This document discusses pharmacology considerations for pediatric anesthesia. It covers several key topics: 1) Developmental pharmacology - Drugs affect infants and children differently due to factors like body composition, organ maturity, and blood-brain barrier development. This impacts drug dosing, distribution, and elimination. 2) Inhalational agents - Sevoflurane and isoflurane are commonly used and have advantages like rapid induction/recovery, but sevoflurane can cause renal damage with prolonged use. 3) Intravenous agents - Propofol, ketamine, midazolam, fentanyl and other opioids are discussed. Propofol requires higher doses in children and should not be used for prolonged sedation in those under 12

1. Pharmacology for pediatric anaesthesia
Moderator: Dr. Chandak Sir
Conductor: Dr. Sen Mam
Presenter: Dr. Deepak Gupta

2. Developmental pharmacology
• The response of infants and children (particularly neonates) to medications is
modified by many factors such as:
o Body composition
o Protein binding
o Body temperature
o Distribution of cardiac output
o Functional organ (heart, liver, kidneys) maturity
o Maturation of the blood-brain barrier, the relative size of the liver and kidneys
o The presence or absence of elevated intraabdominal pressure (gastroschisis
or omphalocele closure) or congenital malformations.

3. Developmental pharmacology
• The body compartments (e.g., fat, muscle, water) change with age.
Fig: representing the body
composition in terms of total
body water, muscle mass and fat.

4. Developmental pharmacology
• These alterations in body composition have several clinical implications
for neonates.
• For example:
o A drug that is water soluble has a large volume of distribution requires a
large initial dose (mg/kg) to achieve the desired blood level (e.g., most
antibiotics, succinylcholine).
o Because the neonate has less fat, a drug that depends on the
redistribution into fat for the termination of its action will have a long
clinical effect.
o A drug that redistributes into muscle may have a long clinical effect (e.g.,
fentanyl).

5. Developmental pharmacology
• In addition to these very basic concepts, other important factors play a
role in the neonate’s response to medications and include the following:
o Delayed excretion secondary to the larger volume of distribution.
o Immature hepatic and renal function.
o Altered drug excretion caused by lower protein binding.

6. General pharmacology
• Absorption:
• Gastric emptying rate is reduced in the neonate.
• This may reduce the rate of absorption of orally administered drugs.
• The pH and volume of gastric secretions attains the adult values by two
years of age as well as by the gastric emptying time the adult value of
which is achieved by six to eight months of age.

7. • Drugs administered intra-muscularly in children exhibit a more rapid
onset of action than in adults because of the relatively higher cardiac
output and increased muscle blood flow.
• Inhalational agents are taken up and eliminated more rapidly in children.

8. • This occurs because tidal volumes remain relatively constant throughout
life at approximately 7 ml kg–1 but the ratio of minute ventilation to the
functional residual capacity is 5:1 in infants compared with 1.4:1 in
adults.
• Additionally, the tissue:gas and blood:gas solubility of volatile agents is
reduced in infants.

9. Distribution:
• The drug distribution is directly related to the lipid solubility and
inversely related to the protein binding.
• Neonates have high total body water content. Therefore water soluble
drugs like neuromuscular blocking drugs, aminoglycides have high
requirement of initial dose in neonates

10. • Neonates lack in muscle and fat content; resulting in prolonged clinical
effect of the drugs like thiopentone which redistribute to muscle and fat.
• The concentration of albumin and alpha1 acid glycoprotein which bind
to the acidic and basic drugs respectively is decreased in neonates
thereby requiring great caution when administering drugs like
phenytoin, theophylline and certain antibiotics which are highly protein
bound.
• Immaturity of blood brain barrier in neonates also increases the risk of
toxicity of otherwise lipid insoluble drugs like morphine.

11. • Increased cardiac output allows a more rapid delivery of drugs to the
target tissues, with a greater proportion being directed to the vessel rich
tissues such as the brain.

12. • Metabolism
• The liver is the principal site of drug metabolism.
• Hepatically metabolised drugs may exhibit a prolonged half-life
compared with adults.
• Phase I reactions reach adult levels a few days after birth, whilst phase II
reactions mature by 3 months.

13. • Excretion
• The excretion of drugs and their metabolites from the kidneys is influenced by
the glomerular filtration rate (GFR), clearance and proximal tubular secretion.
All of these are reduced in infants, particularly premature neonates. GFR
approaches adult values by 1 month, clearance by 3 months and proximal
tubular secretion by 5 months.
• Neonates are obligate sodium losers and cannot concentrate urine. Therefore,
adequate exogenous sodium and water must be provided during the
perioperative period. Conversely, neonates are likely to excrete volume loads
more slowly and are therefore more susceptible to fluid overload.

14. • Temperature regulation is important in pediatric anesthesia. Young
children have disproportionately large body surface areas, and heat loss
is exaggerated during anesthesia, especially during the induction of
anesthesia, unless this is actively prevented. Hypothermia, particularly
in neonates, delays the metabolism and excretion of anesthetic agents
and can also potentiate neuromuscular blockade.

