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287 Cards in this Set
- Front
- Back
targets for G-proteins
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-adenylate cyclase/cAMP system
-phospholipase C/inositol phosphate system -regulation of ion channels |
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cyclic AMP
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-alpha subunit activate adenylate cyclase
-adenylate cyclase hydrolyzes ATP to cAMP (secondary messenger) -cAMP activates protein kinase A -cascade response: phosphorylation (response short lived) |
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IP3, DAG, & calcium
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-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 |
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regulation of ion channels
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-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 |
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drug specificity
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-binding site specificity
-ligand specific -biological specificity -no drug has complete specificity (side effects) |
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EC50
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-concentration that produces 50% of maximal response
-measure of efficacy: the lower the EC50 the more potent the drug |
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Kd
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-concentration at which 50% of receptors are filled
-measure of binding affinity: the lower the Kd the higher the binding affinity |
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spare receptors
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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"
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ED50
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-dose required to be effective in 50% of population
-varies depending on application (eg. asparin for headache vs chronic arthritis) |
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LD50
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dose that will be lethal in 50% of population
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therapeutic index
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-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) |
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affinity vs efficacy
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-affinity: ability to bind to receptor
-efficacy: ability, once bound, to elicit effect |
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alterations in drug receptor activity
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-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) |
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pH & ion trapping
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-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) |
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plasma protein binding
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-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 |
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partition into body fat (& othe tissues)
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-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) |
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body fluid compartments
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-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 |
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blood brain barrier (BBB)
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-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 |
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volume of distribution (Vd)
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-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. |
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metabolism (phase I vs phase II)
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-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 |
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first pass metabolism
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-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 |
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microsomal enzymes
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-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 |
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drug excretion
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-glomerular filtration
-tubular secretion & reabsorption -tubular diffusion -clearance -biliary excretion & enterohepatic circulation |
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clearance
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-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 |
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renal clearance
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-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 |
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biliary excretion & enterohepatic circulation
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-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) |
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single compartment pharmacokinetics
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-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 |
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zero order kinetics
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-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 |
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first order kinetics
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-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 |
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half life of elimination
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-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 |
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loading dose (LD)
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-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 |
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bioavailability
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-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 |
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two compartment model of pharacokinetics
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-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 |
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veterinary drug residues
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-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 |
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residues (consquences)
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-direct toxicity (allergy, etc)
-carcinogenicity -mutagenicity -teratogenicity (congenital malformation) |
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how do drugs act on nerve terminal?
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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 |
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alpha-1 adrenoreceptors
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-stimulate activity (increase IP3 & DAG --> increase Ca from SR)
-vascular smooth muscle: vasoconstriction -myocardium: postive inotropic effect -prostatic smooth muscle: contraction |
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alpha-2 adreonreceptors
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-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 |
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beta-1 adrenoreceptors
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-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) |
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beta-2 adrenoreceptors
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-stimulatory & inhibitory (increase or decrease cAMP)
-smooth muscle: relaxation (bronchodilation, vasodilation in skeletal muscle) -stabilize respiratory mast cells |
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sympathomimetics
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-mimic SNS (stimulatory)
-non selective agonists (alpha & beta) -selective agonists (eg. beta-1 only) |
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sympatholytics
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-antagonists (SNS)
-non selective (alpha & beta) -selective (eg. alpha-1 only) |
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non-selective agonists (SNS)
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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 |
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ephedrine
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-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 |
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dopamine
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-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) |
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non-selective beta agonists in SNS
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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) |
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non-selective alpha agonists in SNS
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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) |
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beta-1 agonists (selective)
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-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) |
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beta-2 agonists (selective)
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-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 |
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alpha-1 agonists (selective)
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-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 |
