Discussion in 'Horse Health' started by Tess, Jan 18, 2005.
Does anyone know if there are side effects from prolonged use of ventipulmin?
I have used it but not for longer than a couple of weeks - I will look at the info sheet tomorrow and post if I see any warnings
I have looked it up - there is no mention of using it over a long period of time - how long has your horse been on it?
Here is some research on it (long article!!!)
Dr. N. Edward Robinson
College of Veterinary Medicine
Michigan State University
The recent FDA approval and launch of Ventipulmin® syrup for horses have provoked a lot of comment from veterinarians and from the horse industry. As veterinarians who deal daily with the horse industry, you will be asked for your opinion about Ventipulmin® and the articles written about it. AAEP asked Dr. Ed Robinson to put together a review and present you with some facts about Ventipulmin® and its active ingredient, clenbuterol hydrochloride.
Ventipulmin® syrup is an orally administered beta-2 agonist approved by FDA for management of airway obstruction, such as COPD. It is the first approved bronchodilator for use in horses. Bronchodilators relieve the airway obstruction associated with inflammatory airway disease and they work most effectively when combined with allergen and dust avoidance or corticosteroid administration. Like all approved drugs, Ventipulmin® has side effects when given in high doses but, at present, there is no published evidence that Ventipulmin® administered at the recommended dose has any effect on performance.
Pharmacology of beta-2 agonists: Clenbuterol hydrochloride is a beta-2-adrenergic agonist, the most widely used class of bronchodilator drugs for the treatment of human asthma. Other drugs in this class include albuterol, pirbuterol, terbutaline and salmeterol. When these agonists bind to beta-2 adrenoceptors, they activate adenyl cyclase which leads to an increase in the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). In the tracheobronchial tree, beta-2 agonists, cAMP and PKA inhibit smooth muscle contraction by opening K+ channels and by down-regulation of myosin light chain kinase activity.
In the airways, beta-2 adrenoceptors are not restricted to smooth muscle. They also occur on epithelium, inflammatory cells, and the vasculature. When epithelial beta adrenoceptors are activated, cilliary beat frequency increases. The effect on mucus secretion is less consistent, but the weight of opinion indicates that beta-2 agonists increase mucocillary clearance. Activation of beta-2 adrenoceptors on inflammatory cells reduces the release of inflammatory mediators, and activation of those in vasculature can inhibit the permeability increase that occurs in inflammation.
Indications for use of beta-2 agonists: Because beta-2 agonists inhibit airway smooth muscle contraction, they are very useful for the treatment of conditions in which bronchospasm is leading to airway obstruction. In the horse, heaves (also known as COPD) is characterized by severe bronchospasm, and beta-2 agonists are effective at reversing the smooth muscle contraction and relieving the respiratory distress.
It has been demonstrated in animal models of airway disease and in humans that enhanced reactivity of airway smooth muscle to spasmogens is a feature of inflammatory airway diseases induced by allergen challenge, viral infection and pollutant gas exposure. It is likely that the horse also has hyperreactive airways when exposed to similar agents. This airway hyperreactivity makes animals more likely to develop bronchospasm in response to inhalation of irritants. Beta-2 agonists are useful in this situation because they inhibit smooth muscle contraction.
Inflammatory airway diseases are characterized by bronchospasm, mucus accumulation in the airways and airway wall thickening. Beta-2 agonists are beneficial not only because they inhibit bronchospasm but also because they increase mucocillary clearance and inhibit the release of mediators. In horses with COPD, the beneficial effect of beta-2 agonists on mucociliary clearance has been demonstrated in the case of clenbuterol (Turgut and Sasse 1989).
Ventipulmin® syrup: Ventipulmin® syrup is the first beta-2 agonist approved for use in the horse in the USA. In Europe, Australia, Canada and South America, Ventipulmin® has been available for ten years or more. In these countries, Ventipulmin® is administered at a dose of 0.8 micrograms/kg and is used as an adjunct to other treatments that will reduce airway inflammation, for example, corticosteroid administration or antigen avoidance by environmental modification. In the USA, the Food and Drug Administration required proof of efficacy in the absence of these other treatments. In many horses, this required use of a dose greater than 0.8 micrograms/kg (Erichsen et al.,1994). Hence the label for Ventipulmin® in the USA recommends a variable dose schedule. However, the experience in the rest of the world is that Ventipulmin® is effective at a dose of 0.8 micrograms/kg, twice daily, when coupled with other therapy to reduce airway inflammation.
