Intravenous anaesthetic agents

Classification rapid acting barbiturates methohexitone, thiopentone imidazole derivatives etomidate hindered phenols propofol steroids althesin, pregnanolone eugenols propanidid slower acting benzodiazepines diazepam, midazolam arylcycloalkylamine derivatives ketamine opioids large dose fentanyl butyrophenones droperidol imidazole derivatives dexmedetomidine General properties high lipid solubility, poor water solubility at physiological pH most are weak acids (except etomidate, ketamine, dexmedetomidine) best modelled using a 3 compartment model low initial volume of distribution V1 (0.1-0.2 L/kg), except ketamine 1L/kg action terminated by distribution to VD of 15/L/kg, over the next 5 minutes most are extensively protein bound part of their activity is mediated by GABAA receptors (except ketamine and dexmedetomidine) myocardial depressants, with an addtional hypotensive effect due to vasodilation most will cause dose related respiratory depression (ketamine less than the others) most are anticonvulsant, (except etomidate or methohexitone) most reduce ICP, CBF and CMRO2, but not ketamine hepatic metabolism BARBITURATES Barbituric acid 2,4,6-tri-oxo-hexa-hydropyrimidine the condensation of urea and malonic acid barbituric acid and water barbituric acid itself lacks central depressant activity

Tautomerism the condition, quality, or relation of metameric substances, or their respective derivatives, which are more or less interchangeable, according as one form or the other is the more stable. the lactam and the lactim compounds exhibit tautomerism metameric different arrangement of the same constituents in the molecule (methyl ether and ethyl alcohol are metameric compounds) Structure activity - alkyl or aryl groups at C5 confers sedative-hypnotic activity increase in the length of one, or both the alkyl side chains up (to 5-6 carbon atoms) increases hypnotic potency above this number, potency is reduced and convulsant properties may result oxidation of radicals (to alcohols, ketones, phenols or carboxylic acids) terminates the activity the presence of a phenyl group at C5, or on one of the ring nitrogens confers anticonvulsant activity (eg. phenobarbital) Structure activity substitution at C2 oxybarbiturates (O=C) thiobarbiturates (S=C) higher lipid solubility, producing more rapid onset and shorter duration of action than oxybarbiturate

carbonyl group at position 2 takes on acidic character because of lactam (keto) - lactim (enol) tautomerization

Structure activity - methyl or ethyl substitution at N1 increases lipid solubility rapid onset shortens duration of action rapid recovery methylated oxybarbiturates (methohexitone), methylated thiobarbiturate subsequent demethylation may occur resulting in a longer acting metabolite these compound have a high incidence of excitatory phenomena tremor, increased muscle tone, involuntary movements Structural activity lipid solubility in general, structural changes which increase lipophilicity (thiobarbiturate, methyl or ethyl substitution at N1), increase hypnotic potency fast on-fast off rapid onset shorter duration of action rapid recovery accelerate metabolic degradation

Structure activity stereospecificity compounds possessing asymmetrical carbon atoms all have side chains l-isomers are twice as potentcompared to d-isomers despite similar access to the CNS methohexital has four stereoisomers due to an asymmetric centre at C5 the -l-isomer is 4 times as potent as the -lisomer, however also produces excessive motor activity, and the marketed solution is a racemic mixture of the -dl isomers Mechanism of action GABAA receptor complex is the major site of barbiturate action Cl- conductance binding to the GABAA receptor complex, decreasing rate of GABA dissociation, prolonging duration of GABA activated Clchannel opening direct activation of Cl- channel at higher concentrations (GABA-mimetic) Ca++ conductance decreases Ca++ dependent release of neurotransmitters depresses Ca++ dependent action potentials + conductance Na inhibit the function of voltage-dependent Na+ channel K+ conductance at higher concentrations, voltage-dependent K+ conductance is reduced mesencephalic ascending reticular activating system (ARAS) is sensitive to the drugs action and the effects are stereospecific barbiturates preferentially suppress polysynaptic responses inhibition is postsynaptic in supraspinal (cortical, diencephalic and cerebellar) regions presynaptic in the spinal cord mutiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anaesthesia more pronounced central depressant effects compared to benzodiazepines