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alpha-2 agonists (selective)
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-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 |
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non-selective alpha antagonists in SNS
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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 |
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non-selective beta antagonist in SNS
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-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) |
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alpha-1 antagonist (selective)
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-smooth muscle relaxation: vasodilation & relaxation of urinary sphincter
PRAZOSIN: urinary retention -SE: hypotension TERAZOSIN & ALFUZASIN: treatment of BPH in man |
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alpha-2 antagonist (selective)
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-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) |
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beta-1 antagonists (selective)
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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) |
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nicotinic receptors (PNS)
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-ligand gated ion channels
-increase permeability to Na & K (stimulatory) -3 types (differentially sensitive): 1. skeletal muscle (Nm) 2. ganglia (Ng) 3. brain (Nn) |
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muscarinic receptors (PNS)
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-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) |
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Nm receptor agonists
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-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) |
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non-specific muscarinic agonists
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-parasympathomimetics (not commonly used in vet med)
-2 groups: 1. synthetic choline esters (similar to ACh) & ACh 2. naturally occurring cholinomimetic alkaloids (plant derived) |
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non-specific muscarinic agonists (choline esters)
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BETHANECHOL
-M selective -GI stimulant via M3 receptors -used to increase bladder tone in urinary retention CARBACHOL -topically to induce miosis (glaucoma) |
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non-specific muscarinic agonists (cholinomimetic alkaloids)
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PILOCARPINE
-glaucoma treatment: topical to induce miosis ARECOLINE -was used against internal parasites in dogs (increase GI motility) |
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anticholinesterase agents (AChEI)
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-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 |
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anticholinesterase agents (irreversible AChEI)
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-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 |
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anticholinesterase agents (reversible AChEI)
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-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) |
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anticholinesterase agents (AChEI toxicity)
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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) |
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muscarinic antagonists (parasympatholytics)
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-competetive: similar structure to ACh
-ATROPINE -SCOPOLAMINE (hyoscine) -GLYCOPYRRONIUM BROMIDE (Robinul) -IPRATOPIUM BROMIDE (Atrovent) -PROPANTHELINE BROMIDE -CYCLOPENTOLATE -TROPICAMIDE |
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atropine
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-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 |
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scopolamine
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-muscarinic antagonist
-naturally occurring -used for drying secretions -contained in antispasmodic Buscopan together with dipyrone/meamizole for spasmodic colic -antiemetic properties |
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glycopyrronium bromide
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-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 |
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muscarinic antagonists (others)
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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) |
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nicotinic antagonists (Ng)
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-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 |
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nicotinic antagonists (Nm receptor)
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-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 |
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pharmacological manipulaton of ANS (eye)
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-glaucoma: cholomimetics (stimulate PNS), beta blockers
-mydriasis for exams: muscarinic antagonists, alpha-1 agonists |
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pharmacological manipulaton of ANS (lung)
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-bronchodilation: beta-2 agonists, muscarinic antagonists
-bronchoconstriction: muscarinic agonists |
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pharmacological manipulaton of ANS (heart)
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-muscarinic & beta-1
-increase HR, contractility & CO: sympathetic agonists, beta-1 agonists -increase HR: muscarinic antagonists -decrease HR, contractility & CO: beta-1 antagonists |
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pharmacological manipulaton of ANS (GI)
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-decrease motility & secretion: sympathomimetics, muscarinic antagonists
-increase motility & secretion: muscarinic agonists |
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pharmacological manipulaton of ANS (bladder)
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-increase bladder function (non-obstructive disease): muscarinic agonists, alpha agonists
-urinary incontinence (increase smooth m. tone): muscarinic antagonists, alpha antagonists |
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pain
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-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 |
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nociceptor innervation (fibres)
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C fibres: small & slow (dull pain)
A delta fibres: large & fast (sharp pain) |
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dorsal horn
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-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 |
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ascending pathways
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-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 |
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peripheral sensitization
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-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 |
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neuropathic pain
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-pain without external noxious cause
-pain without nociception |
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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) |
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local anasthetics (physiology)
|
reduce excitability by:
1. blocking Na channels* 2. activating K channels |
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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 |
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local anasthetics (side effects)
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-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
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-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 |
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Bupivacaine
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-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 |
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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 |
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Mepivacaine
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-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) |
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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 |
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opioids (endogenous ligands)
|
3 families with opioid activity (will compete for morphine binding):
1. enkephalins 2. endorphins 3. dynorphins |
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opioids (examples)
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-AGONISTS: morphine, pethidine, methadone, fentanyl, alfentanil, loperamide, codeine, dextro-proxyphene, etorphine
-PARTIAL AGONISTS: buprenorphine, butorphanol, nalbuphine -ANTAGONISTS: naloxone, diprenorphine |
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opioids (mechanism of action)
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-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) |
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opioids (CNS effects)
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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 |
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opioids (GIT effects)
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-via Ca channel: decrease ACh release
