Functional Pharmacology 2020 Final PDF

Copyright reserved GENERAL VETERINARY PHARMACOLOGY 300 (VPH300) FUNCTIONAL PHARMACOLOGY Department of Paraclinical Sciences Faculty of Veterinary Science ONDERSTEPOORT...

Copyright reserved GENERAL VETERINARY PHARMACOLOGY 300 (VPH300) FUNCTIONAL PHARMACOLOGY Department of Paraclinical Sciences Faculty of Veterinary Science ONDERSTEPOORT 2020  Contents 1. AUTONOMIC NERVOUS SYSTEM............................................................................... 3 2. CENTRAL NERVOUS SYSTEM.................................................................................. 29 3. LOCAL ANAESTHETICS............................................................................................ 52 4. TRANQUILLIZERS AND SEDATIVES....................................................................... 56 5. ANTICONVULSANT AND ANTI-EPILEPTIC DRUGS.............................................. 67 6. ANALGESICS............................................................................................................... 72 7. MUSCLE RELAXANTS............................................................................................... 90 8. ANALEPTICS............................................................................................................. 966 9. AUTACOIDS................................................................................................................ 99 2  a) FUNCTIONAL PHARMACOLOGY OUTCOME STATEMENT The student must know and understand the effects, purpose and application of the various drugs and groups of drugs used within the central and peripheral nervous system. 1. AUTONOMIC NERVOUS SYSTEM KNOWLEDGE REQUIRED Prerequisite knowledge required for this sub-theme is the knowledge of:  The neurohumoral transmission and the receptors of the adrenergic and cholinergic divisions of the ANS.  The main localities of the adrenergic and cholinergic receptors and their mechanisms. Learning objectives:  Summarise the categorization of sympathomimetic drugs based on their affinities for the different autonomic receptors.  Discuss the mechanism of action of the indirect acting sympathomimetic drugs like ephedrine and name their clinical indication(s).  Summarise the classification of sympatholytic drugs and explain their pharmacological actions.  Compare the drug classification “parasympathomimetic” with “cholinergic”.  Explain the mechanism of action of parasympatholytic drugs.  Discuss the clinical usage of dopamine blockers.  Discuss the following compounds with regards to their classification, available dosage forms, route of administration, absorption, pharmacological effects, clinical uses, side effects and contraindications: o Adrenaline o Atropine o Clenbuterol o Dopamine/Dobutamine o Neostigmine 3  KNOWLEDGE REQUIRED  For the following compounds briefly discuss their classification and clinical indications: o Bethanecol o Ephedrine o Glycopyrrolate o Isoproterenol o Pilocarpine o Prazosin o Propranolol o Scopolamine o Zilpaterol o Phenylpropanolamine  Compare the differences in pharmacological effects of metaclopramide and domperidone in terms of their disposition and explain the significance hereof. 1.1 INTRODUCTION (Review the anatomy and general physiology of the autonomic nervous system). 1.1.1 NEUROHUMORAL TRANSMISSION Sympathetic and parasympathetic outflow tracts comprise preganglionic neurons and post ganglion neurons. Preganglionic fibres of both divisions release acetylcholine at the autonomic ganglia. Post ganglionic fibre neurotransmitters, however, differ and the characteristic response depends on the specific neurotransmitter released. The parasympathetic mediator is acetylcholine and the response is described as cholinergic, whereas the sympathetic mediator is noradrenaline and the response is described as adrenergic. The adrenal medulla is innervated by preganglionic nerves which are cholinergic. Stimulation of these fibres, or the injection of large amounts of acetylcholine result in the release of large amounts of adrenaline and some noradrenaline into the general circulation. Fig 1: Axonal neurotransmission 4 1.1.2 ADRENERGIC NEUROTRANSMISSION AND RECEPTORS 1.1.2 ADRENERGIC NEUROTRANSMISSION AND RECEPTORS Noradrenaline, adrenaline and dopamine are endogenous catecholamines and are the sympathetic neural and humoral transmitter substances in most mammalian species. Noradrenaline is the neurotransmitter at most peripheral sympathetic neuroeffector junctions and is stored in minute granular vesicles in the nerve terminals. Adrenaline and noradrenaline are stored in chromaffin granules in the adrenal medulla. Following stimulation of the adrenergic nerves or adrenal medulla, noradrenaline and adrenaline are released and produce their characteristic responses on receptive tissue. The termination of action of noradrenaline and adrenaline is mainly due to reuptake into the sympathetic nerve endings, as well as uptake into surrounding tissue. Extraneuronal and intraneuronal metabolic transformation of catecholamines may also occur through the enzymes catechol-o-methyl transferase (COMT) and monoamine oxidase (MAO), respectively. Adrenergic receptors are generally divided in α, ß and dopaminergic-receptors. The α and ß receptors are further subdivided into α1, α 2 and ß1, ß2 receptors, respectively. α 1-receptors occur on post synaptic effector cells especially of smooth muscle. The physiological reaction that results from stimulation includes contraction of all vascular smooth muscle, but particularly the arteries of the skin and mucous membranes, as well as liver glycogenolysis. α 2-receptors occur both pre- and post-synaptically. Generally post-synaptic α2-receptors occur peripherally and pre-synaptic α2-receptors centrally. They also occur on fat cells and on blood platelets. Physiological effects upon stimulation include inhibition of noradrenaline release from both central and peripheral adrenergic nerves. Smooth muscle contraction of arteries, inhibition of lipolysis and possibly platelet aggregation. ßl-receptors occur on post synaptic effector cells, particularly at the atria, ventricles and conduction tissue of the heart. Stimulation of these receptors activates adenylcyclase which converts intracellular ATP to cAMP and causes positive inotropic, chronotropic and dromotropic effects on the heart. It also increases lipolysis. ß2-receptors occur post-synaptically on effector cells of especially the smooth muscle of the bronchi, skeletal muscle arterioles and uterus. Stimulation of these receptors, similar to ßl-receptors, activates adenylcyclase resulting in increased formation of cAMP. Physiological reactions observed upon stimulation include smooth muscle relaxation of the bronchi, skeletal muscle arterioles and uterus, as well as liver glycogenolysis and gluconeogenesis. Dopaminergic receptors occur pre- and post-synaptically and may be either inhibitory (eg. basal ganglia) or excitatory (eg. chemo-emetic trigger zone) in nature. Dopamine receptors occur in the smooth muscle of the renal, mesenteric, coronary and cerebral arteries. Stimulation activates cell membrane adenylcyclase which increases formation of cAMP and results in arterial dilation. 5 Peripheral Nervous System 6 7 1.1.3 CHOLINERGIC NEUROTRANSMISSION AND RECEPTORS Acetylcholine (ACh) is the neurohumoral transmitter of all preganglionic autonomic fibres, all post ganglionic parasympathetic fibres, a few post ganglionic sympathetic fibres and at the neuromuscular junction. Ach is synthesized within cholinergic nerves and stored within axonal vesicular structures in a concentrated solution or bound to membranes or both. Ach is released from these stores on the arrival of a nerve impulse. When the released acetylcholine comes into contact with an adjacent neuron it causes depolarization and propagation of the nerve impulse in the second nerve fibre. Once ACh has been liberated it is rapidly inactivated in the junctional space by the enzyme acetylcholine esterase viz: (Acetylcholine esterase) Acetylcholine ----------------------------> Acetic acid and Choline Acetylcholine esterase is present in cholinergic nerves, autonomic ganglia and neuromuscular and neuroeffector junctions. In addition to the highly specific acetylcholine esterase, there are other choline esterases found in various concentrations in the plasma, liver, pancreas and intestines of various species. These are termed non- specific or "pseudo" choline esterases because they hydrolyse many different choline esters and other drugs with ester linkages eg procaine. There are two basic types of cholinergic receptors within the peripheral efferent autonomic nerve tracts viz: muscarinic and nicotinic. Muscarinic receptors occur on all post-synaptic effector cells including smooth muscle, heart muscle and conduction (only supraventricular) tissue, exocrine glands and central nervous cells. Nicotinic receptor sites are present in autonomic nervous ganglia, adrenal medullary chromaffin tissue as well as the neuromuscular endplate of the somatic nervous system (striated muscle). A nicotinic response usually denotes an excitatory response whereas muscarinic receptor activation may cause an excitatory (e.g. in GIT) or inhibitory (e.g. in heart muscle) response. 1.2 SYMPATHOMIMETIC (ADRENERGIC) DRUGS Sympathomimetic or adrenergic drugs are amine substances that cause physiological responses similar to the endogenous adrenergic mediator adrenaline (adrenal glands) and noradrenaline (nerve terminals). 1.2.1 CLASSIFICATION OF SYMPATHOMIMETIC DRUGS 1. Direct acting. a. Natural occurring catecholamines. Noradrenaline, Adrenaline, Dopamine. b. Synthetic catecholamines. Isoproterenol, Dobutamine. c. Non-catecholamines. Clenbuterol, Phenylephrine. 