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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.
Veterinary Therapeutics
SOME RECENT ADVANCES
J. M. KEEP, B.V.Sc., Faculty of Veterinary Science, The University of Sydney
Introduction
The advent of a new group of therapeutic agents follows a set pattern. Firstly the discoverer makes a modest announcement in the scientific press; then the interested manufacturers proclaim loudly, by means of multi-coloured literature, the wonders of their new product. Next, popular magazines are filled with pseudoscientific articles about the new 'wonder drugs' and clinical articles based on shaky evidence and insufficient material, make outlandish claims for cures of disease conditions, in which the mode of action of the drug could have no possible bearing on the pathogenesis of the condition.
Under pressure of bombardment from the drug firms and the general public, it is quite understandable that the poor practitioner is quite confused regarding the true potentialities, side effects and dangers of new products, and it usually takes several years for confusion and hysteria to abate and for compounds to reach their true position and value in the range of therapeutic agents which are now available.
At the moment we are fortunate in that we are not in the midst of one of these 'wonder drug' enthusiasms, and can discuss critically the advances in the therapeutic field that have been made over the last few years. These have been many and varied, but here it is intended to deal only with the corticosteroids, tranquillizing drugs antibiotics and anaesthetics.
CORTICO-STEROIDS
The steroids to be discussed are the adrenal cortical steroids of the anti—inflammatory type — Cortisone and Hydrocortisone; and the more recently developed modifications — Prednisone and Prednisolone. A.C.T.H. may in general be used interchangeably with the steroids except in those cases where the adrenal cortex is unresponsive. In some diseases there is even evidence that A.C.T.H. is superior to the steroids. The newer synthetic products, Prednisone and Prednisolone, represent an attempt to enhance the desired effects whilst modifying the undesired effects. Weight for weight they are about more effective than Cortisone and do at least partly achieve this object.
Prolonged administration of therapeutic doses of the steroids will suppress the action of the adrenal cortex. Sudden withdrawal is likely to cause a reaction due to lack of natural hormone; with symptoms of weakness and depression as well as a flare up of the disease for which the hormone was given (unless this is self limiting). Withdrawal is likely to be fatal if the stress of infection or surgical operation is superimposed. Steroid therapy may be ceased abruptly if the administration has not exceeded a week. Otherwise the reduction of dosage should be gradual in steps of 12.5 mg. a day; or 2.5 mg. in the case of Prednisone. Some clinicians use a stimulating dose of A.C.T.H. at the end of the course to help the patients adrenals to recover.
The main effect exploited in therapy is the ability of the corticosteroids to modify inflammatory and antigen-antibody responses. Such responses may have disadvantageous results in the body leading to tissue damage, which may be suppressed by the steroids. The suppression lasts while the steroid is being administered, the duration of the therapy being therefore determined by the natural course of the underlying process, itself unaffected by the steroid. Other pharmacological responses to the steroids include salt retention increased potassium loss, increased stimulation of acid and pepsin secretion in the stomach, insulin resistance, stimulation of the cerebral cortex and reduction in wound healing. There are certain contra-indications for the use of the steroids, such as chronic granulating infection (e.g. tuberculosis) or gastric ulceration. Their use should never be undertaken without careful thought. Fatal complications may follow steroid therapy in disease otherwise non-fatal.
Before prescribing corticosteroids, the veterinarian should ask himself the following questions:—
- Are there clear cut indications?
- Are there any other equally effective agents available?
- Is there any clinical contra-indication?
- Will their use be temporary or continued?
- What will happen when they are withdrawn?
INDICATIONS
The corticosteroids have been recommended for a great variety of separate conditions, but their usefulness has been established definitely in the following general veterinary fields.
a. Skin: As a local application in the form of an ointment or lotion to afford symptomatic relief in acute and chronic inflammatory skin conditions. This has the effect of making the animal leave the lesions alone and gives the clinician an opportunity to attack the underlying cause.
b. Eye: Used to minimise inflammatory changes within the eye, and on the cornea; resulting in decreased permanent scarring and more speedy return of vision. Used in the form of an eye ointment or drop usually in combination with a wide range antibiotic. May be administered by sub-conjunctival injection.
c. Alimentary Tract: Chronic ulcerative colitis. Systemic administration, usually oral tablets.
d. Chronic inflammatory conditions of bones, tendons and joints: Arthritis, periostitis, bursitis, chronic sprains, exostosis. Used to minimise the amount of inflammatory change and so reduce pain and mechanical interference with movement. Can be given orally, parenterally or by local infiltration into a joint.
e. Adrenal insufficiency states: Poor surgical risks, severe injury, shock, acute hypersensitivity reactions, overwhelming systemic infections. Administered intravenously.
f. Miscellaneous: Acetonaemia in the bovine — produces hyperglycaemia by insulin resistance. Only of value if used in conjunction with normal therapy (glycerol,etc.).
