Sedatives & Non-Opioid Analgesics PDF

Sedatives & non opioid analgesi Why do we need premedication Relieve stress & anxiety Facilitate handling of excited, frightened or vicious animals. Provide analgesia + muscle relaxation. Decreases anaesthetic requirement...

Sedatives & non opioid analgesi Why do we need premedication Relieve stress & anxiety Facilitate handling of excited, frightened or vicious animals. Provide analgesia + muscle relaxation. Decreases anaesthetic requirements for induction agents and inhalants which have adverse side effects Prom es smo h induction and recovery from general anaesthesia. Obtund catecholamine induced excitatory response and reduce likelihood of arrhythmias and tachycardia. Drug MOA Effects Side effects Contraindications Phen hiazine Antagonises No analgesia Hyp ension Boxers prone to bradycardia & - acepromazin Dopamine receptors (central effects) Onset 15-20 min IV or 30 – 40 min IM or SC ○ Decreased cardiac output hyp ension due to a1 adrenergic receptors Duration of action = 6 – 8 hours ○ Vasodilation ○ Vasovagal syncope (cardiovascular effects) ○ N reversible Decrease lower oesophageal sphincter ○ Orthostatic hyp ension muscarinic, ser onergic and Decreases inhalant by 30 – 40% tone No evidence that p entiates seizures histamine receptors Antihistamine ○ Increase risk of Stallions Mild anti-emetic regurgitation esp ruminants ○ Priapism or penile paralysis Reduces anaesthetic related death in horses Hyp hermia Dehydrated, hypovolaemic or patients in ○ May improve recovery Red cell uptake into spleen shock ○ Reduces shunt fraction & increases the ○ PCV can decrease by 20 – ○ hyp ension oxygenation in horses 30% Animals with noise phobia Decreased platelet aggregation ○ may become e remely distressed as they are exposed to a trigger but cann respond by fleeing Benzodiazepines Enhance binding of GABA to the receptor Anxiolytic May lead to excitation or aggression - Diazepam & complex Unreliable sedation in young/heathy animals midazolam ↓ Reduces inhibition increases Cl- conductance and hyperpolarization Muscle relaxation, No analgesia of postsynapic membrane of excitatory cells Decrease induction & inhalant requirement - The specific benzodiazepine receptor is part of Minimal to no adverse cardiovascular effects the GABA complex May be use l in pediatri , geriatri or severely ill patients  Anticonvulsants Midazolam Rapid onset Short acting Diazepam Solubilise in Propylene glycol carrier Pain on IM injection so do IV Rapid onset Longer acting a2 adrenergic Binds to a2 adrenergic receptors in central & Dose dependent Sedation Avoid in patients w agonists peripheral nervous system + her organs - Sedation, analgesia & mm relaxation respond aggressively to touch or ○ CVS disease - xylazine, - Release catecholamines Administered IM, IV, transmucosally & intranasally stimulation so care l gentle handling is ○ Paediatri detomidine, - Release neur ransmitters required ○ Geriatri medetomidine, Also bind to a1 adrenergic receptors ○ approached slowly & dexmedetomidine cautiously and romifidine ○ ameliorated by combining an a2 adrenergic agonist with an opioid Bradycardic ○ B4 treating bradycardia w anticholinergic, check bp Intracar id injection can result in seizures CVS - phase 1 Peripheral vasoconstriction Increase blood pressure Reflex decrease in heart rate - Phase 2 Centrally mediated reduction in sympathetic outflow Return to normal bp or hyp ension  Bradycardia Decreased Cardiac Output Will Remain - arrhythmias - peripheral vasoconstriction & bradycardia => ↓CO Resp Resp depression may occur w high doses Small ruminants can become hypoxic Urinary ↓sensitivity or production of ADH => ↑urinary output ↑ Uterine tone GIT Ileus Vomiting (especially cats) Salivation ↓ Platelet aggregation a2 adrenergic Atipamezole is the most a2 specific Atipamezole: IM better than IV Rapid reversal can result in antagonists apprehension, excitement, aggression and tremors Yohimbine and tolazoline should be very slowly to avoid vasodilation and hyp ension Deaths have been reported with IV use Ketamine Non-competitive antagonist of Analgesia, sedation & induction of anaesthesia Dose dependant respiratory depression NMDA receptor - prevents binding when combine w benzo when used with her anaesthetic and of glutamate ○ Deep sedation w a2 adrenergic agonist analgesic agents Also has some action on opioid, & opioids Muscle rigidity - can be reduced by a2 monoaminergic (dopamine, ○ Used as analgesic as a CRI intra adrenergic agonist &/or benzo noradrenaline, adrenaline and ○ and postoperatively eyes remain open with little to no ser onin) and muscarinic receptors ○ Has been used anecd ally to treat lacrimation - need pr ection from Depresses brain’s thalamocortical, chronic pain such as osteoarthritis drying and sunlight limbic and reticular activating Modify central sensitisation Crosses placenta - associated with systems => dose-dependent CVS depression of neonates dissociative state or catalepsy catecholamine release - ↑ sympathetic nervous system tone ○ Does n occur in animals in shock due  to neur ransmitter exhaustion and a decrease in CO will result. ↑ HR, cardiac output and blood pressure Direct myocardial depression Respiratory CNS ↑ cerebral metabolic requirement for oxygen May increase cerebral blood flow and ICP Ocular ↑ Intraocular pressure Amantadine NMDA receptor antagonist Analgesia for chronic pain such as osteoarthritis and agitation and diarrhoea Increases dopamine release and neuropathic pain in dogs and