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287 Cards in this Set

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targets for G-proteins
-adenylate cyclase/cAMP system
-phospholipase C/inositol phosphate system
-regulation of ion channels
cyclic AMP
-alpha subunit activate adenylate cyclase
-adenylate cyclase hydrolyzes ATP to cAMP (secondary messenger)
-cAMP activates protein kinase A
-cascade response: phosphorylation (response short lived)
IP3, DAG, & calcium
-phospholipase C (alpha subunit - GTP bound) activates inositol phospholipid (membrane bound)
-IP3 & DAG activated
-IP3 diffuses into cytosol: binds to receptors on ER & opens Ca channels (increases intracellular Ca: contraction)
-DAG activates protein kinase C: cascade results in increased intracellular Ca
regulation of ion channels
-no 2nd messenger
-G-protein interacts directly with the channel
-either alpha or beta/gamma subunit may be mediator which controls channel
-eg. muscarinic ACh in cardiac cells increase K permeability
drug specificity
-binding site specificity
-ligand specific
-biological specificity
-no drug has complete specificity (side effects)
EC50
-concentration that produces 50% of maximal response
-measure of efficacy: the lower the EC50 the more potent the drug
Kd
-concentration at which 50% of receptors are filled
-measure of binding affinity: the lower the Kd the higher the binding affinity
spare receptors
if a response can occur when only a small fraction of the receptors are ccupied the system is said to possess "spare receptors" or a "receptor reserve"
ED50
-dose required to be effective in 50% of population
-varies depending on application (eg. asparin for headache vs chronic arthritis)
LD50
dose that will be lethal in 50% of population
therapeutic index
-maximum non-toxic dose / minimum effective dose
-LD50 / ED50
-wide therapeutic index: wide range of effective dose without toxicity
-narrow therapeutic range: small effective dose range without toxicity (must be cautious)
affinity vs efficacy
-affinity: ability to bind to receptor
-efficacy: ability, once bound, to elicit effect
alterations in drug receptor activity
-esensitization / tachyphylaxis: rapid loss of activity in response to frequent exposure
-tolerance: similar but longer time frame
-refractoriness: treatment becomes ineffective (increased dose does not overcome)
-resistance: target has developed innate ability to resist drug (change in receptor, loss of receptor, exhaustion of mediator, increased metabolic degradation, physiological adaptation, active extrusion of drug from cells)
pH & ion trapping
-2 compartment of different pH can result in ion trapping
-acids unionized in acidic environment and dissociate in basic environments (bases opposite)
-unionized form(uncharged/undissociated) is lipid soluble & can cross plasma membrane
-weak acids trapped in alkaline environment (weak bases trapped in acidic environment)
-eg. asparin (weak acid): limited dissociation in gastric juice (acidic); high dissociation in urine (basic)
-eg. pethidine (weak base): high dissociation in gastric juice; limited dissociation in urine
-pH of urine can affect excretion
-plasma pH can influence movement across blood brain barrier (eg. if want acids out of CNS, increase plasma pH)
-bases not well absorbed in oral admin (ok if GIT is site of action)
plasma protein binding
-albumen binds many acidic drugs & some basic drugs (2 binding sites)
-small increase in total drug concentration can result in large increase in free drug concentration as albumin binding becomes saturated (can get sudden increase in toxicity)
-extensive binding can slow elimination
-amound of binding depends on free drug concentration, affinity for binding sites, protein concentration
partition into body fat (& othe tissues)
-fat: large non-polar compartment
-fat:water partition coefficient is normally quite low (poor blood supply)
-if high fat:water partition coefficient then lipid soluble & will partition into fat compartment (eg. E2)
-general anasthetics are lipid souluble so must be careful or fat will become a resevoir (increased time of action & potential for toxicity)
-bones & teeth can be a resevoir (eg. tetracyclines - can't give pregnant)
-melanin can be a resevoir (eg. chloroquine)
body fluid compartments
-plasma water: ~5%
-intersitial water: ~16%
-intracellular water: ~35%
-transcellular water: ~2% (eg. CSF, sinovial fluid, etc)
-fat: ~20%
-NB: only free drugs (not protein bound) can move between compartments
blood brain barrier (BBB)
-continuous layer of endothelia cells joined by tight junctions (inaccessible by many drugs)
-if high lipid solubility: can cross BBB
-chemoreceptor trigger zone (detects poisoning) is leaky
volume of distribution (Vd)
-volume of plasma that would contain the total body content of the drug at a concentrtion equal to that in the plasma
-Vd = total amount of drug in body / concentration of drug in plasma
-fluid volume in which a drug seems to be dissolved
-eg. give 100mg drug i.v., allow time for distribution around body, then measure concentration in plasma (15mg/l): Vd = 100mg / 15mg/l = 6.67l
-must relate to body weight (eg. patient weighs 60kg): 6.67l / 60kg = 0.11l/kg (approx 1/2 plasma volume [0.05l/kg] so about 1/2 of drug enters tissues)
-drugs may preferentially distribute to tissue other than blood (eg. drugs with very high Vd have high concentration in extravascular tissue)
-may be due to: ion trapping, highly lipid soluble, irreversible receptor binding, incorporation into tisse, etc.
metabolism (phase I vs phase II)
-phase I: oxidation, reduction, hydrolysis, hydration
phase II: conjugation - glucuronyl (cats deficient), sulphate, methyl, acetyl (dgos deficient), glycyl, glutathione
-conjugation adds large polar group which decreases lipid solubility & increases water solubility
first pass metabolism
-presystemic metabolism (oral admin): liver (or gut wall) metabolized the drug before it reaches the systemic circulation
-consequences: poor bioavailability, larger dose needed, marked inter-individual variation (not predictable)
-eg. morphine & asparin have high 1st pass metabolism
microsomal enzymes
-some drugs induces cynthesis of microsomal enzymes which increase metabolism
-can increase or decrease toxicity (metabolite may be more toxic than parent compound)
-can affect other drugs given simultaneously
drug excretion
-glomerular filtration
-tubular secretion & reabsorption
-tubular diffusion
-clearance
-biliary excretion & enterohepatic circulation
clearance
-efficiency of the irreversible elimination of a drug from the system circulation or volume of blood cleared of a drug per unit time (renal, hepatic, whole body, etc)
-eg. clearance of drug X by liver is 60l/hr & liver blood flow is 90l/hr so clearance = 60/90 = 2/3 is irreversible removed by the liver (cleared) in 1 pass
renal clearance
-volume of plasma containing the amount of substance that is removed by the kidney in unit time
-ranges from < 1ml/min to 700ml/min (max renal blood flow)
-compound may be cleared unchanged
biliary excretion & enterohepatic circulation
-liver has similar transport systems as kidney for excreting substances in bile
-gut is able to breakdown molecules
-gut is able to reverse action of liver: bile excreted into gut where it removes conjugation (eg. glucuronides by liver) & reactivates (reabsorbs: up to 20% of total drug)
-can end up with circulating resevoir of drug as it is metabolized and reactivated (eg. morphine)
single compartment pharmacokinetics
-simplified model: a single, well stirred compartment into which a drug is introduced & from which it is eliminated
-after injection drug is instantly "everywhere" at a single concentration (not realistic)
-concentration at time t will depend on the rate of elimination
-follow zero order kinetics: concentration declines linearly with time (rare - true of alcohol)
-does not matter how much drug is given
zero order kinetics
-concentration declines linearly with time (regardless how much drug is given)
-rate of change in concentratoin over time = a constant
-rare in practice (true of alcohol)
-relationship between dose & steady state plasma concentrtion is steep & unpredictable: would quickly pass through therapeutic range into toxic
first order kinetics
-most drugs
-concentration declines exponentially with time
-rate of change of concentration over time = a constant proportion of the concentration
-asymptotoic curve: the more drugs in the body, the faster the body will try to eliminate
-the rate of elimination is directly proportional to the drug concentration
half life of elimination
-independent of dose
-determined by volume of distribution (Vd) & clearance (Cls)
-the further the drug distributes (high Vd), the longer the half life
-the larger the clearance, the shorter the half life
loading dose (LD)
-if a drug takes a long time to reach therapeutic levels, then a higher dose (the loading dose) may be given initially before dropping down to a lower maintenance dose
-rapid effect then achieves steady state within therapeutic range (avoids large fluctuations)
-LD = Vd x Ceff
-Vd = volume of distribution
-Ceff = the effective peak concentration you want to acheive
-normal kinetics result in steady state within 3-5 plasma half lives
bioavailability
-fraction absorbed (F) = AUC (oral) / AUC (IV)
-AUC is area under curve
-IV is assumed to have 100% bioavailability so F = a fraction of IV
two compartment model of pharacokinetics
-admin i.v. central compartment
-distribute to peripheral compartment (plasma to tissue): fast alpha phase
-elimination from plasma: slow beta phase (must return to plasma from tissues)
-initially Cp falls rapidly b/c fast distribution to tissues
-later Cp is a function of beta phase
-more realistic than single compartment model
veterinary drug residues
-pharmacologically active substances (whether active principles, excipients or degradation products) & their metabolites which remain in foodstuffs obtained from animals
-maximum residue lmimits (MRL)
-minimum required performance limit (MRPL): banned substances have no MRL so need a limit
-acceptable daily intake (ADI)
-withdrawl periods
residues (consquences)
-direct toxicity (allergy, etc)
-carcinogenicity
-mutagenicity
-teratogenicity (congenital malformation)
how do drugs act on nerve terminal?
