Basic principles 2

Question 1

What influences drug absorption rates?

Answer 1

Medication Property

• Molecular size and drug structure
• Degree of ionization (pH) - Positive or negative charge
• Lipid solubility - aqueous and lipid**

Route/Site of administration

• Blood flow to site of absorption

Drug formulation

• Liquid, enteric coated tablet, delayed release formula

Bioavailability - fraction of unchanged drug reaching the systemic circulation following administration of any route

Question 2

Oral absorption of different formulations

Answer 2

Slowest

Coated tablets

Tables

Capsules

Powders

Liquids, elixirs, syrups

Fastest

Question 3

Absorption in neonates/infants

Answer 3

Most variability in neonates and infants

• Higher gastric pH
  
  • Improved absorption of weak bases - penicillin
  • Decreased absorption of weak acid - phenobarbital
• Gastric emptying is delayed
  
  • Increased drug contact time
    
    • = Increased drug absorption
• Irregular peristalsis – enhance absorption
• Intestinal transit time influenced by type of feeding
  
  • Breast-fed infants greater than formula-fed infants

Question 4

Percutaneous Absorption in neonates

Answer 4

Neonates

• Thinner stratum corneum
  
  • Increased cutaneous perfusion
• Increased absorption
  
  • Higher serum concentrations of topical medications
    
    • Corticosteroids & lidocaine
    • Additives: propylene glycol
• Limit topical medications to smallest amount

Question 5

Distribution

Answer 5

Blood flow and tissue volume play a large role in rate of delivery and amount of drug distributed to tissues

• Plasma protein binding
  
  • Note: protein bound drugs are not free to yield activity; only unbound drug is free to yield activity at site of action
• Tissue binding
  
  • Drugs can accumulate in tissues at higher concentrations than in extracellular fluid
  • Liver, bone, fat

Question 6

Volume of Distribution (Vd)

Answer 6

Relates amount of drug in the body to the concentration (C) in the blood or plasma

Vd = Amount of drug in body (mg)

C (mg/L)

• May be defined with respect to blood, plasma, or water (unbound drug) depending on the C in the equation
• C can = C_blood, C_plasma, C_unbound

Preemie ~85-90% water

NB ~80% water

Adult ~60% water

Question 7

Tissue Distribution in children

Answer 7

Blood Brain Barrier

• Functionally inefficient in neonates (
  
  • Increased permeability of drugs
  • Increased CNS effects of medications

• Consider Gentamicin Pharmacokinetics (neo meningitis)

• Can cross BBB in neonates for meningitis but never in adults because it does cannot cross the adult BBB
• Infant needs 5mg/kg
• Adult - 2.5 mg/kg

Question 8

Protein Binding in children

Answer 8

Less ability for protein binding = more unbound drug

Albumin

• Neonates & Infants have LOW serum albumin
• Decreased affinity for binding results in displacing drugs
• Reach adult level ~1 year

Bilirubin (binds to albumin)

• Neonates have increased production & decreased clearance
• Drugs can displace bilirubin bound to albumin
• Increased unbound bilirubin, increases risk of kernicterus

Question 9

Metabolism – Liver Biotransformation

Answer 9

Prodrug

• Pharmacologically inactive compound must be converted to biologically active metabolite(s) to maximize amount of active drug that reaches site of action
• Example: Enalapril (prodrug) –>> Enalaprilat (active drug)
• First-pass effect
• Phase I Reactions
• Phase II Reactions

Must consider patient’s baseline hepatic function

Question 10

Metabolism for pediatric patients - factors to consider

Answer 10

Rate of metabolism varies by:

• Metabolism pathway
• Genetic predisposition
• Stage of development
• Delayed significantly at birth and through infancy
• Activity matures rapidly and peaks @ 1-9y
  
  • Peak rates exceed adult metabolism
  • Slowly decrease to adult level @ 9-12y

Question 11

First Pass Metabolism

Answer 11

First Pass Effect:

• Metabolism of orally administered drugs by hepatic enzymes or gut lumen, resulting in significant reduction in the dose reaching the systemic circulation

Avoided by certain formulations

• Sub-lingual tablet administration
• Transdermal
• Intravenous
• Inhalation
• Intramuscular

