Intravenous Agent

8/2/2019 Intravenous Agent

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Classification

rapid acting

barbiturates

methohexitone, thiopentone

imidazole derivatives

etomidate

hindered phenols

propofol

steroidsalthesin, pregnanolone

eugenols

propanidid

slower acting

benzodiazepines

diazepam, midazolam

arylcycloalkylamine derivatives

ketamine

opioids

large dose fentanyl

butyrophenones

droperidol

imidazole derivatives

dexmedetomidine

General properties

high lipid solubility, poor water solubility at

physiological pH

most are weak acids (except etomidate, ketamine,

dexmedetomidine)

best modelled using a 3 compartment model

low initial volume of distribution V1 (0.1-0.2

L/kg), except ketamine 1L/kg

action terminated by distribution to VD of 1-

5/L/kg, over the next 5 minutes

most are extensively protein bound

part of their activity is mediated by GABAA receptors

(except ketamine and dexmedetomidine)

myocardial depressants, with an addtional hypotensive

effect due to vasodilation

most will cause dose related respiratory depression

(ketamine less than the others)

most are anticonvulsant, (except etomidate or

methohexitone)most reduce ICP, CBF and CMRO2, but not ketamine

hepatic metabolism

BARBITURATES

Barbituric acid

2,4,6-tri-oxo-hexa-hydropyrimidine

the condensation of urea and malonic acid barbituric

acid and water

barbituric acid itself lacks central depressant activity

carbonyl group at position 2 takes on acidic character

because of lactam (keto) - lactim (enol) tautomerization

Tautomerism

the condition, quality, or relation of metameric substances,

or their respective derivatives, which are more or less

interchangeable, according as one form or the other is themore stable.

the lactam and the lactim compounds exhibit

tautomerism

metameric different arrangement of the same

constituents in the molecule (methyl ether and

ethyl alcohol are metameric compounds)

Structure activity - alkyl or aryl groups at C5confers sedative-hypnotic activity

increase in the length of one, or both the alkyl side chains

up (to 5-6 carbon atoms) increases hypnotic potency

above this number, potency is reduced and

convulsant properties may result

oxidation of radicals (to alcohols, ketones, phenols or

carboxylic acids) terminates the activity

the presence of a phenyl group at C5, or on one of the ring

nitrogens confers anticonvulsant activity (eg.

phenobarbital)

Structure activity substitution at C2

oxybarbiturates (O=C)

thiobarbiturates (S=C)

higher lipid solubility, producing more rapid

onset and shorter duration of action than

oxybarbiturate

Structure activity - methyl or ethyl substitution at N1

increases lipid solubility

rapid onsetshortens duration of action

rapid recovery

methylated oxybarbiturates (methohexitone), methylated

thiobarbiturate

subsequent demethylation may occur resulting in a longer

acting metabolite

these compound have a high incidence of excitatory

phenomena

tremor, increased muscle tone, involuntary

movements

Structural activity lipid solubilityin general, structural changes which increase lipophilicity

(thiobarbiturate, methyl or ethyl substitution at N1),

increase hypnotic potency

fast on-fast off

rapid onset

shorter duration of action

rapid recovery

accelerate metabolic degradation

Intravenous anaesthetic agents

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Structure activity stereospecificity

compounds possessing asymmetrical carbon atoms

all have side chains

l-isomers are twice as potentcompared to d-isomers

despite similar access to the CNS

methohexital has four stereoisomers due to an

asymmetric centre at C5

the -l-isomer is 4 times as potent as the -l-

isomer, however also produces excessive motor

activity, and the marketed solution is a racemicmixture of the -dl isomers

Mechanism of action

GABAA receptor complex is the major site of barbiturate

action

Cl- conductance

binding to the GABAA receptor complex,

decreasing rate of GABA dissociation,

prolonging duration of GABA activated 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

Na+ conductance

inhibit the function of voltage-dependent Na+

channel

K+ conductance

at higher concentrations, voltage-dependent K+

conductance is reduced

mesencephalic ascending reticular activating system

(ARAS) is sensitive to the drugs action and the effects

are stereospecific

barbiturates preferentially suppress polysynaptic

responses

inhibition is

postsynaptic in supraspinal (cortical,

diencephalic and cerebellar) regions

presynaptic in the spinal cord

mutiplicity of sites of action of barbiturates

may be the basis for their ability to induce full

surgical anaesthesia

more pronounced central depressant effectscompared to benzodiazepines

GABAA receptor

pentameric structure

5 protein subunits arranged in a circle forming an Cl-

channel that remains closed until GABA binds to the

recognition site

permutations of 6 subunit classes 1-6,1-4,1-

4,,,

each subunit has 4 transmembrane (4TM)