1. interfere with NT synthesis
2. competition for metabolic pathway
3. block reuptake (also build up at synapse)
4. block transport and/or affect storage
5. displace NT (into synaptic cleft)
6. block NT release
7. agonist
8. antagonist
9. inhibit degradation of NT
10. postsynaptic modulation
alpha-1 adrenoreceptors
-stimulate activity (increase IP3 & DAG --> increase Ca from SR)
-vascular smooth muscle: vasoconstriction
-myocardium: postive inotropic effect
-prostatic smooth muscle: contraction
alpha-2 adreonreceptors
-inhibit activity (decrease adenylyl cyclase --> decrease cAMP)
-also inhibit voltage gated calcium channels & activate Ca dependent Ca channels
-prejunctionally (alpha-2a): inhibit NT release
-postjunctionally (alpha-2b in vascular smooth muscle): vasoconstriction
-CNS: mediates sedation & analgesia
beta-1 adrenoreceptors
-stimulatory (increases adenylyl cyclase --> increased cAMP --> increased PKA --> increased Ca)
-mainly in heart: increased force of contraction, increased conduction, & incresaed rate of pulse formation (HR)
beta-2 adrenoreceptors
-stimulatory & inhibitory (increase or decrease cAMP)
-smooth muscle: relaxation (bronchodilation, vasodilation in skeletal muscle)
-stabilize respiratory mast cells
sympathomimetics
-mimic SNS (stimulatory)
-non selective agonists (alpha & beta)
-selective agonists (eg. beta-1 only)
sympatholytics
-antagonists (SNS)
-non selective (alpha & beta)
-selective (eg. alpha-1 only)
non-selective agonists (SNS)
adrenaline/epinephrine:
-alpha-1: vasoconstriction (topically minimize blood loss, sc limit local anasthetic spread, anaphylaxis: decrease blood flow & oedema)
-beta-1: increased HR & force of contraction (cardiac arrest)
-beta-2: bronchodilation (anaphylaxis)
-side effects: can induce tachycardia & arrhythmias
ephedrine
-sympathomimetic (not a true agonist)
-displaces NA from nerve terminals & stimulates SNS
-not widely used due wide ranging effects
-induces bronchodilation
-increases tone of internal bladder sphincter in urinary incontinence
-PK: metabolized by liver, excreted in urine (oral, i.m, or s.c. admin)
-side effects: can induce arrhythmias, tachycardia, & anorexia
dopamine
-sympathomimetic (usually CNS transmitter)
-catecholamine (has own receptors)
-low doses: increases intracellular cAMP & vasodilation (increased renal perfusion & filtration in acute renal failure)
-higher doses (short term treatment of heart failure):
1. vasoconstriction (vascular alpha-1)
2. +ve intrope (myocardial beta-1)
non-selective beta agonists in SNS
1. ISOPRENALINE (not often used):
-positive inotropic & chronotropic effects (beta-1)
-can be used with sick sinus syndrome or tertiary AV block (till pacemaker)
-PK: metab in liver (COMT), not taken into nerve terminal, IV admin
-side effects: arrhythmias, tachycardia, myocardial necrosis (severe cases)

2. ISOXUPRINE:
-treatment of navicular disease, laminitis (??)
-vasodilation (beta-2 effect)
-decrease uterine contraction to delay parturition (tocolytic effect: can be reversed with oxytocin)
-PK: high 1st pass metab, higher beta-2 affinity at normal dose, large Vd, t1/2 < 3hr, oral biovailability low)
-side effects: tachycardia (reduced by oral admin)
non-selective alpha agonists in SNS
PHENYLPROPANOLAMINE (Propalin, Vetoquinol)
-treatment of urinary incontinence in the bitch (increased sphincter tone): most important use
-nasal decongestion (vasoconstriction)
-PK: oral
-side effects: hyperexcitability, aggression, cardia arrhythmias, hypertension (esp. cats)
beta-1 agonists (selective)
-primarily cardiac effects: increase HR & force of contraction
DOBUTAMINE (Dobutrex):
-equine anasthesia: maintain mean arterial pressure above 70mm Hg
-acute cardiac crisi: inotropic support
-minimal effects on HR & systemic vascular resistance
-PK: i.v. infusion b/c short t1/2 & rapid metabolism
-side effects: can induce tacharrhythmias & seizures (esp. cats)
beta-2 agonists (selective)
-smooth muscle relaxation: bronchodilation, uterine relaxation
-illegally used as a growth promtotant (repartitioning agent: hypertrophy of muscle fibres, protein deposition & lipolysis in adipose cells) SECURE STORAGE
1. CLENBUTEROL (Ventipulmin, Planipart):
-allergic respiratory disease/infection + inflammation (eg. RAO in horses)
-acts on large airways (can cause mucus backflow & exacerbate RAO)
-side effects: vasodilation & tachycardia, sweating, muscle tremors
2. TERBUTALINE (Bricanyl):
-bronchodilator for respiratory diseases (not horses)
-more cardiac side effects than clenbuterol
3. SALBUTEMOL (Ventolin):
-bronchodilator (short acting) for rescue treatment
-inhalation so local with few side effects
4. SALMETEROL (Serevent):
-analogue of salbutemol: increased lipophilicity (prolonged pulmonary retention) & increased beta-2 affinity/selectivity
alpha-1 agonists (selective)
-vasoconstriction: can increase force of myocardial contraction (increased arterial pressure & via baroreceptor reflex decreased HR)
PHENYLEPHRINE:
-used in ocular preparations to induce mydriasis in dogs (not cats)
-PK: administered topically
-side effects: cardiac effects if sytemic absorption
alpha-2 agonists (selective)
-central sedative effects
-can cause vasoconstriction
-highest concentration of alpha-2 in CNS (also VSM, uterus, GIT)
XYLAZINE, METOMIDINE, ROMIFIDINE, DETOMIDINE:
-side effects: bradicardia (result of initial hypertension)
CLONODINE
-diagnosis of growth hormone deficiency (stimulates release of GHRF)
-side effects: temporary sedation, bradycardia
non-selective alpha antagonists in SNS
PHENOXYBENZAMINE (oral)
-irreversible (preference for alpha-1)
-treatment of laminitis
-urinary retention (antagonising alpha-1 receptors of bladder neck & proximal urethra to allow sphincter to open)
-SE: hypertension
ACEPROMAZINE (ACP), CHLORPROMAZINE
-preop sedative
-antagonizes alpha-1,2 (+ histamine & dopamine receptors)
-also used (initially) in undiagnosed vomiting, treatment of motion sickness
non-selective beta antagonist in SNS
-cardiac drugs
PROPRANOLOL
-used against atrial arrhythmias (sometimes anxiety)
-SE: bronchoconstriction, bradycardia
TIMOLOL
-glaucoma treatment: acts on ciliary epithelium to reduce aqueous humor secretion (topical)
alpha-1 antagonist (selective)
-smooth muscle relaxation: vasodilation & relaxation of urinary sphincter
PRAZOSIN: urinary retention
-SE: hypotension
TERAZOSIN & ALFUZASIN: treatment of BPH in man
alpha-2 antagonist (selective)
-reverse sedation induced by alpha-2 agonists
ATIPAMEZOLE (Antiseden):
-most specific alpha-2 antagonist
-licensed for reversal of metomidine (short acting: beware of re-sedation)
-SE: hypotension
YOHIMBE:
-less alpha-2 specific (more alpha-1 side effects: tachycardia, muscle tremor)
beta-1 antagonists (selective)
anti-arrhythmic
ATENOLOL:
-cats with hypertrophic cardiomyopathy or hypertension (long acting)
METOPROLOL: used in preference to atenolol in cats & dogs
ESMOLOL (Brevibloc): investigation & immed. treatment of tachycardia (short acting)
nicotinic receptors (PNS)
-ligand gated ion channels
-increase permeability to Na & K (stimulatory)
-3 types (differentially sensitive):
1. skeletal muscle (Nm)
2. ganglia (Ng)
3. brain (Nn)
muscarinic receptors (PNS)
-G protein coupled receptors
-M1 (neural stimulatory): ganglia, CNS, gastric parietal cells (activate PLC leading IP3 & DAG: decrease K)
-M2 (cardiac inhib): all areas of heart + brain stem, presynaptic inputs to peripheral & central neurones (inhib adenylate cyclase opens K channels & inhibits Ca)
-M3 (glandular/SM stimulate): sm. muscle, glandular tissue, cerebral cortex (activate PLC)
-M4 (CNS inhib)
-M5 (CNS stim)
Nm receptor agonists
-part of somatic efferent system (ANS side effects)
-depolarizing neuromuscular blockers: irreversible binding (slow to dissociate from receptors) desensitizes (blocks)
SUXAMETHONIUM:
-used to assist in endotracheal intubation (short acting)
-SE: due to altered ANS activity (bradycardia/tachycardia, hypo/hypertension, increased intraocular pressure
-anticholinesterase drugs cannot reverse (b/c binds irreversibly)
non-specific muscarinic agonists
-parasympathomimetics (not commonly used in vet med)
-2 groups:
1. synthetic choline esters (similar to ACh) & ACh
2. naturally occurring cholinomimetic alkaloids (plant derived)
non-specific muscarinic agonists (choline esters)
BETHANECHOL
-M selective
-GI stimulant via M3 receptors
-used to increase bladder tone in urinary retention
CARBACHOL
-topically to induce miosis (glaucoma)
non-specific muscarinic agonists (cholinomimetic alkaloids)
PILOCARPINE
-glaucoma treatment: topical to induce miosis
ARECOLINE
-was used against internal parasites in dogs (increase GI motility)
anticholinesterase agents (AChEI)
-nicotinic effects at NMJ (like stimulating)
-2 categories: irreversible (organophosphates) & reversible (physostigmine)
-have cholinergic effect (stim) initially, but proloned depolarization may result in opposite effect
-may act as direct agonist or antagonist
anticholinesterase agents (irreversible AChEI)
-organophosphates
-volatile, lipid soluble: easily absorbed through mucous membranes & even unbroken skin
-nerve gases: sarin, tobun, soman
-insecticides: selective action in insects at doses used
anticholinesterase agents (reversible AChEI)
-reversal of non-depolarizing muscle blockers (Neostigmine)
-diagnosis (Edrophonium) & treatment (Neostigmine, Pyridostigmine) of myasthenia gravis: compete for binding & displace blocker
EDROPHONIUM CHLORIDE: reversal of non-depolarizing muscle relaxants & diagnosis of myashtenia gravis (short acting)
NESTIGMINE: reversal of non-depolarizing muscle relaxants & trtment of myasthenia gravis (moderate duration)
PYRIDOSTIGMINE (Mestinon): trt myasthenia gravis (moderate duration)
anticholinesterase agents (AChEI toxicity)
due to building ACh affecting SNS & PNS:
-salivation
-muscle tremor
-defecation
-miosis
-collapse
-bradycardia

NB: have antimuscarinic agents close to hand (atropine: antagonistic to ACh)
muscarinic antagonists (parasympatholytics)
-competetive: similar structure to ACh
-ATROPINE
-SCOPOLAMINE (hyoscine)
-GLYCOPYRRONIUM BROMIDE (Robinul)
-IPRATOPIUM BROMIDE (Atrovent)
-PROPANTHELINE BROMIDE
-CYCLOPENTOLATE
-TROPICAMIDE
atropine
-muscarinic antagonist
-premedicant to decrease salivation (ruminants), manage bradycardia assoc. with some anasthetics
-antispasmodic in GI & can decrease gastric secretion
-treatment of organophosphate toxicity
-dilation of pupil for exam
-incrase HR
