intravenous anesthetics

Views:
 
Category: Entertainment
     
 

Presentation Description

No description available.

Comments

By: vutkur (41 month(s) ago)

hello sir.. nice presentation.. can u pls mail it if u can at venkatesh.vutkur@gmail.com ... thank you sir.......

Presentation Transcript

INTRAVENOUS ANAESTHETIC AGENTS:

INTRAVENOUS ANAESTHETIC AGENTS CHAIRPERSON: DR. SHASHIKALA T K Assistant Professor SPEAKER : DR.DATTATRAYA M D

Classification:

Classification rapid acting barbiturates methohexitone, thiopentone imidazole derivatives etomidate hindered phenols propofol steroids althesin, pregnanolone eugenols propanidid slower acting benzodiazepines diazepam, midazolam arylcycloalkylamine derivatives ketamine opioids large dose fentanyl butyrophenones droperidol

General properties:

General properties high lipid solubility, poor water solubility at physiological pH most are weak acids (except Etomidate and Ketamine) best modelled using a 3 compartment model low initial volume of distribution V 1 (0.1-0.2 L/kg), except ketamine 1L/kg action terminated by distribution to VD of 1-5/L/kg, over the next 5 minutes most are extensively protein bound

General properties:

General properties part of their activity is mediated by GABA A receptors (except ketamine ) myocardial depressants, with an addtional hypotensive effect due to vasodilation most will cause dose related respiratory depression ( ketamine less than the others) most are anticonvulsant, (except etomidate or methohexitone ) most reduce ICP, CBF and CMRO 2 , but not ketamine hepatic metabolism

IV ANAESTHETIC AGENTS:

IV ANAESTHETIC AGENTS THIOPENTONE SODIUM PROPOFOL KETAMINE MIDAZOLAM

Barbiturates:

Barbiturates

Barbituric acid:

O=C NH 2 NH 2 Barbituric acid 2,4,6-tri-oxo-hexa-hydro pyrimidine the condensation of urea and malonic acid  barbituric acid and water O Barbituric acid itself lacks central depressant activity. + HO-C CH 2 HO-C O H 2 O 1 2 6 O= H O H O N N 5 4

Barbituric acid:

Barbituric acid carbonyl group at position 2 takes on acidic character because of lactam (keto) - lactim (enol) tautomerization 1 2 6 O= H O H O N N 5 4 1 2 6 HO= O H O N N 5 4

Structure activity - alkyl or aryl groups at C5:

Structure activity - alkyl or aryl groups at C 5 confers sedative-hypnotic activity increase in the length of one, or both the alkyl side chains up (to 5-6 carbon atoms) increases hypnotic potency above this number, potency is reduced and convulsant properties may result oxidation of radicals (to alcohols, ketones, phenols or carboxylic acids) terminates the activity the presence of a phenyl group at C 5 , or on one of the ring nitrogens confers anticonvulsant activity (eg. phenobarbital) R’ R” 1 2 6 O= H O H O N N 5 4

Structure activity – substitution at C2:

Structure activity – substitution at C 2 oxybarbiturates (O=C) thiobarbiturates (S=C) higher lipid solubility, producing more rapid onset and shorter duration of action than oxybarbiturate R’ R” 1 2 6 O= H O H O N N 5 4 C 2 H 5 CH(CH 2 ) 2 CH 3 1 2 6 S= H O H O N N 5 4 CH 3 Thiopentone

Structure activity - methyl or ethyl substitution at N1:

Structure activity - methyl or ethyl substitution at N 1 increases lipid solubility rapid onset shortens duration of action rapid recovery methylated oxybarbiturates (methohexitone), methylated thiobarbiturate subsequent demethylation may occur resulting in a longer acting metabolite these compound have a high incidence of excitatory phenomena tremor, increased muscle tone, involuntary movements R’ R” 1 2 6 O= H O H O N N 5 4

Structure activity - lipid solubility:

Structure activity - lipid solubility in general, structural changes which increase lipophilicity (thiobarbiturate, methyl or ethyl substitution at N 1 ), increase hypnotic potency “fast on-fast off” rapid onset shorter duration of action rapid recovery accelerate metabolic degradation

Mechanism of action:

Mechanism of action Cl - conductance binding to the GABA A receptor complex, decreasing rate of GABA dissociation, prolonging duration of GABA activated Cl - channel opening direct activation of Cl - channel at higher concentrations (GABA-mimetic) Ca ++ conductance decreases Ca ++ dependent release of neurotransmitters depresses Ca ++ dependent action potentials

Mechanism of action:

Mechanism of action Na + conductance inhibit the function of voltage-dependent Na + channel K + conductance at higher concentrations, voltage-dependent K + conductance is reduced GABA A receptor complex is the major site of barbiturate action mesencephalic ascending reticular activating system (ARAS) is sensitive to the drug’s action and the effects are stereospecific

Mechanism of action:

Mechanism of action barbiturates preferentially suppress polysynaptic responses inhibition is postsynaptic in supraspinal (cortical, diencephalic and cerebellar) regions presynaptic in the spinal cord mutiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anaesthesia more pronounced central depressant effects compared to benzodiazepines

GABAA receptor:

GABA A receptor GABA A receptors in different areas of the CNS contain different combinations of the essential subunits conferring different pharmacologic properties on GABA A subtypes stimulation by GABA results in opening of a chloride channel influx of Cl - hyperpolarisation and inhibition of postsynaptic cell

GABAA receptor:

GABA A receptor 5 binding sites at extracellular end of the channel GABA binding site benzodiazepine binding site inside the Cl - channel barbiturate binding site steroid binding site picrotoxinin binding site specific GABA A agonist - muscimol specific GABA A antagonist - bicuculline

