consideraciones en farmacologia en paciente pediatrico

1. Pharmacology
for Infants &
Children
Martina Downard, MD
Wake Forest Baptist Health,
Brenner Children’s Hospital
Updated 7/2019

2. Learning Objectives
1. Increase understanding of
frequently used medications in the
perioperative period in infants and
children
2. Review mechanisms, effects and
doses of commonly used anesthesia
medications in children

3. Disclosures
No relevant financial relationships

4. Outline
1. Pharmacokinetics and pharmacodynamics
2. Inhalation anesthetic agents
3. IV anesthetics
4. Neuromuscular blocking drugs and antagonists
5. Opioids
6. NSAIDs & acetaminophen
7. Sedatives: benzodiazepines, dexmedetomidine and
chloral hydrate
8. Opioid & benzodiazepine antagonists

5. Pharmacokinetics & Pharmacodynamics
● Pharmacokinetics: How the patient/body affects the drug
or how drug concentrations in the body change over time
- Altered by immature kidney or liver function
- Altered by protein binding
- Altered by body composition (fat/muscle/total body
fluid/ volume of distribution)
● Pharmacodynamics: How the drug affects the
patient/body

6. Drug distribution in neonates
Remember:
• Acidic drugs bind mostly to albumin, e.g
diazepam or barbiturates
• Basic drugs bind to globulins, lipoproteins, and
plasma alpha-1-acid glycoproteins, e.g.
lidocaine or alfentanil

7. Drug distribution in neonates
● Neonates have reduced total protein & albumin
levels – result: increase levels & effect from
“unbound” medications
● Neonates have reduced clearance of drugs from
decreased renal/hepatic clearance – result: increase
medication levels
● Neonates have increased volume of distribution of
drugs (increase in total body water) – result: decrease
medication levels

8. Drug distribution
Medications can compete with bilirubin to bind
to albumin, causing hyperbilirubinemia or
kernicterus in neonates
• Ex. phenytoin, salicylate, caffeine, ceftriaxone,
Hypaque (diatrizoate)
Changes in tissue binding with maturation
• Ex. digoxin, opioids

9. Body composition
• Preterm & term infants have larger % body water
than older children
- Result - overall, increased loading dose
- larger distribution volumes for water-soluble drugs &
smaller for lipophilic drugs
• Preterm and term infants have less muscle & fat
- Less area for redistribution = prolonged peak blood
concentrations
- Example: opioids with prolonged sedation/respiratory
depression

10. Absorption
● Slower enteral absorption until 8 months old
● Larger skin surface area to body size = increased
skin absorption
- EMLA more likely to cause
methemoglobinemia (prilocaine)
- Iodine antiseptics likely to cause
hypothyroidism

11. Metabolism
● Reduced function & blood flow to liver in infants
● Drugs dependent on liver glucuronidation:
- Morphine, acetaminophen, dexmedetomidine,
lorazepam
- Clearance reaches adult levels ~ 5 - 6 months of age
● Extrahepatic
- Nonspecific esterases in tissues & erythrocytes are
mature at birth
- No change in remifentanil and succinylcholine clearance

12. Renal Excretion
Glomerular filtration & tubular function fully mature by 12 to
24 months of age
• Aminoglycoside & cephalosporin antibiotics have
prolonged duration of action in neonates

13. Pharmacokinetics & Pharmacodynamics
SUMMARY
• Decreased circulating protein levels,
metabolism and excretion – suggest
decreasing drug dose
• Increased volume of distribution & total
body water – suggest increasing drug
dose
• REALITY – dosing of medications in
neonates & children requires careful
titration

14. Inhalation agents - MAC
MAC = minimum alveolar anesthetic
concentration at which 50% patients
don’t move to noxious stimuli.
Why is MAC altered in children?
1. Change in cerebral blood flow?
2. GABA receptors?
3. Regulation of chloride
transporters?
** Except Sevoflurane! Peak
MAC as full term neonate.

