti cough FDC formulations listed in Indian Drug Review (IDR).Objectives of the study

This study was planned with the following objectives:1) To evaluate the anti cough

preparations on the basis of type of formulation, constituents, number of ingredients.

2) To indentify the rationality on the basis of guidelines issued by WHO and their usage and check the dose used.

3) To find out cost per day of therapy with anti cough formulations.

Material & Methods

Total four hundred and seventy cough preparations of different manufacturing companies were taken from IDR.7 The following information was noted:1) E x p e c t o r a n t s , c o u g h

suppressants, mucolytics and decongestants were classified according to A to J classification.

2) The rationality of FDC formulations was studied on the basis of FDCs recommended in WHO EML8

3) Type of formulation: solid or liquid.

4) Number of ingredients in each formulation.

5) Cost of therapy /day.The anti cough formulations

were classified according to previous study9

A - Only Antitussive (which suppress the cough reflex)

B - Only Expectorant (which helps in bringing out the sputum)

C - Only Mucolytics (which liquefies the sputum)

D - Only Bronchodilator (which dilates the bronchi)

E - Only Antihistamine (anti-allergic compounds)

F - Only Decongestant G - Expectorant + AntitussiveH - Expectorant + BronchodilatorI - Expectorant + MucolyticsJ - Expectorant + AntihistaminesK - Having >2 of the A, B,

C, D, E, FL - B r o n c h o d i l a t o r +

Antihistamine M - Bronchodilator + Mucolytics Results

We studied 470 anti cough formulations manufactured by different pharmaceutical companies, of which 88.49 % were liquid formulations (Table 1). Only 10.66 % preparations were tablets /capsules while 0.85 % preparations were in other forms like nasal drops, lozenges. After reviewing various categories of cough formulations, it was noted that 93% of the formulations were combinations of expectorant + mucolytics, expectorant + antitussives and expectorant + antihistaminic or expectorant + bronchodilators and even having >2 of the above in combinations. Only 8% cough preparations were expectorants containing antitussives + bronchodilators, antitussives + antihistaminic,

15 THE ANTISEPTIC September 2016

antitussives + decongestants and expectorant + bronchodilator. 80% of cough preparations were combinations of expectorant + antitussives drugs. 20.26% of cough preparations were rational as per the WHO EML.(Table 2)

In present scenario, multiple ingredients are incorporated in the cough formulations. In present study 71% anti cough formulations three to four ingredients were present while 11% anti-cough formulations were having five ingredients. In 3% of anti cough preparations seven to eight ingredients were present. In one formulation there were 11 ingredients. (Table 3)

After calculating the cost per day for use of anti cough preparations it was observed that 42 % anti cough preparations required three to four rupees per day for treatment and 33% anti cough preparations required four to five rupees per day for treatment. Only 13 % preparations required two to three rupees per day for treatment. 85% anti cough preparations required an average 2 -5 Rs/day for treatment.Discussion

In the present study 20.26% of cough formulations were identified as rational as per WHO EML. The anti cough combinations of antitussive, expectorant and antihistaminic have no rational basis, so also the combinations of dextromethorphan salt, a CNS antitussive with phenylephrine hydrochloride - a nasal decongestant and chlorpheniramine maleate - an antihistaminic. This is because mixing of antitussives with expectorant is not justified because these two categories are used for opposite pathological conditions. Many anti cold combinations contain phenyl propanolamine (PPA) e.g. cetirizine with PPA and dextromethorphan or cetirizine + PPA + paracetamol. PPA is a banned drug in many countries and has been reported to have potential to cause stroke (more so in hypertensive) and can aggravate diabetes, glaucoma and prostatic hypertrophy.Following criteria need to be considered for rational anti-cough FDCs:a) Each formulation should only have one, evidence

based, potent constituent which offers the desired efficacy. For suppression of unproductive dry cough, it may contain noscapine or codeine as a single constituent.

b) If the sputum expectoration has to be facilitated, it may contain an expectorant like potassium iodide.

c) In any single formulation, combination of two expectorants does not offer any added advantage.

