Non Volatile Anesthetic Agents

8/9/2019 Non Volatile Anesthetic Agents

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Pharmacologic Principles

• Pharmacokinetics:

What the body does to the drugs

• Pharmacodynamics:

What the drugs does to the body


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Pharmacokinetics

Absorption, Distribution, Biotransformation, excretio


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Absorption Absorption

• The process by which a drug leaves its site ofadministration to enter the blood stream

• Affected by: – Characteristic of the drugs:

• Solubility, pKa, Concentration

– Site of absorption:

• Circulation, p!, surface area


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Route of absorptiuon:

• "eroral

• Sublingual

• #ectal

• Transdermal

• "arenteral:

•Subcutaneous

•$ntramuscular

•$ntravascular %completely by pass absorption process&


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'istribution• 'epend primary on:

– (rgan perfusion

– "rotein binding

– )ipid solubility

Tissue group composition

Tissue group Composition Body mass(%) Cardiac output

*essel rich +rain,heart,liver,

idney,endocringlands

-. /0

muscle 1uscle, sin 0. -2

3at 3at 4. 5

*essel poor +one,ligament,cartilage

4. .


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"rotein binding

• As long as drug is bind to plasma protein it6s

unavailable for uptae


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Biotransformation

• Alteration of substance by metabolic processes• "rimary organ: )iver

• 'ivide into 4 phase:

– "hase $ reaction including o7idation, reduction,hydrolysis in order to convert a drug into more polarsubstance

– "hase $$ reaction is con8ugation a parent drugs orphase $ metabolite with an endogenous substrate to

convert it into highly polar substance that can beeliminated by urine


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Hepatic Clearance

• #ate of elimination of drugs as a result of liver biotransformation

• 97press in 1ililitersminute

•'epend on:

•!epatic blood flow

•3raction of the drugs remove from the blood by liver


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97cretion

• "rincipal (rgans: Kidney• (thers (rgan: )ungs %for e7cretion of volatile agents&

• #enal Clearence:

#ate of elimination of a drug from idney e7cretion

• 'epend on : – "rotein +inding:

• ;on protein bound drugs freely cross glomerular filtrate

– $oni


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Pharmacodynamics


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on!olatile "nesthetic "gents


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Barbiturates

• 1echanisms of Action – 'epress #AS

– Suppress transmission of e7citatory

neurotransmitters %eg, Acetylcholine& – 9nhance transmission of inhibitory

neurotransmitters %eg, =A+A&


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Structure>Activity #elationships


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Pharmacokinetics

• "bsorption – #ectal %induction for Children&

– $1 %for premedication&

– $* %1ost fre?uent route for induction&

• #istribution –#edistribution determined the duration of action not the drug

metabolism or elimination

–3or !ighly soluable barbiturates ma7imal brain up tae within@. sec, subse?uent redistribution to peripheral compartment

within 4.>@. min%redistribution lowers -. of plasma Bbrain Concentration&


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• +iotransformation

• +iotransformation• Biotransformation

• "rincipally involves !epatic (7idation

• $nvolves in drugs duration of action when barbirurates given inrepeated doses

• $cretion• !igh "rotein binding decrease glomerular filtration #ate

• !igh lipid solubility increase reabsorption• )ess protein bound and less lipid soluble drugs such as

phenobarbital ,renal e7cretion limited to water soluble end

product


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9ffect (n (rgan Systems

• Cardiovascular #epression of medullary &asomotor center Peripheral

&asodilatation

Hipotension

Central &agolytic effect

Tacycardia

'yocard #epression

Baroreceptor

Response

"deuate

Poor

Cardiac utput

maintained


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Respiratory

•'epression of medulary ventilatory center hich decrease the

ventilatory responses to hypercapnia and hypo7ia

•Dpper airway obstruction due to barbiturates sedation effect

•'o not Completely depress no7ious airway refle7

•+ronchospasme due to cholinergic stimulation (because Barbiturates

do not Completely depress noxious airway reflex), histamine release,

direct bronchial smooth muscle stimulation


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CerebralCerebral


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Renal

• #educe #enal +lood flow and glomerular filtration rates

Hepatic

• !epatic +lood 3low 'ecreased

• Combination with Cytocrome ">E0. $nterferes biotransformatio

of other drugs*mmunologic

• Anaphylactic B Anaphylactoid allergies are rare• Sulfur containing barbiturates evoe histamine release, while

o7y barbiturates do not


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#rugs *nteraction

•Contras media, sulfonamides potentiate 9ffect of barbiturates

•9thanol, narcotics, antihistamines, other C;S depressant

potentiate sedative effect of barbiturates


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+ses and dosages commonly used

Agent Use Route Concentration(%) Dose(mg/kg)

ThiopentalThiamylal

InductionSedation

IVIV

2.52.5

3-!.5-".5

Methohexital Induction

SedationInduction

IV

IVRecta# (Ci#dren)

"

""!

