IntrVen Pharmac Lect 2

8/2/2019 IntrVen Pharmac Lect 2

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Dr. Vithal DhulkhedProfessor and Head

Department of AnesthesiologyKIMSU,Karad,

19/04/2012 Dr. Vithal Dhulkhed 1


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Historically, anaesthesia was by inhalation

However, patients frequently passed through stage

of hyperexcitability Guedel termed this stage 2. Chloral hydrate was first IV agent(1870s)

IV route not popular until 1930s, with the use of

barbiturates.



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INTRA VEnoUS ANAESTHETIC AGENT

Objectives

Properties of the ideal IV anesthetic agent

Classification

The present commonly used agentsTarget-controlled Infusions

Chirality

New drugs and technologies



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IDEAL IV ANAESTHETIC AGENT

Rapid onset:

A- un-ionized at blood ph(7.35

7.45)B- highly lipid soluble

these properties permit penetration of the BBB

2-rapid recovery -by redistribution from brain



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analgesia at sub anesthetic concentrations

minimal cardiovascular and resp. depression

No emetic effects

No excitatory phenomena

No emergence phenomena

No interaction with neuromuscular blocking




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No pain on injection, no venous sequelae

No toxic effects on other organs

No release of histamineNo hypersensitivity reactions

Water soluble formulation

Long shelf life :

No stimulation of porphyria




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Pharmacokinetics basics

By knowing VD ,T1/2 calculate dose required and dosinginterval to attain serum therapeutic level

VD (Vol of distrn) = dose/conc of drug; after bolus (VC)at steady state (SS) after infusion (Vss).

Clearance = Elimination * VD.

The desired conc for therapeutic effect (Cp)

Loading dose = Cpss* VC ;Bolus = (Cnew - Cactual) * VC

Inf rate to maintain SS= Cpss* Clearance

M: LBM = 1.1 * wt - 128 * {wt/ht} F: LBM = 1.07 * wt 148 * {wt/ht}



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Intravenous anaesthetic agents

BarbiturateSodium thiopental

non barbiturate

Propofol (newly introduced)Ketamine (infrequently used)

Etomidate

Other adjuvant IV agents(benzodiazepines, midazolam,diazepam,)



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Sodium thiopental (pentothal)

Ultra short acting IV anesthetic-hypnotic

Yellow powder,-highly lipid soluble,2.5% soln used

Combined with sodium carbonate,(30mg) it becomeswater soluble.When injected ,sodium carbonate isneutralized and the thiopental is converted to its lipidsoluble non ionazed form (40% ionized at pH=7.4)

Bacteriostatic ,and has a pH of 10.6 to10.8

It is highly protien bound by albumen(75%)



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Derived from Barbituric acid(2,4,6-trioxohexahydropyrimidine,condensation of malonic acid and urea)

Alkyl/aryl groups at C5 (i.e.CH2)-sedative hypnoticactivity

Sulfa group (C2-S)increase lipid solubility

Phenyl group at C5, or on N - anticonvulsant activity

(e.g. phenobarbital),Long alkyl side chains at C5 increase hypnotic potency

from 5 to 6 C atoms length (above this, convulsantproperties may result)


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PharmacokineticsInduces liver enzymes, increasing cyto P450 activity

Metabolism primarily in the liver (apprx 10 to15%per hour

Desulfuration to pentobarbital which is oxidised toinactive thiopental carboxylic acid

Less than 1% unchanged urine excretion

If large doses or infusions are used, metabolismbecomes zero order and delayed recovery.




