Intravenous Fluid

Intravenous Anaesthetics
HISTORY
intravenous anaesthesia as we know it today, dates from the introduction of thiopentone in 1934 this was actually preceded by hexobarbital in 1932 prior to this, the triad of anaesthesia, hypnosis, analgesia and muscle relaxation had been provided by a single inhalation agent, eg., ether or chloroform intravenous agents may be used for, a. b. c. d. induction of anaesthesia as a sole agent to supplement general anaesthesia or regional anaesthesia for sedation
Sir Christopher Wren is usually given the credit for the first intravenous injection of fluids and drugs with anaesthetic properties in 1665 he reported to the Royal Society the injection of wine using a pig bladder and quill the hollow needle was perfected by Francis Rynd of Dublin (1845) the syringe was developed by Alexander Wood of Edinburgh (1855) both injected morphine to relieve pain the first GA was administered in 1846 but an inhalation anaesthetic agent was used ether & chloroform were used successfully as sole agents until the beginning of this century, though, some also added a N2O/O2 mixture diluted ether and chloroform have also been administered intravenously but this has never gained popularity
Barbiturates
barbituric acid, a malonylurea devoid of hypnotic properties, was first prepared by Von Baeyer of Germany in 1864 the first sedative barbiturate, diethyl barbituric acid or barbitone was described by Fischer and Von Mering in 1903 and enjoyed popularity as long lasting hypnotic sedative for many years phenobarbitone was discovered in 1912 is still used as anticonvulsant somnifene, a mixture of diethyl amines, diethyl and diallyl barbituric acids, was the first barbiturate used intravenously in 1921 however pernoston, introduced by a German obstetrician, Bumm (1927), was the first barbiturate to gain widespread use as an intravenous anaesthetic hexobarbitone, introduced by Weese & Scharpff (1932) was popular in Europe ~ 10 million anaesthetics in its first 10 years of use thiopentone was first administered by Lundy & Waters in 1934 early use was associated with a large number of disasters due to the lack of knowledge of the drugs pharmacokinetics use of the drug for the induction and maintenance of anaesthesia for casualties in Pearl Harbour resulted in its description as "an ideal method of euthanasia" methohexitone used first by Stoelting (1957) is still used today
Non-Barbiturates
Eugenols there are chief constituent of oil of cloves, thus are insoluble in water propanadid was initially solubilized in Cremophor EL first used in Germany (1956), now withdrawn from the market due to hypersensitivity reactions to Cremophor Steroids hydroxydione (1955) was never popular due to a high incidence of thrombophlebitis althesin, a mixture of alphaxolone and alphadolone in cremophor EL, provided a rapid onset and rapid recovery, however also had a high incidence of hypersensitivity reactions and was withdrawn from the market minaxolone (1978) produced a rapid onset with somewhat slower recovery than althesin toxicity in rats in some studies led to its withdrawal from clinical studies Phencyclidine Derivatives ketamine "dissociative anaesthesia" was introduced in 1965 Propofol first clinical trials in 1977 by Kay and Rolly initially solubilized in Cremophor EL but later changed to intralipid Benzodiazepines diazepam was first available in 1960 as a sedative water insoluble, therefore solubilised in propylene glycol but now also available in intralipid midazolam is water soluble and was introduced in 1978 Analgesic-Hypnotic Combinations a. b. c. neurolept analgesia, a state of indifference to pain neurolept anaesthesia narcotics as sole anaesthetic agents
Balanced Anaesthesia term first used by Lundy to describe combination of light general anaesthesia with nerve block later this was revised to include muscle relaxation, hypnosis and narcotic analgesia
BARBITURATE INTRAVENOUS ANAESTHETICS
barbituric acid, 2,4,6-trioxohexahydropyrimidine, is the condensation of malonic acid and urea the carbonyl group at position 2 takes on acidic character because of lactam (keto) - lactim (enol) tautomerization the lactim form is favoured in alkaline solutions and substitution of Na+ for the H-atom of the lactim form results in water soluble and often unstable salts the barbituric acid derivatives are poorly water soluble but dissolve readily in nonpolar solvents barbituric acid itself lacks central depressant activity, but the presence of alkyl or aryl groups at position C5 confers sedative-hypnotic activity the presence of a phenyl group at C5, or on one of the ring nitrogens confers anticonvulsant activity (eg. phenobarbital) increases in the length of one, or both the alkyl side chains at C5 increases hypnotic potency up to 5-6 carbon atoms, above this potency is reduced and convulsant properties may result compounds possessing the C2=O are known as oxybarbiturates, those having a C2=S substitution as thiobarbiturates the thiobarbiturates have higher lipid solubilities than their corresponding oxybarbiturate in general, structural changes which increase lipophilicity, a. b. c. d. decrease the latency of onset decrease the duration of action accelerate metabolic degradation often increase hypnotic potency
each of these subclasses may be methylated, giving rise to 4 groups methyl or ethyl substitution at the N1 position increases lipid solubility and shortens duration of action subsequent demethylation may occur resulting in a longer acting metabolite these compound have a high incidence of excitatory phenomena pentobarbital, secobarbital, thiopental, thiamylal and methohexital all posses asymmetrical carbon atoms in their side chains the l-isomers are ~ 2x as potent, despite similar access to the CNS cf. the d-isomers methohexital has four stereoisomers due to an asymmetric centre at C5, the -l-isomer being nearly 4 times as potent as the -l-isomer however, the former also produces excessive motor activity, and the marketed solution is a racemic mixture of the -isomers NB: this specificity of action lead to the hypothesis that the barbiturates acted at some specific CNS receptor
Mechanisms of Action
the GABA receptor complex is the most likely site of barbiturate action the mesencephalic ARAS is exquisitely sensitive to these agents of the various effects of the barbiturates seen at a cellular level, only their effects at the GABA receptor complex, 1. 2. 3. occur at clinical concentrations correlate with their anaesthetic potency are stereospecific
NB: inhibition is postsynaptic in the cortical, diencephalic and cerebellar regions, and presynaptic in the spinal cord this occurs only at GABA-ergic sites, but the effect is not totally mediated by GABA that is, barbiturates both enhance and mimic the action of GABA, by binding to the receptor they, a. b. c. decrease the rate of GABA dissociation increase the duration of GABA activated Cl- channel opening at higher concentrations directly activate Cl- channel
consequently, in whatever neuraxis, these agents preferentially suppress polysynaptic responses, a. b. c. they depress Ca++ dependent AP's decrease Ca++ dependent release of neurotransmitters enhance gCl- in the absence of GABA
the barbiturate sedative-hypnotic activity probably relates to enhancement of GABA activity, whereas, barbiturate anaesthesia from their so-called "GABA-mimetic action" therefore, the action is probably at the GABAA receptor, as the GABAB subtype results in an increase in gK+ and gNa+ these effects have similarities with the benzodiazepines, but there are significant differences, a. b. barbiturates increase the duration of channel opening benzodiazepines increase the frequency of channel openings
NB: both lead to an increase in gCl- flux, however, the benzodiazepines act only in the presence of GABA
Classification
traditionally classified according to their half-lives,
Group Long Acting Medium Acting Short Acting Ultra-Short Acting
Half-life 24-96 hrs 21-42 hrs 20-28 hrs 10 hrs
Example phenobarbital pentobarbital secobarbital thiopentone, methohexital
the duration of action of the ultra-short acting compounds is due to rapid redistribution, however excretion may take much longer these agents are used principally as intravenous induction agents the medium acting agents have been essentially superseded for sedative-hypnotic use by the safer benzodiazepines the long acting agents are still useful in the management of epilepsy
PHARMACOKINETICS Distribution
the latency of onset for these agents is determined by the rapidity with which they cross the BBB this, in turn, is dependent upon their lipid solubility and degree of ionization as their MW's are all very similar, this factor can be ignored Degree of Ionization the barbiturates are weak acids, with pKA's slightly above 7.4 thiopental (STP) has a pKA ~ 7.6 ~ 40% ionised at physiological pH methohexital (MOX) is ~ 25% ionised at physiological pH phenobarbital, with a pKA slightly below 7.4, is 60% ionised acidosis will therefore increase the non-ionised fraction and favour transfer of these agents into the brain (brain ECF pH = 7.36) in the stomach these agents exist almost entirely in the non-ionised form and are absorbed according to their lipid solubilities the degree of ionization also affects renal excretion back-diffusion will be less if the drug is highly ionised and this is the basis of forced alkaline diuresis in the management of overdosage with phenobarbitone
Lipid Solubility the rapidly acting agents are relatively unionised at plasma pH and are absorbed according to their lipid solubility thiopentone, being highly lipid soluble, equilibrates with the brain rapidly phenobarbital, with relatively low lipid solubility, may take over 15 mins to achieve unconsciousness when given IV Protein Binding these agents are bound principally to plasma albumin binding for thiopentone varies between 65-85% and it may be competitively displaced by other drugs, eg. sulfisoxazole further, protein binding may be reduced in disease states where plasma albumin is altered, ie. renal and hepatic disease Placental Transfer the factors determining access to the foetus are identical to those determining access to the brain thiopentone and the other highly lipid soluble agents readily cross the placenta maximum foetal blood thiopentone concentrations being seen within 3 mins of IV administration of thiopentone
Uptake & Redistribution

the termination of action is the sum of redistribution, metabolism and renal excretion in the case of thiopentone, metabolism is too slow to account for its short duration of action and the return of consciousness is governed by two factors, 1. 2. mixing of the bolus with circulating blood volume redistribution from the brain (VRG)
Body Tissue Compartments

