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Pulmonary & Critical Care Bulletin
Vol. VII, No. 3, July 15, 2001
In this issue :

From Editor's Desk

(Dr. Uma Maheswari,)

(R. S. Bedi & U.S. Bedi)

16th Annual Meeting on Pulmonary and Critical Care Medicine
(Dr. S. K. Jindal)

Publihed under the auspices of:
Pulmonary C. M. E. Programme

Editorial Board :

Department of Pulmonary Medecine
Post Graduate Institute of Medical Education & Research (PGIMER) Chandigarh. INDIA-160012

Subscription :

Metered Dose Inhalers : Chlorofluorocarbon (CFC) to Hydroflouroalkane (HFA) Transition - where do we stand now ?

Since the birth of metered dose inhalers (MDI) in 1950's, CFC has been used as propellant in the MDI. The ozone depleting effects of CFC were reported in 1970's. Since then, there has been a growing concern over its use in MDI and a gradual changeover to an environmental friendly substance was proposed. An alternative substance that was accepted by medical fraternity and environmentalist is a Hydrofluoroalkane. The physicians, pharmacologists and the pharmaceutical manufacturers are apprehensive about a smooth changeover from CFC to HFA inhalers. Is it going to be similar to a smooth Y2K changeover or not ? This largely depends on the combined efforts of medical community, environmentalists, patients and the governments.

CFC : It is a hydrocarbon in which the hydrogen ion is replaced by either chloride or fluoride and was considered to be an excellent propellant in MDI because, it :

1. is chemically stable
2. is liquid at high pressure
3. evaporates rapidly at atmospheric pressure at a given speed in a pointed direction
4. is non-flammable at atmospheric pressure and
5. has extremely low toxicity.

Despite the above properties, the CFC driven inhalers are going out of favour because of their ozone depleting effects. As CFC is not metabolized in the lung, it is remitted into the atmosphere when the patient exhales after taking a dose of MDI. The inert CFC in the atmosphere resists degradation and slowly ascends to stratosphere, to remain there for decades (40-150 years). Chlorine gas is released when the CFC undergoes photodissociation, which breaks the ozone layer. As a result of this, ultra violet rays enter the earth through the holes in the ozone layer. The UV rays are potential health hazard and can produce various diseases such as squamous cell carcinoma, basal cell carcinoma, Melanoma, actinic keratosis, photoaging, sunburn, cataract, pterygium, retinal damage, melanoma of uvea etc. Apart from this, the UV rays can cause harm to crops, marine life, and plastics.

Apart from MDI's, CFC is used in foams, refrigerators, and air-conditioners. In 1987, Montreal protocol, a Conference held on Ozone depleting substances (ODS) decided to reduce the use of ODS to 50% by 1998 and to ban ODS totally by 2000. The use of CFC in MDI was exempted from the above ban under Essential Use Act. However, this exemption was not permanent. So, the pharmaceutical companies and medical personnel worked together and introduced a new propellant in 1990, called hydrofluroalkane.

FDA approved the use of HFA as a propellant in MDI's in the year 1996. The advantages of HFA driven MDI are discussed under the following headings.

1. Environmental problems :

Though HFA is a non-ODS, it causes heat trapping in atmosphere and contributes to global warming. So, the Environment Protection Act (EPA) opposed the use of HFA in MDI's Considering its essentiality and lack of a good alternative, the Kyoto Protocol (1997), a Conference on Greenhouse Gases, made following suggestions :

i) Control of the production of HFA for the use of non-essential items.
ii) No ban on the use of HFA in essential products such as MDI till an alternative substance is available for use.

2. Technical Problems

i) Suspension stability : The drugs in MDI's are made miscible with the propellant by means of a surfactant. In case of CFC driven MDI's the surfactants used are oleic acid, lecithin and sorbitan, which give a specific taste to the CFC-MDI's. In HFA driven MDI's, these surfactants are insoluble in HFA and need a co-solvent such as alcohol. This changes the taste of the MDI. In addition, alcohol can cause some problems in certain individuals.

ii) Valve material incompatibility : The valves in MDI are made up of different materials such as metal, rubber and plastic. These materials do not interact with CFC or its surfactant, but they react with the co-solvent used in HFA-MDI leading to impaired valve performance.

iii) Filling Equipment : The boiling point of HFA is lesser than CFC. So, new boiling points have to be established.

iv) Moisture Transport : HFA has increased affinity or moisture and hence high water ingress rates. This is worsened by use of alcohol as co-solvent. This leads to decreased bioavailability of drugs due to deposition on the walls of apparatus.

3. Pharmacological Problems

A. Efficacy of various preparations ? There are limited studies which compare the efficacy of CFC-MDI and HFA-MDI of various groups of drugs.

i) B2 agonists ? The CFC-MDI and HFA-MDI preparations of B2 agonists are bio-equivalent and their clinical efficacies were found to be similar in different studies.

ii) Steroids ? Studies conducted on CFC and HFA preparations of beclamethasone di propionate (BDP) showed the following findings :

a) The lung bio-availability of HFA-BDP is 60% whereas it is 10% for CFC-BDP.
b) HFA-BDP is predominantly deposited in smaller airways whereas CFC-BDP in larger airways.
c) Even after an uncoordinated inhalation, 30% of HFA-BDP is available in lungs. So, HFA-BDP is called the `the forgiving drug'.

These findings are attributed to the smaller particle size of HFA-BDP. So, only half of thedose of HFA-BDP is required to achieve the therapeutic response. However, the systemic effects are similar in both preparations. It is also interesting to note that the other steroid preparation (Budesonide and Fluticasone) are bio-equivalent, for unknown reasons.

B. Safety of Drugs : Before a drug is accepted for routine clinical use, it should undergo toxicology screening, drug interaction tests, safety testing in patients and post marketing surveillance. These procedures are cumbersome and time consuming and hence the changeover is a slow process.

4. Economical problems

HFA inhalers are costlier than CFC inhalers because of a greater expenditure involved in research and patent issues.

5. Clinical problems

i) Patient related problems

  • Anxiety about using a new preparation
  • Misinformation about the product
  • Change in taste
  • Change in the dose (especially steroid products)
  • Lack of confidence in a new product
  • Objection to changes imposed on them and
  • Guilt of using CFC inhalers which are hazardous to environment

ii) Physician related problems

  • Ignorance about changeover
  • Lack of knowledge about efficacy and side effects of individuals preparations
  • To effect a gradual changeover without untoward effects and
  • Communication problems with patients.

Current scenario in India

India signed the Montreal Protocol in 1992. Indian government had announced the phase out of ODS by January 2003 and CFC-MDI by January 2020. One pharmaceutical company had already marketed HFA-MDI of salbutamol and is planning to introduce HFA-MDI of budesonide.

Dr. Mahendran Chetty, MD
Senior Resident,
Deptt. Of Pulmonary Medicine
PGIMR, Chandigarh

Dr. Mahendran Chetty

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