Even though Ventipulmin® can be administered at up to 3.2 micrograms/kg, this dose must be approached with care. Initially giving this high dose will result in side effects of sweating, trembling, tachycardia and excitement. If the dose is approached gradually as recommended on the label, tolerance to side effects will develop.
The label states that Ventipulmin® is indicated for management of horses with airway obstruction such as COPD. Thus the indication is not restricted to horses with heaves, but the drug can be used in any animal the veterinarian judges there is airway obstruction as a result of inflammation, bronchospasm and mucus accumulation. Inflammatory airway disease of race horses in training would fall into this category.
Untoward effects of Ventipulmin® are like those of other beta-2 agonists. These agents are only selective for beta-2 adrenoceptors but, when used in high enough doses, will activate beta-1 adrenoceptors. Activation of beta-1 adrenoceptors causes tachycardia, excitement and sweating. Because of the potential tachycardia, Ventipulmin® is not recommended for use in horses with cardiac disease. Ventipulmin® should not be used in mares that are near term because the myomentrium has many beta-2 adrenoceptors, activation of which inhibits uterine contraction.
If a horse is exhibiting signs of beta-2 agonist overdose, it should be left in a quiet stall until signs pass, generally one to two hours. Subsequent doses should be decreased.
Interactions of Ventipulmin® with other drugs: Because they share a common mechanism of action, one should use great caution when administering Ventipulmin® with other beta-2 agonists either by the oral or nasal route. Overdose of beta-2 agonists will be indicated by anxiety, sweating and trembling. Phosphodiesterase inhibition (theophylline and aminophyline) prevents the breakdown of cAMP, and their use with beta-2 agonists is highly likely to lead to signs of toxicity.
Ventipulmin® can be used in conjunction with the inhaled anticholinergic bronchodilator ipratropium. This treatment would only be indicated in an animal with severe bronchospasm that seemed unresponsive to either agent given alone. Because they inhibit the release of acetylcholine from para sympathetic nerves, alpha-2 agonists such as xylazine cause bronchodilation in horses with COPD. Combining Ventipulmin® with an alpha-2 agonist should not cause problems. There are no known contraindications to the use of Ventipulmin® with any antibiotic, dewormer, diuretic or endocrine medication.
Pharmacokinetics: Following oral administration of 0.8 micrograms/kg, clenbuterol is 92% bioavailable and reaches a maximal plasma concentration in 2 hours. When administered b.i.d., a steady state plasma concentration of 0.6-1.6 ng/ml is achieved in 3-5 days. The plasma elimination half life is10-20 hours with 70-91% of the drug being excreted through the kidney (45% as parent substance) and 6 -15% in the feces (Boehringer Ingelheim Vetmedica, Inc.). Canadian Pari-Mutuel Agency indicates that clenbuterol is below its limits of detection 72 hours after a single dose.
After 10 days of treatment (0.8 micrograms/kg, b.i.d.) in 14 warmbloods, urine concentrations generally fell below the limit of quantification (0.05 ng/ml) by day 7 but were detected in some individual horses up to 13 days. In the same group of animals, plasma concentrations fell below limit of detection (0.025 ng/ml) by day 3 (Boehringer Ingelheim Vetmedica, Inc.). When six Standardbreds received 0.8 micrograms/kg b.i.d. for 5.5 days, clenbuterol was not detected in the plasma of any horse 96 hours after the last dose [level of detection <0.1ng/ml (Kallings et al., 1991)].
Receptor down-regulation: There is always a concern about loss of effectiveness of beta-2 agonists due to a process known as down regulation. In vitro it can be demonstrated that administration of beta-2 agonists causes internalization of beta-adrenoceptors into the cell and uncoupling of receptors from the intracellular pathway. This probably also occurs in vivo but is not very important from a clinical standpoint. The asthmatics who fail to respond to beta-agonists usually have severe disease, and it is likely that it is the severity of their disease rather than receptor down-regulation that makes them unresponsive to therapy (McFadden 1995).
Corticosteroids increase the expression of beta adrenoceptors, and their use with Ventipulmin® is therefore indicated for two reasons: relief of inflammation and prevention of receptor down-regulation.
Comparison of Ventipulmin® to other bronchodilators: All beta-2 agonists given at an adequate dose cause bronchodilation in COPD-affected horses. Aerosol administration delivers bronchodilator concentrations directly into the airways with less likelihood of side effects. Aerosol delivery of any product approved for human use can be achieved by use of the Aeromask® (Trudell Medical London, Ontario). While orally administered albuterol has been used extensively for treatment of COPD, there are currently no published papers on the bioavailability of albuterol or its efficacy as a bronchodilator in horses.