15. Inhalation agents
Wash-in = ratio of alveolar to inspired anesthetic partial pressure (FA/FI)
Faster Wash-In in neonates than in adults:
• Greater alveolar ventilation (VA) to functional residual capacity
(FRC) in neonates (5:1) than in adults (1.5:1)
• Greater percent of cardiac output distributed to vessel-rich
groups (brain, heart, kidney, organs) in neonates
• Neonates have ½ the tissue/blood solubility of adults
• Reduced blood/gas solubility in neonates

16. Inhalation agents
● Second gas effect
- When two anesthetics given simultaneously, small
concentration of 1 may increase the uptake of the 2nd
anesthetic. E.g. nitrous oxide & sevoflurane/isoflurane
- Weak effect, if at all
● Speed of induction determined by:
- Solubility of agent – less soluble = faster induction
- Rate of increase of inspired concentration
- Max inspired concentration
- Respirations

17. Inhalation agents
Cardiovascular effects: Volatile agents decrease
the calcium influx by inhibiting sodium-calcium
pumps
Neonates more commonly have bradycardia & hypotension with
increasing volatile % compared to adults
• Immature sarcoplasmic reticulum in cardiac cells leading to poor
calcium retention and release
• Increased sensitivity/dependence on calcium for contractility
• Fewer & less organized contractile elements

18. Inhalation agents
• Side effects by volatile agent:
• Halothane – depression of sinoatrial
node, slowing myocardial conduction,
predispose to ventricular arrhythmias by
sensitizing heart to adrenaline
• Isoflurane & Sevoflurane – decrease SVR
to decrease BP, blunt baroreceptor
responses, no effect on arrhythmias

19. IV Anesthetic agents
Propofol
• Contains: soybean oil, egg lecithin (yolk), glycerol, EDTA
• Pediatric IV induction dose: 3-4 mg/kg
• Pediatric maintenance infusion rate: 200-250 mcg/kg/min
• Highly lipophilic, pain on injection (“warmth” or “sunshine on your
arm”)
• Rapid re-distribution, hepatic and extrahepatic clearance (lung,
kidney)
• Associated with less emergence delirium than inhalational agents
• Associated with a decreased incidence of nausea and vomiting

20. IV Anesthetic agents
Methohexital (brevital)
• Short-acting barbiturate
• IV induction dose: 1-2 mg/kg
• Side effects:
- Pain on injection
- Hiccups
- Seizure-like activity
• Can also be given rectally as a premedication

21. IV Anesthetic agents
Thiopental
• Binds GABAA receptors to prolong chloride
channel opening
• IV induction 3-4 mg/kg
• Myocardial depressant & weak vasodilator

22. IV anesthetic agents: Ketamine
Ketamine: NMDA receptor Antagonist
• Effects:
- Analgesic & amnestic, dissociative amnesia
- Increased HR & BP, little effect on pulmonary artery pressure
- Direct cardiac depressant
- Bronchodilator
• May precipitate seizures in susceptible children
• Side effects: nystagmus, increased secretions, 30% increase intraocular
pressure, increased intracranial pressure (cerebral vasodilation) &
CMRO2
• 1 - 3 mg/kg IV, 5-10 mg/kg intramuscular
- Doses typically larger in children due to greater clearance than adults
- IM dose useful for combative larger children

23. IV anesthetic agents
Etomidate: steroid based hypnotic induction agent
• 0.2 - 0.3 mg/kg IV, typically 30% increase dose in children
due to increased volume of distribution
• Effects:
- No effect on hemodynamics
- Great for head injury or unstable CV status!
• Side effects:
- Adrenal suppression
- Pain on injection
- Emesis

24. Neuromuscular blocking agents
● Neonates have increased sensitivity
- Neuromuscular transmission immature until 2 months old
- Reduction in acetylcholine released
- Reduced muscle mass
- Reduced clearance
● Neonate diaphragm function may be more preserved
- Type 1 (slow twitch) diaphragm muscle fibers most sensitive to NMBDs
- Preterm neonate has only ~10% type 1 fibers
- Therefore, diaphragm function may recover earlier than peripheral
muscles
● Infants require larger dose than adults
- Larger volume of distribution due to greater total body water &
extracellular fluid
● Neonates - faster onset due to greater cardiac output

25. Neuromuscular blocking drugs
Succinylcholine: depolarizing muscle relaxant
• Infants more resistant than adults
- Rapid redistribution in extracellular fluid volume
- Dose: infants ~ 3mg/kg IV/ 5mg/kg IV; children ~1.5 mg/kg IV/
4mg/kg IM
• Possible side effects:
- Increased masseter muscle tone when given with halothane -
masseter spasm potential sign of malignant hyperthermia
- Arrhythmia - bradycardia due to choline metabolites; more likely
with 2nd dose
- Hyperkalemia - normal increase K+~ 1 mEq/L; higher in burns,
motor neuron lesions & neuromuscular disease
- Increased intraocular pressure
- Fasciculations

26. Neuromuscular blocking agents
Suggested intubating doses:
muscle relaxant: Infants (mg/kg) Children (mg/kg)
succinylcholine 3 1.5-2
rocuronium 0.25 - 0.5 0.6 - 1.2 (1.2 for RSI)
vecuronium 0.07 - 0.1 0.1
pancuronium 0.1 0.1
cisatracurium 0.1 0.1 - 0.2
atracurium 0.5 0.5
Cote & Lerman’s A Practice of Anesthesia for Infants and Children, 5th edition. p122.

