Basic principles 2 Flashcards
What influences drug absorption rates?
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
Oral absorption of different formulations
Slowest
Coated tablets
Tables
Capsules
Powders
Liquids, elixirs, syrups
Fastest
Absorption in neonates/infants
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
- Increased drug contact time
- Irregular peristalsis – enhance absorption
- Intestinal transit time influenced by type of feeding
- Breast-fed infants greater than formula-fed infants
Percutaneous Absorption in neonates
Neonates
- Thinner stratum corneum
- Increased cutaneous perfusion
- Increased absorption
- Higher serum concentrations of topical medications
- Corticosteroids & lidocaine
- Additives: propylene glycol
- Higher serum concentrations of topical medications
- Limit topical medications to smallest amount
Distribution
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
Volume of Distribution (Vd)
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 = Cblood, Cplasma, Cunbound
Preemie ~85-90% water
NB ~80% water
Adult ~60% water
Tissue Distribution in children
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
Protein Binding in children
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
Metabolism – Liver Biotransformation
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
Metabolism for pediatric patients - factors to consider
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
First Pass Metabolism
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
Phase I Reactions
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
Phase II Reactions
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
Glucuronidation Conjugation
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
Glycine Conjugation
• 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
Cytochrome P450 Metabolism
- Most common:
- 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, 3A4
Elimination
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
Renal Elimination
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
Calculating CrCl
• 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 / SCr
CrCl is expressed as mL/min/1.73 m2
K = age specific proportionality constant
L=length (cm)
SCr = in mg/dL
Bedside Schwartz:
CrCl = (0.413*L) / SCr
Steady State Concentration
- Attained after ~4 half-times
- Time to steady state independent of dosage
Half-life (T1⁄2)
- Time it takes for plasma concentration to be reduced by 50%
- Changes based on clearance and Vd
t1/2 = 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
Gestational age (GA)
Estimates time “immediately before” conception until birth
- # weeks from onset of mother’s last menstrual period to date of birth
Postnatal age (PNA) or Chronological age (CA)
Age from birth to present
Postmenstrual age (PMA) or Postconceptional age (PCA)
Gestational age plus chronological age (PMA = GA + PNA)
Corrected age
Describes the age of children who were born premature
- Postnatal age reduced by number of weeks born before 40 weeks gestation