2. Indirect acting. Amphetamine. Sympathomimetic drugs are also classified according to their effect on the receptors, as either: mixed (α & ß) sympathomimetic drugs, α l-agonists, α 2-agonists, mixed ß agonists, ß l agonists and ß2 agonists. Examples of drugs within each of these groups are given within the text. 8 1.2.2 EFFECT OF SYMPATHOMIMETIC DRUGS ON ADRENERGIC RECEPTORS All sympathomimetic drugs do not necessarily produce the same effects. Responses to sympathetic drugs differ according to their affinities for the various types of receptors. Sympathomimetic drugs may either be predominantly α, ß or mixed α and ß agonists. The main drugs and the adrenergic receptor affected by each are: Adrenaline αl ßl ß2 Noradrenaline α1 ß1 Isoproterenol ßl ß2 Dopamine αl(HD) ßl(HD) Dobutamine αl(HD) ßl(LD) Phenylephrine αl Clenbuterol ß2 HD = High dose LD = Low dose 1.2.3 MIXED SYMPATHOMIMETIC DRUGS Adrenaline Adrenaline is either prepared from an acid extract of the adrenal gland (from abattoir material) or synthetically. It is a white or light brown crystalline powder which is insoluble in water. The hydrocloride salt is water soluble and is the form most commonly used. However, unless buffered and a suitable antioxidant is added, solutions of adrenaline are very unstable. Oxidation is evidenced by the development of a pink and finally a brown colour. Pharmacological action (a) Cardiovascular system. (i) Action on the heart. Inotropic, chronotropic and dromotropic effect on the heart as result of stimulation of the ß1- receptors. Coronary vasodilation (ß2-effect) Reflex slowing at high doses. Increases the irritability of the myocardium. Occurs particularly during anaesthesia with certain agents eg. halothane, thiopentone. (ii) Action on blood vessels Viscerocutaneous vasoconstriction through α 1-receptor stimulation. Vasodilation of the arterioles of skeletal muscle (ß2-effect). Greatest vasoconstriction is in the splanchnic area. (iii) Effects on the spleen Splenic capsule is contracted through α1-stimulation. Important in equids. 9  (iv) Blood pressure Initially at sufficiently large doses, both systolic and diastolic pressures rise rapidly to a peak. Thereafter the pressures tend to return to below normal before returning to preinjection values. (v) Adrenaline reversal i.e. a pronounced drop in blood pressure. (b) Respiratory system Not a marked respiratory stimulant. Potent bronchodilators (ß2-effect) (c) Gastro- intestinal system Frequency and amplitude of peristaltic contractions of GIT is decreased. (d) Urinary tract Small doses increases blood flow in the kidney and therefore also urine production. Larger doses shut down the capillary bed of the kidney through α1-receptor activation, thereby reducing GFR and urine production. Relaxes the bladder. (e) Uterus Uterine muscle exhibits variable responses. Normally relaxation occurs. (f) Eye Mydriatic (α l-receptor effect on radial muscles). Nictitating membrane is retracted via α 1-receptors Conjunctival and scleral blood vessels are constricted and a decrease in intra-ocular pressure may occur. (g) Skin Piloerection. Blanching / paling of the skin due to vasoconstriction occurring. (h) Skeletal muscle Increased force of contraction. (i) Metabolic effect Has an overall calorigenic effect. Increased glycogenolysis occurs in the liver and skeletal muscle (α and ß effects). Fatty acid mobilization is accelerated resulting in increased lactic acid formation. 10 (j) Sweat glands Marked sweating occurs in the horse (β2 effect - probably also occurs in sheep). Other domestic species appear to have cholinergic sweat glands. (k) CNS Little stimulating effect on the CNS, except in large i/v doses or small doses in the carotid artery. Absorption Given i/v - not effective when given orally because it is rapidly destroyed in the gastrointestinal tract. Also ionized at physiological pH. Absorption from the subcutaneous site is delayed by local vasoconstriction. Distribution Does not normally penetrate the blood brain barrier (poorly lipid soluble). Biotransformation and excretion Rapidly inactivated in the body. Adrenaline has a very short half-life, lasting only a few minutes. Clinical uses (a) Combined with local anaesthetics eg. procaine, usually at concentrations of 1:100,000 (low concentration) to prolong the effects of the local anaesthetic. (b) Local haemostatic Applied locally it is useful in the control of superficial bleeding from the skin and mucous membranes (α l-effect). It is applied directly to the bleeding surfaces in the form of a spray, drops or on cotton gauze swabs. It is effective only against bleeding from smaller arterioles and not against bleeding from larger vessels. (c) Emergency treatment of anaphylaxis due to its potent bronchodilatory properties and vasoconstrictive effects (stabilizes blood pressure and reduces tissue oedema – particulary in the upper airways). Not the best drug in cases of asthma due to arrhythmogenicity, short half-life and the possibility of aggrevating ventilation perfusion mismatching, since blood flow is improved to poorly ventilated lung areas. (d) Cardiac arrest (except if halothane is in use). Intravenous injection of adrenaline in cases of cardiac arrest will occasionally revive the heart. (A dose of 5 mg/kg and upwards is given). (e) Congestion of the nasal mucosa. (f) Treat extreme hypotension (shock) 11 Side effects (a) Tachyarrhythmias (potentially fatal). Usually dose related Halothane, thiobarbiturates and cardiac glycosides increase the potential for development of tachyarrhythmias. (b) Myocardial infarction. Preparation Adrenaline hydrochloride solutions. 1:1,000 (1 mg/ml - 0,1 %). 1:10,000 (0,1 mg/ml - 0,01 %). Can be administered parenterally, topically or by inhalation. 1.2.4 α1-AGONISTS Phenylephrine (Neosynephrine). Methoxamine (Vasoxyl). Sodium phazoline. Oxymetazoline. Used mainly as decongestant, especially in eye and nasal mucosa. A rebound effect will occur since the cause of the congestion is not treated. 1.2.5 α 2-AGONIST Xylazine (Rompun). Detomidine (Domosedan) Medetomidine (Domitor) Dexmedetomidine (Dexdomitor) Romifidine (Sedivet) Theses drugs are discussed later, under the sedatives. 1.2.6 MIXED ß-AGONISTS Isoproterenol (or Isuprenaline) It is a synthetic mixed ß agonist (ß1 + ß2) Available as a solution of 0,2 mg/ml ("Isuprel") or 30 mg tablets (in a sustained action form ("Saventrine"). Pharmacological effects (a) Positive inotropic and chronotropic actions increase cardiac output. (b) Peripheral vasodilation. Diastolic pressure may be expected to fall. 12  (c) Rate of discharge of the SA node is increased. Increases response of tissue to stimuli (positive bathmotropic effect). (d) Relaxes most smooth muscle, the most pronounced effect being on bronchial and gastrointestinal muscle. Its bronchodilatory effect is 10 times as potent as adrenaline. Clinical indications (a) Bronchospasm - except in the case of anaphylaxis (due to the possible further decrease in blood pressure). (b) As an adjunct in the treatment of shock (c) For the treatment and prevention of cardiac arrest and cardiac arrhythmias, especially ventricular arrhythmias and fibrillation occuring during the course of atrioventricular block. Although isoproterenol is a potent cardiac stimulant it has little or no tendency to cause ventricular fibrillation. Dosage Parenterally at approximately 10 mg/kg, normally given by infusion. Orally ½ - l tablet, 8 hourly for an average dog (the bioavailability is very poor due to large first pass effect). Side effects (a) Isoproterenol and adrenaline should not be administered simultaneously since both drugs are direct cardiac stimulants and their combined effects may induce serious arrhythmia. (b) Overdose could lead to infarction of the cardiac muscle. 1.2.7 BETA 3 AGONISTS Ractopamine and Zilpaterol Ractopamine and Zilpaterol are mixed ß-agonists, with specific affinity for β3 receptors. They produce a metabolic effect known as repartitioning, in production animals. Collectively they are known as the repartitioning agents. Their use results in decreased fat deposition, increased protein synthesis and a decrease in potein degredation. These drugs are mainly used by the feedlot industry to enhance growth rates. 1.2.8 CARDIOSELECTIVE SYMPATHOMIMETICS Dopamine “Intropin", "Dopamin-Nutterman" It is a synthetic product available only as a solution - 50 mg/ml. This drug is very short acting and must be administered intravenously by constant rate infusion (CRI). When administered orally a 100% pre-systemic elimination results. Pharmacological effects (a) Increases the heart rate and myocardial contractility by directly activating ß receptors and releasing neuronal stores of endogenous noradrenaline. 13  (b) Large doses (> 10 mg/kg) activate αl-receptors of blood vessels resulting in vasoconstriction and a pressor response. (c) Low doses selectively dilate mesenteric and renal arterial beds (and perhaps cerebral and coronary arterial beds) by activation of dopamine responsive receptors. Dopamine infusion may directly suppress adrenal secretion of aldosterone and cause diuresis and natriuretic effects Clinical uses (a) Cardiac stimulant. (b) For correction of circulatory disturbances arising during shock, eg. septic shock from endotoxic septicaemia, or haemorrhagic shock from trauma or surgery. (c) Improve poor renal perfusion eg. during renal shutdown. Dosage Up to 10 ųg/kg/minute, given by constant infusion. Normally these drugs should not be mixed with sodium bicarbonate solutions or other alkaline infusion solutions. Side effects (a) As for adrenaline. (b) α -effect is undesirable. (c) Nausea and vomition may result from stimulation of central dopaminergic receptors. Dobutamine "Dobutrex". Is a synthetic derivative of isoprenaline. Available as a solution of 250 mg per 20 ml vials. Pharmacological effects (a) Has direct selective action on ß1-receptors with greater inotropic than chronotropic effects. More cardio-selective than either the naturally occuring catecholamines (noradrenaline, adrenaline, dopamine) or isoproterenol. Has some α1 effects at high doses. The onset of action is within one to two minutes with peak effect of a particular dose reached at approximately 10 minutes. The half-life of the product is short (2 minutes in humans). As for dopamine this drug needs to be administered by constant rate infusion to ensure adequate plasma levels. The drug can not be administed orally due to a high first pass effect. (b) Systemic vascular resistance usually decreases at all dose levels. (c) Has no effect on dopamine receptors. Clinical uses 14  Solely for cardiac support (positive inotropy). Has no effect on kidney since it does not affect the dopamine receptors. Side effects (a) Cardiac arrhythmias which may also lead to infarction. Less arrhythmogenic than adrenaline. (b) α stimulatory effect at high doses. Dosage 2,5 to 10 mg/kg/minute. Occasionally doses as low as 0,5 mg/kg/minute may also elicit response. Given by infusion. 