-increased tone & decreased motility (constipation) -increased water absorption b/c decreased rate of passage -constriction of biliary sphincter |
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opioids (other effects)
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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") |
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opioids (pharmokinetics)
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-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 |
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morphine
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-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 |
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pethidine
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-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 |
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fentanyl
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-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) |
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etorphine
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-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 |
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codeine (methyl morphine) phosphate
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-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 |
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tramadol
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-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 |
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buprenorphine
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-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 |
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butorphanol
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-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) |
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analgesia (sites of drug action)
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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) |
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analgesia (strategies)
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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) |
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diprenorphine
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-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) |
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naloxone
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-classic opioid antagonist (full): reverses all opioid effects
-rapid effect & short duration (30min - 2hr) -narcotic effects may reappear: may need to give repeated doses |
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opioid analgesics (others)
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-papaveretum: contains morphine (50%), papaverine, & codeine
-alfentanil -remifentanil: instant on/off (very short duration without accumulation) |
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NSAIDs (therapeutic actions)
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1. anti-inflammatory
2. analgesic 3. anti-pyretic: lower temperatur 4. anti-thrombotic: reduced platelet aggregation (reduces thromboxane) |
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NSAIDs (clinical uses)
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-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) |
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NSAIDs
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-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) |
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prostanoids
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-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 |
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leukotrienes (inflammation)
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-contract smooth muscle
-affects vascular permeability -strong attraction of polymorphonuclear leukocytes |
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cyclooxygenase (COX)
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-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? |
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NSAIDs (differential selectivity for COX-1 & COX-2)
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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 |
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NSAIDs (analgesic effects)
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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 |
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NSAIDs (anti-pyretic effects)
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-decrease PGE2 (COX-2 inhib) prevents increase temp associated with fever
-no effect on normal body temp |
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NSAIDs (anti-thrombotic effects)
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-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 |
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NSAIDs (anti-inflammatory effects)
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inhibit COX induction & release of prostanoids at site of inflammation to:
1. decrease vasodilator prostaglandins (reduces oedema) 2. reduces inflammatory response (prevent peripheral sensitization) |
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NSAIDs (anti-endotoxic action)
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-endotoxins are LPS generated by gram -ve bacteria
-damage WBCs & vascular endothelium thus releasing vasoactive mediators -NSAIDs prevent generation of vasoactive mediators during endotoxaemia |
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NSAIDs (pharmokinetics)
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-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 |
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NSAIDs (adverse effects)
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-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 |
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NSAIDs (contraindications)
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-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 |
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aspirin
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-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 |
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paracetamol (acetaminophen)
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-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) |
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phenylbutazone
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-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 |
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flunixin
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-NSAID: horses, cattle, pigs
-potent COX inhibitor (non-selective): anti-inflammatory & analgesic -GIT ulceration & nephrotoxicity in small mammals -IV, paste, granules |
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ketoprofen
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-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 |
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carprofen
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-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 |
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meloxicam
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-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 |
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tepoxalin
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-NSAID (new): dogs
-musculoskeletal inflammation/pain -dual COX & lipoxygenase (LOX) inhibitor: less PG & leukotreine (no asthma problem); less GIT ulceration |
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firocoxib
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-NSAID: dogs (newly licensed)
-osteoarthritis -COX-2 selective (most selective availble): improved GIT tolerance |
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sedation (drug classes)
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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) |
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tranqulizers
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-phenothiazines (eg. ACP)
-butyropherenones (pigs & small furries) |
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phenothiazines
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-tranquilizers
-acepromazine / acetlypromazine (ACP) -chlorpomazine, promazine, trimeprazine / alimemazine, promethazine |
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phenothiazines (physiology)
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-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 |
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phenothiazines (CV effects)
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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 |
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phenothiazines (respiratory effects)
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-generally minimal
-sedation may worsen degree of respiratory distress in dyspnoeic patients |
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phenothiazines (anti-emetic effect)
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-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) |
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phenothiazines (antihistamine action)
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-all drugs have some effect
-promethazine is most potent |
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phenothiazines (hypothermic effects)
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-due to peripheral vasodilation
-direct hypothermic effect -also lack of body movement |
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phenothiazines (effect on seizure threshold)