Group VC VRG MG FG Blood Flow (% CO) 100% 70-75% ~ 20% ~ 5% Size (% body weight) ~ 38% 10-15% ~ 50% 15-20% Equilibrium (min) ~ 0.5 ~ 1-3 15-30 200-300+
NB: the relative rates at which various tissue groups take up thiopentone will depend upon their blood flow and the tissue solubility (see W&W fig. 8-6)
this, and other compartmental models of the plasma concentration/time curve, have largely replaced physiological models, as these require extensive human data the VC above is that for thiopentone, the VC 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 ~ 1/6th of the cardiac output, therefore a large bolus of lipid soluble, unionised drug is presented to the brain within one arm-brain circulation time peak plasma concentrations of thiopentone ~ 175 mg/l, are achieved within 30 secs of IV administration of 350 mg internal jugular concentrations are much lower ~ 75 mg/l this equates to a brain extraction ratio ~ 60% the VRG includes the heart, liver, kidney and brain the high myocardial blood flow, ~ 70 ml/100g/min (~ 225 ml/min), accounting for the rapidity with which CVS depression follows administration of thiopentone blood flow to the muscles (20% of CO) is less and 15-30 mins are required for equilibration although thiopentone is highly soluble in fat, the poor blood supply to this tissue results in a prolonged equilibrium time NB: thus, the redistribution of thiopentone within the first 30 mins after IV bolus is predominantly to the muscle group
Metabolism
most members have high lipid:water partition coefficients and are significantly protein bound, therefore, a. b. c. they are poorly filtered at the glomerulus they readily back-diffuse across the late tubular segments excretion is largely dependent upon prior metabolism which occurs in the liver
biotransformation is usually via oxidation of radicals at the ring C5 to alcohols, ketones, phenols or carboxylic acids these are then conjugated with glucuronic acid and excreted other biotransformations occur, such as N-hydroxylation, N-dealkylation etc., however side chain oxidation is the most important Brodie calculated that ~ 10-15% of thiopentone was metabolised however, other workers have demonstrated a hepatic extraction 50% therefore, metabolism may play some part in the termination of activity of thiopentone
Renal Excretion a few barbiturates have low lipid:water coefficients, such as aprobarbital and phenobarbital thus, these members are significant excreted unchanged in the urine, phenobarbital ~ 25% both osmotic & alkaline diuresis enhance excretion of these drugs impaired renal function may result in severe CNS and CVS depression with these agents, further decreasing renal elimination Prolonged Administration data of the half-lives of these agents shows, that for the medium acting agents used for sedative-hypnotic effects, non of the drugs will be significantly excreted in 24 hours therefore, all of these agents will accumulate with repeated administration thiopentone has a half life considerably longer than its clinical effects therefore, with repeated doses or continuous infusion, the dose required progressively decreases
THIOPENTONE
Structure:
Chemical name: Introduced: Lipid Solubility: Acid dissociation K: Solution pH: Protein binding: Pharmacokinetics:
5-ethyl-5-(1-methyl-butyl)-2-thiobarbituric acid 1934 high pKA pH 75-85 % ClSS VdSS t ER = = = = 3.4 0.5 2.5 1.0 11.6 6.0 0.15 ml/kg/min l/kg hrs = 7.6 = 10.6 Lundy & Waters
Chemistry
first used in clinical anaesthesia in mid 1934 by Lundy and Waters it is the sulphur analogue of pentobarbitone, ie. is a thiobarbiturate highly lipid soluble, with a pKA = 7.6 presented as a sodium salt (STP) in order to ensure total solution of the drug, a. b. c. d. pale yellow powder mixed with anhydrous sodium carbonate 6% ampoule atmosphere is N2 at 0.8 bar 2.5% solution has a pH = 10.6 (not HCO3-)
the solution not stable and should be used within 24-48 hrs Miller states the prepared solution may be kept up to a week if refrigerated
Pharmacokinetics
thiopentone has rapid onset with a short duration of action from a single bolus dose the decline in plasma concentration follows a multi-compartment model, with short distribution half-lives a long elimination half-life, i. t1 ~ 2.8 min ii. t2 ~ 48.7 min iii. t ~ 5-12 hrs the rapid recovery is due to redistribution of the drug, principally to muscle & liver tissue this is due to the greater perfusion of muscle and liver tissues, despite the greater solubility of thiopentone in fat plasma clearance ~ 1.6-4.3 ml/kg/min, is slow and almost entirely due to hepatic metabolism oxidation to a pharmacologically inactive metabolite
correspondingly, the hepatic extraction ratio ~ 0.1-0.2 is low reversibly to albumin, high protein binding ~ 75-85% therefore the free fraction varies from 0.15 to 0.25 steady state VdSS ~ 1.7-2.5 l/kg, is greater than body volume, reflecting extensive tissue uptake the combination of low clearance and large volume of distribution results in the relatively long elimination half-life, ie. most of the drug is in the tissues rather than plasma and thus is not available for hepatic elimination with larger or repeated doses, recovery is slow as there is accumulation of the drug in the peripheral tissues some evidence suggests that with larger doses the behaviour of thiopentone changes from first-order to zero-order kinetics as such only a constant mass of drug is removed per unit time, and as the dose is increased the plasma concentration rises rapidly the pharmacokinetics of thiopentone are not affected by surgical stress, or the addition of either N2O or Enflurane (Ghonheim 1978)
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Effects of Physiological and Pathological States
Age there is a decreased requirement of thiopentone with increasing age the elimination half-life is prolonged in the elderly, however, this alone shouldn't alter the effects of a single dose in the elderly, for a given dose, the peak plasma levels of thiopentone are greater than those found in young adults this difference is explained by, a. b. c. the volume of the central compartment is reduced decreased albumin binding 18-22% increase in free fraction decreased rate of redistribution (reduced CO) increased penetration of BBB (Muravchick & Mandel 1982)
consequently, the induction dose should be decreased to prevent excessive depression of CNS and CVS function the elimination half-life is increased due to an increased VdSS, (b) above techniques employing repeated boluses should be avoided children have a similar VdSS/kg to adults, while clearance ~ 2x the adult value thus the elimination half-life ~ that of adults repeated dosage therefore leads to less accumulation in children higher MRO2 and CI leads to more rapid redistribution and faster awakening from a single dose Pregnancy at term, the clearance ~ 1.5x that of the non-pregnant probably due to increased hepatic metabolism, ? steroid hormone induction albumin binding is unchanged VdSS 2x that of the non-pregnant, thus the elimination half-life is longer (~ 26 hrs) the volume of the central compartment is unchanged, therefore, at least theoretically the induction dose/kg should be the same as in the non-pregnant state repeated doses cause greater accumulation Obesity due to high lipid solubility, the VdSS is increased albumin binding and clearance are unchanged, therefore the elimination half-life is prolonged the volume of the central compartment is greater in obese than lean patients this is due to a larger blood volume, myocardial hypertrophy and fatty infiltration of the liver however, when expressed in l/kg, it is similar to that of lean patients therefore, according to Hudson and Stanski, it would be logical to give the same induction dose/kg total body weight, in obese and lean individuals multiple injection techniques are not advisable due to the prolonged elimination time
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Renal Failure uraemia causes a decrease in albumin binding of thiopentone, with a consequent doubling in the plasma free-fraction and an increase in the unionised fraction more is available to cross the BBB with an increased depth of anaesthesia for a given dose there is also increased CVS depression (myocardial depression and hypotension), therefore the induction dose should be decreased (by 50%) however, redistribution is more rapid with a quicker recovery, thus there is a chance of inadequate anaesthesia at intubation the elimination half-life remains normal despite an increased VdSS as the total clearance is increased, due to the increased free fraction increasing availability for metabolism therefore, the recommendations are, a. b. use a slow rate of induction, or give in 2 or 3 doses, the total dose being unchanged for maintenance with a repeated dose technique, decrease the individual doses by 50-75% and give more often
NB: recovery may be more rapid if the total dose is small Hepatic Failure there is a decrease in protein binding of thiopentone in cirrhotics, directly related to decreased plasma albumin (~ 50%) therefore, cirrhotics behave similarly to those with renal failure and induction doses should be reduced ~ 50-75% VdSS is increased, clearance decreased, and the elimination half-life prolonged a standard induction dose of thiopentone will therefore have a prolonged recovery Hypovolaemia the decreased central compartment leads to increased concentration of the drug reaching the brain and heart, with resulting severe respiratory and CVS depression there is also a decreased rate of redistribution
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Pharmacodynamics
Recommended Dosage a. b. c. healthy adults > 65 yrs children (5-15) ~ 3.0 to 5.0 mg/kg ~ 1.8 to 2.5 mg/kg ~ 5.0 to 7.0 mg/kg (Cote et al 1981) (Stanley 1981)
Concentration - Response the required total plasma [STP] for surgical anaesthesia ~ 40 g/ml (Becker 1978) the free fraction of thiopentone ~ 15%, equating to a free drug level of ~ 6 g/ml plasma levels of ~ 30-50 g/ml are required for total saturation of the metabolic pathway zero order kinetics
opioid premedication reduces thiopentone requirements by ~ 50% N2O/O2 (67%) reduces the thiopentone anaesthetic concentration by 65-70% there are conflicting reports on acute tolerance but it is probably of little or no clinical significance the original reports (Brodie et al., Toner et al.) used venous plasma levels, which were subsequently shown not to correlate well with internal jugular/brain venous levels
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Pharmacological Actions
CNS Effects 1. Sleep injection of 3.5-4.0 mg/kg results in a smooth onset of sleep & unconsciousness usually unaccompanied by spontaneous movement or respiratory excitatory phenomena Analgesia the barbiturates are poor analgesics in subanaesthetic doses and hyperaesthesia to surgical stimuli may occur when given in low doses (25-150 mg of thiopentone) this may manifest as i. tachycardia ii. hypertension iii. diaphoresis iv. tearing v. tachypnoea vi. increased laryngeal & pharyngeal reflexes vii. postoperative restlessness these features are more common in children Anaesthesia thiopentone usually produces short-lived surgical anaesthesia within 1-2 mins of injection, lasting from 5-8 minutes however, surgical stimulation at this time may lead to laryngeal spasm deeper levels of anaesthesia can be achieved which avoid this, however there may be significant CVS/CNS depression Cerebral Metabolism & Circulation there is a decrease of cerebral blood flow (CBF ~ 50%) and cerebral metabolism (CMRO2 ~ 50%) with anaesthetic doses of thiopentone in patients with decreased intracranial compliance, or increased ICP, the barbiturates increase the cerebral perfusion pressure,
2.
3.
4.
CPP = MAP - ICP