GABAB receptor:

GABA B receptor lacks affinity for specific GABA A agonist - muscimol specific GABA A antagonist - bicuculline selective affinity for specific agonist baclofen specific antagonist phaclofen located presynaptically acts through G proteins to inhibit cAMP production, opens a K + channel, decrease Ca ++ influx, reducing the presynaptic release of GABA

Pharmacokinetics of barbiturates:

Pharmacokinetics of barbiturates barbiturates are weak acids thiopentone pKa 7.6, 60% unionised at pH 7.4 methohexitone pKa 7.9, ~ 39% unionised at pH = 7.4

Onset of action:

Onset of action the latency of onset determined by the rapidity with which they cross the BBB dependent upon lipid solubility increased with thiobarbiturate, and methyl or ethyl substitution at N 1 degree of ionization with relatively acidic medium (blood, ECF, acidaemia), increase unionised fraction, increase transfer into brain loading dose (Fick’s Law of Passive Diffusion)

Degree of ionization:

Degree of ionization ionization also affects renal excretion increased ionization decreases back-diffusion basis of forced alkaline diuresis in the management of overdosage

Lipid solubility:

Lipid solubility thiopentone highly lipid soluble relatively unionized at plasma pH equilibrates with the brain rapidly (rapid acting) phenobarbital relatively low lipid solubility may take over 15 minutes to achieve unconsciousness when given intravenously

Placental transfer:

Placental transfer thiopentone and the other highly lipid soluble agents readily cross the placenta maximum foetal blood thiopentone concentrations being seen within 3 minutes of intravenous administration of thiopentone

Duration of action:

Duration of action dependent on concentration gradient at plasma:effector site administered dosage, rate of administration, dissociation from receptor site, redistribution, clearance for thiopentone, metabolism is too slow to account for its short duration of action return of consciousness is governed by two factors the bolus mixing with circulating blood volume redistribution from the brain (VRG)

Compartment kinetics:

Compartment kinetics Compartment Blood flow Body mass Equilibrium % CO % time Vcentral (STP) 100 ~ 38 0.5min VRG 75 < 10 3-10min MG 20 45-50 1-4 h FG 5 15-20 < 5 d NB: the relative rates at which various tissue groups take up thiopentone will depend upon their blood flow and the tissue solubility

Distribution:

Distribution central compartment V C for sodium thiopentone ≈ 38% body weight for methohexital ≈ 35% these exceed intravascular space and combined with the rate of equilibration with brain suggests that brain should be considered as a part of V C cerebral blood flow ≈ 15-18% of the CO a large bolus of lipid soluble, unionised drug is presented to the brain within one arm-brain circulation time following administration of the drug

Cerebral Uptake:

Cerebral Uptake brain extraction ratio of sodium thiopentone is approximately 60% peak plasma concentrations of sodium thiopentone (175 mg/l) are achieved within 30 seconds of intravenous administration of 350 mg internal jugular concentrations are lower (75 mg/l)

Redistribution:

Redistribution vessel rich group includes the heart, liver, kidney and brain due to high myocardial blood flow about 70 ml/100g/min, accounts for the rapidity of cardiovascular depression muscle blood flow (20% of CO) about 15-30 minutes are required for equilibration

Redistribution:

Redistribution despite high lipid solubility, blood flow to fat is so low the equilibrium time for thiopentone is prolonged thus, redistribution of thiopentone within the first 30 minutes after intravenous bolus administration is mainly to the muscle group

Metabolism :

Metabolism oxidation of radicals at the ring C 5 (to alcohols, ketones, phenols or carboxylic acids), important for termination of biological activity conjugation with glucuronic acid and excreted N-hydroxylation N-dealkylation

Metabolism:

Metabolism following a bolus dose barbiturates combine with several species of cytochrome P450 and competitively interfere with biotransformation of other drugs and endogenous substances other substrates may reciprocally inhibit barbiturate biotransformation

Metabolism:

Metabolism following chronic administration marked increase in protein and lipid content of hepatic smooth endoplasmic reticulum, the activities of glucuronyl transferase and the cytochrome P450-dependent mixed function oxidase system enzyme inducing effect results in an increased rate of metabolism of steroid hormones, cholesterol, bile salts, vitamin K and D, and barbiturate explains tolerance to barbiturates

Elimination:

Elimination most barbiturates have high lipid:water partition coefficients and are significantly protein bound poorly filtered at the glomerulus readily back-diffuse in the late tubular segments excretion is largely dependent upon prior hepatic metabolism

Thiopentone Sodium:

Thiopentone Sodium 5-ethyl-5-(1-methyl-butyl)-2-thiobarbituric acid introduced in 1934 by Lundy and Waters distribution 75-85% bound to plasma protein highly lipid soluble pKa 7.6 pH 10.5 Vdss of 2.5 L/kg clearance Clss 2-4 ml/kg/min t ½ α 2-6 min; β 5-12 h C 2 H 5 CH(CH 2 ) 2 CH 3 1 2 6 S= H O H O N N 5 4 CH 3 Thiopentone

Sodium thiopentone:

Sodium thiopentone with repeated doses various body stores begin to fill up and the drug accumulates in the body may be asleep for many days reason why thiopentone is not used as a sole anaesthetic agent except for very short duration ED 50 /LD 50 = 4.6 (26.4 for etomidate)

Sodium thiopentone:

Sodium thiopentone preparation presented as a sodium salt to ensure total solution of the drug pale yellow powder mixed with anhydrous sodium carbonate 6% (not HCO 3 - ) ampoule atmosphere is N 2 , at 0.8 bar 2.5% solution has a pH = 10.6, (increasing solubility of weak acid in alkaline medium) the solution is not stable, should be used within 24-48 hrs Preservative- 6% sodium carbonate prevents precipitation of barbituric acid by atmospheric CO 2 Space above the powder in the vial is filled with nitrogen instead of air to prevent precipitation

Pharmacodynamics:

Pharmacodynamics central nervous system sleep antanalgesia or hyperalgesia anaesthesia anticonvulsant reduced cerebral metabolism cerebral vasoconstriction in dose-dependent fashion may increase cerebral blood flow due to raised PaCO 2 secondary to respiratory depression

Slide 40:

Pharmacodynamics: Central nervous system : decreases cerebral blood flow (CBF), CMRO2, thereby decreases the ICP. It acts as a free radical scavenger, has anti epileptic properties, produces burst suppression of EEG hence used as a cerebral protective agent Produces hypnosis.

