Basic Principles VI

Question 1

drug administration

Answer 1

-absorption and elimination can occur simultaneously

Question 2

steady state

Answer 2

• drug enters a compartment at a constant rate and is eliminated in a manner proportional to the concentration in the Vd
• eventually the elimination increases to equal the rate of entry and steady state is achieved
• stable plasma levels result in a stable patient dose
• continuous infusions
• ct vs number of half lives
• usually takes 4 half lives to get there
• time required to reach ss is independent of dose
• concentration at ss is directly proportional to dose, and inversely proportional to clearance

Question 3

half life

Answer 3

• 0.693/ ke

- time required to reach Css only depends on half life

Question 4

steady state 2

Answer 4

• Ra =Re

- absorption= clearance

Question 5

individual variation

Answer 5

-some people have higher clearance, reach ss after two half lives or more than 4, just need to adjust dose because that changes concentration at ss in order to get desired therapeutic limit.

Question 6

repeated administration

Answer 6

• IV or other route
• repeated administration of a fixed dose of a drug at a fixed tim interval
• first order absorption plus first order elimination
• plasma concentration reaches steady state level

Question 7

achievement of a steady state

Answer 7

• single doses
• when dose interval is much greater than t1/2
• antibiotics, diuretic
• peaks and falls

Question 8

achievement of a steady state with repeat individual doses

Answer 8

• when dose interval is approx equal to t1/2 or less a steady state can be achieved
• antihypertensives
• rises over min effective concentration and rises and falls within a therapeutic range
• Css = Cav
• amount of fluctuation depends on the dose and time interval

Question 9

dose per unit time

Answer 9

• determines Css average- not route of administration
• the same dose per unit time even if given different ways results in same Css
• may have wide swings or constant rise
• wide swings may not be tolerable due to tox or subtherapeutic

Question 10

achievement of steady state relationship to t1/2

Answer 10

• if elimination is 1st order then approach to steady state is also first order and depends on the Ke of elimination process
• it takes approx 4 times t1.2 to achieve steady state
• dose does not affect time, only concentration
• fast elimination rate= fast to SS, short half life

Question 11

Css

Answer 11

• 2 x Cp at 1st half life

- see graph

Question 12

loading doses

Answer 12

• rapid attainment of therapeutic plasma level (not SS)
• used to change the SS concentration
• loading dose followed by maintenance doses
• doesn’t shorted tim to SS in the plasma, just ups the concentration for immediate need
• sometimes loading dose starts to decrease before maintenance dose gets enough concentration, symptoms might come back- might need incremental loading dose

Question 13

drug tox

Answer 13

• lots of factors
• route, time, disease, drug hx- absorption
• age, weight, sex, route- distribution
• age, sex, species, genetics, route, time, disease, drug hx- biotransformation
• age, disease, drug hx- excretion
• emotional factors
• all lead to pharmacological response
• bell curve- freq of response vs dose required- sensitive people, normal people, resistant people

Question 14

iatrogenic

Answer 14

• may be predictable, not dose dependent

- chemo, nitro

Question 15

spontaneous

Answer 15

• not predictable, not dose dependent
• allergy-immunolgically mediated- reproducible in same patient
• idiosyncratic- not immunologic- not necessarily reproducible

Question 16

tolerance

Answer 16

• decreased response to continued admin
• decrease receptors
• increased metabolism

Question 17

resistance

Answer 17

-refractoriness to the drug effect- bacteria, receptors

Question 18

side effects

Answer 18

• secondary effects
• may be toxic, innocuous or beneficial
• secondary receptors or actions

Question 19

cumulation

Answer 19

• drug administered faster than it can be eliminated

- increase in plasma levels- toxicity possible

Question 20

drug dependence/ addiction

Answer 20

• tolerance
• homeostasis
• physical withdrawal syndromes

Question 21

therapeutic index

Answer 21

• toxic dose/ therapeutic dose
• TD50/ ED50
• ideal clinical is TD1/ED99
• plotted as log dose curves and decide upper limit of therapeutic window to get most response in most people, less than 10% toxic
• TI from 50 on toxic curve over 50 from normal curve- 15/5= 3
• see graph

Question 22

margin of safety

Answer 22

-TD50- ED50

Question 23

drug interactions

Answer 23

• direct molecular-antacids combine with gastric acids, antibiotics and Ca
• change absorption-charcoal binds molecules
• protein binding and displacement- can create tox for old drug
• receptor effects- competitive/ non competitive inhibition
• change metabolism- induction or inhibition
• change excretion- active transport inhibitors or simple competition for a transporter
• change pH or other electrolytes- alter excretion or protein binding

Question 24

unique features of newborn phys

Answer 24

• increased extracellular fluid
• immature enzyme systems
• decreased renal function
• constant alteration of fluid composition with age
• redistribution of circulation with shunting

Question 25

factors influencing oral drug absorption in newborn

Answer 25

• gestational age
• solubility of drug
• gastric emptying time- shortening increases absorption
• gastric acidity
• intestinal motility
• presence of food in the stomach
• splanchnic circulation

Question 26

causes of low drug binding in the newborn

Answer 26

• low albumin (qualitative differences??)
• competitive binding- bilirubin and sufonamids, phenytoin
• results in an increases apparent Vd

Question 27

drug biotransformation in newborns

Answer 27

1. introduction of polar groups- hydroxylation, oxidation, dealkylation, reduction
2. conjugation- glucaronidation, sulfation, glycine conjugation, glutatmine, acetate conjugations
   - slow in the newborn
   - oxidation slow- multiple p450
   - glucuronidation deficient at birth
   - acetylation somewhat deficient
   - hydroxylation depressed
   - sulfation active, acetaminophen
   - rate varies with gestational maturity
   - marked inter patient variability
   - post natal maturation for individual drugs variable
   - vulnerability to pathologic states
   - alternative pathway activation

Question 28

factors influencing renal excretion in newborn

Answer 28

• low renal blood flow- Cpah lower in neonates
• low GFR- 30-40% of an adults
• low tubular function- FT 20-30% of an adult
• glomerular predominance
• nephron heterogeneity

Question 29

plasma half life in newborn

Answer 29

• much longer than in adults
• very large variability
• phenobarb

Question 30

therapeutic considerations in the newborn

Answer 30

• elimination of drug (B phase) prolonged compared with distribution
• apparent volume of distribution increased
• loading dose higher- higher AVd
• maintenance dose lower- longer t1/2