1.2.9 ß2-AGONISTS Clenbutarol, Salbutamol and Terbutaline Used mainly for the treatment of asthma. They are also used to relax the smooth muscle of the uterus and thereby prolong partus. Clenbutarol (Planipart, Ventipulmin) is used most commonly in veterinary science. Available as an injectable solution (0,1 mg/10 mL) and tablets (0,2 mg). Clenbutarol HCl has a prolonged duration of action (6 - 8 hrs) and is relatively free of side effects, especially in the oral form. It is mainly used as a bronchodilator but also stabilizes mast cell and increases mucocilliary clearance. Horses tend to sweat profusely after treatment and show muscular tremor for approximately 10 minutes. It is also used as a tocolytic agent to delay parturition in cattle. Dose Clenbutarol can improve airway resistance at 0,8 mg/kg. A transient severe reflex tachycardia occurs lasting for < 2 minutes due to ß2 vasodilation and hypotension. 1.2.10 INDIRECT ACTING SYMPATHOMIMETICS Indirect acting drugs are not of much clinical importance in veterinary medicine. These drugs act mainly by releasing endogenous catecholamines from their stores. Ephedrine It is an alkaloid obtained from several plants of the genus Ephedra but is also produced synthetically. Similar to noradrenaline but has a slower onset and duration of effect (7 - 10 times). Primarily an α1-agonist but also has some ß1-action. Has a CNS stimulant effect as result of corticomedullary and respiratory centre stimulation Tachyphylaxis results after prolonged usage. 15 Used mainly as a decongestant. The decongestant effect of the drug is short lived. Phenylpropanolamine Similar to Ephedrine. Has less of a CNS stimulant effect. Used in the management of urinary incontinence in spayed bitches. Amphetamine and Dextro-amphetamine "Benzidine" and "Dexadrine". Are Schedule 6 substances. Are potent CNS stimulants, which stimulate the entire CNS. Used commonly for doping purposes in horses. Prolonged duration of action exhibits of tachyphylaxis. 1.3 SYMPATHOLYTIC DRUGS Sympatholytic drugs are pharmacological antagonists of the sympathetic receptors. They are also known as adrenergic blocking agents. 1.3.1 CLASSIFICATION 1. Alpha-blockers. a. Competitive α1 blockers eg. prazosin. b. Non-competitive α1 blockers eg. phenoxybenzamine. c. α2 blockers eg. Yohimbine and atipamezole. 2. Beta-blockers. a. Mixed ß1 and ß2-blockers eg. propranolol. b. Cardioselective ß blockers eg. metoprolol. 3. Dopamine-antagonists eg. metoclopramide. 4. Catecholamine depleting agents and adrenergic neuron blocking drugs eg. reserpine. 1.3.2 α1- BLOCKERS These drugs oppose the pressor responses to sympathetic nerve stimulation. The chronotropic and inotropic effects are not inhibited. They unmask the ß effects of adrenaline on bloodvessels resulting in adrenaline reversal, in which the pressor effects are changed into depressor effects. Although these drugs do not block the chronotropic and inotropic effects of adrenaline on the heart, they protect it against adrenaline-halogenated general anaesthetic arrhythmias and fibrillation. Cardiac output may be increased. 16 1.3.2.1 COMPETITIVE α1-BLOCKERS Prazosin HCl (Minipress) Available as tablets (1, 2 and 5 mg) and an injectable formulation. Good oral absorption with a relatively good bioavailability (± 60 %) although a substantial presystemic elimination occurs. Biotransformed with most of the metabolites excreted in the urine. T½ is approximately 3 - 6 hours. Pharmacological action Mixed vasodilator, including bloodvessels on the arterial and venous side of the circulation. Clinical use 1. Used in the treatment of cardiac failure (congestive heart failure) in dogs and cats as a mixed cardiac load reducer. Dosage Given orally. The dose is established by upward titration starting at 0,25 mg total dose, twice daily. Final dose is normally 0,1 - 0,2 mg/kg, twice daily. Prazosin can be used in renal failure because renal blood flow is not altered. Side effects Excessive dosage can cause hypotension, weakness, syncope and possible mortality. Actions are potentiated by other α blockers eg. ACP. Phenothiazine derivatives Acetylpromazine (ACP), Chlorpromazine. Are multipotent blocking agents. Mainly used as tranquillizers or as antihistamines and for α adrenergic blocking effect in the myocardium. Chlorpromazine and acetylpromazine have also been shown to prevent anaesthetic induced sensitization of the myocardium to catecholamines. 1.3.2.2 NON-COMPETIVE α1-BLOCKERS Phenoxybenzamine (Dibenzyline and Dibenamine) 17 Are haloalkylamine derivatives, that bind to the α receptors in a covalent fashion and are therefore long acting. Phenoxybenzamine produces sphincter relaxation and is often used for urinary retention in patients with spinal trauma or prostatic disease. Dose 0,25 - 0,5 mg/kg every 6 -8 hours. 1.3.3 α 2-BLOCKERS Yohimbine, Tolazoline (Priscoline), Atipamezole. Used as pharmacological antagonists of the sedatives such as xylazine (Rompun), detomidine (Domosedan), medetomidine (Domitor) and romifidine (Sedivet). 1.3.4.1 MIXED ß-BLOCKERS Under most physiological conditions ß vascular receptors participate extensively in blood pressure regulation. The β blocking agents affect blood pressure, through their effects on cardiac output and by inhibiting the release of rennin by the juxtaglomerular apparatus. Propranolol (Inderal) Available as tablets and an injectable formulation It is highly lipid soluble and is well absorbed from the GIT. However, due to a high presystemic elimination its bioavailability is poor (approx. 20 %). Biotransformation is rapid in the liver and has a short T½ of approximately 2 - 4 hours. Several active metabolites have been identified. Pharmacological effects Blocks competitively ß 1- and ß2-receptors, and causes: (a) Negative chronotropic, inotropic and dromotropic effects on the heart which decreases cardiac output and myocardial oxygen utilization as well as a tendency to decrease arterial blood pressure. (b) Anti-arrhythmogenic Mainly due to ß-effect but it may also be related to other mechanisms eg. it causes direct stabilization of cell membranes that somewhat resembles the effects caused by local anaesthetics. (c) Mild sedative effect Mainly as result of its cardiac sympatholytic effect but also penetrates the blood-brain barrier to some extent. (d) Decrease in blood pressure via an indirect action within the kidney. Once the receptors are antagonised within the juxtaglomerular apparatus, the release of rennin is inhibited. The net effect is a decrease in the activation of angiotensin and a decrease in both preload and afterload. This effect occurs at a lower dose than that which results in a decrease in cardiac output. Clinical uses (a) Hypertrophic cardiac myopathies (a disease characterised by a thickening of the heart wall in combination with decreased ability of the muscle to relax), especially in cats but also to some extent in dogs. 18  Heart muscle gets very thick resulting in narrowing of the left ventricle outflow tract (increased afterload) which causes difficulty in discharging blood from the left ventricle. ß blockers increase the diameter of the outflow tract, by decreasing blood pressure. It also decreased impulse transmission via the AV node, allowing the ventricles a greater period of rest. (b) Cardiac arrhythmias. Used for the treatment of atrial tachyarrhythmias in the absence of congestive heart failure. Side effects (a) Bronchoconstriction Not very important in animals. (b) Potential for precipitating congestive heart failure due to its negative inotropic effect if the animal has a weak heart. (c) Heart block. - Intermittent effect at the SA node. Second degree AV block (P wave is not followed by a QRS complex). Contra-indications Heart blockade - existing congestive heart failure (unless the animal is already on digitalis therapy). Dosage Enteral dose is much larger than the i/v dose due to the first pass effect. The dose is titrated upwards starting i/v at 0,1 mg/kg with constant monitoring and orally at 0,5 - l,0 mg/kg bid to 4 times per day. It does not pass the blood brain barrier to any appreciable degree and so exerts relatively little effect on cerebral dopaminergic receptors. In humans it is rapidly absorbed with peak plasma levels which are reached 15 - 30 minutes after oral administration. The plasma half-life is approximately 7 hours. 1.3.4.2 CARDIOSELECTIVE ß-BLOCKERS Metoprolol (Atenolol). These products is not commonly used in veterinary medicine. It is useful for the management of feline hypertension and certain arrhythmias. 1.3.5 DOPAMINE-BLOCKERS Butyrophenone derivatives (azaperone, droperidol, haloperidol) Primarily dopaminergic blockers but also have a degree of α 1 blocking. Used mainly as tranquillizers. 19  Metoclopramide (Maxolon) Restores normal gastric function. It relieves spasm of the stomach and pyloric sphincter, speeds up gastric emptying by slightly accelerating peristaltic movements and prevents stasis of food. Passes the blood-brain barrier and can result in extrapyramidal effects. Is an effective anti-emetic agent in controlling nausea and vomition. An interaction with serotonin receptors, have been proposed as an alternate mechanism for the increased motility seen. Domperidone (Motilium) Is a very potent dopamine-receptor blocking agent, used commonly in horses. It acts on the dopamine receptors in the chemo-emetic trigger zone to produce a powerful anti-emetic effect. It also blocks peripheral dopamine receptors in the gastrointestinal tract producing anti-emesis, dilation of the pylorus, increased gastric peristalsis and a more rapid rate of gastric emptying. Does not pass the blood-brain barrier. 1.3.6 ADRENERGIC NEURON BLOCKERS AND CATECHOLAMINE DEPLETING AGENTS Reserpine (Serpasil) Comes from a plant Rauwolfia. It decreases the storage of catecholamines in the CNS and the rest of the body. In veterinary medicine is principly used as a doping agent in horses (Calms excited animals). 1.4 PARASYMPATHOMIMETIC (CHOLINERGIC) DRUGS Cholinergic drugs are substances that act by direct action on the muscarinic and nicotinic cholinergic receptors or by indirect action through inhibition of acetylcholine esterase to cause physiological response similar to acetylcholine release in the body. Cholinergic effects refer to acetylcholine effects without distinction as to the anatomical site of action, whereas parasympathomimetic effects refer to acetylcholine effects on effector cells innervated by post- ganglionic fibres of the parasympathetic nervous system. 