Basic Principles of Pharmacology VI

Question 1

Drug Administration

Answer 1

-absorption and elimination can occur simultaneously- will only disucss first order process

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
• importance: stable plasma levels result in a stable patient response
• continuous IV infusions
• at SS: rate of absorption = rate of elimination
• obtained after approximately four half times
• time to steady state independent of dosage
• directly proportional to dose/dosage interval
• inversely proportional to Cl
• NB t1/2 = .693/ke
• the time required to achieve Css: only depends on t1/2
• NB at steady state absorption= clearance

Question 3

Relationship of t1/2, Vd and clearance-

Answer 3

• clearance and t1/2 can vary in a patient over time or among patients in a given population (if they are rapid metabolizers or not)
• patient may begin to take a second drug that interferes with the clearance of the first drug
• patient may develop renal failure or liver failure
• fast metabolizers- ultra rapid P450 patients
• Vd remaining the same

Question 4

Repeated Administration

Answer 4

• IV or other route
• repeated administration of a fixed dose of a drug at a fixed time interval
• first-order absorption plus first order elimination
• e.g. repeated oral administration
• plasma concentration reaches steady state (plateau) level

Question 5

Achievement of Steady State

Answer 5

• single doses when dose interval is much greater than t1/2

- antibiotics, diuretics

Question 6

Achieving Steady State with Repeat Individual Doses

Answer 6

• when does interval is approximately equal to t1/2 or less a steady state can be achieved
• antihypertensives
• Css is really an average because of fluctuation between the doses. The amount of fluctuation depends on the dose and time interval
• dose interval is less than or equal to t1/2

Question 7

Achieving Steady State- Doses per unit time-

Answer 7

• dose per unit time determines the Css average- not the route of administration- the same dose per unit time- even if given in different ways- yields the same final Css average
• wide swings in Css may not be tolerable due either to toxicity or subtherapeutic Cp
• sometimes wide swings are desirable

Question 8

Achievement of Steady State Relationship to t1/2

Answer 8

• if elimination is first order then approach to steady state is also first order and depends on the Ke of the elimination process
• it takes approximately 4 times t1/2 to achieve steady state
• dose does not affect time to achieve steady state
• fast elimination rate= fast tp steady state ie minutes
• slow elimination rate= slow to steady state ie days or weeks

Question 9

Loading Doses

Answer 9

• rapid attrainment of therapeutic plasma level (not steady state)
• use to change the steady state concentration
• e.g repeated administration: loading dose followed by maintenance doses
• this does not shorten the time needed to get to the steady state
• loading dose= Cp x Vd

Question 10

Drug absorption, distribution, excretion, biotransformation

Answer 10

• absorption effected by- route of administration, time of administration (meals), disease, drug history
• distribution effected by- age, body weight, sex, route of administration
• biotransformation effected by- age, sex, species variation, genetic factors, routes of administration, time of administration, disease, drug history
• excretion effected by age, disease, drug history
• emotional factors- placebo effect

Question 11

Iatrogenic

Answer 11

• adverse drug reaction
• may be predictable
• may be dose dependent

Question 12

Spontaneous adverse reaction

Answer 12

• not predictable- not dose dependent
• allergy- immunologically mediated- reproducible in the same patient
• idiosyncratic- not immunologic- not necessarily reproducible

Question 13

Tolerance

Answer 13

• decreased reponse to continued administration
• receptors
• metabolism

Question 14

Resistance

Answer 14

• refractoriness to the drug effect

- bacteria, receptors

Question 15

Side effects

Answer 15

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

Question 16

Cumulation

Answer 16

• drug administered faster than it can be eliminated

- increase in plasma levels- toxicity possible

Question 17

Drug Dependence/Drug Addiction

Answer 17

• tolerance
• homeostasis
• physical withdrawl syndromes

Question 18

Therapeutic Index

Answer 18

• TI= Toxic Dose/ Therapeutic Dose = TD50/ED50- comparisons
• ED50- effective dose in 50% of the population
• TD50- toxic dose in 50% of the population
• LD50- lethal dose in 50% of the population
• ideal clinical= TD1/ED99
• margin of safety: TD50-ED50

Question 19

Drug Interactions

Answer 19

• Direct molecular- antacids combine with gastric acids, or antibiotics and calcium
• change absorption- charcoal binds drug molecules- decrease absorption
• protein binding and displacement- one drug can displace another from binding sites and cause potential toxicity
• receptor effects- competitive or noncompetitive 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
• Drug interaction profile- Lexicon via UpToDate

Question 20

Unique Features of Newborn Physiology

Answer 20

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

Question 21

Factors influencing oral drug absorption in the Newborn

Answer 21

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

Question 22

Causes of Low Drug Binding in the Newborn

Answer 22

• low albumen
• competitive binding- bilirubin, sufonamides, phenytoin and bilirubin
• result- increased apparent VD

Question 23

Drug Biotransformation in the Newborn

Answer 23

• Introduction of polar groups- hydroxylation, oxidation, dealkylation, reduction
• conjugation- glucuronidation, sulfation, glycine conjugation, glutamine, acetate conjugations

Question 24

Rate of biotransformation slower in newborns

Answer 24

• oxidation reactions slow (multiple forms of cytochrome P450)
• glucuronidation deficient at birth, eg D-barb, morphine
• acetylation somewhat deficient
• hydroxylation depressed
• sulfation active e.g. acetaminophen
• rate varies with gestational maturity
• marked interpatient variability
• postnatal maturation for individual drugs variable
• vulnerability to pathologic states
• alternative pathway activation

Question 25

Factors influencing renal excretion of drugs in the newborn

Answer 25

• low renal blood flow- CPAH lower in neonates
• lower GPR- 30-40% of adult
• low tubular function- FT, 20-30% of adult
• glomerular predominance
• nephron heterogeneity

Question 26

Plasma Half-Life in Newborn

Answer 26

• much longer than in adults
• very large individual variability
• example: phenobarbital

Question 27

Therapeutic Considerations in the Newborn

Answer 27

• elimination (beta-phase) prolonged compared with distribution (alpha-phase)
• apparent volume of distribution increased
• maintenance dose lower (prolonged t1/2)