27. Neuromuscular blocking agents-
non- depolarizing relaxants
● Cisatracurium
- Spontaneous degradation not dependent on plasma cholinesterase
- Faster recovery in children due to greater volume of distribution & total
body clearance
● Vecuronium
- Metabolized by liver, excreted in bile
- No CV effects
● Rocuronium
- Fastest onset of non-depolarizing relaxants
- Can be used for rapid sequence intubation
- Metabolized in liver, excreted in urine
● Pancuronium
- Long-acting
- > 50% excreted in urine unchanged, 10% in bile
- Side effect: tachycardia - blocks presynaptic noradrenaline uptake

28. Antagonism of muscle relaxants
• Neonates at greater risk for residual neuromuscular
blockade:
- Immature neuromuscular system
- Greater elimination half-life of relaxants
- Reduced type 1, fatigue resistant, muscle fibers in diaphragm
- Closing lung volume occurs within tidal volume in neonate (increased alveoli
closure)
• Suggested doses for reversal:
- Neostigmine (0.07mg/kg) with atropine (10-20 mcg/kg) or glycopyrrolate 5-
10 mcg/kg
- Always give atropine or glycopyrolate 1st to avoid bradycardia & ↓ cardiac
output
or
- Sugammadex (2-16 mg/kg) which encapsulates rocuronium to reverse
neuromuscular blockade
- Limited use due to expense $$$$

29. Opioids
Morphine
• Analgesic effect by activating μ1 receptor
• Water soluble, poor lipid soluble
• High hepatic clearance - metabolized into morphine-3-glucuronide
(M3G) & morphine-6-glucuronide (M6G). M6G causes respiratory
suppression
• Reduced liver and renal function causes M3G & M6G accumulation,
leading to increased respiratory suppression in children & neonates
relative to adults
• Side effects: itching, nausea
• Dose: 0.05 - 0.2 mg/kg

30. Opioids
Meperidine
• Weak opioid, 1/10th strength of morphine
• Prolonged elimination ½ time in neonates
• Mainly used to stop shivering
• Metabolite, normeperidine, causes seizures
• No longer recommended for use in children
Hydromorphone
• Synthetic opioid, 5-7.5 more potent than morphine
• Dose 0.01-0.02 mg/kg IV
• Metabolites do not cause respiratory suppression

31. Opioids
Methadone
• Synthetic opioid, similar potency to morphine but greater ½
life
• Highly variable elimination ½ life in neonates 3.8 - 62 hours
• Analgesic effect by activating μ1 receptor & NMDA receptor
antagonist
• Dose ~0.1-0.2mg/kg
• Lipid soluble - penetrates blood brain barrier
• May cause QT prolongation

32. Opioids
Fentanyl
• Rapid onset, short duration, lipid soluble
• Potent μreceptor agonist 70 - 125 times morphine
• Most commonly used narcotic in infants & children
• Metabolized by CYP3A4 in liver to non-active metabolites
• Clearance reduced 70-80% compared to adults
• May cause chest wall or glottic rigidity after IV push
• Dose 1-3 mcg/kg (minor surgery) to 100 mcg/kg (cardiac surgery)

33. Opioids - infusions
● Sufentanil
- 5-10 times more potent than fentanyl
- Common infusion for cardiac & spine surgery
- Metabolized by CYP3A4
- Dose 0.3 mcg/kg/hour
● Alfentanil
- ¼ potency of fentanyl
- Rapid onset, brief duration of action, more protein bound than fentanyl
- May also cause chest wall rigidity
- Dose 0.5-3 mcg/kg/min or 10 mcg/kg for intubation
● Remifentanil
- Rapid onset, brief ½ life (3-6 minutes!!)
- Metabolized by nonspecific blood esterases that are mature at birth
- Flat context-sensitive ½ time
- Dose 0.05-0.3 mcg/kg/min

34. Opioids
Codeine
• Weak, 1/10th potency of morphine BUT ~10% metabolized
into morphine
• Analgesia depends on how much is metabolized into
morphine
• Metabolized by CYP2D6 which has many polymorphisms:
- poor metabolizers
- intermediate metabolizers
- ultra-rapid metabolizers (produces the most morphine)
• May lead to accidental overdose, respiratory suppression to
cause death
• Not recommended for children