1.4.1 CLASSIFICATION Direct acting agents - activate the cholinergic receptors of the effector cells. -Plant alkaloids - Pilocarpine - Arecoline -Choline esters - Metacholine - Carbachol - Bethanecol Indirect acting - inhibit cholinesterase, allowing endogenous acetylcholine to accumulate and thereby intensify and prolong its action. 20  - Reversible acetylcholine esterase inhibitors. - neostigmine - physostigmine - carbamates Refer to toxicology notes - Irreversible acetylcholine esterase inhibitors. - organophosphors Receptive macromolecules that recognise and bind acetylcholine (i.e. cholinergic receptors and cholinesterases) contain two receptor sites viz. anionic and esterophilic (or esteratic site in the case of cholinesterases). Acetylcholine binds with both the esterophilic and anionic sites of both nicotinic and muscarinic receptors. Binding of acetylcholine with cholinesterase, by combination of the esteratic site with the carboxyl group, results in hydrolysis of the ester. 1.4.2 PHARMACOLOGICAL ACTIONS OF CHOLINERGIC DRUGS – IMPORTANT!! Muscarinic effects (a) Cardiovascular system Causes vasodilation and a fall in blood pressure (hypotension). Large doses cause bradycardia and various cardiac arrhythmias. Effects are more marked on the AV-node and Bundle of His, than on the SA-node. (b) Gastrointestinal tract Activity is enhanced with increase in peristaltic activity. Large doses of these drugs cause spasticity, abdominal cramping and pain. Excessive stimulation may cause intussusception. May also cause vomiting (c) Glands All glands with cholinergic innervation are affected. The salivary glands are particularly affected, resulting in profound salivation. (d) Eye Causes mainly miosis, but the lens is also fixed for close vision (animal appears blind). (e) Respiratory system Bronchoconstriction (f) Urinary Tract Simulates the detrusor muscle of bladder which may result in bladder emptying. 21  The peristaltic waves of the ureters are also enhanced, which causes frequent attempts at urination. Nicotinic Effects Causes muscle tremors resulting in eventual muscle weakness, exhaustion and finally paralysis (muscle remains depolarised for long periods). May cause death due to paralysis of the respiratory muscles. 1.4.3 CLINICAL USES (a) Miotics eg. pilocarpine and neostigmine (b) Treat paralysis of bladder eg. bethanechol. (c) Diagnosis and treatment of myasthenia gravis, using edrophonium, and neostigmine, respectively. (d) Reversal of the effects of curare (competitive antagonism of acetylcholine receptors at neuromuscular endplates) - neostigmine. (e) Treatment of atropine poisoning. (f) Anticestodal effect. 1.4.4 CONTRA- INDICATIONS Mechanical obstruction of GIT or urinary tract. The use of, e.g. carbachol may result in rupture or intussusception Asthma. 1.4.5 SIDE EFFECTS Dyspnoea due to constriction of bronchioles. Hypotension and bradycardia. Abortions, especially late. Colic, especially in horses. Treatment - atropine as it blocks the muscarinic receptors. 1.4.5.1 PLANT ALKALOIDS Pilocarpine It has primarily muscarinic effects (+++) but also some nicotinic effects (+). Primarily used as a miotic, as a solution of 0,5 - 4,0 % instilled directly into the eye. It may cause pain on application, as well as blurring of vision (lens becomes fixed for near vision). Miosis develops within 15 minutes and persists for 12-24 hours. Lens fixation lasts only 1-2 hours. 22 1.4.5.2 CHOLINE ESTERS Carbachol (Lentin ) It is a powerful cholinergic agent, having mixed muscarinic and nicotinic effects It is fairly long acting and is almost completely resistant to inactivation by cholinesterases. More active on the smooth muscle of the GI tract and urinary bladder than on the cardiovascular system. Used as a laxative in cattle and relief of urinary retention. Co-ordinated cyclic contractions of the rumen are disturbed and the reticulum becomes paralyzed. Causes drastic colic and profuse sweating in horses. Abortions and contractions of the uterus in the latter part of pregnancy. Bethanecol ( Urecholine) Very similar to carbachol, except that it is primarily a muscarinic agonist. It is also relatively long-acting and is mainly active on the smooth muscle of the GI tract and urinary bladder. Used regularly in veterinary medicine for treatment of bladder paralysis and paralytic ileus (a condition occuring particularly after abdominal surgery or trauma). No longer available in South Africa as a commercial product. The product can be bought from a compounding pharmacy. Dose 1 mg s/c twice daily has been used to treat urinary bladder atony in cats after urolithiasis Care should be taken to ensure that the urethra is completely patent. 1.4.6 INDIRECT ACTING DRUGS 1.4.6.1 REVERSIBLE ACETYLCHOLINE ESTERASE INHIBITORS Neostigmine (Prostigmin) Synthetic product. Neostigmine bromide is available for oral use and neostigmine methyl sulphate for parenteral use. Bioavailability is poor and must therefore be given in large doses if given orally. Duration of effect is approximately 2 hours. Does not cross the blood-brain barrier to any major extent. Clinical uses Diagnosis (lower dose) and treatment of Myaesthenia gravis. Treatment of poisoning from overdose of non-depolarizing muscle relaxants. - Gallamine 23 Dosage Parenteral dose of approximately 25 mg/kg, which is reached slowly by titration, usually by subcutaneous injection. Side effects Toxic doses produces skeletal muscle weakness, nausea, vomition, colic and diarrhoea. Dyspnoea also occurs as result of bronchoconstriction. Endrophonium (Tensilon) Is a synthetic very short acting (5 - 10 minutes) drug. Used for the diagnosis of Myaesthenia gravis. Carbamates Insecticide for use either on crops or animals. These reversible inhibitors of Acetylcholine esterase are very important agents as they feature as one of the more common poisonings in the country. For more information please refer to your toxicology notes or the section on ectoparasiticides. 1.4.6.2 IRREVERSIBLE ACETYLCHOLINE ESTERASE INHIBITORS (See Toxicology notes) eg. Organophosphors Organophosphors are commonly used pharmacologically as anthelmintics (eg. trichlorphon, dichlorphos, haloxon) and pesticides (eg. chlorfenphinphos, quinthiophos, malathion, etc). These irreversible inhibitors of acetylcholine esterase produce typical nicotinic and muscarinic clinical signs. (for more information please refer to the toxicology notes or the section on ectoparasiticides). Treatment of toxicity Cholinesterase reactivators: The oximes, react directly with alkylphosphate compounds and free the enzyme. Pralidoxime methiodide (PAM) and obidoxime (Toxogonin) are effective in reactivating phosphorylate enzyme and may be used as an antidote for the treatment of poisoning with organic phosphates. Pralidoxine and obidoxime are more active at the neuromuscuiar junction than CNS and not effective at the muscarinic sites. Obidoxime can pass the bloodbrain barrier. The recommended dose of PAM is 13 mg/kg every 4 hrs. For obidoxime it is 4 - 8 mg/kg, i/v. If the animal responds, give every 2 hrs, 2 - 3 times. Only effective up to 36 - 48 hrs after poisoning. Start with atropine and 5 minutes later give obidoxime. Receptor antagonists: These drugs are pharmacological atagonists of the cholinergic receptor and prevent the clinical signs of toxicity from resulting. They do not interact with the toxin or enhance the elimination of the toxin. Their duration of use will depend on the duration of clinical signs. In most cases treatment will have to be administered until the organophosphor in question have been naturally eliminated. Muscarinic Antagonist: Atropine Nicotining Antagonist: Diphenhydramine Physical Antagonists: A portion of the organophosphor can also be bound within the GIT with the aid of activated charcoal. The drug has three beneficial effects: It will bind to any organophosphor free within the GIT, it will bind to organophosphors excreted via the bile (predominant route of organophosphor excretion), it will cause retrodiffusion of organophosphors from the blood back into the GIT tract. Thus irrespective of the route of poisoning it is always beneficical to place an animal on activated charcoal therapy. 24 1.5 PARASYMPATHOLYTICS Parasympatholytics are competitive pharmacological antogonists of the muscarinic receptors. These products are also known as muscarinic-blockers or antimuscarinics. 1.5.1 CLASSIFICATION Belladonna alkaloids -Natural. -Synthetic. Synthetic antimuscarinic compounds. 1.5.2 NATURAL BELLADONNA ALKALOIDS They are widely distributed in nature, especially in solanaceae plants eg. Deadly Night Shade (Atropa belladonna), Jimson weed (Datura strumonium) and Hembane (Hyoscyamus niger) Drugs Atropine (dl-hyoscyamine). Scopolamine (l-hyoscyamine) (Scopolamine hydrobromide, methylscopolamine and n-butylscopolamine). Hyoscine butylbromine (Buscopan). 1.5.3 SYNTHETIC AND SEMISYNTHETIC BELLADONNA ALKALOIDS Many attempts have been made to develop drugs similar to atropine with a more specific action for a given organ. Atropine affects many organs and when used for a specific effect the other actions may be undesirable, ie. the long action on the eye or the drying of the mouth. One of the main uses of the belladonna alkaloids is for their antispasmodic effect on the GIT. In man they are used for the treatment of gastric and duodenal ulcers, gastric hyperacidity and hypermotility, etc. The synthetic substitutes have been introduced for clinical use in ophthalmology (mydriatics and cycloplegics) and in gastroenterology (anti-ulcer and spasmolytic agents). Only a few of the agents are used to any extent in veterinary medicine. Some of these compounds are: Semisynthetic compounds Atropine methylnitrate Homotropine Eucatropine 1.5.4 SYNTHETIC ANTIMUSCARINIC COMPOUNDS Methantheline (Banthene) Propantheline (Probanthine) Glycopyrolate Glycopyrolate at 0,75 mg/kg was shown to be better than either atropine or hyoscine as a premedication. In canine anaesthesia it maintained pulse at the same level throughout and did not produce a tachycardia as in the case of atropine and hyoscine. It does not cross the blood brain barrier therefore has less CNS side effects. 