-PK: i/m, i/v, p.o., s/c; widely distrib; metab in liver & also excreted by kidney; crosses gut, conjuctival sac & BBB
scopolamine
-muscarinic antagonist
-naturally occurring
-used for drying secretions
-contained in antispasmodic Buscopan together with dipyrone/meamizole for spasmodic colic
-antiemetic properties
glycopyrronium bromide
-muscarinic antagonist
-synthetic
-does not cross BBB (less CNS effects)
-does cross placenta (useful in C-section)
-less tachycardia
-used in ocular surgery to prevent vagal stimulation
-treatment of bradycardia/incomplete A-V block & sinoatrial arrest in cats/dogs
muscarinic antagonists (others)
IPRATOPIUM BROMIDE (Atrovent): bronchodilation in horses (RAO) - inhalation
PROPANTHELINE BROMIDE: urinary incontinence in dogs caused by detrussor hyperreflexia
CYCLOPENTOATE: similar to atropine (long duration in cats/dogs), topical solution to induce mydriasis
TROPICAMIDE: mydriatic of choice for intraoccular exams & fundoscopy (short acting, rapid onset)
nicotinic antagonists (Ng)
-ganglionic blockers (eg. hexamethonium) thus both parasympatholytic and sympatholytic effects
-profound physio effects: hypotension, loss of CV reflexes)
-little or no effect at NMJ
-superseded by beta blockers so not relevant in vet med
nicotinic antagonists (Nm receptor)
-part of somatic efferent system but side effects due to ANS effects
-non depolarizing muscle blockers: block receptors and/or ion channels but don't induce depolarization
-eg. CURARE, TUBOCRARINE, PANCURONIUM, VECURONIUM, CISATRACURIUM, GALLAMINE, ATRACURIUM
-produce significant autonomic effects due to actions at ganglia: tachycardia, fall in arterial pressure, GI paralysis, histamine release
-anticholinesterase drugs can reverse effects
pharmacological manipulaton of ANS (eye)
-glaucoma: cholomimetics (stimulate PNS), beta blockers
-mydriasis for exams: muscarinic antagonists, alpha-1 agonists
pharmacological manipulaton of ANS (lung)
-bronchodilation: beta-2 agonists, muscarinic antagonists
-bronchoconstriction: muscarinic agonists
pharmacological manipulaton of ANS (heart)
-muscarinic & beta-1
-increase HR, contractility & CO: sympathetic agonists, beta-1 agonists
-increase HR: muscarinic antagonists
-decrease HR, contractility & CO: beta-1 antagonists
pharmacological manipulaton of ANS (GI)
-decrease motility & secretion: sympathomimetics, muscarinic antagonists
-increase motility & secretion: muscarinic agonists
pharmacological manipulaton of ANS (bladder)
-increase bladder function (non-obstructive disease): muscarinic agonists, alpha agonists
-urinary incontinence (increase smooth m. tone): muscarinic antagonists, alpha antagonists
pain
-unpleasant sensory & emotional experience associated with actual or potential tissue damage, or described in terms of such damage
-always subjective
-phenomena of consciousness (not observable)
-components:
1. sensory-discriminative: ID location, intensity, duration
2. motivational: modifies behavior
3. cognitive & evaluation: anticipation, attention, suggestion & past experience
nociceptor innervation (fibres)
C fibres: small & slow (dull pain)
A delta fibres: large & fast (sharp pain)
dorsal horn
-divided into 6 layers (laminae) which proces sensory info
-laminae I-II: known as superficial dorsal horn & receive input from C and Ad fibres (nociceptors)
-other laminae mostly receive input from innocuous stimulation
-nociceptor axons enter spinal cord, snapse on spinal interneurons which send axons that cross over & ascend spinothalmic tract
-role in modulating pain transmission through spinal & supraspinal mechanisms
-regulatory circuits involve primary afferents, spinal interneurons & descending fibres
-processing at level of spinal cord
ascending pathways
-discriminitive pain reaches thalmus directly w/o making connections elsewhere in the nervous system
-arousal-emotional pain reaches thalmus indirectly via connections with brainstem regions
peripheral sensitization
-nociceptors become increasingly reactive (hyperexcitable) with continuing or repeated stimulation
-threshold decreased such that react to even gentle stimuli
-hyperalgiesia: increased response to a normally painful stimulus (primary: damaged tissue; secondary: area around damaged tissue)
-allodynia: pain due to stimulus which does not normally provoke pain
neuropathic pain
-pain without external noxious cause
-pain without nociception
analgesic strategies
1. pre-emptive analgesia:
-limit central sensitization
-post op pain easier to manage
2. multimodal analgesia:
-drugs that act at different ponts in nociceptive pathway
-fewer adverse effects
3. adjunctive analgisia:
-chronic pain
-drugs not normally used to alleviate pain (eg. NMDA receptor antagonists, anticonvulsants)
local anasthetics (physiology)
reduce excitability by:
1. blocking Na channels*
2. activating K channels
local anasthetics (physical properties)
-weak bases: largely ionized at physiological pH (absorbed more slowly when ionized)
-inflamed tissues may be resistant (acidic): bicarbonate may be added to increase pH
-potency relates to lipid solubility (pass through membrane) & duration to protein binding
-ester linked: rapidly hydrolyzed & short t1/2
-amide linked: metab in liver & longer t1/2
local anasthetics (side effects)
-CNS: initial stimulation (muscle twitching, seizure) leading to convulsions, later dpression leading to coma & death
-CVS: mycoardial contractility & HR fall (peripheral vasodilation & decreased BP)
-alergic reactions: rare (ester > amide)
-methaemoglobinaemia (Fe2+ --> Fe3+)
Lignocaine/Lidocaine
-local anasthetic: used in all types of techniquies
-also antidysrhythmic & GIT prokinetic agent (colic)
-dogs, cats, horses (not food animals)
-rapid onset (25% unionized at pH7.4) & duration of 1-2h (70% protein bound)
-metabolized in liver (amide linked)
-SE: CNS toxicity & seizures
Bupivacaine
-local anasthetic
-mostly small animals: therapeutic nerve blocks & epidural techniques
-no vet license (via cascade only - b/c longer duration)
-slow onset (15% uionized but can add bicarbonate to increase) but long duration (4-8hr: 95% bound)
-metab in liver (glucuronide conjugation)
-SE: CV toxicity (L isomer less but use racemic mix) & bradycardia
Procaine
-peripheral nerve blocks
-cats, dogs, cattle (food animals), horses
-slow onset (3% unionized) & short duration (45-60min: 6% bound)
-prep. contains adrenaline (vasoconstriction slows rate of removal & less reaches heart)
-hydrolyzed by plasma cholinesterase enzymes: metabolite (PABA) antagonized sulphonamide antimicrobials (potential drug reaction)
-SE: CNS toxicity (at lower dose than Lidocaine) & seizures; potential hypersensitivity
-ester linked
Mepivacaine
-infiltration, nerve blocks, intra-articular & epidural anasthetic in horses
-rapid onset (39% ionized) & duration of 90-180min (77% bound)
-no adrenaline
-SE: CNS toxicity (seizures)
local anasthetics (others)
-Cocaine
-Rapivicaine: new, gaining popularity in human med b/c less motor blockade(L isomer only)
-Proxymetaccaine (topical): opthalmic
-EMLA cream: mix of lignocaine & prilocaine for skin desensitization
opioids (endogenous ligands)
3 families with opioid activity (will compete for morphine binding):
1. enkephalins
2. endorphins
3. dynorphins
opioids (examples)
-AGONISTS: morphine, pethidine, methadone, fentanyl, alfentanil, loperamide, codeine, dextro-proxyphene, etorphine
-PARTIAL AGONISTS: buprenorphine, butorphanol, nalbuphine
-ANTAGONISTS: naloxone, diprenorphine
opioids (mechanism of action)
-bind to opioid receptors in brain, spinal cord, periphery
-G protein coupled receptors: 1. inhibit adenylate cyclase --> decrease cAMP 2. opening of K channels
3. inhibit opening of voltage gated Ca channels
-decrease neuronal excitability (K channels increase) & transmitter release (Ca channels decrease)
opioids (CNS effects)
1. analgesia: central (transmission) & peripheral sites, acute & chronic pain (more effective), reduce effective component of pain
2. euphoria: depends on status (ephoria if no pain)
3. respiratory depression: decreased sensitivity to Pco2 (increased arterial Pco2 & altered tidal volume)
4. depression of cough reflex
5. nausea & vomiting (& defecation): up to 40% of patients (transient)
6. pupillary constriction: pinpoint pupils (diagnostic in OD); species variation: mydriasis (dilation of pupil) in cat & miosis (constriction) in dog
opioids (GIT effects)
-via Ca channel: decrease ACh release
-increased tone & decreased motility (constipation)
-increased water absorption b/c decreased rate of passage
-constriction of biliary sphincter
opioids (other effects)
1. histamine release from mast cells: urticaria (itching), bronchoconstriction, hypotension
2. CVS (large doses): hypotension, bradycardia
3. tolerance: increase in dose required to produce pharmacological effect
4. dependence: abstinence syndrome (irritability, body shakes, piloerection ("cold turkey")
opioids (pharmokinetics)
-oral absorption variable
-considerable first pass metabolism
-t1/2: 3-6hr
-hepatic metabolism: usualy conjugation by glucuronide; also de-methylation (pethidine) & hydrolysis (diamorphine to morphine)
-excreted in urine & bile
morphine
-analgesic of choice for severe acute pain
-mu selective agonist
-IM (preferred), IV or SC
-slow onset (15-30min
-duration = 4hr (6hr in cats or 10+hr following epidural)
-SE: vomiting (esp. if not in pain), respiratory depression (not usually a problem), behavior change (high dose: excitement in cats & box walking in horses), excitement in horses
pethidine
-moderate/severe pain & sedation
-horses, cats, dogs
-mu selective agonist
-IM or SC (not IV: histimine release)
-rapid onset, good distribution
-duration: 1-2hr in dog/cat; 1hr in horse
-SE: no vomiting, mydriasis (atropine like: dilate pupil), bradycardis less likely, spasmolytic (atropine-like: decrease GIT motility), histimine release if IV admin
fentanyl
-severe acute pain including intra-operative "rescue analgesia (also chronic pain: transdermal patch)
-no vet license (tho component of Hypnorm with fluanisone: small mammal sedative)
-potent pure mu selective agonist
-injectable: rapid onset (1min IV) & short duration (5-20min)
-transdermal patch: slow onset (24hr in dogs), variable absorption
-SE: bradycardia (hypotension with higer doses) & respiratory depression (significant in anesthetized patients)
etorphine
-neuroleptanalgesia
-component of immobilon (with ACP)
-horses & deer (not recommended for use in domestic spp.)
