PHARMACOKINETICS AND
PHARMACODYNAMICS OF
INTRAVENOUS ANESTHETICS
AGENTS
PRESENTER: Dr.SUCHETHA.S
MODERATOR: Dr.SAGAR.S.M
HEAD OF DEPT: Dr.ARUN KUMAR.A.

⦿PHARMACOKINETICS: the study of absorption,
distribution,metabolism and excretion of the
injected and inhaled drugs and their
metabolites.
⦿PHARMACODYNAMICS: study of the
responsiveness of the body to a drug and the
mechanism by which the effects occur.

⦿An induction agent is the one which causes
rapid reversible loss of consciousness.

FACTORS AFFECTING THE
INDUCTION DOSE
⦿Route of administration
⦿Age
⦿Lean body mass
⦿Low cardiac output states
⦿Hypoproteinemia

INDUCTION AGENTS
⦿PROPOFOL- ISOPROPYL PHENOL
⦿BARBITURATES(THIOPENTAL)
⦿KETAMINE- PHENCYCLIDINE
⦿ETOMIDATE-IMIDAZOLE
⦿BENZODIAZEPINES

MECHANISM OF ACTION
⦿GABA is the principle inhibitory neuro
transmitter in the brain. Acts by increasing
the chloride conductance causing hyper
polarization of post synaptic membrane and
functional inhibition.
⦿Propofol , thiopentone and etomidate acts
via the GABA receptor.
.

KETAMINE
⦿NMDA antagonism
⦿Mu,gamma and kappa opiod receptors
⦿Monoaminergic receptors
⦿Muscuranic receptors
⦿Sodium channel
⦿Neuronal nAch receptors

FORMULATIONS
PROPOFOL THIOPENTONE KETAMINE
MILKY WHITE EMULSION YELLOW AMORPHOUS
POWDER
CLEAR AQEOUS
SOLUTION
10%soyabean oil+
2.25%glycerol+1.2% egg
phosphatide
Sodium salts

PH-7 10.5 3.5-5.5.
Pka 11 7.6 7.5
PRESERVATIVE
Sodium
metabisulphate
Chlorbutanol

METABOLISM
PROPOFOL THIOPENTONE KETAMINE
Hepatic :oxidative
metabolism by cyt p450
into water soluble
sulphate and glucuronic
acid metabolites.
Pulmonary: converted to
di iso propyl quinol.
Renal
No evidence of impaired
elimination in patients
with cirrhosis of liver and
renal dysfunction
(1)oxidation of the aryl,
alkyl, or phenyl moiety at
C5
(2)N-dealkylation
(3) desulfuration of the
thiobarbiturates at C2
(4) destruction of the
barbituric acid ring.
Metabolized by hepatic
microsomal enzymes.
Ketamine to norketamine
to hydroxyl norketamine
Norketamine has 20-30%
activity.

PHARMACOKINETICS
⦿volume of distribution: The theoretical
volume that would be necessary to contain
the total amount of an administered drug at
the same concentration that it is observed in
the blood plasma.
⦿ The volume of distribution is useful in
estimating the dose required to achieve a
given plasma concentration .

⦿Context-sensitive half-life or context
sensitive half-time is defined as the time
taken for blood plasma concentration of a
drug to decline by one half after an infusion
designed to maintain a steady state (i.e. a
constant plasma concentration) has been
stopped.
⦿The "context" is the duration of infusion.
( how long does the effects of the drugs last
after stopping the infusion)

⦿Drug clearance is concerned with the rate at
which the active drug is removed from the
body.
⦿ Clearance is defined as the rate of drug
elimination divided by the plasma
concentration of the drug.