Pharmacodynamics:

Pharmacodynamics cardiovascular system hypotension is dependent on the dose and rate of administration increase myocardial blood flow and oxygen utilisation myocardial depression at high doses venous thrombosis after 5% intra-arterial injection releases noradrenaline from vessel wall inducing vasoconstriction

Slide 42:

Cardiovascular system : In therapeutic induction doses,(3 – 5 mg/kg), when given slowly in normal persons it doesnot produce myocardial depression and doesnot decrease peripheral vascular resistance but produces venodilatation and increases heart rate. Doesnot produce significant change in cardiac output. But when given rapidly or in high doses and in patients with cardiac diseases and hypovolemic states, produces severe myocardial depression, decreases peripheral vascular resistance and venodilatation producing severe reduction in cardiac output.

Slide 43:

Respiratory system : it’s a central respiratory depressant, brief period of apnoea is very common with induction doses. In lighter planes, it sensitizes the laryngeal & bronchial reflexes thereby producing laryngospasm and bronchospasm. Other effects: decreases hepatic blood flow, renal blood flow and GFR.

Pharmacodynamics –other effects:

Pharmacodynamics –other effects tissue necrosis and sloughing after extravasation induction of ALA-synthetase in liver mitochondria producing excessive amounts of delta-aminolaevulinic acid, porphobilinogen and other porphyrins in individuals with deficiencies in the enzymes involved in the production of haem, phophyria results deficiency of porphobilinogen deaminase results in acute intermittent porphyria deficiency of protoporphyrinogen oxidase results in variegate porphyria

Slide 45:

cytosol mitochondria succinyl CoA + glycine Amino-laevulinic acid (ALA) Porphobilinogen (PBG) Hydroxymethylbilane (HMB) UroP’ogen I UroP’ogen III CoproP’ogen I CoproP’ogen III ProtoP’ogen IX CoproP’ogen oxidase ProtoP’ IX Haem ALA synthase ProtoP’ogen oxidase Ferrochelatase ALA dehydrogenase PBG deaminase uroP’ogen III cosynthase uroP’ogen decarboxylase (P’ = porphyrin)

Porphyrias: unsafe drugs (strong evidence):

Porphyrias: unsafe drugs (strong evidence) androgens barbiturates estrogens ethanol griseofulvin hydantoins progesterones sulfonamides

Porphyrias: unsafe drugs (probably or possibly unsafe):

Porphyrias: unsafe drugs (probably or possibly unsafe) drugs affecting the central nervous system anaesthetic agents (benzodiazepines, etomidate, ketamine, enflurane, halothane) local anaesthetic agent (mepivacaine) opioids (pentazocine, trimethadone) others (carbamazepine, glutethimide, imipramine, nikethamide, nortriptyline, primidone, valproate) drugs affecting the cardiovascular system clonidine, disopyramide, ergotamine, hydralazine, methyldopa, nifedipine, phenoxybenzamine, verapamil

Porphyrias: unsafe drugs (probably or possibly unsafe):

Porphyrias: unsafe drugs (probably or possibly unsafe) drugs affecting the respiratory system aminophylline , theophylline drugs affecting the endocrine system chlorpropamide , tolazamide , tolbutamide antimicrobial / antiparasitic drugs chloramphenicol , chloroquine , dapsone , ketoconazole , miconazole , metronidazole , nalidixic acid, rifampin other drugs alkylkating agents, danazol , metyrapone , phenylbutazone , spironolactone

Slide 49:

Pharmacokinetics: causes unconsciousness in 30 sec. consciousness returns due to rapid redistribution from the brain to the inactive tissues in about 5 – 8 mins highly lipid soluble,protein binding – to albumin, 72 – 86%. Metabolism 10 -25% is metabolized each hour. Metabolized to hydroxy thiopentone and carboxylic acid derivatives.

Uses:

Uses Induction of Anaesthesia Induction dose 3-4 mg/kg Onset 10-30 sec Infusion for brain protection 150-200µg/kg/min after loading dose of 25mg/kg Anti epileptic dose 1 mg/kg

SIDE EFFECTS:

SIDE EFFECTS CVS- Cardiovascular depression- result of central & peripheral effects -peripheral vasodilatation- pooling of blood in the venous system - mechanism for the decrease in cardiac output 1. direct negative inotropic action 2. decreased ventricular filling 3. transiently decreased sympathetic outflow from the CVS

Slide 52:

Cardiac index is unchanged or decreased MAP is maintained or decreased Increase in heart rate (11%-36%) with coronary artery disease Thiopental should be avoided in hypovolemic patients because there is a significant reduction in cardiac output & a significant decrease in blood pressure

Slide 53:

RS- produce dose related central respiratory depression - significant incidence of transient apnea after induction of anaesthesia - decreased minute ventilation - patients with chronic lung disease are slightly more susceptible to respiratory depression - apnea occurs during anaesthesia induction with thiopentone in atleast 20% of cases but the duration of apnea is short- 25 sec - ventilatory pattern with thiopental induction has been described as double apnea