-potent non-selective agonist (1000x morphine)
-IV or IM
-SE (horse): hypertension, tachycardia, cardiac arrhythmias, respiratory depression
codeine (methyl morphine) phosphate
-analgesic, anti-tussive, anti-diarrheal
-component of Pardale-V (with paracetamol)
-dogs
-weak analgesic activity (10% of dose metabolized to morphine)
-SE: conistapation (extended use)
-NB: dextro-propoxyphene (similar to codeine) used orally in cats & dogs
tramadol
-used increasingly in mgmt of chronic pain
-no vet license
-synthetic (not chemically related to other opiods): mu receptors
-only partly antagonized by naloxone
-other actions: inhibition of reuptake of noradrenaline & seratonin (sensory inhibitor in dorsal horn)
-contraindicated with monoamine oxidase inhibitors
-avoid in patients with history of seizures
buprenorphine
-potent partial agonist (mu receptors)
-mild/moderate pain & sedation
-high affinity for receptor (hard to reverse with antagonist): can use to displace morphine to tone down effect
-slow onset (up to 45min) & long duration (up to 12hr)
-SE: mild sedation
butorphanol
-mixed agonist/antagonist (kappa: partial agonist; mu: antagonist)
-mild pain (unreliable)
-effective sedative & anti-tussive
-horses, cats, dogs
-short duration (up to 2hr after injection)
-IV, IM, SC, oral (tablets)
-SE: dysphoria with high dose (kappa receptor; euphoria: mu)
-opioid of choice for birds (kappa receptor predominates)
analgesia (sites of drug action)
1. local inflmmatory mediators (NSAIDS, corticosteroids)
2. peripheral nerve fibres (local anasthetics)
3. central transmission of pain impulses (opioids, alpha-2 adrenoreceptor agonists)
4. central conscious perception of pain: emotional perception (opioids)
analgesia (strategies)
1. pre-emptive: limit central sensitization, post-op pain easier to control)
2. multimodial: combo of drugs acting at different points in nociceptive pathway (more effective analgesia, fewer adverse side effects)
3. "adjunctive" (not normally used for pain): when not responding to conventional approach (eg. NMDA receptor antagonists: ketamine, anticonvulsants, tricyclic antidepressants)
diprenorphine
-used to antagonize etorphine (Immobilon)
-horses & deer (licensed as Revivon)
-mixed agonist/antagonist (mu: antagonist, kappa: partial agonist)
-dosage: volume equivalent to that of Immobilon (injected slowly IV)
naloxone
-classic opioid antagonist (full): reverses all opioid effects
-rapid effect & short duration (30min - 2hr)
-narcotic effects may reappear: may need to give repeated doses
opioid analgesics (others)
-papaveretum: contains morphine (50%), papaverine, & codeine
-alfentanil
-remifentanil: instant on/off (very short duration without accumulation)
NSAIDs (therapeutic actions)
1. anti-inflammatory
2. analgesic
3. anti-pyretic: lower temperatur
4. anti-thrombotic: reduced platelet aggregation (reduces thromboxane)
NSAIDs (clinical uses)
-inflammatory disorders: osteoarthritis, opthalmological conditions (keratitis/uveitis)
-pain: acute (trauma/surgery) & chronic (osteoarthritis, cancer, dental)
-prothrombotic states: feline hypertrophic cardiomyopathy (prevent aortic embolism)
-endotoxic shock (large animals): reduce inflammatory cascade (equine colic, bovine toxic mastitis, lung infections)
NSAIDs
-none ideal controlling inflammation
-virtually all of unwanted side-effects
-considerable variation in induvidual tolerance & response
-release pro-inflammatory mediators: reduces redness, heat, swelling, & loss of function
-inhibit COX (catalyzes arachadonic acid --> prostaglandins & thromboxanes)
prostanoids
-always accompanies inflammatory response: generated by local tissues & BVs
-PGE2, PGI2, PG2: vasodilators (redness, indreased blood flow)
-potentiates effect of other inflammatory mediators (sensitizes afferent C fibres)
-other roles (potential side effects): immune system, GIT, CVS, kidney, lungs, reproduction, brain & spinal cord
leukotrienes (inflammation)
-contract smooth muscle
-affects vascular permeability
-strong attraction of polymorphonuclear leukocytes
cyclooxygenase (COX)
-enzyme which converts arachidonic acid to prostaglandin precursor PGH2
-COX-1 (constitutively present): "housekeeping enzyme" responsible for physiological activities of prostaglandins (eg. maintaining GIT mucosa)
-explains action of NSAIDs: anti-inflammatory, GI toxicity, antithrombotic
-COX-2: induced under inflammatory conditions (inflammatory prostaglandins that produce pain & high temp)
-both COX-1 & COX-2 have physiological & pathological roles
-COX-3: predominantly in CNS (analgesia & anti-pyretic acitivty); target for paracetamol?
NSAIDs (differential selectivity for COX-1 & COX-2)
1. COX-1 selctive: none clinically available (no reason for them)
2. non-selective COX inhibitor: most commonly used
3. preferential COX-2 inhibitors: meloxicam, diclofenac
4. specific COX-2 inhibitors: rofecoxib, celecoxib, firocoxib (vet licensed)
5. specific COX-3 inhibitors: not yet
NSAIDs (analgesic effects)
1. peripheral action: decrease PG production at site of inflammation - reduced sensitization of nociceptive nerve endings to inflammatory mediators
2. central action: block PG release & neuronal excitation - reduced central sensitization
NSAIDs (anti-pyretic effects)
-decrease PGE2 (COX-2 inhib) prevents increase temp associated with fever
-no effect on normal body temp
NSAIDs (anti-thrombotic effects)
-inhibit thromboxanes (TXA2) inhibiting platelet aggregtion
-more effective as anti-thrombotic at low doses (TXA2 inhibited but PGI2 not)
-also enhanced nitric oxide effect on platelet aggregatoin
NSAIDs (anti-inflammatory effects)
inhibit COX induction & release of prostanoids at site of inflammation to:
1. decrease vasodilator prostaglandins (reduces oedema)
2. reduces inflammatory response (prevent peripheral sensitization)
NSAIDs (anti-endotoxic action)
-endotoxins are LPS generated by gram -ve bacteria
-damage WBCs & vascular endothelium thus releasing vasoactive mediators
-NSAIDs prevent generation of vasoactive mediators during endotoxaemia
NSAIDs (pharmokinetics)
-most well absorbed orally (upper GI)
-relatively small Vd (extracellular)
-highly plasma protein bound (>99%): good penetration into acute inflammatory exudate (largely unionized)
-metabolism: mostly conjugation & renal elimination of metabolites (some biliary elimination) - marked interspecies variation
NSAIDs (adverse effects)
-dyspepsia, nausea, vomiting
-GIT ulceration: : COX-1 inhibition reduces PGs (mucosal ischaemia, impairment of protective mucus barrier)
-renal toxicity: inhibition of PGs (PGE2: renal medulla & PGI2: glomeruls) impairs renal flow - not problem unless hypovolaemic
-hepatotoxicity: uncommon (dogs: carprofen; horses: phenylbutazone)
-cartilage damage: if osteoarthritis (esp. aspirin, ibuprofen, naproxen)
-asthma: increased leucotrine production
-breeding, pregnant, lactating: potentiall teratogenic; PG role in ovulation, embryo implantation & parturition
-hypovolaemia (eg. congestive heart failure, hypotension, shock)
-animals treated with corticosteroids: blocks step about arachidonic acid cascade than NSAIDs
NSAIDs (contraindications)
-acute/chronic renal insufficiency
-hepatic insufficienty
-gastric ulcerations or GI disorders
-coagulopathies (eg. factor deficiencies, von Willebrand's disease, thrombyocytoopaenia)
-severe or poorly controlled asthma
aspirin
-dog & cat osteoarthritis
-t1/2: 8.5hr dogs, 37.5hr cats (too short to use in horse)
-metabolized to salicylate (active)
-irreversible COX inhibitor
-most effective anticoagulant NSAID
paracetamol (acetaminophen)
-poor anti-inflammatory
-effective analgesic & antipyretic
-mechansim: possible COX-3?