this is due to their greater effect on decreasing ICP than arterial BP this profound cerebral vasoconstriction may be offset by increases in PaCO2 therefore, in the absence of controlled ventilation and normocapnia, thiopentone may increase CBF secondary to decreased respiration 5. Other effects in common with other members, thiopentone possesses anticonvulsant activity
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CVS Effects NB: venous tone consistently decreases with a resulting decrease in venous return and this is the predominant cardiovascular effect total peripheral resistance may either decrease or increase usually the initial decrease in CO & BP are compensated for by increased SNS tone when SNS tone is already high, such as in hypovolaemia from any cause, even small doses of thiopentone may result in profound decreases in CO & BP the vascular effects are due to a central action and to a lesser degree a direct action on venous smooth muscle thiopentone produces a dose related depression of myocardial function, however, this is less than that seen with the volatile agents usual clinical doses 10 to 25% decrease in contractility, related to the speed of injection and the status of the patient there is a reflex increase in HR and myocardial MRO2, leading to a decrease in coronary vascular resistance and an increase in coronary blood flow the arteriocoronary venous O2 difference remains unchanged, providing mean arterial pressure is not drastically lowered thus, if coronary perfusion is decreased due to lowered BP, ischaemia may result and thiopentone should be used cautiously in patients with heart disease particularly conditions where an increase in HR or reduction in preload may be detrimental, such as, i. pericardial tamponade ii. valvular heart disease iii. CCF iv. IHD v. high degree AV block hypotension is greater in both treated and untreated hypertension this may result from blunting of the baroreceptor response, relative hypovolaemia or -blockade Respiratory Effects usual anaesthetic dose of thiopentone 2 or 3 hyperpnoeic breaths followed by apnoea respiratory depression is dose related, with reduction in ventilatory responsiveness to CO2 and hypoxia these effects are potentiated by opioid premedication the respiratory pattern rapidly returns to normal however the CO2/O2 response curves remain depressed for some time hypoxic pulmonary vasoconstriction is unaffected by the intravenous agents in general there is a low incidence of laryngo & bronchospasm, unless the upper airways are stimulated by excess secretions, artificial airways or attempted intubation laryngeal reflexes are not depressed until deep levels of anaesthesia thiopentone is safe in asthmatic patients but does not cause bronchodilatation, as does ketamine
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Hepatic & Renal Effects there are no apparent significant effects on liver function, except that prolonged exposure may cause enzyme induction renal effects are 2 to RBF/GFR which are dependent on cardiac output and reflex SNS tone Other Effects there is a clinically insignificant increase in the BSL and impairment of glucose tolerance plasma insulin levels are unchanged heat loss in increased from peripheral vasodilatation thiopentone decreases plasma cortisol levels but does not blunt the response to surgical stimulation, in contrast to etomidate which does both there is a dose related release of histamine, which is usually not significant thiopentone has no effects on the gravid uterus, although the drug crosses the placenta to foetus foetal levels are low when thiopentone is used as single dose in caesarian section, and are maximal at ~ 3 minutes after injection Kosakas et al. showed no significant foetal depression in 75-95% of infants in doses ranging from 4-7 mg/kg this was due to, a. b. c. foetal hepatic extraction of the drug from umbilical venous blood extensive shunting in the foetal circulation the rapid decrease of maternal blood concentrations
neurobehavioural studies do indicate more neonatal sedation following thiopentone than after ketamine induction or epidural anaesthesia STP has no effects or interactions at the NMJ, though, central effects may decrease muscular tone intraocular pressure is reduced ~ 40% after an induction dose subsequent administration of succinylcholine returns IOP to pre-induction values however, if 2 minutes is allowed to intervene, then IOP is raised above pre-induction values
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Clinical Use
a. b. c. d. e. f. g. induction of anaesthesia as sole anaesthetic as supplementation to other drugs in conjunction with regional anaesthesia to treat status epilepticus as a sedative for cerebral protection with raised ICP
normally given intravenously in a 2.5% solution can also be given per rectum in a 5-10% solution sleep is induced within 10-15 secs in normal individuals the effects of a single dose last for 5-10 mins Brain Protection the principal protective effect of the barbiturates is a dose dependent reduction in CMRO2 this parallels the reduction in EEG activity until the EEG becomes isoelectric after this point no further reduction is achieved proposed that this effect would offer cerebral protection in injuries associated with raised ICP (Shapiro et al. 1973) other protective effects may include, a. b. c. d. e. inverse steal - vasoconstriction in healthy brain shunting blood to diseased areas a reduction in ICP and increase in cerebral perfusion pressure stabilisation of liposomal membranes scavenging of free radicals its anticonvulsant effects
the data are somewhat variable, due to different models and different species a number of randomised studies have shown no improvement in survival in the barbiturate treated group (global ischaemic injury) thus, the addition of barbiturate coma does not seem warranted due to the risk of cardiovascular instability (Matjasko, Pitts & Katz 1986) this contrasts models of focal ischaemia, where barbiturate administration reduces infarct volume the one exception to this is in young head injuries, where the initial response is a dramatic rise in ICP secondary to generalised hyperaemia this is also a group where mannitol is contraindicated
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Contraindications & Precautions
Contraindications a. b. proven allergy - rare but high fatality rate
if airway is obstructed or in doubt - Ludwig's angina - tonsillar bleed - carotid bleed uncompensated heart disease - mitral stenosis - constrictive pericarditis - aortic stenosis - any cause, including Addison's
c.
d. e. f. g.
severe shock or hypovolaemia status asthmaticus porphyria
absence of IV access, or general anaesthetic equipment
Precautions a. b. c. d. e. cardiovascular disease - IHD, hypertension, valvular disease hypovolaemia uraemia septicaemia elderly - haemorrhage, burns, fluid depletion, dehydration
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Porphyria
an inborn error of metabolism with abnormal porphyrin metabolism porphyrin consists of 4 pyrrole rings linked by -CH- bridges found in haemoglobin, plus some of the cytochrome and peroxidase enzymes the rate limiting reaction for its synthesis is catalyzed by -aminolevulinic acid synthetase this is responsible for the production of -ALA from succinate & glycine within the mitochondria this enzyme is induced by the barbiturates and is increased in certain types of porphyria, i. acute intermittent porphyria ii. variagate porphyria iii. coproporphyria not in porphyria cutanea tarda the clinical syndrome includes intermittent attacks of i. nervous system dysfunction ii. abdominal pain iii. skin sensitivity to sunlight (not in AIP) administration of barbiturates to these patients may result in paralysis and death other drugs which may exacerbate the condition include, i. barbiturates ii. diazepam ? rest of benzodiazepines iii. alcohol iv. anticonvulsants v. oestrogen vi. other hormones vii. hypoxia drugs that are usually safe in this condition include, i. propofol ii. opioids iii. volatile anaesthetics iv. N2O v. succinylcholine vi. atropine & neostigmine vii. phenothiazines viii. propranolol treatment of acute attacks includes, a. b. infusion of glucose haematin - negatively feeds-back against ALA-synthetase activity - also acts at this step
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Complications
Local subcutaneous administration causes pain, redness and swelling due to the high alkalinity this may be treated by infiltration of the area with 1% procaine and hyaluronidase intra-arterial injection may result in significant damage to the vessel, a. b. c. vascular spasm & pain loss of distal arterial pulses gangrene and permanent nerve damage
therefore, when giving thiopentone IV, a test dose of 2-4 ml should be given treatment includes, a. b. c. leave the needle in the lumen of the artery dilute with saline & give 0.5% procaine 10-20 ml give papaverine 40-80 mg in 10-20 mls saline if possible, or give an alpha-blocker, or brachial plexus or stellate ganglion block anticoagulants if necessary
d.
thrombophlebitis is uncommon with the 2.5% solution up to 5% of patients may have a painless thrombosis General a. b. c. d. e. overdosage, leading to respiratory, CVS and CNS depression (~ 1:14,000) allergic reactions are rare but usually severe histamine release may occur, with the appearance of an urticarial type rash laryngeal spasm may occur, especially with light anaesthesia bronchospasm, principally in asthmatics due to increased vagal reflexes but rarely severe excitatory phenomena, these may occur but are less than with methohexital and may be reduce by opioid premedication
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METHOHEXITONE
Structure:
Chemical name: Introduced: Lipid Solubility: Acid dissociation K: Solution pH: Protein binding: Pharmacokinetics:
-dl-1-methyl-5-allyl-5-(1-methyl-2-pentynyl) -barbituric acid 1950's high pKA pH 70-80 % ClSS VdSS t ER = = = = 10.9 3.0 2.2 0.7 3.9 2.1 0.5 ml/kg/min l/kg hrs Stoelting (slightly < thiopentone) = 7.9 = 10-11
Chemistry
introduced in the late 1950's (Stoelting) as an agent with a more rapid recovery than thiopentone methohexitone is an oxybarbiturate with a methyl group at the 1-Nitrogen methohexital has 2 asymmetrical C-atoms, thus has 4 isomers which have been divided into 2 pairs -dl & -dl the racemic mixture of all four is a potent agent, however results in excessive skeletal muscular activity and convulsions thus, the available solution is only the -dl pair and is ~ 2-3x as potent as thiopentone it gives minor excitatory effects in ~ 33% of patients presented as a white powder mixed with 6% sodium carbonate to ensure stabilization and is stable for up to 6 weeks after preparation the prepared solution is 1% with a pH ~ 10-11
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Pharmacokinetics
similar to thiopentone, methohexital is highly lipid soluble, is 75% unionised at pH = 7.4 and is 70-80% protein bound therefore, methohexital has similar pharmacokinetics to thiopentone, ie., redistribution from brain to peripheral tissues accounts for rapid recovery after a single dose methohexital is slightly less lipid soluble than thiopentone, thus has a smaller VdSS ~ 1.1-2.2 l/kg, c.f. thiopentone ~ 1.7-2.5 l/kg (W&W) the kinetics follow a 2-compartment model with a short distribution half life, t ~ 6.2 min elimination is almost entirely by the liver the clearance ~ 10-12 ml/kg/min, is about 3x higher than that of thiopentone therefore after multiple doses, despite accumulation of methohexital in the peripheral tissues, recovery is more rapid than with thiopentone the elimination half-life, t ~ 1.6-3.9 hours (W&W = 97 min)
Pharmacodynamics
methohexitone is about 2.5-3.5 times as potent a cerebral depressant as thiopentone it has a shorter duration of action than thiopentone, especially the time to full recovery CNS a 1-1.5 mg/kg dose causes loss of consciousness in one arm/brain circulation time with recovery of consciousness after 2-3 minutes induction is frequently accompanied by transient twitching of skeletal musculature hiccup & laryngospasm occur in up to 45% of unpremedicated patients the incidence is reduced premedication with opiates or benzodiazepines it should not be used in patients with history of epilepsy as convulsions can be precipitated this is generally attributed to the ring N1-methyl group in its structure Respiratory similarly to thiopentone, transient respiratory depression occurs with up to a 50% reduction of respiratory drive for a few minutes after administration methohexital does not cause bronchospasm in asthmatic patients Cardiovascular causes less cardiovascular depression than thiopentone however, also acts on the sympathetic nervous system with resulting vasodilatation in clinical doses there appears to be little effect on arterial blood pressure
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Other Effects methohexitone is non-irritant with low incidence of venous thrombosis or tissue damage after perivenous injection after intra-arterial injection, thrombosis and gangrene may occur, depending on the dosage, concentration and volume injected the 1% solution is relatively safe treatment of intra-arterial injection is the same as for thiopentone
Clinical Use
similar indications to thiopentone but especially useful in the outpatient surgery when rapid recovery is desirable also used for electropexy can also be administered per rectum, 15-20 mg/kg Precautions essentially the same precautions as for thiopentone, but also avoid usage in epileptics
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BENZODIAZEPINES
the benzodiazepines were discovered accidentally chlordiazperoxide (Librium) was synthesised by Sternbach in 1955 but discarded because it was presumed to be inert the sedative hypnotic effects were discovered in mice in 1957 and it was released in 1960 diazepam was synthesised by Sternbach in 1959 and its metabolite, oxazepam, by Bell in 1961 the next major achievement was the synthesis of the water soluble midazolam by Fryer and Walser in 1976 the existence of a benzodiazepine receptor (BZR) was first discussed in Milan in 1971 isolation and receptor-ligand interaction were demonstrated in 1977 this has resulted in the generation of a number of new ligands and a specific antagonist the term benzodiazepine refers to the portion of the structure composed of the following, a. b. a benzene ring, fused to a seven member diazepine ring
NB: however, since all of the important members of the group contain a 5-aryl substituent and a 1,4-diazepine ring, the term has come to refer to the 5-aryl-1,4-benzodiazepines
the 5-aryl ring greatly enhances potency from standpoint of anaesthesia diazepam, lorazepam and midazolam are of particular interest diazepam and lorazepam have quite similar structures, while midazolam contains an imidazole ring bridging R1 and R2 (see G&G. table 17-1) both diazepam and lorazepam are insoluble in water, therefore require solubilizing agents, while the imidazole ring renders midazolam water soluble
24
Pharmacological Properties
Mechanism of Action most, if not all, of the actions of these drugs are the result of potentiation of the neural inhibition mediated by gaba-aminobutyric acid the binding of the benzodiazepines to the receptor is of high affinity, saturable and stereospecific the rank order of receptor affinity is, a. b. c. diazepam x1 midazolam x 3-4 lorazepam x 5
NB: this parallels their respective potencies possible actions which lead to an increased release of GABA cannot be excluded, but most of the action is due to potentiation of GABA induced increases in chloride conductance this accounts for the relative safety of this group, their effects requiring the central release of a neurotransmitter the barbiturates have similar effects in low doses, however, also inhibit the release of excitatory neurotransmitters at high doses dynamic pharmacokinetic models suggest that the different benzodiazepine effects correlate with different levels of receptor occupancy, a. b. c. anxiolysis sedation unconsciousness ~ 20% ~ 20-50% ~ 60%
these neurones are regulated by both feedforward and feedback inhibitory pathways, composed of small GABA'ergic interneurones GABA induced increases in gCl-, especially in the region of the axon hillock, effective shunt electrical currents which would otherwise depolarise the membrane the benzodiazepines decrease spontaneous and evoked electrical activity in major (large) neurones in all regions of the spinal cord and brain the specific binding sites are more concentrated in the brain and binding of benzodiazepines is increased by both Cl- ions and GABA high concentrations are predominantly found in the, a. b. c. limbic system cerebral cortex cerebellum - particularly the hippocampus and amygdala
low concentrations are found in the brain stem and spinal cord there are two subtypes of GABA receptor, the benzodiazepine receptor appearing to be a part of the GABAA complex, located on the subsynaptic membrane of the effector neurone
25
Benzodiazepine/GABA Receptor
this receptor is a tetramer composed of two protein subunits with a central Cl- channel, in an 22 configuration these proteins contain the ligand binding sites for the benzodiazepines, barbiturates and GABA the benzodiazepine site is located on the -subunit, while that for GABA is on the -subunit there are three subclasses of receptor ligands for the benzodiazepine portion of the GABAA receptor, 1. 2. 3. agonists antagonists inverse agonists - benzodiazepines & barbiturates - flumazenil - DMCM
the benzodiazepines alter the conformation of the receptor such that the affinity for GABA is increased with a resultant increase in Cl- channel activation antagonists occupy the receptor but have no intrinsic activity, therefore they prevent the effects of both agonists and inverse agonists, ie. they do not affect the binding of GABA NB: inverse agonists occupy the receptor and reduce the affinity for GABA, thus they result in CNS stimulation
Central Nervous System