Slide 54:

Rarely intra arterial injection can occur- results in immediate intense vasoconstriction & excruciating pain that radiates along the distribution of the artery Vasoconstriction may obscure distal arterial pulses & blanching of the extremity is followed by cyanosis Gangrene & permanent nerve damage can occur MECHANISM OF DAMAGE- precipitation of the thiopental crystals in the arterial vessels leading to an inflammatory response and arteritis TREATMENT- dilution of the drug by administration of saline into the artery, heparinisation to prevent thrombosis, brachial plexus block

CONTRAINDICATIONS:

CONTRAINDICATIONS When there is respiratory obstruction or an inadequate airway- may worsen respiratory depression Severe cardiovascular instability or shock Status asthmaticus Porphyria Without proper equipments( IV instumentation & airway equipments )

Benzodiazepines:

Benzodiazepines

Benzodiazepines:

Benzodiazepines the term benzodiazepine refers to the portion of the structure composed of the following, a benzene ring (A), fused to a 7-membered diazepine ring (B) all of the important members contain 5-aryl substituent (ring C), and 1,4-diazepine ring the term benzodiazepine now come to mean the 5-aryl-1,4-benzodiazepines N—C C — N C A R 1 R 2 -R 3 R 4 R 2 ’- R 7 - — 1 2 3 4 5 B C

Types:

Types 4 categories based on elimination half-lives ultra-short acting short-acting (t ½ less than 6 hours e.g. midazolam) intermediate-acting ( t ½ 6 to 24 hours e.g. temazepam) long-acting ( t ½ greater than 24 hours e.g. diazepam)

Mechanism of action:

Mechanism of action the benzodiazepine receptor forms part of the GABA A complex, located on the postsynaptic membrane of the effector neurone high concentrations of GABA A receptors in limbic system, particularly the hippocampus and amygdala cerebral cortex cerebellum

Mechanism of action:

Mechanism of action the binding of the benzodiazepines to the GABA A complex receptor increased by both Cl - and GABA potentiates neural inhibition mediated by GABA, increase frequency of Cl- channel opening and influx of Cl - is of high affinity, saturable and stereospecific receptor affinity and potency diazepam>midazolam>lorazepam

Benzodiazepine binding site on the GABAA receptor:

Benzodiazepine binding site on the GABA A receptor α α β γ 2 β benzodiazepine binding site ion channel pore Cl - extracellular intracellular GABA binding site

Other sites of action of benzodiazepines :

Other sites of action of benzodiazepines hippocampal neurons inhibition of uptake of adenosine resultant potentiation of the actions of this endogenous neuronal depressant (in coronary arteries) inhibition of Ca ++ conductance and Ca ++ dependent release of neurotransmitters inhibits tetrodotoxin-sensitive Na + channels

Benzodiazepine receptor ligands:

Benzodiazepine receptor ligands agonists – benzodiazepines, alter the conformation of the receptor such that the affinity for GABA is increased, enhancing GABA’s effects, with a resultant increase in the frequency of Cl- channel opening events antagonists - flumazenil, occupy the receptor but have no intrinsic activity, preventing the effects of both agonists and inverse agonists, without affecting the binding of GABA inverse agonists - β -carbolines, occupy the receptor and reduce the affinity for GABA, resulting in CNS stimulation

Pharmacodynamics - central nervous system:

Pharmacodynamics - central nervous system anxiolytic sedative hypnotic muscle relaxant antegrade amnesia anticonvulsant, tolerance may develop and this limits their usefulness in the long-term management of epilepsy the drugs do not cause true general anaesthesia, since awareness usually persists and relaxation sufficient for surgery cannot be achieved

Effects on sleep:

Effects on sleep decreased sleep latency, diminished the number of awakenings and time spent in stage of wakefulness, increased total sleep time increase in REM latency, decreased time spent in REM sleep*, decreased frequency of eye movement during REM sleep and increased time in major non-REM component * with the exception of temazepam

Pharmacodynamics - neuromuscular system:

Pharmacodynamics - neuromuscular system blockade at very high doses induce muscle hypotonia, without interfering with locomotion, and may decrease decerebrate rigidity

Pharmacodynamics - respiratory system:

Pharmacodynamics - respiratory system the slopes of the ventilatory/CO 2 response curves are flatter, however, they are not shifted to the right, as occurs with the opioids the peak onset of ventilatory depression following midazolam is at ~ 3 minutes and lasts for ~ 15 minutes may cause apnoea during anaesthesia, or when given in conjunction with the opioids other factors likely to increase the incidence of significant respiratory depression, or apnoea, include, old age, debilitating disease, and co-administration of other respiratory depressant drugs

Pharmacodynamics - cardiovascular system:

Pharmacodynamics - cardiovascular system baroreceptor reflexes generally remain intact, though, there is some depression midazolam > flunitrazepam at decreasing peripheral resistance , and is dose related, the hypotensive effect is minimal and usually less than that seen with thiopentone in patients with elevated cardiac filling pressures, both midazolam and diazepam produce a " nitroglycerine like " effect , causing venodilatation and reducing preload resultant hypotension activates baroreceptor reflex arc

Slide 69:

when combined with opioids there is a synergistic effect, the combination producing greater decreases in blood pressure than either agent alone diazepam and lorazepam decrease left ventricular work and cardiac output diazepam increases coronary blood flow, possibly by increasing interstitial concentrations of adenosine, thus, diazepam may provide some protective function in patients with ischaemic heart disease

Absorption:

Absorption absorption all have high lipid:water distribution coefficient in unionised form absorption by oral route complete either unchanged, or metabolised (clorazepate, prazepam, flurazepam)