-metabolized by glucuronidation, sulfation, & oxidation (phase I metabolite of oxidation, NABQ, is hepatotoxic if not conjucated with glutathione)
-narrow safety margin in cats (should not be used): facial oedema, methaemoglobinaemia, haemolytic anaemia & icterus
-licensed in dogs (with codeine: Pardale-V)
phenylbutazone
-NSAID: horses & dogs
-more potent anti-inflammatory than analgesic
-irreversible COX inhibitor
-toxicity: similar to aspirin (GIT ulceration most common, hepatotoxicity in aged horses)
-IV, paste, granules, tablets
flunixin
-NSAID: horses, cattle, pigs
-potent COX inhibitor (non-selective): anti-inflammatory & analgesic
-GIT ulceration & nephrotoxicity in small mammals
-IV, paste, granules
ketoprofen
-NSAID: dogs, cats, horses, cattle, pigs
-post op analgesia in dogs & cats (potential side effects from anasthesia in others)
-COX inhibitor
-relatively good safety profile (GI disturbances: vomiting & diarrhea)
-IV, IM, SC, tablets
carprofen
-NSAID: dogs, cats, horses, cattle
-perioperative analgesic in dogs & cats
-COX-2 preferential
-good GI saftey profile in dogs (incl. long term use)
-haptotoxicity rare (but reported)
-IV, SC, tablets (palatable), granules
meloxicam
-NSAID: dogs, cats, horses, cattle, pigs
-perioperative analagesic in dogs & cats
-COX-2 preferential
-good safety profile (incl. long term use)
-minimal anti-thromboxane activity
-IV, SC, IM, tablets (chewable), oral suspension
tepoxalin
-NSAID (new): dogs
-musculoskeletal inflammation/pain
-dual COX & lipoxygenase (LOX) inhibitor: less PG & leukotreine (no asthma problem); less GIT ulceration
firocoxib
-NSAID: dogs (newly licensed)
-osteoarthritis
-COX-2 selective (most selective availble): improved GIT tolerance
sedation (drug classes)
in order of increasing unresponsiveness:
1. tranquilizer: induces sleep without drowsiness, calming effect, pre-medicant (eg. phenothiazines, butyrophenones)
2. neuroleptic: tranquilizer used in treatment of psychosis (phenotiazines)
3. sedative: sedation without drowsiness (eg. alpha-2 adrenoreceptor agonists)
4. hypnotic: induces sleep (eg. benzodiazepines: thiopentone, propfol)
NB: sedative & tranqulizer often used interchangeably (eg. ACP technically a tranquilizer but often called a sedative)
tranqulizers
-phenothiazines (eg. ACP)
-butyropherenones (pigs & small furries)
phenothiazines
-tranquilizers
-acepromazine / acetlypromazine (ACP)
-chlorpomazine, promazine, trimeprazine / alimemazine, promethazine
phenothiazines (physiology)
-mechanism: non-selective dompamine antagonists (activity in basal ganglia, limbic system, etc)
-most affect other receptor systems (alpha-1 adrenoreceptors, 5-HT1 receptors, H1 receptors, muscarinic receptors)
-CNS: tranquilizer
-also CVS, respiratory, GIT/anti-emetic, antihistimine, hypothermia, decrease seizure threshold
phenothiazines (CV effects)
1. arterial hypotension (10-20% decrease ABP)
-peripheral vasodilatoin (alpha adrenergic blockade)
-direct action on vascular smooth muscle
-central actions, medulla (decreased sympathetic outflow)
-minimal myocardial depression
2. mild tachycardia: response to hypotension (anti-muscarinic effect)
3. anti-arrhythmic action: raise threshold to adrenaline induced arrhythmias
phenothiazines (respiratory effects)
-generally minimal
-sedation may worsen degree of respiratory distress in dyspnoeic patients
phenothiazines (anti-emetic effect)
-dopamine antagonism (central trigger zone - CTZ)
-decrease GI smooth muscle activity (anti-muscarinic action)
-delayed gastric emptying
-decrease gastro-oesophageal sphincter tone
-decreased saliva production (anti-sialagogue)
phenothiazines (antihistamine action)
-all drugs have some effect
-promethazine is most potent
phenothiazines (hypothermic effects)
-due to peripheral vasodilation
-direct hypothermic effect
-also lack of body movement
phenothiazines (effect on seizure threshold)
-lower seizure threshold (increased chance)
-can induce EEG discharge patterns associated with epileptic seizure disorders
-may be clinically significant in animals with epilepsy or who are predisposed to seizures
phenothiazines (other effects)
-penile prolapse: correlates with onset & duration of sedation (priapism in stallions)
-decrease PCV: uptake of RBCs in spleen
-potentiate effect of other drugs: opioid analgesics, local anasthetics, neuromuscular blocking drugs (reduce induction & maintenance anasthetic requirements)
butyrophenones
-tranquilizers (eg. ACP)
-mechanism: dopamine antagonists
-CNS: sedative action + antiemetic properties (hallucinations, agiation, etc. in people)
-CVS: some vasodilation & hypotension (alpha-1 adrenergic antagonism)
acepromazine (ACP)
-phenothyazine (tranquilizer)
-dog, cat, horse
-high therapeutic index (safe)
-poor dose-response relationship: little correlation between plasma levels & clinical effect (so if don't get good response, increasing dose will only prolong with greater side effects & little increased effectiveness)
-duration: 4-6hr (can be up to 24hr)
-IM preferred: also SC (slow absorption) & IV (must be low dose)
-liver metabolism: glucuronide metabolites (excretion in urine)
-caution: breeding stallion & bulls, hypovolaemic (hypotension can be precipitous b/c vasodilation), epileptic, boxer dogs (may faint so use low dose), giant breeds
phenothiazines (clinical use)
-premedicant prior to general anasthesia (alone or with opioids: neuroleptanalgesia to reduce amount & side effects)
-sedation for minor procedures
-control of motion sickness
-calming (eg. fireworks)
-eg. ACP
azeperone (Stresnil)
-butyrophenone (tranquilizer)
-sedate/modify behavior in pigs (eg. when mixing groups of pigs)
-deep IM injection (leave undisturbed for 30min)
-duration 2-3hr
-SE (similar to ACP): hypotension (mild), hyothermia, priapism, minimal respiratory effects
alpha-2 adrenoreceptors
-receptors located prejunctional: inhibit neurotransmitter release (noradrenaline)
-postjunctually in VSM: vasoconstriction
-CNS: mediate sedation & analgesia
-G protein: inhibit adenylyl cyclase: decrease cAMP
-also inhibit voltage gated calcium channels & activate Ca dependent K channels
alpha-2 adrenoceptor agonists (CNS)
-sedative, analgesic, muscle releaxant: presynaptic decrease in NA release (decrease impulse transmission)
-decreased sympathetic drive (predominance of vagal drive: enhanced parasympathetic)
alpha-2 agonists (drugs: ratio of alph-2:alpha-1 selectivity)
-metdetomidine 1620:1
-detomidine 260:1
-xylazine 160:1
NB: not totally selective for alpha-2
alpha-2 receptor subtypes
alpha-2a: presynaptic (sympathetic drive)
alpha-2b: postsynaptic (direct vasoconstriction)
alpha-2 agonists (blood pressure)
1. vascular tone:
-peripheral postsynaptic alpha-1 & alpha-1: vasoconstriction
-peripheral & central presynaptic: vasodilation
2. bradycardia (reflex)
-baroreceptor response: detect vasoconstriction & slow heart to reduce BP
-central decrease in sympathetic drive
-sustained fall of BP as central effects dominate
alpha-2 agonists (use of anticholinergics)
-alpha-2s decrease CO & increase CVP
-anticholinergics to prevent/treat alpha-2 induced bradycardia (blocking enhanced vagal tone)
alpha-2 agonists (analgesic effects)
-potent
-central action (spinal: receptors dense in laminae I & II of dorsal horn; supraspinal: receptors associated with pain info processing)
-dose dependent
-shorter than sedation
alpha-2 agonists (CV effects)
-hypertension --> hypotension / normotension
-marked bradycardia
alpha-2 agonists (respiratory effects)
-mild to moderate depression: cat, dog, horse
-ruminants more severe: arterial hypoxaemia (mismatch of pulmonary perfusion & ventilation)
alpha-2 agonists (GIT effects)
-vomiting in some species
-GIT motility is depressed
-increased gut transit time (ACh inhibition)
alpha-2 agonists (endocrine effects)
-inhibition of ADH: diuresis
-inhibition of insulin release: hyperglycaemia
alpha-2 agonists (other effects)
-uterine contraction: dose dependent (inhibited at low doses & stimulated at higher doses)
-marked anasthetic sparing effect: can use less opioid & anasthesia
alpha-2 agonists (uses)
-sedation / premedication
-offset muscly hypertonicity with ketamine
-analgesia: colic (horses) & during anaesthesia
-IM*, IV, SC, epidural (concentrated alpha-2 recepors in dorsal horn)
-oral: high 1st pass metabolism (but does cross membranes)
alpha-2 agonists (drugs)
-xylazin
-detomidine (horses & cattle?)