GABAA receptor pentameric structure 5 protein subunits arranged in a circle forming an Clchannel that remains closed until GABA binds to the recognition site permutations of 6 subunit classes 1-6,1-4,14,,, each subunit has 4 transmembrane (4TM) domains M1-4 M2 and M3 have intraluminal sites for binding of anaesthetics, M3 has a binding site for alcohol anaesthetic site is near the extracellular side of the membrane GABAA receptors in different areas of the CNS contain different combinations of the essential subunits conferring different pharmacologic properties on GABAA subtypes stimulation by GABA results in opening of a chloride channel influx of Clhyperpolarisation and inhibition of postsynaptic cell 5 binding sites at extracellular end of the channel GABA binding site benzodiazepine binding site inside the Cl- channel barbiturate binding site steroid binding site picrotoxinin binding site specific GABAA agonist - muscimol specific GABAA antagonist - bicuculline Pharmacokinetics barbiturates are weak acids thiopentone pKa 7.6, 60% unionised at pH 7.4 methohexitone pKa 7.9, ~ 39% unionised at pH = 7.4 Onset of action the latency of onset determined by the rapidity with which they cross the BBB dependent upon lipid solubility increased with thiobarbiturate, and methyl or ethyl substitution at N1 degree of ionization with relatively acidic medium (blood, ECF, acidaemia), increase unionised fraction, increase transfer into brain ionization also affects renal excretion increased ionization decreases backdiffusion basis of forced alkaline diuresis in the management of overdosage loading dose (Ficks Law of Passive Diffusion) lipid solubility thiopentone highly lipid soluble relatively unionized at plasma pH equilibrates with the brain rapidly (rapid acting) phenobarbital relatively low lipid solubility may take over 15 minutes to achieve unconsciousness when given intravenously

transfer across placenta thiopentone and the other highly lipid soluble agents readily cross the placenta maximum foetal blood thiopentone concentrations being seen within 3 minutes of intravenous administration of thiopentone Duration of action dependent on concentration gradient at plasma:effector site administered dosage, rate of administration, dissociation from receptor site, redistribution, clearance for thiopentone, metabolism is too slow to account for its short duration of action return of consciousness is governed by two factors the bolus mixing with circulating blood volume redistribution from the brain (VRG) Distribution central compartment VC for sodium thiopentone 38% body weight for methohexital 35% these exceed intravascular space and combined with the rate of equilibration with brain suggests that brain should be considered as a part of VC cerebral blood flow 15-18% of the CO a large bolus of lipid soluble, unionised drug is presented to the brain within one arm-brain circulation time following administration of the drug

Cerebral uptake brain extraction ratio of sodium thiopentone is approximately 60% peak plasma concentrations of sodium thiopentone (175 mg/L) are achieved within 30 seconds of intravenous administration of 350 mg internal jugular concentrations are lower (75 mg/L) median effective serum thiopentone concentrations (EC50) - 50 mg/L for recovery of pupillary responsiveness and 12 mg/L for the recovery of motor responsiveness.

Redistribution vessel rich group includes the heart, liver, kidney and brain due to high myocardial blood flow, about 70 ml/100g/min, accounts for the rapidity of cardiovascular depression muscle blood flow (20% of CO) about 15-30 minutes are required for equilibration despite high lipid solubility, blood flow to fat is so low the equilibrium time for thiopentone is prolonged thus, redistribution of thiopentone within the first 30 minutes after intravenous bolus administration is mainly to the muscle group Metabolism oxidation of radicals at the ring C5 (to alcohols, ketones, phenols or carboxylic acids), important for termination of biological activity conjugation with glucuronic acid and excreted N-hydroxylation N-dealkylation following a bolus dose barbiturates combine with several species of cytochrome P450 and competitively interfere with biotransformation of other drugs and endogenous substances other substrates may reciprocally inhibit barbiturate biotransformation following chronic administration marked increase in protein and lipid content of hepatic smooth endoplasmic reticulum, the activities of glucuronyl transferase and the cytochrome P450-dependent mixed function oxidase system enzyme inducing effect results in an increased rate of metabolism of steroid hormones, cholesterol, bile salts, vitamin K and D, and barbiturate explains tolerance to barbiturates Elimination most barbiturates have high lipid:water partition coefficients and are significantly protein bound poorly filtered at the glomerulus readily back-diffuse in the late tubular segments excretion is largely dependent upon prior hepatic metabolism Sodium thiopentone 5-ethyl-5-(1-methyl-butyl)-2-thiobarbituric acid introduced in 1934 by Lundy and Waters distribution 75-85% bound to plasma protein highly lipid soluble pKa 7.6 Vdss of 2.5 L/kg ER 0.15 clearance Clss 2-4 ml/kg/min t 2-6 min; 5-12 h with repeated doses various body stores begin to fill up and the drug accumulates in the body may be asleep for many days reason why thiopentone is not used as a sole anaesthetic agent except for very short duration ED50/LD50 = 4.6 (26.4 for etomidate)

preparation presented as a sodium salt to ensure total solution of the drug pale yellow powder mixed with anhydrous sodium carbonate 6% (not HCO3-) ampoule atmosphere is nitrogen, at 0.8 bar 2.5% solution has a pH = 10.6, (increasing solubility of weak acid in alkaline medium) the solution is not stable, should be used within 24-48 h Pharmacodynamics central nervous system sleep antanalgesia or hyperalgesia anaesthesia anticonvulsant reduced cerebral metabolism cerebral vasoconstriction in dose-dependent fashion may increase cerebral blood flow due to raised PaCO2 secondary to respiratory depression cardiovascular system hypotension is dependent on the dose and rate of administration increase myocardial blood flow and oxygen utilisation myocardial depression at high doses venous thrombosis after 5% intra-arterial injection releases noradrenaline from vessel wall inducing vasoconstriction respiratory system reduction in sensitivity of the central nervous system to carbon dioxide tissue necrosis and sloughing after extravasation induction of ALA-synthetase in liver mitochondria producing excessive amounts of delta-aminolaevulinic acid, porphobilinogen and other porphyrins in individuals with deficiencies in the enzymes involved in the production of haem, phophyria results deficiency of porphobilinogen deaminase results in acute intermittent porphyria deficiency of protoporphyrinogen oxidase results in variegate porphyria