Phosphodiesterase inhibitors (aminophylline and theophylline) are not as reliably effective as beta-2 agonists or anticholinergics. At therapeutic doses, side effects can be considerable (McKiernan et al. 1990).
Anticholinergics are very effective bronchodilators in horses with COPD. However, when administered by aerosol or intravenously, atropine may reduce intestinal motility. Ipratropium bromide administered by inhalation is effective (Robinson et. al., 1993) and because it is not absorbed, it is unlikely to have gastrointestinal effects.
Intratracheal injection of Ventipulmin®: All beta-2 agonists, including clenbuterol, are effective bronchodilators when administered as an inhaled aerosol. However, Ventipulmin® syrup is designed for oral use. It is viscous and hypertonic and is not designed for use in nebulizers or for intratracheal injection. The tonicity of Ventipulmin® suggests it will be irritating to the airway and will cause mucus secretion. There are no published reports that indicate any beneficial effect of intratracheal injection of clenbuterol or Ventipulmin® syrup.
Clenbuterol and performance: There is no published evidence that clenbuterol has any performance-enhancing effect in healthy horses. Airway smooth muscle is relaxed in healthy horses so clenbuterol cannot dilate the airways further.
In Australia, Rose and Evans (1987) conducted a maximal exercise test on fit Thoroughbreds that received either saline or clenbuterol (0.8 micrograms/kg i/v/) 30 minutes before exercise. There were no beneficial effects of clenbuterol. In a Swedish study, six Standardbreds were treated b.i.d. with 0.8 micrograms/kg for 5.5 days (11 doses) (Kallings et al., 1991).The horses performed an incremental exercise test on an inclined treadmill two consecutive days before the start of dosing and two hours after the 9th and 11th dose i.e. on days 5 and 6. Clenbuterol had no effect on oxygen uptake, lactate accumulation, blood gases, heart rate or minute ventilation. There was a minor increase in arterial pH after clenbuterol.
Clenbuterol and repartitioning: There are many published reports of the use of clenbuterol as a repartitioning agent in the livestock industry. When food animals are fed clenbuterol, they accumulate less carcase fat and more muscle. Clenbuterol also stimulates muscle growth in rats. The reported doses of clenbuterol that have been used to have this effect are highly variable but are generally 10-20 times greater than the 0.8 micrograms/kg bronchodilator dose recommended for horses. In rats, doses greater than 10 micrograms/kg increase the rate of growth of skeletal and cardiac muscle (Reed et al., 1986). A dose of 2 mg/kg has been used in several studies of rats in which investigators wanted a distinct effect on muscle growth. In 350 kg steers, 10 mg/head/day (approx. 14 micro-grams/kg b.i.d.) for 88 days caused an 11% increase in the cross sectional area of the longissimus muscle (Ricks et al., 1984). Clenbuterol is also used by human athletes to develop muscle (Prather et al., 1995) but there are not peer-reviewed reports of its efficacy. There are no published reports on the efficacy of clenbuterol as a repartitioning agent in horses. · –by Dr. N. Edward Robinson, College of Veterinary Medicine, Michigan State University.
Thanx so much for the letter.
My horse has been on some ventipullmin (lots at first-15cc-2x p/day. Now only as needed-3to5cc-1x p/day/1-3 days at a time) for 3 and a half months. I am hoping and praying that once we get through this "bout" we will not have another one - ever. But, realistically I will always have ventipulmin on hand-just in case.
We used ventipullmin for a while on a mare at our stud, it did work but we found in prolonged use it seems to stop working, on asking around i found two more people with this problem. A friend with a pony with bad COPD found the ventipullmin became ineffective she changed to keeping the pony out as much as poss and using herbal cough syrup, such as 'Koff Syrup' (dont know if you can get this in america). i have used it on my mare who has mild dust allergy and it worked.
I have had my mare on Ventipulmin for about 4mos now and to be honest I don't know how well its working. When I started her on it she was coughing really bad, had a snotty nose, and her heave lines were showing. She seemed to get better only to get a TON worse a few weeks ago to where she wasn't rideable at all. But now in the last couple weeks she has been great, no coughing, her lines went away and I have ridden her 4 times. It always seems to start when the days heat up but then it actually almost been in the 80's here this week and she hasn't coughed so I don't know what is going on with her. Trust me I am ecstatic that she is seeming to do alright but also wonder what the deal is because only a few weeks ago the vet wanted to start her on steroid injections because she was so bad. Anyone have this happen?
The only real side effects that I've seen are mouth sores from prolonged use, and ocassionally a horse will get hyper and break out in a sweat... if that happens we split the dose up.
Separate names with a comma.