-romifidine (dogs, cats, horses)
-medetomidine (dogs, cats)
-dexmedetomidine (racemic mixture of active & inactive)
xylazine (Rompun)
-alpha-2 agonist: dogs, cats, horses
-least alpha-2 specific (alpha-1 side effects)
-CVS: arrhythmogenic (sensitized heart to catecholamines)
-urogenital: contraction of uterine smooth muscle
-sensitivity: ruminant > horse/dog > pig
-shortest acting
-not used much ("dirty" drug)
-IM or IV
detomidine (Domosedan)
-alpha-2 agonist: horses (recently cattle)
-longer duration: 1-2hr (horse)
-equipotent in horses & cattle
-effects: typical alpha-2 (sedative & analgesic with CV & resp effects)
-IV or IM
romifidine (Sedivet)
-alpha-2 agonist: horses (recently dogs & cats)
-duration: up to 3hr
-effects: typical alpha-2
-CNS: less ataxia in horses (less wobbly for standing procedures)
medetomidine (Domitor)
-alpha-2 agonist (racemic mix): dogs, cats, exotics
-very selective for alpha-2
-very potent: sedation may be profound (rapid onset)
-duration: up to 3hr
-effects: typical alpha-2
-CVS: may be anti-arrhythmic (does NOT sensitize heart to catecholamines like xylazine)
-vomiting in 20-30% (less than xylazine)
alpha-2 agonists (licensed agents)
-dog & cat: xylazine, medetomidine, romifidine
-cattle: xylazine, detomidine
-horses: xylazine, detomidine, romifidine*
alpha-2 antagonists
-atipamezole (Antisedan): dogs & cats only (IM)
-will antagonize any alpha-2 agonist (esp. medetomidine)
-analgesia also reversed
-others alpha-2 antagonists: yohimbine (in USA) & tolazoline
benzodiazepines (BZPs)
-hypnotics: used as sedative/premedicant (also anticonvulsant)
-anxiolytics in man (diazepam: valium)
-mechanism: increase affinity of GABA (main inhibitory transmitter in CNS) & enhances effect
-different binding site than GABA (non-competetive)
-CNS: primarily anxiolytic, muscle relaxation (good with ketamine), anticonvulsant
-CVS/resp: minimal depression
-no analgesic properties (unlike alpha-2 agonists)
benzodiazepines (BZPs): pharmacokinetics
-well absorbed orally (low 1st pass metabolism)
-highly plasm protein bound
-lipid soluble: very good distribution & pass through BBB
-metabolism: glucuronidation in liver (excreted in urine)
benzodiazepines (BZPs): toxicity
-acute: less dangerous than other hypnotics
-little CVS & respiratory effects
benzodiazepines (BZPs): uses
-good sedation in sick & elderly
-paradoxical excitement in healthy patients
diazepam (Valium)
-benzodiazepine (BZPs)
-rapid onset & short duration (IV)
-liver metabolism (some metabolites active) & excreted in urine
-2 preparations:
1. valium: in propylene glycol (may induce throbophlebitis: inflamed veins)
2. diazemuls: emulsion formulation (better for veins but maybe less bioavailability)
midazolam (hynovel)
-benzodiazepine (BZPs)
-water soluble: conformation change at physio PH to become lipid soluble
-rapidly metabolized: short duration
-similar to diazepam (2x potentcy)
-IV, IM, oral
benzodiazepines (BZPs): uses
-NONE licensed in animals
-neuroleptanalgesia: combined with opioid for synergistic effect
-premed/hypnosis of sick animals (paradoxical excitement in healthy)
-control or pre-empt seizures
-induce eating (cats)
-muscle relaxation (with ketamine)
-alter behavior (occasionally)
benzodiazepine (BZPs) antagonists
flumazenil:
-antagonism of diazepam/midazolam
-not licensed in animals
-widely used in human med
neuroleptanalgesia
-patient, though not entirely unconscious, is insensitive to painful stimuli (deep sedation & analgesia)
-produced by combo of a neuroleptic (eg. phenothiazines, butyrophenones) & an opioid analgesic
-loosely extended in vet med to include combo of a sedative or hypnotic (eg. alpha-2 agonist, benzodiazepine) & an opioid analgesic
-licensed preparations: Immobilon (large animals) & Hypnorm (small furries)
Hypnorm
-neuroleptanalgesia: combo of fluanisone & fentanyl
-widely used in small furries
-long duration (large dose of fentanyl)
-IM or IP
-can be antagonized by "sequential analgesia": follow 1 analgesic with another (mu opioid antagonist will know off fentanyl: eg. bupenorphine or butorphanol partial agonists)
Immobilon
-neuroleptanalgesia: combo of ACP & etorphine
-horses & deer (not fallow)
-very potent: horse becomes recumbent
-tachycardia & hypertension
-marked respiratory tremors
-muscle tremors
-hazards: risk to horse & vet (self injection, absorption through skin), must have antidote & trained assistance, enter-hepatic recycling reactivates (esp. donekeys)
Immobilon (antagonism)
-diprenorphine (Revivon)
-weak partial agonist (sequential analgesia)
-may require redosing depending on time between admin of Immobilon & Revivon (1/2 dose SC)
-dose required same as dose of Immobilon
-can't be used to treat accidental self exposure in humans: naloxone (Narcan) treatment of choice in man (very short duration)
-IV admin
muscle relaxants (use)
-offset muscle hypertonicity with ketamine (also BZPs, alpha-2s)
-facilitate smooth induction of anasthesia in large animals (GGE)
-relieve muscle spasms (BZPs)
-improve surgical conditions
muscle relaxation (approaches)
-deep general anasthesia: too much required (side effects: hypotention)
-local anasthesia
-centrally acting muscle relaxants
-neuromuscular blocking agents* (NMBs): just at NMJ so effects less widespread
muscle relaxants (interference of transmission at NMJ)
-inhibit ACh synthesis
-inhibit ACh release
-interfere with post synaptic action of Ach*: NMBs (non-depolarizing & depolarizing)
muscle relaxants (inhibition of ACh synthesis)
-transport of choline into nerve terminal is rate limiting step (so big results if can effect)
-hemicholinium & triethylcholine are competitive inhibitors
-blocking effect slow
-NOT CLINICALLY USEFUL
muscle relaxants (inhibition of ACh release)
-local anasthetics block nerve impulse
-magnesium ions & aminoglycosides block Ca entry
-botulinum toxin (Clostridium botulinum): Botox
-beta-bungarotoxin (snake venom)
muscle relants: neuromuscular blockers (NMBs)
-interfere with post-synaptic action of ACh:
1. non-depolarizing: tubocurarine, gallamine, pancuronium, vecuronium, atracurium, rocuronium
2. depolarizing: suxamethonium
muscle relaxants: non-depolarizing NMBs (mechanism of action)
-competitive antagonist at nicotinic ACh receport (NMJ endplate)
-reveresed by anticholinesterases
-need to block ~80% of receptor sites (b/c "spare receptors": amount of ACh release is far in excess of what's needed)
-transmission all or nothing
-rigid, bulky molecules with quaternary N
-muscle can still respond to K or direct electrical stimulation (can still contract)
muscle relaxants: non-depolarizing NMBs (effects)
-flaccid motor paralysis (initially muscle capable of fast response)
-respiratory muscle last to be effected & first to recover
-consciousness & perception of pain are normal
-SE (b/c non-selective): fall in blood pressure (ganglion block / histimine release), tachycardia: muscarinic receptor block
muscle relaxants: non-depolarizing NMBs (pharmokinetics)
-not lipid soluble: slow absorption & distribution
-IV admin
-metabolized by liver or excreted unchanged
-do not cross BBB (can be used in C-section)
muscle relaxants: non-depolarizing NMBs (groups)
-aminosteroids (-onium): panacuronium, vecuronium, rocuronium)
-benzylisopuinolines: atracurium, cisatracurium, mivacurium
tubocurarine
-muscle relaxant (non-depolarizing NMB)
-histamine release: hypotension, bronchoconstriction (massive effects)
-ganglion block
-side effects too great for use
pancuronium
-muscle relaxant (non-depolarizing NMB)
-moderate onset (2-3min)
-moderate duration (30-45min): not used much b/c too short
-steroid compound
-muscarinic antagonist: tachycardia
-30% metabolized by liver (the rest excreted unchanged: kideny disease will prolong)
-increased BP (sympathomimetic effect)
vecuronium
-muscle relaxant (non-depolarizing NMB)
-no ganglion, histamine, or anti-muscarinic effect
-moderate onset (2-3min)
-moderate duration (15-25min)
-excreted unchanged in bile (hepatic disease can prolong)
-not cumulative
-almost no effect on CVS
-steroid compound
rocuronium
-muscle relaxant (non-depolarizing NMB)
-fast onset (<2min)
-moderate duration (<30min)
-stable haemodynamics (occasional mild tachycardia in dogs
-designed to facilitate intubation after induction
atracurium
-muscle relaxant (non-depolarizing NMB)
-can release histamine (uncomon in animals but avoid if asthmatic)
-Hoffman elimination: spontaneous degradation at physiological pH & temp (good if hepatic & renal disease)
-moderate onset (2-3min)
-moderate duration (<30min)
-breakdown product (laudanosine) may cause seizure in high concentrations
-not cumulative
cisatracurium (Nimbex)
-most potent isomer of atracurium
-no histamine release
-less laudanosine production
mivacurium (Mivacron)
-short acting in man & cat but not dog
-partially metabolized by plasma cholinesterase
muscle relaxants (NMBs: practical use)
-only IV admin
-induce apnoea so patient must be mechanically ventilated
-only admin to anasthatized patients: otherwise panic from sense of paralysis
-no anasthetic or analgesic effects
-can be topped up or infustion (non-depolarizing)
-diaphragm and intercostal mm. most resistant: last to become affected & first to start working again
-muscles of pharyngeal area highly sensitive: possible to start breathing again as effects wear off but not able to maintain patent airway
-NONE LICENSED: cascade
muscle relaxant (depolarizing NMBs)
-agonist of nicotinic ACh receptor but metabolized very slowly
-persistent stimulation that desensitizes (loss of electrical excitability of muscle cell: flaccid paralysis)
-enhanced by anticholinesterases
-no longer responds to K or electrical stimulation
-initial fasciculation (muscle twitching) before excitability is lost
muscle relaxant (depolarizing NMBs: phases)
PHASE I: depolarizing, muscle twitching, presence of agonist prevents repolarization, muscle can't contract
PHASE II: desensitizing, ion channels in a prolonged closed state, channel block, development of unexcitable tissue
muscle relaxant (depolarizing NMBs: side effects)
-bradycardia (non-specific)
-potassium release
-increase intra-occular pressure: not good for eye surgery
-prolonged paralysis: if hepatic disease or treated with anticholinesterase (some genetically deficient in plasma cholinesterase that breaks it down)
-malignant hyperthermia
-NB: can't be antagonized
suxamethonium (succinylcholine)
-muscle relaxant: depolarizing NMB
-fastest onset time of any relaxant (<1min)
-short duration (3-6min cats, 15-20min dogs)
-used in endotracheal intubation: if need to control airway fast
-seldom used in vet
-can't top up like non-depolarizing: single dose can lead to phase II block
-occasionally used for equine castration (but no analgesia)
muscle relaxants (NMBs: uses)
-facilitate endotracheal intubation
-relax skeltal muscle for easier surgical access (eg. deep access like kidney)
-control ventilation during anasthesia (if open thorax surgery)
-opthalmic surgery (in GA eye muscles rotate down: difficult)
-reduce amount of anasthetic required: reduces afferent nerve impulses (less traffic)
muscle relaxant (NMBs: recovering from NM blockade)
-will occur spontaneously: as plasm concentration declines (b/c broken down in plasma) drug will move down its concentration gradient from NMJ into plasm
-can be hastened with non-depolarizing relaxants by administering anticholinesterases (increases ACh effect) b/c competitive agonists
-if ACh increases sufficiently transmission restored
muscle relaxant (NMBs: anticholinesterases for reversal)
-neostigmine
-edrophonium
-(physostigmine)
-only effective agains non-depolarizing relaxants (b/c competitive agonists)
-ACh increases throughout body (not just NMJ)
-SE: bradycardia, salivation, bronchoconstriction, urination & defacation
