Principles VI

Principles VI

1. Drug Administration

   • absorption and elimination occur at the same time
   • Steady State
     • attained after approximately 4 half lives
       • have to wait to see if drug will have the effect
     • Concentrations
       • directly proportional dose/dosage interval
       • Inversely proportional to clearance
       • possibly could have wide swings between doses
         • sometimes desired
         • possible toxic or subtherapeutic effects
     • want to maintain plasma levels of drugs
     • rate of absorption = rate of elimination
     • faster clearance makes lower half lives
     • Single Doses
       • dose interval greater than half life
     • Repeated Individual Doses
       • interval is approximately half life
     • SS concentration is an average because of the fluctuation between doses
     • route of administration, dose does not effect steady state concentration
     • Elimination Rate
       • Fast
         • fast to steady state
       • Slow
         • slow to steady state
   • Repeated Administration
     • fixed dose of drug at a fixed time interval

2. Loading Doses

   • Rapid attainment of therapeutic plasma level
   • use to change the steady state concentration
   • clinical problem could return between administration and steady state

3. Drug Toxicity

   • Some people will experience toxicity earlier or later than most of the population
   • Adverse Drug Reactions
     • Iatrogenic
       • may be predictable, dose dependent
       • doctor caused it
     • Spontaneous
       • Allergy
         • Reproducible
         • immunologically mediated
       • Idiosyncratic
         • not immunologic
         • Not necessarily reproducible
   • Tolerance
     • decreased response to continued administration
       • through receptors or metabolism
     • Cumulation
       • drug administered faster than it can be eliminated, increase plasma levels, toxicity possible
     • Drug Dependence/Addiction
       • Tolerance
       • Homeostasis
       • Physical Withdrawal Syndromes
   • Therapeutic Index= Toxic Dose/Therapeutic Dose
     • Margin of Safety = TD50 - ED50

4. Drug Interactions

   • Direct Molecular
   • Change Absorption
   • Protein binding and displacement
   • Receptor effects
   • Change metabolism
   • change excretion
   • change pH or other electorlytes

5. Neonatal Pharmacokinetics

   • Unique features of physiology
     • increased extracellular fluid
     • immature enzyme systems
     • decreased renal functions
     • constant alteration of fluid composition with age
     • redistribution of circulation with shunting
   • Factors influencing oral drug absorption in the newborn
     • gestational age
     • solubility of the drug
     • gastric emptying time
       • shorter increases absorption
     • gastric acidity
     • intestinal motility
     • presence of food in the stomach
     • splanchnic circulation
   • causes of low drug binding
     • Low albumin
     • competitive binding
     • increased apparent volume of distribution
   • Biotransformation
     • introduction of polar groups
       • hydroxylation, oxidation, dealkylation, reduction
     • Conjugation
       • glucuronidation, sulfation, glycine conjugation, glutamine, acetate conjugations
     • Rate is slower
       • glucuronidation deficient
       • acetylation somewhat deficient
       • hydroxylation depressed
       • sulfation active
       • varies with gestational maturity
       • interpatient variability
       • postnatal maturation for individual drugs variable
       • vulnerability to pathologic states
       • alternative pathway activation
   • Renal excretion
     • low renal blood flow, GFR, tubular function
     • glomerular predominance
     • nephron heterogeneity
   • Plasma half-life
     • longer than in adults
     • very large individual variability
   • Therapeutic considerations
     • elimination prolonged compared with distribution (beta compared to alpha)
     • Apparent volume of distribution increased (high AVd)
     • Loading dose higher
     • Maintenance dose lower (prolonged half life)