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Acts on Cl-channels,hyperpolarise post synapticmembrane

Facilitates inhibitory neurotrasmitter GABA,

mimics its actionsInhibits synaptic transmission of Glutamate,Ach

Decrease both cerebral electrical & metabolic

activityAnticonvulsant,reduction of ICP and IOP

Anti-analgesic effect



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Thiopental causes a dose related depression ofmyocardial function -venous tone decreases

Depression of the respiratory response to

hypercarbia and hypoxia

Laryngospasm and bronchoconstriction

FRC is reduced by 20% with induction



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indications

Induction of anesthesia

Maintenance of anesthesia for short procedures

Control of convulsive states

For supplement of regional anesthesia or low potencyanesthesia



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Absolute contraindications

Airway obstruction , porphyria,H/O hypersensitivity

Precuations

CVS disease , severe hepatic disease ,renal disease

Rarely, intra-arterial injection can occur



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Physical and chemical properties

Intravenous anaesthetic/hypnotic.(2,6-diisopropylphenol) Akylphenolwhite oil-in-water emulsion, pH of 71% propofol 10mg/ml,10% soyabean oil.2.25 %glycerol,1.2% purified egg phosphatide.

Acts on B1 subunit of GABA

NMDA receptor



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Propofol

Physical and chemical properties Propofol is a highly lipid soluble.

Has No effects on muscle relaxants.

Associated with low incidence of nausea &

vomiting. Metabolism to glucurone metabolites excreted in

urine.



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Propofol

Dosage

For healthy unpremedicated 2.5-3 mg/kg.

For premedicated 1.5-2 mg/kg.

Elderly patients


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PropofolPropofol has antiemetic, antipruritic, and

anticonvulsant properties.

Hypotension secondary to a drop in systemicvascular resistance, contractility, and preload.Hypotension is more pronounced than withthiopental. Propofol markedly impairs thenormal arterial baroreflex response tohypotension.

excitatory side effects such as myoclonus.



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PropofolCauses profound respiratory depression. Depression of upper

airway reflexes exceeds that of thiopental.

Venous irritation:

Pain on injection is more common than withthiopental.Reduced by

Concomitant lidocaine, administering through more proximalIV line.

not licensed for use in children < 3 years-reports of unexpecteddeaths -due to metabolic acidosis and myocardial failure afterlong-term use in ICU.



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Propofol

indication Approved Patient PopulationInitiation and maintenance ofMonitored Anesthesia Caresedation

Adults only

Combined sedation and regional

anesthesiaAdults only (See Precations )

Induction of General Anesthesia Patients 3 years of age

Mainenance of General Anesthesia Patients 2 months of age

Intensive Care Unit (ICU) sedationof intubated, mechanically

ventilated patients

Adults only



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Ketamine

Its a dissociative anesthetic

agent.

by dissociative we mean thatthe patient is unconscious but

appears awake and doesnt

feel pain.It has anesthetic and

analgesic effect



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Ketamine

Physical & chemical Properties chemically related to the psychotropic drug( e.g. phencyclidine).Racemic mixture,S-more analgesia,rapid metabolism,fewer

emergence reactions.MW 238 Water soluble, and 10x more lipid soluble

than thiopental.

pH=3.5 - 5.5 Converted to norketamine(20-30% activity)

then tohydroxynorketamine



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KetaminePharmacokinetics

Dosage

IM 5 10 mg/kg. peak plasma level reach

approx 15 minutes

IV 1 2 mg/kg. dissociated stage is noted in15 seconds. intense analgesia, amnesia &unconciousness occur within 45-60 minutes

subsequent IV doses of 1/3 of the initialdose maybe required



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KETMINE

METABOLISM It has a rapid absorption and distribution to the

vessel rich groups like THIOPENTAL

Hepatic metabolism is required for elimination


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KETMINE

Mechanism of action There are 3 theories explains the MOA of ketamines :1 N-methyl aspartate receptor theory :

NMDA receptors may represent a subgroup of the sigma opiatereceptors (the PCP site) that blocks spinal pain reflexes.

2 Opiate receptor theory :Ketamine may have some affinity for opiatereceptors,mu,kappa,delta;but its effect cant be reversed withnaloxone.

3- Miscellaneous receptor theory :

It reacts with muscarinic, cholinergic and serotonergic receptors.