-due to muscarinic effects usually combined with antimuscarinic (anticholinergic) drugs: atropine, glycopyrrolate
myasthenia gravis
-neuromuscular blockage from auto-immunity agains ACh receptor
-muscle weakness, oesophageal regurgitation, paralysis
sugammadex
-novel antagonist to rocuronium
-surround rocuronium rendering inactive
-no antimuscarinic needed
-new in human med
muscle relaxants: factors affecting neuromuscular blockade
-other drugs: anasthetics, antibiotics, anticholinesterases
-pathophysiological conditions: hepatic/renal impairment, age, temp
muscle relaxants: centrally acting
-benzodiazepams (BZPs): diazepam, midazolam
-guaifenesin (GGE)
guaifenesin (GGE)
-muscle relaxant (centrally acting)
-blocks impulse transmission at internuncial neurones within spinal cord & brain stem
-relaxes limb > respiratory muscles (no CV effects)
-mild sedation but no anasthesia
-uses: smooth induction of anasthesia in horses (Myolaxan) & cattle (dilute or haemolysis)
-irritant: IV catheter necessary
dantrolene
-treatment of malignant hyperthermia (eg. depolarizing NMBs: suxamethonium)
-direct action on skeletal muscle cell
-decrease Ca release from SR
-reduces force of contraction
-reflex > voluntary
-malignant hyperthermia more a pig problem
-SE: possible hepatotoxicity
muscle relaxants: centrally acting
-benzodiazepams (BZPs): diazepam, midazolam
-guaifenesin (GGE)
guaifenesin (GGE)
-muscle relaxant (centrally acting)
-blocks impulse transmission at internuncial neurones within spinal cord & brain stem
-relaxes limb > respiratory muscles (no CV effects)
-mild sedation but no anasthesia
-uses: smooth induction of anasthesia in horses (Myolaxan) & cattle (dilute or haemolysis)
-irritant: IV catheter necessary
dantrolene
-treatment of malignant hyperthermia (eg. depolarizing NMBs: suxamethonium)
-direct action on skeletal muscle cell
-decrease Ca release from SR
-reduces force of contraction
-reflex > voluntary
-malignant hyperthermia more a pig problem
-SE: possible hepatotoxicity
anaesthesia (terminology)
1. premedicant drugs: prior to general anaesthetic (typically a sedative-opioid combo)
2. induction drugs: acheive transition from consciousness to unconsciousness
3. maintenance drugs: maintain anaesthetic state
anaesthesia (definition)
-loss of feeling: general (whole body) & local
-unconsciousness with reduced sensitivity & response to stimuli
-3 components (triad): unconsciousness, analgesia, muscle relaxation
-combo of drugs safer than high dose of a single drug
anaesthesia (stages)
with increasing depression of CNS function:
1. voluntary movement: unconsciousness at end of stage 1
2. involuntary movement
3. surgical anaesthesia
4. medullary paralysis
(5.) death
anaesthesia: lipid theory
-potency directly related to increased lipid fluidity: change spatial relationship of membrane bilary components (eg. G proteins) causing receptor & effector to become unlinked
-not likely theory: temp affects fluidity w/o anaesthesia, both isomers of drug have equal fluidity but different anaesthetic properties
anaesthesia: protein theory
-GABA (inhibitory neurotransmitter in CNS) is much more responsive in presence of anaesthetic
-more likely than protein theory
general anaesthesia: effects on CVS & respiration
-decrease contractility of isolated heart preparations
-effects on CO & BP may vary
-cardia dysrrhythmia: heart more sensitive to catecholamines
-decreased respiration
-increased arterial Pco2
general anaesthesia: effects on nervous system
-inhibit conduction of action potentials: increased threshold
-inhibit transmission at synapses: decreased NT release, decreased action of NT, decreased excitability of post-synaptic cell
-brain regions: reticular formation (cortical arousal), hippocampus (short term memory)
anaesthesia (induction: advantages of IV over inhalation)
-short acting IV anaesthetic
-rapid smooth induction (minimal excitement)
-rapid protection of airway (inhalation takes longer)
-no environmental pollution
-disadvantages: IV access required
anaesthesia: ideal properties for IV agent (none exhibit all)
-stable on storage
-non-irritant to veins or perimuscular tissues
-rapid metabolism
-rapid/smooth emergence & recovery
-non-toxic
-minimal adverse CVS or respiratory effects
-good analgesic
-good muscle relaxant
-inexpensive
anaesthesia (IV agents: induction)
-barbiturates*:thiopentone, pentobarbitone
-propofol*
-imidazole derivatives: etomidate, metomidate
-dissociative agents: ketamine*, tiletamine
-steroid anaesthetics: alfaxalone*
thiopentone (mechanism)
-reversible depress activity of all excitable tissue
-enhance inhibitory action of GABA
-allosteric site: promotes GABA binding
-enlargement of GABA-induced chloride currents
barbiturates (pharmokinetics)
-thiopentone & pentobarbitone
-weak acids
->60% unionized (ionized form active): small pH shift to ionized
->80% plasma protein bound
-lipophilic so reaches brain easily
thiopentone (pharmokinetics)
-5 to 10 min of surgical anaesthisia: loss of consciousness in 20sec (fast distribution)
-can't top up: stores build up in fat (not suitable for maintenance or TIVA)
-effects may be enhanced if hypoproteinaemia (unbound)
-effects may be prolonged if emaciated (less fat for storage)
-metabolism: hepatic oxidation, conjugation, renal excretion
propofol
-enhanced GABA transmission
-as rapid as thiopentone
-short acting, smooth & rapid recovery
-suitable for TIVA (unlike thiopentone)
-oil at room temp (emulsion)
propofol (pharmicokinetics)
-large Vd (>3L/kg)
-rapid redistribution & metabolism/clearance (sulphate & glucuronide conjugation in liver & "another site") so short acting
-effects may be enhanced in hypoproteinaemia (less bound)
-NOT prolonged if: repeated IV doses, emaciated, hepatic dysfunction (metab at "other site")
-suitable for maintenance in dogs
-may be prolonged in cats
thiopentone (effects on central nervous system)
-rapid loss of consciousness without specific analgesia
-reduced cerebral metabolic rate & blood flow: decreased intracranial pressure
-anticonvulsant action
thiopentone (effects on CVS)
-transient fall in BP due to vasodilation & mild myocardial depression
-compensatory increase in HR
-care in shocked/hypovolaemic patients
-sensitization to arrhythmogenic action of catecholamines
thiopentone (effects on respiratory system)
-depression
-post induction apnoea not uncommon (not problem since usually intubated)
-laryngeal/bronchial reflexes only depressed by high dose (coughing/spasm)
thiopentone (other effects)
-tissue necrosis or skin sloughing if injected perivascularly (only give IV)
-engorgement of reticuloendothelial system with blood (esp. spleen)
thiopentone (clinical summary)
-IV induction agent (barbiturate)
-caution in: site hounds & emaciated patients, shocked & hypovolaemic patients, pre-existing arrhythmia, if vascular accss not secure
-5 to 10 min of surgical anasthesia
-vet preps no longer available (tho still licensed): may disappear from use
thiopentone (mechanism)
-reversible depress activity of all excitable tissue
-enhance inhibitory action of GABA
-allosteric site: promotes GABA binding
-enlargement of GABA-induced chloride currents
barbiturates (pharmokinetics)
-thiopentone & pentobarbitone
-weak acids
->60% unionized (ionized form active): small pH shift to ionized
->80% plasma protein bound
-lipophilic so reaches brain easily
thiopentone (pharmokinetics)
-5 to 10 min of surgical anaesthisia: loss of consciousness in 20sec (fast distribution)
-can't top up: stores build up in fat (not suitable for maintenance or TIVA)
-effects may be enhanced if hypoproteinaemia (unbound)
-effects may be prolonged if emaciated (less fat for storage)
-metabolism: hepatic oxidation, conjugation, renal excretion
propofol
-enhanced GABA transmission
-as rapid as thiopentone
-short acting, smooth & rapid recovery
-suitable for TIVA (unlike thiopentone)
-oil at room temp (emulsion)
propofol (pharmicokinetics)
-large Vd (>3L/kg)
-rapid redistribution & metabolism/clearance (sulphate & glucuronide conjugation in liver & "another site") so short acting
-effects may be enhanced in hypoproteinaemia (less bound)
-NOT prolonged if: repeated IV doses, emaciated, hepatic dysfunction (metab at "other site")
-suitable for maintenance in dogs
-may be prolonged in cats
thiopentone (effects on central nervous system)
-rapid loss of consciousness without specific analgesia
-reduced cerebral metabolic rate & blood flow: decreased intracranial pressure (ok for head injuries)
-anticonvulsant action
thiopentone (effects on CVS)
-transient fall in BP due to vasodilation & mild myocardial depression
-compensatory increase in HR
-care in shocked/hypovolaemic patients
-sensitization to arrhythmogenic action of catecholamines
thiopentone (effects on respiratory system)
-depression
-post induction apnoea not uncommon (tho not a problem b/c usually intubated)
-laryngeal/bronchial reflexes only depressed by high doses (less effect than others)
thiopentone (other effects)
-tissue necrosis/skin sloughing if injected perivascularly (only IV admin)
-engorgement of reticuloendothelial system with blood (esp. spleen)
thiopentone (clinical summary)
-IV induction agent (barbiturate)
-5 to 10 min of surgical anasthesia
-caution in: sight hounds & emaciated, shocked & hypovolaemic, pre-existing arrhythmia, where vascular access not secure
-vet prep no longer available (tho still licensed): may disappear from vet use
pentobarbitone
-barbiturate
-less plasma protein bound & lower lipid solubility than thiopentone
-slow onset (b/c low lipid solubility): beware not to overdose
-respiratory depression more pronounced
-licensed only for euthanasia (tho used by some for certain situations)
-30 to 40 min of surgical anaesthesia
-NOT recommended as an induction agent
propofol (effects on central nervous system)
-rapid loss of conscousness without specific analgesia
-reduced cerebral metabolic rate & blood floow: decreased intracranial pressure (ok for head trauma)
-anticonvulsant action
-generally similar to thiopentone
propofol (effects on CVS)
-transienet fall in BP due to vasodilation & mild mycardial depression (like thiopentone)
-HR usually unchanged (unlike thiopentone)
-not inherently arrhythmogenic: does not lower threshold for catecholamine (unlike thiopentone)
-care in shocked/hypovolaemic patients
-generally better choice for dysrrhythmic patients
propofol (effects on respiratory system & other organs)
-post induction apnoea not uncommon (ok b/c usually intubated)
-not irritant if injected perivascularaly (unlike thiopentone)
-occasional muscle twitching/rigidity
-repeated use can cause oxidative damage (Heinz body anaemia)
propofol (clinical summary)
-IV induction agent
-maintenance agent in dogs
-licensed in dogs & cats
-caution in: shocked / hypovolaemic, cats with hepatic dysfunction, cats requiring repeat anaesthetics
imidazole derivatives
-induction agents
-etomidate
-metomidate
etomidate
-induction agent (imidazole derivative)
-potent, short acting non-barbiturate
-similar action to thiopentone: enhance inhibitory action of GABA
-rapid induction & recovery
-poor quality of anaesthesia: muscle hypertonicity, tremor, panting, excitability
dissociative anaesthetics
-induction agents
-ketamine & tiletamine
-different "quality" of anaesthesia
-sensory loss with analgesia
-increased muscle tone
-eyes open +/- slow mystagmus (makes difficult to judge depth)
-active reflexes (incl. laryngeal & pharyngeal)
-less profound CVS & respiratory depression
ketamine (effects on CNS)
-loss of consciousness with analgesia
-increased cereberal oxygen consumptoin & blood flow: increased intracranial pressure (not good for head trauma)
-convulsions in dogs/horses if used as sole agent
-hallucinations / emergence delirium (recover not as smooth)
ketamine (effects on...)