domains M1-4

M2 and M3 have intraluminal sites forbinding of anaesthetics, M3 has a binding

site for alcohol

anaesthetic site is near the extracellular side of the

membrane

GABAA receptors in different areas of the CNS contain

different combinations of the essential subunits conferring

different pharmacologic properties on GABAA subtypes

stimulation by GABA results in

opening of a chloride channel

influx of Cl-

hyperpolarisation and inhibition of postsynaptic

cell

5 binding sites

at extracellular end of the channel

GABA binding site

benzodiazepine binding site

inside the Cl- channel

barbiturate binding site

steroid binding site

picrotoxinin binding site

specific GABAA agonist - muscimol

specific GABAA antagonist - bicuculline

Pharmacokinetics

barbiturates are weak acids

thiopentone pKa 7.6, 60% unionised at pH 7.4

methohexitone pKa 7.9, ~ 39% unionised at pH = 7.4

Onset of action

the latency of onset determined by the rapidity with which

they cross the BBB dependent upon

lipid solubility

increased with thiobarbiturate, and

methyl or ethyl substitution at N1

degree of ionization

with relatively acidic medium (blood,ECF, acidaemia), increase unionised

fraction, increase transfer into brain

ionization also affects renal excretion

increased ionization decreases back-

diffusion

basis of forced alkaline diuresis in the

management of overdosage

loading dose (Ficks Law of Passive Diffusion)

lipid solubility

thiopentone

highly lipid solublerelatively 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 2


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transfer across placenta

thiopentone and the other highly lipid soluble agents

readily cross the placenta

maximum foetal blood thiopentone

concentrations being seen within 3 minutes of

intravenous administration of thiopentone

Duration of action

dependent on concentration gradient at plasma:effector

site

administered dosage, rate of administration,dissociation from receptor site, redistribution,

clearance

for thiopentone, metabolism is too slow to account for its

short duration of action

return of consciousness is governed by two

factors

the bolus mixing with circulating blood

volume

redistribution from the brain (VRG)

Distribution

central compartment VC

for sodium thiopentone 38% body weight

for methohexital 35%

these exceed intravascular space and combined

with the rate of equilibration with brain suggests

that brain should be considered as a part of VC

cerebral blood flow 15-18% of the CO

a large bolus of lipid soluble, unionised drug is

presented to the brain within one arm-brain

circulation time following administration of the

drug

Cerebral uptake

brain extraction ratio of sodium thiopentone is

approximately 60%

peak plasma concentrations of sodiumthiopentone (175 mg/L) are achieved within 30

seconds of intravenous administration of 350 mg

internal jugular concentrations are lower (75

mg/L)

median effective serum thiopentone concentrations

(EC50) - 50 mg/L for recovery of pupillary

responsiveness and 12 mg/L for the recovery of motor

responsiveness.

Redistribution

vessel rich group

includes the heart, liver, kidney and brain

due to high myocardial blood flow, about 70

ml/100g/min, accounts for the rapidity of

cardiovascular depression

muscle blood flow (20% of CO)

about 15-30 minutes are required for equilibration

despite high lipid solubility, blood flow to fat is so low the

equilibrium time for thiopentone is prolongedthus, redistribution of thiopentone within the first 30

minutes after intravenous bolus administration is mainly to

the muscle group

Metabolism

oxidation of radicals at the ring C5 (to alcohols, ketones,

phenols or carboxylic acids), important for termination of

biological activity

conjugation with glucuronic acid and excreted

N-hydroxylation

N-dealkylation

following a bolus dose

barbiturates combine with several species of

cytochrome P450 and competitively interfere with

biotransformation of other drugs and endogenous

substances

other substrates may reciprocally inhibit

barbiturate biotransformation

following chronic administration

marked increase in protein and lipid content of

hepatic smooth endoplasmic reticulum, the

activities of glucuronyl transferase and the

cytochrome P450-dependent mixed function

oxidase system

enzyme inducing effect results in an increased

rate of metabolism of steroid hormones,

cholesterol, bile salts, vitamin K and D, and

barbiturate

explains tolerance to barbiturates

Elimination

most barbiturates have high lipid:water partition

coefficients and are significantly protein bound

poorly filtered at the glomerulus

readily back-diffuse in the late tubular segments

excretion is largely dependent upon prior hepaticmetabolism

Sodium thiopentone

5-ethyl-5-(1-methyl-butyl)-2-thiobarbituric acid

introduced in 1934 by Lundy and Waters

distribution

75-85% bound to plasma protein

highly lipid soluble

pKa 7.6

Vdss of 2.5 L/kg

ER 0.15

clearanceClss 2-4 ml/kg/min

t 2-6 min; 5-12 h

with repeated doses various body stores begin to fill up

and the drug accumulates in the body

may be asleep for many days

reason why thiopentone is not used as a sole

anaesthetic agent except for very short duration

ED50/LD50 = 4.6 (26.4 for etomidate) 3


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Porphyria unsafe drugs (strong evidence)

