Basic PK Principles Flashcards
pharmacokinetics is
- the study of what the body does to the drug
- i.e. what happens to the drug concentration as it moves through the body
Elimination includes these two things
Excretion and metabolism
Bioavailability is the measurement of
the extent and rate of absorption of a drug or the fraction of the administered dose that reaches systemic circulation
what a drug does to the body including mechanism of action
Pharmacodynamics
Pharmacogenetics is the study of…
the differences in response as a result of genetic differences in populations
the ratio of the dose of drug producing an undesirable effect to the dose producing the desired therapeutic effect is known as…
Therapeutic index or the margin of safety of a drug
A drug with a high therapeutic index has a small or large margin of safety
Large Margin of safety
drugs with low margin of safety require this and why
monitoring of plasma concentration levels to minimize potential toxic effects due to increases in plasma concentration
Pharmacokinetics is used to determine these 6 things
- Bioavailability (rate and extent of drug absorption)
- drug interactions
- dosing regimen
- altered dosing regiment for comorbid conditions e.g. liver disease/renal impairment
- dose adjustments for individual pt variables such as obesity, diet, smoking
- quantify or predict drug residues in tissues (animals meat producers)
Represents a grouping of tissues or a volume of fluid representing the body
Compartment
why is plasma a good reference tissue (2 reasons)
- easy to sample
- comes into contact will all tissues
what is the driving force for pK
the speed with which drug is cleared
what determines whether a one, two or multicompartment model is used
- the rate at which drug is distributed
- slow - more compartments
- fast - 1 compartment
- how much is known about the drug
- what you are trying to understand i.e. 1 compartment for dosing; 2 or multicompartment for drug interactions or distribution in tissues
the Central Compartment is made up of
well profused tissue like heart, kidneys, plasma
Fat, muscle and cerebrospinal fluid make up this compartment
Peripheral Compartment
which compartment model is the most highly used
one compartment model
what assumptions are made in the compartment models (2)
- that drug distributes instantaneously
- that drug distributes linearly to all tissues
- the compartment is well stirred and homogeneous i.e. the same concentration throughout the compartment
how does assuming linear distribution of drugs to tissues help in pK modeling
allows for the use of a reference tissue such as plasma, saliva or urine
most drugs follow Zero or First order kinetics
First
What is t1/2? (2)
- half life of a drug
- loss of drug from the body
what is t½ = 0.693/K
half life
what are the two calculations by which half life can be calculated
- t½ = 0.693/K where K is the slope or elimination rate constant
- t½ = 0.693 Vd/Cl where Vd = volume of distribution and Cl = clearance
simplest pK model describing distribution and elimination
one compartment model
when is IV bolus commonly used in pharmacokinetics
when trying to develop a model for drug distribution or dosing
why is IV bolus administration commonly used in pK modeling (3 reasons)
- because absorption is immediate
- there are no input kinetics
- behaviour of drug determined based solely on distribution and elimination
Absorption, Distribution, Metabolism and Execretion are part of pharmacokinetics or pharmacodynamics
Pharmacokinetics
what are the parameters of compartment models (2)
volumes and rate constants
aside from plasma, what are two other reference tissues used in pK analysis
Urine and saliva
one compartment models are commonly used for:
- dose determination
When are 2 or more compartment models used (2)
- mechanism of drug interaction
- Tissue concentration
Pharmacokinetic models allow for the prediction of
time course of drug concentration or the amount in one or more compartments
What is the equation for the amount in body (Ab) for a one compartment model
Ab = Cp x V
Where Cp is concentration of drug in the compartment
V is the volume of the compartment
What is Cp
- Plasma Concentration or concentration in the compartment
- Cp = D/V
Pharmacodynamics refers to the relationship of drug concentrations to
drug effect
The EC50 refers to the drug concentration at which
one half of the maximum effect is achieved
The therapeutic range is the range of plasma drug concentrations that will
Most likely result in desired drug effect and minimal risk of drug toxicity
The most important concept in therapeutic drug monitoring is
drug effect is related to plasma concentration
Factors (3) that may result in variability in plasma drug concentrations after the same drug dose is given to different patients includes variations in
- Drug absorption
- Genetic differences in metabolism
- Body weight
- comorbid conditions e.g. renal insufficiency,
An example of a situation that would not support therapeutic drug monitoring with plasma drug concentrations would be one in which
The toxic plasma concentration is much higher than the therapeutic concentration range
For a drug with a narrow therapeutic index, the plasma concentration required for therapeutic effects is near the concentration that produces toxic effects. (True/False)
True
The central compartment includes fat tissue, muscle tissue, and cerebrospinal fluid. (True/False)
False
The theoretical volume required to account for all of the drug in the body, if the concentration in all tissues is the same as the plasma concentra tion, is defined as the
Volume of distribution
Vd = X or D/Cp
where X or D = drug dose
Cp = drug concentration in plasma at time zero
Volume of Distribution
Are compartment models deterministic or probabalistic, why?