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-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 |
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phenothiazines (other effects)
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-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) |
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butyrophenones
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-tranquilizers (eg. ACP)
-mechanism: dopamine antagonists -CNS: sedative action + antiemetic properties (hallucinations, agiation, etc. in people) -CVS: some vasodilation & hypotension (alpha-1 adrenergic antagonism) |
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acepromazine (ACP)
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-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 |
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phenothiazines (clinical use)
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-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 |
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azeperone (Stresnil)
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-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 |
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alpha-2 adrenoreceptors
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-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 |
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alpha-2 adrenoceptor agonists (CNS)
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-sedative, analgesic, muscle releaxant: presynaptic decrease in NA release (decrease impulse transmission)
-decreased sympathetic drive (predominance of vagal drive: enhanced parasympathetic) |
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alpha-2 agonists (drugs: ratio of alph-2:alpha-1 selectivity)
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-metdetomidine 1620:1
-detomidine 260:1 -xylazine 160:1 NB: not totally selective for alpha-2 |
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alpha-2 receptor subtypes
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alpha-2a: presynaptic (sympathetic drive)
alpha-2b: postsynaptic (direct vasoconstriction) |
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alpha-2 agonists (blood pressure)
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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 |
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alpha-2 agonists (use of anticholinergics)
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-alpha-2s decrease CO & increase CVP
-anticholinergics to prevent/treat alpha-2 induced bradycardia (blocking enhanced vagal tone) |
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alpha-2 agonists (analgesic effects)
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-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 |
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alpha-2 agonists (CV effects)
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-hypertension --> hypotension / normotension
-marked bradycardia |
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alpha-2 agonists (respiratory effects)
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-mild to moderate depression: cat, dog, horse
-ruminants more severe: arterial hypoxaemia (mismatch of pulmonary perfusion & ventilation) |
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alpha-2 agonists (GIT effects)
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-vomiting in some species
-GIT motility is depressed -increased gut transit time (ACh inhibition) |
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alpha-2 agonists (endocrine effects)
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-inhibition of ADH: diuresis
-inhibition of insulin release: hyperglycaemia |
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alpha-2 agonists (other effects)
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-uterine contraction: dose dependent (inhibited at low doses & stimulated at higher doses)
-marked anasthetic sparing effect: can use less opioid & anasthesia |
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alpha-2 agonists (uses)
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-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) |
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alpha-2 agonists (drugs)
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-xylazin
-detomidine (horses & cattle?) -romifidine (dogs, cats, horses) -medetomidine (dogs, cats) -dexmedetomidine (racemic mixture of active & inactive) |
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xylazine (Rompun)
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-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 |
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detomidine (Domosedan)
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-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 |
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romifidine (Sedivet)
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-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) |
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medetomidine (Domitor)
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-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) |
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alpha-2 agonists (licensed agents)
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-dog & cat: xylazine, medetomidine, romifidine
-cattle: xylazine, detomidine -horses: xylazine, detomidine, romifidine* |
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alpha-2 antagonists
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-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 |
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benzodiazepines (BZPs)
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-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) |
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benzodiazepines (BZPs): pharmacokinetics
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-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) |
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benzodiazepines (BZPs): toxicity
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-acute: less dangerous than other hypnotics
-little CVS & respiratory effects |
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benzodiazepines (BZPs): uses
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-good sedation in sick & elderly
-paradoxical excitement in healthy patients |
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diazepam (Valium)
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-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) |
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midazolam (hynovel)
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-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 |
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benzodiazepines (BZPs): uses
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-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) |
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benzodiazepine (BZPs) antagonists
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flumazenil:
-antagonism of diazepam/midazolam -not licensed in animals -widely used in human med |
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neuroleptanalgesia
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-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) |
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Hypnorm
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-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) |
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Immobilon
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-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) |
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Immobilon (antagonism)
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-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 |
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muscle relaxants (use)
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-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 |
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muscle relaxation (approaches)
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-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 |
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muscle relaxants (interference of transmission at NMJ)
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-inhibit ACh synthesis
-inhibit ACh release -interfere with post synaptic action of Ach*: NMBs (non-depolarizing & depolarizing) |
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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 |
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muscle relaxants (inhibition of ACh release)
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-local anasthetics block nerve impulse
-magnesium ions & aminoglycosides block Ca entry -botulinum toxin (Clostridium botulinum): Botox -beta-bungarotoxin (snake venom) |
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muscle relants: neuromuscular blockers (NMBs)
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-interfere with post-synaptic action of ACh:
1. non-depolarizing: tubocurarine, gallamine, pancuronium, vecuronium, atracurium, rocuronium 2. depolarizing: suxamethonium |
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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) |
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muscle relaxants: non-depolarizing NMBs (effects)
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-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 |
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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) |
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muscle relaxants: non-depolarizing NMBs (groups)
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-aminosteroids (-onium): panacuronium, vecuronium, rocuronium)
-benzylisopuinolines: atracurium, cisatracurium, mivacurium |
