Injectable Anaesthetic Drugs PDF

INJECTABLE ANAESTHETIC DRUGS MIMV 3rd year – 1st semester 04 September 2024 Ricardo Felisberto, DVM, Dipl. ECVAA, MRCVS  INJECTABLE AGENTS Mechanisms of action: Potentiation of the effects of the inhibitory GABA neurotr...

INJECTABLE ANAESTHETIC DRUGS MIMV 3rd year – 1st semester 04 September 2024 Ricardo Felisberto, DVM, Dipl. ECVAA, MRCVS  INJECTABLE AGENTS Mechanisms of action: Potentiation of the effects of the inhibitory GABA neurotransmitter at the GABAA receptors (Chloride channels) (positive allosteric modulators, or can also be direct agonists, usually at higher doses) Inhibit L-type Ca2+ channels Inhibit neuronal hyperpolarisation-activated nucleotide-gated non-selective cation channel 1 (HCN-1) GABA: inhibitory neurotransmitter in the brain GABAa receptors: chloride channels that can when activated make the neuron less likely to fire Injectable agent bind to different site on the GABAa and make it more responsive to GABA So at high doses, they act as direct agonist, can activate GABAa without GABA and inhibit neuron activity L-type is important bcs allowing Ca to flow into cells, important for release neurotransmitter and contraction muscles Injectable agent reduce influx of Ca and help decrease neuronal excitability HCN-1 keep resting membrane potential and regulate neuron excitability When stop them make neuron more hyperpolarized (less excitable) so anesthetic effects  IDEAL INJECTABLE AGENT Fast onset of action (lipid soluble to cross blood brain barrier) Smooth induction; Smooth recovery Non-irritant on injection and with High bioavailability if IM Short duration of action and non-cumulative Fast metabolism Non-toxic or without active metabolites Antagonisable No histamine release Minimal cardiovascular and respiratory depression Muscle relaxation Analgesia Stable for storage for long periods Cheap High therapeutic index Low environmental pollution impact  INJECTABLE AGENTS Advantages over inhalant agents: Rapid onset Bypasses stage II of anaesthesia depth that may be associated with excessive movement Easy to administer No equipment required Cheap Less environmental pollution Disadvantages over inhalant agents: Retrieval once injected is not possible Weight of the patient should be accurate (ideally lean body weight if obese!) Requires learning curve to evaluate anaesthesia depth High doses are required for CNS depression and muscle relaxation (lower doses can lead to hyperextension of limbs – extra-pyramidal effects) Low tolerance in shock or septic patients Human abuse Volume is too high and too cost prohibited in larger animals (and lack of licence and authorisation)  INJECTABLE AGENTS Pharmacokinetics: how drugs move through the body, how fast the drug is bsorbed, distributed, metabolized and excreted Depends on: Drug factors: Dose administered high volum: stronger and longer effect Rate of injection fast: increase side effects like hypotension Concentration of the drug more cocentrate: act faster Bioavailability from other routes rather than IV if given by other route than IV Lipid solubility (cross blood brain barrier) lipid-soluble drug pass through BBB easily Protein binding (free drug) Degree of ionisation (pH, pKa) Volume of distribution to other tissues Lung Metabolism / lung drug sequestration Active metabolites Patient factors: How much blood is pump by heart/min if low, drug take longer to go where it needs easily Cardiac output (influences absorption from IM or IP; affected by HR, SV [preload, afterload, contractility]) Cerebral blood flow Amout of blood going to brain, if high blood flow, drugs act faster Fat content how much fat patient has, high fat, drugs get strored in fat and take longer to leave the body, delay waking up  INJECTABLE AGENTS Effect-site equilibration time: Time lag: Time between injection and loss of consciousness (biophase delay) Depends on Cardiac Output; 1st pass metabolism; drug dose / concentration; drug pKa; Drug degree of ionisation; lipid solubility; molecular size; protein binding