deterministic
because the observed drug concentration determines the type of compartment model required for pK
what is the basic concept in a two compartment model (3)
- The drug profuses quickly into the first compartment (central compartment) (blood, hear, liver, kidneys)
- then drug profuses from central to peripheral more slowly establishing equilibrium
- elimination occurs from first compartment
When volume of distribution (Vd) is large (2)
- drug is distributed in a large volume i.e. not plasma bound
- bound to proteins of extravascular tissue or the peripheral comparment tissues
- Plasma concentration is low
- may need to have a load dose
- larger dose required to get target plasma concentration
when volume of distribution is low (2)
- drug is mainly bound to plasma, i.e. limited distribution
- Cp is high
- if highly bound to plasma less drug ciruclating in body
- dosing regimen is important as toxic effects or drug interactions can be seen
- if highly bound to plasma less drug ciruclating in body
drugs which are lipid soluble have higher or lower Vd than hyrdophilic or water soluble drugs
Higer Vd
is free or bound drug active
free drug
what are common pharmacokinetic parameters (4)
- Volume of Distribution (Vd)
- Clearance (Cl)
- Bioavailability
- 1/2 life (t1/2)
what is clearance
- the volume of blood or plasma cleared of drug per unit time
What pk parameter (A,D,M or E) does clearance describe
Elimination
Is clearance a dependent or independent pK parameter
Independent
how is clearance calculated? (2)
- Cl = K x Vd or
- Cl = K / Cp where Cp = D/Vd or amt in body/Vd
what are 2 reasons why is Vd useful
- because you can’t measure amount in body
- used to calculate the dose required to get the target plasma concentration
what is the formula for calculating slope
Slope = log y2-y1/ x2-x1
The steeper the slope the higher or lower K and t1/2?
K is higher; t1/2 lower
K or the elimination rate constant can be calculated using slope by the following formula
k = - slope (2.303)
when the amount of drug lost equals the amount of durg administered
steady state concentration
Poor bioavailiability may be the result of these 4 things
- poor solubility
- incomplete absorption in GI tract
- metabolism in lining of GI tract
- first pass metabolism
Bioavailability is
the fraction of drug reaching systemic circulation after administration
how is bioavailability calculated
Bioavailability (F) = (AUC oral/AUC iv) x (dose iv/dose oral)
how is bioavailability often compared (2)
- by comparing AUD oral vs. IV in cross over study design
- if the dose is not the same then dose adjust
Maintenance dose rate is calculated by:
Target Cp x Clearance
Loading dose is calcuated by
Css (mg/l) x Vd (L)
where Css is the target drug concentration
Area under the curve is calculated by
AUC = Cp0/K
where 0 = time zero; plasma drug concentration plotted over time
Elimination from the body occurs by these two processes
biotransformation and excretion
Elimination generally occurs wehre
liver and kidneys
Elimination processes generally follow first or zero order kinetics
- First order kinetics
- i.e. the rate of elimination is directly proportional to the amount of drug in the body
Absolute bioavailability is
F = Auc (oral) / Auc (iv)
rate of urinary excretion (equation)
KuAb = DAu/Dt
where Au = amount of drug excreted in uring
Ku = urinary elimination rate constant
Besides direct measurement in plasma, describe another way that drug plasma concentration can be obtained
- by back extrapolating on a concentration vs. time graph
- the intersect with the y axis is the T0 concentration
the larger the Vd the larger or smaller the dose must be?
Larger, directly proportional
how is total clearance calculated
Clt = Clr + Clm + Clb + Cl other, where: Clt = total body clearance (from all mechanisms, where t refers to total)
Clr = renal clearance (through renal excretion)
Clm = clearance by liver metabolism or biotransformation
Clb = biliary clearance (through biliary excretion)
Clother = clearance by all other routes (gastrointestinal tract, pulmonary, etc.)
assumes instantaneous distribution, linear distribution in all tissues, and instantaneous elimination
one compartment model