"-2

!.2-!.&25

Secobarbitalpentobarbital

'remedication ra#I

Recta# su**

5 2-&2-&3


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+en


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"icture (fchemical

structure


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Pharmacokinetics

• "bsorption – "(

• 'ia


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• Biotransformation

• They rely on liver biotranformation

"gents Hepaticetraction ratio

&d $limination halflife

'ia


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$ffect on the organs

• Cardio!ascular – 1inimal cardiovascular depressant effect

• +", C(, "*# decline slightly, !# sometimes rises

• 1ida


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#rug interactions

• Cimetidine reduce metabolism of dia


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+ses and doses commonly used

"gents +se Route #ose

('g12g)

#ia0epam "remedication

Sedation

$nduction

(ral

$*

$*

.,4>.,0 ('a 34mg)

.,.E>.,4

.,@>.,5

'ida0olam "remedication

Sedation

$nduction

$1

$ntranasalF+uccalF

SublingualF

$*

$*

.,./>.,-0

.,4>.,@.,./

.,-

.,.->.,-

.,->.,E

5ora0epam(not recommended for children)

"remedication

Sedation

(ral

$1

$*

.,.0

.,.@>.,.0

.,.@>.,.E

F 3or "ediatric atient


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2etamine

• 'echanism f "ction – Blocking polysynaptic reflees in the spinal cord

– *nhibiting ecitatory neurotransmitter effect in selected

area of the brain that cause dissociati!e anesthesia.

• /tructure acti!ity relationship

– Analogue of phencyclidine

– 97istence of stereospecific effect $ncrease anesthetic potency

and decrease psycotomimetic side effect %SG vs #>&


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Pharmacokinetics

• "bsorption – $1

– $*

%"ea "lasma level usually achieved within -.>-0 min after $1&

• #istribution – Ketamine is more lipid soluble and less protein binding than

thiopental that leads to rapid brain uptae and subse?uent

redistribution %distribution half time -.>-0 min&

– #edistribution responsible for awaening


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•Biotransformation

•+iotransformation in the liver

•!igh hepatic ratio Short elimination half time %4

hrs&

•$cretion•97creted renally


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$ffect n organs

• Cardiovascular – 1yocardial 'epression, %hen given in large dose or

concomitant with $nhaled anesthetic agents&

– Central sympatetic stimulation

+",C(,!#

Pulmonary arterial pressure

'yocardial 6ork

> $nhibiting reuptae of norepinefrin


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•Respiratory

•*entilatory drive is minimally affected

•"otent broncodilator

•$ncrease in salivation

•Cerebral

•$ncreasing cerebral (4 consumption

•$ncreasing Cerebral +lood flow

•$ncreasing intracranial pressure

•"sycotomimetic effect on recovery %less common in children orpatient receiving ben


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#rug interaction

• "otentiated ;on depolari


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+ses and doses

"gent +se Route #ose(mg1kg)

2etamine $nduction $*

$1

->4

@>0


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Propofol

• 1echanism of Action – 3acilitation of inhibitory neurotransmission mediated by

=A+A

• Structure Activity #elationship

– Consist of "henol ring with 4 isoprophy groups – Altering the side chain length influence potency, induction,

recovery characteristic

– ;ot water soluble

• Available in - oil in water solution that contain Soy bean, oil, 9gg

lecithin, =lycerol This formulation Cause pain in in8ection


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Pharmacokinetics

• "bsorption – nly for *& "dministration

• #istribution

– High lipid solubility Rapid nset

– #istribution half life 789 min

– 6omen reuired higher dose and a,aken faster

– #ecreasing dose for elderly because small &d in

elderly.

•Biotransformation


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•"ropofol clearence e7ceed hepatic blood flow %implicating

e7istance of e7tra hepatic metabolism& this properties responsib

for propofol rapid recovery

•Con8ugation in liver result in>active metabolite

•)ong term sedation used propofol can cause lipema, metabolic

acidosis B death

•$cretion

•1ainly e7creted in urine

•Chronic #enal failure does not affect clearence of propofol

ff


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$ffect on organs

• Cardio!ascular – 'ecrease +"

– 'ecrease systemic vascular resistance

– 'ecrease cardiac contractility

– 'ecrease "reload, can lead vagal mediated

bradycardia

– $mpaired arterial barorefle7

–!ypotension usually reverse by laryngoscopy andintubation stimulation

•Respiratory


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Respiratory

•$t6s a profound respiratory depressant

•$nhibits hypo7ic ventillatory drive

•'epress normal response to hypercarbia

•'ecrease upper airway refle7, %very helpful in facilitating

tracheal intubation&•Can cause histamine release, but it6s not contraindicated for

astmatic patient

•Cerebral


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Cerebral

•Cerebral +lood flow

•$C"

• Anticonvulsant properties

•$ntra ocular pressure

• Antipruritic properties

• Anti emetic effect

# i t ti


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#rug interaction

• Contained cremophor formulation of propofol,potentiated ;ondepolari

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Non Volatile Anesthetic Agents

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