Distribution:

Distribution bind to albumin extend of binding correlates strongly with lipid solubility and ranges from 70% for alprazolam to 99% for diazepam plasma albumin concentration governs Vd decreased plasma albumin concentration results in increased VD Vd is large especially in elderly concentration in cerebrospinal fluid parallels the concentration of free drug in plasma

Distribution:

Distribution 3-compartment model appear to be more appropriate for highly lipid soluble drug plasma rapidly equilibrating tissues slowly equilibrating tissues rapid uptake into brain and other highly perfused organs after intravenous administration, or oral administration of a rapidly absorbed drug

Distribution:

Distribution redistribution rapid uptake is followed by a redistribution into tissues that are less well perfused (muscle and fat) most rapid for drugs with highest lipid solubility kinetics of redistribution complicated by enterohepatic circulation cross placental barrier secreted into breast milk

Metabolism:

Metabolism by microsomal enzyme systems in the liver some are inactivated by the initial reaction important determinant of their duration of action oxazepam, lorazepam, temazepam, triazolam, midazolam most have active metabolites that are biotransformed more slowly than the parent compound flurazepam and N-desalkylflurazepam

Metabolism:

Metabolism 3 stages N-dealkylation at position 1 (or 2), usually yields N-desalkylated compounds, (active) hydroxylation at position 3, usually yields active metabolite (3-hydroxyl compound) conjugation of the 3-hydroxyl compounds, principally with glucuronic acid N-dealkylation and 3-hydroxylation reactions reduced by cimetidine and oral contraceptive reduced to a greater extent in aged, chronic liver disease, than are those involving conjugations

Midazolam:

Midazolam water-soluble benzodiazepine 0.15 - 0.4 mg/kg, induces unconsciousness in 60s duration of sleep 7-15 minutes Cl N N N F C C CH 3

Slide 77:

PHYSICOCHEMICAL PROPERTIES: MIDAZOLAM SOLUTION (1-5mg/ml) CONTAINS 0.8% SODIUM CL, 0.01% DISODIUM EDETATE,1% BENZYL ALCOHOL AS PRESERVATIVE. PH-3.5 , HIGHLY LIPID SOLUBLE ACCOUNTS FOR RAPID CNS EFFECT AND LARGE Vd.

Slide 78:

Metabolism: biotransformation of bzds occur in liver. hepatic microsomal oxidation and glucuronide conjugation. age, smoking, no effect on midazolam biotransformation. alcohol consumption increases biotransformation of midazolam. excreted largely by kidneys, can cause profound sedation in patients with renal impairment.

Slide 79:

Pharmacokinetics: midazolam is a short acting drug with clearance rate 6-11ml/kg/min, as compared to lorazepam .8-1.8ml/kg/min, and diazepam .2-.5ml/kg/min. termination of action is primarily by redistribution. age, gender, race, enzyme induction, hepatic and renal diseases are factors influencing pharmacokinetics. in obese pts VD is increased as drug accumulates in adipose tissues, elimination ½ life prolonged.

Slide 80:

Pharmacodynamics Central nervous system: dose related reduction in cmro2 , cerebral blood flow by 34% with induction dose of 0.15mg/kg. increases seizure threshold. Respiratory system dose related central respiratory depression. co2 response curve slope is flatter, 0.13-0.2mg/kg dose of midazolam produces ventilatory depression depends on the rate of administration. Cardiovascular system reduction in arterial blood pressure due to decrease in systemic vascular system. Heart rate, cardiac output, ventricular filling pressure is maintained.

Slide 81:

M.O.A: SPECIFIC RECEPTOR SITE THAT R PART OF GABA RECEPTOR COMPLEX. INCREASES EFFICIENCY OF COUPLING OF GABA RECEPTOR N CL CHANNEL COMPLEX. PRODUCES CEILING EFFECT.

Slide 82:

DOSAGE : MIDAZOLAM INDUCTION- 0.1-0.2mg/kg. MAINTAINANCE- 0.05mg/kg. SEDATION -0.5-1mg.

Slide 83:

USES: INDUCTION : MIDAZOLAM IS THE B Z D OF CHOICE FOR INDUCTION, 0.2mg/kg DOSE INDUCES ANESTHESIA IN 28sec ABOVE 55yrs AND ASA STATUS III .REQUIRE 20% OR MORE REDUCTION DOSE. IV SEDATION: PRE-OP MEDICATION, INTRA-OP REGIONAL/LOCAL ANESTHESIA. POST-OP. ORAL SEDATION PONV.

SIDE EFFECTS & CONTRAINDICATIONS:

SIDE EFFECTS & CONTRAINDICATIONS The most significant problem with midazolam is respiratory depression When used as sedatives or for induction and maintenance of anaesthesia BZD’s can produce an undesirable degree or prolonged interval of postop amnesia, sedation and rarely respiratory depression These residual effects can be reversed with flumazenil

Propofol:

Propofol INTRODUCED IN THE YEAR 1977. PROPOFOL IS THE MOST COMMONLY USED IV ANESTHETIC TODAY. USED FOR INDUCTION,MAINTAINANCE, AND FOR SEDATION IN AND OUTSIDE OPERATING ROOM. ( ICU).

Slide 86:

hindered phenol - 2,6-diisopropylphenol weak acid prepared as in 1% [or 2%] aqueous emulsion with 10% soya bean oil (as a solubilizing agent) 2.25% glycerol (render isotonic) 1.2% egg phosphatide (as emulsifying agent) sodium hydroxide (to adjust pH between 6 and 8.5) sealed under nitrogen (to prevent oxidative degradation in the presence of oxygen) (addition of medium chain triglycerides, and sodium oleate in Propofol-Lipuro 1%) disodium edetate(0.005%)added as retardant of microbial growth.