1.5.5 EFFECTS OF PARASYMPATHOLYTICS Mechanism of Action 25 Are competitive antagonists of the muscarinic receptors. Pharmacological effects (a) Central nervous system Atropine has a stimulatory action on the CNS - minimal at therapeutic doses (due to the lower ability of the drug to penetrate the blood brain barrier). Large doses cause restlessness, irritability, disorientation, hallucinations and delirium which is eventually followed by depression, medullary paralysis and death. Scopolamine stimulates, rather than depresses respiration. (Scopolamine is more lipid soluble than atropine and can therefore cross the blood brain barrier more easily. In dogs small doses of scopolamine produce sedation and sleep and stabilize vestibular function (one of the best drugs against motion sickness). Large doses cause restlessness, ataxia and often emesis. (b) Heart Atropine may cause initial slowing of heart rate, probably from stimulation of the central vagal centres, followed by cardiac acceleration in most species. Blocks transmission of vagal impulses to the heart, the degree of effect will depend on the amount of vagal tone. (c) Circulation Atropine does not produce marked or constant effects on blood vessels or blood pressure. (d) Secretions Salivary secretions are markedly inhibited, causing a dry mouth and difficulty in swallowing. Glands of the mouth, throat, nose and respiratory passages are inhibited and the mucous membranes become dry. The secretion of tears is diminished. The secretion of sweat is inhibited. Local application of atropine to the skin has no effect on sweat secretion. After administration of atropine the skin tends to become dry and hot (important clinical sign in people). (e) Gastrointestinal tract Atropine completely antagonizes the effects of acetylcholine and parasympathomimetic drugs on the GIT. It has little effect on normal peristalsis but tends to arrest certain forms of violent contractions. (f) Respiratory tract Atropine blocks the cholinergic responses of bronchial muscles and causes bronchodilation. (g) Eye Causes mydriasis and cycloplegia. The mydriasis is caused by blocking of the cholinergic innervation of the constrictor muscles of the iris and the cycloplegia by blocking of the cholinergic innervation of the ciliary muscles. (cycloplegia: Paralysis of the ciliary muscles) 26  When applied topically, atropine affects only the eye to which it is applied. It is possible to dilate one pupil with atropine and constrict the other with pilocarpine, etc. Atropine has little effect on the intra-ocular pressure in the normal eye, but may increase tension in glaucoma. (h) Other organs Atropine has a spasmolytic effect on the urinary bladder, ureters, biliary tract. Its effect on the uterus is negligible. (i) Body temperature High doses cause an increase in body temperature. In animals that do not sweat profusely and in which heat loss occurs principally through other channels, such as the dog, a rise in temperature does not occur. (j) Local analgesic effects Atropine has only very mild local anesthetic properties. (k) Tolerance Most animals are more tolerant to atropine than man. Toxic effects Clinical signs include; dry mouth, thirst, dysphagia, constipation, mydriasis, tachycardia, Hyperpnoea, restlessness, deliruim, ataxia and muscle trembling. Convulsions, respiratory depression and respiratory failure lead to death. 1.5.6 PHARMACOKINETICS Belladonna alkaloids are absorbed from the GIT (10 - 25 %) the eye, and to some extent, from the skin. Most of the alkaloid is destroyed in the liver by enzymatic hydrolysis of the ester to tropine and tropic acid. Atropine has a T½ of ca 2.5 hr. The remainder is eliminated in the urine. The excretion of free belladonna alkaloids in the urine allows for their recognition by a rapid and sensitive presumptive test viz: a single drop of urine placed in a cat's eye will dilate the pupil if it contains atropine (0,0003 mg) or scopolamine (0,00002 mg). 1.5.7 THERAPEUTIC USES – IMPORTANT!!! (a) Spasmolytic To relax gastrointestinal smooth muscle in colic, enteritis, peritonitis, etc. (Atropine is no longer a recognised agent in the treatment of diarrhoea) To relax the bronchial muscles in asthma and in heaves of horses. In asthma the use of adrenergics drugs are more reliable. To relax other smooth muscles ie. in spasmodic contraction of the ureters due to calculi. (b) Checks excessive secretions, especially of saliva, excessive sweating, or bronchial or nasal secretions. (c) Mydriatic - ½ to 1 % solution of atropine SO4 applied topically. 27 (d) As an antidote for overdoses of parasympathomimetic agents and for poisoning due to anticholinesterase insecticides. Start at 0,4 mg/kg i.e. 10 times the normal dose. (e) As a pre-anaesthetic medication. (f) Prevention of motion sickness. (g) Treat sinus bradycardia, sinoatrial arrest and incomplete AV blocks 28  2. CENTRAL NERVOUS SYSTEM KNOWLEDGE REQUIRED Leaning objectives:  Explain the mode of action of general anaesthetics.  Define premedication, explain its purpose and list drug types commonly used.  Compare the advantages and disadvantages of inhalation vs. parenteral anaesthetics.  With regards to inhalation anaesthesia, discuss the following: o uptake, distribution and elimination o administration techniques o pharmacological effects o side/toxic effects  Discuss the classification, pharmacological effects, anaesthetic properties, clinical uses, species indicated, side/toxic effects and contraindications of: o Alfaxalone o Halothane o Isoflurane o Ketamine o Nitrous oxide o Propofol o Sevoflurane o Thiopentone  Compare the duration of action and clinical uses of the following barbiturates: thiopentone, pentobarbitone and phenobarbitone.  Discuss the treatment procedure in the case of general anaesthetic overdose. 29 2.1 TERMINOLOGY AND DEFINITIONS Anaesthesia: Loss of consciousness with loss of pain perception. Hypnotic: A substance which produces sleep (ie. a physiological state from which the patient can easily be aroused). Narcotic: A substance which produces a state of deep sleep and analgesia eg. morphine. Sedative: A substance used to cause a dose-related state of mild CNS depression; leaves the patient free of anxiety. Analgesic: A substance which temporarily abolishes (or decreases) the awareness of pain without affecting consciousness. Tranquillizer: Same as sedative, except that it is not as potent. The difference is a matter of degree. Tranquillizer = ataractic = neuroleptic. The effects of a tranquillizer are also not dose-related. Catalepsy: A state in which there is waxy rigidity of the limbs which may be placed in various positions and maintained for some time; the subject is unresponsive to stimuli. Stimulants: Those agents which increase mental and motor activity. Analeptics: Are stimulant drugs which are used to reverse respiratory and/or circulatory collapse especially in the case of anaesthetic overdose. 2.2 GENERAL ANAESTHESIA 2.2.1 MODE OF ACTION Anaesthetics may act pre and/or post synaptically and affect both excitatory and inhibitory synaptic transmission in the CNS. Effects on the excitatory synapses are chiefly depressant, whereas they may either depress or enhance inhibitory synaptic transmission. Anaesthetics are non specific and act on a variety of cell types and functions. Various theories try to explain the mode of action. Currently two theories explain the mode of action of anaesthetic agents: i) The physicochemical theory: dealing with the deformation of biomembranes through expansion, volume change and fluidization. ii) The receptor based theory: dealing with specific receptor based pharmacological actions of the anaesthetic agents. This is the most widely recognised theory. The receptors identified to date include GABA, Glycine and the NMDA receptors. 30 2.2.2 SIGNS AND STAGES Have been established for uncomplicated diethylether anaesthesia in man. Generally there is a predictable sequence of events from the early stages of anaesthesia to the stage of complete medullary paralysis. However, variation among species, patients and anaesthetic agents is common. The more rapid the induction of anaesthesia, the less obvious is the transition from one level of anaesthesia to another. The classical stages of anaesthesia are as follows: (a) Stage I: Voluntary excitement Stage of anaesthesia without loss of consciousness - some disorientation. Lasts from the beginning of anaesthesia to the loss of consciousness. (b) Stage II: Involuntary excitement. Patient has lost consciousness. Certain inhibitory areas of the brain are inhibited leading to facilitation and possible involuntary muscle movement, especially in dogs (howling, kicking). Stage I and II together make up the induction period of anaesthesia. They are unwanted effects and the aim is to get an animal through these stages as rapidly as possible. This can be done by either premedication and/or the use of i/v anaesthetics. (c) Stage III: Surgical anaesthesia. Consciousness, pain sensation and powers of co-ordinated movement are lost. Polysynaptic (eg. withdrawal reflex) spinal reflexes are suppressed whereas monosynaptic (eg. stretch reflexes) spinal reflexes are unaffected. In the dog and cat the interdigital skin is mainly used to test for this stage. Arbitrarily this stage is divided into 4 planes viz. plane 1 (light), plane 2 (medium), plane 3 (deep) and plane 4 (dangerously deep). Most major surgical procedures are done at stage II and plane III. (d) Stage IV: Medullary paralysis Characterized by jerky irregular respiration and respiratory arrest. Cardiac arrest follows closely. All reflex activity is lost. At this point immediate and vigorous corrective therapy is required to successfully resuscitate the patient. 31 2.2.3 PREMEDICATION Includes all drugs administered prior to general anaesthesia. Generally premedications are given to make the induction and maintenance of anaesthesia easier for the anaesthetist, while at the same time rendering the experience safer and more comfortable for the patient. Purpose (a) To reduce anxiety. (b) To facilitate smooth rapid induction. (c) To relieve pre- and post-operative pain. (d) To reduce the amount of dose in the case of intravenous drugs or concentration in the case of inhaled drugs and thereby increase the level of safety. (e) As a protection against anaesthetics that induce cardiac arrhythmias. (f) To abolish / minimise unwanted side-effects eg. salivary flow, vomiting, diarrhoea. (g) To smooth (but sometimes to prolong) recovery. Classes of drugs commonly used in premedication (a) Hypnotics eg. barbiturates, chloralhydrate. (b) Tranquillizers eg. phenothiazines, benzodiazepines. (c) Sedatives eg. Benzodiazepines (d) Opioids eg. morphine. Important (e) Anti-emetics eg. phenothiazines, butyrophenones. (f) Antimuscarines eg. atropine, scopolamine. (g) Antiarrhythmics eg. lignocaine, phenothiazines. 