Porphyria unsafe drugs (strong evidence) androgens barbiturates estrogens ethanol griseofulvin hydantoins progesterones sulfonamides Porphyria unsafe drugs (probably or possibly unsafe) drugs affecting the central nervous system anaesthetic agents (benzodiazepines, etomidate, ketamine, enflurane, halothane) local anaesthetic agent (mepivacaine) opioids (pentazocine, trimethadone) others (carbamazepine, glutethimide, imipramine, nikethamide, nortriptyline, primidone, valproate) drugs affecting the cardiovascular system clonidine, disopyramide, ergotamine, hydralazine, methyldopa, nifedipine, phenoxybenzamine, verapamil drugs affecting the respiratory system aminophylline, theophylline drugs affecting the endocrine system chlorpropamide, tolazamide, tolbutamide antimicrobial / antiparasitic drugs chloramphenicol, chloroquine, dapsone, ketoconazole, miconazole, metronidazole, nalidixic acid, rifampin other drugs alkylkating agents, danazol, metyrapone, phenylbutazone, spironolactone Compare and contrast pharmacokinetics of methohexitone with thiopentone

structure

pKa solubility p-binding Vd t metabolism

clearance

BENZODIAZEPINES the term benzodiazepine refers to the portion of the structure composed of the following, a benzene ring (A), fused to a 7-membered diazepine ring (B) all of the important members contain 5-aryl substituent (ring C), and 1,4-diazepine ring the term benzodiazepine now come to mean the 5-aryl1,4-benzodiazepines the 5-aryl ring greatly enhances potency
R1 NC
A

other sites of action inhibition of uptake of adenosine, potentiating the actions of this endogenous neuronal depressant (in coronary arteries) inhibition of Ca++ conductance and Ca++ dependent release of neurotransmitters inhibits tetrodotoxin-sensitive Na+ channels Benzodiazepine binding site on the GABAA receptor

R2

R7-

C N
C

1 2 B 3 C -R3 5 4

R4 R2-

4 categories based on elimination half-lives ultra-short acting short-acting (t less than 6 hours e.g. midazolam) intermediate-acting (t 6 to 24 hours e.g. temazepam) long-acting (t greater than 24 hours e.g. diazepam)

Benzodiazepine receptor ligands agonists benzodiazepines, alter the conformation of the receptor such that the affinity for GABA is increased, enhancing GABAs effects, with a resultant increase in the frequency of Cl- channel opening events antagonists - flumazenil, occupy the receptor but have no intrinsic activity, preventing the effects of both agonists and inverse agonists, without affecting the binding of GABA inverse agonists - -carbolines, occupy the receptor and reduce the affinity for GABA, resulting in CNS stimulation Receptor mediated response Agonist Ractive Rinactive Partial agonist Antagonist Inverse agonist log [drug] Pharmacodynamics central nervous system anxiolytic sedative hypnotic muscle relaxant antegrade amnesia anticonvulsant, tolerance may develop and this limits their usefulness in the long-term management of epilepsy the drugs do not cause true general anaesthesia, since awareness usually persists and relaxation sufficient for surgery cannot be achieved effect on sleep decreased sleep latency, diminished the number of awakenings and time spent in stage of wakefulness, increased total sleep time increase in REM latency, decreased time spent in REM sleep*, decreased frequency of eye movement during REM sleep and increased time in major non-REM component * with the exception of temazepam
5

midazolam contains an imidazole ring bridging R1 and R2 both diazepam and lorazepam are insoluble in water, therefore require solubilizing agents, while the imidazole ring renders midazolam water soluble Mechanism of action the benzodiazepine receptor forms part of the GABAA complex, located on the postsynaptic membrane of the effector neurone high concentrations of GABAA receptors in limbic system, particularly the hippocampus and amygdala cerebral cortex cerebellum high affinity, saturable and stereospecific binding of the benzodiazepines to the GABAA complex receptor is increased by both Cl- and GABA results in potentiation of neural inhibition mediated by GABA, increased frequency of Clchannel opening and influx of Clreceptor affinity and potency: diazepam>midazolam>lorazepam

