Pharmacokinetics Flashcards
Dose-concentration
Pharmacokinetics
Effects of the biologic system on drugs
Pharmacokinetics
Deals with the processes of absorption, distribution and elimination of drugs
Pharmacokinetics
Makes possible the calculation of loading and maintenance doses
Pharmacokinetics
Concentration of a drug at the receptor site (in contrast to drug concentrations that are more rapidly measured, eg, blood)
Effective Drug Concentration
What the body can do to the drug
Pharmacokinetics
The amount of drug waiting to associate with its receptor
Effective Drug Concentration
How much of the drug can you give initially to a patient.
Loading Dose
How much of the drug should you give to a patient everyday, for the drug to maintain a
certain concentration in the blood of the patient.
Maintenance Dose
Based on trials in healthy volunteers and patients with
average ability to absorb, distribute, and eliminate the drug
“Standard” Dose of a Drug
2 Pharmacokinetic Parameters
1) Volume of Distribution (Vd)
2) Clearance (CL)
Modified by the physiologic and pathologic processes
Pharmacokinetic Parameters
Measure of the ability of the body to eliminate the drug
Clearance
Measure of the apparent space in the body available to contain the drug
Volume of Distribution
Amount of drug in the body to the plasma/serum concentration
Volume of Distribution
Intracellular and extracellular compartments
Volume of Distribution
T/F: Not all of the drug that a patient takes in will take effect, only the effective drug concentration will have an effect on the body.
T
Relates the amount of drug in the body to the concentration of drug (C) in blood or plasma
Volume of Distribution
Drugs with very high volumes of distribution have much _[higher/lower]_ concentrations in extravascular tissue than in the vascular compartment, ie, they are not _[homogeneously/heterogeneously]_ distributed
higher ; homogeneously
T/F: Distribution is faster in muscle, viscera, fat and skin
T
T/F: Initial distribution is in the liver, kidney and brain
T
T/F: Distribution happens in the interstitial and intracellular fluids.
T
Rate of input of the drug (by absorption) into the plasma
Plasma Concentration
Rate of elimination, or loss, from the body
Plasma Concentration
Distribute the drug inside the tissues
Intracellular
Distribute drug outside the cells (e.g. surrounding fluid, blood / systemic circulation)
Extracellular
T/F: Calculated V is an apparent volume that may be appreciated by comparing the volumes of distribution of drugs (e.g., digoxin, chloroquine) with some of the physical volumes of the body.
T
T/F: Volume of Distribution can exceed any physical volume in the body
T
T/F: When a drug is avidly bound in peripheral tissues, it’s concentration in plasma may drop to very high values even if the total amount in the body is large
F; very low values
When a drug is completely retained in the plasma
compartment
High Vd
Volume of distribution is (>, <, =) to the plasma volume
=
2 Major Sites of Drug Elimination
Liver & Kidney
↑ Vd = ___ Plasma Conc.
↓
↑ Vd = Distributed to
Tissues e.g. Urine, Brain
↓ Vd = Stays in the
Blood e.g. Septicemia
Rate of elimination compared to plasma concentration
Clearance (CL)
Depends on the drug and the organs of elimination in the patient
Clearance (CL)
Small water-soluble molecules
Total Body Water (0.6 L/kg)
Ethanol
Total Body Water (0.6 L/kg)
Larger water-soluble molecules
Extracellular Water (0.2 L/kg)
Gentamicin
Extracellular Water (0.2 L/kg)
Large protein molecules
Plasma (0.04 L/kg)
Antibodies
Plasma (0.04 L/kg)
Highly lipid-soluble molecules
Fat (0.2-0.35 L/kg)
Diazepam
Fat (0.2-0.35 L/kg)
Certain ions e.g. lead, fluoride
Bone (0.07 L/kg)
T/F: Total body water in a young lean person might
be 0.5 L/kg; in an obese person, 0.7 L/kg.
F; Young Lean = 0.5, Obese = 0.7
T/F: High Vd can be found in the blood
F; Nowhere to be found in the blood. No matter how much blood taking is performed.