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tubocurarine
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-muscle relaxant (non-depolarizing NMB)
-histamine release: hypotension, bronchoconstriction (massive effects) -ganglion block -side effects too great for use |
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pancuronium
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-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) |
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vecuronium
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-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 |
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rocuronium
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-muscle relaxant (non-depolarizing NMB)
-fast onset (<2min) -moderate duration (<30min) -stable haemodynamics (occasional mild tachycardia in dogs -designed to facilitate intubation after induction |
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atracurium
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-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 |
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cisatracurium (Nimbex)
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-most potent isomer of atracurium
-no histamine release -less laudanosine production |
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mivacurium (Mivacron)
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-short acting in man & cat but not dog
-partially metabolized by plasma cholinesterase |
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muscle relaxants (NMBs: practical use)
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-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 |
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muscle relaxant (depolarizing NMBs)
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-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 |
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muscle relaxant (depolarizing NMBs: phases)
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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 |
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muscle relaxant (depolarizing NMBs: side effects)
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-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 |
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suxamethonium (succinylcholine)
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-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) |
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muscle relaxants (NMBs: uses)
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-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) |
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muscle relaxant (NMBs: recovering from NM blockade)
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-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 |
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muscle relaxant (NMBs: anticholinesterases for reversal)
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-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 |
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myasthenia gravis
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-neuromuscular blockage from auto-immunity agains ACh receptor
-muscle weakness, oesophageal regurgitation, paralysis |
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sugammadex
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-novel antagonist to rocuronium
-surround rocuronium rendering inactive -no antimuscarinic needed -new in human med |
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muscle relaxants: factors affecting neuromuscular blockade
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-other drugs: anasthetics, antibiotics, anticholinesterases
-pathophysiological conditions: hepatic/renal impairment, age, temp |
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muscle relaxants: centrally acting
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-benzodiazepams (BZPs): diazepam, midazolam
-guaifenesin (GGE) |
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guaifenesin (GGE)
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-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 |
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dantrolene
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-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 |
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muscle relaxants: centrally acting
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-benzodiazepams (BZPs): diazepam, midazolam
-guaifenesin (GGE) |
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guaifenesin (GGE)
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-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 |
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dantrolene
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-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 |
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anaesthesia (terminology)
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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 |
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anaesthesia (definition)
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-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 |
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anaesthesia (stages)
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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 |
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anaesthesia: lipid theory
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-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 |
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anaesthesia: protein theory
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-GABA (inhibitory neurotransmitter in CNS) is much more responsive in presence of anaesthetic
-more likely than protein theory |
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general anaesthesia: effects on CVS & respiration
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-decrease contractility of isolated heart preparations
-effects on CO & BP may vary -cardia dysrrhythmia: heart more sensitive to catecholamines -decreased respiration -increased arterial Pco2 |
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general anaesthesia: effects on nervous system
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-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) |
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anaesthesia (induction: advantages of IV over inhalation)
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-short acting IV anaesthetic
-rapid smooth induction (minimal excitement) -rapid protection of airway (inhalation takes longer) -no environmental pollution -disadvantages: IV access required |
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anaesthesia: ideal properties for IV agent (none exhibit all)
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-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 |
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anaesthesia (IV agents: induction)
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-barbiturates*:thiopentone, pentobarbitone
-propofol* -imidazole derivatives: etomidate, metomidate -dissociative agents: ketamine*, tiletamine -steroid anaesthetics: alfaxalone* |
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thiopentone (mechanism)
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-reversible depress activity of all excitable tissue
-enhance inhibitory action of GABA -allosteric site: promotes GABA binding -enlargement of GABA-induced chloride currents |
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barbiturates (pharmokinetics)
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-thiopentone & pentobarbitone
-weak acids ->60% unionized (ionized form active): small pH shift to ionized ->80% plasma protein bound -lipophilic so reaches brain easily |
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thiopentone (pharmokinetics)
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-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 |
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propofol
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-enhanced GABA transmission
-as rapid as thiopentone -short acting, smooth & rapid recovery -suitable for TIVA (unlike thiopentone) -oil at room temp (emulsion) |
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propofol (pharmicokinetics)
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-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 |
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thiopentone (effects on central nervous system)
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-rapid loss of consciousness without specific analgesia
-reduced cerebral metabolic rate & blood flow: decreased intracranial pressure -anticonvulsant action |
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thiopentone (effects on CVS)
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-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 |
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thiopentone (effects on respiratory system)
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-depression
-post induction apnoea not uncommon (not problem since usually intubated) -laryngeal/bronchial reflexes only depressed by high dose (coughing/spasm) |
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thiopentone (other effects)
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-tissue necrosis or skin sloughing if injected perivascularly (only give IV)
-engorgement of reticuloendothelial system with blood (esp. spleen) |
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thiopentone (clinical summary)
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-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 |
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thiopentone (mechanism)