cardiovascular system baroreceptor reflexes generally remain intact, though, there is some depression midazolam > flunitrazepam at decreasing peripheral resistance, and is dose related, the hypotensive effect is minimal and usually less than that seen with thiopentone in patients with elevated cardiac filling pressures, both midazolam and diazepam produce a "nitroglycerine like" effect, causing venodilatation and reducing preload resultant hypotension activates baroreceptor reflex arc when combined with opioids there is a synergistic effect, the combination producing greater decreases in blood pressure than either agent alone diazepam and lorazepam decrease left ventricular work and cardiac output diazepam increases coronary blood flow, possibly by increasing interstitial concentrations of adenosine, thus, diazepam may provide some protective function in patients with ischaemic heart disease contraindications obstetric and perinatal anaesthesia Pharmacokinetics absorption all have high lipid:water distribution coefficient in unionised form absorption by oral route complete either unchanged, or metabolised (clorazepate, prazepam, flurazepam) distribution bind to albumin extend of binding correlates strongly with lipid solubility and ranges from 70% for alprazolam to 99% for diazepam plasma albumin concentration governs Vd decreased plasma albumin concentration results in increased VD Vd is large especially in elderly concentration in cerebrospinal fluid parallels the concentration of free drug in plasma

Pulmonary ventilation (l/min)

neuromuscular system blockade at very high doses induce muscle hypotonia, without interfering with locomotion, and may decrease decerebrate rigidity respiratory system the slopes of the ventilatory/CO2 response curves are flatter, however, they are not shifted to the right, as occurs with the opioids the peak onset of ventilatory depression following midazolam is at ~ 3 minutes and lasts for ~ 15 minutes may cause apnoea during anaesthesia, or when given in conjunction with the opioids other factors likely to increase the incidence of significant respiratory depression, or apnoea, include, old age, debilitating disease, and co-administration of other respiratory depressant drugs effect on minute ventilation 15 awake anaesthetised 10 5 0 30 40 50 60 Alveolar PCO2 (mmHg)

3-compartment model appear to be more appropriate for highly lipid soluble drug plasma rapidly equilibrating tissues slowly equilibrating tissues rapid uptake into brain and other highly perfused organs after intravenous administration, or oral administration of a rapidly absorbed drug redistribution rapid uptake is followed by a redistribution into tissues that are less well perfused (muscle and fat) most rapid for drugs with highest lipid solubility kinetics of redistribution complicated by enterohepatic circulation cross placental barrier secreted into breast milk metabolism by microsomal enzyme systems in the liver some are inactivated by the first pass reaction important determinant of their duration of action oxazepam, lorazepam, temazepam, triazolam, midazolam most have active metabolites that are biotransformed more slowly than the parent compound flurazepam and N-desalkylflurazepam 3 stages N-dealkylation at position 1 (or 2), usually yields N-desalkylated compounds, (active) hydroxylation at position 3, usually yields active metabolite (3-hydroxyl compound) conjugation of the 3-hydroxyl compounds, principally with glucuronic acid N-dealkylation and 3-hydroxylation reactions reduced by cimetidine and oral contraceptive reduced to a greater extent in aged, chronic liver disease, than are those involving conjugations Midazolam water-soluble benzodiazepine 0.15 - 0.4 mg/kg, induces unconsciousness in 60s duration of sleep 7-15 minutes hydroxylation of methyl group on the fused imidazo ring by CYP3A isoforms forming 1-OH-methylmidazolam conjugation with glucuronic acid forms 1-OHmethylmidazolam glucuronide, t 1 hour, 1/10th activity of parent drug, prolonged effect with renal impairment Benzodiazepine antagonist flumazenil an imidazobenzodiazepine clinical use in 1991 only available as intravenous formulation initial dose of 0.1 mg, followed by 0.1mg incremental dose until effect is seen (>5ng/ml) pharmacokinetics 50% bound to plasma protein Vd of 0.9 L/kg clearance 17 ml/min/kg eliminated almost entirely by hepatic metabolism to inactive products with a half-life of 1 hour duration of clinical effect 1 to 3.5 hours <1% excreted in the urine unchanged
6

Metabolism of flumazenil

Compare and contrast diazepam with midazolam Diazepam Midazolam structure no imidazole ring imidazole ring pKa 3.4 6.2 solubility not water soluble good in acidic requires solvent solution pH<4 lipid solubility high high bioavailability 100% 45% onset rapid rapid protein binding (%) 99 95 Vd (L/kg) 1.1-1.4 1.1-2.5 t (min) 30-40 6-30 first-pass pulmonary uptake clearance (ml/min/kg) 0.38 6-11 t (h) 24 57 2-5 80-90 in elderly 5.6 in elderly urinary excretion < 1% 50% metabolism liver, demethylation liver (perfusion to desmethyldiazepam dependent), 30has sedative effect 50% extraction hydroxylation to extrahepatic; 3-OH diazepam hydroxylation, (temazepam), both followed by then converted to conjugation; oxazepam, followed metabolites nonby conjugation sedative affected by cirrhosis Phase I inducible by barbiturate, anticonvulsant, inhibited by cimetidine (imidazole derivative) intravenous thrombophlebitis both unlikely injection thrombosis site of action benzodiazepine-GABA receptor complex induction smooth/pain smooth central nervous anxiolytic, sedative, anticonvulsant system prolonged action with diazepam cardiovascular coronary vasodilatation respiratory depression depression analgesia slight none amnesia antegrade antegrade (>) emergence slow intermediate