androgens

barbiturates

estrogens

ethanol

griseofulvin

hydantoins

progesterones

sulfonamides

Porphyria unsafe drugs (probably or possibly unsafe)drugs affecting the central nervous system

anaesthetic agents (benzodiazepines, etomidate,

ketamine, enflurane, halothane)

local anaesthetic agent (mepivacaine)

opioids (pentazocine, trimethadone)

others (carbamazepine, glutethimide, imipramine,

nikethamide, nortriptyline, primidone, valproate)

drugs affecting the cardiovascular system

clonidine, disopyramide, ergotamine,

hydralazine, methyldopa, nifedipine,

phenoxybenzamine, verapamil

drugs affecting the respiratory system

aminophylline, theophylline

drugs affecting the endocrine system

chlorpropamide, tolazamide, tolbutamide

antimicrobial / antiparasitic drugs

chloramphenicol, chloroquine, dapsone,

ketoconazole, miconazole, metronidazole,

nalidixic acid, rifampin

other drugs

alkylkating agents, danazol, metyrapone,

phenylbutazone, spironolactone

Compare and contrast pharmacokinetics of

methohexitone with thiopentone

structure

pKa

solubility

p-binding

Vd

t

metabolism

clearance

preparation

presented as a sodium salt to ensure total solution of the

drug

pale yellow powder

mixed with anhydrous sodium carbonate 6% (not HCO3-)

ampoule atmosphere is nitrogen, at 0.8 bar

2.5% solution has a pH = 10.6, (increasing solubility of

weak acid in alkaline medium)

the solution is not stable, should be used within 24-48 h

Pharmacodynamicscentral 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 PaCO2secondary to respiratory depression

cardiovascular system

hypotension is dependent on the dose and rate of

administration

increase myocardial blood flow and oxygen utilisation

myocardial depression at high doses

venous thrombosis after 5%

intra-arterial injection releases noradrenaline from vessel

wall inducing vasoconstriction

respiratory system

reduction in sensitivity of the central nervous system to

carbon dioxide

tissue necrosis and sloughing after extravasation

induction of ALA-synthetase in liver mitochondria

producing excessive amounts of delta-aminolaevulinic

acid, porphobilinogen and other porphyrins

in individuals with deficiencies in the enzymes involved

in the production of haem, phophyria results

deficiency of porphobilinogen deaminase results in acute

intermittent porphyria

deficiency of protoporphyrinogen oxidase results in

variegate porphyria

4


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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-benzodiazepinesthe 5-aryl ring greatly enhances potency

4 categories based on elimination half-lives

ultra-short acting

short-acting (t less than 6 hours e.g.

midazolam)

intermediate-acting (t 6 to 24 hours e.g.

temazepam)

long-acting (t greater than 24 hours e.g.

diazepam)

midazolam contains an imidazole ring bridging R1 and

R2

both diazepam and lorazepam are insoluble in water,

therefore require solubilizing agents, while the imidazole

ring renders midazolam water soluble

Mechanism of action

the benzodiazepine receptor forms part of the GABAAcomplex, located on the postsynaptic membrane of the

effector neurone

high concentrations of GABAA receptors in

limbic system, particularly the hippocampus and

amygdala

cerebral cortex

cerebellum

high affinity, saturable and stereospecific binding of the

benzodiazepines to the GABAA complex receptor

is increased by both Cl- and GABA

results in potentiation of neural inhibitionmediated by GABA, increased frequency of Cl-

channel opening and influx of Cl-

receptor affinity and potency:

diazepam>midazolam>lorazepam

other sites of action

inhibition of uptake of adenosine, potentiating the

actions of this endogenous neuronal depressant (in

coronary arteries)