the pharmacological effects of the benzodiazepines all result from actions in the CNS, and include, a. b. c. d. e. f. anxiolytic sedative hypnotic muscle relaxant amnesic anticonvulsant
only one member, alprazolam, appears to have antidepressant activity only two effects appear to result from actions in the periphery, 1. 2. coronary vasodilatation, seen after IV injection of some agents neuromuscular blockade, only at very high doses
the benzodiazepines are not general neuronal depressants, as are the barbiturates, and all members have a similar pharmacological profile the exception of the anticonvulsant and possibly analgesic effects of certain members in man, as the dose is increased, sedation progresses to hypnosis then stupor
26
the drugs do not cause true general anaesthesia, since awareness usually persists and relaxation sufficient for surgery cannot be achieved they do cause anterograde amnesia (following injection) which gives the illusion of anaesthesia some members induce muscle hypotonia, without interfering with locomotion, and may decrease decerebrate rigidity tolerance develops to both of these effects similarly, tolerance develops to their anticonvulsant activity and this limits their usefulness in the long-term management of epilepsy the effects on sleep are similar for most members, i. decreased sleep latency ii. diminished number of awakenings and time in stage 0 iii. time in stage 2 (major non-REM component) is increased iv. marked decrease in slow wave sleep (stages 3&4)* v. increase in REM latency (onset of spindle to 1st REM burst) vi. decreased frequency of eye movement during REM sleep vii. decreased time spent in REM sleep* but increased number viii. increased total sleep time NB: *with the exception of temazepam the amnesic effects are useful for preventing awareness during anaesthesia and the sedative effects are useful in ICU and during regional anaesthesia (this is incorrect !!, they prevent recall of awareness, anxiety & autonomic response still occur) benzodiazepines generally have no analgesic properties but they appear to potentiate the effects of both the narcotics and anaesthetics diazepam causes transient analgesia after IV administration but this has not been reported with any other agents unlike the barbiturates, they do not cause hyperalgesia the benzodiazepines produce a dose related reduction in CMRO2 and cerebral blood flow in human volunteers, midazolam 0.15 mg/kg induces sleep and reduces CBF ~ 34%, despite an increase in PaCO2 from 34 to 39 mmHg EEG studies during the IV administration of midazolam show, i. rhythmic -activity ~ 22 Hz ~ 15-30 s ii. a second -rhythm ~ 15 Hz ~ 60 s iii. reappearance of -rhythm ~ 30 minutes however, even after 60 minutes there was resistant rhythmic -activity of 15-20 V amplitude similar EEG changes are seen with diazepam and are not generally consistent with light sleep, though, patients are such clinically thus, the effects on the waking EEG are similar to other sedative-hypnotic drugs, i. alpha activity is decreased ii. increase in low voltage, fast activity, especially beta iii. the amplitude of somato-sensory EP's is reduced NB: (b) & (c) correlate with the anxiolytic effects
27
Common EEG Patterns

Beta Rhythm 15-30 Hz alert, active patient lower voltage predominantly in the frontal regions possibly a harmonic of the -rhythm 50 V maximal in the parieto-occipital area awake man, eyes closed, mind wandering large, regular waves originate in the hippocampus seen in children present with onset of sleep anaesthetic induction deepening anaesthesia
Alpha Rhythm
8-12 Hz
Theta Rhythm
4-7 Hz
Delta Waves
4 Hz
Respiration
the benzodiazepines have little effect on respiration, hypnotic doses are without effect in normal subjects the effects of midazolam may be greater in this area, though, comparative studies do not exist "pre-anaesthetic" doses do cause a decrease in alveolar ventilation and a respiratory acidosis 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 in patients with obstructive pulmonary disease they may result in significant respiratory depression, CO2 retention and narcosis diazepam 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, a. b. c. old age debilitating disease other respiratory depressant drugs
28
Cardiovascular
the CVS effects are minor, except after severe intoxication in "pre-anaesthetic" doses they decrease the BP and increase the HR, a. b. decrease peripheral resistance decrease LV work and cardiac output - flunitrazepam - midazolam - diazepam - lorazepam
baroreceptor reflexes generally remain intact, though, there is some depression the hypotensive effect is minimal and usually less than that seen with thiopentone the effect is possibly slightly greater with midazolam and is dose related in patients with elevated cardiac filling pressures, both midazolam and diazepam produce a "nitroglycerine like" effect, reducing preload and increasing cardiac output diazepam increases coronary blood flow in man, possibly by increasing interstitial concentrations of adenosine thus, diazepam may provide some protective function in patients with IHD used alone they do not provide protection against the stress of endotracheal intubation the addition of N2O has minimal haemodynamic effect however, when combined with opioids there is a synergistic effect, the combination producing greater decreases in BP than either agent alone NB: there are few contraindications except for obstetric and perinatal anaesthesia
Pharmacokinetics
all members have high lipid:water partition coefficients in the non-ionised form however, lipophilicity varies over 50-fold according to the polarity of the ring substituents all members are essentially completely absorbed after oral administration, with the exception of cloazepate, which is converted to nordiazepam in the stomach, then absorbed after oral absorption, the time to peak plasma concentrations varies from 0.5 to 8 hrs with the exception of lorazepam, most members are erratically absorbed after IM injection the benzodiazepines, and their active metabolites, bind to plasma proteins in direct correlation with their lipid solubility ranging from alprazolam ~ 70% to diazepam ~ 99% the concentrations in CSF are approximately equal to the plasma free fraction competition with other protein bound drugs may occur, however there are no clinically significant examples redistribution is the major determinant of the onset and duration of effect after a single IV dose, not the rate of elimination most benzodiazepines exhibit patterns consistent with two or three-compartment models the kinetics of diazepam and the other highly lipid soluble agents are complicated by enterohepatic circulation with repeated dosages, the elimination half-life and plasma clearance remain determining factors
29
due to the slow onset of hypnosis, benzodiazepines are not generally good induction agents for routine anaesthesia, with the possible exception of midazolam they are useful when CVS stability is important and slow induction permissible the volumes of distribution are large and many are increased in the elderly these drugs readily cross the placenta and are excreted in the breast milk
Classification by Duration of Action

Longer acting t > 24 hrs diazepam ~ 40 hrs nitrazepam flunitrazepam clorazepate lorazepam temazepam oxazepam lormetazepam midazolam ~ 2 hrs triazolam
Intermediate
t ~ 6-24 hrs
Shorter acting
t < 5 hrs
the longer acting agents are metabolised in the liver by microsomal mixed function oxygenase enzyme systems many of the metabolites (eg., desmethyldiazepam) are pharmacologically active, contributing to clinical effect of the drugs and extending the effective half-life (see G&G table 17-3) these agents cause minimal enzyme induction intermediate and short acting agents are inactivated by glucuronidation and then eliminated by renal excretion therefore, for the elderly and patients with hepatic disease, the intermediate and shorter acting agents are preferable cimetidine prolongs the effect of those agents susceptible to liver MFO systems ranitidine has no effect on metabolism of any benzodiazepines factors known to influence the pharmacokinetics of the benzodiazepines include, i. age ii. gender iii. race iv. enzyme induction v. hepatic disease vi. renal disease these drugs are all affected by obesity, the increased lipid stores increasing their respective volumes of distribution and elimination half lives therefore, induction doses need to be increased, whereas infusion rates are unaltered
30
Adverse Reactions & Precautions
at peak plasma concentrations these agents will produce varying degrees of, i. light-headedness ii. lassitude iii. slowed reaction time iv. ataxia v. confusion vi. dysarthria vii. anterograde amnesia viii. impairment of cognitive function interactions with ethanol may be serious psychotic ideation rarely occurs but is more common in mentally ill patients rebound anxiety, "withdrawal type" syndromes occur after cessation of prolonged therapy and are probably more common than reported rebound insomnia also may occur after cessation with chronic use they may lead to abuse & dependence, though, this is far less than with the barbiturates
31
DIAZEPAM
first synthesised in 1959 and later introduced in 1961 insoluble in water, therefore prepared commercially in an organic solvent, each ml of solution containing, a. b. c. d. e. diazepam propylene glycol ethyl alcohol benzyl alcohol sodium benzoic acid 5 mg 0.4 ml 0.1 ml 0.015 ml to pH = 6.2-6.9
now available also as an intralipid / water emulsion (Diazemuls) despite its high lipid solubility, the CNS effects (drowsiness and hypnosis) after intravenous administration have a slow or irregular onset and thus it is not very useful as an induction agent more commonly used as a sedative in premedication and during regional procedures premedication is usually given in oral form with peak plasma levels occurring between 30-60 minutes after oral administration the clearance of diazepam is dependent on phase I hepatic metabolism, being oxidised and reduced to form active metabolites, a. b. c. desmethyldiazepam 3-hydroxydiazepam oxazepam - N-desmethylation - ring hydroxylation - ring hydroxylation
NB:
these prolong the duration of CNS effects
these undergo phase II reactions with conjugation to form inactive water soluble glucuronides
Pharmacokinetic Data - Diazepam