cats blocks dopamine reuptake Anticholinergic Amitriptyline Tricyclic antidepressant Constipation & urinary retention Antagonism of ser onin & Polyuria and polydipsia noradrenalin reuptake pumps P entiate seizures Central & peripheral anticholinergic P ential to contribute to ser onin syndrome activity treatment of neuropathic pain in dogs and cats NMDA receptor antagonist provide analgesia for urethral spasm in cats a1 adrenergic antagonist Histamine (H)1 antagonism Enhance adenosine and GABAB receptors Glutamate receptor antagonism Sodium channel blockade Trazadone Antagonist of ser onin 2A and 2C Anxiolytic, antidepressant and anticompulsive Hypersalivation receptors and inhibitor of ser onin More frequently given to cats and dogs prior to Colitis uptake presentation to decrease anxiety and facilitate Gagging weak ser onin reuptake inhibitor handling Counter surfing Reduction of GABA within CNS & Facilitate post surgical confinement in dogs P ential for ser onin syndrome increase 5HT in cerebral cortex In cats used to decrease anxiety during transport ○ Grp of physiological effects Possible analgesic role via and facilitate handling. caused by excess ser onin ○ Increase inhibition at Signs of sedation in dogs and cats ○ Affect resp, CVS, NS, GIT, dorsal horn of spinal metabolic & endocrine  cord ○ Signs ○ Presynaptic inhibition of Tachypnoea substance P release Tachycardia Vomit, coma Diarrhoea Mm tremor Aggression Seizures ○ Drugs tht can cause SSRIs (fluoxetin) TCAs (clomipramine) Monoamine oxidase inhibitors (selegiline) Opioids Tramadol Propofol Phen hiazines (acepromazin) Gabapentin and Structural analogues of GABA but do Treat neuropathic & postoperative pain in some Gabapentin Pregabalin n alter GABA binding conditions (generally n suitable as a sole agent) Avoid human product which contains Binds to a2d ligand of N-type voltage Treat seizures Xylitol which is toxic to dogs and cats gated calcium channels => reduction In cats: reduce stress and improve handling and Hypersalivation of calcium influx into the cell => compliance Ataxia and sedation at higher doses reduction of excitatory and inhibitory In dogs : reduce indicators of stress Seizures if administration ceased neur ransmitters such as glutamate Possibly for analgesia in dogs. following chronic use May also block sodium channels Elimination of ectopic nerve activity Anticholinergi and Catecholamines Drug MOA Effects Side effects Contraindications Anticholinergi Binds to muscarinic cholinergic receptors Ileus in the parasympathetic nervous system Decrease oesophageal tone ↓ Decreased salivation Prevents acetylcholine from binding to ○ Makes saliva thick and sticky postsynaptic receptors ○ ET tube and airway obstruction ↓ No analgesia Decreases vagal tone (parasympathetic Mydriasis nervous system) Mild bronchodilation No effect may be seen in hyp hermic animal Allows sympathetic nervous system to CVS predominate ↑ HR ↓ Administer when HR is adversely affecting cardiac Increases heart rate performance Chron ropes (rate of contraction) * only use when needed Catecholamine Low doses: activate dopamine receptors Increased systemic and pulmonary vascular - dopamine ↓ resistance, venous return, and PCV due to splenic release norepinephrine from presynaptic nerves contraction. ○ Increase bp in dogs and cats Moderate dose: activate b1 receptors very short half life (3min) - administered as ↓ constant rate in sion (CRI) increase contractility & hence CO higher doses: activates a1 receptors ↓ increases MAP via vasoconstriction Dobutamine b1 and b2 adrenergic agonist E remely short half life so is administered as an - causes increase in contractility in sion a1 adrenergic actions at high doses ↑ contractility  - causes increase in systemic vascular ↑ CO and therefore may ↑ arterial bp resistance May cause vasoconstriction high doses Increases sinoatrial node automaticity and atrioventricular node conductivity ○ -> Tachycardia Sometimes rebound bradycardia may be seen Mainly used to ↑ bp in hyp ensive horses & foals Has been used in small animal to augment low CO due to decreased myocardial nction Phenylephrine a1 adrenergic agonist Short half life so administered as CRI May see reflex bradycardia associated vasoconstriction and hence ↑systemic vascular with increased MAP resistance and MAP Reduction in splanchnic per sion Can cause splenic contraction so is used to treat nephrosplenic entrapment in horses Causes localised vasoconstriction - used as nasal decongestant in horses that have nasal oedema as a result of dorsal recumbency during general anaesthesia Can also be used to reduce nasal bleeding in horses associated with iatrogenic trauma associated with stomach tube placement O en used to manage isoflurane caused hyp ension in cats with hypertrophic cardiomyopathy Noradrenaline Stimulates a1, a2, b1 adrenergic receptors Short half life so is administered as CRI Predominant action is on adrenergic very low doses: b1 adrenergic result in ↑ CO & HR receptorsStimulates a1, a2, b1 and b2 ○ ↑ CO, myocardial oxygen consumption - adrenergic receptors & coronary artery higher doses: a1 adrenergic effects predominate ○ ↑ systemic vascular resistance and MAP ↓ CO & ↑ myocardial oxygen requirement Coronary vasodilation occurs at lower doses and splanchnic per sion is maintained treat severe or refractory hyp ension in  vasodilatory shock eg. sepsis treat anaphylaxis and in cardiopulmonary resuscitation P entiates catecholamine induced arrhythmias Adrenaline Stimulates release of endogenous