inhibition of Ca++ conductance and Ca++

dependent release of neurotransmitters

inhibits tetrodotoxin-sensitive Na+ channels

Benzodiazepine binding site on the GABAA receptor

Benzodiazepine receptor ligands

agonists benzodiazepines, alter the conformation of the

receptor such that the affinity for GABA is increased,

enhancing GABAs effects, with a resultant increase in the

frequency of Cl- channel opening events

antagonists - flumazenil, occupy the receptor but have no

intrinsic activity, preventing the effects of both agonists and

inverse agonists, without affecting the binding of GABA

inverse agonists - -carbolines, occupy the receptor and

reduce the affinity for GABA, resulting in CNS stimulation

Receptor mediated response

Pharmacodynamics

central nervous system

anxiolyticsedative

hypnotic

muscle relaxant

antegrade amnesia

anticonvulsant, tolerance may develop and this limits their

usefulness in the long-term management of epilepsy

the drugs do not cause true general anaesthesia, since

awareness usually persists and relaxation sufficient for

surgery cannot be achieved

effect on sleep

decreased sleep latency, diminished the numberof 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

NC

C N

CA

R1R2

-R3

R4

R2-

R7-

1 23

45

B

C

log [drug]

Ractive

Rinactive

Agonist

Partial agonist

Antagonist

Inverse agonist

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neuromuscular system

blockade at very high doses

induce muscle hypotonia, without interfering with

locomotion, and may decrease decerebrate rigidity

respiratory system

the slopes of the ventilatory/CO2 response curves are

flatter, however, they are not shifted to the right, as occurs

with the opioids

the peak onset of ventilatory depression following

midazolam is at ~ 3 minutes and lasts for ~ 15 minutesmay cause apnoea during anaesthesia, or when given in

conjunction with the opioids

other factors likely to increase the incidence of

significant respiratory depression, or apnoea, include, old

age, debilitating disease, and co-administration of other

respiratory depressant drugs

effect on minute ventilation


baroreceptor reflexes generally remain intact, though,

there is some depression

midazolam > flunitrazepam at decreasing peripheral

resistance, and is dose related, the hypotensive effect is

minimal and usually less than that seen with thiopentone

in patients with elevated cardiac filling pressures, both

midazolam and diazepam produce a "nitroglycerine like"

effect, causing venodilatation and reducing preload

resultant hypotension activates baroreceptor reflex arc

when combined with opioids there is a synergistic effect,

the combination producing greater decreases in blood

pressure than either agent alone

diazepam and lorazepam decrease left ventricular work

and cardiac output

diazepam increases coronary blood flow, possibly by

increasing interstitial concentrations of adenosine, thus,

diazepam may provide some protective function in

patients with ischaemic heart disease

contraindicationsobstetric and perinatal anaesthesia

Pharmacokinetics

absorption

all have high lipid:water distribution coefficient in

unionised form

absorption by oral route complete either unchanged, or

metabolised (clorazepate, prazepam, flurazepam)

distribution

bind to albumin

extend of binding correlates strongly with lipid

solubility and ranges from 70% for alprazolam to99% 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

3-compartment model appear to be more appropriate for

highly lipid soluble drug

plasma

rapidly equilibrating tissues

slowly equilibrating tissues

rapid uptake into brain and other highly perfused organs

after intravenous administration, or oral administration of a

rapidly absorbed drug

redistribution

rapid uptake is followed by a redistribution intotissues that are less well perfused (muscle and fat)

most rapid for drugs with highest lipid solubility

kinetics of redistribution complicated by

enterohepatic circulation

cross placental barrier

secreted into breast milk

metabolism

by microsomal enzyme systems in the liver

some are inactivated by the first pass reaction

important determinant of their duration of action

oxazepam, lorazepam, temazepam,

triazolam, midazolam

most have active metabolites that are biotransformed more

slowly than the parent compound

flurazepam and N-desalkylflurazepam

3 stages

N-dealkylation at position 1 (or 2), usually yields

N-desalkylated compounds, (active)

hydroxylation at position 3, usually yields active

metabolite (3-hydroxyl compound)

conjugation of the 3-hydroxyl compounds,

principally with glucuronic acid

N-dealkylation and 3-hydroxylation reactions

reduced by cimetidine and oral contraceptive

reduced to a greater extent in aged, chronic liver

disease, than are those involving conjugations

Midazolam

water-soluble benzodiazepine

0.15 - 0.4 mg/kg, induces unconsciousness in 60s

duration of sleep 7-15 minutes

hydroxylation of methyl group on the fused imidazo ring

by CYP3A isoforms forming 1-OH-methylmidazolam

conjugation with glucuronic acid forms 1-OH-methylmidazolam glucuronide, t 1 hour, 1/10th activity