VdSS Clearance Hepatic extraction ratio Elimination half-life, t Plasma free fraction ~ 0.7 - 1.7 ~ 0.2 - 0.5 ~ 0.01 - 0.025 ~ 20 - 50 ~1-2% hrs l/kg ml/kg/min
32
plasma binding can be influenced by age and disease states other drugs can affect its clearance and thus its elimination half-life during labour diazepam accumulates in foetal blood, where its free fraction may be as high as 15% with marked effects on the new-born in liver disease VdSS is increased and together with a reduced capacity for metabolism thus the elimination half-life may be increased up to 2-fold chronic renal failure results in an increase of the unbound fraction this would increase clearance by 2-3 times, shortening its half-life, however, there is also an increase in VdSS counteracting this effect in the elderly the elimination half-life is increased due to changes in both tissue distribution and protein binding there is a great inter-individual variation with dose-effect
Pharmacology
no significant effects on CO or BP may increase heart rate and (?) decrease peripheral vascular resistance no effect on cerebral blood flow (G&G) dose dependent reduction in CMRO2 and reduction in CBF by 30% (Miller) decreases the MAC of inhalational anaesthetics (eg. Halothane ~ 30%) there are slight but insignificant effects on breathing in clinical doses relieves muscle spasm and spasticity via a central effect probably no significant interaction with muscle relaxants though Feldman and Crawley (1970) found that diazepam potentiated non-depolarizing agents and prolonged the effects of suxamethonium the findings of this study have not been confirmed by others
33
MIDAZOLAM
a water-soluble, short acting drug synthesised in 1976 by Fryer and Walser it displays pH dependent opening of the benzodiazepine ring below a pH ~ 4.0 thus, at physiological pH the ring is closed and lipid solubility is increased, with increased penetration of the BBB useful in oral, IM and IV administration its water solubility minimizes the pain on injection and the incidence of venous thrombosis midazolam has about 3x the sedative potency of diazepam anxiolytic, anticonvulsant, sleep inducing, "muscle relaxant" and anterograde amnesic actions are qualitatively similar to diazepam anterograde amnesia is shorter than that of lorazepam the induction dose for anaesthesia ~ 0.15-0.36 mg/kg, cf. sedation doses ~ 0.01-0.08 mg/kg the onset is slow ~ 2-3 mins and individual variability of response is wide recovery is rapid, making it a suitable agent for outpatient anaesthesia causes minimal changes in CVS function with a small increase in heart rate and a decrease in systemic vascular resistance therefore, midazolam is useful in patients with compromised cardiac function as the reduction in preload and afterload may improve the performance of the failing heart midazolam reduces the adrenergic, but not cortisol or renin, responses to surgical stress there is a decrease in blood flow to the liver and kidneys but no significant prolonged reduction in respective function cerebral and myocardial blood flow are reduced in proportion to respective reductions in MRO2
Pharmacokinetics Pharmacokinetic Data - Midazolam

VdSS Clearance Hepatic extraction ratio Elimination half-life, t Plasma free fraction ~ 1.1 - 1.7 ~ 6.4 - 11 ~ 0.3 - 0.5 ~ 1.7 - 2.6 ~3-4% hrs l/kg ml/kg/min
after IV injection there is rapid distribution/redistribution oral doses of 10-40 mg produce peak plasma levels within 30 minutes the VdSS ~ 1.1-1.7 l/kg and is increased in, i. women ii. obese individuals iii. the elderly
34
there is extensive plasma protein binding ~ 96-97% has a high clearance = 6.4-11 ml/kg/min, being, a. b. ~ 5 x that of lorazepam ~ 10 x that of diazepam
this more extensive hepatic metabolism is also due to the presence of the imidazole ring the extraction ratio ~ 0.3-0.5 metabolism occurs by oxidation, conjugation to water soluble glucuronides and then excretion by the kidneys thus, its eliminated half-life, t = 1.7-2.6 hrs, is shorter than any other benzodiazepine used in anaesthesia midazolam, therefore, is a useful drug, a. b. c. in outpatient anaesthesia for sedation in minor procedures and regional anaesthesia for sedation in intensive care
LORAZEPAM
less lipid soluble than diazepam with slow entry into CNS and a slower onset of action therefore, it is not very useful as induction agent and thus its major use in anaesthesia is for premedication both oral and intramuscular administration results in reliable absorption clearance is dependent on hepatic metabolism, the drug being directly conjugated to glucuronides
Pharmacokinetic Data - Lorazepam

VdSS Clearance Hepatic extraction ratio Elimination half-life, t Plasma free fraction ~ 0.8 - 1.3 ~ 0.8 - 1.8 ~ 0.3 - 0.5 ~ 11 - 22 ~ 10 % hrs l/kg ml/kg/min
drug disposition is not significantly affected by age its elimination half-life is unaltered in renal disease hepatic disease causes an increase in the elimination half-life (protein binding and tissue distribution)
35
Approximate Pharmacokinetic Data

Drug Diazepam Midazolam Lorazepam VdSS 1 - 1.5 1 - 1.5 1 - 1.5 l l l t 20-40 2-4 10-20 hrs hrs hrs Dose (70 kg) 10-20 10-40 1-3 mg mg mg
FLUMAZENIL
(ANEXATE)
synthesised in 1979, this is the first benzodiazepine antagonist released for clinical use it is structurally similar to midazolam, except, a. b. the 5-phenyl group is replaced by a carbonyl group the benzene ring has an F- substitution cf. the usual Cl-
it is a competitive ligand with minimal intrinsic activity and high receptor affinity thus, its actions are, a. b. c. concentration dependent reversible, and surmountable
the proportion of receptors occupied by agonist obeys the law of mass action and depends upon the respective receptor affinities and concentration of the two ligands being a high affinity ligand it will readily replace weak affinity agonists such as diazepam, providing a sufficient concentration is achieved flumazenil is, however, rapidly cleared and the potential for resedation exists this is less likely to occur with midazolam, both agents being cleared at a similar rate given alone it may produce withdrawal phenomena in humans or animals physically dependent upon benzodiazepines this is not a problem with acute reversal post-anaesthesia the onset of effect is rapid, reaching a maximum at ~ 1-3 minutes due to the different affinities of the respective agonists, different plasma levels of flumazenil are required for adequate reversal studies indicate it is devoid of the cardiovascular and respiratory effects of the agonist agents incremental doses up to 3.0 mg in patients with IHD had no effect on CVS variables administration to patients given agonists is also free of cardiovascular effects, unlike opioid reversal by naloxone the opioid reversal hyperdynamic response, believed to be due to catechol release, is not seen however, the rise in catecholamines seen with arousal is more rapid after flumazenil
36
Usual Doses of Flumazenil
Reversal of benzodiazepines Infusion rates Diagnosis of Coma
1
0.1 - 0.2 mg 3.0 mg 0.5 mg 1.0
maximum
0.5 - 1.0 g/kg/min mg maximum1
studies suggest there is no "safe" upper limit, however if coma is due to BZD overdose, then some reversal should be seen at this dose.
Pharmacokinetics Pharmacokinetic Data - Flumazenil

VdSS Clearance Hepatic extraction ratio Elimination half-life, t Plasma free fraction ~ 0.6 - 1.6 ~ 5 - 20 ~ 0.25 - 0.9 ~ 0.7 - 1.3 ~ 55-65 hrs % l/kg ml/kg/min
undergoes hepatic metabolism to 3 metabolites, which are subsequently conjugated and excreted the activity of these species is unknown the clearance is the highest of any of these agents, partly due to the presence of the imidazole ring but also due to the high free fraction repeated administration or continuous infusion is required to maintain therapeutic levels there are no specific contraindications to its use large oral doses appear to be devoid of toxic local or systemic side effects ICU studies in the management of drug overdosage have used "massive doses" with relative clinical impunity the only potential hazard could be the occurrence of seizure activity in patients chronically addicted to benzodiazepines the major precaution is re-sedation due to the rapid elimination
37
PROPOFOL
Structure:
(DIPRIVAN)
Chemical name: Introduced: Lipid Solubility: Solution pH: Protein binding: Pharmacokinetics:
2,6-di-isopropyl-phenol 1977 high pH ~ 90 % ClSS VdSS t ER = = = > 20-30 2.0-10 4-7 1.0 ml/kg/min l/kg hrs = 7.0 Kay and Rolly
2,6-diisopropyl-phenol, a member of the group of hindered phenols, an alkylphenol derivative first clinical trials in 1977 by Kay and Rolly propofol is insoluble in water and was first solubilised in cremophor EL this was withdrawn from the market due to anaphylactoid reactions it was subsequently reformulated in an emulsion with intralipid, a. b. c. d. propofol soyabean oil glycerol purified egg phosphatide 1% wt./vol. 10% 2.25% 1.2%
the solution has a pH ~ 7.0 and is stable at room temperature and not sensitive to light it is compatible in 5% dextrose if dilution is required
38
Pharmacokinetics Pharmacokinetic Data - Propofol Adults Children1
VdInit. VdSS Clearance Hepatic extraction ratio
2
~ 0.2 - 0.6 ~ 1.1 - 1.7 ~ 20 - 30 1.0 ~2-8 ~ 30 - 60 ~ 240 - 420 ~ 2 - 10 %
l/kg l/kg ml/kg/min min min min
~ 0.3 - 0.7 ~ 2 - 24 30 - 40 1.0 1 - 6.5 9 - 56 210 - 735
l/kg l/kg ml/kg/min min min min
Distribution half-life t1 Distribution half-life t2 Elimination half-life Plasma free fraction