35. Relative Opioid Potencies
Drug Potency
morphine 1
methadone 1
meperidine 0.1
hydromorphone 5 - 7.5
alfentanil 40
fentanyl 150
sufentanil 1500

36. Acetaminophen & NSAIDS
● Acetaminophen/tylenol/paracetamol
- Inhibits prostaglandin H2 synthetase (PGHS) - no anti-inflammatory
effect
- Doses: 10 - 15 mg/kg PO or IV, 20 - 40 mg/kg PR
- Toxic metabolite NAPQI binds hepatic macromolecules to cause
necrosis
● NSAIDS
- Heterogeneous group that all have antipyretic, analgesic and anti-
inflammatory effects
- Inhibit COX-1, COX-2 or both
- COX-1 - protects gastric mucosa, regulate renal blood flow, induce platelet
aggregation
- COX-2 - inflammatory pathway

37. NSAIDS
Ketorolac
• Analgesia similar to low-dose morphine
• No respiratory suppression
• Side effects:
- Inhibits platelet function & increases bleeding
time
- Altered bone healing if given in high doses
- Bradycardia after rapid IV administration

38. Sedatives
Benzodiazepines: GABA receptor agonists
• Midazolam
- Antegrade amnesia
- Water soluble, no pain on injection
- Possible respiratory depression & hypotension with co-
administration of fentanyl
- Dose: 0.1 mg/kg IV, 0.5 - 0.75 mg/kg PO, 0.2 mg/kg nasal
• Diazepam
- Reduces seizures & muscle spasms
- Pain on injection
- Prolonged ½ life in neonates & infants
- Dose: 0.2 - 0.3 mg/kg IV

39. Sedatives
Dexmedetomidine
• 𝜶2-agonist, affinity 1600:1 specificity ratio for 𝜶2: 𝜶1
• 7-8 x more affinity than clonidine
• Decreases sympathetic outflow from CNS by hyperpolarization of
noradrenergic neurons in the locus coeruleus
• No ventilatory depression
• Shorter elimination ½ life than clonidine, 2 hours vs. 8 hours
• Effects:
- Anxiolysis, analgesia, decrease HR, decrease emergence delirium
- Dose: loading IV 1 mcg/kg, infusion 0.5 - 2.0 mcg/kg/hour*
- Can be given intranasal 1 - 2 mcg/kg for sedation

40. Sedatives
Chloral hydrate
• Activates GABA to produce sedation
• Dose 20-75 mg/kg PO or PR
• Side effects: airway obstruction, apnea, bradycardia,
hypotension
• Metabolites may be carcinogenic/toxic, leading to
metabolic acidosis, renal failure & hypotonia
• Interferes with bilirubin binding to albumin in neonates
• Long ½ life - may have re-sedation
• No longer produced in USA

41. Antagonists - when your dose goes to far ….
• Naloxone
- Opioid antagonist, greatest affinity at 𝜇-receptor
- Rapid onset ~30 seconds
- Longer ½ life in neonates of 3 hours vs. 1-1.5 hours in adults
- Dose: IV 0.25 -0.5 mcg/kg (mild overdose) to 10-100 mcg/kg (severe)
- If treating opioid induced respiratory depression, must observe respiratory
status minimum of 2 hours after naloxone administration
● Flumazenil
- Competitive antagonist at GABAA receptor to reverse BZD
- Why reverse? excessive sedation or paradoxical response to BZD
- Dose: 10 - 25 mcg/kg IV
- Short ½ life: ~35 min

42. Conclusions:
• Volume of distribution and clearance
vary with age
• Drug doses are frequently age and
weight dependent in neonates and
children
• Anesthesia management of infants and
children involve careful knowledge of
pharmacology and physical development

43. References:
1. Cote & Lerman’s A Practice of Anesthesia for Infants and Children, 5th
edition. P 77-149.
2. Smith’s Anesthesia for Infants and Children, 8th edition. p 179-261.
3. Mason KP, et al. Incidence and predictors of hypertension during high-
dose dexmedetomidine sedation for pediatric MRI. Paediatr Anaesth.
2010 Jun;20(6):516-23.
4. Mason KP, et al. High dose dexmedetomidine as the sole sedative for
pediatric MRI. Paediatr Anaesth. 2008 May;18(5):403-11.
5. Wu J, et al. Comparison of propofol and dexmedetomidine techniques
in children undergoing magnetic resonance imaging. Paediatr Anaesth
2014 Aug;24(8):813-8.