PROPOFOL hindered phenol - 2,6-diisopropylphenol weak acid Physicochemical properties oil at room temperature emulsion is isotonic pH 6-8.5 pKa of the drug in water is 11 octanol : water partition coefficient at physiological pH is 6761 : 1 Preparation 1% [or 2%] aqueous emulsion with 10% soya bean oil (as a solubilizing agent) 2.25% glycerol (render isotonic) 1.2% egg phosphatide (as emulsifying agent) sodium hydroxide (to adjust pH between 6 and 8.5) sealed under nitrogen (to prevent oxidative degradation in the presence of oxygen) addition of medium chain triglycerides, and sodium oleate in Propofol-Lipuro 1% Propofol emulsion containing disodium edetate (0.005%) Distribution following a single bolus dose, half-time of blood : brain equilibration (keo) is 1-3 minutes rapid decline in plasma concentration, described by 3 compartment model (plasma, rapidly equilibrating tissues, slowly equilibrating tissues) t 5 minutes patient will wake up in 5-10 minutes Clearance biphasic elimination, two elimination half-lives 60% metabolised by cytochrome P450-dependent mixed function oxidase system to 2,6 diisopropyl-1,4-quinol, which is then conjugated to glucuronide or sulphate 40% found as propofol-glucuronide or -sulphate t 1-3 hours dependent on duration of infusion pharmacokinetics not affected by liver and renal disease Cl 23-50 ml/kg/min context-sensitive half time is 5 minutes after 1 hour infusion, 7 minutes after 10 h infusion
Context half time (min) 10 5 0 0 5 10 Time(hr)

Adverse effects pain on injection of propofol into peripheral veins immediate and delayed cardiovascular effects hypotension negative chronotropic and dromotropic effects bradycardia, tachycardia, arrhythmias transient apnoea myoclonia, convulsions, opisthotonus anaphylaxis rarely (bronchospasm, erythema, hypotension)

Pain on injection of propofol mechanism of immediate pain probably due to direct irritant effect of phenol pain detected by free afferent nerve endings between media and intima of vein wall concentration of propofol in aqueous phase, reduced with intralipid formulation outer aqueous phase comes into contact with intima of vein during administration may be due to production of irritant substances when propofol comes into contact with silicone lubricant in plastic disposible syringes mechanism of delayed pain probably result from indirect effect release of kininogen via kinin cascade latency of 10-20s Factors influencing the incidence of pain site of injection size of vein speed of injection propofol concentration in aqueous phase buffering effect of blood speed of intravenous carrier fluid temperature of propofol syringe material Factors reducing incidence of pain premedication with pethidine, NSAIDs use of large veins, at least antecubical speed of injection speed of infusion carrier pretreatment with lignocaine (also mixture), prilocaine, procaine, opioids (alfentanil, fentanyl, pethidine), metoclopramide (weak local anaesthetic effect), thiopentone, ketamine (local anaesthetic effect) mixing with blood (reduction of concentration in aqueous phase or release of kinins) cooling to 4oC or warming to 37oC Negative inotropy mediated in part by activation of M2Ach receptor, activating M2Ach NO cGMP signal pathway stimulation of M2Ach receptor inhibits adenylyl cyclase by a Gi proteinmediated mechanism; decreasing cAMP production with inhibition of transmembrane Ca++ influx through voltage-activated Ca++ channels (ICa(L)) activates constitutive NO synthase and increasing NO production, activation of guanylyl cyclase and increasing cellular level of cGMP, cGMP inhibits ICa(L) by: activation of cGMP-dependent protein kinase (PKG) and phosphorylation of ICa(L) or some regulatory protein activation of cGMP-stimulated cAMPspecific PDE, lowering cAMP level