Is the factor that predicts the rate of elimination in relation
to the drug concentration
Clearance
Is similar to clearance concepts of renal physiology
Drug Clearance Principles
T/F: In clearance, drugs are eliminated with first-order kinetics
T
Clearance First-Order Kinetics
Elimination Rate is ____ to Clearance x Plasma Conc.
equal
First-Order = _ Drug Conc., _ Elimination
both ↑
T/F: Clearance is constant and can be calculated via area under the curve (AUC)
T
T/F: Continuous elimination half-life makes the initial concentration smaller & smaller; thus slowing down elimination
T
Clearance of unchanged drug in the urine represents renal clearance
Kidney
Drug elimination occurs via biotransformation, excretion or combination of both
Liver
T/F: For most drugs, clearance is constant over the concentration range encountered in clinical settings
T
2 Types of Elimination in Clearance
1) Capacity-Limited Elimination
2) Flow-Dependent Elimination
T/F: In Capacity-Limited Elimination, clearance will vary depending on the
concentration of the drug achieved
T
A state of “pseudo-zero order” elimination
Capacity-Limited Elimination
Pseudo-Zero Order: At concentrations that are high relative to the Km, the elimination rate is almost __________ of concentration
Independent
T/F: In Capacity-Limited Elimination, if dosing rate exceeds elimination capacity, steady state cannot be achieved
T
T/F: Clearance has no real meaning for drugs with capacity-limited elimination, therefore, AUC should not be used.
T
Drugs are very readily cleared by the organ of elimination
Flow-Dependent Elimination
These drugs are called “high-extraction” drugs
Flow-Dependent Elimination
Type of elimination when blood flow to an organ does not limit elimination, the relation between elimination rate and concentration (C) is expressed mathematically in equation
Capacity-Limited Elimination
Main determinant of drug delivery in flow-dependent elimination
Blood Flow pero pd rin plasma protein binding / blood cell partitioning
Type of elimination when most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it.
Flow-Dependent Elimination
Type of elimination wherein it will primarily depend on rate of drug delivery to the organ of elimination
Flow-Dependent Elimination
The time required to change the amount of drug in the
body by one-half during elimination (or during a constant infusion).
Half-Life (t1/2)
Time it takes for the amount of concentration of a drug to
fall to 50% of an earlier measurement
Half-Life (t1/2)
The most useful in designing drug dosage regimens and indicates the time required to attain 50% of steady state or
to decay 50% from steady-state conditions after a change in the rate of drug administration.
Half-Life (t1/2)
T/F: Drugs eliminated by first-order kinetics are constant regardless of concentration
T
T/F: Drugs eliminated by zero-order kinetics are not constant
T
Determines the rate at which blood concentration rises during a constant infusion and falls after administration is stopped
Half-Life (t1/2)
T/F: Half-life depends on both the volume of distribution and the clearance
T
T/F: Drug accumulation happens when repeated drug doses will be accumulated until dosing stops
T
T/F: A change in half-life will not necessarily reflect a change in drug elimination.
T
Rate of drug administration is equal to rate of elimination
Steady State Concentration
Dose in = Dose out
Steady State Concentration
Inversely proportional to the fraction of the dose lost in each dosing interval
Drug Accumulation
A convenient index of accumulation is the
Accumulation Factor
T/F: The fraction lost is 1 minus the fraction remaining just before the next dose. The fraction remaining can be predicted from the dosing
interval and the half-life
T
The fraction of unchanged drug reaching the systemic
circulation following administration by any route
Bioavailability
Equal to the amount absorbed over the amount administered
Bioavailability
T/F: The area under the blood concentration-time curve (AUC) is proportional to the dose and the extent of bioavailability for a drug if its elimination is zero-order.
F; first-order
Bioavailability Unity or 100%
Intravenous administration
Bioavailability < 100% First-pass elimination by the liver
Oral Administration
T/F: Drugs are more absorbed in the small intestines because it has a larger surface area
T
Liver immediately metabolizes and makes it water soluble to make it easier to be excreted via kidneys.
First pass metabolism
A drug may be incompletely absorbed due to lack of absorption from the gut
Extent of Absorption
T/F: Other drugs are either too hydrophilic (eg, atenolol) or too lipophilic (eg, acyclovir) to be absorbed easily, and their low bioavailability is also due to incomplete absorption.
T
May not be absorbed because of a reverse transporter
associated with P-glycoprotein.