PHARMACOKINETICS
PROPOFOL THIOPENTONE KETAMINE
ONSET One arm brain
circulation
One arm brain
circulation
One arm brain
circulation
PEAK ACTION 100-120s 90-100s 60s
AWAKENING 6-10mins 5-10 min 10-15 mins

VOLUME OF
DISTRIBUTION
4l/kg 2-4l/kg 3l/kg
ELIMINATION
HALF LIFE
4-7 hrs 7-17hrs 2-3hrs
CONTEXT
SENSITIVE HALF
LIFE
8hrs-40min
CLEARANCE 20-30ml/kg/min 3-4 ml/kg/min 12-17ml/kg/min

PHARMACODYNAMICS
PROPOFOL THIOPENTONE KETAMINE
CNS •Primary site of action is
beta subunit of GABA
receptor.
•Increases the dopamine
concentration in nucleus
accumbens: sense of well
being.
•Anti emetic effect :
decreases the serotonin
level in area prostema
Decreases
CMRO2,CBF,ICP.
Decreases CPP.
NEUROPROTECTIVE
Attenuation of changes in
ATP, Na+,Ca2+,K+ caused
by hypoxic injury.
Inhibiting lipid
Reduces the
CMRO2,CBP,ICP.
Maintains CPP.
Free radical
scavenging
Robinhood
phenomenon
Primary site of
action is the
thalamoneocorti
co projection
system.
Increases
CMRO2,CBP and
ICP.
?antiapoptotic
effect after
cerebral
ischemia and
reperfusion.

KETAMINE
⦿Dissociative anesthesia
⦿Upper airway reflexes(cough, corneal,
swallow)
⦿Salivation and lacrimation
⦿Nystagmus
⦿Skeletal muscle tone.

PROPOFOL THIOPENTONE KETAMINE
CVS Decreases the
SBP,DBP,MAP,CO
,SV.
1.Inhibition of
smooth muscle Ca2+
mobilization.
2.Decreases the
angiotensin-2
elicited Ca2+ entry.
3.Stimulation of
nitric oxide.
4.Activation of K+-
ATP channels.
Inhibits the
baroreflex and
prevents
tachycardia to
hypotnsion.
Cardio vascular
depression :
1.Direct negative
inotropic effect by
decreasing the Ca2+
influx.
2.Peripheral
vasodilatation causing
decresed ventricular
filling pressures .
3.Transient decreased
sympathetic outflow
from CNS.
Decreased CO,SVR,HR
1.Systemic
release of
catecholamines
2.Inhibition of
vagal nerve.
3.Inhibition of
NE reuptake at
peripheral
nerves and non
neuronal tissue.
Increases the
SVR,CO,HR.
Decreased
coronary
vascular
resistance.
Premedicate
with midazolam
and glyco
pyrrolate.

PROPOFOL THIOPENTONE KETAMINE
RS APNOEA
Dose dependent
Depresses the ventilatory
response to hypoxia by
direct action on carotid
body receptors.
With infusion TV
decreased, RR incrased.MV
maintained.
BRONCHODILATION
(+)
Inhibits the vagal induced
broncho constriction by
inhibition of Ca2+ influx.
Potentiates hypoxic
pulmonary
vasoconstriction.
Central
respiratory
depression.
Double apnoea.
Minimal central
respiratory
depression.
Bronchodilation
1.Sympathomi
metic effect.
2.Directly
antagonize the
spasmogenic
effect of
histamine.

DOSES
PROPOFOL THIOPENTONE KETAMINE
INDUCTION 1.5-2.5mg/kg. 3-5mg/kg 1-2mg/kg i.v
4-8mg/kg i.m
MAINTAINENCE 100-
300mcg/kg/min
50-100mg every
10min
0.5-1mg/kg
with 50%N2o
SEDATION 25-
100mcg/kg/min
.
0.2-0.8mg/kg
i.v
2-4mg/kg i.m

PROPOFOL
⦿USES
⦿ANTIEMETIC
10mg i.v bolus followed by
10mcg/kg/min infusion.
⦿Used in chemotherapy induced and post
operative nausea vomiting.
⦿Inhibition of the sub cortical pathway.
⦿ANTIPRURITIC
⦿ANTICONVULSANT
⦿ATTENUATION OF BRONCHO CONSTRICTION

SIDE EFFECTS
⦿Allergic reactions.
⦿Abuse potential
⦿Bacterial growth
⦿Antioxidant properties.
⦿Pain on injection.
⦿Inhibits phagocytosis and killing of
Staphylococcus aureus and Escherichia coli.