of parent drug, prolonged effect with renal impairment

Benzodiazepine antagonist flumazenil

an imidazobenzodiazepine

clinical use in 1991

only available as intravenous formulation

initial dose of 0.1 mg, followed by 0.1mg incremental dose

until effect is seen (>5ng/ml)

pharmacokinetics

50% bound to plasma proteinVd of 0.9 L/kg

clearance 17 ml/min/kg

eliminated almost entirely by hepatic metabolism to

inactive products with a half-life of 1 hour

duration of clinical effect 1 to 3.5 hours


7/12

Metabolism of flumazenil

Compare and contrast diazepam with midazolam

Diazepam Midazolam

structure no imidazole ring imidazole ring

pKa 3.4 6.2

solubility not water soluble good in acidic

requires solvent solution pH)

emergence slow intermediate

PROPOFOL

hindered phenol - 2,6-diisopropylphenol

weak acid

Physicochemical properties

oil at room temperature

emulsion is isotonic

pH 6-8.5

pKa of the drug in water is 11

octanol : water partition coefficient at physiological pH is

6761 : 1Preparation

1% [or 2%] aqueous emulsion with

10% soya bean oil (as a solubilizing agent)

2.25% glycerol (render isotonic)

1.2% egg phosphatide (as emulsifying agent)

sodium hydroxide (to adjust pH between 6 and

8.5)

sealed under nitrogen (to prevent oxidative

degradation in the presence of oxygen)

addition of medium chain triglycerides, and sodium oleate

in Propofol-Lipuro 1%

Propofol emulsion containing disodium edetate (0.005%)

Distribution

following a single bolus dose, half-time of blood : brain

equilibration (keo) is 1-3 minutes

rapid decline in plasma concentration, described by 3

compartment model (plasma, rapidly equilibrating tissues,

slowly equilibrating tissues)

t 5 minutes

patient will wake up in 5-10 minutes

Clearance

biphasic elimination, two elimination half-lives

60% metabolised by cytochrome P450-dependent mixed

function oxidase system to 2,6 diisopropyl-1,4-quinol,

which is then conjugated to glucuronide or sulphate

40% found as propofol-glucuronide or -sulphate

t 1-3 hours dependent on duration of infusion

pharmacokinetics not affected by liver and renal disease

Cl 23-50 ml/kg/min

context-sensitive half time is 5 minutes after 1 hour

infusion, 7 minutes after 10 h infusion

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, opisthotonusanaphylaxis rarely (bronchospasm, erythema,

hypotension)

0 5 10

Time(hr)

Contexthalf

time(min)10

5

0

7


8/12

Pain on injection of propofol

mechanism of immediate pain

probably due to direct irritant effect of phenol

pain detected by free afferent nerve

endings between media and intima of

vein wall

concentration of propofol in aqueous

phase, reduced with intralipid

formulation

outer aqueous phase comes into contactwith intima of vein during

administration

may be due to production of irritant substances

when propofol comes into contact with silicone

lubricant in plastic disposible syringes

mechanism of delayed pain

probably result from indirect effect

release of kininogen via kinin cascade

latency of 10-20s

Factors influencing the incidence of pain

site of injection

size of vein

speed of injection

propofol concentration in aqueous phase

buffering effect of blood

speed of intravenous carrier fluid

temperature of propofol

syringe material

Factors reducing incidence of pain

premedication with pethidine, NSAIDs

use of large veins, at least antecubical

speed of injection

speed of infusion carrier

pretreatment with lignocaine (also mixture),

prilocaine, procaine, opioids (alfentanil, fentanyl,

pethidine), metoclopramide (weak local

anaesthetic effect), thiopentone, ketamine (local

anaesthetic effect)

mixing with blood (reduction of concentration

in aqueous phase or release of kinins)

cooling to 4oC or warming to 37oC

Negative inotropy

mediated in part by activation of M2Ach receptor,

activating M2Ach NO cGMP signal pathwaystimulation of M2Ach receptor

inhibits adenylyl cyclase by a Gi protein-

mediated mechanism; decreasing cAMP

production with inhibition of transmembrane

Ca++ influx through voltage-activated Ca++

channels (ICa(L))

activates constitutive NO synthase and

increasing NO production, activation of guanylyl

cyclase and increasing cellular level of cGMP,

cGMP inhibits ICa(L) by:

activation of cGMP-dependent proteinkinase (PKG) and phosphorylation of

ICa(L) or some regulatory protein

activation of cGMP-stimulated cAMP-

specific PDE, lowering cAMP level

however, plasma concentration of propofol in clinical use

is in the range of 3M to 90M, with protein binding of

propofol in the range of 97%-99%, effective free propofol

is


9/12

ETOMIDATE

a hypnotic agent without analgesic activity

synthesized (1964), clinical practice (1973)

