Unit 1 - Drug Administration Flashcards
define steady state (SS)
- drug enters compartment at constant rate, and is eliminated in manner proportional to concentration in Vd
- eventually elimination increases to equal rate of entry to achieve steady state
* stable plasma levels result in stable patient response (like with continous IV infusions)
approximately when is steady state achieved? what is its relationship to dosage? what about steady state concentrations?
attained after ~4 half lives
- time to steady state is independent of dosag
- Css is directly proportional to dose/dosage interval, and inversely proportional to Cl
what happens during repeated administration (IV or other route)
fixed dose at a fixed time interval
- first order absorption plus first order elimination
- plasma concentration reaches steady state (plateau) level
can you achieve steady state if dose interval is much greater than half-life?
no steady state
can you achieve steady state if dose interval is equal or less than half life?
yes, steady state can be achieved
- Css (concentration at steady state) is average due to fluctuation between doses
- amt of fluctuation depends on dose and time interval
what determines the Css average?
dose per unit time, NOT route of administration
-same dose per unit time, given in different ways, has same final Css average, but infusions will be smoother than injections
achievement of steady state relationship to t 1/2
if elimination is first order, then approach to steady state is also first order, and depends on Ke of elmination process
- takes about 4x t 1/2 to achieve steady state
- dose does NOT affect time to achieve steady state
- 2 * Cp at first 1 t 1/2 = Css
what is the relationship between elimination rate and steady state?
fast elimination rate = fast to steady state
slow elimination rate = slow to steady state (days, weeks)
explain the mechanisms for loading dose and the equation
- rapid attainment of therapeutic plasma level (NOT steady state)
- temporary fix to control problem, then maintain later with infusion - use this to change steady state concentration
- DOES NOT get one to steady state faster
loading dose = Cp * Vd
what is an incremental loading dose?
given if the initial loading dose wears off before infusion is able to take effect
what does iatrogenic mean in terms of adverse drug reactions?
may be predictable and dose dependent
what does spontaneous mean in terms of adverse drug reactions?
not predictable and not dose dependent
- allergy - immunologically mediated and reproducible in the same patient (predictable to a certain extent)
- idiosyncratic - not immunologic, reproducible, or predictable
what does tolerance mean in terms of adverse drug reactions?
decreased response to continued administration (receptors, metabolism)
- resistance - refractoriness to drug effect (bacteria, receptors)
- “side effects” - secondary effects may be toxic, innocuous, beneficial, and vary in people
- cumulation - drug administered faster than can be eliminated (increase in plasma levels –> possible toxicity)
- drug dependence/addiction
- -tolerance, homeostasis, physical withdrawal syndromes
what is the equation for therapeutic index?
TI = toxic dose / therapeutic dose = TD50 / ED50
what is the ideal clinical dose?
IC = TD1 / ED99 = toxic dose in 1% / effective dose in 99%
what is the margin of safety?
TD50 - ED50
what are some drug interactions?
- direct molecular (antacids + gastric acids, antibiotic + Ca)
- charge absorption (charcoal binds drugs)
- protein binding and displacement
- receptor effects (competitive or noncompetitive)
- change metabolism (induction VS inhibition)
- change excretion (active transport inhibitors or simple competition for transporter)
- change pH or other electrolytes (alter excretion or protein binding)
what are unique features of newborn physiology?
- increased ECF
- immature enzyme systems
- decreased renal function
- constant alteration of fluid composition with age
- redistribution of circulation with shunting
what are factors influencing oral drug absorption in the newborn?
- gestational age
- solubility of the drug
- gastric emptying time (shortening increases absorption)
- gastric acidity
- infestinal motility
- presence of food in stomach
- splanchnic circulation
what are causes of low drug binding in newborn?
- low albumen
- competitive binding
- -> result is increased AVd (apparent Vd)
what are the types of drug biotransformation in the newborn?
- introduction of polar groups (hydroxylation, oxidation, dealkylation, reduction
- conjugation (glucoronidation, sulfation, glycine conjugation, glutamine, acetate conjugation)
why is the rate of biotransformation slower in newborns?
- oxidation reactions slow (multiple forms of cyt P450)
- glucuronidation deficient at birth
- acetylation somewhat deficient
- hydroxylation depressed
- sulfation active (acetaminophen)
- rate varies with gestational maturity
- marked interpatient variability
- postnatal maturation for individual drugs variable
- vulnerability to pathologic states
- alternative pathway activation
what are factors influencing renal excretion of drugs in the newborn?
- low renal blood flow (CPAH lower in neonates)
- low GFR (30-40% of adults)
- low tubular function (FT, 20-30% of adult)
- glomerular predominance
- nephron heterogeneity
plasma half-life in the newborn
- much longer than in adults
2. very large individual variability
what are therapeutic considerations in the newborn?
- elimination (beta-phase) prolonged compared with distribution (alpha-phase)
- apparent volume of distribution increased
- loading dose higher (higher AVd)
- maintenance dose lower (prolonged t 1/2)