15. Inhalational agents
Table representing the commonly
used inhalational agents
The MAC of an inhaled anesthetic is the alveolar
concentration that prevents
movement in 50% of patients in response to a
standardized stimulus (eg, surgical
incision).

16. Properties of inhalational anaesthetics

17. Inhalational agents
The expired minimum alveolar concentration (MAC)
of an inhaled anesthetic required in children
changes with age as shown in the figure.

18. • Uptake of volatile anesthetics is more rapid in children because of an
increased respiratory rate and cardiac index and a greater proportional
distribution of cardiac output to vessel-rich organs.
• Sevoflurane has a pleasant smell and a blood gas solubility coefficient of
0.68 allowing rapid induction and recovery in children.
• The low blood:gas solubility coefficient allows a more rapid recovery.
• Sevoflurane is relatively cardiostable, causing less tachycardia

19. • The MAC for sevoflurane is highest in young patients: 3.3% for neonates,
3.2% for infants 1 to 6 months old, and 2.5% for children older than 6
months.
• Children older than 3 years of age usually experience an increase in
heart rate and no change in systolic blood pressure with sevoflurane.

20. • Isoflurane maintains cardiac output and cerebral perfusion better than
halothane.
• It is also less of a respiratory depressant than halothane. Emergence
from anesthesia with isoflurane is quite smooth and faster than with
halothane.
• Isoflurane is pungent and a significant airway irritant with an
unacceptably high incidence of laryngospasm; therefore, it should not
be used to induce anesthesia.

21. • Because isoflurane is not a suitable induction agent, induction with
sevoflurane, and maintenance with isoflurane, is a common pediatric
anesthesia practice.
• The major use of sevoflurane is induction of anesthesia in children.
Metabolism of sevoflurane yields free fluoride, which may cause renal
damage; therefore, the FDA has restricted the use of sevoflurane to less
than two MAC hours, preferably with fresh gas flow rates in excess of 2
L/min.

22. Intravenous anaesthetic agents
• Classification of intravenous agents based on their chemical structure as
follows:
• Barbiturates: Thiopentone
• Phenols: Propofol
• Imidazoles: Etomidate
• Phencyclidine: Ketamine
• Benzodiazepines: Midazolam, diazepam, lorazepam
• Opioids: Morphine, fentanyl, alfentanil, sufentanil

23. Intravenous agents
Propofol:
• There is increased requirement of induction dose of propofol in children
because of larger central volume of distribution and higher clearance
rate.
• Children require approximately 50% more propofol than adults for the
maintenance of anaesthesia.
• There is no compensatory tachycardia and bradycardia may occur,
particularly if anaesthesia is maintained with propofol in combination
with vagotonic drugs or vagally stimulating surgical procedures in
children aged 2 years or less.

24. • Propofol is associated with pain on IV administration, particularly in small
veins. As little as 0.2 mg/kg of lidocaine (mixed with the propofol) has been
effective in reducing this discomfort.
• The induction dose is larger in younger children (2.9 mg/kg for infants
younger than 2 years of age) than in older children (2.2 mg/kg for children 6
to 12 years of age).
• After induction of anesthesia, propofol is considered a useful agent for
maintaining hypnosis and amnesia. It can be used as a sole anesthetic agent
for nonpainful procedures.
• Combined with narcotics, propofol provides excellent, brief anesthesia for
painful procedures.

25. • Propofol should not be used in children younger than 12 years of age for
prolonged sedation because of the risk of serious consequences (e.g.,
hemodynamic collapse, metabolic acidosis, cardiac failure, profound
shock, and death).
• Additionally, the use of propofol for prolonged sedation in the critical
care setting is also not advised.

26. Ketamine:
• Ketamine causes central dissociation of the cerebral cortex while
providing analgesia and amnesia.
• In addition to the intravenous and intramuscular routes, ketamine may
be administered rectally (10 mg/kg), orally (6 to 10 mg/kg), or
intranasally (3 to 6 mg/kg). The combination of oral ketamine (4 to 6
mg/kg), oral midazolam (0.5 mg/kg), and oral atropine (0.02 mg/kg)
provides a deeply-sedated child.

27. • Intravenous administration of doses as low as 0.25 to 0.5 mg/kg may be
used to provide sedation and analgesia for painful procedures, whereas
doses of 1 to 2 mg/kg produce sedation sufficient for a smooth
transition to general anesthesia.
• Larger doses (up to 10 mg/kg intramuscularly) provide sufficient
analgesia for the insertion of invasive monitoring devices before the
induction of anesthesia or in children with limited venous access.

28. • A major side effect, increased production of secretions, usually requires
the administration of an antisialagogue agent. Other undesirable side
effects include vomiting and postoperative “dreaming” or hallucinations;
the incidence of dreaming may be reduced by the concomitant
administration of a benzodiazepine.

29. • Contraindications to the use of ketamine in children include the
presence of an active upper respiratory infection (URI), increased
intracranial pressure, open-globe injury, and a psychiatric or seizure
disorder.
• Ketamine does not preserve the gag reflex and thus should not be used
as the sole anesthetic for children with a full stomach or a hiatal hernia.