however, plasma concentration of propofol in clinical use is in the range of 3M to 90M, with protein binding of propofol in the range of 97%-99%, effective free propofol is <1mM at 1mM, propofol causes only 5% decrease in heart beating rate (of cultured rat ventricular myocytes) hence, direct effect of dosage of propofol in clinical use may be slight in vivo Vasodilatation stimulation of NO production in aortic endothelial cells, distal coronary arteries causes blockade of voltage-gated influx of extracellular Ca++ and reduction of sympathetic tone Non-ideal features of propofol pharmaceutical complex formulation, possible bacterial growth, incompatibilities and difficulty in detection, glass packaging, expense pharmacokinetics hepatic (almost) organ dependent clearance, offset of effect mostly dependent on redistribution, high lipid solubility with consequent easy transfer across placenta pharmacodynamics central nervous system: decreased cerebral perfusion pressure, excitatory phenomenon, not analgesic, no antidote, mechanism of action not fully understood (other than at GABAA?) with 70% N2O in oxygen, EC50 2.2 g/mL and EC95 8.2 g/mL cardiovascular system: vasodilatation, negative inotropic effect with higher plasma concentrations, hypotension, depression of baroreceptor response, bradycardia respiratory system: decreased CO2 and hypoxic response, depressed minute ventilation with possible apnoea, depressed airway reflexes/tone with possible aspiration, and/or obstruction others: pain on injection, occasional thrombophlebitis, rarely anaphylaxis Compare and contrast propofol with midazolam Comparison Propofol Midazolam structure hindered phenol imidazo-benzodiazepine weak acid weak acid solubility egg lecithin emulsion water dose 1.5-3.0 mg/kg 0.2-0.4 mg/kg venous irritationmoderate (pain) none onset 15-45 s 30-60 s duration 5-10 min 15-30 min induction smooth/pain smooth CNS can cause fits anticonvulsant CVS vasodilatation (Ca++L) vasodilatation (Ca++L) fall in BP,CO,HR minimal change respiratory moderate less depression analgesia none none amnesia minimal yes emergence rapid, minimal intermediate, hangover, euphoria sedation dizziness drowsiness
8

ETOMIDATE a hypnotic agent without analgesic activity synthesized (1964), clinical practice (1973) a carboxylated methylbenzyl imidazole derivative weak base, pKa 3 rapid onset, duration is dose dependent, relatively brief usually 3-5 minutes after an induction dose of 0.3mg/kg etomidate ED50/LD50 = 26.4 (4.6 for thiopental) safe in patients susceptible to malignant hyperthermia Preparations aqueous preparation in propylene glycol osmolality and pH unphysiological, resulting in thrombophlebitis, pain during injection, histamine release, anaphylactoid reactions, haemolysis, lactic acidosis, pulmonary hypertension emulsion preparation emulsion containing soya oil, medium-chain triglycerides, glycerol, egg lecithin, sodium oleate, water physiological osmolality, none of the complication of propylene glycol formulation Mechanism of action dependent upon subunit subtype present within the GABAA receptor only 2 and 3 subunits are highly sensitive to etomidate a single amino acid residue is crucial for the interaction of etomidate with the 3 subunit

least effect on L-type Ca++-channels compared with midazolam and propofol (isolated canine ventricular cells and rat myocardial cell membrane) inhibition of adrenal steroidogenesis concentration dependent inhibition of cytochrome P450 dependent mitochondrial enzymes (17-hydroxylase and 11 hydroxylase) with decreased production of 17hydroxyprogesterone, cortisol, corticosterone, and aldosterone after single dose: 0.3mg/kg, suppression in cortisol production is brief, serum concentration restored after 2-6 hours after etomidate infusion: serum cortisol concentration returned to baseline 1 hour after infusion ended, and were significantly increased after 6 and 20 hours, CABG patients (Crozier et al,1994 vs Ledingham and Watt,1983) cholesterol

17 hydroxylase

pregnenolone progesterone 17 hydroxylase 11 deoxycorticosterone 11 hydroxylase corticosterone aldosterone

17 hydroxypregnenolone 17 hydroxyprogesterone 11 deoxycortisol 11 hydroxylase cortisol

Pharmacokinetics distribution 75% bound to plasma proteins (albumin), unbound fraction increased in hypoalbuminaemia dose reduction in elderly decreased Vd decrease clearance Vd 2.3-4.5 L/kg very short duration of action, t 2.6-4 minutes consciousness regained in 5-10 minutes clearance hepatic extraction of 0.67 ester hydrolysis or N-dealkylation in the liver 11-25 ml/min/kg t 2.9 hours being a substituted imidazole derivative, inhibits hepatic metabolism of other drugs, similar to cimetidine Pharmacodynamics cardiovascular system lack of effect on both the sympathetic system and on baroreceptor function less negative inotropic effect compared with propofol and thiopentone (isolated guinea pig heart)

myoclonia transient disinhibition of subcortical structures (diencephalic excitations) and alteration in balance of inhibitory and excitatory influences in the thalamocortical tracts during transformation from consciousness to unconsciousness, result of unsynchronous onset of drug action at various sites of the CNS due to differences in receptor affinity, regional receptor distribution, or local blood flow differences within the CNS immune system interleukene-6 greater at 6 and 12 hours after etomidate compared with thiopentone less marked lymphopenia at 4 hours after etomidate compared with thiopentone Major advantages lack of cardiovascular side effects neuroprotective Adverse effects adrenal suppression (early 1980s) cannot be used for long-term administration myoclonia pain on injection emesis Contraindications known hypersensitivity patients with hereditary disorder for haem biosynthesis porphyrogenic potential newborns and infants up to age of 6 months

