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This article was published in 1960
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INSTITUTE OF INSPECTORS OF STOCK OF N.S.W. YEAR BOOK.

Toxicity of Phenothiazine in Sheep

J. H. IRVINE, B.V.Sc., Veterinary Inspector, Bathurst

Introduction

Apart from its excellent anthelmintic efficiency, one great advantage of phenothiazine is its high safety margin in sheep. Although in N.S.W. millions of sheep are drenched with phenothiazine every year, reports of untoward sequelae attending its use are not common; whilst mortalities directly attributable to the drug are rare. Mostly, fatalities following drenching with phenothiazine are discovered to be due either to the production of a foreign body pneumonia, or to rough handling causing injury to the pharynx, with resultant invasion by pyogenic organisms. In general, it may be said that phenothiazine is both effective and safe, but there are some risks attending its use. Losses do not appear to be related to the dose rate of phenothiazine used, but rather to some unknown factor affecting the susceptibility of certain sheep.

SYMPTOMS OF TOXICITY

The symptoms of phenothiazine toxicity are varied but for convenience may be grouped within the following syndromes:

1. DEPRESSION OF APPETITE

The effects of phenothiazine on the appetite of sheep have long been known, and there have been many reports from stock-owners of loss of vitality in lambs subsequent to its use. In trials it has been found that drenching with phenothiazine may reduce the appetite to the extent of retarding weight gains in young sheep over the following week or two. Although this feature is not of significant practical importance. It does draw attention to the inadvisability of unnecessary drenching; particularly in the case of lambs destined for the fat lamb market. Both in trials and in the field, sheep have been dosed with very high dose rates on many occasions, with no apparent ill effect. In one trial (Malone, 1956) nineteen lambs were dosed with fine particle phenothiazine at varying dose rates from 15 to 120 gm. but no evidence of toxicity was found.

2. ABORTION AND STILLBIRTHS

It is well known that phenothiazine may be dangerous to use in ewes within one month of lambing. Abortion and stillbirths in lambs have been reported both in the field and in trials. It appears that abortion follows death of the foetal lamb. Warwick (1946) has suggested that the danger period is during the last two or three weeks prior to parturition.

It is obvious that phenothiazine is not always toxic to ewes in advanced pregnancy, as many thousands of ewes have been drenched with phenothiazine within a few weeks, or even days of lambing, without all effects. It may be that phenothiazine usually is harmless when used in advanced pregnancy and produces toxicity only under certain conditions. Hungerford and Howe (1944) drenched twelve ewes in advanced pregnancy with 225 gm. of phenothiazine. Five out of the twelve ewes delivered stillborn lambs. Controls, consisting of ewes drenched with copper sulphate-nicotine sulphate and undrenched ewes, showed 100 per cent. normal births. Gadzhiev (1951) used phenothiazine in pregnant ewes during the second half of pregnancy at the comparatively small dose rate of 0.5 gm. per kg body weight. The sheep were in poor condition, and in three days several aborted. Leiper (1951) dosed ewes with 30 gm. of phenothiazine ten days prior to lambing and continued the treatment by adding 1 gm. of phenothiazine to the daily allowance per ewe of 1 lb. of concentrate mixture.

Abortion did not result. It is interesting to note that Blackwell and Allen (1955) found that dosing with phenothiazine prior to mating had no effect on the conception rate in ewes, or on early embryonic development.

3. PHOTOSENSITISATION

Outbreaks of photosensitisation in sheep following drenching with phenothiazine have been reported in this state and others from time to time, but such outbreaks have been infrequent and rarely have symptoms been severe. In such outbreaks, the first symptoms usually are noticed within about forty-eight hours of drenching; when affected animals appear dull and listless and show evidence of irritation shaking their heads and scratching their eyes and ears and showing excessive lachrymation. Later, the skin over the muzzle and ears undergoes reddening and wrinkling and the ears become thickened and droop. Cloudiness of the cornea may be in evidence. There may be impaired vision and in some cases corneal opacity. A severe keratitis may develop, with odd cases of blindness. It seems most likely that the diet may exert an important influence as the predisposing cause rendering the sheep susceptible to phenothiazine photosensitisation.

