Science of Medicine Week 22 Flashcards
define dose
a predetermined amount of the drug administered at one time to produce a certain degree of biological response
give an example of a dose
the analgesic dose of aspirin for headache is 300-600mg
define dosage
a predetermined amount and rate of administration of a drug for a patient - adds also how often
give an example of a dose
200mg of ibuprofen once daily
define dosage form
the physical form in which a precise mixture of API and excipients are presented to help administration, deliver to sites of action, achieved fast onset of action and improve bioavailability
give an example of a dosage form
200mg ibuprofen tablet
define dosage regimen
the schedule of doses of a therapeutic agent (drug) per unit of time, including: the time between doses, or the time when the dose(s) are given and the amount of a medicine to be given at each specific time
give an example of a dosage regimen
aspirin 300mg, 4 times daily repeated every 6 hours according to the response for mild to moderate pain and fever
define medicinal product
a substance or combination of substances that is intended to treat, prevent or diagnose a disease or to modify physiological functions
define active ingredient
the substance in a medicinal product that is biologically active
define excipient
any other ingredient in a medicinal product other than the active ingredient
When designing a dosage regimen, what do we assume the plasma concentration of drug is equal to?
the concentration of drug at the site of action
How are pharmacokinetics, plasma concentration and pharmacodynamics linked?
- pharmacokinetics links the dosage regimen with the plasma concentration
- pharmacodynamics links the plasma concentration with the effects of the drug
define pharmacokinetics
the study of the movement (dynamics) of foreign chemicals during their passage through the body - includes kinetics of absorption, distribution, metabolism and excretion
What does the pharmacokinetic phase cover?
the relationship between drug input and the drug concentration achieved with time
What does the pharmacodynamic phase cover?
links the plasma concentration of drug with the desired and adverse effect produced - what they drug does to the body
define therapeutic range
the concentration of drug in plasma in which the drug has sufficient efficacy, but not toxicity
define pharmacokinetic parameters
constants defined by the model which are characteristic for each drug
What are examples of pharmacokinetic parameters?
volume of disitribution, clearance, elimination rate constant, elimination half life, absorption rate constant, fraction absorbed
define parenteral
a sterile preparation of drug to be injected through one or more layers of skin or mucous membrane
define IV administration
when the formulation is directly injected into a vein
define IV bolus
the solution of a drug is directly injected into a vein via a syringe/needle over a short period of time
What is an advantage of IV bolus?
you get a high concentration of the drug very fast - so useful for emergencies
What is a disadvantage of IV bolus administration?
- you need to monitor closely for toxicity
- risk of irritation
Which ADME processes are involved in IV bolus administration?
- distribution
- metabolism
- elimination (excretion and metabolism)
- disposition (distribution and elimination)
- plasma binding
- NO ABSORPTION
What are the 2 stages of plasma profiles for IV bolus administration?
- distribution phase
- elimination phase
What happens in the distribution phase?
the decline in plasma levels is primarily determined by the distribution of the drug to the tissues
What happens in the elimination phase?
the equilibrium of distribution in plasma and tissue is achieved and the decline is plasma levels is due to loss of drug from body
Why do we only see the elimination phase on most graphs?
the distribution phase is so rapid
What does the one-compartment model suggest?
the drug is assumed to rapidly distribute into a homogenous fluid volume in the body - we assume the human body is one compartment
What are the assumptions of the one-compartment model for IV bolus administration?
- the volume of the compartment = the volume of distribution
- elimination is a 1st order process (k=rate constant)
- elimination follows linear kinetics (no saturation of enzymes or transporters)
What is the equation for the rate of elimination?
dA/dt = -k x A = rate of elimination = -k x amount of drug
What is the rate of elimination directly proportional to?
the amount of drug in the body
What is the integrated equation for the amount of drug in the body?
ln A = lnA0 - k x t
ln (amount of drug) = ln (amount of drug at time 0) - k x time
What is k?
the elimination rate constant linking the rate of elimination with the amount of drug in the body
What is the equation for k?
k = rate of elimination / A
What can k be considered as?
the fractional rate of drug removal
What does a k of 0.14 h-1 mean?
14% of the drug is removed from the body every hour
How do we link the amount of drug in the body to the concentration?
using volume of distribution
C x V = A
What is the equation for the concentration of drug in the body after an IV bolus injection?
C = C0 x e ^-k x t
At time 0 (or the time of injection), what does C0 equal?
C0 = A / V = dose / V
How does the drug concentration decline after injection?
exponentially due to the elimination (1st order) process
What must you know to predict A and C after injection?
k!