PRINCIPAL PREPARATIONS
a. Local:—
1. Cortisone and hydrocortisone eye/ear ointments 0.5 per cent., 1 per cent., 1.5 per cent., 2.5 per cent.
2. Cortisone and hydrocortisone eye/ear drops 1 per cent., 1.5 per cent.
3. Cortisone and hydrocortisone ointments 0.5 per cent., 1 per cent., 2.5 per cent.
4. Cortisone and hydrocortisone skin lotion 0.25 per cent., 0.5 per cent., 1 per cent.
(All the above can be obtained also in combination with a wide range antibiotic).
b. Parenteral:—
1. Cortisone and hydrocortisone acetate 25 mg./ml. in normal saline for intra-articular injection.
2. Cortisone and hydrocortisone in alcoholic
solution for intravenous injection.
100 mg./ml. Must be diluted with 500 - 1,000 ml. normal saline before use.
3. Cortisone and hydrocortisone acetate 25 mg./ml. Aqueous suspension for intramuscular injection.
4. A.C.T.H. and A.C.T.H. long acting, 10, 25, 50 IU. For intramuscular injection.
5 Prednisolone for systemic and intra-articular use. 10 mg/ml. aqueous suspension.
c. Oral—
1. Cortisone and hydrocortisone acetate, 25 mg. tablets.
2. Prednisolone tablets — 5 mg.
3. Prednisone tablets — 5 mg.
4. Prednisolone 0.5 mg. and acetylsalicylic acid 5 gr. tablets.
DOSAGE
1. Cortisone and hydrocortisone:
Small animals — 1 - 2 mg. per lb. daily.
Pigs — 100 - 300 mg. daily.
Horses and Cattle — 1 - 1.5 mg. daily.
2. Cortisone and hydrocortisone intra-articular:
25 mg. for a major joint.
3. Prednisolone and prednisone:
1/5 dosage for cortisone and hydrocortisone.
4. A.C.T.H.:
Cats — 1 - 2 IU.
Dogs — 2 - 10 IU.
Sheep — 25 IU.
Pigs — 25 - 30 IU.
Horses — 50 - 100 IU.
Cattle — 100 - 200 IU.
Remember stepwise reduction in dosage if course continues over one week; to prevent withdrawal syndrome.
TRANQUILLISING DRUGS
Veterinary surgeons have for many years been faced with the problem of providing satisfactory chemical restraint, and the traditional drugs, chloral hydrate, bromides, barbiturates and narcotics, have only partly fulfilled their requirements. Some of these drugs have proved unsatisfactory for all species; whilst others carry the risk of development of tolerance or have undesirable side-effects. Low doses of barbiturates may cause excitement instead of mild central depression. In many cases sedated animals are incapable of eating or drinking. The discovery of the tranquillising action of Reserpine raised hopes of finding more suitable restraining agents for use in animals. The tranquillising drugs now available provide both humane and pleasant restraint and have been found to be both safe and effective. Unlike the barbiturates and other sedatives, the tranquillisers allow the animal to remain conscious and alert and respond normally to the stimuli of hunger and thirst. Treated animals are usually quiet and co-operative, so that handling is greatly simplified, time is saved and stress and anxiety are mitigated.
INDICATIONS
Tranquillisers are used to provide effective chemical restraint without depression in a wide variety of conditions in domestic animals. In cattle they can be useful in preparing animals for shipment, in the management of belligerent animals during examination, replacement of prolapsed uterus, dystocia, minor teat surgery, examination of the mouth cavity, trimming of horns or hoofs or insertion of nose rings. Tranquillisers used parenterally in cattle become effective within a minute of administration. The animals submit to the procedures without apprehension, become tractable and are less aggressive.