4. GASTRO-ENTERITIS

This type does not appear to be recorded, although it has been reported on a few occasions. It occurs in lambs drenched under the age of two months and may result in heavy mortality. An excessive dose of phenothiazine is sometimes correlated with this effect. The prominent symptom is a severe gastro-enteritis, although there may be some slight kidney damage. Other symptoms are weakness, staggering gait, tucked-up appearance and inability to walk. Up to 50 per cent. of the flock may be affected, and the recovered animals show a loss of condition. On post-mortem examination there is usually moderate to severe patchy congestion of the mucosa of the small intestine and there may be some congestion of the renal cortex.

5. LOSSES ASSOCIATED WITH SHEARING,etc.

Here toxicity may be associated with shearing, crutching, or some other operation within a day or two of drenching. Symptoms develop rapidly and may be observed within two to 24 hours of drenching, and as many as 70 per cent. of the flock may be affected to some degree. There is partial loss of control of the hind limbs: varying in degree from a swaying of the hind-quarters to an inability to move the hind limbs forward, so that the animals tend to adopt a dog sitting attitude. If sheep are able to walk, the condition is accentuated by movement, and they will go down if driven; with partial recovery on rest. Within a few days, sheep completely recover the use their hindquarters. Some deaths may result. Cloudiness of the cornea, with impaired vision, may be present also; while odd cases may show corneal opacity. If allowed to remain in the sun, keratitis may develop, but if shedded, the corneal cloudiness disappears within four to five days. Sainty (1959) reported a case in which together with the loss of control of the hind limbs, a soft swelling developed on the undersurface of the abdomen in about 70 per cent of the sheep drenched, and within eighteen hours of drenching. Swellings varied from 5in. to 6in. in diameter. The swellings disappeared within about 42 hours of drenching. In this outbreak. there were no corneal lesions.

6. LOSSES FOLLOWING DRENCHING IN HOT WEATHER

In New Zealand, losses have been reported in sheep drenched with phenothiazine during hot, dry weather. Deaths commenced within two to four days following drenching and continued in some outbreaks for several weeks. Feed was very dry at the time and no drinking water was provided. Salisbury (1956) suggests that in the circumstances, it is unwise to drench sheep with phenothiazine during hot, dry periods, because of the risk of toxicity, and in any case the likelihood of animals becoming infested with worms during hot, dry weather is remote; such weather, of course, being unfavourable for the survival of larvae. It appears that dehydration is the predisposing cause in this type of toxicity.

7. LOSSES IN EMACIATED SHEEP

This type recently occurred in emaciated sheep at Glenfield following drenching with phenothiazine. The sheep had been on drought rations of low quality roughage. A liberal supply of water was available. Deaths occurred and the post-mortem picture revealed kidney damage, gastro-enteritis and an empty alimentary tract. Greyish phenothiazine material was present in the small intestine. The sheep that died had been losing condition and obviously had not been eating. An attempt was made to induce similar toxic symptoms in sheep from the same pens, but this was unsuccessful.

8. ANAEMIA

In the horse, phenothiazine is capable of inducing haemolysis of the red blood cells, with the production of anaemia; and in more serious cases, haemolytic jaundice, with haemoglobinuria and albuminuria. However, this condition, in the past, has not been reported in sheep. Holman and Pattison (1942) found no specific change in the blood of lambs receiving a dose of phenothiazine ranging from 5-160 gm. Gadzhiev (1951) found a great reduction in the number of red blood corpuscles and haemoglobin level of sheep dosed with phenothiazine. More recently. C.S.I.R.O. workers have found anaemia developing in four sheep following drenching. The four sheep concerned were in fair condition, but on drought rations supplemented with a small amount of protein. The sheep treated by Gadzhiev were ewes in advanced pregnancy and in poor condition.

It has been suggested in the past that phenothiazine exerts an anti-thyroid effect on various animals, including sheep, as measured by a reduction in the rate of uptake of radio-iodine by the thyroid glands. However, Andrews and Whitten (1956) have shown that regular doses of phenothiazine do not increase the size of the thyroid of sheep, and enhance rather than diminish its iodine content. They conclude from this that the drug does not exert a goitrogenic effect.