2.2.4 ROUTES OF ADMINISTRATION OF GENERAL ANAESTHETICS (a) Inhalation (b) Intravenous (c) Intramuscular (d) Intraperitoneal (e) Intrathoracic (f) Oral 2.2.5 INHALATION ANAESTHETICS An inhalation anaesthetic cannot be introduced into the brain without at the same time being distributed throughout the entire body. This distribution exerts a controlling influence over the rate of uptake or elimination of the anaesthetic in the brain. Administration techniques (a) Auto-inhalation Air is inhaled through or over the anaesthetic on a pad soaked in anaesthetic (open or semi-open methods of administration can be used). Auto-inhalation methods are wasteful and unpleasant for the anaesthetist. It is useful where more sophisticated equipment is not available. (b) Positive feed methods Gaseous anaesthetics are passed under pressure into a mask or endotracheal tube to the animal. In the case of volatile anaesthetics, air (occasionally combined with nitrous oxide) is bubbled through or 32  passed over the anaesthetic which carries into the mask or endotracheal tube a quantity of anaesthetic vapour. REFER to anaesthesiology notes for administering systems Uptake and distribution The uptake and distribution of inhalation anaesthetics can be divided into two phases: Pulmonary phase Circulatory phase (a) Pulmonary phase This is the build-up of a significant anaesthetic alveolar tension. Since diffusion across the alveolar membrane is rarely a limiting process the arterial tension is usually equal to alveolar tension, and therefore directly controls the depth of anaesthesia. Factors which regulate the rate of development of alveolar tension: (i) Inhaled tension. Mainly dependent on the rate at which the anaesthetic is delivered. However, it is also influenced by factors such as the physical characteristics of the agent and design and volume of anaesthetic circuit of the inhalation equipment. (ii) Alveolar ventilation. Inhalation induction is hastened by an increased rate and depth of respiration and is slowed by apnoea, breath-holding and hypoventilation. (iii) Transfer of gases from alveoli to blood. The alveolus acts as a variable permeable container and allows some agents to escape into the bloodstream. The most important factors which influence this transfer are: Blood / gas partition coefficient or solubility of the agent. Insoluble agent - anaesthetic capability nil. Slightly soluble agent - eg. nitrous oxide (0,47) cyclopropane (0,46). Alveolar tension rapidly approaches inspired tension. Moderately soluble agent - eg. halothane (3,6) chloroform (7,3). Alveolar tension slowly approaches inspired tension. Very soluble agent eg. methoxyflurane (13,0) ether (15,0). Alveolar tension will never reach inspired tension. (iv) Pulmonary blood flow. Pulmonary blood flow is directly proportional to the cardiac output. (v) Partial pressure of anaesthetic agents in venous blood (pulmonary arterial blood). (vi) Alveolar membrane. 33  In disease states (pulmonary oedema, fibrosis) diffusion may be impaired. (vii) Ventilation perfusion relationships. (b) Circulatory phase Circulatory factors which will affect the rate of induction and duration of inhalation anaesthetics are: (i) Cardiac output. (ii) Cerebral blood flow. (iii) Secondary saturation of body tissues. Tissue blood flow eg. fat. Tissue / blood partition coefficients ie. the solubility of agents in various tissues relative to solubility in blood. All drugs that affect the CNS must be lipid soluble. Minimum alveolar concentration This is the minimum alveolar anaesthetic concentration (MAC) (usually %) which is required to abolish movement or response to skin incision in 50 % of individuals in a state of equilibrated anaesthesia. On this basis anaesthetic agents can be compared for equipotency. Metabolism and excretion Lungs are the most important route of excretion. There is very little hepatic biotransformation. The extent of biotransformation is dependent on the product and level of anaesthesia and appears to be first order kinetics. Metabolites may or may not be toxic. Some anaesthetics are also excreted through the urine. When the administration of inhalation anaesthetics is terminated its concentration in the inspired air cannot be reduced to zero. The volume of anaesthetics of expired air exceeds the inspired volume by as much as 10 % in the first 10 minutes. This outpouring of anaesthetic dilutes the alveolar oxygen tension and can result in "diffusion hypoxia" - more significant with anaesthetics with low solubility. Inhalation agents General Mechanism of Action At present all gas anesthetics, with the exception of nitrous oxide are believed to function by the same mechanisms. These drugs enhance the sensitivity of the GABA receptors to the effects of the GABA neurotransmitter. With GABA being an inhibitory neurotransmitter, a decrease in CNS activity results. Volatile liquids (a) Halothane "Fluothane" (b) Methoxyflurane "Metofane". (c) Diethyl-ether "Ether". (d) Enflurane "Ethrane". (e) Isoflurane "Forane". (f) Desflurane (g) Sevoflurane 34  Gases (a) Nitrous oxide (b) Cyclopropane Halothane "Fluothane" Physical properties Clear fluid at room temperature. Highly volatile. Vapour - sweet, pungent odour, non-irritating. Non-flammable or explosive. Light sensitive - protected by amber coloured bottle. Anaesthetic and pharmacological properties (a) Clinically a potent, predictable, potentially dangerous agent. MAC of 0,75 - 0,87 %. Ideally requires the use of accurately calibrated vaporizers which should be located out of circuit. (b) Moderate solubility in blood (B/G 3,6) and gives rapid induction and recovery and rapid changes between levels. (c) Depresses ventilation in proportion to its alveolar concentration. Very high concentration causes apnoea and respiratory arrest. (d) Suppresses cardiac function. (e) Causes peripheral vasodilation. (f) Suppresses hypothalmic thermoregulation and the animal becomes poikilothermic. Usually the body temperature decreases as the temperature within theatre is kept at 20° C Causes malignant hyperthermia in susceptible pigs, mainly in the Landrace and is known as porcine stress syndrome (PSS). (This gene has largely been outbred) Halothane test is used to identify susceptible pigs. (g) Highly lipid soluble - also crosses the placenta. Foetusses can survive lower concentrations - used in caesarian sections. (h) Relaxation of skeletal muscle is medium to poor. (i) Relaxes uterine muscle and increases uterine bleeding in some species (man, pig, and possibly the horse). (j) No inherent analgesic properties. (k) Dose dependent respiratory depression. Produces bronchodilation and is non-irritant to respiratory passages but slightly pungent smell 35 (l) Arrhythmogenic - sensitizes the myocardium to circulating catecholamines. The interaction is potentiated by thiobarbiturates. Acetylpromazine (ACP) premedication will protect against this arrhythmogenic effect. Other phenothiazine tranquillizers and diazepam may also suppress adrenaline induced ventricular arrhythmias. The other alpha-2-acting sedatives can be cardio-protection, when used at premedication doses (At normal sedative doses, they are themselves arrhythmogenic). Clinical uses Usually used as maintenance agent following i/v induction. Is used in all animal species including lab and exotic animals. Side and toxic effects (a) Dose related cardiovascular and respiratory depression. This hypotension is most severe in the horse (these animal require intra-operative support with a positive inotropic agent) (b) Arrhythmogenicity. (c) Poikilothermia and malignant hyperthermia. (d) Potentially hepatotoxic due to the formation of hepatotoxic metabolites in some individuals (man mostly), especially if hypoxaemic. Has been reported in goats 24 hours after halothane administration. Isoflurane Isoflorane is a structural isomer of enflurane. Physical properties Similar to halothane. Non-flammable or explosive. Isoflorane is a colourless liquid and has a pungent, musty ethereal odour. It is highly volatile with a boiling point of 48.5°C at 760 mm Hg and a vapour pressure of 238 mm Hg at 20°C. Anaesthetic and pharmacological properties a) Slightly less potent than halothane. MAC varies between 1.2 - 1.7 % depending on animal species. Isoflurane should be used with a specific vapouriser. b) Due to a lower blood: gas partition coefficient (blood: gas of 1.43) than halothane it gives more rapid induction of anaesthesia, more rapid changes between different planes of anaesthesia and more rapid recovery than halothane. c) Causes a dose related cardiac and respiratory depression. Heart rate appears to be better maintained than halothane and remains relatively constant at a range of isoflorane doses. The duration of isoflorane anaesthesia influences the magnitude of cardiovascular adverse effects. Can cause apnoea at very high alveolar concentrations (2.5 MAC for dog and 2.3 MAC for horse). d) It has very little catecholamine myocardial sensitization effect. 