Slower for propofol (3 minutes) than thiopental (1 minute), due to: ↑↑ protein binding propo slower bcs bind more to proteins and taken by lungs ↑↑ Lung uptake (sequestration / metabolism) Causes cerebral vasoconstriction (↓ cerebral blood flow) This means = slow injection! Because once a high dose has been administered, the time lag won’t allow immediate endotracheal intubation, and when it is possible overdose may have occurred. Thiopental: injection over 10-30 seconds, wait 30 seconds. Propofol: injection over 1-2 minutes, wait 1-2 minutes. Alfaxalone: injection over 30-60 seconds, wait 45-60 seconds. Context sensitive half-time (CSHT): INJECTABLE AGENTS Time for blood or plasma concentration to drop by 50% after an infusion, designed to maintain a steady plasma concentration, has been stopped. Varies according to the duration of infusion (context); the longer the infusion has been going, the longer it will take for the drug effect to wear off. If the initial concentration is 10 units/ml, and the half-time is 30 minutes, then the concentration is 5 units /ml at 30 minutes, and 2.5 units/ml at 60 minutes. Depends on 2 major factors: Volume of the drug in the central compartment. Drug with high volume of distribution have a small volume in the central compartment. Rate of systemic clearance of the drug from the body. Examples (comparison of two drugs): Fentanyl: larger volume of distribution (small volume in central compartment) + slower clearance - ↑↑ CSHT (accumulation) Remifentanil: smaller volume of distribution + fast clearance - ↓↓ CSHT This means that Fentanyl tends to accumulate in the body (fat) after long infusions (> 90 minutes).  INJECTABLE AGENTS Body compartments: Blood is the central compartment that distributes to the other compartments: Vessel rich organs (vital organs – heart, brain, lungs, liver, kidneys) They have their own time Intermediate vascularity (muscles, skin) constant Vessel poor organs (fat, bones, cartilages) Time-constant: Measure of time required for the particular compartment to reach equilibrium with the central compartment (Blood( once any change occurs in the central compartment Directly proportional to volume of compartment (larger compartment = larger time- constant) Inversely proportional to its perfusion (larger perfusion = smaller time-constant) 𝐶𝑜𝑚𝑝𝑎𝑟𝑡𝑚𝑒𝑛𝑡 𝑉𝑜𝑙𝑢𝑚𝑒 𝑇𝑖𝑚𝑒 𝐶𝑜𝑛𝑠𝑡𝑎𝑛𝑡 = 𝐶𝑜𝑚𝑝𝑎𝑟𝑡𝑚𝑒𝑛𝑡 𝑃𝑒𝑟𝑓𝑢𝑠𝑖𝑜𝑛 For the Brain: Small time-constant (rapid equilibration with blood) due to small volume and high perfusion (15% of resting cardiac output) For the Fat: Large time-constant due to large volume and low perfusion  INJECTABLE AGENTS Thio: bind less to proteins so more in bloodstream (the drugs that bind to protein are « innactive »), and fat help to distribute more equilibré drugs and not just in brain But bcs low fat dog has no fat so drug stay more in brain et en plus si on prend thio bah elle s’accroche pas au prot donc on va avoir big quantité dans sang donc ↑ lipid soluble drugs: reach the brain quickly and equilibrium is fast (↓ time- aie aie pr les chiens pr recovery constant) Obese patients: ↑↑ fat compartment = allows re-equilibrium of the drug concentration from the brain to the fat, which helps recovering from anaesthesia (metabolism and excretion occur during this re-distribution process) Thin animals (e.g., Greyhounds) = have less re-distribution of injectable drugs, thus concentration in the brain is maintained high (slowing recovering of general anaesthesia) Thiopental in greyhounds should be avoided due to prolonged recovery. Greyhounds also have slower metabolism of propofol (deficient in Cytochrome P2B11 (↓ propofol hydroxylation)  INJECTABLE AGENTS Injectable drugs can be used to induce and maintain general anaesthesia: Induction: IV bolus give single, quick anesthetic drug Maintenance (total intravenous anaesthesia – TIVA): Intermittent IV bolus; Continuous rate infusion (CRI); Variable rate infusion (VRI) or Target controlled infusion (TCI) Minimum Infusion rate (MIR): infusion rate of the injectable anaesthetic drug at which 50% of the patients are unresponsive to a standard noxious stimulus (similar to median effective dose or ED50) Essential for the development of TCI, which consists of a syringe driver coupled with a computer / internal software with pharmacokinetic parameters of the specific drug in a particular species. This system calculates the effect-site (brain) and plasma concentration over time and calculates the infusion rate necessary to maintain a specific set blood target concentration. Conventional pumps, run a specific set infusion rate that only changes if we change it manually.  