1 2
data for children show wide variations, only a small numer of studies, poorly controlled for age etc. plasma clearance > hepatic blood flow, therefore either extrahepatic clearance, or simply measuring redistribution to lipid stores
IV administration of propofol results in rapid loss of consciousness, slightly slower than IV barbiturates, with a very rapid recovery following single dose or infusion the mean recovery time after a bolus dose of 2 mg/kg is ~ 4-5 mins as with other induction agents, redistribution causes the rapid recovery due to rapid metabolism there is minimal accumulation after repeated doses the VdSS ~ 4.6 l/kg is very high, representing a large tissue depot the clearance ~ 20-30 ml/kg/min, is greater than hepatic blood flow originally it was suggested there may be extrahepatic elimination of the drug this figure actually represents redistribution plus liver metabolism the majority of metabolism does occur in the liver the "effective" elimination half-life for single bolus injections, or small multiple boluses, therefore becomes, t2 ~ 30-60 mins only with prolonged administration does the true elimination half life become clinically significant, t ~ 4-7 hr
39
the pharmacokinetics are altered by a number of factors, a. the elderly clearance is significantly decreased due to decreased hepatic blood flow the initial volume of distribution is decreased therefore, the dose should be decreased in elderly patients women higher volumes of distribution and clearance rates the elimination half live is however similar hepatic disease both the central and steady state Vd are increased clearance is unchanged the elimination half life is slightly prolonged renal disease little effect on the pharmacokinetics of propofol confirs the high capacity of the liver to metabolize the drug fentanyl administration may decrease the clearance of propofol
b.
c.
d.
e.
Usual Doses of Propofol

Induction of Anaesthesia 2.5-3.5 mg/kg (child) 1.0-2.5 mg/kg (adult) less if age > 50 yrs 50-150 g/kg/min1 N2O opiates g/kg/min
Maintenance of Anaesthesia
Sedation
1
25-75
1 ml/kg/hr
start at
= 10 mg/kg/hr = 166 g/kg/min ~ 1.0 ml/kg/hr and adjust to clinical effect
40
Pharmacodynamics
Central Nervous System propofol is primarily hypnotic unlike the barbiturates it is not antalgesic but it has not been established if it has analgesic actions the average induction dose ~ 2-2.5 mg/kg results in unconsciousness in one arm-brain circulation time this should be decreased in patients who are heavily premedicated, in the elderly, or patients with debilitating disease ~ 1.5-2 mg/kg for maintenance, intermittent doses or an infusion can be used at a rate of 6-12 mg/kg/h there is an increased incidence of spontaneous movement, though, less than that seen with methohexitone propofol displays hysteresis of its hypnotic effect lower doses can induce anaesthesia (1-1.5 mg/kg) but the time to onset is longer the duration of hypnosis is also dose dependent, generally lasting 5-15 minutes after a 2-2.5 mg/kg induction dose propofol alters mood less than thiopentone after short procedures and tends to produce a general state of well being initial studies in mice indicated it was neither anticonvulsant nor epileptogenic it does, however, result in a shorter duration of motor and EEG activity following ECT, as compared to thiopentone & methohexital there are isolated reports of it being used to treat seizures conversely, it has been associated with grand mal seizures and has been used for cortical mapping of epileptogenic foci there is a strong correlation between the log blood propofol level and percent EEG -activity and an inverse correlation with percent -activity propofol will decrease ICP in patients with both normal and raised ICP in normals there is an associated small (~10%) decrease in cerebral perfusion pressure the addition of small doses of fentanyl, or supplemental doses of propofol are sufficient to blunt the rise in ICP associated with intubation normal vascular reactivity to PaCO2 is retained in the presence of raised ICP, there may be a large fall in CPP (30-50%), which may clearly be detrimental there is a reduction in CMRO2 ~ 36% propofol acutely reduced intraocular pressure by 30-40% this effect is greater than seen with thiopentone, and following a supplemental dose is more effective in preventing the rise in IOP associated with succinylcholine or intubation
41
Respiratory Effects there is a higher incidence of apnoea compared to other IV anaesthetics and the incidence is increased by, a. b. c. opioid or other premedication higher doses the rate of injection
a standard induction dose will produce apnoea in ~ 25-30% the major difference to other induction agents is that apnoea may be prolonged, lasting 30 secs following a 2.5 mg/kg induction dose, a. b. the respiratory rate is significantly reduced for 2 minutes tidal volume is significantly reduced for up to 4 minutes
maintenance of propofol anaesthesia by infusion at 100 g/kg/min results in, a. b. c. d. a decrease in tidal volume an increase in respiratory frequency unpredictable effects on minute volume a similar reduction in the slope of the CO2/ventilation response curve to that seen with 1 MAC halothane 6 mg/hr/kg = 0.6 ml/kg/hr ~ 40% ~ 20%
NB: 100 g/kg/min
doubling the infusion rate to 200 g/kg/min produces only a small decrease in tidal volume and a minimal decrease in the CO2 response curve this is in contrast to the volatile agents, where a doubling of FA will halve the CO2 response curve an induction dose of 1.5-2.5 mg/kg will cause a rise in PaCO2 of 15-25%, with a corresponding decrease in arterial pH PaO2 does not usually alter Cardiovascular the most prominent effect of propofol is a decrease in arterial BP during induction of anaesthesia 2-2.5 mg/kg results in a decrease of 25-40% in both systolic and diastolic blood pressures, while the heart rate remains stable this is associated with a decrease in CI, LVSWI, SVR, mean PAP, and PAOP the effect is maximal at ~ 2 mins after induction, and is due to, 1. 2. direct myocardial depression, plus decreased peripheral resistance and preload
NB: as HR is unaltered, it has been suggested that propofol "resets" the baroreceptor reflex
42
the hypotensive effect of propofol is potentiated by, a. b. c. d. e. f. large doses of propofol pre-existing CVS disease hypovolaemia or CVS decompensation advanced age premedication with opiates the concomitant use of N2O
care should be practiced with patients who are hypovolaemic or have poor LV function both coronary blood flow and myocardial MRO2 are reduced, implying that global myocardial supply-demand is maintained Other Effects the most significant side effect is pain on injection, especially in small veins incidence can be decreased by using larger veins, or mixing the drug with lignocaine propofol can be administered by infusion to sedate ICU patients prolonged infusions must consider the effect of volume as well as energy provided by intralipid NB: 3 mg/kg/hr provides ~ 555 kcal/24 hours this is equivalent to 25% of calorie requirements and 50% of lipid requirements per day the reports investigating C3 complement, immunoglobulin or histamine release following intravenous propofol have not found any changes in the levels of these in healthy volunteers prolonged infusion does not impair cortisol synthesis or the response to ACTH preliminary studies indicate it does not trigger malignant hyperpyrexia case reports suggest its use is safe in porphyria
43
KETAMINE
Structure:
Chemical name: Introduced: Lipid Solubility: Acid dissociation K: Solution pH: Protein binding: Pharmacokinetics: 1966 high pKA pH 45 - 50 % ClSS VdSS t t ER = = = = = 12 - 20 2.3 - 3.1 11 - 16 120 - 180 0.5 - 0.9 ml/kg/min l/kg min min Corssen & Domino (> thiopentone) = 7.5 = 3.5 - 5.5
phencyclidine was the first drug of this class to be used in anaesthesia it was synthesised by Maddox and introduced into clinical use by Greifenstein in 1959 although a useful anaesthetic, it had a high incidence of psychotomimetic side effects cyclohexamine, a cogner of phencyclidine was trialed in 1959 but was less efficacious and had the same side effects ketamine was synthesised by Stevens in 1962 and first introduced to clinical anaesthesia by Corssen and Domino in 1966 it was released for clinical use in 1970 it is an arylcyclohexylamine structurally related to phencyclidine it contains an asymmetrical C-atom, hence has two isomers the d-isomer is more potent but the parenteral solution is a racemic mixture ketamine hydrochloride is a white crystalline solid, soluble in water supplied in 1, 5, and 10% solutions which are stable at room temperature benzethonium chloride is added as preservative the solution has a pH ~ 3.5 to 5.5 ketamine has a pKA ~ 7.5 it has a lipid solubility ~ 5-10 times that of thiopentone
44
Pharmacokinetics
has similarities with STP ketamine is extremely soluble in fat, 5-10 times more soluble than STP however, plasma protein binding is limited 45-50% after intravenous injection, consciousness is lost within 1-2 minutes and the resultant anaesthesia lasts for ~ 20 minutes the distribution half-life is longer, t ~ 11-16 mins and the elimination half-life t ~ 2-3 hrs (W&W = 2.5) termination of the anaesthetic action is due to redistribution from the central compartment, early metabolism playing a lesser part the VdSS ~ 2.3 to 3.1 l/kg consistent with its high lipid solubility however, the clearance ~ 17.5-20 ml/kg/min, is rapid resulting in the relatively short elimination half life this is due to both the high hepatic extraction ratio ~ 0.9 and limited protein binding therefore, clearance will be sensitive to hepatic blood flow and agents such as halothane, which reduce this will decrease the clearance it can be administered IM with 93% bioavailability, but there is a delay of 20-25 mins prior to adequate anaesthetic levels the major pathway of metabolism is in the liver, with N-demethylation of the cyclohexylamine ring, forming norketamine (metabolite I) this is then hydroxylated to form hydroxy-norketamines, with up to 8 metabolites which may contribute to the undesirable side effects the activity of these metabolites has not been well studied, however, norketamine has ~ 20-30% of the activity of ketamine these are subsequently conjugated and excreted in the urine
45
Pharmacodynamics
Central Nervous System causes a "dissociative anaesthetic state" this is a functional and electrophysiological dissociation between the thalamocortical & limbic systems (ie., blocks transmission between thalamus and cortex) this state is characterised by catalepsy in which eyes remain open with slow nystagmic gaze, while corneal and light reflexes remain intact when administered in subanaesthetic concentrations, ketamine produces good analgesia at plasma levels one-eighth those required for anaesthesia this may be related to its ability to suppress laminae specific spinal cord activity (opioid -receptors, ? laminae II & III) ketamine induced psychotomimetic activity, emergence reactions, can be disturbing to physicians, nurses, other patients and the patient him/herself vivid dreams, hallucinations, and delirium are unpleasant for the patient and may occur in 5-30% a higher incidence of reactions is associated with, a. b. c. d. e. f. age sex > 16 yrs female > male
larger doses> 2mg/kg IV rapid IV administration subjects who normally dream during sleep history of personality problems
the incidence is not affected by covering eyes during emergence, nor by allowing the patient to emerge in a quiet room adverse reactions may be lessened by preoperative discussion with the patient atropine & droperidol may increase the incidence, while nitrous oxide supplementation decreases the dosage of ketamine and therefore the incidence of reactions benzodiazepines are the most effective drugs for attenuating the psychic reactions both preoperatively and for their treatment diazepam (0.15-0.3 mg/kg IV), lorazepam (2-4 mg PO or IV), or midazolam ketamine increases CMRO2, cerebral blood flow and intracranial pressure the excitatory CNS effects of ketamine can be detected by the development of theta-activity and "petit-mal like" seizure activity this is associated with an increased CMRO2, however, CBF increases to a greater degree this is probably due to cerebral vasodilatation and a rise in systemic blood pressure cerebrovascular responses to PaCO2 remain intact however, due to these effects ketamine should be avoided in patients with potentially raised ICP
46
Cardiovascular Effects ketamine produces unique cardiovascular effects there is an increase in mean arterial BP, HR, pulmonary arterial and central venous pressures this is related to sympathetic stimulation, with increased circulating levels of adrenaline & noradrenaline, resulting in peripheral vasoconstriction and direct cardiac stimulation the haemodynamic changes are not related to the dose of ketamine there being no difference after administration of 0.5 or 1.5 mg/kg further, subsequent doses do not produce the same effect and may even be associated with cardiovascular depression the mechanism for this effect is uncertain direct intrathecal administration is associated with an immediate increase in SNS outflow this effect can be blocked by prior administration of barbiturates, droperidol and benzodiazepines stimulation of the cardiovascular system is not always desirable and the benzodiazepines appear the most effective in attenuating this response peripheral effects play an undetermined role both inhibition of neuronal uptake of catecholamines, similar to cocaine, and inhibition of extraneuronal catecholamine uptake have been demonstrated its direct effects are depressant on myocardium and dilatory on smooth muscle, but these are normally countered by the increased SNS activity the effects on peripheral resistance are variable ketamine abolishes adrenaline-induced arrhythmias by prolonging the relative refractory period in congenital heart disease patients there is no significant change in shunt direction or fraction, or systemic oxygen flux after ketamine NB: used in paediatric cardiac catheterisation with less arrhythmias in the normal heart, coronary blood flow increases secondary to the increased myocardial O2 consumption and stroke work increases pulmonary vascular resistance, thus increasing pulmonary artery pressure and right ventricular stroke work therefore, the drug is a valuable induction agent for poor risk and hypovolaemic patients the (+)'ve chronotropic & inotropic effects are contraindicated in patients with IHD or minimal right ventricular reserve in patients with elevated pulmonary vascular pressures, ketamine appears to produce a more pronounced increase in PVR than in SVR
47
Respiratory Effects respiratory depression is minimal with anaesthetic doses but may be depressed with large doses results in bronchodilatation and this is a useful agent for asthmatics or patients with CAO in patients with reactive airway disease, ketamine decreases airway resistance and bronchospasm to the volatile agents ketamine produces marked salivation, especially in children, therefore an antisialogogue should be administered prior to its use there are opposing views on its effectiveness in preserving pharyngeal reflexes and the patency of the upper airway thus it is not a substitute for good airway management W&W states laryngeal & pharyngeal reflexes remain active and that aspiration is less likely but still possible (Miller holds the same view) Other Effects there is a transient rise in intraocular pressure eye movements and nystagmus may occur nausea and vomiting are fairly common after sole administration
Pharmacodynamics Usual Doses of Ketamine