36 e) Although the decrease in peripheral vascular resistance is slightly greater with isoflorane than halothane a similar degree of hypotension occurs with both products due to a reduction in cardiac output. f) Its muscle relaxant effect is normally adequate for general abdominal surgery. It has a greater enhancing effect on non depolarising neuromuscular blocking agents than halothane. g) May also trigger malignant hyperthermia. h) Unlike enflurane it does not produce seizure activity and normally exhibits anticonvulsant effects. Similar to halothane and the other halogenated volatile anaesthetic drugs it does produce a species specific, isolated EEG spiking in the cat. i) Poor analgesic properties j) Has a pungent odour and therefore animals may hold their breaths if the drug is used for induction of anaesthesia. Clinical indications Isoflorane is the anaesthetic of choice in the critically ill patient and in birds. It is also especially useful in larger animals such as the horse since it minimises the risk of hypoxaemia and injury in the recovery phase. Side and Toxic effects (a) Dose related cardiovascular and respiratory depression. (b) Reduced incidence of catecholamine induced cardiac arrhythmogenicity. (c) Poikilothermia and malignant hyperthermia (d) Lack of direct renal and hepatic toxicity due to very little hepatic metabolism (0.2%) and absence of significant quantities of metabolites. Others Desflurane Very similar to isoflurane The drug does, however have a greater respiratory depressant effect, and is still poikilothermic and a cause of malignant hyperthermia in pigs. It has the same degree of depression on the cardio-vascular system, but is devoid of sensitisation. Requires a specialised electronic heated vapouriser. Sevoflurane It has similar anaesthetic and pharmacological properties to isoflurane while being deficient of a cardiac sensitising affect. Compared to isoflurane, anaesthesia induction and recovery is more rapid (low blood:gas partition coefficient = 0.6). MAC varies between 2.1 – 3.3 % depending on animal species. It has a non-irritant effect on the airways and is better for use in inhalation induction. It does not sensitize the heart to catecholamines and has less cardiorespiratory depressant effects compared to halothane and isoflurane. Sevoflurane should be used with a specific vapouriser. 37  Nitrous oxide (N2O - laughing gas) Physical properties Inert gas Colourless, non-flammable, non-explosive, non-irritant gas. Relatively insoluble (B/G 0,47). Non-flammable per se but does support combustion. Stable with soda-lime. Pharmacological properties The mechanism of action is currently unknown. The drug is believed to in part produce its effect by interacting with opiod receptors Sedation. Good analgesic effects. Synergistic CNS depression with other anaesthetics, especially halothane. Has minimal cardiovascular effect in absence of hypoxia. Causes some peripheral vasodilation. Slight stimulation of respiration commonly occurs. Poor skeletal muscle relaxant. Anaesthetic properties and clinical uses Low potency (MAC > 100 %) cannot achieve stage III on its own. The MAC is about twice that of humans in most animal species. Onset of effects rapid (function of solubility). Used with O2 in concentrations of 50 - 70 % of inspired gas mixture - must ensure that O2 concentration is at least 30 %. Mainly used as adjunct (supplementary) to general anaesthesia, typically with O2 and halothane (60 % N2O, 39 % O2, 1 % halothane). Used with halothane to decrease the MAC for halothane. Main clinical application in veterinary anaesthesia is in debilitated or ill small animals which are less tolerant of other potent cardiovascular and respiratory depressant agents. Side effects and toxicity Safe below 65 % - at high concentrations always a risk of hypoxia. 38 At high concentrations diffuse rapidly into gas filled pockets expands them eg. in cases of pneumothorax it will aggravate the condition. Diffusion hypoxia. A cause of pernicious anaemia when used for prolonged periods. 39 2.2.6 INTRAVENOUS AND PARENTERAL ANAESTHETICS Types (a) Barbiturates. (b) Dissociative agents (Cyclohexylamines). (c) Steroidal anaesthetics (Eugenols). (d) Imidazoles. (e) Alkylphenols (Propofol). (f) Diazepines (Midazolam). The intravenous anaesthetics are useful for the induction of anaesthesia which is to be continued by an inhalation technique, or where the operation to be performed is of relative short duration. Advantages Induction time is very short - can eliminate stage II. Expensive apparatus is not required. Drugs are relatively cheap. Safeguards the patients, veterinarians and handlers from most hazards connected with restraining the animal. Can be administered safely in the presence of diathermy or thermocautery. Does not interfere with the operative areas about the head (no endotracheal tube is required). Disadvantages Depth or level of anaesthesia is less readily controlled. Potentially more dangerous - once injected it must then be eliminated by the animal. Unable to do thoracic surgery unless other means for artificial respiration are available. 2.2.6.1 BARBITURATES Barbiturates are derivatives of barbituric acid. There are two main groups viz: oxybarbiturates and thiobarbiturates. Thiobarbiturates have a sulphur in the C2 position of the barbiturate structure. Physical characteristics Light white/yellow bitter tasting powder. Thiobarbiturate usually yellow. Low solubility but Na-salts highly water soluble. Relatively unstable and are broken down by heat, light and air. Should be stored in a dark bottle, in a cool place. All barbiturates are sufficiently lipid soluble to cross the blood-brain barrier. Increase in lipid solubility results in a decrease in duration of action and an increase in potency. Phenobarbitone is relatively poorly lipid soluble and can therefore not be used as an anaesthetic. Thiobarbiturates are more lipid soluble than their oxy-analogues. 40 Classification of barbiturates according to duration of action Long acting - Phenobarbitone. Medium acting - Amobarbitone, Secobarbital Short acting - Pentobarbitone. Ultra short acting - Methohexitone (Brietal), thiamylal sodium, thiopentone. Mechanism of action The hypnotic action of barbiturates appears to be related to prolongation of central inhibitory transmission processes mediated by GABA. Stimulation of the GABA receptors enhances their sentivity to the endogenous GABA. This stimulates an opening of membrane chloride channel with a subsequent influx of the electrolyte. The nett effect is nerve hyperpolarisation and decreased conduction i.e. decreased activity resulting in CNS depression. In addition the barbiturates raise the threshold of spinal reflexes. They decrease the sensitivity of polysynaptic junctions to the depolarizing action of acetylcholine. They also have the ability to decrease the oxygen consumption by the brain. Anaesthetic properties (a) Dose related CNS depression. Depresses cortex of the brain. Since the motor areas of the brain are depressed it can be used to control convulsions. Sensory nerve fibres are less sensitive. (b) Large doses are required to achieve analgesia. (c) Dose related respiratory depression. Death from overdose is usually due to respiratory failure. Cats are especially sensitive to respiratory depression. (d) Dose related cardiovascular depression. Very large doses cause the heart to fail even with respiration supported. The experimental dose for cardiac arrest is approximately 4 times the anaesthetic dose. Cardiac arrest usually follows respiratory arrest. Causes a dose related vasodilation. In deep barbiturate depression hypotension is primarily due to the hypoxia caused by respiratory depression. When this is relieved, the cardiovascular effects usually correct themselves. (e) Severe inhibitors of foetal respiration. Are slowly metabolized by the fetus. Thiopentone is not as depressant to the fetus as pentobarbital. (f) Potently poikilothermic. Normally operations are done in a cool environment and therefore results mainly in hypothermia. The lower the temperature, the slower the metabolism and the slower the recovery. In a "normal" dog at 27 °C the recovery is 3.5 times longer. (g) Skeletal muscle relaxation is relatively poor but is usually adequate for general surgery. 41 (h) It has no direct effect on the kidneys but decreased perfusion results in a decrease in urine production. (i) Causes a decrease in the tone of GIT but this action is of no great importance clinically. (j) The spleen is dilated by pentobarbital. Absorption Readily absorbed from the GIT. The oral route is practically never used, except for phenobarbitone which is used as an anticonvulsive drug. Also well absorbed when administered i/p or i/t – NOT thiopentone though Asorption from i/m is irregular and slow. Distribution High volumes of distribution. All readily penetrate the blood-brain barrier. The rate of penetration is positively correlated with lipid solubility. Thiobarbiturates are therefore faster than oxybarbiturates. All readily cross the placental barrier. Thiobarbiturates localizes in fat depots and about 60 - 75 % of thiopentone retained in the body after 24 hours is found in the fat. Redistribution is the main factor that accounts for the short action of the thiobarbiturates. Metabolism Biotransformation is mainly hepatic and the extent varies between the various barbiturates, depending on their lipid solubility. The less lipid soluble the barbiturate is, the less it is metabolized and the more the product is excreted unchanged. There is great species difference in the rate and extent of biotransformation. In order of decreasing ability to biotransform barbiturates are: Adult ruminants and equine - good. Dog and swine - moderate. Cat - poor. Microsomal inducers eg. phenobarbital will increase metabolism. Excretion The urine is the main route of elimination of barbiturates and their metabolites. Excretion may be more rapid in the ruminant as result a secretion of large quantities of bicarbonate. If an animal received a course of chloramphenicol, pentobarbital should not be used for at least 25 days following. Thiopentone metabolism does not appear to be affected. Tolerance Following administration of one or two doses of a barbiturate a decrease in sleeping time may occur. This is due to activation of metabolic enzyme systems. Tolerance due to adaptation of the CNS may also occur. The sensitivity of animals to barbiturate may be increased by uremia. 42 Treatment of overdose Artificial respiration. With concommitant cardiac arrest - heart massage and catecholamine influsion. (Always use adrenaline with caution, as they can be arrhythmogenic.) Monitor body temperature. Can give i/v infusions - do not give sugar containing drips eg. dextrose, since they potentiate the barbiturate effect. Position the animal in such a way that the lungs do not become congested on one side. Alkalinize the urine - usually anaesthetized animals have a respiratory acidosis due to hypoventilation, as well as a metabolic acidosis due to hypoperfusion. Analeptics - to stimulate respiratory and cardiovascular medullary centres eg. doxapram (Dopram). It establishes effective ventilation but unfortunately the T1/2 is much shorter than for pentobarbitone. A B PC I PC II PC I PC II 3 4 5 3 Saturation 2 2 CC Elimination CC Elimination 1 1 Dose iv Repeated dose iv Reason for rapid recovery Reason for longer sleeping time Fig: Illustration of the redistribution of thiopentone PC I : Peripheral compartment I-includes the brain and other well perfused organs PC II: Peripheral compartment II-includes the fat layers and other poorer perfused areas CC: The central compartment 1-5: Phase of drug movement A: 3 and 4, Dog wakes up due to the drug redistributing to the fat B: Due to the saturation of the fat stores, the drug can no longer re-distribute B: 2 and 3, the drug circulates between the central compartment and the CNS resulting in prolonged sleeping time. At this stage the body is completely reliant on metabolism to excrete the drug and to lower the anaesthetic plane. 