INJECTABLE AGENTS Dose-dependent effects: Low doses – sedation High doses – general anaesthesia Extrapyramidal dysfunction: May be observed with propofol (propofol twitches) but also alfaxalone Dystonia (muscle spasms); dyskinesia (uncontrolled movements); akathisia (muscle restlessness); Athetosis (slow involuntary movements); opisthotonus (spine and limbs hyperextension) etc. Associated with sub-cortical activity rather than cortical (therefore, its not seizures) Due to ↓ dopamine neurotransmission + excitation of subcortical pathways + extended refractory periods of inhibitory pathways in the brainstem / spinal cord (dis- inhibition) No treatment guidelines, but suggested therapies: Anti-muscarinic drugs: Benzatropine; Diphenhydramine Anti-histaminic drug: Chlorphenamine (with weak anti-muscarinic effect)  PROPOFOL Macroemulsion 1% (10 mg/ml): pH 7.8, pKa 11 In Soybean oil; glycerol; egg yolk; lecithin 2 main preparations in the market: With preservative: benzyl alcohol (PropofloTM) – avoid using for TIVA, to avoid benzyl alcohol toxicity (mainly in cats); can be used up to 28 days of opening. Without preservative: Propofol-Lipuro VetTM – single use; avoid using if bottle has been broached over 24h, as it supports bacterial growth (refrigerate immediately after broached); it has medium- and long-chain triglycerides to which the propofol molecules are bound; this solution is associated with less pain on injection (possibly due to less propofol present in the aqueous solution). Microemulsion 1% (10 mg/ml): PropoclearTM: lipid-free (aqueous only) nano-droplets formulation; associated with pain on injection, thrombophlebitis and injection site reactions (thus withdrawn from the market) – possibly due to rapid release of propofol molecules from the nano-droplets to which propofol binds, which would lead to a high propofol Licenced in dogs and cats molecules concentration at the site of injection.  PROPOFOL Protein binding 98% (mainly albumin in blood) ↑↑↑ lipid soluble GABAA receptor agonist Not usually irritant if extravascular deposition (but low bioavailability if not IV) Macro-emulsion may cause pain after IV injection (injecting lidocaine before propofol may reduce pain) Smooth induction and recovery from general anaesthesia Recovery : After single injection bolus: recovery mainly due to re-distribution + metabolism After infusion: recovery mainly due to metabolism No accumulation (no “hangover”): Very fast metabolism in liver, lungs, kidneys and GI tract Glucuronidation and hydroxylation (important for metabolism of phenolic compounds) Cats may accumulate propofol due to less glucuronidation capacity (slower metabolism) Greyhounds have less hydroxylation capacity (slower metabolism) No active metabolites May have some accumulation in fat in prolonged infusions If multiple propofol injections or prolonged infusions were administered in cats: phenol toxicity is a possibility, which could lead to Heinz body production (haemolytic anaemia), malaise, anorexia and diarrhoea. Can lead to urine coloration (green), due to excretion of phenolic metabolites of propofol (quinols).  