Question 12

Phase I Reactions

Answer 12

Phase I: introduces or exposes a functional group on the parent compound yielding a water soluble compound

Common Reactions:

• Oxidation
  
  • Cytochrome P450
• Reduction
• Hydrolysis
• Deamination
• Desulfuration

Question 13

Phase II Reactions

Answer 13

Phase II: enzymes catalyze conjugation of drug with another molecule to produce a metabolite with improved water solubility – results in elimination of drug from tissue

• May occur in combination with Phase I reactions

Common Reactions

• Glucuronidation
• Gycineconjugation
• Acetylation
• Glutathioneconjugation
• Methylation
• Sulfation

Question 15

Glucuronidation Conjugation

Answer 15

Immature in neonates and infants

• Adult values at 3-4 years of age
• Drugs metabolism may be shunted toward more active pathway
• Phase II metabolism

• What’s the effect on drugs??

• Chloramphenicol toxicity in neonates

Question 16

Glycine Conjugation

Answer 16

• Activity reaches adult values by 8 weeks

Effect on drugs

• Benzyl alcohol or benzoic acid preservative
  
  • Preservative found in IV or PO medications
• Inability to metabolize leads to toxic accumulation of benzoic acid metabolite
• Gasping syndrome: hypotension, resp depression, metabolic acidosis, seizures, gasping respirations

Question 17

Cytochrome P450 Metabolism

Answer 17

• Most common:
  
  • 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, 3A4

Question 18

Elimination

Answer 18

Clearance – measure of body’s ability to eliminate the drug

Renal Elimination

• Glomerular Filtration: passive diffusion; depends on:
  
  • Molecular size, protein binding, kidney function
• Tubular Secretion & Tubular Reabsorption
  
  • Actively secreted from the proximal tubules and passively in the distal tubules

Hepatic Elimination

• Biliary Excretion
  
  • Most drugs actively transported by liver cells from blood to bile
  • Drugs or a conjugated metabolite of a drug is excreted in the bile and enters the GI tract, where it is excreted in the feces

Question 19

Renal Elimination

Answer 19

Reduced in neonates & slowest in premature neonates

• Increase in glomeruli formation through 34-36 weeks gestation
• Doubles by about 2 weeks of life
• Increases to adult values by 8-12 months
• Peaks at 3-12 years, then gradual decline to adult values
• What’s the effect on drugs?
  
  • Preemie and Neonates
  • Children

Question 20

Calculating CrCl

Answer 20

• Cockroft-Gault or Jelliffe equations

• Not recommended for patients < 18 years of age

• Schwartz Equation and/or Bedside Schwartz Equation

• Ideal for pediatric patients
• Considers serum Cr, height, gender, and age
• Will not provide an accurate estimate in patients with:
  
  • Rapidly changing serum creatinine (Pediatric ICU)
  • Infants younger than 1 week
  • Patients with obesity, malnutrition or muscle wasting

Schwartz:

CrCl = K*L / S_Cr
CrCl is expressed as mL/min/1.73 m2
K = age specific proportionality constant

L=length (cm)

S_Cr = in mg/dL

Bedside Schwartz:

CrCl = (0.413*L) / S_Cr

Question 21

Steady State Concentration

Answer 21

• Attained after ~4 half-times
• Time to steady state independent of dosage

Question 22

Half-life (T_1⁄2)

Answer 22

• Time it takes for plasma concentration to be reduced by 50%
• Changes based on clearance and Vd

t_1/2 = 0.7 * Vd / clearance

• Determines how often the drug is to be administered
• Not dose dependent
  
  • Doubling the dose does NOT double the half-life

Question 23

Gestational age (GA)

Answer 23

Estimates time “immediately before” conception until birth

• # weeks from onset of mother’s last menstrual period to date of birth

Question 24

Postnatal age (PNA) or Chronological age (CA)

Answer 24

Age from birth to present

Question 25

Postmenstrual age (PMA) or Postconceptional age (PCA)

Answer 25

Gestational age plus chronological age (PMA = GA + PNA)

Question 26

Corrected age

Answer 26

Describes the age of children who were born premature

• Postnatal age reduced by number of weeks born before 40 weeks gestation