Duration of action is longer than her Ephedrine noradrenaline which stimulates a1, a2 Similar effects to noradrenaline but n as profound and b1 adrenergic receptors ○ ↑ CO, HR, bp, coronary blood flow, and myocardial oxygen consumption treat mild hyp ension Duration of action ↓ with repeated use as endogenous noradrenaline supplies are exhausted Reduction in renal and splanchnic per sion stimulate CNS - lighten plane of anaesthesia Opioids Opioids = All exogenous substances that bind specifically to opioid receptors and produce some morphine like (agonist) effects ○ Endogenous opioids - Present in the body: b-endorphin, enkaphalins, dynorphins ○ Naturally occurring opioids: Morphine, codeine ○ Semisynthetic opioids: Buprenorphine, apomorphine, heroin, hydromorphone, etorphine ○ Synthetic opioids: Butorphanol, methadone, pethidine, fentanyl Opioids work by binding and activating receptors -> Inhibit release of Acetycholine, dopamine, noradrenaline, substance P (Pre-synaptic) + Inhibits post synaptic activity (post synaptic) Have excitatory actions ○ Indirectly by removing interneuron inhibition - Descending pathways ○ Directly by neuronal excitation Descending pain modulation pathway ○ Opioids bind to inhibitory interneurons -> excitation of descending pathways -> cause analgesia Uses of opioids - pain relief & sedation Physiology of pain: transduction > transmission > modulation > projection > perception Opioids are Controlled drugs/S8 ○ Use is governed by the Medicines and Poisons Act (2019) and the Therapeutic Goods Act (2019) ○ When received a veterinarian must Check invoice matches drugs  Sign drugs into controlled drug book - Date, address of supplier, amount of drug, invoice no. signature of endorsed person ○ Removal of drugs from safe To an her ward safe - Date, destination safe, amount removed, signature At the ward safe - Date, origin, amount added, signature To a patient - Date, Name of patient, address of owner, amount dispensed, signature ○ Who can administer Registered Veterinarian Veterinary Nurse A person (a veterinary nurse) who is employed to practise veterinary nursing; and holds a qualification that makes the person eligible for ll membership of the Veterinary Nurses Council of Australia Inc. the medicine is administered at veterinary premises ○ when a veterinary surgeon is n able to be physically present but is available to be contacted using technology to communicate with a veterinary nurse in real time ○ the medicine has been pre-prepared into a treatment dose by a veterinary surgeon or a pharmacist; ○ the medicine is administered on a prescription or in accordance with the medicine’s approved label Opioid receptor types: μ (mu), 𝜿 (kappa), δ (delta) Types of opioids ○ Agonist binds to a receptor and stimulates that receptor to induce a physiological response Eg. Morphine ○ Partial agonists binds to a receptor and stimulates that receptor to produce a partial response compared to a ll agonist eg. Buprenorphine ○ Antagonists binds to receptor and blocks the effect of an agonist eg Naloxalone Crucial concepts ○ Effect vs Concentration/Dose Curves As the dose or concentration increases the effect is measured - The effect is a result of the drug binding to receptor ○ Efficacy The ability of a drug to interact with its target receptor and elicitma biological response Efficacy of ll agonists is greater than partial agonists or k agonist/µ antagonists Pure µ agonists (morphine, methadone, fentanyl and hydromorphone) - moderate to severe pain Partial µ agonists (buprenorphine) - mild pain in dogs and mild to moderate pain in cats  k agonists/µ anatagonists (butorphanol) - mild pain in dogs and cats ○ Intrinsic activity Capacity to produce receptor activation ○ Drugs may possess agonist and antagonist properties - eg. butorphanol ○ Affinity Ability of a drug to bind to a receptor ○ P ency The dose/concentration of a drug required to produce a given efffect Side effects ○ Respiratory depression The control of ventilation is determined by the partial pressure of carbon dioxide, oxygen and hydrogen ions (pH) in the blood ○ decrease ability to recognise carbon dioxide as a stimulus to breath Decrease ventilation by decreasing respiratory rate and tidal volume ○ Bradycardia Increases parasympathetic tone via the vagus + Analgesia may decrease sympathetic tone -> a decrease in heart rate ○ Excitation Some species eg. cats and horses may show exicitment versus sedation eg. dogs A healthy horse n in pain should n be given an opioid without prior administration of sedation ○ Gastrointestinal and urinary tract effects Ileus and urinary retention ○ Histamine release Uticaria Tachycardia Hyp ension Shock ○ Methods of adminstration IM, SQ, epidural, transdermal IV Bolus ○ Less equipment required In sion ○ Avoids “rollercoaster” pharmacokineti ○ Better analgesia and less side effects Epidural Analgesia for up to 24 hours with minimal systemic effects Severe puritis Urinary retention Can provide analgesia from lumbosacral to thorax  Transdermal Patch Lipophilic opioids such as fentanyl and buprenorphine Factors that effect absorption ○ Blood flow (can be affected by temperature) ○ Thickness of skin ○ Temperature local and systemic ○ Lipid content of skin (preparation) ○ Damage to the skin - Clipping/preparation Transdermal fentanyl patch Take time for peak effect Must be placed ahead of time Transdermal buprenorphine patch pharmacokineti questions effectiveness NSAIDS & EP4 Antagonist Definitions ○ Constitutive Forming a part of