Extrapyramidal symptoms may develop PROPOFOL Not analgesic Hypotension: Direct myocardial depression (negative inotropy) + venodilation (due to ↑ nitric oxide release from vascular endothelium + ↓ SNS) ↓ baroreceptor reflex: reflex tachycardia and vasoconstriction tend not to occur following hypotension. May cause arterial vasoconstriction (high doses can cause arterial dilation), but not sufficient to avoid hypotension due to negative inotropy and venodilation. Respiratory depression: induces apnoea after rapid IV injection of large propofol dose. Depresses chemoreceptor function: ↓ sensitivity to low PaO2 and high PaCO2. Potentiates hypoxic pulmonary vasoconstriction (HPV), by inhibition of the KATP channel-mediated vasodilation Bronchodilation May cause cyanosis if animals haven’t been pre-oxygenated (due to opening of intra-pulmonary shunts, due to slowing blood flow in pulmonary capillaries) Muscle relaxation Neuroprotection: due to reduction of metabolic rate for oxygen, which results in cerebral vasoconstriction and ↓ cerebral blood flow, ↓ cerebral blood volume and ↓ intracranial pressure. Maintains: cerebral metabolic rate and cerebral blood flow coupling Reduces Lower Oesophageal Sphincter tone (dogs +++, cats +): may induce gastro-oesophageal reflux Pancreatitis: high lipid content may trigger or worsen pancreatitis  PROPOFOL Splenic engorgement due to venodilation, can lead to blood sequestration, make difficult abdominal ultrasound interpretation and ↑ risk of puncture if laparoscopic techniques are used Variable platelet effects: Low doses: enhances platelet aggregation (thrombotic) High doses: suppresses platelet aggregation (anti-thrombotic) Reduces intra-ocular pressure (but depends on premedication and head positioning) Anti-oxidant effects: due to resemblance of vitamin E molecular structure, and may enhance cellular glutathione anti-oxidant system Anti-inflammatory effects: due to suppression of PGE2 production Natural killer cells function is preserved (does not promote tumour metastasis) Dose: Induction of general anaesthesia in unpremedicated dogs: 6.5 mg/kg Induction of general anaesthesia in unpremedicated cats: 8 mg/kg Induction of general anaesthesia in premedicated dogs and cats: 1-4 mg/kg Significantly reduced by administration of α2-agonists as premedication Infusion for TIVA: 0.1-0.4 mg/kg/min Target blood concentration for TCI: 3-6 ng/mL  ALFAXALONE Aqueous solution in 2-hydroxypropylbeta cyclodextrin 10 mg/ml (Alfaxan®) (neuroactive steroid) pH of the solution 6.5-7.0 Licenced in dogs, cats, rabbits (induction and maintenance of general anaesthesia) Suitable for immersion anaesthesia in amphibians, fish and reptiles Preserved solution: 28 days Unpreserved solution: single use (not after 24h) Protein binding to plasma proteins 17.6-50% Mechanism of action at the GABAA receptors: Low doses: positive allosteric modulator of GABAA receptors High doses: GABAA receptor agonist Also, anti-muscarinic effects (anti- M1 and M3) Can be administered IM (off-licence) for sedation of general anaesthesia depending on the dose administered Beware of total volume for IM injection No histamine release + No pain on injection + NOT analgesic Induction and recovery from general anaesthesia is usually smooth, but recovery can be associated with delirium, trembling, paddling, disorientation (cats +++) Recovery: After single injection: mainly due to re-distribution + metabolism After infusion: mainly due to metabolism  ALFAXALONE Metabolism and excretion: Hepatic metabolism by oxidation (cytochrome P450), glucuronidation and sulphation Some extra-hepatic metabolism too (lungs) Cats: non-linear pharmacokinetics, which means that they have different pharmacokinetic profiles at different doses At lower doses: as the dose increase → metabolic rate increases linearly At higher doses: as the dose increase → the enzyme system becomes saturated, and the metabolic rate does not increase accordingly (accumulation may occur) (Michaelis-Menten kinetics – rate of maximum enzymatic reaction) Renal excretion Dose-dependent cardiovascular depression: Hypotension (direct myocardial negative inotropy + vasodilation) Preserves the baroreceptor reflex Can cause tachycardia (especially in poorly sedated animals prior to anaesthesia) Dose-dependent respiratory depression: Hypoventilation that may cause