Ketamine is a potent analgesic at subanesthetic plasmaconcentrations.

It has a wide margin of safety ( up to 10x the usual dose )



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KETMINE

PharmacodynamicsCNS :1. ketamine increases cerebral oxygen consumption, cerebral

blood flow, and intracranial pressure

2- generalized increase in the muscle tone and purposful

movements.3- Unpleasant dreams, hallucinations or frank delirium (esp.

females & large doze of ketamine).

incidence of dilirium in 15-35 year old pts is approx. 20%

Respiratory system:It preserves laryngeal &pharyngeal airway reflexes.

Ketamine is a potent bronchodilator



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KETMINE

PharmacodynamicsCVS: It produces central sympathetic stimulation,

which increases:

1. arterial blood pressure, heart rate, and cardiacoutput.

2. Pulmonary artery pressure.

3. Coronary blood flow.

4. Myocardail oxygen uptake.It may cause myocardial depression if the

sympathetic nervous sys is exhausted orblocked.



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KETMINE

PharmacodynamicsGIMinimal anorexia, nausea & vomiting.

GUPlacental transfer does occur, but neonatal depression

hasnt been observed if the doze is limited to < 1mg/kg.

Muscle systemGeneralized increase in skeletal muscle tone.

Increases the effects of muscle relaxants.Endocrine Sys.Increased sympathetic stimulation increased blood

glucose, increased plasma cortisol, increased heartrate.



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KETMINE

Indications1- sole anesthetic for diagnosis and surgical

procedures

2- induction of anesthesia

3- to supplement regional or local anesthetictechniques

4- for anesthetic induction in severe asthmatic pts. Orpatients with cardiovascular collapse requiringemergency surgery



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KETMINE

Contraindications1- lack of knowledge of the drug

2- lack of resuscitative equipment

3- inability to maintain a patent airways

4- allergy to ketamine

5- history of psychosis

6- cerebro-vascular disease

7- Patients. For whom hypertention is hazardous



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ETOMIDATE

Carboxylated imidazole.watersol at phys pH

Only D-isomer is actve

0.2%soln.35% propylene glycol,pH 8.1-painful,littlerisk of pptn. 10ml ampoule,2mg/ml

Acts on GABA,no intrinsic analgesic activity

75% prot binding,rapid onset 30sec,

Metabolised to inactive carboxylic acidmetabolitehepatic enzymes and plasma esterases,kidney elimn.

Dose .3mg/kg19/04/2012 Dr. Vithal Dhulkhed 33


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Cardiostable,not sympathomimetic like ketamine Pain on injection,no histamine release.

increases epileptogenic activity in patients with seizurefoci.

frequent myotonic activity during induction,decreased by opioid or benzodiazepine premedication.

The incidence of nausea and vomiting seems to bemore common with etomidate than others

inhibition of corticoid synthesis by reversible block of11-beta-hydroxylase.



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BenzodiazepinesFeatures which result in their popularity as

adjuvant IV anaesthetic agents:

1 amnesia2 minimal cardiarespiretory depressant

effect.

3 anticonvulsant activity.

4 low incidence of tolerance anddependence.



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Benzodiazepines

They inhibit the actions of glycine (by increasing theconc. Of a glycine inhibitory neurotransmitter) which willlead to antianxiety and skeletal muscle relaxant effects.

2 Bind to GABA ,increase Cl- conductance , facilitatethe actions of the inhibitory neurotransmitter GABA

Benzodiazepines are highly lipid soluble. Midazolam (Versed) exhibitssignificant lipid solubility, following injection, because thepreviously open imidazole ring closes at physiological pH (7.4).

They are highly protein bound (albumin).

They are metabolized by the liver through conjugation withglucoronic acid and excreted by the kidneys.