In the horse, tranquillisers are used to facilitate showing, clipping and dental work and before shipment or X-ray exam also have been used in heat stroke, and may be combined with antitoxin and antibiotic therapy in the treatment of tetanus in this species. These drugs may be used also as premedication in horses to enable the use of infiltration anaesthesia or standing castration.
Dogs which are frightened, restless, or irritable become quiet, and eat and drink normally without deep sedatives following the administration of tranquillisers. They submit to grooming and treatment without protest and remain calm for X-ray examination, removal of sutures and splinting. Minor surgery is often possible without further anaesthesia. Tranquillisers also prevent mutilation of wounds, lesions or dressings and reduce anxiety due to pain, trauma, shock or pruritus.
In all species, tranquillisers may be used before surgery to make anaesthesia safer and more comfortable. The anaesthetic can be given in smaller dosage, with minimal excitement, and post-anaesthetic struggling is usually absent.
Commonly used tranquillisers:—
1. Reserpine — Alkaloid of Rauwolfia serpentina. Most commonly used in man for hypertension. Veterinary use very limited in this country. It can be toxic in cattle.
2. The Phenothiazine derivatives.
a. Chlorpromazine.
b. Promazine.
c. Perphenazine.
d. Mepazine.
All very similar in action, they have an extra property of antagonising the emetic effects of motion sickness and certain drugs by inhibiting the vomiting centre.
Chlorpromazine is one of the most commonly used tranquillisers in animals, and is referred to often under one of its trade names — "Largactil'.
3. The Promanediol derivatives.
Meprobamate is the most popular of these. However, it must be given orally as it is only slightly soluble and although there is a latent period of about one hour before it is fully effective, the tranquillisation obtained is long lasting.
DOSAGE
Cattle:
Reserpine ...... 0.07 - 0.75 mg./lb. i/m.
Chlorpromazine ...... 0.5 - 1.0 mg/lb. i/m.
Promazine ...... 0.1 - 0.5 mg/lb. i/v.
Perphenazine ...... 0.1 mg/lb. i/m. or i/v.
Horses:
Reserpine ...... May cause colic. Do not use.
Chlorpromazine ...... 0.05 - 0.1 mg/lb. 1/m.
Promazine ...... 0.5 - 1.0 mg./lb. i/m.
Dogs:
Chlorpromazine ...... 1.0 - 1.5 mg./lb.
Orally.
...... 0.25 - 2 mg./lb. i/v.
...... 0.5 - 3 mg/lb. i/m.
Promazine ...... 1.0 - 2.0 mg./lb. All routes.
Perphenazine ...... 0.25 - 1 mg/lb. 1/m. or i/v.
Meprobamate ...... 5 - 10 mg/lb. Oral only.
Mepazine ...... 2.5 - 5 mg/lb. All routes.
Cats:
Chlorpromazine ...... 1.0 - 1.5 mg./lb.
Oral.
...... 1.0 - 3.0 mg/lb. i/m.
...... 0.25 - 2 mg/lb. i/v.
Sheep and Goats:
Chlorpromazine ...... 1.0 - 3.0 mg./lb.
i/m.
...... 0.25 - 2 mg. i/v.
Pigs:
Chlorpromazine ...... 1 - 2 mg./lb. i/m.
Perphenazine ...... 0.1 mg/lb. i/m. or i/v.
ANTIBIOTICS
At the moment the position of antibiotics is highly satisfactory. The majority of bacterial infections can be cured simply and effectively with what now have become well established drugs. The recent trend in these is towards the development of more selective antibiotics rather than newer drugs of the wide range type. This is due to the increasing difficulty encountered with antibiotic resistant organisms, particularly the staphylococci. Over the last few years the following antibiotics have proved their value in dealing with the gram positive organisms which have become resistant to penicillin and other antibiotics:
Erythromycin
Novobiocin (Albamycin)
Spiramycin (Rovamycin)
Olendamycin.
In all cases these antibiotics are used only after organisms have been typed and drug sensitivity tests have been carried out. Their use in the veterinary field is therefore somewhat limited. Most of them are available in tablets, oral suspension and a soluble form for intramuscular and intravenous injection. Dose rates are similar to those of the other antibiotics, namely 25 - 50 mg/Kg.
Of particular interest in the antibiotic field is the anti-fungal antibiotic, Griseofulvin. Originally developed against fungal infections in plants, it has been found capable of combining with the keratin of the skin, hair and nails after oral administration in animals. By this mode of action it is therefore able to exert a powerful influence on the dermatophytes or skin fungal infections — tinea and ringworm of man and animals.