something Relates to an enzyme or enzyme system that is continuously produced by the organism, regardless of the needs of cells ○ Induced or inducible Bring about or give rise to. ○ Homeostatic property of a system in which variables are regulated so that internal conditions remain stable and relatively constant. Schedule 4 (S4) Drugs ○ Prescription only medicine ○ Veterinary nurse (technician) May administer with appropriate training Under supervision of a veterinarian or may administer a dispensed drug according to the label ○ Trainee veterinarians or nurse (technician) Under supervision of veterinarian, trained VN or VT Owner with prescription may administer a dispensed drug according to the label ○ Storage Must be kept in a cupboard, dispensary, drawer, storeroom or her part of the place to which the public does n have access MOA of NSAIDs ○ Inhibit COX 1 and 2 -> inhibit PGE2 production from arachidonic acid  Arachidonic acid can produce eicosanoids (prostaglandins & thromboxane) under normal cascade which has harm l & unpleasant effects ○ Vasodilation ○ Pain Peripheral sensitization Central sensitization Peripheral sensitization Central sensitization Occurs as a consequence of tissue trauma and inflammation Occurs because of severe or chronic noxious stimuli Results in hyperalgesia at the site of injury Impulse from nociceptor to spinal cord -> increases impulse traffic -> p entiated state -> “Sensitising soup” changes high threshold nociceptors to low threshold nociceptors - allodynia amplifies the pain response Also activate “silent” nociceptors Has beneficial effects ○ Gastrointestinal pr ective effects ○ Renal pr ective effects ○ Pro-coagulant and anti-coagulant effects - Balances haemostasis COX 1 - constitutive ○ Produce PGs that have house keeper nction GIT pr ection Increased secretion of bicarbonate in the duodenum Increased mucous production Increased turnover of mucosal cells Decreased gastric acid secretion ○ Renal regulation of fluid balance and blood pressure Mediate arteriolar dilation in response to volume depletion and hyp ension ○ Balance of haemostasis ○ Bone metabolism ○ Reproduction COX 2 - constitutive & inducible ○ Produce PGs that have house keeper roles Central nervous system Renal system Reproductive system Tissue repair especially GIT  ○ Harm l Inflammatory soup Vasodilation Peripheral and central sensitization Types of NSAIDs ○ Non-selective COX Inhibitors ○ Selective or preferential COX 2 inhibitors Initially believed that COX 2 had no constitutive nction (all bad) and it inhibition would prevent the side effects associated with NSAIDs Tend to minimise GIT side effects in those animals with normal gut COX inhibition is measured a number of ways - results vary due to different assays, laboratories and species ○ To compare, IC50 is used Ideally: COX 2 IC80 for analgesia COX 1 IC20 to minimise side effects NSAIDs ○ The good Pain relief - Remove the peripheral and central sensitization effects of PGs Anti-pyretic ○ The bad GIT Gastritis and enteritis - Ulceration Hematemesis and melena In severe cases an ulcer may perforate resulting in a septic abdomen and death Renal Removes the pr ective effect of PGs in the presence of hypovolaemia and hyp ension Acute renal failure Liver Anorexia, vomiting and icterus Increased liver enzymes Haemostasis inhibit platelet activity and platelet aggregation ○ Uses Analgesi , anti-inflammatory and antipyretic  Don’t produce sedation or ataxia seen with her Use one NSAID at a time Adapt therapy to the patient N all patients respond the same to the same NSAID Analgesia may vary Side effect may vary Observe for toxicity - Ensure owner knows signs Check renal and liver toxicity prior to therapy analgesi Follow label instructions care lly - Some products are to be given with food, hers n. Care in Cats - Reduced ability to metabolise NSAIDs N all NSAIDs are registered in cats May require different doses to dogs Duration of therapy may be much shorter ○ Contraindictions Patient receiving her NSAID - If change need washout time Washout is usually 3 to 5 times the half life In most NSAIDs this is equivalent to a Washout of at least 48 – 72 hours unless ○ Asprin - 10 – 14 days to allow platelet regeneration ○ Mavacoxib - Long acting ½ life of minimum of 2 weeks Small animal patient receiving glucocorticoids Co-existing disease renal low volume status liver coagulopathies EP4 antagonist ○ MOA Blocks the EP4 receptor for prostaglandin PGE2 Prostaglandin E2 ○ Is the most plenti l prostaglandin the joint ○ Has a major role in the development of joint inflammation and pain associated with osteoarthritis By antagonising EP4, Grapriprant should relieve pain associated with joint inflammation Developed so that the homeostatic mechanisms of prostaglandins are preserved ○ Side effects  Vomiting Lethargy Diarrhoea or so faeces (mucoid, watery and or bloody) Increased ALP and ALT Decreased appetite Decreased albumin and t al plasma pr ein ○ Clinical Use Osteoarthritis (chronic) in dogs N as effective as firocoxib or carprofen when used in dogs with acute arthritis May be use l in dogs that have osteoarthritis that have side effects associated with NSAID use or in which NSAIDs are contraindicated Paracetamol (Acetaminophen) ○ Mechanism of Action Unknown It is n known if paracetamol is metabolised to AM404 in dogs and horses Other proposed mechanisms are Inhibition of cyclooxygenase and peroxidase sites on prostaglandin H2 synthetase Ser onergic activity ○ DO NOT USE IN CATS Will cause death in cats