Induction of Anaesthesia Maintenance of Anaesthesia + N2O/O2 or opiates Sedation 0.5-2.0 4.0-6.0 50-90 0.5-1.0 15-30 0.2-0.8 2.0-4.0 mg/kg IV mg/kg IM g/kg/min mg/kg IV prn or, g/kg/min mg/kg IV mg/kg IM
48
Induction especially poor risk patients, a. b. ASA Class IV cardiac disorders especially hypovolaemia, intrinsic myocardial disease, congenital heart disease, tamponade, restrictive pericarditis * with the exception of IHD respiratory disorders especially bronchospastic airways disease otherwise healthy patients with trauma/hypovolaemia
c. d.
recommended IV induction dose ~ 1.0-2.0 mg/kg and unconsciousness usually lasts 5-15 mins incremental doses may be given if a longer duration is required combination of ketamine & midazolam by infusion is useful for valvular or IHD the addition of a BZD attenuates or eliminates the unwanted hyperdynamic response to ketamine Anaesthesia produces analgesia without loss of consciousness at infusion rates ~ 50 g/kg/min may also be used in conjunction with N2O & muscle relaxants to provide sleep and analgesia at doses of 15-30 g/kg/min muscle relaxants are often necessary as ketamine increases muscle tone Obstetrics reportedly used successfully as an induction agent in caesarean section but doses > 1.5 mg/kg IV may lead to foetal depression useful as a supplement to epidural insertion or LUSCS in low "analgesic" doses (0.2-0.3 mg/kg) Day Surgery useful in children for short procedures as it may be given IV, IM, orally or rectally IM doses for children are ~ 5-10 mg/kg with an onset of surgical anaesthesia in 3-5 mins and a duration of 10-30 mins the use in children is more versatile as the incidence of emergence reactions is much lower lower dose may be used for diagnostic procedures such as cardiac catheterization, radiation therapy, dressing changes, or dental work may also be used in adults in conjunction with the benzodiazepines but these prolong recovery Adjunct to Local and Regional Anaesthesia during performance of painful blocks ketamine produces analgesia, sedation and amnesia without CVS depression also used for sedation during regional anaesthesia in combination with benzodiazepines
49
Burns Patients used extensively for dressing changes, debridements and skin grafting (1.5-2.5 mg/kg IM) however, tolerance appears to develop, necessitating increasing the dosage with time higher dosages (4-6 mg/kg) are adequate for eschar excision only 10%, in one study, were found to have mild emergence reactions Miscellaneous successfully used in patients with MH susceptibility, myopathias, porphyria, etc. in acute hypovolaemia, the use of ketamine results in a more stable and better functioning cardiovascular system than with other induction agents
Toxicity & Precautions

Disadvantages 1. 2. 3. 4. 5. 6. 7. 8. 9. the slow onset of action increased muscle tone spontaneous movements during induction & anaesthesia CVS stimulation slow recovery emergence reactions postoperative nausea & vomiting elevated ICP & IOP potent sialogogue, especially in children
Contraindications 1. 2. 3. 4. 5. 6. 7. 8. poorly controlled hypertension unstable angina or recent myocardial infarction right or left heart failure valvular heart disease cerebrovascular disease raised ICP recent penetrating eye injury - but may be useful in CHD intracranial, thoracic or abdominal aneurysms
50
ETOMIDATE
an imidazole derivative synthesised in 1964 and introduced into clinical practice in 1973 the structure is unrelated to any other IV anaesthetic it exists as two isomers, only the (+)-isomer being active presented in 10 ml ampoules containing 2 mg/ml dissolved in water with 35% propylene glycol the solution has a pH ~ 8.1 and an osmolality of 4,640 mosm/l
Pharmacokinetics Pharmacokinetic Data - Etomidate

VdSS Clearance Hepatic extraction ratio Distribution half-life t1 Distribution half-life t2 Elimination half-life Plasma free fraction t ~ 2.5 - 4.5 l/kg ~ 18 - 25 ml/kg/min ~ 0.65 - 1.0 ~ 3 min ~ 29 min ~ 2.9 - 5.3 hr ~ 25 %
the kinetics following an open 3 compartment model induction is rapid, sleep being produced within one arm-brain circulation time redistribution from the brain to peripheral tissues being responsible for the short duration of clinical action there is minimal accumulation following repeated doses highly lipid soluble and protein binding ~ 75%, therefore is susceptible to factors which later protein binding the clearance ~ 18-25 ml/kg/min, is 5-6x that of STP, and may be equal or above liver blood flow metabolism occurs rapidly by hepatic enzymes and plasma esterases to an inactive carboxylic acid metabolite the VdSS ~ 2.2-4.5 l/kg due to its large volume of distribution there is slow return of etomidate into blood, thus increasing its elimination half-life, t ~ 2.5-4.5 hrs cirrhosis increases the volume of distribution and therefore the elimination half-life similar effects are seen in renal disease due to altered protein binding
51
CNS Effects etomidate is primarily a hypnotic agent and the duration of CNS effects are dose dependent a usual induction dose ~ 0.3 mg/kg is effective in one arm-brain circulation and consciousness is regained in 5-8 mins (W&W: 7-14 mins) it has no intrinsic analgesia activity etomidate decreases the CMRO2, cerebral blood flow and ICP some studies suggest a possible protective action on the brain as mean arterial pressure is unaltered and cerebral perfusion pressure is increased etomidate has been associated with grand mal seizures and does increase epileptogenic activity in patients with seizure foci there is frequent myotonic activity during induction but this is not related to epilepti-form discharges and may by decreased by opioid or benzodiazepine premedication the incidence of nausea and vomiting appears to be more common with etomidate than with other IV agents the incidence is decreased by droperidol from ~ 40% to 20% CVS Effects minimal effects in both normal patients and those with cardiac disease clinical doses do cause a fall in arterial blood pressure, cardiac index and peripheral resistance but this is not significant (~ 10%) with 1-2 g/kg fentanyl, 0.3 mg/kg etomidate blocks the CVS response to intubation there is a high incidence of pain at the site of injection (25 - 50%) Respiratory Effects etomidate produces a dose related depression of respiratory rate and tidal volume, though, less than with STP induction often produces a brief period of hyperventilation, which is occasionally followed by apnoea it does not induce histamine release, nor increase bronchial reactivity Endocrine Effects etomidate results in inhibition of adrenal corticoid synthesis by a concentration dependent, reversible block of 11--hydroxylase this occurs after both induction doses and particularly when used as an infusion in ICU this results in inhibition of ascorbic acid resynthesis, required for steroid synthesis in humans vitamin C supplementation restores cortisol levels following the use of etomidate this inhibition is probably not significant when used as an induction agent Clinical Uses as induction agent in patients with compromised cardiovascular function may be useful when rapid recovery is required as in outpatient anaesthesia
52
PROPANIDID
first used in 1956 and is a eugenol derivative, chemically related to the constituents present in oil of cloves presented as a yellow oil, prepared as a 5% solution in Cremaphor EL
Pharmacokinetic Data - Propanidid