-musculoskeletel: tone increased
-CVS: mild increases in BP, HR, & CO (less side effects)
-respiration: minimal effect
ketamine (clinical uses)
-never sole agent for anaesthesia: need drug to counter hypertonicity
-dogs, cats, horses, primates
-induction agent: combine with benzodiazepine (IV)
-induction/maintanence (30-45min): combine with alpha-2 agonist (IV)
-analgesic: much lower doses given IM or by IV infusion
steroid anaesthetics
alfoxalone
alfoxalone (effects on...)
-CNS (like propofol & thiopentone): rapid loss of consciousness w/o specific analgesia; reduced cerebral metabolic rate, blood flow & intracranial pressure
-CVS: mild hypotension
-respiratory: apnoea rare (advantage)
alfaxalone (clinical use)
-IV induction (steroid anaesthetic)
-maintenance for short anesthesia in dogs (cats?)
-fast metabolism: does not accumulate
-licensed in dogs & cats: Alfaxan
-little tissue toxicity if injected perivascularly (can be given IM but less reliable)
Total Intravenous Anaesthesia (TIVA)
-anaesthesia maintained by intermittent boluses or continuous infusion (top up)
-easy to administer (minimal equipment)
-inhalational anaesthetics not suitable for some
-avoids risk to people administering (eg. no environmental pollution)
-pharmacokinetics are known
TIVA (agents)
-propofol: no analgesia, CVS & respiratory depression, caution in cats
-propofol + specific analgesic (ketamin, fentanyl, alpha-2 agonist)
-alfoxalone (?)
-"triple drip": popular field anaesthesia for horses (alpha-2 agonist + GGE + ketamine)
anesthesia (maintenance)
-typically use inhalational anesthetic
-advantages: delivery/elimination depends on ventilation (rapid adjustment)
-disadvantages: equipment required (entotracheal tube, carrier gass: O2, vaporiser, breathing system, etc), environmental pollution
inhalational anaesthetics (pharmacokinetics)
-speed of induction/recovery dependent on:
1. blood:gas partition coefficient (low b:g gives rapid induction/recover because need few molecules to reach equilibrium)
2. oil:gas partition coefficient (high o:g gives high potency)
3. physiological: alveolar ventilation rate & CO
-metab: elimination primarily by exhalation, metabolism in liver depends on agent, potential production of toxic metabolites
minimum alveolar concentration (MAC)
-minimum alveolar concentration at which 50% of patients will not respond to a particular stiumlus
-compares potency of different inhalational anaesthetics: the lower the MAC value the more potent
-used as starting point for dose (values are for dogs so must adjust for other species)
-factors: species, age (MAC lower in geriatrics & neonates), pregnancy (MAC reduced), hypothermia (MAC reduced), drugs (premedicants can greatly reduce MAC)
inhalational anaesthetic (ideal properties)
-stable on storage
-easily vaporized (liquid at room temp)
-nonflammable
-non-irritant to airways & not pungent
-compatible with equipment (incl. soda lime)
-undergoes minimum metabolism (non-toxic)
-low blood:gas partition coefficient
-minimal adverse CVS or respiratory effects
-good analgesic & muscle relaxant
anesthetics (inhalational)
-halothane
-isoflurane
-desflurane
-sevoflurane
-nitrous oxide (gas)
halothane (physical properties)
-inhalational maintenance anaesthetic
-MAC(%) = 0.9 (low so potent)
-blood:gas partition coefficient = 2.5 (reasonably low)
-oil:gas partition coefficient = 224
-vapor pressure (mmHg) = 244 (higher pressure the more easily vaporized)
-% metabolized = ~20 (high: bad)
halothane (effects on CNS)
-dose dependent depression w/o specific analgesia
-reduced metabolic O2 consumption
-potent cerebral vasodilator: increased intracranial pressure (no good for head trauma)
halothane (effects on CNS & CVS)
1. CVS:
-hypotension (depression of myocardial contractility & SV)
-minimal change in peripheral resistance
-sensitizes myocardium to catecholamines
2. respiratory: dose dependent depression (apnoea at ~2x MAC)
halothane (effects on...)
-liver: mild transient hepatic dysfunction due to hypoxia (b/c decreased CO)
-kidney: reduced blood flow (decreased CO)
-muscle: moderate relaxation (potentiates NMBs), uterine relaxation, malignant hyperthermia (esp. pigs)
halothane (clinical summary)
-licensed in non-food producing animals (none of the volatiles licensed in FPAs)
-potent
-moderate speed of induction/recovery
-relatively high rate of metabolism
-significant myocardial depression
-potentially arrhythmogenic
-decreasing in usage
isoflurane (physical properties)
-MAC (%) = 1.3 (higher than halothane but still potent)
-blood:gass partition coefficient = 1.5 (relatively high)
-old:gas partition coefficient = 91 (lower than halothane)
-vapor pressure = 240 (easily vaporized)
-% metabolized: 0.2 (very low: inert)
isoflurane (effects on CNS)
-dose dependent depression w/o specific analgesia
-reduces metabolic oxygen consumption (no convulsive activity)
-less cerebral vasodilation than halothane (still potential increase in intracranial pressure)
-responsiveness to CO2 retained (CO2 potent vasodilator so can ventilate to lower CO2)
isoflurane (effects on CVS & respiratory)
-CVS: hypotension (CO maintained but peripheral resistance falls b/c vasodilation) - healthier than change in SV b/c CO maintained
-respiratory: dose dependent depression (> halothane)
isoflurane (effects on...)
-liver: hepatic dysfunction less likely (cf. halothane), minimal metabolism, hepatic blood flow better maintained
-kidney: reduced blood flow (still better than halothane b/c better CO)
-muscle: good relaxation (potentiates NMBs) & uterine relaxation, trigger for malignant hyperthermia (esp. pigs)
isoflurane (clinical summary)
evaluation (cf. halothane):
-licensed in non-food producing animals
-faster induction/recovery (less soluble in blood)
-pungent odor (not ideal for induction)
-minimal metabolism
-CO better maintained
-less arrhythmogenic
-has largely replace halothane (comparable price)
sevoflurane (physical properties)
-MAC (%) = 2.3 (less potent)
-blod:gas partition coefficient = 0.69 (lower so faster)
-oil:gas partition coefficient = 47 (lower so less potent)
-vapor pressure = 170 (lower but ok)
-% metabolized = 3 (pretty low)
sevoflurane (effects on...)
-mostly similar to isoflurane
-CVS: increased HR less likely (cf. isoflurane & desflurane)
-respiratory: minimal airway irritation (pleasant odor)
-kidney (theoretical only b/c metab low): metabolite potential nephrotoxic, reacts with soda lime (CO2 absorbant in equipment) - caution if renal problems
sevoflurane (clinical summary)
-licensed in dogs
-rapid induction, recovery, change of depth
-pleasant odor & minimal airway irritation
-low rate of metabolism
-caution in patients with renal insufficiency
-gaining popularity despite higher cost
desflurane (physical properties)
-MAC (%) = 7.2 (significantly less potent)
-blood:gas partition coefficient = 0.42 (very high so slow)
-oil:gas partition coefficient = 970 (very high so potent)
-vapor pressure = 23 (very low so not very volatile)
-% metabolized - 50 (very high)
-metabolized to potentially nephrotoxic F-
nitrous oxide (physical properties)
-MAC (%) = >100 (very high so not very potent)
-blood:gas partition coefficient = 0.47 (pretty low so fast)
-oil:gas partition coefficient = 1.4 (low so not potent)
-% metabolized = <0.01 (very low)
nitrous oxide (effects on...)
-organs: generally minimal
-CNS: analgesia (NMDA receptor antagonist)
-SE: nausea/vomiting (humans), prolonged exposure inactivates vit B12 dependent enzymes (bone marrow suppression: anaemia & leucopenia; defective myelination: polyneuropathy), teratogenic
nitrous oxide (clinical uses)
-adjunct to anaesthesia (not sole agent): 50-70% N2O has sparing effect on volatile agent (must have minimum 30% O2)
-speed induction: high volume uptake of N2O has concentrating effect on volatile in alveoli (known as "second gas effect")
-diffusion hypoxia @ end of anaesthesia: N2O diffuses back into alveoli lowering arterial Po2 (100% O2 for 10min after N2O turned off)
-caution: expands gas filled cavities (contraindicated in ruminants, gastric dilation & volvulus, pneumothorax, etc
anesthesia (mask induction)
sevoflurane most suitable but inhalants not typically used for induction