What information must you know to work out k?
either A0 or C0
AND either A or C at a different time ‘t’
How do you work out k?
- plot lnC or lnA against time
- calculate gradient
- gradient = -k
define apparent volume of distribution
the (apparent) volume into which a drug distributes in the body at equilibrium
What is the equation for volume of distribution?
V= A / C
What is the equation for the bolus dose to get C required?
bolus dose = V x C required
In the one-compartment model, what does the volume of distribution equal?
the volume of the compartment
What must you know to calculate V?
- the amount of drug in body
- C required (desired drug concentration)
- that the equilibrium of distribution if achieved
When do we always know both A and C?
time 0
at time 0:
A = A0 = dose
C = C0
How do we find C0?
by extrapolation!
What is the equation for V?
V = dose / C0
define clearance
the proportionality factor linking the rate of drug elimination (dA/dt) to the plasma drug concentration
What is the equation for the rate of drug elimination?
dA/dt = Cl x C
Following an IV bolus injection, which equation describes the drug concentration?
Cp = C0 x e ^ -k x t
What is the equation for the elimination rate of a drug following an IV bolus injection?
dA/dt = Cl x C = Cl x C0 x e ^ -kt
Following an IV bolus injection, how does the elimination rate of the drug decline?
exponentially with time
What is the equation for the elimination rate of a drug after IV bolus injection?
dA/dt = k x A
What is the equation for the amount of drug in the body after an IV bolus injection?
A = A0 x e ^ -kt
What is another equation for the elimination rate?
dA/dt = k x A
dA/dt = k x A0 x e^ -kt
Simplify these equations
Cl x (C0 x e ^ -kt) = (A0 x e ^ -kt) x k
Cl x C0 = A0 x k
Cl = (A0/C0) x k
Cl = V x k
therefore what is k equal to?
k = Cl / V
What does the k for clearance depend on?
clearance and volume of distribution
What essentially is k?
the elimination rate constant
define the elimination half-life
the time needed for the drug concentration (and amount of the drug) in the body to fall by 1/2
What is the equation for t1/2?
t1/2 = 0.693 / k
What is the equation used to work out the concentration of drug after a half life?
C = C0 x e ^ -0.693/t1/2
What is the general equation used to predict the concentration of drug in plasma after ‘n’ half lives?
C = C0 x e ^ (-0.693/t1/2)^t
C = C0 x (1/2)^n
What is the equation for the fraction of drug remaining?
fraction remaining = )e^-0.693)^n = (1/2)^n
Which graph is the AUC used for?
concentration of drug x time
What is the equation for AUC?
C0 / k
How do you link AUC to clearance?
AUC = D / k x V = D / Cl
How do you use AUC to estimate clearance?
Cl = Dose / AUC
How do you get AUC data?
using the trapezium rule
What is the equation for the area of a trapezium?
)(a + b) x h) / 2
define absolute bioavailability of a formulation
the ratio of the AUC got with an extravascular formuation and AUC with IV administration
What is the equation for the AUC extravascular?
AUC extravascular = F x Dose / Cl
What does F stand for?
bioavailability extravascularly = the fraction of the administered dose that reaches systemic circulation
What is the equation for the fraction of absolute bioavailability?
F absolute = (AUC oral)/(Dose oral) / (AUC IV)/(Dose IV)
define continuous infusion
when the drug is added to a large volume of parenteral fluid (up to 1L) and this solution is slowly and continuously administered into a vein
What are the advantages of IV infusion?
- drug plasma levels are easily controlled by adjusting the infusion rate (R)
- a constant drug plasma level can be achieved
- less issues with irritation and toxicity
What are the disadvantages of IV infusion?
- need continuous monitoring to check infusion is proceeding
- some drugs may not be very soluble
- risky for fluid-restricted patients e.g. babies
Which ADME processes are involved in IV infusion?
NO absorption, but distribution, elimination and metabolism
What is the equation for a constant rate of infusion (R)?
rate of infusion (R) = mass of drug infused / time
What is the equation for the drug concentration in plasma?
amount of drug in body / volume of distribution
What are the assumptions used in the one-compartment model for IV infusion?
- elimination is a 1st order process
- drug input is a zero-order process
- linear kinetics
What does the variation of A in the compartment (body) with time result from?
the input rate into the body (infusion rate) and the rate out of the body (elimination rate)
What is the input rate?
the infusion rate (R)
- this is the mass of drug entering circulation per unit time
- zero order
- A is a constant value
What is the output rate?