hypoxaemia if no oxygen supplementation is allowed PPV if alfaxalone TIVA Post-induction Apnoea: 60 seconds of apnoea following alfaxalone injection Muscle relaxation Offers good conditions for laryngeal examination Reduces lower oesophageal sphincter tone → ↑ gastro-oesophageal reflux Reduces cerebral metabolic rate → cerebral vasoconstriction → reduces cerebral blood flow → reduces intracranial pressure. Maintains metabolic rate to perfusion coupling Neuroprotective → maintenance of the cerebral metabolic rate and perfusion coupling + reduces electroencephalogram abnormalities  PROPOFOL VS ALFAXALONE Baroreceptor Preparation Site of action Bioavailability Metabolism Toxicity Cats reflex - Emulsion With CNS Low if not IV Hepatic ++ - Heinz bodies Blunted Heinz bodies preservative GABAA receptors Extra-hepatic ++ formation due to formation and - Emulsion preservative possible Propofol Without (Benzyl alcohol) haemolytic preservative - Pancreatitis anaemia worsening (infusions) - Solution With CNS High if not IV Hepatic +++ N/A Preserved Accumulate if preservative GABAA receptors (can be Extra-hepatic + administered at - Solution Without Low doses – administered off high doses preservative positive allosteric licence IM) modulator Alfaxalone (enhances response to GAGA) High doses – GABAA receptor agonist  ALFAXALONE Doses: Induction of general anaesthesia in unpremedicated dogs: 2 - 4.5 mg/kg Induction of general anaesthesia in unpremedicated cats: 5 mg/kg Induction of general anaesthesia in unpremedicated rabbits: 3 - 10 mg/kg Induction of general anaesthesia in premedicated dogs and cats: 0.5 - 3 mg/kg Significantly reduced by administration of α2-agonists as premedication Infusion for TIVA: 0.05 - 0.2 mg/kg/min  PHENCYCLIDINE DERIVATIVES Phencyclidine; Tiletamine; Ketamine: Phencyclidine → most potent; longest acting Ketamine → shortest acting Tiletamine → most used in combination with a benzodiazepine (tiletamine + zolazepam – Zoletil® in Europe; Telazol® in USA) Ketamine: Aqueous solution; 10% (100 mg/mL); pH 3.5-5.5 (pain on injection) Protein binding 50% mainly to α1-acid glycoprotein Basic drug, only stable in solution at low pH (in which most ionised or water-soluble form is in higher proportion) At body pH (7.4) the unionised form is favoured (+++ lipid soluble) → crosses membranes quickly for a fast onset of action In Racemic mixture: S(+) enantiomer – 2 – 4 x more potent and less psychoactive than R(-) enantiomer IV; IM; oral transmucosal  KETAMINE Causes dissociative anaesthesia: Profound analgesia; Light sleep / unconsciousness? Amnesia; Catatonia / catalepsy Poor muscle relaxation / spontaneous movements Hypersensitivity to noise Active cranial nerve reflexes (maintenance of blink; swallowing) Transient convulsive-like activity Stimulation of the thalamic and limbic system (disorganisation of the CNS activity – abnormal response to environment) Slow onset of anaesthesia action (1-2 minutes); because it produces dissociatice effects rather than unconsciousness  KETAMINE Metabolism: After single bolus: redistribution + metabolism After infusion: metabolism + excretion It is metabolised into an active metabolite (norketamine) via cytochrome P450. Norketamine (product of ketamine N-demethylation) has 20-30% activity of ketamine (only 10% in cats), and can be responsible for the slow recovery after long infusions. Dogs and Horses: metabolise norketamine further into hydroxy-norketamine and dehydro-norketamine Cats: cannot further metabolise norketamine and both ketamine and norketamine must be excreted via urine (thus care in chronic or acute kidney failure, due to risk of drug accumulation) Racemic mixture: Presence of R(-) enantiomer slows metabolism of S(+) enantiomer  KETAMINE Analgesia and anti-hyperalgesia: Due to NMDA antagonist at spinal; supraspinal; peripheral sites of action Only NMDA receptor blockade may not stop pain pathway; but reduces the change of hypersensitisation of the CNS (anti-hyperalgesic) May also prevent tolerance to opioid analgesics and