Midazolam and Diazepam are the most commonly usedbenzodiazepines during operative procedures. cause anterograde

amnesia



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Benzodiazepines

Midazolam and diazepam They are commonly used to provide:

IV sedation.amnesia. reducing anxiety.

structure composed of a benzene ring, fused to aseven-member diazepine ring

Both diazepam and lorazepam are insoluble in

water, and therefore require solubilizing agents,while the imidazole ring renders midazolam watersoluble


azo am an azepam


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azo am an azepamTHEDIFFERENCESBETWEENTHEM

Midazolam is 2-3 times more potent thandiazepam:

The dose for IV conscious sedation: 0.5 3 mgup to 0.1 mg/kg for midazolam, and 1-10 mg for

diazepam.The dose for inducing anesthesia: 0.2 0.4mg/kg for midazolam , and 0.15-1.5 mg/kg fordiazepam.

Midazolam has a more rapid onset, greateramnestic effect, less postoperative sedativeeffects than diazepam.



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BenzodiazepinesMidazolam and diazepam

THEDIFFERENCES

Pain on injection and thrombophlebitis is lesslikely with midazolam

.

Elimination half time for midazolam range from1-4 hours, and for diazepam from 21-37 hours.



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Benzodiazepine antagonists (Flumazenil)

Its an imidazobenzodiazepine.

Antagonizes by copetative inhibition.

Its elimination half-time is1hour, considerably less

than most benzodiazepines; therefore we will need

repeated administrations of flumazenil to

antagonize a benzodiazepine with a longer half-

time.



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Benzodiazepine antagonists (Flumazenil)

The usual initial dose is 0.2 mg over 15 seconds,if the desired level of consiousness is not

obtained within one minute of administration wecan give repeated doses of 0.1 mg every minuteup to the maximum of 2 mg, and if sedationrecurs we can use infusions of 0.1-0.4 mg/hour.

The most common side effect is nausea (4%)



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Narcotic Agonists

Opium derivedfrom dried juice ofpoppy plant which

contains over 20plant alkaloids.including morphine

& codiene.



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Narcotic AgonistsSite of Action

Opioid receptors are predominantly located in the:

Brain stem (amygdala, corpus striatum, periaqueductal graymatter and medulla),Spinal cord(substantia gelatinosa), GIT

3 types of receptors:Mu receptors (): analgesia, resp depression,

euphoria, & physical dependence.

Kappa receptors (K): analgesia, sedation,

resp depression, miosis.

Sigma receptors(a): dysphoria, hallucination,tachypnea, tachycardia.



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Narcotic Agonists

Pharmacokinetics

Rapid distribution through the body

following IV injection.

Its metabolized by the liver and the

majority of the inactive metabolites areexcreted unchanged in the urine.



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Narcotic Agonists

Pharmacodynamics

Sedation through interfering with sensory

perception of painful stimuli.Large doses produce unconsciousness but they

are generally incapable of producing anesthesiaand it cant guarantee total amnesia.

It may produce nausea & emesis throughstimulation of the chemoreceptor trigger zone.



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Narcotic Agonists

Pharmacodynamics

Dose related depression of respiratory rate

and minute ventilation and increase thetidal volume which will lead to a slow deeprespiration.

Reversed by naloxone administration.


N ti A i t


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Narcotic AgonistsPharmacodynamics

CVS Opioids have little myocardial depressant effect

With either N2O or benzodiazepines may depress

cardiac output.

They decrease SVR,either by decreasingsympathetic outflow or by releasing histamine (asmorphine)

Synthetic opioids are less likely to release

histamine.

They produce bradycardia by stimulation vagalnucleus in the brain stem.


N ti A i t


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Narcotic AgonistsPharmacodynamics

Slow GI mobility-constipation,post op ileus.

Increase biliary tract tone -biliary colic withpatients with bile stones.

Increases the bladder sphincters tone urineretention.

Anaphylactic reactions, bronchospasm, chest

wall rigidity and pruritis.