Elimination
dA/dt= k x A
What is the equation for the variation of the amount of drug in the body? (equation 1)
dA/dt = R - k x A
What is the equation for the amount of drug in the body at time t? (equation 2)
A = R/k x (1-e^-kt)
What is the equation for the concentration of drug in plasma at time t during IV infusion? (equation 3)
C= R/k x V (1-e^-kt)
C= R/Cl (1-e^-kt)
Which other types of drug administration can we apply the IV infusion model to?
any other drug administration in which the input of drug into the body corresponds to a zero-order process e.g. some transdermal patches or oral forms
What are the 3 main phases in IV infusion drug plasma profiles?
- accumulation phase
- plateau (steady state) phase
- exponential decline
What does equation 3 predict?
a drug concentration in plasma during an IV infusion
What is the equation 3 at time 0?
C0 = R/k x V (1-e^-kt)
= 0!
concentration of drug in plasma at time 0 is 0!
What is the equation for drug concentration in plasma at any time ‘t’ during the infusion?
C = R/k x V (1-e^-kt)
What is the equation 3 at long time where t=infinity?
Css = R/k x V (1-e^-kxinfinity)
Css = R/ k x V = R / Cl = constant
When ONLY is the Css equation valid?
when in the plateau stage of the infusion and infusion rate = clearance
What 2 things happen as the infusion proceeds?
- the input rate (infusion rate) remains constant
- the elimination rate increases with time as the amount of drug in the body increases
When has the steady-state been reached?
when elimination rate = infusion rate
dA/dt = R
What happens at the steady state?
the drug concentration in the compartment becomes constant
What is the equation for Css?
Css = R / Cl
What else can you use the Css equation for?
predicting the clearance and rate of infusion
What happens after the IV infusion is stopped?
- the input rate = 0
- the elimination rate = dA/dt = k x A = C x Cl
there is only elimination, so drug concentration levels will decline exponentially with time similar to IV bolus
What is the equation for the concentration of drug in plasma after the infusion is stopped?
C = C0 x e ^-kt
What does C0 stand for in this equation?
the value of C at the time the INFUSION WAS STOPPED - don’t start from start of infusion
What is the equation for getting the k and t1/2 from post-infusion data?
lnC = lnC0 - k x t
(t will be the time gone since INFUSION WAS STOPPED)
How is the use of this equation different to that in IV bolus?
the extrapolation to lnC0 does not allow estimation of the volume of distribution as the amount of drug in the body at the time the infusion was stopped is unknown
What is the equation for the fraction of the equilibrium attained at a given time?
F = C / Css
What is the equation used to predict when Css will be reached?
c / Css = (1-e^-kt)
1- c / Css = e^-kt
ln (1- C / Css) = -k x t
ln (1-F) = -k x tF
ln (1-F) = -0.693 / t1/2 x Tf
Which 2 factors ONLY does the time taken to reach a fraction of the steady state depend on?
the t1/2, so clearance and volume of distribution
What is the equation for t 1/2?
t1/2 = 0.693 / k
t1/2 = 0.693 / V x Cl
What is the equation for tF?
tF = t 1/2 x ln (1-F) / -0.693
tF = (-1) x (V x ln(1-F)) / Cl
What are the advantages of IV bolus?
- highest concentration of drug is achieved upon injection at C0
- achieves the C required immediately
What are the disadvantages of IV bolus?
the concentration of drug in plasma continuously declines from time 0 as the drug is eliminated and not replaced
What are the advantages of IV infusion?
- once Css is reached, it will be maintained as the infusion rate replaces the drug eliminated
What are the disadvantages of IV infusion?
- the concentration of drug starts at 0 as builds up over time towards Css
- if the C required is Css, 4-5x the half life is needed to get Css
How do we combine IV bolus and infusion?
- administer an IV bolus to achieved C required with no delay
- then, start an infusion to maintain the C required
What can we assume from IV bolus and infusion together because we have linear kinetics?
the drug in the body from IV bolus and the drug in the body from IV infusion behave independently, and at any time the total C will be the sum of both fractions
What is the equation for A total?
A total = A infusion + A bolus
What is the equation for the concentration of drug in plasma from both bolus and infusion?
C = C0 x e^-kt + Css (1-e^-kt)
If we start one IV infusion and stop it, to start another one, what is the equation?
C = C0 x e^-kxt + Css (1-e^-kt)
we only have elimination after the first infusion is stopped, so follows IV bolus elimination kinetics
What will C0 be in this case?
the CONCENTRATION at which the drug was in plasma when the 1st infusion was STOPPED