opioid-induced hyperalgesia Cardiovascular effects: Stimulation due to increase SNS output Direct negative inotropy (observed effect in patients in which the SNS is maximally stimulated due to disease process – e.g., colic horse) Direct vasodilator (calcium channel blocker) Animals in shock: sympathetically exhausted; so no further sympathetic stimulation is possible and only the negative inotropic effects are noted In animals with hyperthyroidism / phaeochromocytomas: may induce arrhythmias Respiratory effects: Minimal respiratory depression, but can induce post-induction apnoea Maintains ventilatory response to CO2 Maintain hypoxic pulmonary vasoconstriction Causes irregular breathing patterns (apneustic → end-inspiratory pause rather than end-expiratory pause) Bronchodilation → may reduce bronchospasm  KETAMINE CNS: Increases intracranial pressure due to increased CBF Neuroprotective properties: due to calcium channel and NMDA blockade; thus, reducing intracellular calcium accumulation Low doses can be administered for refractory seizures Can be administered intra-thecal for spinal anaesthesia (but must be preservative free) May increase intraocular pressure due to increased contraction of extra-ocular muscles Muscles: Does not change the lower oesophageal sphincter tone May increase muscle contractions (unvoluntary) Anti-inflammatory / immune system: Suppresses natural killer cells; reduces oxidation + phagocytosis by neutrophils and macrophages Reduces Nuclear transcription factor –Kβ; blunts Tumour necrosis factor α; reduces cytokine production Impairs Natural-killer cells → promotes tumour metastasis progression  KETAMINE Non-competitive antagonism of NMDA receptor (binds to the phencyclidine binding site) Antagonism at non-NMDA glutamate receptors µ-antagonism; κ-agonism; δ-agonism GABAA receptor antagonism Anti- Nicotinic and muscarinic effects Inhibition of re-uptake of serotonin and noradrenaline Local anaesthetic-like activity (sodium channel blockade) Anti-inflammatory / immuno-modulatory effects  KETAMINE Doses: Dogs and cats 2.5mg/kg bolus (higher doses IM in cats may be required) Horses and farm animals 2.2 mg/kg or higher (up to 5 mg/kg) Analgesic Infusion doses (intra and/or post-operative): 0.2 mg/kg IV bolus followed by 5 – 20 µg/kg/min (intra-operatively), and 2 – 5 µg/kg/min (post- operatively) Can be used to maintain anaesthesia in horses; but the accumulation of norketamine limits TIVA in horses to a maximum of 90 minutes duration Licenced in dogs, cats, horses, cattle, sheep, pigs  BARBITURATES Derived from barbituric acid (condensation of urea + malonic acid) Classification according to duration of action: Long acting: 8 – 12h (phenobarbital) Short acting: 45 to 90 minutes (pentobarbital) Ultra-short acting: 5 to 15 minutes (thiopental) Classification according to O2 position at C2 position: Oxybarbiturates: Oxygen at C2 position (less lipid soluble; less protein binding; excreted unchanged in urine) Thiobarbiturates: Oxygen replaced by sulphur at C2 position (more lipid soluble; higher protein binding; liver metabolism is required)  BARBITURATES Water soluble only at high pH (lipid soluble at neutral pH) Tautomerism: via Keto-enol transformation (enol form = water soluble; keto form = lipid soluble) Thiopental: Sulphur analogue of pentobarbital In yellow powder in a vial containing: Sodium carbonate (Na2CO3) - Na2CO3 + H2O → NaHCO3 + Na+ + OH- (results in high pH [10.5], due to NaHCO3) Nitrogen (N2) – Air contains traces of CO2 which can decrease pH and decrease water soluble of the drug; Nitrogen avoids this. These 2 measures favour a higher pH and the presence of the enol form. Once injected into body pH (7.4) = favours Keto form (more lipid soluble)  THIOPENTAL Protein binding 80%, pKa 7.6 At pH 7.4 thiopental has the following gamblegram NSAIDs decrease protein binding of thiopental as they bind to the same proteins (this increases thiopental free fraction, potentially allowing its dose reduction) If injected intra-arterial: Quick Keto-enol