Table 1: Categories of the anti cough formulations

Category Rational Irrational Formulation Formulation No. (%) No. (%) A 8 - B 2 - C 14 - D 0 - E 4 - F 5 - G 0 5 H 2 - I 2 - J 0 55 K 53 314 L 0 - M 5 - Total 95 (20.26%) 374 (79.74%)

Table 2: Types of anti cough formulations

Type of formulation No. (%)Tablets /capsules 50 (10.66%)Liquid /syrups 415 (88.49 %)Other formulations 4 (00.85 %)Total 469 (100.0 %)

Table 3: Number of ingredients in anti cough formulations

No of Ingredients No.(%) 1 13 (2.77) 2 47 (10.02) 3 167 (35.61) 4 169 (36.03) 5 52(11.09) 6 13 (2.77) 7 4 (0.85) 8 3 (0.64) 9 0 (0) 10 0 (0) 11 1 (0.22) 12 0 (0) Total 469

September 201616 THE ANTISEPTIC

d) For patients of asthma or chronic bronchitis, where dilatation of airways and keeping the airways clear of excess secretions is desired, it could contain bronchodilator like salbutamol, ephedrine etc.We noted that many anti cough

formulations had ingredients in lesser than the recommended therapeutic concentrations. It is desired that when such ingredients are added, they should be in sufficient doses to offer therapeutic benefit.7 Our findings reveal that liquid anti cough formulations constituted 88.48% of the total. These render soothing effect to the pharyngeal mucosa especially when the dry irritating cough is present. For dry cough the populations can be mass educated to opt for the easy home remedy like drinking hot fluids / sugar based syrups / sucking candy or sugar, instead of going for anti cough mixtures.

We found that 93% preparations were combinations of expectorants and suppressants and antihistamines. In case of such formulations with multiple ingredients, it is necessary to ensure that the ingredients do not antagonise each other’s actions e.g. a cough suppressant should not be combined with an expectorant or an antihistaminic and a bronchodilator should not be

combined with an antihistamine or a cough suppressant. For the non-infective and allergic origin cough, only symptomatic relief is required. But in case of accompanying infections, it may need rational use of antimicrobials. To ensure affordability of the treatment it is desired that the cost of therapy is reasonable. Hence the prescribers should pay attention to economics of the prescribed medicines. The lowest priced generic should be preferred which has essential constituents meant for anticipated therapeutic benefit. We found that the cost of therapy with most of anti cough formulations ranged between rupees three to five per day.Disadvantages of FDCs4

1) Ineffective combinations lead to unnecessary polypharmacy. In cough formulations even antipyretic or antihistaminic are added, which is irrational.

2) If the biological half life of different compounds of a FDC are different, it may affect the drug availability in plasma and hence the overall efficacy of the formulation.

3) Patients differ in sensitivity and response to drugs hence titration of dose and adjustment of dose interval may be necessary. Such change in schedule of one drug of a combination cannot be done without also changing the other drug of the combination, thus affecting the efficacy and toxicity of the combination.

4) One drug may antagonize the actions of other one present in the combination. Cough suppressants depress respiratory system and cause broncho constriction and can reduce the bronchodilator’s action.

5) Combinations deny the prescribing doctor a flexible control of therapy.

Advantages of FDCs

1) Clinical benefits in the form of increased efficacy and / or reduced incidence of ADRs for e.g. in anti cough formulation containing Ambroxol 15mg, Guaifenesin 50mg and Salbutamol 1mg, mucolytic Ambroxol thins the secretions to make it less viscous, Guaiphensin increases the secretions and Salbutamol dilates the bronchi so one drug helps the action of other drug and all together help to expectorate.

2) Lower cost of manufacturing FDC compared to the cost of producing separate products.

3) Reduced complexity of a disease regimen increases the patient compliance.

