Beta-agonists

Changed on: 20.07.2021

The β-agonists designated as β2-sympathomimetic drugs or β2-adrenoreceptor agonists are used therapeutically both in human and veterinary medicine for broncholysis in asthmatic disease of the respiratory tract, for tocolysis (inhibition of birth contractions) and for treatment of peripheral circulation problems.

Their action as a bronchodilator is based on the fact that by stimulating the β2 adrenoreceptor β-agonists causes the bronchial muscles to slacken. The only bronchodilator commercially available as a veterinary drug is clenbuterol. Human preparations such as terbutaline, fenoterol or salbutamol are also occasionally used in horses.

Their action as a tocolytic is based on the relaxation of the gravid uterus and thus inhibition of contractions e.g. to prevent premature birth. The commonest tocolytic drug is clenbuterol.
In high dosages some β-agonists affect the protein-fat ratio, increasing the proportion of protein. The elevated protein synthesis in the muscle cells leads to an increase in muscle mass and thus makes β-agonists of interest in terms of their use as a growth stimulant in animal fattening, which is prohibited in Europe, as well as in the human realm as a performance-enhancing drug. Clenbuterol - the best known and most effective member of this group of substances - was and still is used illegally. But the illegal use of other β-agonists such as brombuterol, cimaterol, cimbuterol, mabuterol, mapenterol, ractopamine, salbutamol, terbutaline or zilpaterol is well known.

Typical side effects of β-agonists include tachycardia (palpitations), arrhythmia (irregular heartbeat), tremors (shaking), hyperglycaemia (elevated blood glucose levels) and hypokalaemia (low blood potassium levels).

In cases of overdose, all side effects occur to a greater degree and life-threatening tachyarrhythmia may occur.

The β-agonists designated as β2-sympathomimetic drugs or β2-adrenoreceptor agonists are used therapeutically both in human and veterinary medicine for broncholysis in asthmatic disease of the respiratory tract, for tocolysis (inhibition of birth contractions) and for treatment of peripheral circulation problems.

Their action as a bronchodilator is based on the fact that by stimulating the β2 adrenoreceptor β-agonists causes the bronchial muscles to slacken. The only bronchodilator commercially available as a veterinary drug is clenbuterol. Human preparations such as terbutaline, fenoterol or salbutamol are also occasionally used in horses.

Their action as a tocolytic is based on the relaxation of the gravid uterus and thus inhibition of contractions e.g. to prevent premature birth. The commonest tocolytic drug is clenbuterol.
In high dosages some β-agonists affect the protein-fat ratio, increasing the proportion of protein. The elevated protein synthesis in the muscle cells leads to an increase in muscle mass and thus makes β-agonists of interest in terms of their use as a growth stimulant in animal fattening, which is prohibited in Europe, as well as in the human realm as a performance-enhancing drug. Clenbuterol - the best known and most effective member of this group of substances - was and still is used illegally. But the illegal use of other β-agonists such as brombuterol, cimaterol, cimbuterol, mabuterol, mapenterol, ractopamine, salbutamol, terbutaline or zilpaterol is well known.

Typical side effects of β-agonists include tachycardia (palpitations), arrhythmia (irregular heartbeat), tremors (shaking), hyperglycaemia (elevated blood glucose levels) and hypokalaemia (low blood potassium levels).

In cases of overdose, all side effects occur to a greater degree and life-threatening tachyarrhythmia may occur.

Legal basis

Legal basis

The use of β-agonists as growth promoters in livestock farming is prohibited in the European Union in accordance with Council Directive 96/22/EC. Annex 1 of this directive lists the β-agonists in Group A (substances with anabolic action and non-authorised substances) as Subgroup A5.

Directive 96/22/EC was most recently amended by Directive 2008/97/EC of the European Parliament and of the Council of 19 November 2008, although the prohibition of β-agonists in animal production remains unaffected by this.

Directive 96/22/EC was implemented in Austrian law via a regulation of 25/9/1997(Federal Law Gazette No. 280/1997) and by the Hormone Regulation of 25/10/2005 (Federal Law Gazette II No. 352/2005).

Beta-agonists may only be used as veterinary drugs in horses that are not intended for the production of meat to induce tocolysis and to treat diseases of the respiratory tract and in female cattle to induce tocolysis.

Regulation (EU)37/2010 only sets maximum levels for clenbuterol for bovine and equine animals. For all other β-agonists, no detectable residues are permitted in animal matrices.

Legal basis

Council Directive 96/22/EC of 29 April 1996 concerning the prohibition of the use in stockfarming of certain substances having a hormonal or thyrostatic action and of ß-agonists and repealing Directives 81/602/EEC, 88/146/EEC and 88/299/EEC (OJ EC No L125 of 23/5/1996).

Regulation by the Federal Minister for Labour, Health and Social Affairs concerning the prohibition of veterinary drugs containing certain substances having a hormonal or thyrostatic action or β-agonists (Federal Law Gazette II No. 280/1997 of 25/09/1997).

Regulation by the Federal Minister for Health and Women concerning the prohibition of bringing to market any veterinary drugs containing certain substances having a hormonal or thyrostatic action or β-agonists (Federal Law Gazette II No. 430/2004 of 2/11/2004).

Regulation by the Federal Minister for Labour, Health and Social Affairs concerning the use of certain substances having a hormonal or thyrostatic action and of β-agonists in animal stockfarming (Hormone Regulation) (Federal Law Gazette II No. 352/2005 of 25/10/2005).
Directive 2008/97/EC of the European Parliament and of the Council of 19 November 2008 amending Council Directive 96/22/EC concerning the prohibition on the use in stockfarming of certain substances having a hormonal or thyrostatic action and of beta-agonists (OJ EC No. L 318 of 28/11/2008).

Commission Regulation (EU) No. 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin (OJ EU No L 15 of 20/1/2010).

Commission Decision 2002/657/EC of 12 August 2002 implementing Council Directive 96/23/EC concerning the performance of analytical methods and the interpretation of results (OJ EC No. L 221 of 17/8/2002).

Monitoring and residues

Monitoring and residues

The illegal use of β-agonists as growth promoters in stockfarming and the observance of maximum levels of clenbuterol are both monitored within the scope of the National Residue Control Plan (NRKP). Live animals as well as animals at the time of slaughter are monitored in such a way that traceability back to the producer is guaranteed. Since the NRKP is aimed at preventative consumer protection, targeted sampling is carried out, in that knowledge of regional or local circumstances is taken into consideration or indications or suspicions of unauthorised animal treatment are investigated.

The Centre of Competence for Veterinary Drugs and Hormones (CC TAHO) is entrusted with testing for illegal use of β-agonists within the scope of the NRKP and is the national reference laboratory for these substances.

Analyses and range of testing

Analyses and range of testing

The β-agonists examined in the CC TAHO belong to the chemical class of substituted phenyl ethanolamines:

Brombuterol, carbuterol, cimaterol, cimbuterol, clenbuterol, fenoterol, isoxsuprine, mabuterol, mapenterol, ractopamine, salbutamol, terbutaline, zilpaterol.

The range of analytes is constantly being extended. The matrices investigated are liver, urine and blood plasma.

The analytic procedure employed is high performance liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS).

(In accordance with Commission Decision 2002/657/EC, a mass spectrometric method of confirming detection of prohibited substances is required.)

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