VdSS Clearance Hepatic extraction ratio Distribution half-life t Elimination half-life Plasma free fraction t ~ ~ ~ ~ 3 min ~ 10 min ~ 60 %
protein binding ~ 40%, therefore has a large free fraction more lipid soluble than STP, which accounts for its rapid onset of action its short duration of action is due to rapid hydrolysis by plasma and liver esterases to the main metabolite phenylacetic acid there is interaction between suxamethonium and propanidid due to common metabolism by pseudocholinesterase this explains the prolonged apnoea when these two are given concomitantly induction dose ~ 3-8 mg/kg, after which there is 2-5 mins of unconsciousness pharmacokinetic studies carried out on propanidid showed a distribution half-life, t ~ 3 mins and an elimination half-life, t ~ 10 mins the elimination half-life is expected to be increased with plasma pseudocholinesterase deficiency there is no accumulation after repeated doses CNS Effects sleep occurs within one arm-circulation time may cause unwanted muscular movements on induction, the incidence of which is related to the dose used, the rapidity of injection, and type of premedication, eg., narcotics decrease the incidence and anticholinergics increase the incidence the incidence is slightly higher than STP but much less than methohexital Cardiovascular Effects there is a dose related depression of the cardiovascular system due to a negative inotropic action and a decrease in afterload this may result in a reflex tachycardia
53
Respiratory there is often marked hyperpnoea after an induction dose followed by apnoea which marks onset of sleep there is a high incidence of coughing and hiccups Neuromuscular Effects potentiates the effect of suxamethonium due to the common metabolic pathway Adverse Effects there is a higher incidence of nausea and vomiting than with barbiturates problems with this drug are cardiovascular depression and hypersensitivity reactions to its solubilizing agent (Cremophor EL) NB: Withdrawn from market!
54
ALTHESIN
a mixture of 2 water insoluble steroids, a. b. c. alphaxalone 9 mg/ml, and alphadolone 3 mg/ml in 20% Cremaphor EL = propylene glycol + castor oil + parabenz
alphaxolone is the major active component and alphadolone is added to increase solubility
Pharmacokinetics
althesin has a rapid onset of action and a high potency, both related to the free 3--OH group on the steroid molecule usual induction dose ~ 20-50 l/kg (or 0.3-0.6 mg/kg total steroid) plasma protein binding ~ 50% (albumin and -lipoproteins) the rapid recovery from anaesthesia is due to redistribution and early metabolism of the drug, duration of action ~ 5-13 mins the VdSS ~ 0.7-0.9 l/kg and clearance ~ 17-21 ml/kg/min most of the drug being cleared after one passage through the liver, plasma clearance thus being dependent on hepatic blood flow the elimination half-life, t ~ 0.5-1.0 hrs, thus there is no accumulation following repeated doses or infusion CNS anaesthetic state achieved as rapidly as thiopentone cerebral blood flow, cerebral oxygen uptake and intracranial pressure are all decreased there is a high incidence muscle tremors and movements, though, less than with methohexitone CVS has a negative inotropic effect with decreased peripheral resistance, decreased stroke volume and decreased blood pressure similar to the barbiturates this is seldom a problem clinically Respiratory produces an initial hyperventilation followed by apnoea then dose dependent respiratory depression may cause hiccups, coughing and laryngospasm Adverse Effects side effects and adverse effects occur with 1:1900 to 1:300 frequency and are characterised by flushing, skin rash, marked complement C3 and massive histamine release NB: Withdrawn from market!
55
MINAXOLONE
is a water soluble steroid derived from alphaxolone given by bolus injection of 0.5 mg/kg it produces rapid induction of anaesthesia lasting ~ 20 mins there is a high incidence of side effects accompanying induction, ie., movement, hiccups and laryngeal spasm, the frequency being reduced by narcotic premedication and by slow injection of the drug
Pharmacokinetics
the VdSS ~ 1.6-2.3 l/kg and the clearance ~ 17-26 ml/kg/min the distribution half-life, t ~ 2-8 mins, and the elimination half-life, t ~ 0.8-1.5 hrs, which probably contributes to speed of recovery NB: Before much more work was done on minaxolone it was withdrawn from clinical studies to evaluate reports of possible toxic effects on rats and despite these findings being unsubstantiated by further animal studies, it has not been re-introduced
GAMMA HYDROXY BUTYRIC ACID

first used in 1960 and supplied as a 20% solution a basal anaesthetic derived from GABA clinical effects are probably in the cortex rather than the midbrain has slow onset of action (10-15 mins) and therefore dose of 60-80 mg/kg is combined with STP 1 mg/kg for induction action lasts for 60-90 mins respiratory and cardiovascular effects not marked adverse effects include, a. b. c. d. Uses has been recommended for paediatric surgical procedures and as sedation for regional anaesthesia seldom used in Australia (or UK) prolonged recovery emergence delerium extrapyramidal side-effects, clonic movements venous irritation
56
NEUROLEPT ANALGESIA
Def'n: the state of neuroleptanalgesia, or neuroleptanaesthesia may be obtained using a combination of a potent analgesic and a neuroleptic tranquiliser drug this produces a state of indifference to pain, eg., droperidol and fentanyl (or phenoperidine) initially used to provide sedation for surgical procedures but now also used for procedures with general anaesthesia, N2O/O2 + droperidol + fentanyl + muscle relaxant
first described by Delay (1959) in drug induced behaviour syndromes this syndrome includes, a. b. c. d. e. 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, a. b. c. d. e. f. -adrenergic blockade hypotension hypothermia sedation extrapyramidal effects anticholinergic properties
a number of agents will induce this state, the two most common groups being, a. b. the phenothiazines the butyrophenones - chlorpromazine is the prototype - droperidol & haloperidol
NB: the mechanism of action of these agents is thought to be competitive antagonism at dopaminergic receptors in the brain these agents have a predilection for certain areas in the brain rich in DA-receptors, especially the CTZ and the extrapyramidal nigrostriatum
57
DROPERIDOL
first synthesised by Janssen, droperidol is a butyrophenone, a fluorinated derivative of the phenothiazines frequently used in conjunction with fentanyl it has a faster onset and shorter duration of action than haloperidol the elimination half-life, t ~ 2-2.5 hrs, is not dissimilar to that of fentanyl however, the effects frequently outlast those of fentanyl, possibly due to increased affinity for CNS receptors it has been postulated that the butyrophenones may occupy GABA receptors on the post-synaptic membrane, thereby reducing the build-up of dopamine in the synaptic cleft it is a potent anti-emetic and is effective against opioid induced vomiting it produces extrapyramidal side-effects respiratory effects are minimal and in general the CVS effects are small however, droperidol may cause a profound fall in peripheral resistance and BP in patients receiving vasodilator therapy and in those with a decreased circulating blood volume, due to both a CNS and peripheral -blocking effect cardiac arrhythmias are infrequent in combination with fentanyl, there is little effect, or a small reduction in cerebral blood flow it has no analgesic effect in man and the metabolic effects are minimal Dosage & Administration droperidol is available for parenteral use as a 10 mg/2 ml solution was available in a fixed mixture with fentanyl, "Innovar", but no longer available in Australia for premedication, dose = 0.1-0.15 mg/kg IM, or 5-10 mg for an adult droperidol alone is unsatisfactory for surgery, being associated with increased anxiety, poor sedation and even refusal of surgery for induction, a dose ~ 10 mg, alone or in combination with fentanyl a neuroleptanaesthesia regimen would involve, a. b. c. fentanyl 4 g/kg & droperidol 0.2 mg/kg N2O/O2 a muscle relaxant
with this technique, unless the total opioid dose is low, there will be profound respiratory depression and ventilation should be controlled NB: ** droperidol should be avoided in patients with Parkinsonism
58
Ideal Intravenous Anaesthetic Agent
the ideal intravenous anaesthetic, according to Dundee, should be, a. b. c. d. e. f. non-irritant rapid induction short duration of action good analgesia nontoxic - with inactive, nontoxic metabolites high specificity of action i. minimal cardiorespiratory depression ii. no increase in muscle tone no hypersensitivity, or histamine release physical properties i. water soluble - therefore require no solvent ii. stable in solution over long periods of time iii. not adsorbed onto glass or plastic - IV or IA - sleep in one arm-brain circulation time - elimination by metabolism - no cumulative properties
g. h.
Adverse Reactions
NB: usefully described under four headings; 1. reactions on induction - pain on injection - muscle movements - cough & hiccup - cardiorespiratory depression - psychic problems - motor disturbances - pain - nausea & vomiting - prolonged somnolescence - respiratory depression - local tissue damage - thrombophlebitis at the site of injection - anaphylatic reactions - anaphylactoid reactions - histamine release - skin rashes - bronchospasm
2.
reactions on recovery
3. 4.
tissue complications hypersensitivity
59
Pharmacokinetic Data of the Intravenous Anaesthetics

Drug Dose mg/kg 4-7 1-1.5 2 1-2 0.1-0.3 0.15-0.36 0.1-0.2
0.3
VdSS l/kg 1.7-2.5 1.1-2.2 2.0-10 2.3-3.1 1-1.5 0.8-1.5 2

2.2-4.5
t hr 5-12 1.6-2.9 4.0-7.0 2.5-2.8 20-40 1.7-2.6 1.7-2.2

2.0-5.3
Clearance1 ml/kg/min 1.6-4.3 10-12 20-30 17.5-20 0.2-0.5 6.4-11 14

15-26
Protein Binding 75-85% 70-80%
Thiopentone Methohexitone Propofol Ketamine Diazepam Midazolam Droperidol

Etomidate
1
45-50% 98-99% 96-97%
75%
NB:
liver blood flow ~ 21.5 ml/kg/min
60

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Intravenous Anaesthetics

Group Long Acting Medium Acting Short Acting Ultra-Short Acting

Half-life 24-96 hrs 21-42 hrs 20-28 hrs 10 hrs

Example phenobarbital pentobarbital secobarbital thiopentone, methohexital

Uptake & Redistribution

Body Tissue Compartments

CPP = MAP - ICP

severe shock or hypovolaemia status asthmaticus porphyria

absence of IV access, or general anaesthetic equipment

Central Nervous System

Common EEG Patterns

Classification by Duration of Action

these prolong the duration of CNS effects

Pharmacokinetic Data - Diazepam

Pharmacokinetics Pharmacokinetic Data - Midazolam

Pharmacokinetic Data - Lorazepam

Approximate Pharmacokinetic Data

0.1 - 0.2 mg 3.0 mg 0.5 mg 1.0

0.5 - 1.0 g/kg/min mg maximum1

Pharmacokinetics Pharmacokinetic Data - Flumazenil

~ 0.2 - 0.6 ~ 1.1 - 1.7 ~ 20 - 30 1.0 ~2-8 ~ 30 - 60 ~ 240 - 420 ~ 2 - 10 %

l/kg l/kg ml/kg/min min min min

~ 0.3 - 0.7 ~ 2 - 24 30 - 40 1.0 1 - 6.5 9 - 56 210 - 735

l/kg l/kg ml/kg/min min min min

Distribution half-life t1 Distribution half-life t2 Elimination half-life Plasma free fraction

Usual Doses of Propofol

= 10 mg/kg/hr = 166 g/kg/min ~ 1.0 ml/kg/hr and adjust to clinical effect

NB: 100 g/kg/min

Pharmacodynamics Usual Doses of Ketamine

Toxicity & Precautions

Pharmacokinetics Pharmacokinetic Data - Etomidate

Pharmacokinetic Data - Propanidid

GAMMA HYDROXY BUTYRIC ACID

tissue complications hypersensitivity

Pharmacokinetic Data of the Intravenous Anaesthetics

VdSS l/kg 1.7-2.5 1.1-2.2 2.0-10 2.3-3.1 1-1.5 0.8-1.5 2

t hr 5-12 1.6-2.9 4.0-7.0 2.5-2.8 20-40 1.7-2.6 1.7-2.2

Clearance1 ml/kg/min 1.6-4.3 10-12 20-30 17.5-20 0.2-0.5 6.4-11 14

Protein Binding 75-85% 70-80%

Thiopentone Methohexitone Propofol Ketamine Diazepam Midazolam Droperidol

45-50% 98-99% 96-97%

liver blood flow ~ 21.5 ml/kg/min

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