43 Drugs Pentobarbitone Sobental, Sagatal, Nembutal: 50 mg/ml. Euthatal, Euthanaze: 180 - 200 mg/ml. Anaesthetic properties The stronger solutions are usually coloured (green/blue) and come in a different type of bottle. When properly administered i/v, induction is smooth, rapid and free from excitation. Surgical anaesthesia in dog lasts for 45 - 90 minutes. Recovery is prolonged. Dogs usually do not regain their feet for 4 hours and do not completely recover for 6 hours or more. Recovery is accompanied by whining, running movements, pitching and futile attempts to stand. Recovery in some cats may be particularly long, 24 hours or more. Has been used with variable degree of success in a wide variety of domestic and wild animals. It is generally considered to have a narrow margin of safety, including chickens. It causes excessive tracheo-bronchial secretion and salivation in the goat. Goats also seem to metabolize the drug more rapidly and require repeated injections for prolonged procedures. Horses tend to remain recumbent for long periods and recovery may be accompanied by a considerable amount of struggling. It is usually used in large animals in combination with drugs such as chloral hydrate and magnesium sulphate. Clinical uses (a) For surgical procedures where volatile anaesthetics are not available. The average dose for most species is 30 mg/kg. (b) Treatment of dogs in strychnine poisoning. Strychnine inhibits the inhibitory system (glycine) of the spinal cord resulting in motor convulsion. (Pentobarbitone is also an agonists of the glycine receptors) Pentobarbitone increases the threshold for convulsions ie. anticonvulsant (GABA agonists). (c) Euthanasia. 3 - 4 times overdose is injected intravenously rapidly. Can give it i/p, i/t or s/c, but these routes could be very painful. Occasionally given i/m Intracardiac administration is considered inhumane, due to the pain on administration (Euthanase solutions are non-sterile and should never be used for anaesthesia) (d) The drug is used in the treatment of convulsions. A single dose intravenously will induce anaesthesia and decrease CNS activity. (f) The drug is an agent of choice for the management of CNS trauma. By decreasing brain oxygen consumption the drug decreases the overall blood supply to the brain. This decreases intracranial pressure and allows the brain time to heal. Thiopentone sodium Intraval - for veterinary use. Pentothal - for use in humans. Physicochemical characteristics Available as a dry powder in vials or bottles in 5 g, 1 g, 0,5 g and 0,25 g amounts which is then made up before use to a 5 % solution. It may be made up into a weaker solution particularly for small cats and dogs or stronger for large animals. 44  The solution is unstable and will last for only up to 7 days when kept in a refrigerator (at room temperature it will last for approximately 3 days). It produces anaesthesia of 15 to 30 minutes duration. Induction is usually rapid and recovery uneventful and of short duration. Animals are generally ambulatory within 1 hour. Sodium carbonate is included as buffer. The solutions are alkaline and caustic. Disposition Is a weak organic acid (pKa 7,4). Must only be given i/v (solution it is dissolved in has very basic pH 10) Perivascular infiltration may cause necrosis and sloughing. Intra-arterial administration causes vasospasm and gangreen. After a rapid single intravenous administration of thiopentone the drug distributes rapidly from the central compartment into the well perfused tissues such as brain, myocardium and kidney (peripheral compartment I). Thereafter redistribution occurs from these tissues to the poorer perfused tissues such as the fat, muscle and skin (peripheral compartment II). Redistribution is responsible for the waking up process and is normally rapid (+ 3 minutes). Changes in blood pH may result in extensive changes in ionization of thiopentone in body. Clearance of thiopentone is significantly higher in pediatric patients than in adults, this has been described as being due to a greater hepatic clearance. The factors which govern the duration and depth of narcosis due to an injection of thiopentone are: (a) The amount of drug injected. (b) The speed of injection. (c) The mass of peripheral compartment II. (d) Age of animal. (e) Plasma pH. Clinical uses (a) Induction prior to use of volatile anaesthetics. (b) As a sole GA in combination with a sedative for short procedures eg. castration, teeth extraction, suturing of skin wounds etc. (c) Dose for small animals is calculated at 15 - 17 mg/kg for the dog and 9 - 11 mg/kg for the cat. 30 - 50 % of the dose is given rapidly i/v as "knock down" dose (has an excellent "knock down" effect). Side effects and toxicology (a) Dose related respiratory and cardiovascular depression. (b) Induction apnoea. Can last for approximately 1 minute. Cats are especially sensitive. If persists longer take action. (c) Dangers of perivascular and intra-arterial injections. Treatment of perivacular administration: (i) Infiltration of saline solution in the same area to dilute the drug. (ii) Corticosteroids. (iii) Procaine HCl solution which is acidic and neutralizes thiopentone. (iv) Massage area. (d) Post induction arrhythmias. It is not dangerous and soon disappears. 45 (e) Greyhounds, Afghans and Borsois compared to other canine species show an increased sensitivity to thiopentone. This is due to a smaller volume of distribution and metabolism saturation. In Greyhounds thiopentone reduces systemic arterial pressure by about 40 % immediately after injection. Returns to normal within 5 mins. (f) Barbiturates are not recommended in myelography. Sodium methiodal, a contrast medium, may displace bound thiopentone and induce anaesthetic complications. 2.2.6.2 DISSOCIATIVE AGENTS (CYCLOHEXYLAMINES) Includes phencyclidine hydrochloride and its congeners, ketamine hydrochloride and tiletamine hydrochloride. Causes a cataleptic type state of anaesthesia referred to as dissociative anaesthesia and is accompanied by marked analgesia in most species. The term dissociative anaesthesia originates from the use of ketamine in human medicine which causes the patient to feel dissociated or unaware of the environment during induction. Dissociative anaesthetics interrupt the flow of information from the unconscious to the conscious parts of the brain. Ketamine (Ketalar, Ketaset, Vetalar) More commonly used in combination with other anaesthetic agents. It is an extremely versatile agent because it can be administered either by the intramuscular or intravenous route. Ketamine is currently a restricted schedule 5 drug. The drug has severe abuse potential and should be properly locked up in a scheduled drug cupboard. Disposition Highly lipid soluble (5 - 10 times that of thiopentone). Although it is readily absorbed from the gut it is not usually given orally due to the delay in the onset of anaesthesia, except in the case of caged wild cats (the drug is squirted in the mouth of these animals). Although the drug can be given i/m the i/v route is preferred. I/m injection is painful (pH 3,5). It has a high volume of distribution and is rapidly distributed into all body tissues, primarily the adipose tissue, liver, lung and brain. Rapidly penetrates the blood-brain barrier. Biotransformation occurs in the liver by N-demethylation and hydroxylation with the formation of water soluble conjugates that are eliminated in the urine As with thiopentone redistribution plays a role in the waking up process. The elimination phase is approximately 40 minutes. Mode of action The anaesthetic action of ketamines requires the presence of a functioning cerebral cortex. Ketamine is an antagonist of the excitatory NMDA system (glutamate and aspartate receptors). Inhibition of this system decreases the excitatory activity within the cerebral cortex. (Its’ analgesic properties may result from the direct stimulation of the opiod receptors.) 46 Pharmacological effects (a) CNS - Alters the reactivity of the CNS to various sensory impulses without blocking sensory input at spinal or brain stem levels. Increases cerebral blood flow and intracranial pressure. (Should be used with caution in patients with cerebral trauma or intracranial masses). It increases O2 utilization in the brain (opposite to other anaesthetics) which lasts 3 - 40 minutes. Convulsogenic. (b) Eye is centrally fixed, and palpebral and corneal reflex are also normally present and are only suppressed at deep levels of anaesethesia Causes mydriasis. Damage to cornea is a danger. Must protect the eyes by using either an ointment indoors or a wet pad outdoors. (c) Pharyngeal and laryngeal reflexes are only minimally depressed and therefore it may not be possible or difficult to insert an endotracheal tube. Premedicating an animal with a muscle relaxant will eliminate these side effects. (d) Has good inherent analgesic properties. (e) Poor skeletal muscle relaxant. Muscle tremor of the limbs and in isolated cases convulsions, especially during recovery may occur. The drug is usually combined with diazepam or midazolam, to reduce the degree of muscle stiffness during surgery. (f) Cardiovascular function is stimulated slightly. Blood pressure and cardiac output is increased. There is an increase of adrenaline and decrease of vagal tone. Has a potent anti-arrhythmogenic effect. (g) Ventilation is well maintained. Pharyngeal and laryngeal reflexes remain active - intubation can add to laryngospasm and bronchospasm. (h) Salivation may be severe. (i) Causes poikilothermia, but due to increased muscular activity this leads to hyperthermia, especially in a warm environment. (j) Compatable with volatile anaesthetics and barbituates. (k) Readily transferred across the placenta of several animals and may have depressive effects on newborn. Clinical uses (a) Short surgical procedures, in combination with