Propofol emulsion containing disodium edetate (0.005%):

Propofol emulsion containing disodium edetate (0.005%) EDTA is a strong chelator of trace metals – including zinc and at high doses (2-3 grams per day), is toxic to the renal tubules propofol emulsion with disodium edetate should not be infused for longer than 5 days without providing a drug holiday to safely replace estimated or measured urine zinc losses in patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then be monitored on alternate days during sedation.

Propofol:

Propofol physicochemical properties oil at room temperature emulsion is isotonic pH 6-8.5 pKa of the drug in water is 11 octanol : water partition coefficient at physiological pH is 6761 : 1

Propofol - distribution:

Propofol - distribution following a single bolus dose, half-time of blood : brain equilibration (k eo ) is 1-3 minutes rapid decline in plasma concentration, described by 3 compartment model (plasma, rapidly equilibrating tisues, slowly equilibrating tissues) rapid drug distribution into tissues t ½ α 5 minutes patient will wake up in 5-10 minutes

Propofol - clearance:

Propofol - clearance biphasic elimination, two elimination half-lives 60% metabolised by cytochrome P450-dependent mixed function oxidase system to 2,6 diisopropyl-1,4-quinol, which is then conjugated to glucuronide or sulphate 40% found as propofol-glucuronide or -sulphate t ½ β 1-3 hours dependent on duration of infusion pharmacokinetics not affected by liver and renal disease Cl 23-50 ml/kg/min context-sensitive half time is 5 minutes after 1 hour infusion, 7 minutes after 10 h infusion 0 5 10 Time(hr) Context half time (min) 10 5 0

Slide 91:

Pharmacodynamics Central nervous system – effects similar to thiopentone. Acts on GABA A receptors. Decreases CMRO 2 , cerebral blood flow and intra cranial pressure. Has neuroprotective properties like thiopentone, but increased hypotension can decrease cerebral blood flow & cerebral perfusion pressure. Sedative doses unlike thiopentone doesnot produce hyperalgesia. Also produces significant amnesia. Induction doses causes non epileptic myoclonic movements.

Slide 92:

Respiratory system depresses respiratory center, induction doses produce apnoea for a few minutes. Airway reflexes are obtunded & incidence of cough & laryngospasm are greatly reduced ,useful for LMA insertion. Produces bronchodilatation and hence advantageous in hyperactive airway diseases.

Slide 93:

Cardiovascular system produces greater decrease in blood pressure than thiopentone. Decreased myocardial contractility, decreased venous & arteriolar peripheral vascular resistance leads to decrease in both preload & afterload. Blunts barostatic reflex – slower heart rate for a given decrease in blood pressure.

Slide 94:

Other effects decreased renal blood flow & hepatic blood flow. Decreased PONV, has antipruritic effect, has arrhythmic effect. Safe in patients with porphyria & malignant hyperthermia.

Slide 95:

Pharmacokinetics Lipid siolubility – most lipid soluble drug used in medicine. Oil/water partition co-efficient is 4700 – 10 times higher than thiopentone. High lipid solubility & increased blood flow to the brain→faster onset of action. Protein binding – 98% protein bound. To be given in lesser doses in patients with hypoproteinemia. Redistribution – redistribution half life is 1 – 2 min. effect is terminated due to redistribution from brain to skeletal system in 3 – 5 min

Slide 96:

Metabolism & elimination terminal half life – 4 – 6 hrs. Undergoes hydroxylation & conjugation in liver. Has high hepatic extraction ratio. 60% metabolism in liver & 40% in the kidneys.

Slide 97:

Factors affecting pharmacodynamics and pharmacokinetics elderly patients require less dose - ↓sensitivity of the brain & ↓ plasma protein concentration & ↓hepatic blood flow. Hypovolemic patients and cardiac patients require titrating doses.

Slide 98:

DOSAGE- INDUCTION-GA:1-2.5mg/kg REDUCED WITH INCREASING AGE. MAINTAINANCE-GA : 50-150mcg/kg/min COMBINED WITH NITROUS/OPIATE. SEDATION : 25-75mcg/kg/min iv ANTIEMETIC : 10-20mg iv can repeat every 5-10min.

Slide 99:

USES : IV INDUCTION OF ANESTHESIA IV SEDATION MAINTAINANCE OF ANESTHESIA NON HYPNOTIC THERAUPATIC APPLICATIONS: ANTIEMETIC ANTIPRURITIC-10mgIV IN PRURITIS WITH NEURAXIAL OPIODS AND CHOLESTASES. ANTICONVULSANT: 1mg/kg iv ATTENUATION OF BRONCHOCONSTRICTION.

Adverse effects:

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

Mechanism of immediate pain:

Mechanism of immediate pain probably due to direct irritant effect of phenol pain detected by free afferent nerve endings between media and intima of vein wall concentration of propofol in aqueous phase, reduced with intralipid formulation outer aqueous phase comes into contact with intima of vein during administration may be due to production of irritant substances when propofol comes into contact with silicone lubricant in plastic disposible syringes

Mechanism of delayed pain:

Mechanism of delayed pain probably result from indirect effect release of kininogen via kinin cascade latency of 10-20s

Factors influencing incidence of pain on injection of propofol:

Factors influencing incidence of pain on injection of propofol site of injection size of vein speed of injection propofol concentration in aqueous phase buffering effect of blood speed of intravenous carrier fluid temperature of propofol syringe material

Reducing incidence of pain on injection of propofol:

Reducing incidence of pain on injection of propofol premedication with pethidine, NSAIDs use of large veins, at least antecubical speed of injection speed of infusion carrier pretreatment with lignocaine (also mixture), prilocaine, procaine, opioids (alfentanil, fentanyl, pethidine), metoclopramide (weak local anaesthetic effect), thiopentone, ketamine (local anaesthetic effect) mixing with blood (reduction of concentration in aqueous phase or release of kinins) cooling to 4 o C or warming to 37 o C

Slide 105:

SIDE EFFECTS : OF PROPOFOL DUE TO PARENT DRUG OR ATTRIBUTED TO OIL:WATER EMULSION. M/C SIDE EFFECT IS HYPOTENSION BRADYCARDIA INFECTION :PROPOFOL STRONGLY SUPPORTS GROWTH OF E-COLI,PSEUDOMONAS.AEROGENOSA. AND IS BACTERIOSTATIC TO C.ALBICANS. FOR THIS REASON-AN ASEPTIC TECHNIQUE BE USED IN HANDELING PROPOFOL THE CONTENTS OF VIAL SHOULD BE WITHDRAWN IN A STERILE SYRINGE IMMIDIATELY AFTER OPENNING AND PROMPTLY ADMINISTERED. DISCARD REMAINING CONTENTS IF NT USED WITHIN 6hrs. IN ICU-DICARD AFTER 12hrs.

Slide 106:

PROPOFOL INFUSION SYNDROME: LACTIC ACIDOSES, ITS RARE BUT LETHAL SYNDROME, ASSOCIATED WITH INFUSION OF PROPOFOL AT 4mg/kg or more FOR 48hrs OR LONGER, IT WAS FIRST DESCRIBED IN CHILDREN . C/F: BRADYCARDIA L/T ASYSTOLE, MET.ACIDOSES,RHABDOMYOLYSES, HYPERLIPIDEMIA,FATTY LIVER, HYPERKALEMIA,SKELETAL MYOPATHY, THEORIES ON CAUSES:MITOCHONDRIAL TOXICITY,DEFECT,CARBOHYDRATE DEFICIENCY,IMPAIRED TISSUE OXYGENATION.

MISCELLANEOUS:

MISCELLANEOUS MISCELLANEOUS EFFECTS: DOES NOT TRIGGER MALIGNANT HYPERTHERMIA. USED IN COPROPORPHYRIA. NO INFLUENCE ON CORTISOL SECRETION EVEN ON PROLONGED PERIODS OF ADMINISTRATION.

Ketamine:

Ketamine KETAMINE :{KETALAR,KETAJECT} ITS A PHENCYCLIDINE.(ARYLCYCLOHEXYL AMINE). 1962:FIRST SYNTHESISED BY DR.CALVIN. 1966:DISSOCIATIVE ANESTHESIA WAS CREATED – GUENTER CORRSEN. WAS THE FIRST ANESTHETIC TO BE USED. SINCE 1970 ITS BEEN CLINICALLY USED.

Ketamine:

Ketamine a phenylcyclohexylamine derivative ketamine hydrochloride (2-[o-chlorophenyl]-2-[methylamino] cyclohexanone hydrochloride) introduced in 1965 for dissociative anaesthesia available as racemic mixture exists as 2 isomers, R(-) and S(+) forms S(+) more potent lipophilic rapidly distributed into highly vascular organs, and brain

Slide 110:

PHYSICO CHEMICAL PROPERTIES: MW-238kd, water soluble COMPOUND. ph- 3.5. PRESERVATIVE USED IS BENZOTHORIUM CL. PRODUCES PROFOUND ANALGESIA, PRODUCES DISSOCIATIVE ANESTHESIA CHARACTERISED BY DISSOCIATION BTWN THALAMO CORTICAL AND LIMBIC SYSTEM . RESEMBLES A CATALEPTIC STATE WITH VARYING DEGREES OF HYPERTONIC,PURPOSEFULL SKELETAL MOVEMENTS.EYES OPEN , NYSTAGMUS GAZE,PT IS NONCOMMUNICATIVE. PRODUCES EMERGENCE DELIRIUM.

Slide 111:

PHARMACO KINETIC: HIGH LIPID SOLUBILITY-LARGE Vd , ELIMINATION ½ LIFE-2-3hrs. AVAILABLE IN 1%,5%,10%AQUEOUS SOLUTON. METABOLISM: MET.EXTENSIVELY IN LIVER. CYTO-P450:DEMETHYLATION L/T NORKETAMINE(ACTIVE METABOLITE) 1/3-1/5 th AS POTENT AS KETAMINE. ITS RESPONSIBLE FOR PROLONGED EFFECTS OF ANALGESIA.ON RPTD DOSE/INFUSION. EXCRETED THROUGH KIDNEY.

Pharmacokinetics:

Pharmacokinetics distribution initially distributed to highly perfused tissues and is then redistributed to less well perfused tissues redistribution results in termination of its action t ½ α is about 10-15 minutes

Pharmacokinetics:

Pharmacokinetics metabolism extensively metabolised in liver hydroxylation and N-demethylation of the cyclohexamine ring to form norketamine (has 20-30% potency of ketamine) norketamine hydroxylated to hydroxy-norketamine and then conjugated to form water-soluble compound for renal excretion t ½ β of 2-3 h

Slide 114:

Pharmacodynamics Central nervous system produces dissociative anaesthesia . Dissociates thalamocortical system from limbic system . Patients appear to be dissociated from the environment. Depresses CNS by blocking the NMDA receptors. Ketamine causes profound analgesia. ↑cerebral blood flow, CMRO 2 , & intracranial pressure – not ideal for neurosurgery & patients with raised intracranial pressure. Produces emergent phenomenon, can be prevented by prior administration of benzodiazepines – not recommended in patients with h/o psychiatric disease. Can stimulate seizure focus – not indicated in epileptic patients.