It has been used successfully in cattle and small animals against infections by Trichophyton and Microsporum in dose rates ranging from 30 to 60 mg/Kg. This therapy should still be supported by the usual fungicidal measures.
ANAESTHETICS
In this particular field attention has been centred mainly on the muscular relaxants, analeptics and premedicating agents.
Muscular relaxants with a curare-like action have been in use for many years, but now the depolarising relaxants have largely replaced these competitive blocking agents, and drugs of the suxamethonium type are the most commonly used — in veterinary practice, suxamethonium chloride.
Suxamethonium is supplied as a solution containing 50 mg./ml. and should be stored in a cold, dark place. When it is to be given in combination with barbiturates the combination should be injected immediately. Given on its own the required amount of drug is drawn into the syringe, made up with 5 ml. sterile distilled water, and injected immediately. Fibrillation and muscle contraction occur in the horse within 20 to 30 seconds. This is followed by collapse and apnoea lasting from ½ — 1 minute. Compensatory hyper-ventilation develops and later intercostal breathing. The horse rises again within 4 to 8 minutes.
The efficiency of suxamethonium in horses is due to its very short action. It provides excellent means of restraint for castration and minor surgery. There is some doubt, however, as to whether it is humane to use relaxants alone for such procedures. Some authors recommend the administration of 15 - 30 ml. of 6 per cent. pentobarbitone sodium in combination with the relaxing agent. In this country, where castration usually is performed without anaesthetic, the use of a relaxant alone may be considered less terrifying than normal restraint.
The dose of suxamethonium recommended for horses is 0.17 mg./Kg. or 8 mg./100 lb. for thoroughbred and saddle horses or 6 mg./100 lb. for draught horses.
Underdosage is dangerous; due to the difficulties of restraint. If intramuscular administration is the route of choice, at least four times the intravenous dose should be given.
As far as other species are concerned, 0.02 mg./Kg. has proved adequate for cattle and 1 mg. per 4 to 8 Kg. provides maximum muscular relaxation in the dog.
Recently, work carried out on the thoroughbred and trotter has indicated that suxamethonium administered in normal dosage may cause some degree of permanent myocardial injury and many veterinarians are wary of the use of the drug in these breeds, where maximum cardiac efficiency is essential. Further work is at present in progress to determine if the intramuscular use of this drug will prevent this undesirable side effect.
As regards the analeptics, bemegride and aniphenazole have become available for the treatment of barbiturate poisoning. To date, in the veterinary field, their use has been confined largely to small animals for collapse under barbiturate anaesthesia. These compounds are administered intravenously in anaesthetic emergencies and are given slowly to effect. The starting dose varied from 3 to 10 ml. of a 0.05 per cent. solution. Some animals show excessive excitement during recovery but this soon disappears.
Thiambutene hydrochloride is a compound resembling morphine, without morphine's undesirable effects. It is used in dogs for its analgesic, hypnotic and narcotic effect in pre-anaesthetic medication. When used in conjunction with Nalorphine, its specific antagonist, short term anaesthesia for minor surgical procedures can be obtained.
This procedure has proved of great value to the small animal practitioner. Thiambutene hydrochloride can be administered sub-cutaneously at a rate of 10 mg./Kg., intramuscularly at 5 mg./Kg. or intravenously at 1 to 4 mg./Kg. Good anaesthesia for minor procedures is then obtained; following which an intravenous injection of Nalorphine at a rate of 2 mg./Kg. will bring about complete recovery in one minute and the animal can walk from the surgery. Intramuscular injection of Nalorphine takes approximately 15 to 20 minutes before the animal awakes.
DOSAGE SUMMARY:
Suxamethonium chloride
Horses ...... 0.17 mg./Kg. i/v.
Cattle ...... 0.02 mg/Kg. i/v.
Dogs ...... 1.0 mg./4-8 kg. 1/v.
Intramuscular administration at least 4 times above.
Bemegride
Small animals ...... Initial 3 - 10 ml. i/v.
...... Give to effect.
Thiambutene HCl
Dogs only ...... 10 mg./Kg. s/c.
...... 5 mg./Kg. i/m.
...... 1 - 4 mg./Kg. i/v.
Nalorphine
To antagonise above ...... 2 mg/Kg. i/v.