Extent of Absorption
Inhibition of P-glycoprotein and gut wall metabolism, eg, by grapefruit juice, may be associated with substantially
[increased / decreased] drug absorption.
increased
Routes with low bioavailability
1) Sublingual
2) Rectal
3) Inhalation / Nasal
4) Transdermal Patches
T/F: Bioavailability is dependent on extent of absorption, first-pass effect, rate of elimination and side of administration
F; rate of absorption
100% Bioavailability and most rapid onset
Intravenous (IV)
75 to ≤100 Bioavailability & Large volumes often feasible; may be painful
Intramuscular (IM)
75 to ≤100 Bioavailability & Smaller volumes than IM; may be painful
Subcutaneous (SC)
5 to <100 Bioavailability & Most convenient; first-pass effect may be important
Oral (PO)
30 to <100 Less Bioavailability & first-pass effect than oral
Rectal (PR)
5 to <100 Bioavailability & Often very rapid onset
Inhalation
80 to ≤100 Bioavailability & Usually very slow absorption; used for lack of first-pass effect; prolonged duration of action
Transdermal
Overall process that can contribute to the reduction in bioavailability
First-Pass Elimination
First-Pass Elimination: A drug can be metabolized in the gut wall
CYP3A4 enzyme system
T/F: In First-Pass Elimination, drugs can also be metabolized in the portal blood
T
T/F: In First-Pass Elimination, the most common is the liver
T
Determined by the site of administration and the drug formulation
Rate of Absorption
T/F: Both the rate of absorption and the extent of input can’t influence the clinical effectiveness of a drug
F; can influence
T/F: The mechanism of drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut.
T
T/F: The mechanism of drug absorption is said to be first-order when the rate of absorption is proportional to the gastrointestinal fluid concentration.
T
T/F: Drugs that are poorly extracted by the liver, shunting of blood past the liver will cause massive change in availability
F; little change
T/F: Drugs that are highly extracted by the liver, bypassing hepatic sites of elimination will result in substantial increases
in drug availability
T
Systemic clearance is not affected by bioavailability.
Extraction Ratio & the First-Pass Effect
T/F: Drugs with high extraction ratios will show marked variations in bioavailability between subjects because of differences in hepatic function and blood flow
T
For maximum concentration at the site of action and minimize it elsewhere
Topical
To prolong the duration of drug absorption
Transdermal
To avoid the first-pass effect
Rectal & Sublingual
Alternative routes direct access to systemic but not portal veins
Sublingual absorption & Transdermal route
Alternative route drain into the inferior vena cava, thus bypassing the liver
Lower rectum suppositories
Alternative route bypass first-pass effect by inhalation to lungs
Non gastrointestinal (“parenteral”) routes.
Is used to calculate the bioavailability of a drugs
Area under the curve (AUC)
The principles of pharmacokinetics and those of pharmacodynamics provide a framework for understanding the time course of drug effect.
Time Course of Drug Effects
Directly related to concentration (e.g. anticoagulants; warfarin, coumadin, heparin)
Immediate Effect
Due to distributional delay
Delayed Effect
T/F: In Immediate Effect, drug effects are directly related to plasma concentrations,
but this does not necessarily mean that effects simply
parallel the time course of concentrations
T
T/F: In Immediate Effect, relationship between drug concentration and effect is linear
F; not linear
Delayed expression of the physiologic substance needed
for the effect
Delayed Effect
T/F: Changes in drug effects are often delayed in relation to changes in plasma concentration
T
T/F: In delayed effect, one reason of the delay is the slow turnover of a physiologic substance that is involved in the expression of the drug effect
T
Constant infusion
Cumulative Effect
Aminoglycosides causes renal toxicity if given constantly
Cumulative Effect
Intermittent dosing only
Cumulative Effect
Fraction of the drug removed from the perfusing blood during passage to the organ
Extraction Ratio
T/F: Drugs with high hepatic extraction ratio have large first pass effect
T
Measure of the elimination of the drug by that organ
Extraction
↑ Hepatic Extraction __ First-Pass Effect
↑
Drugs are eliminated, unchanged or as metabolites
Excretion
Polar compounds are more efficiently eliminated
Excretion
Desired therapeutic effects are produced
Target Concentration
Based on the assumption that there is a target concentration that will produce the desired
therapeutic effect.
