2. A Flashcards
What are frequency distribution curves?
a graphical representation of the number of patients responding to a drug at different doses during clinical trials
-follows normal distribution
What is the ED50?
median effective dose
the dose required to produce a specific therapeutic response in 50% of a group of patients
-standard or average dose
True or false: the ED50 applies to everyone
false
What is the TD50?
median toxicity dose
the dose required to produce a given toxicity in 50% of a group of patients
At what stage of studies are lethal doses observed? Is it tested in humans?
pre-clinical stage (in cells and animals)
we dont test lethal dose in humans, we determine toxicity from adverse effects
Describe the dose-response relationship.
looking at an individuals response to a drug, three phases
phase 1: very few targeted cells are affected by the drug
phase 2: shows the linear relationship between amount of drug administered and degree of response obtained
phase 3: plateau, no further responses
Why do we plateau in phase 3 of the dose-response relationship?
all receptors are occupied, obtained 100% relief
True or false: not all drugs demonstrate a linear relationship
true
What is the goal of a dosage regimen?
attain and maintain therapeutic concentrations to treat a condition effectively
Why should another dose be given before the minimum effective concentration is reached?
our goal is a plateau (steady state, Css) drug plasma level
How many half lives does it take to reach plateau?
5-7 half lives of the drug
What is the therapeutic window?
the range of drug plasma concentration which produces desired clinical response in a patient
the goal is to be between toxic and sub-therapeutic
What is the therapeutic range?
the dose needed to achieve the therapeutic window of a population
Why do we use the dose ranges of a sample population instead of the individuals therapeutic window?
we dont know the individuals therapeutic window
What is the therapeutic index?
the ratio of toxic plasma concentration to effective plasma concentration values, comparing the amount of drug that causes the effect to the amount of drug that causes toxicity
wide index: safe drug, monitoring unnecessary
narrow index: monitoring necessary
What is a loading dose?
how we attain the desired therapeutic concentration
sometimes we cant wait 5-7 half lives to reach Css
only once
What is a maintenance dose?
how we maintain the desired therapeutic concentration, the regular dose that we want to maintain
How do we calculate maintenance dose?
MD=Css x Cls/S x F
What is pharmacokinetics?
drug movement in the body
study of time course of drug in the body (ADME)
Explain what happens to Cp with linear and non-linear PK.
linear PK: proportional increase in Cp with increased dose (predictable)
non-linear PK: disproportional increase in Cp with increases dose (unpredictable)
Explain each component of ADME.
Absorption: drug moving from site of administration to circulation
Distribution: where the drug is going in the body
Metabolism: changes drug to inactive/drug and/or make it more likely to be excreted
Excretion: drug leaving body
Why do we need pharmacokinetics?
allows us to predict drug plasma concentrations
What are the primary PK parameters? How are they determined?
absorption rate constant (Ka)
oral bioavailability (F)
hepatic clearance (Clh)
renal clearance (Clr)
volume of distribution (Vd)
determined by the physiology of the individual
What are the secondary PK parameters? How are they determined?
elimination half life (t1/2)
elimination rate constant (K)
fraction excreted unchanged (fe)
determined by primary PK parameters
What is pharmacodynamics?
what the drug is doing to the body
what is happening at the drug receptor
What does the rate of absorption tell us?
onset of action
What are the parameters that describe absorption?
absorption rate constant (Ka): primary PK parameter, rate of absorption
bioavailability (F): primary PK parameter, extent of absorption
Cmax: descriptive PK parameter, extent of absorption, max concentration reached
Tmax: descriptive PK parameter, rate of absorption, time at which Cmax occurs
What are the parameters that describe distribution?
volume of distribution: extent of distribution
fraction unbound: extent of distribution
Explain the volume of distribution.
volume of distribution represents the apparent volume into which the drug is distributed to provide the same concentration as it currently is in the blood plasma
amount of fluid necessary for drug concentrations that result in a clinical response
Explain fraction unbound.
the amount of drug that is free to bind to receptors
drugs can bind to proteins, forming a complex=unable to bind to receptors
When does elimination start?
as soon as the drug is absorbed
Which processes make up elimination?
metabolism and excretion
What is systemic clearance?
the efficiency of elimination mechanisms involved in drug removal from the body
the sum of all individual and simultaneously occurring elimination pathways
liver and kidney are principal clearance mechanisms
What determines hepatic clearance?
hepatic blood flow (most important factor)
fraction of drug unbound
intrinsic clearance
What is intrinsic clearance?
maximum ability of the drug to be removed by the liver in the absence of anything impeding blood flow and no protein binding occurred
What determines renal clearance?
glomerular filtration rate
tubular secretion
tubular reabsorption
What is half-life? What does it determine?
amount of time it takes for a drugs serum concentration to decrease by half
determines: time it takes to reach Css and dosing intervals
What is the elimination rate constant?
the fraction of drug eliminated per unit of time
describes elimination but also takes distribution into account
What determines the transport of a drug?
size
ionization
solubility
What are the characteristics of drugs that can use passive diffusion to pass through polarized epithelia?
small
non-ionized
lipid soluble
What is the bile salt export pump? What happens if a drug inhibits the BSEP?
transports bile salts out of hepatocytes for excretion
if inhibited then toxic levels of bile salts are possible
What are the elements of the dosage regimen?
attain (loading dose) and maintain (maintenance dose)
What are the determinants of the dosage regimen?
Activity-toxicity
Pharmacokinetics
Clinical factors
Other factors
What are the components of the plasma concentration vs time curve?
onset: patient is starting to receive a response
intensity: the effects of the drug have peaked, phase 2
duration: how long the effects of the drug lasted
What are the units for therapeutic index?
none
its a ratio
How do we calculate loading dose?
LD=Cther x Vd/S x F
How do we calculate Css?
Css=dosage regimen/systemic clearance
=MD/Cls
What are the determinants of the dosage regimen?
activity-toxicity
pharmacokinetics
clinical factors (state of patient and management of therapy)
other factors
Explain how PK and PD are related.
PK assumes that there is a relationship between drug plasma concentration and the drug concentration at the receptor site
this is how PK connects to the clinical response
Explain why distribution is reversible.
there is a constant transfer between systemic circulation and the tissue, it exists it in a state of constant equilibrium
this is not the same as absorbing
What is the biophase?
the effect site of the drug
During pharmacokinetics, when does the response occur?
distribution
What is the formula for Vd?
Vd=dose/Co (plasma concentration)
If a drug has a large Vd, what can we infer?
the drug is distributed widely throughout the tissues
If we say that warfarin is 99% plasma-protein bound, what does this mean?
only 1% of the warfarin gets to the receptors
99% of the warfarin cannot bind to a receptor as it has formed a complex with a protein
Why do we have to take elimination into consideration when we look at dosage regimens?
drug concentrations are always changing, the drug is constantly distributing and eliminating
Why is systemic clearance so important in the dosage regimen?
systemic clearance determines the steady state concentration
we must know variables that affect Cls in order to determine dosage regimens
What are the methods of transport across polarized epithelia?
passive diffusion
endo/exocytosis
carried mediated
-facilitated diffusion
-active
What are the primary PK parameters and what do they measure?
absorption:
-absorption rate constant (Ka)
-bioavailability (F)
distribution
-volume of distribution (Vd)
metabolism and excretion (elimination)
-hepatic clearance (Clh)
-renal clearance (Clr)
What is the measurement for elimination?
volume of blood cleared of the drug per unit of time
ex: mg/min