transformation and formation of crystals in the arteries, which become wedged in smaller arteries, causing pain and ischaemia The same doesn’t occur in venous blood as there is a large volume of 80% protein bound drug venous blood to dilute the thiopental Treatment: lidocaine IV (to vasodilate) If injected extra-vascularly: Causes irritation and even tissue necrosis (lidocaine administration for 8% ionised analgesia and vasodilation) 20% free drug 12% unionised – more Fast onset of action (30 seconds) lipid soluble, ready to Preserves laryngeal muscles function (ideal for laryngeal function cross membranes assessment) Can be used for induction of anaesthesia / maintenance as IV bolus (preferred over ketamine due to its fast onset) Can be an alternative to ketamine if intracranial disease is suspected in large animals and farm animals  CARBOXYLATED IMIDAZOLES Etomidate: Ester of a carboxylated imidazole, not licenced for veterinary species. Formulations: Hypnomidate® - 0.2% (2 mg/ml) in 35% propylene glycol; can cause pain on injection, respiratory depression, hypotension, arrhythmias, negative inotropy, haemolysis if prolonged infusions (mainly due to the propylene glycol) Etomidate-Lipuro 0.2% (2mg/mL) in lipid emulsion; much less side effects. pH 6.9; may cause pain on injection. Weak base with pKa 4.2; if acidic pH = ionised form +++ (water soluble); at body pH 99% unionised (lipid soluble) Extra-vascular injection – irritant (mainly if with propylene glycol) R(+) enantiomer is the most active; therefore, the available marketed etomidate is only this enantiomer Stereoselectivity for the GABAA receptor (agonist) + anti-nicotinic and anti-muscarinic effects Protein binding 75% (mainly to albumin!) No histamine release No analgesia Poor quality induction of anaesthesia (due to excessive muscular activity) – requires combination with benzodiazepine) Recovery: After single bolus: redistribution + metabolism After infusion: metabolism No accumulation due to production of inactive metabolites  CARBOXYLATED IMIDAZOLES Adreno-cortical function suppression: For 2-6h in healthy animals For 6-48h in ill animals Inhibits activity of 11-β-hydroxylase and 17-α-hydroxylase essential for cortisol production Critical ill patients require endogenous cortisol production during induction, maintenance and post-operative to help maintaining stable cardiovascular function If etomidate must be administered in a critically ill animal, consider administration of hydrocortisone (0.5 mg/kg IM) prior to induction and infusion at 0.25-0.5 mg/kg/h IV) during anaesthesia and post-operative period Newer formulations (carboetomidate) do not suppress the adrenal function as much (not yet available)  CARBOXYLATED IMIDAZOLES Metabolism: Rapid – by liver and plasma esterases Cardiovascular effects: Minimal cardiovascular depression May reduce arterial blood pressure Slight negative inotropy Respiratory effects: Transient apnoea Inhibits hypoxic pulmonary vasoconstriction Muscle: Poor muscle relaxation Can cause muscle hypertonus thus benzodiazepine is required as co-induction Neuroprotection: Decreases intracranial pressure by cerebral vasoconstriction + reduces cerebral metabolic rate for Oxygen, maintaining Metabolic rate : perfusion coupling GI tract: Maintains GI motility; may cause vomiting and salivation Doses: 1 – 3 mg/kg IV bolus for induction of anaesthesia + benzodiazepines (midazolam 0.2 – 0.3 mg/kg IV)  CO-INDUCTION Combination of injectable anaesthetics and other injectable drugs to reduce the primary injectable drug thus, reducing its cardiovascular and respiratory effects. Combinations: Opioid – administered before injectable agent Benzodiazepine – administered after deep sedation with a low dose of primary injectable agent (auto-priming) Midazolam: reduces propofol dose Diazepam and midazolam: reduces alfaxalone dose Lidocaine – cough suppression during endotracheal intubation; reduces cardiovascular responses to orotracheal intubation Essential if the primary injectable agent is ketamine or etomidate