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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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