N ti A i t


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Narcotic AgonistsFentanyl and Morphine

Fentanyl -most narcotic agent used duringinduction of anaesthesia due to its rapid onset(highly lipid soluble) and predictable duration

of action (30 minutes).Morphine is used in the perioperative period to

provide long lasting analgesia



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Narcotic Agonists

Fentanyl and Morphine Low doseAnalgesic dosePotency Ratio0.05 - 0.2 mg/kg10 mg1Morphine

0.5 3 mic g/kg100 mcg100Fentanyl



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Narcotic Antagonists (Naloxone)

Naloxone competes with opioids at the mu, delta,

kappa and sigma receptors.

Ampules of 0.02, 0.4 and 1 mg/ml.

Peak effect 1-2 min.

Duration of action 30-60 min.

Used in perioperative surgical patients with excessive

sedation or respiratory sedation secondary to opioids.



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Narcotic Antagonists (Naloxone)Given in small incremental doses.

High doses of naloxone will result in suddenreversal of analgesic effects leading to abrupt

return of pain resulting in hypertension,tachycardia, pulmonary edema, ventriculardysrhythmias and cardiac arrests.

If sedation or respiratory depression recurs,

continuous infusion of 3-10 micg/kg/hour ofnaloxone is required.



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Agents of research interestDexmedetomidine -alpha 2-adrenoreceptor agonist

with sedative and analgesic properties.

Used via infusion (for up to 24 hours).

Antisympathetic effects -cardiovascular stability

Used as an adjunct to other anaesthetics



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Current clinical practice - focused on two compounds,midazolam and propofol.

Why then look for new compounds?

The answer is both have limitations.

Have relatively steep doseresponse curves

Propofol causes pain on injection,also supports bacterial

growth,causes haemodynamic depression,occasionallycauses excitation



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Midazolamhas a slow, time-to-peak effect

has an active metabolite, 1-hydroxymidazolam

CNS7056 is a new esterase-hydrolysed benzodiazepine

with rapid onset, short duration of action, and a fastrecovery profile in animal models

JM-1232 () evaluated in man as MR04A3 is a novelisoindoline derivative benzodiazepine receptor site

agonist fully reversible by flumazenil Both onset and offset times were faster than literature

values for midazolam



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Etomidate Derivatives

Improved understanding of action at a molecular levelchemical modification to allow esterase hydrolysis

Potentiates GABAAreceptor activation. receptors arepentameric with two binding sites

Methanethiosulphate-etomidate (MTS-etomidate)forms covalent bond to one binding site

Considered a molecular probe to interrogate thebinding site



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Methoxycarbonyl-etomidate -MOC-etomidate-rapidlymetabolized. Only during infusion adrenocorticaldepression

Anaesthesia induced by MOC-etomidate is dose-independent

Infusion require a substantial mass of drug withsubsequent metabolism to carboxylic acid andmethanol

Its proper evaluation requires human exposure



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Carboetomidate

In contrast, offers a pharmacodynamicsolutionremoving the nitrogen atom frometomidate massively decreases adrenocorticaldepression

What is unclear is whether the unwelcome effectsof etomidatemyoclonus and nausea andvomiting remain unchanged



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AZD3043 - allosteric modulator of GABAAsimilar topropanidid ,tested in man by bolus injection andinfusion with 4 studies registered at

www.clinicaltrials.gov,

PF0713, (R, R)-2,6-di-sec-butylphenol, similar topropofol but with larger sidechain, slower onset ofaction and longer duration ,without pain on injectiondue to reduction in the aqueous phase concentration

http://www.clinicaltrials.gov/http://www.clinicaltrials.gov/


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Fospropofol

Is a phosphate pro-drug for propofol -converted topropofol in a few minutes of i.v. injection. -time-to-peak effect is longer, recovery slower

(FDA) approved for 'moderate sedation'. does notcause pain on injection ,water soluble

However perineal pain or paraesthesia



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! One approach to containing drug costs

Use a cheap agent for induction and maintenanceswitch to a more expensive short-acting agent towards

the end of surgery for rapid recovery

Perhaps, a truly short-acting benzodiazepine agonist,

or one with a faster onset than midazolam, mightallow benzodiazepine anaesthesia to be revisited.