a carboxylated methylbenzyl imidazole derivative

weak base, pKa 3

rapid onset, duration is dose dependent, relatively brief

usually 3-5 minutes after an induction dose of 0.3mg/kg

etomidate ED50/LD50 = 26.4 (4.6 for thiopental)

safe in patients susceptible to malignant hyperthermia

Preparationsaqueous preparation

in propylene glycol

osmolality and pH unphysiological, resulting in

thrombophlebitis, pain during injection, histamine

release, anaphylactoid reactions, haemolysis, lactic

acidosis, pulmonary hypertension

emulsion preparation

emulsion containing soya oil, medium-chain

triglycerides, glycerol, egg lecithin, sodium oleate, water

physiological osmolality, none of the complication of

propylene glycol formulation

Mechanism of action

dependent upon subunit subtype present within the

GABAA receptor

only 2 and 3 subunits are highly sensitive to etomidate

a single amino acid residue is crucial for the interaction

of etomidate with the 3 subunit

Pharmacokinetics

distribution

75% bound to plasma proteins (albumin),

unbound fraction increased in

hypoalbuminaemia

dose reduction in elderly

decreased Vd

decrease clearanceVd 2.3-4.5 L/kg

very short duration of action,

t 2.6-4 minutes

consciousness regained in 5-10 minutes

clearance

hepatic extraction of 0.67

ester hydrolysis or N-dealkylation in the liver

11-25 ml/min/kg

t 2.9 hours

being a substituted imidazole derivative, inhibits hepatic

metabolism of other drugs, similar to cimetidinePharmacodynamics


lack of effect on both the sympathetic system and on

baroreceptor function

less negative inotropic effect compared with propofol

and thiopentone (isolated guinea pig heart)

least effect on L-type Ca++-channels compared with

midazolam and propofol (isolated canine ventricular cells

and rat myocardial cell membrane)

inhibition of adrenal steroidogenesis

concentration dependent inhibition of cytochrome P450

dependent mitochondrial enzymes (17-hydroxylase and

11 hydroxylase) with decreased production of 17-

hydroxyprogesterone, cortisol, corticosterone, and

aldosterone

after single dose: 0.3mg/kg, suppression in cortisolproduction is brief, serum concentration restored after 2-6

hours

after etomidate infusion: serum cortisol concentration

returned to baseline 1 hour after infusion ended, and were

significantly increased after 6 and 20 hours, CABG patients

(Crozier et al,1994 vs Ledingham and Watt,1983)

myoclonia

transient disinhibition of subcortical structures

(diencephalic excitations) and alteration in balance of

inhibitory and excitatory influences in the thalamocortical

tracts during transformation from consciousness to

unconsciousness, result of unsynchronous onset of drug

action at various sites of the CNS due to differences in

receptor affinity, regional receptor distribution, or local

blood flow differences within the CNS

immune system

interleukene-6 greater at 6 and 12 hours after etomidate

compared with thiopentoneless marked lymphopenia at 4 hours after etomidate

compared with thiopentone

Major advantages

lack of cardiovascular side effects

neuroprotective

Adverse effects

adrenal suppression (early 1980s)

cannot be used for long-term administration

myoclonia

pain on injection

emesisContraindications

known hypersensitivity

patients with hereditary disorder for haem biosynthesis

porphyrogenic potential

newborns and infants up to age of 6 months

cholesterol

pregnenolone

17 hydroxypregnenolone

17 hydroxyprogesterone

progesterone

11 deoxycortisol

11 deoxycorticosterone

cortisol

corticosterone

aldosterone

17 hydroxylase

17 hydroxylase

11 hydroxylase

11 hydroxylase

9


10/12

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 brainDissociative anaesthesia

immobility, amnesia and marked analgesia without actual

loss of consciousness

functional and electrophysiological separation of the

normal communications between the sensory cortex and

the association areas of the brain

Cataleptic state

patients are non communicative, although they appear to

be awake; eyes may remain wide open with slow

nystagmus and intact corneal reflexes

various degrees of skeletal muscle hypertonus may be

present along with non-purposeful skeletal muscle

movements that are independent of surgical stimulation

Mechanisms of action

interacts with

NMDA (N-methyl-D-aspartate) glutamic acid

Ca++ channel receptors in cortex and limbic

system

central opioid receptors (, )