30. Midazolam
• Midazolam is water soluble and therefore not generally painful on
intravenous administration.
• As it is water soluble, its onset of action is longer as compared to fat
soluble diazepam.
• Severe hypotension has occurred in neonates after bolus administration,
and the potential for this problem is apparently increased in neonates
also receiving fentanyl.
• Midazolam probably augments the respiratory depressant effects of
opioids.

31. • One important interaction is that erythromycin, calcium channel
blockers, protease inhibitors, and even grapefruit juice produce a
clinically important delay in midazolam metabolism because of
inhibition of cytochrome P450. In this circumstance, either midazolam
should be avoided or the dose reduced by 50%.

32. Opioids
• Clearance of opioids increases significantly as the age progresses from
neonate to infant. Hence the dosage of opioids should be decreased in
neonates.
• Fentanyl:
• Fentanyl is the most commonly used opioid in infants and children. Its
major advantages relate to its rapid onset and brief duration of action.
• Fentanyl induces a very stable cardiovascular response while providing
an anesthetic state.

33. • Because the cardiac output of neonates is determined by the heart rate,
fentanyl-induced bradycardia may require the administration of a
vagolytic drug, such as atropine or even pancuronium during long
procedures.
• Clearance in preterm neonates is markedly reduced contributing to
prolonged respiratory depression.
• Alfentanil:
• Alfentanil is more rapidly eliminated than fentanyl.
• Its pharmacokinetic effects are independent of dose, which may provide
a margin of safety because the greater the administered dose, the
greater the elimination.

34. • Sufentanil:
• Sufentanil has been primarily used for cardiac anesthesia.
• Children are able to clear sufentanil more rapidly than adults.
• This drug must be administered with caution because severe
bradycardia and asystole have been reported when a vagolytic drug was
not simultaneously administered.

35. • Ramifentanil:
• Remifentanil is the most recent addition to the opioids available for the
care of children.
• The main advantage of this opioid is its extremely brief half-life.
Induction dose is 0.25-1 mcg/kg while maintenance dose is 0.05-2
mcg/kg/min.
• Remifentanil is degraded by nonspecific plasma and tissue esterases and
the importance of maturation of renal and hepatic function is minimal.
• Therefore this drug has great utility in infants with hepatic or renal
failure.

36. • The particularly favorable pharmacokinetics in neonates allows the
provision of a deep opioid-induced plane of anesthesia while avoiding
cardiovascular depression and the need for postoperative ventilation.
• Remifentanil is extremely helpful in the anesthetic management of older
children where neurologic status must be rapidly assessed.
• This drug is also very useful for cardiac surgery in children as a means of
providing adequate opioid analgesia, cardiovascular stability, and early
extubation while transitioning to longer-acting low dose opioids.

37. Classification of muscle relaxant
• Depolarizing:
o Succinylcholine
• Non depolarizing:
o Pancuronium(long acting)
o Atracuronium(intermediate acting)
o Vecuronium(intermediate acting)
o Cisatracuronium(intermediate acting)
o Mivacurium(short acting)

38. Muscle relaxant – Depolarizing
• Succinylcholine is highly water soluble and rapidly redistributes into the
extracellular fluid volume. For this reason, the dose required for
intravenous administration of this depolarizing muscle relaxant in
infants (2.0 mg/kg) is approximately twice that for older children (1.0
mg/kg).
• Succinylcholine has received significant attention because of the severity
of its possible complications. The potential for rhabdomyolysis and
hyperkalemia (particularly in boys younger than 8 years of age who have
unrecognized muscular dystrophy), as well as the risk for masseter
spasm and malignant hyperthermia, suggests that succinylcholine
should not be routinely used in children.

39. • With the foregoing cautions in mind, succinylcholine remains valued
because it is the only commercially available ultrashort-acting muscle
relaxant that provides a dependable, rapid onset of action.
• Intravenous use of this drug should be limited to children who have a
full stomach or to treat laryngospasm; intramuscular or submental
(intralingual) administration is indicated for children with difficult
intravenous access when control of the airway is deemed essential.

40. Muscle relaxant- Non depolarizing
• A comparison of infants with older children or adults regarding their
responses to nondepolarizing muscle relaxants shows that infants are
generally more sensitive to these drugs and that their responses vary to
a greater degree.
• The choice of nondepolarizing muscle relaxant depends on the side
effects and the duration of the desired muscle relaxation. If tachycardia
is desired (e.g., with fentanyl anesthesia), then pancuronium may be an
appropriate choice. Vecuronium, atracurium, rocuronium, and
cisatracurium are useful for shorter procedures in infants and children;
they may also be administered as a constant infusion.

41. • The method of excretion of atracurium and cisatracurium (Hofmann
elimination and ester hydrolysis) makes these relaxants particularly
useful in newborns and children with immature or abnormal hepatic or
renal function. Vecuronium is valuable because no histamine is released;
however, its duration of action is prolonged in newborns, which makes it
similar to pancuronium.

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