Rational Dosage Regimen
Plan for drug administration over a period
Dosage Regimens
Achievement of therapeutic levels of the drug in the body
without exceeding the minimum toxic concentration
Dosage Regimens
Drugs administered to maintain a steady state in the body
Maintenance Dose
Most important parameter in defining rational drug dosage
Clearance
Maintain plasma concentration within a specified range over long periods of therapy
Maintenance Dose
Dose needed to maintain a steady state of concentration
Maintenance Dose
For drugs with long half-lives and longer time to reach a steady state
Loading Dose
It is desirable to administer drug in loading doses that promptly raises the concentration of drug in the plasma to achieve
target concentration.
Loading Dose
T/F: Amount of loading dose is computed. Not the rate of
administration
T
↑ Vd __ Loading Dose
↑
Important factor to consider in loading dose
Volume of Distribution
4 Pharmacokinetic Variables
1) Absorption
2) Clearance
3) Volume of Distribution
4) Half-Life
- Amount of drug the enters the body depends on:
o Patient’s adherence on the prescribed regimen
o Rate and extent of transfer from the site of administration to the blood.
Absorption
Overdosage or Underdosage
Failure of adherence
T/F: Abnormal clearances may be an indication of the impairment of the kidney, liver, and heart.
T
A useful indicator of functional consequences of those organs and often have greater precision than clinical findings and laboratory tests.
Drug Clearance
Most important parameter in design dosage regimen
Clearance
Most important organ for clearance
Kidneys
Good indicator of renal function
Creatinine Clearance
↓ Vd __ binding of plasma protein
↑
↑ Vd __ binding of tissues
↑
T/F: ↑ Vd = drug distributed to body waters, extracellular accumulation of body fluids
T
Recognition of maximum effect is helpful in avoiding
ineffectual increases of dose with the attendant risk of
toxicity.
Maximum Effect
No more increase in effect even if the concentration is
increasing
Maximum Effect
No matter how high the drug concentration goes, a point will be reached beyond which no further increment in response is achieved.
Maximum Effect
Increased, exaggerated response to small doses
Sensitivity
Increased activity is characterized by having exaggerated
response in small or moderate doses.
Sensitivity
Sensitivity of the target organ to drug concentration is
reflected by the concentration required to produce ______________
50% of maximum effect, the C50
T/F: Diminished sensitivities may be a result of an abnormal
physiology.
T
Acidic drugs bind to ____
Albumin (Circulating Protein)
Most appropriate time to measure drug concentration:
1) Absorption is complete
2) 2 hours after the dose
More highly protein bound drug will displace the less protein bound drug and it is inert
Plasma Binding Proteins
Basic Drugs bind to ____
alpha 1 acid glycoprotein
Average total amount of drug in the body does not change
over multiple dosing intervals
Steady State Concentration
Rate of drug input equals the rate of elimination
Steady State Concentration
Condition in 3 to 4 t1⁄2 must elapse before checking drug blood
concentration
Steady State Concentration
T/F: Drugs given intermittently are in steady state of concentration
T
Safe “opening” between the MEC and the MTC of the drug
Therapeutic Window
Used to determine the range of plasma levels that is
acceptable when designing a dosing regimen
Therapeutic Window
Determines the desired trough levels of a drug given
intermittently
Minimum Effective Concentration
determines the permissible peak plasma concentration
Minimum Toxic Concentration
Single most important factor on determining drug
concentrations.
Clearance
3 Factors Influencing Clearance
1) Dose
2) Organ Blood Flow
3) Intrinsic Function of Liver and Kidneys
4 Factors affecting protein binding
1) Albumin Concentration
2) Alpha1-acid glycoprotein concentration
3) Capacity Limited Protein Binding
4) Binding to red blood cells
↓ Albumin in diseased states __ Total drug concentration
↓
__ in acute inflammatory disorders = change
in total plasma concentration
↑
Essential if one is to obtain maximum value from a drug
concentration measurement.
Dosing History
If unknown / incomplete, drug concentration measurement
lose all predictive value.
Dosing History
Absorption usually occurs during the first __ hours after a drug dose and varies according to food intake, posture, and activity.
2
T/F: Drawing blood is alright even though absorption isn’t complete.
F; Avoid drawing blood until absorption is complete.
T/F: With maintenance dose drugs, you’ve already reached the steady state concentration
T
First Order Kinetics ↑ Drug Conc ___ Rate of Elimination
↑
↑ Vd = Distributed to tissues ___ Half-Life
↑
↓ Vd = stays in the blood ___ half-life
↓
↑ Drug Accumulation ___ fraction of the dose lost in each interval
↓
↓ Affinity Drugs ___ Plasma Conc
↑