PROPOFOL INFUSION SYNDROME
⦿ Infusion of propofol at 4 mg/kg/hour or more for
48 hours or longer.
⦿ Impaired fatty acid metabolism, such as
medium-chain acyl coenzyme A (MCAD)
deficiency and low carbohydrate supply.
⦿ The symptoms and signs are the result of muscle
injury and the release of intracellular toxic
contents.
⦿ Acute refractory bradycardia leading to asystole
in the presence of one or more of the following
⦿ Metabolic acidosis (base deficit >10 mmol/L),
⦿ Rhabdomyolysis,
⦿ Hyperlipidemia
⦿ Enlarged or fatty liver.
⦿ Cardiomyopathy with acute cardiac failure,
skeletal myopathy.

BARBITURATES
⦿USES
⦿Induction and
maintenance of
anaesthesia.
⦿Metho hexital –drug
of choice for electro
convulsive therapy
⦿Methohexital can be
used as a
premedication in
paediatrics.
⦿SIDE EFFECTS
⦿Allergic reaction
⦿Urticarial rash and
tissue necrosis
⦿Cough,hiccoughs,tre
mors
⦿Inducer of cytp450

KETAMINE
⦿USES
⦿Induction in hypovolemic patient
⦿Cardiac tamponade, restrictive
pericarditis ,congenital heart disease
⦿ANALGESIA
⦿Change of burn dressing
⦿Debridements
⦿Skin grafting.
⦿Status asthamaticus
⦿Reversal of opioid tolerance
⦿Improvement of post operative
depressed state.

SIDE EFFECTS
⦿Intact sympathetic system
⦿Direct myocardial depressant.
⦿EMERGENCE REACTION:
⦿Secondary to ketamine induced depression of
auditory and visual relay nuclei, leading to
misperception and misinterpretation of
stimuli.

ETOMIDATE
⦿ Carboxylated imidazole .
⦿ Mechanism of action: used as a single isomer
R(+) isomer. Selective modulator of gaba A
receptor.
⦿ Pharmacokinetics: large Vd. Present in unionised
form at physiologic ph. Crosses the blood brain
barrier .70% of the drug bound to albumin
independent of plasma drug concentration.
⦿ Metabolism :hepatic microsomal enzymes and
plasma estarases causes hydrolysis of ethyl ester
side chain. Elimination half life 2-5 hrs.

⦿PHARMACOKINETIC
⦿Ph4.2
⦿Pka8.2
⦿Elimination half life:2-5 hrs.
⦿DOSE
⦿The induction dose of etomidate is 0.2 to
0.6 mg/kg

PHARMACO DYNAMICS
⦿CNS
Decreases CMRO2,CBF AND ICP.
⦿CVS- lack of effect on the sympathetic
nervous system and on the function of the
baroreceptor.
Minimal changes in HR,stroke volume,cardiac
output.
Fall in SVR by 15%
⦿RS
Decreased TV, increased RR.
Stimulates ventilation independent of
hypercapnoiec drive

USES
⦿ Etomidate has been used for induction in
patients with a compromised cardiovascular
system
⦿ coronary artery bypass surgery
⦿ valve surgery
⦿ percutaneous transluminal coronary angioplasty
⦿ aortic aneurysm repair
⦿ Thoracic surgery.
⦿ cardioversion.
⦿ neurosurgical procedures such
⦿ as giant aneurysm clipping

SIDE EFFECTS
⦿Adreno-cortical suppression
⦿Myoclonus
⦿Allergic reactions
⦿Pain on injection.

REFERNCES
⦿MILLER’S ANESTHESIA, 8th edition.
⦿STOELTING’S PHARMACOLOGY AND
PHYSIOLOGY IN ANESTHETIC PRACTICE, 5th
edition.

THANK YOU