Dissociative anaesthesia:

Dissociative anaesthesia immobility, amnesia and marked analgesia without actual loss of consciousness functional and electrophysiological separation of the normal communications between the sensory cortex and the association areas of the brain

Dissociative anaesthesia:

Dissociative anaesthesia cataleptic state patients are non communicative, although they appear to be awake; eyes may remain wide open with slow nystagmus and intact corneal reflexes various degrees of skeletal muscle hypertonus may be present along with non-purposeful skeletal muscle movements that are independent of surgical stimulation

Slide 117:

Cardiovascular system ↑ myocardial contractility, heart rate, systemic vascular resistance, blood pressure & cardiac output → indirect effects of increased centrally mediated release of catecholamines from adreal medulla – not indicated in patients with coronary artery disease and hypertension. Drug of choice in patients with hypovolemia and low cardiac output states and also in patients with rt →lt shunts.

Slide 118:

Respiratory system little effect on ventilatory drive in normal persons. Can produce apnoea in infants & neonates when given intravenously. Produces Bronchodilatation – useful in patients with bronchial asthma. Near normal airway reflexes are preserved. Induces copius salivation, hence an anti sialogogue drug has to be administered. Other effects : High risk of PONV. Prevents post operative shivering. Per operative analgesic dose decreases post operative morphine requirement.

Ketamine - mechanism of action:

Ketamine - mechanism of action interacts with NMDA (N-methyl-D-aspartate) glutamic acid Ca ++ channel receptors in cortex and limbic system central opioid receptors ( μ , κ ) monoaminergic receptors in spinal cord voltage-gated Ca ++ channels voltage-gated Na + channels analgesic effect via inhibition of Ca ++ influx at presynaptic nerve terminals ( κ opioid receptor, monoaminergic receptors in spinal cord, monoaminergic receptors in spinal cord) at postsynaptic NMDA receptors

Ketamine - mechanism of action:

Ketamine - mechanism of action non-competitive antagonism of NMDA receptor Ca ++ channel pore interacts with phencyclidine binding site stereoselectively, leading to significant inhibition of receptor activity, this only occurs when the channel is opened

NMDA receptor:

NMDA receptor

Ketamine – mechanism of action:

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

Ketamine – mechanism of action:

Ketamine – mechanism of action effect on descending inhibitory monoaminergic pain pathways analgesic property may involve these pathways, although difficult to separate ketamine-sensitive opioid receptor action local anaesthetic action blockade of Na + channel effect on muscarinic receptors antagonistic action as ketamine produces anticholinergic symptoms (postanaesthetic delirium, bronchodilatation, sympathomimetic action)

Slide 124:

DOSE: INDUCTION-GA:0.5-2mg/kg iv 4-6mg/kg im. MAINTAINANCE-GA : 0.5-1mg/kg iv SEDATION : 0.2-0.8mg/kg iv over 2-3 min .

Clinical use of ketamine:

Clinical use of ketamine pain control (limited value) ketamine can only inhibit NMDA activity when the receptor-operated ion channel had been opened by nociceptive stimulation, hence pre-emptive analgesia with ketamine is ineffective routes of administration intramuscular, intravenous epidural ketamine is rapidly absorbed into plasma, producing spinal and systemic effects, intrathecal cause dizziness, drowsiness

Clinical use of ketamine:

Clinical use of ketamine neuroprotection activation of NMDA receptor is implicated in cerebral ischaemic damage, hence by blocking the receptor, ketamine has neuroprotective potential by a mechanism related to a reduction in plasma catecholamine concentrations septic shock reduce the need for inotropes via inhibition of catecholamine uptake reduce pulmonary injury via a reduction in endotoxin-induced pulmonary hypertension and extravasation

Clinical use of ketamine:

Clinical use of ketamine asthma therapy anti-inflammatory spasmolytic increased catecholamine concentrations, inhibition of catecholamine uptake, voltage-sensitive Ca ++ channel blockade, inhibition of postsynaptic nicotinic or muscarinic receptors anaesthesia for haemorrhagic shock patients sympathomimetic effects

Slide 128:

analgesia-greater for somatic than visceral pain induction of anesthesia- most candidates belong to asa -grade 4.and cvs disorders( ihd ), reactive airway disease, septic shock , hypovolemia . in malignant hyperthermia, congenital heart disease with risk of rt – lt shunts. pain management-cancer pain,neuropathic pain, ischemic/ phantum limb. sedation-pediatric group they have fewer adverse emergence reaction . reversal of opiod toleranse . restless leg syndrome

Slide 129:

SIDE EFFECTS- EMERGENCE REACTION. CONTRAIDICATED- PTS WITH HIGH ICP, ICSOL, OPEN EYE INJURY,, VASCULAR ANNEURYSMS,PTS WITH PSYCHIATRIC DISORDERS(SCHIZOPHRENIA).

Ideal intravenous anaesthetic agent:

Ideal intravenous anaesthetic agent

Ideal intravenous anaesthetic agent:

Ideal intravenous anaesthetic agent physical properties water soluble, does not require solvent stable in solution over long periods of time not adsorbed onto glass or plastic pharmacokinetics elimination independent of liver or renal function, with inactive, nontoxic metabolites

Ideal intravenous anaesthetic agent:

Ideal intravenous anaesthetic agent pharmacodynamics non-irritant on injection whether- intravenous or intraarterial non-allergenic, should not cause histamine release rapid onset of action, high specificity of action short duration of action - elimination by metabolism, no cumulative properties minimal cardiorespiratory depression no increase in muscle tone good analgesia

Slide 133:

THANK YOU