monoaminergic receptors in spinal cord

voltage-gated Ca++ channels

voltage-gated Na+ channels

analgesic effect via inhibition of Ca++ influx

at presynaptic nerve terminals ( opioid

receptor, monoaminergic receptors in spinal

cord, monoaminergic receptors in spinal cord)

at postsynaptic NMDA receptors

non-competitive antagonism of NMDA receptor Ca++

channel pore

interacts with phencyclidine binding site

stereoselectively, leading to significant inhibition

of receptor activity, this only occurs when the

channel is opened

effect on voltage-sensitive Ca++ channelsproduces non-competitive inhibition of K+-

stimulated increased intracellular Ca++

effect on opioid receptors

antagonist at , agonist at

S(+) ketamine is 2-3 times more potent than R(-

) ketamine as an analgesic

affinity for receptor is 10000 fold weaker than

that of morphine

effect on descending inhibitory monoaminergic pain

pathways

analgesic property may involve these pathways,

although difficult to separate ketamine-sensitive

opioid receptor action

local anaesthetic action, blockade of Na+ channel

effect on muscarinic receptors

antagonistic action as ketamine produces

anticholinergic symptoms (postanaesthetic

delirium, bronchodilatation, sympathomimeticaction)

Pharmacodynamic effects


stimulation, with peak increase in heart rate, arterial blood

pressure and cardiac output in 2-4 minutes after intravenous

injection, slow decline to normal in the next 10-20 minutes

by excitation of the central sympathetic nervous

system and

possibly by inhibition of the uptake of

noradrenaline at sympathetic nerve terminals

respiratory system

decreases the respiratory rate slightly for 2-3 minutes

upper airway muscle tone is well maintained

upper airway reflexes are usually active

central nervous system

increases cerebral blood flow, oxygen consumption, and

intracranial pressure

resembles inhalational anaesthetics in this respect

associated with disorientation, sensory and perceptual

illusions, vivid dreams following anaesthesia - emergence

phenomena

secretions

potent stimulator of salivary and tracheobronchial

secretions

atropine often administered concurrently

Pharmacokinetics

routes of administration

intramuscular, intravenous

epidural

ketamine is rapidly absorbed into plasma,

producing spinal and systemic effects,

intrathecal

cause dizziness, drowsiness

distributioninitially distributed to highly perfused tissues and is then

redistributed to less well perfused tissues

redistribution results in termination of its action

t is about 10-15 minutes

metabolism

extensively metabolised in liver

hydroxylation and N-demethylation of the cyclohexamine

ring to form norketamine (has 20-30% potency of

ketamine)