KETAMINE a phenylcyclohexylamine derivative ketamine hydrochloride (2-[o-chlorophenyl]-2[methylamino] cyclohexanone hydrochloride) introduced in 1965 for dissociative anaesthesia available as racemic mixture exists as 2 isomers, R(-) and S(+) forms S(+) more potent lipophilic, rapidly distributed into highly vascular organs, and brain Dissociative anaesthesia immobility, amnesia and marked analgesia without actual loss of consciousness functional and electrophysiological separation of the normal communications between the sensory cortex and the association areas of the brain Cataleptic state patients are non communicative, although they appear to be awake; eyes may remain wide open with slow nystagmus and intact corneal reflexes various degrees of skeletal muscle hypertonus may be present along with non-purposeful skeletal muscle movements that are independent of surgical stimulation Mechanisms of action interacts with NMDA (N-methyl-D-aspartate) glutamic acid Ca++ channel receptors in cortex and limbic system central opioid receptors (, ) monoaminergic receptors in spinal cord voltage-gated Ca++ channels voltage-gated Na+ channels analgesic effect via inhibition of Ca++ influx at presynaptic nerve terminals ( opioid receptor, monoaminergic receptors in spinal cord, monoaminergic receptors in spinal cord) at postsynaptic NMDA receptors non-competitive antagonism of NMDA receptor Ca++ channel pore interacts with phencyclidine binding site stereoselectively, leading to significant inhibition of receptor activity, this only occurs when the channel is opened

effect on voltage-sensitive Ca++ channels produces non-competitive inhibition of K+stimulated increased intracellular Ca++ effect on opioid receptors antagonist at , agonist at S(+) ketamine is 2-3 times more potent than R() ketamine as an analgesic affinity for receptor is 10000 fold weaker than that of morphine

effect on descending inhibitory monoaminergic pain pathways analgesic property may involve these pathways, although difficult to separate ketamine-sensitive opioid receptor action local anaesthetic action, blockade of Na+ channel effect on muscarinic receptors antagonistic action as ketamine produces anticholinergic symptoms (postanaesthetic delirium, bronchodilatation, sympathomimetic action) Pharmacodynamic effects cardiovascular system stimulation, with peak increase in heart rate, arterial blood pressure and cardiac output in 2-4 minutes after intravenous injection, slow decline to normal in the next 10-20 minutes by excitation of the central sympathetic nervous system and possibly by inhibition of the uptake of noradrenaline at sympathetic nerve terminals respiratory system decreases the respiratory rate slightly for 2-3 minutes upper airway muscle tone is well maintained upper airway reflexes are usually active central nervous system increases cerebral blood flow, oxygen consumption, and intracranial pressure resembles inhalational anaesthetics in this respect associated with disorientation, sensory and perceptual illusions, vivid dreams following anaesthesia - emergence phenomena secretions potent stimulator of salivary and tracheobronchial secretions atropine often administered concurrently Pharmacokinetics routes of administration intramuscular, intravenous epidural ketamine is rapidly absorbed into plasma, producing spinal and systemic effects, intrathecal cause dizziness, drowsiness distribution initially distributed to highly perfused tissues and is then redistributed to less well perfused tissues redistribution results in termination of its action t is about 10-15 minutes metabolism extensively metabolised in liver hydroxylation and N-demethylation of the cyclohexamine ring to form norketamine (has 20-30% potency of ketamine) norketamine hydroxylated to hydroxy-norketamine and then conjugated to form water-soluble compound for renal excretion t of 2-3 h

10

Clinical use of ketamine pain control (limited value) ketamine can only inhibit NMDA activity when the receptor-operated ion channel had been opened by nociceptive stimulation, hence preemptive analgesia with ketamine is ineffective neuroprotection activation of NMDA receptor is implicated in cerebral ischaemic damage, hence by blocking the receptor, ketamine has neuroprotective potential by a mechanism related to a reduction in plasma catecholamine concentrations in patients with septic shock reduce the need for inotropes via inhibition of catecholamine uptake reduce pulmonary injury via a reduction in endotoxin-induced pulmonary hypertension and extravasation asthma therapy anti-inflammatory spasmolytic increased catecholamine concentrations, inhibition of catecholamine uptake, voltage-sensitive Ca++ channel blockade, inhibition of postsynaptic nicotinic or muscarinic receptors anaesthesia for haemorrhagic shock patients sympathomimetic effects BUTYROPHENONE Droperidol a butyrophenone, a fluorinated derivative of the phenothiazines first synthesised by Janssen it has a faster onset and shorter duration of action than haloperidol frequently used in conjunction with fentanyl t ~ 2-2.5 hrs, is similar to that of fentanyl however, the effects frequently outlast those of fentanyl, possibly due to increased affinity for CNS receptors mechanism of action act at post-synaptic GABA receptors Pharmacodynamic effects a potent anti-emetic and is effective against opioid induced vomiting produces extrapyramidal side-effects should be avoided in patients with Parkinsonism may cause a profound fall in peripheral resistance and blood pressure in patients receiving vasodilator therapy and in those with a decreased circulating blood volume, due to both a CNS and peripheral -blocking effect Neuroleptanalgesia a state of drug-induced depression of activity, lack of initiative, and reduced response to external stimuli the state of neuroleptanalgesia, or neurolept-anaesthesia may be obtained using a combination of a potent analgesic and a neuroleptic tranquiliser drug