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Target Controlled Infusion


*concentration of agent in the brain for any given blood concentration

Improved administration technique based onpharmacokinetics

Infusion pump technology, better estimations of effect

site conc* facilitated TCI Set initial target blood (or effect site) conc required

based on BWt

Blood (or effect site) conc display -

estimates from large trials


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Determine for each drug PK data set, simulation ofthe conc obtained with a given dosage.

choose the drug that servesbest. calculate optimal

dosing schemes to obtain a blood or effect site concin the therapeutic range rapidly with minimalovershooting.

Couple the pharmacokinetic information with a

computer-controlled administration device:

TCI systems, blood conc or effect-site conccontrolled.


T l l d d


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Target conc are calculated, not measured.

TCI maintain 3 superimposed infusions, one at a constantrate to replace drug elimn and second exponentially

decreasing infusions to match drug removed from centralcompartment to others

At present there is no method of measuring drug concnsreal time analogous to the ET volatile concn



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Using Technology to Support Drug

Administration TCI of propofol has been adopted worldwide with the

exception of the USA

Generic or 'open' TCI -implement published

TCI remains strictly 'open loop', -No feedback of aneffect measure to TCI system

The Open TCI initiative,www.opentci.org, brings

together academics and manufacturers to share dataand develop best practice in TCI. Currently available

http://www.opentci.org/http://www.opentci.org/


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The choice of math model and the question of its

appropriateness to the individual patient remain theresponsibility of the anaesthetist

Closed-loop anaesthesia has been the subject ofconsiderable research but has not been developed

commercially



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Sedasys(Ethicon Endo Surgery, Inc., Cincinnati, OH,USA) new proprietary system for propofol delivers afixed sedation protocol or a subset of it and reacts to

protect patient safety. Provided satisfactory sedation without device-related

adverse events during endoscopy

It monitors ECG, SaO2

, Et CO2

, and patientresponsiveness to auditory commands.

Slow titration in small increments



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chiral drugs The configuration defined by Cahn-Ingold-Prelog

sequence rule



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This is an exciting time for anaesthetic drugdevelopment

Anaesthetics may be neuro-protective,effect (ornot) preconditioning,[ alter immunity and cell

proliferation, may cause neurotoxicity in infantbrain.

Researchers are working to clarify these andidentify how to exploit beneficial effects and

moderate or avoid harmful ones.



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Chirality and anaesthetic drugs

Enantiomers are moleculesthat exist as Rt-handed andLt-handed forms -non-

superimposable mirrorimages.

Such compounds are alsosaid to be chiral

Diastereoisomers refer tostereoisomeric compoundsnot enantiomeric,


Dextro propoxypheneAnalgesic

LevoAntitussive


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more than half ofsynthetic agents arechiral

Administered as racemic

mixture,i.e. two virtually separate

drugs are being given atthe same time with

differentpharmacodynamics andpharmacokinetics


Group priority (atomic size) is indicated asA>B>C>D, A representing the largest size.


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Potential advantages -an increase in the selectivity,improved therapeutic index and less drug interactions

Total plasma Cl and the VDss were significantly greater

for R-thiopental than for S-thiopental

It has twice potentiation of gamma-amino butyric acid(GABA) at GABAAreceptors

Different adverse effect profiles



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Ketamine R(-) isomer is less effective but higherside effects than S(+) enantiomer

Etomidate is optically pure R(+) isomer, which isthe active component

Dexmedetomidine, an imidazole compound, isdextro-enantiomer acting on alpha-2 receptor,especially for the 2A subtype

More effective than clonidine



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IntrVen Pharmac Lect 2