norketamine hydroxylated to hydroxy-norketamine and

then conjugated to form water-soluble compound for renalexcretion

t of 2-3 h

10


11/12

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

neuroprotection

activation of NMDA receptor is implicated in

cerebral ischaemic damage, hence by blocking

the receptor, ketamine has neuroprotectivepotential

by a mechanism related to a reduction in plasma

catecholamine concentrations

in patients with septic shock

reduce the need for inotropes via inhibition of

catecholamine uptake

reduce pulmonary injury via a reduction in

endotoxin-induced pulmonary hypertension and

extravasation

asthma therapy

anti-inflammatory

spasmolytic

increased catecholamine

concentrations, inhibition of

catecholamine uptake,

voltage-sensitive Ca++ channel

blockade,

inhibition of postsynaptic nicotinic or

muscarinic receptors

anaesthesia for haemorrhagic shock patients

sympathomimetic effects

BUTYROPHENONE

Droperidol

a butyrophenone, a fluorinated derivative of the

phenothiazines

first synthesised by Janssen

it has a faster onset and shorter duration of action than

haloperidol

frequently used in conjunction with fentanyl

t ~ 2-2.5 hrs, is similar to that of fentanyl

however, the effects frequently outlast those of

fentanyl, possibly due to increased affinity for

CNS receptorsmechanism of action

act at post-synaptic GABA receptors

Pharmacodynamic effects

a potent anti-emetic and is effective against opioid

induced vomiting

produces extrapyramidal side-effects

should be avoided in patients with Parkinsonism

may cause a profound fall in peripheral resistance and

blood pressure in patients receiving vasodilator therapy

and in those with a decreased circulating blood volume,

due to both a CNS and peripheral -blocking effect

Neuroleptanalgesia

a state of drug-induced depression of activity, lack of

initiative, and reduced response to external stimuli

the state of neuroleptanalgesia, or neurolept-anaesthesia

may be obtained using a combination of a potent

analgesic and a neuroleptic tranquiliser drug

first described by Delay (1959) in drug induced behaviour

syndromes

patient has good analgesia and is sedated, yet is able to

respond to simple commands

the mechanism of action is thought to be competitive

antagonism at dopaminergic receptors in the brain

nigrostriatum

this syndrome includes

inhibition of purposeful movement & conditioned

behaviourinhibition of amphetamine induced arousal

tendency to maintain an induced posture,

catalepsy

marked inhibition of apomorphine induced

vomiting

maintenance of corneal and light reflexes

drugs with neurolept properties may also exhibit

-adrenergic blockade

hypotension

hypothermia

sedation

extrapyramidal effects

anticholinergic properties

competitive antagonism at dopaminergic receptors in the

brain nigrostriatum

these agents have a predilection for certain areas in the

brain rich in DA-receptors, especially the CTZ and the

extrapyramidal nigrostriatum

DEXMEDETOMIDINE

an imidazole derivative

active dextro-rotatory optical isomer of medetomidine

a relatively selective alpha2-adrenoceptor agonist with

sedative and analgesic properties

exhibits, in vitro, an affinity for alpha2-adrenoceptors over

alpha1-adrenoceptors in a ratio of approximately 1620:1

Pharmacodynamics

acting at both presynaptic and postsynaptic alpha2-

adrenoceptor on nerve fibers originating from the locus

ceruleus, dexmedetomidine administration reduces

norepinephrine release from these nerve endings,

moderating sympathetic discharge and resulting in dose

dependent central vasomotor center depression,hypotension, bradycardia, as well as sedation

the distribution of alpha2-adrenoceptor in medullary and

spinal centers involved in the control of parasympathetic

and sympathetic outflow explain the bradycardia and

hypotensive effects of dexmedetomidine

via its imidazole moiety, dexmedetomidine also acts at the

medulla, further reducing the excessive sympathetic

discharge associated with awakening

without depressing respiratory effort dexmedetomidine is

suitable for patients in whom respiratory effort has to be

maintainedantinociceptive action of alpha2- adrenoceptor agonist in

the spinal dorsal horn is due to a direct spinal action and

not activation of descending inhibitionthe

antinociceptic effect is exerted via its activity at

the alpha2A, 2B, and 2C subtype adrenoceptors.

the down-stream signaling mechanism for alpha2-

adrenoceptor is very similar to that of opioid

receptor, involving the calcium ion channel11


12/12

activation of the alpha2B-adrenoceptors located on

vascular smooth muscle appears to mediate

vasoconstriction, and the signalling mechanism involves

the L-type calcium channels

transient increase in blood pressure with reflex

bradycardia is generally observed following a

bolus dose of dexmedetomidine

overdosage has been shown to decrease left

ventricular ejection fraction

Physicochemical properties

white or almost white powder

freely soluble in water

pKa of 7.1

weak base

formulated as a clear, colourless, isotonic solution with a

pH of 4.5 to 7.0.

the solution is preservative-free and contains no

additives or chemical stabilizers.

Pharmacokinetics

elimination t 1.8 to 2.5 hours after stopping infusion

clearance 37-46 L/h

Vdss 89 L to 100 L

increasing duration of dexmedetomidine infusion:

increases Vdss

increases elimination t

reduces clearance

long context-sensitive half-time, lasting 250 minutes

after an 8-hour infusion

biotransformation

Phase I reaction involving cytochrome P450, mainly

CYP2A6

3-OH-dexmedetomidine

3-carboxy-dexmedetomidine

3-OH, N-methyl-dexmedetomidine

3-carboxy N-methyl-dexmedetomidine

Phase II reaction involving N-glucuronidation

3-OH-dexmedetomidine glucuronide

dexmedetomidine-N-methyl O-glucuronide

Adverse effects

hypotension, hypertension

bradycardia, tachycardia, atrial fibrillationnausea, vomiting

fever

dry mouth

rigor

agitation

pain

hyperglycaemia

PHARMACOKINETICS OF INTRAVENOUS

AGENTS

* liver blood flow ~ 21.5 ml/kg/min

IDEAL INTRAVENOUS ANAESTHETIC AGENT

Physical properties

water soluble, does not require solvent

stable in solution over long periods of time

not adsorbed onto glass or plastic

Pharmacokinetics

elimination independent of liver or renal function, with

inactive, nontoxic metabolites

Pharmacodynamics

non-irritant on injection whether- intravenous or

intraarterial

non-allergenic, should not cause histamine release

rapid onset of action, high specificity of action

short duration of action - elimination by metabolism, no

cumulative properties

minimal cardiorespiratory depression

no increase in muscle tone

good analgesia

Intravenous Agent

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