first described by Delay (1959) in drug induced behaviour syndromes patient has good analgesia and is sedated, yet is able to respond to simple commands the mechanism of action is thought to be competitive antagonism at dopaminergic receptors in the brain nigrostriatum this syndrome includes inhibition of purposeful movement & conditioned behaviour inhibition of amphetamine induced arousal tendency to maintain an induced posture, catalepsy marked inhibition of apomorphine induced vomiting maintenance of corneal and light reflexes drugs with neurolept properties may also exhibit -adrenergic blockade hypotension hypothermia sedation extrapyramidal effects anticholinergic properties competitive antagonism at dopaminergic receptors in the brain nigrostriatum these agents have a predilection for certain areas in the brain rich in DA-receptors, especially the CTZ and the extrapyramidal nigrostriatum DEXMEDETOMIDINE an imidazole derivative active dextro-rotatory optical isomer of medetomidine a relatively selective alpha2-adrenoceptor agonist with sedative and analgesic properties exhibits, in vitro, an affinity for alpha2-adrenoceptors over alpha1-adrenoceptors in a ratio of approximately 1620:1 Pharmacodynamics acting at both presynaptic and postsynaptic alpha2adrenoceptor on nerve fibers originating from the locus ceruleus, dexmedetomidine administration reduces norepinephrine release from these nerve endings, moderating sympathetic discharge and resulting in dose dependent central vasomotor center depression, hypotension, bradycardia, as well as sedation the distribution of alpha2-adrenoceptor in medullary and spinal centers involved in the control of parasympathetic and sympathetic outflow explain the bradycardia and hypotensive effects of dexmedetomidine via its imidazole moiety, dexmedetomidine also acts at the medulla, further reducing the excessive sympathetic discharge associated with awakening without depressing respiratory effort dexmedetomidine is suitable for patients in whom respiratory effort has to be maintained antinociceptive action of alpha2- adrenoceptor agonist in the spinal dorsal horn is due to a direct spinal action and not activation of descending inhibitionthe antinociceptic effect is exerted via its activity at the alpha2A, 2B, and 2C subtype adrenoceptors. the down-stream signaling mechanism for alpha2adrenoceptor is very similar to that of opioid receptor, involving the calcium ion channel

11

activation of the alpha2B-adrenoceptors located on vascular smooth muscle appears to mediate vasoconstriction, and the signalling mechanism involves the L-type calcium channels transient increase in blood pressure with reflex bradycardia is generally observed following a bolus dose of dexmedetomidine overdosage has been shown to decrease left ventricular ejection fraction Physicochemical properties white or almost white powder freely soluble in water pKa of 7.1 weak base formulated as a clear, colourless, isotonic solution with a pH of 4.5 to 7.0. the solution is preservative-free and contains no additives or chemical stabilizers. Pharmacokinetics elimination t 1.8 to 2.5 hours after stopping infusion clearance 37-46 L/h Vdss 89 L to 100 L increasing duration of dexmedetomidine infusion: increases Vdss increases elimination t reduces clearance long context-sensitive half-time, lasting 250 minutes after an 8-hour infusion biotransformation Phase I reaction involving cytochrome P450, mainly CYP2A6 3-OH-dexmedetomidine 3-carboxy-dexmedetomidine 3-OH, N-methyl-dexmedetomidine 3-carboxy N-methyl-dexmedetomidine Phase II reaction involving N-glucuronidation 3-OH-dexmedetomidine glucuronide dexmedetomidine-N-methyl O-glucuronide Adverse effects hypotension, hypertension bradycardia, tachycardia, atrial fibrillation nausea, vomiting fever dry mouth rigor agitation pain hyperglycaemia

PHARMACOKINETICS OF INTRAVENOUS AGENTS

* liver blood flow ~ 21.5 ml/kg/min IDEAL INTRAVENOUS ANAESTHETIC AGENT Physical properties water soluble, does not require solvent stable in solution over long periods of time not adsorbed onto glass or plastic Pharmacokinetics elimination independent of liver or renal function, with inactive, nontoxic metabolites Pharmacodynamics non-irritant on injection whether- intravenous or intraarterial non-allergenic, should not cause histamine release rapid onset of action, high specificity of action short duration of action - elimination by metabolism, no cumulative properties minimal cardiorespiratory depression no increase in muscle tone good analgesia

12