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-reversible depress activity of all excitable tissue
-enhance inhibitory action of GABA -allosteric site: promotes GABA binding -enlargement of GABA-induced chloride currents |
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barbiturates (pharmokinetics)
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-thiopentone & pentobarbitone
-weak acids ->60% unionized (ionized form active): small pH shift to ionized ->80% plasma protein bound -lipophilic so reaches brain easily |
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thiopentone (pharmokinetics)
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-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 |
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propofol
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-enhanced GABA transmission
-as rapid as thiopentone -short acting, smooth & rapid recovery -suitable for TIVA (unlike thiopentone) -oil at room temp (emulsion) |
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propofol (pharmicokinetics)
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-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 |
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thiopentone (effects on central nervous system)
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-rapid loss of consciousness without specific analgesia
-reduced cerebral metabolic rate & blood flow: decreased intracranial pressure (ok for head injuries) -anticonvulsant action |
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thiopentone (effects on CVS)
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-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 |
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thiopentone (effects on respiratory system)
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-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) |
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thiopentone (other effects)
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-tissue necrosis/skin sloughing if injected perivascularly (only IV admin)
-engorgement of reticuloendothelial system with blood (esp. spleen) |
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thiopentone (clinical summary)
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-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 |
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pentobarbitone
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-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 |
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propofol (effects on central nervous system)
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-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 |
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propofol (effects on CVS)
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-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 |
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propofol (effects on respiratory system & other organs)
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-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) |
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propofol (clinical summary)
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-IV induction agent
-maintenance agent in dogs -licensed in dogs & cats -caution in: shocked / hypovolaemic, cats with hepatic dysfunction, cats requiring repeat anaesthetics |
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imidazole derivatives
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-induction agents
-etomidate -metomidate |
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etomidate
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-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 |
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dissociative anaesthetics
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-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 |
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ketamine (effects on CNS)
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-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) |
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ketamine (effects on...)
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-musculoskeletel: tone increased
-CVS: mild increases in BP, HR, & CO (less side effects) -respiration: minimal effect |
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ketamine (clinical uses)
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-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 |
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steroid anaesthetics
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alfoxalone
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alfoxalone (effects on...)
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-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) |
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alfaxalone (clinical use)
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-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) |
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Total Intravenous Anaesthesia (TIVA)
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-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 |
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TIVA (agents)
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-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) |
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anesthesia (maintenance)
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-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 |
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inhalational anaesthetics (pharmacokinetics)
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-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 |
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minimum alveolar concentration (MAC)
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-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) |
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inhalational anaesthetic (ideal properties)
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-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 |
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anesthetics (inhalational)
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-halothane
-isoflurane -desflurane -sevoflurane -nitrous oxide (gas) |
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halothane (physical properties)
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-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) |
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halothane (effects on CNS)
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-dose dependent depression w/o specific analgesia
-reduced metabolic O2 consumption -potent cerebral vasodilator: increased intracranial pressure (no good for head trauma) |
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halothane (effects on CNS & CVS)
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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) |
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halothane (effects on...)
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-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) |
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halothane (clinical summary)
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-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 |
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isoflurane (physical properties)
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-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) |
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isoflurane (effects on CNS)
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-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) |
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isoflurane (effects on CVS & respiratory)
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-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) |
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isoflurane (effects on...)
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-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) |
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isoflurane (clinical summary)
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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) |
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sevoflurane (physical properties)
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-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) |
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sevoflurane (effects on...)
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-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 |
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sevoflurane (clinical summary)
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-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 |
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desflurane (physical properties)
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-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- |
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nitrous oxide (physical properties)
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-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) |
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nitrous oxide (effects on...)
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-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 |
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nitrous oxide (clinical uses)
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-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 |
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anesthesia (mask induction)
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sevoflurane most suitable but inhalants not typically used for induction
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