Pharmacology

The precise mode of action of phenothiazine is unknown. There appears to be no doubt that phenothiazine itself is the anthelmintic rather than its derivatives. Its site of absorption from the alimentary tract also is unknown. Work carried out by Clare (1947) has shown that the chief product of oxidation of phenothiazine in both sheep and cattle is phenothiazine sulphoxide. The latter derivate is formed in the alimentary tract and absorbed into the portal blood. The sulphoxide is converted in the liver to leuco-phenothiazine and this is conjugated to form the leuco-phenothiazine ethereal sulphate; in which form it is excreted in the urine and in the bile. Some unconjugated leuco-phenothiazine and leuco-thionol are excreted also in the urine. In addition, phenothiazine appears in the urine as a conjugate. In calves the sulphoxide of phenothiazine can be detected in the blood; from the systemic circulation following drenching with phenothiazine, even at very low dose rates. Whilst it is not found usually in the blood of sheep receiving ordinary doses of phenothiazine, Clare (1947) was able to detect the sulphoxide in the blood of sheep receiving 100 gm. of phenothiazine, and in one old ewe in poor condition receiving 30 gm. In sheep dosed with phenothiazine, both the sulphoxide of phenothiazine and phenothiazine may be detected in the portal circulation; while the systemic circulation is much more efficient in converting the sulphoxide to a more readily excretable derivative than the liver of the call. The sulphoxide of the phenothiazine is able to pass from the systemic circulation into the aqueous humour, whereas neither phenothiazine nor any of its other derivatives can. It has been shown quite definitely by Clare, Whitten and Filmer (1947) that the sulphoxide is the photodynamic agent in the photosensitisation of sheep and calves dosed with phenothiazine. In outbreaks of phenothiazine photosensitisation it would seem reasonable to postulate the existence, prior to drenching of an hepatotoxic factor, possibly dietary in origin, which reduces the ability of the liver to cope with phenothiazine sulphoxide. This theory is supported by the experiences of Gordon (1951) in Tasmania; where he found on a number of holdings, lambs with scabby ears at a time when an outbreak of phenothiazine photosensitisation had occurred.

Phenothiazine of moderately fine particle size has been found to be excreted in the urine and faeces of sheep in approximately equal amounts, and some 90 per cent. or more of the total dose administered is recovered in this manner. With phenothiazine of microfine particle size there is a greater percentage absorption and a greater rate of absorption. Further, a larger proportion must become fixed in the tissues as less is recovered in the urine and faeces. Microfine phenothiazine can be found in the urine of sheep within an hour of drenching, whereas coarser phenothiazine is not detected in the urine until 2 hours following drenching. This gives some indication of the differences in absorption rates. With the more rapid absorption rate of microfine phenothiazine, an increased risk of toxicity might be anticipated; there being a greater functional strain placed on the liver.

Phenothiazine swallowed, or injected directly into the abomasum, is absorbed more rapidly than that going directly into the rumen. This is a disadvantage and provides another argument in favour of drenching with an oesophageal-type gun. When phenothiazine is directed onto the back of the tongue, as can happen when using the ordinary type drenching nozzle, it tends in some cases, to stimulate the oesophageal reflex and portion of it may be diverted directly into the abomasum. However, using an oesophageal tube there is no stimulation to closure of the oesophageal groove and the phenothiazine is swallowed into the rumen.

SUMMARY:

The ill-effects resulting from phenothiazine toxicity are described; an attempt being made to classify them into a number of syndromes.

The pharmacology of phenothiazine is discussed briefly.

Acknowledgements

Alexander, F., et al. (1958)—Arch. int. Pharmacodyn., 113:254. (Abstract in Vet. Bull. 29 : 94.)
Allcroft, Ruth. et al. (1955)—Vet. Rec., 67 : 626
Andrews. E. D., and Whitten. L. K. (1956)—N.Z. J. Sci. Tech. A., 37 : 414
Blackwell, R. L. and Allen, Rex W. (1955)—Amer. J. Vet. Res., 16 : 563
Chandler, R. L. (1956)—Brit. Vet. J., 112 : 387
Clare, N. T. (1947)—Aust. Vet. J., 23 : 340
Clare, N. T., and Simpson, J. E. V. (1943)—Aust. Vet. J., 19 : 116
Dunn, A. M. (1953)—Canad. J. Comp. Med., 17 : 317
Fethers, Geof. (1952)—Pastoral Rev., 62 : 827
Gadzhiev, K. S. (1951)—Veterinariya, 28:28 (Abstract in Helminth. Abstr., 20 : 227.)
Gordon. H. McL. (1953)—Pastoral Rev., 63 : 607
Gordon, H. McL.—Pers. Commun.