due to methemoglobinaemia, haematuria and icterus Cats are unable to glucuronidate paracetamol due to a deficiency in glucuronyl trasferases results in toxic metabolites (oxygen free radicals) which attack red cells resulting in Heinz body formation ○ Side effects and clinical use In dogs overdose can result Hepatic failure Methaemaglobinaemia and anaemia Full blood count montitoring suggested for long term use Usually used as an adjunct for breakthrough pain in chronic pain syndromes For example may be used with codeine in patients where NSAIDs are contraindicated N adequate for post operative pain as a sole agent however has been used in conjunction with opioids Local anaesthetic Pain Pathway ○ LA Works on the 1st two parts of pain pathway Transduction Transmission  Mechanism of Action ○ Reversibly blocks volatage-gated Na+ channels located on the cell membrane of nerve axons Prevents membrane depolarization Inhibits generation and conduction of action p entials in nociceptive fibres thus blocking the transmission of pain impulses ○ Site of action: Nerves (afferent nerve fibres) LAs are weak bases Pharmacology ○ Factors affecting ease of blockade of electrical impulses Density of Na+ channels in tissues concerned (small > large) State of channels Myelinated/non-myelinated Unmyelinated more susceptible – minimal insulation ○ But are less easily blocked than myelinated Myelinated fibres use saltatory conduction ○ Only 3 successive nodes need to be blocked ○ Structure of LAs Lipophilic aromatic group Intermediary link Categories LAs into ○ ester-linked or Procaine – local/perineural Tetracaine – topical ophthalmic ○ amide- linked groups Lidocaine Ropivacaine Mepivacaine Prilocaine Bupivacaine Ester-linked Amide link Poor tissue penetration Good tissue penetration Short duration of action Longer duration of action - Rapid metabolism via hydrolysis (by tissue and plasma esterases/cholinesterases– mostly - Elimination by hepatic metabolism (amidase enzymes CYP450), metabolites excreted in urine  produced by liver) - CSF contains no esterases – accidental intrathecal injection => very long duration of effect Possibly decreased risk of toxicity due to rapid metabolism/ short duration of action Possibly increased risk of toxicity due to slower elimination Possible allergic reactions to a metabolite (para-amino benzoic acid pABA) Possible allergic reactions due to methylparahydroxybenzoate (commonly included preservative that can be broken down to pABA) Prilocaine (esp. right isomer) is metabolized to ortho-toludine which oxidises haemoglobin forming methaemoglobin (methaemoglobinemia) Hydrophilic amine group If pKa is higher than that of physiological pH, higher proportion of ionized form = slower onset of action Pr ein binding: main determinant of duration of action Lipid solubility: main determinant of intrinsic LA p ency (and risk of side effects) No mixing of LAs ○ Mixing alters pH and decreases concentration gradient  ○ Affects onset time, nerve penetration and duration of action Factors influencing LA activity ○ Volume of injection Increased volume, faster onset speed Cranial spread in neuroaxial blocks ○ Concentration Higher concentration, faster onset ○ Site of injection Peripheral > Epidural > Intrathecal (shortest DOA) Inflammation results in more acidic environment = higher ionized fraction, delays onset of action ○ Blood pressure Amides undergo high e raction ratio hepatic metabolism (metabolism is dependent on hepatic blood flow) Lidocaine ○ Commonly available as 1% or 2% hydrochloride solutions; 2-4% for topical application/spray, 2-5% gels and ointments for topical application ○ Amide-linked LA - Rapid onset of action, good spreading properties (penetrance, causing local vasodilation), short duration of action 1-2 hours ○ Can cause some nerve ro (radicular) irritation a er neuraxial administration especially at higher concentrations – probably due to detergent effects on nerve membranes ○ Other properties of Lidocaine include: Anti-arrhythmia Anticonvulsant/proconvulsant Analgesic Prokinetic Anti-inflammatory Bupivacaine ○ Commonly available as 0.5%, 0.25% and 0.125% solutions ○ Amide-linked LA: higher pKa so slower onset (15-45 mins), prolonged duration of action (3-8 hours) as highly pr ein bound, good penetrance (longer side chains than mepivacaine so more lipid soluble) ○ Myocardial depression and arrhythmogenic – 4x as p ent as lidocaine for myocardial depression and 16x as p ent an arrhythmogen. ○ Levo-bupivacaine less cardi oxic ○ Liposome-encapsulated bupivacaine (Nocita) E ended-release formulation Duration of 72 hours Dose of 5.3mg/kg (0.4ml/kg) administered by infiltration injection into tissue layers Licensed in US for wound infiltration post-canine cruciate surgery and 4-point nerve block specific for onychectomy in cats Reported adverse reactions include: discharge from incision, Incisional inflammation, vomiting  Ropivacaine ○ Available in solutions of 1%, 0.75% and 0.2% of S-enantiomer only < 0.5% cause vasoconstriction >1% cause vasodilation ○ Amide-linked LA – slow onset and long duration of action ○ Slightly less cardi oxic than racemic bupivacaine ○ Least chondr oxic of LAs Mepivacaine ○ Commonly available as a 2% hydrochloride solution ○ Amide-linked LA : Quick onset (5-30mins), Intermediate duration of action of 120-180mins Less intrinsic vasodilator activity compared with lidocaine ○ Minimal overall effect on vascular tone ○ Less chondr oxic than lidocaine and bupivacaine ○ Widely used in horses EMLA - Lidocaine and Prilocaine ○ Eutectic mi ure of LAs (lidocaine and prilocaine) ○ pH 9.4 – unionized forms of b h agents favoured (lidocaine pKa 7.9, prilocaine pKa 7.9) -> increasing absorption across relatively fatty skin or mucusa ○ Slower onset of action, spreads less well compared to lidocaine ○ Pre-IV cannula placement Apply and cover with an occlusive dressing Leave on for 30 - 60 mins Prilocaine ○ Amide-linked LA ○ Low toxicity as absorption slow ○ Rapid metabolism ○ Metabolism of R-enantiomer produces ortho-toluidine = oxides haem iron causing methaemoglobinaemia ○ Used for diagnostic nerve blocks and produces very little tissue reaction (minimal local vasom or effect) Tetracaine ○ ter-linked LA ○ Topical anaesthetic of conjunctiva/cornea ○ Available as 0.5% or 1% solution (Stings for 30s or so a er first application, may stimulate lacrimation ○ Topical 4% gel for skin application (Ametop TM), more rapidly acting compared to EMLA and produces less local vasoconstriction = aiding in vessel identification 2-chloroprocaine  ○ ter-linked LA ○ Rapid onset of action despite high pKa due to high tissue penetrance ○ Short duration of action due to rapid hydrolysis Proxymetacaine ○ Topical LA for ocular administration as a 0.5% solution Considerations Prior to Administering LAs ○ Coagulopathies ○ Infection/ Neoplastic tissue ○ Anatomic malformation ○ Previous history of sensitivity to LAs ○ Possible complications Common LA techniques ○ Surface/Topical Application Mucosal surface (larynx for ET intubation, eye drops) Skin (EMLA) Intra-articular Interpleural/ Pleural – via chest drain Intra-abdominal for peritoneal ’splash’ block ○ Infiltration Line block/Intradermal/ Subcutaneous/ ‘L’ blocks Dif sion catheter —----------------------------------------------------------------------------------------> Intra-testicular block for castration LA injected directly into testicle Rapidly dif ses to spermatic cord and associated structures Hypodermic needle (sterile) into testicular body with needle tip directed toward spermatic cord Aspirate to ensure needle tip n in blood vessel Inject half t al recommended dose into each testicle/volume that causes testicle to become slightly more turgid ○ Local/ Regional Nerve Blocks Dental blocks Infraorbital – Infraorbital foramen palpable just rostral to 4th premolar Maxillary – Risk of retrobulbar haemorrhage Mandibular – Foramen located on lingual surface of mandible, 2/3 distance from last molar to angular process Mental – May be difficult to palpate  requiring additional equipment Brachial plexus block (Forelimb) RUUM block (Forelimb) Femoral/ Saphenous & Sciatic nerve block Intercostal block Epidural anaesthesia ○ Intravenous Routes of Administration Intravenous regional anaesthesia - Bier block Systemic administration - Lidocaine Adverse Reactions and Toxicity ○ Allergic reactions ○ Local tissue injury/Neur oxicity ○ Systemic toxicity (LAST – Local Anaesthetic Systemic Toxicity) CNS signs Cardi oxicity ○ Chondr oxicity (Bupivacaine > Lidocaine >> Mepivacaine >> Ropivacaine) ○ Methaemoglobinaemia ○ My oxicity Toxicity ○ CNS abnormalities (nystagmus, twitching, ataxia etc) comes first, then progress to CVS (hyp ension, cvs collapse) ○ Treatment for LA systemic toxicity ○ Lipid emulsion - 20% intra-lipid administered IV as: Bolus of 1.5ml/kg over 1 min then CRI of 0.25-0.5mL/kg/min  With up to 2 e ra 1.5ml/kg boluses @ 5min intervals if required. Until resolution of signs or until maximum t al dose of 12mL/kg has been administered Care of lipid toxicity: occurs at higher doses – dyspnea, pyrexia, seizures, coma, coagulation abnormalities, hepatic dys nction. May also see facial pruritus, pancreatitis and corneal lipidosis Prevention of LA systemic toxicity ○ Aspirate prior to injection Avoids inadvertent intravascular injection ○ Adhere to maximum dose recommendations ○ Consider concurrent use of vasoconstrictors Reduces systemic absorption ○ Care when using multiple regional blocks in a single patient ○ Do n mix LAs ○ IV lidocaine: Slow administration Injectable anaesthesia Anaesthesia: reversible, drug induced loss of consciousness Aims ○ Prevent awareness & response to pain + Provide restraint & immobility & muscle relaxation Without jeopardizing patient safety No single drug able to achieve this ○ Balanced anaesthesia Smaller dose of a combination of drugs - reduce disadvantages associated with using large doses of a single drug Injectable anaesthesia: A drug, or combination of drugs, induce anaesthesia safely & reversibly when injected intravenously at sufficient doses. Such combinations could also be given intermittently, or by continuous in sion, for maintenance of anaesthesia Dosing ○ depends on premeds, patient sensitivity ○ Slow incremental dosing ○ Consider syringe size, dilution w NaCl ○ Route of administration MOA ○ Action at ligand gated ion channels Inhibitory (e.g. GABAA & glycine) or excitatory (e.g. NMDA) Pharmacokinetic considerations ○ Speed of onset – usually in a circulation time ○ Initial volume of distribution May be reason for recovery a er single IV dose Difference between thin & fat animals ○ Clearance Conte sensitive half time & route of elimination Is it cumulative, suitable for TIVA? Species differences, effect of disease? ○ Route of administration Only IV Formulation considerations  ○ Tiletamine-Zolazpam ○ Commercially as Zoletil® - ratio of 1:1 ○ IV & IM (pain l) with prolonged recovery – 4-5 hours ○ smo h recovery in cats (zolazepam t1/2 longer) – Horses, dogs unpredictable & violent ○ O en combined with alpha-2 agonist ○ Use in wildlife ○ Dose dependent resp. & CV effects Physicochemical properties Pharmacokineti Clinical properties Thiopentone - Yellow crystalline powder (weak organic acid) - Cumulative - Smo h induction of anaesthesia (circulation dependent) - Anhydrous Na2CO3 added to prevent precipitation - Redistribution – rapid recovery following single IV injection - Effect of premedicants, disease state of free acid with atmospheric CO2 - Lipophilic w large vol distribution - Ultra short acting with rapid recovery (10-15 minutes) - Reconstitute with sterile water only - Metabolism via liver & is slow - Respiratory: dose dependent ↓ - 1.25% cats/small dogs, 2.5% dogs, 10% - Large or multiple doses given will accumulate in - CVS: ↑HR, ↓ MAP horses/cattle tissues & recovery prolonged - Do n use in hypovolaemia or cardiac arrhythmias - Incompatible with many drugs & analgesi - Low does for Animals with little fat or reduced - Avoid in C-sections, neonates - Very alkaline (pH11-14) & therefore irritant liver enzymes (e.g. greyhounds or neonates) - CNS: ↓ CBF, ICP & metabolism - Only used IV - Highly pr ein bound - Tx seizures, patients w intracranial dx - Refrigerated approx 1 week - Ionization: effected by small changes in pH - Other: no analgesia - Once turbid loses activity - P ent if acidosis (e.g. respiratory acidosis, - No longer commonly used az aemia) Propofol - A phenol that is an oil at room temp - Non-cumulative - Rapid, smo h induction of anaesthesia with rapid recovery - Milk coloured macro emulsion - Suitable for repeated doses and TIVA - Respiratory depression: dose dependent - Some formulations w preservatives - Rapid redistribution & metabolism by liver - CVS: HR ↑↓, MAP ↓ CO ↓, SVR↓ - Prom es bacterial growth - Species differences but generally large Vd & rapid clearance - CNS: ↓CBF, ICP & metabolism - Evidence of ↑ wound infections - Some e rahepatic metabolism - Seizure control but can cause excitation - Refrigerate & use within 24 hrs - Conjugates excreted via the urine - No analgesia  - Aseptic handling - Renal & liver dx minimal effects on PK - Caution: hyperlipidaemia, pancreatitis - Non irritant but IV use only - Greyhounds – longer recovery - Some incidence of pain on injection - Cats – n for TIVA or repeated dosing - Compatible with 5% de rose (for dilution if required) Alfaxalone - Neurosteroid, presented as a clear liquid - Non-cumulative (including cats) - Rapid, smo h induction of anaesthesia with rapid recovery - Solubilized with - Suitable for repeated doses and TIVA - Respiratory depression: dose dependent 2-hydroxypropyl-beta-cyclode rin - Rapid redistribution & metabolism by liver - CVS: HR ↑, MAP ↓, SVR ↓, CO↓ (minimal at clinical dose - No preservative – refrigerated 14 days - Species differences but generally large Vd & rapid clearance rates) - Non-irritant, no pain on injection - Suitable for greyhounds - CNS: ↓ CBF, ICP & metabolism (we think) - Can be given IM - Cats – conjugated in liver but repeated dosing & TIVA ok - No analgesia Ketamine - Phencyclidine derivative - Cumulative – norketamine active metabolite - Dissociative state - Clear liquid, pH 3.5-5.5 - Initial recovery (single injection) via redistribution - Analgesia, amnesia, reflexes maintained (e.g. - Racemic mi ure (S(+)ketamine & R(-)ketamine) - Metabolised in liver (hydroxylation & conjugation) laryngeal, occular etc) & increased muscle tone - Preservative benzethonium chloride - Parent compound & metabolites excreted via kidney - Cataleptic state - stable but pr ect from light - Liver dx prolongs action - NMDA receptor antagonism & hers - Non-irritant - Lower pr ein binding (approx 50%) - Resp: well maintained with clinical doses - IV, SC, IM & transmucosal - Apneustic breathing pattern - Pain on injection - CVS: sympathetic stimulation ↑HR, CO, MAP - ↑myocardial work & O2 consumption - Also direct myocardial depressive effects (high doses or comprimised patients) - CNS: ↑ICP, CBF, metabolic rate - ↑ IOP - Analgesia - In sions of subanaesthetic doses - Part of multimodal pain management plan - N used as sole anaesthetic agent (poor muscle relaxation) – co induction with BZ Summary ○ Propofol & alfaxalone (perhaps thiopentone) suitable for sole induction & maintenance anaesthetic agent ○ Administered to effect N for large animals - give bolus instead ○ All cause dose dependent cardioresp depression hence must titrate & pre-oxygenate TIVA (T al Intravenous Anaesthesia) ○ Induction & maintenance with IV drugs only Small animals propofol & alfaxalone Horses: ketamine combinations, propofol & alfaxalone Length of time administered will depend on drugs ○ Analgesia considerations ○ How do we achieve this? Single induction dose (short procedure) Intermittent bolus dosing patient induced to effect (SA) & intermittent boluses are administered as required ○ Large variation in plasma levels ○ Excessive drug effect at time of bolus ○ Inadequate effect before ne bolus ○ At each bolus, theres a risk of overdosing the patient Continuous variable rate in sions Loading dose and then drug in sed at constant or variable rate ○ Less plasma variation ○ Less variation in pharmacodynamic effect (safer) Target controlled in sions (TCI) Computer controlled in sion regimens Input PK data, patient data, surgery type etc. Expensive, species considerations ○ Conte sensitive half time time taken for plasma conc to decrease by ½ once an IV in sion has been stopped (assuming constant plasma concentration was achieved) ○ Small animals Propofol or alfaxalone No analgesia Opioid, ketamine, alpha 2 agonist Little accumulation even a er prolonged in sion (day) E.g. short conte sensitive half times Ventilation required Examples: Airway surgery, intracranial disease ○ Large animals Ketamine No muscle relaxation  alpha 2 agonist + BZ (or guiafenesin) Accumulation even a er 45min-1hr Drugs &/or metabolites result in prolonged, ataxic recoveries Ventilation usually n required Examples: field surgery ○ TIVA equipment In sion pump: Syringe driver: Inhalational anaesthesia delivery of gases or vapours to the respiratory system to produce anaesthesia ○ Vapours: Isoflurane, sevoflurane, desflurane ○ Gas: Nitrous oxide (N2O) Vaporizers – device that adds clinically use l concentrations of anaesthetic vapour to a stream of carrier gas. ○ Most agents liquid at room temp & pressure & need to be vaporized ○ Saturated Vapour Pressure (SVP) Pressure of vapour existing above the liquid in a closed container when at equilibrium at a stated temperature SVP of most agents at room temp much >>> than that required to produce anaesthesia Ideal inhalational agent ○ Provide good quality anaesthesia & analgesia ○ Allow for rapid induction & recovery ○ Be practical to administer ○ Minimal effects on CV system & ventilation ○ Non-flammable ○ Provide muscle relaxation ○ Stable chemically ○ Non-toxic with no her side effects Pharmacokineti - Uptake & elimination ○ Depends on Physical properties of inhalational agents Blood gas coefficient: amt of gas dissolved in blood - the lower the value, the faster the induction & recovery Desflurane < nitrous oxide < sevoflurane < isoflurane ○ The influence of physiological effect  Ventilation & Cardiac output ○ Fi: inspired gas conc, affected by FGF rate Vol of breathing system - greater = longer to establish a conc of anaesthesia (low Fi) Absorption by the machine or breathing system High FGF rate, smaller breathing system volume & lower circuit absorption will make the patient Fi closer to vap. setting ○ FA: alveolar gas conc, affected by B/G solubility – More soluble agents take longer to establish effective partial pressure = slower induction + slow recovery Cardiac output (pulmonary blood flow) – Low CO may predispose to overdose (with soluble agents) = faster induction Partial pressure difference btw alveolar gas & venous blood = Tissue uptake (e.g. high fat solubility, slow recovery from long anaesthetic) Ventilation Concentration & 2nd gas effect ○ Fa: aterial conc, affected by V/Q mismatch (ventilation/per sion) ○ ‘Overpressure’ = FA/Fi: start w very high anaestheti to establish an effective conc Minimum Alveolar Concentration ○ conc. of agent at 1 atm that prevents movement in 50% of patients exposed to a supramaximal noxious stimulus. ○ a standard measurement of p ency - higher MAC = less p ent Need to lower inhalational agent requirement by using ○ Analgesi (in sions, bolus doses) ○ Regional anaesthetic techniques ○ ‘balanced anaesthesia’ None are analgesi Physical properties Bi ransformation & Toxicity CVS Resp Cerebral Renal & Hepatic Isoflurane - Nonflammable, volatile - 0.2% (low) bi ransformation Dose dependent CV Dose dependent depression Avoid for brain trauma as ↓ blood flow - Vap dial max 5% - Malignant hyperthermia depression - ↓ RMV causes ↑ ICP, CBF & - Pungent ethereal odour - Vasodilation - Block ventilatory ↓CMRO2 - Myocardial response to hypoxia Sevoflurane - Fluorinated ether - 5% metabolised depression & hypercapnia - Dark plastic b tles - Nephr oxicity - Bronchodilation - Nonpungent (mask inductions) - Hydrogen fluoride causing thermal - Vap. Dial max 8% burns  - - Malignant hyperthermia Desflurane - Fluorinated methyl ethyl ether - Minimal metabolism 0.02% - Boils at room temp. & requires - Carbon monoxide with dry soda lime specialised vaporizer - Malignant hyperthermia - Airway irritant – n reported dogs & cats Variable bypass vaporizers ○ Draw over vaporizers e.g. Stephens - Vaporizer in circuit (VIC) ○ Plenum vaporizers – precision vaporizers, flow & temperature compensated Vaporizer out of circuit (VOC) Problems in practice & safety features ○ Only ever 1 vaporizer on machine at a time agents are additive - could overdose patient newer vaporizers have a safety interlock system ○ “Selectatec” mounting ensure ‘O’ rings are in good condition lever in the ‘locked’ position ○ Pressure relief valve ○ Mechanisms to prevent back pressure ○ Tipping or dropping the vaporizer dangerously high output when 1st turned on newer vaporizers (Tec Mk 5) safer always empty before travel purge FGF 5L/min for 30 min with dial at 5% (to make it safe) ○ Keyed filling ports prevent wrong agent to wrong vaporizer reduce spillage Workplace exposure ○ Short term exposure vs chronic exposure ○ Appropriate Scavenging Collects waste anaesthetic gases from system & safely discards of them Types:  Passive scavenging Active scavenging Charcoal canister (passive) ○ Preventative measures Appropriate room ventilation Avoid mask inductions/chambers & maintenance Regular maintenance of anaesthetic machine (leak tests) Always turn off vaporizer when n in use Key indexed vaporizer fillers Empty reservoir bag before disconnecting Low FGF, circle systems Appropriate response/training if large spill ○ Monitoring Environment ○ Contribute to greenhouse gases ○ Global Warming P ential (GWP) Index – Desflurane (worst) > sevoflurane > isoflurane ○ How to reduce effects Regional anaesthesia (MAC sparing) Low flow anaesthesia Desflurane & N2O when indicated only