4) Lower packaging costs and transportation charges.In India manufacture of any

FDC is considered as a new drug under rule 122 e of Drugs & Cosmetics (D & C) Act 1940.4 The Government of India through the Drug Controller General of India (DCGI) holds the right to regulate and prohibit the manufacture of any drug and cost in public interest under rule 26A of D&C 1940. Drugs have to be tested for stability and bioavailability before license is granted for the FDC. However clinical trials are often not carried for new FDCs. In some cases all the three viz. clinical trial, stability, and bioequivalence are done and in some only stability and bioequivalence are carried. Such facilitation may be one of the reasons for alarming rise of so many unscientific FDCs in India. Currently 70 drugs and FDCs are banned in India and 294 irrational FDCs have been identified to be stopped from being manufactured. [4] If only the will to cleanse the drug formulations is there, all irrational FDCs can be weeded out from the market, thus benefiting the society.

Table 4: Cost of per day of anti cough formulation therapy for an adult

Cost / day for No (%) an adult < 1 Re 5 (1.07)Re. 1 to Re 1.99 18 (3.84)Re. 2 to Re. 2.99 57 (12.15)Re. 3 to Re. 3.99 196 (41.79Re. 4 to Re. 4.99 153 (32.62)Re. 5 & > 40 (8.53)Total 469

17 THE ANTISEPTIC September 2016

Conclusion

The FDCs constitute a major segment of medicines available in India. FDCs do have advantages when used rationally, including convenience, improved efficacy, and decreased side effects. However due to many irrational combinations being available OTC in market, apart from increasing the cost of therapy these carry the risk of serious side effects including toxicity and emergence of resistance. It is our moral duty to ensure that any anti-cough formulation that is used, serves the medicinal purpose and not industrial interests.

REFERENCES

1. Benet LZ. Principles of prescription order writing and patient’s compliance instruction In Hardman JG, Limbird LE, Mollinoff PB, Ruddon RW, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th edition New York. Mc Graw Hill, 1996; 1617-706.

2. World health organisation, WHO technical report series. Geneva, Switzerland; 1997,867.

3. World health organisation. Essential drugs: WHO model list (Revised in December) WHO drug information 1998; 12; 22-35.

4. Anand S., Asha A.N., Uday Bhosale and Sarasija Suresh. Emergence of Irrationality in Fixed Dose Combinations, Pharma Times - Vol 40 - No. 9 - September 2008, 17-20.

5. Tripathi K D. Essentials of medical pharmacology. Drugs for cough and bronchial asthma. 6th edition Jaypee Brothers medical publishers (p) Ltd, 2008; 213-231.

6. Wor ld heal th organisat ion, WHO technical report series. Geneva,Switzerland; 1997, 882.

7. Drug today, July-September, 2009 vol. II; 790-818.

8. h t t p : / / w w w . w h o . i n t / m e d i c i n e s /publications/essentialmedicines/en/index.html

9. Appendix 2; survey of cough syrups. The banyan tree, vol I, More toward holistic health. (http://www.healthlibrary.com/book17_chapter132.htm)

The adipocytes have pleiotropic functions and produce adipokines, a bioactive cytokine, which initiates a variety of cell-signaling pathways that control the pathophysiological process of systemic diseases.

Varied adipokine levels can reduce the glomerular filtration rate (GFR) and can cause elevated albuminuria, which are the typical pathophysiological changes of CKD.

Visfatin is a 52-kDa molecule, which is identical to pre-B cell colony-enhancing factor and enzyme nicotinamide phosphoribosyltransferase.

Visfatin is referred as the marker of inflammation, because an elevation in vistafin levels is accompanied with an increase in inflammatory cytokine synthesis. Vistafin has also been recognized as a marker of endothelial dysfunction.

CRD BYTES

Based on study results and widely reported pleiotropic benefits, hydroxychloroquine could emerge as a potential drug for combination with statins for treatment of dyslipidemia.

CMRO

JUPITER trial results support broader recognition of percentage reduction in LDL-C as a more effective therapeutic target.

Point-of-care troponin testing is associated with significantly reduced time to hospital admission/discharge; potential cost savings could be expected.

Heart is the most metabolically active organ of all; metabolic demands are further heightened in the failing heart. As heart failure progresses, there is seen an impaired ability for substrate utilization, including fatty acids and glucose.

American Heart Association