pharmacokinetics in practice and intro to pharmacogenomics Flashcards
what is Cmax and Tmax
Cmax= maximum plasma concentration
tmax= time taken to reach Cmax
what is clearance?
Clearance (CL) = removal of drug by all eliminating organs
whats a modified release drug
one that requires less frequent dosing because its effects last a lot longer
what is the half life of a drug dependant on
- clearance (CL) of drug from body by all eliminating organs (hepatic, renal, faeces, breath)
- Dependent of volume of distribution (Vd) - A drug with large Vd will be cleared more slowly than a drug with a small Vd
- not dependent on drug dose or drug formulation
why is it relevant to understand drug half lives when prescribing
Drug dosing (short t1/2 will need more frequent dosing)
Organ dysfunction (t1/2 may be increased)
Adverse drug reactions or management of toxicity (how long will drug take to be removed and symptoms to resolve)
Short t1/2 increases risk of discontinuation/withdrawal symptoms (such drugs may need dose weaning on cessation)
at what point do we consider a drug to be clinically cleared from the body?
after 5X the half life of the drug
outline characteristics of STAT doses
Single or STAT doses: useful in treating acute conditions
Effects will usually wear off after a few minutes - hours
Most drugs require repeated dosing for a more prolonged therapeutic effect
Continuous IV infusion
Repeat IV dosing
define steady state, Css and time to Css
Steady state = rate of drug input is equal to rate of drug elimination
Css = drug plasma concentration at steady state
Time to Css = 5 x t1/2 (after treatment initiation and after a dose increase)
what effects on Css and time to Css would a 50% reduction is dosage on continuous IV infusion have
50% dose reduction leads to 50% reduction in Css
Time to Css is unchanged (as the t1/2 remains the same)
what is the therapeutic window?
Aim for Css which lies between the Maximum safe concentration (MSC) and minimum effective concentration (MEC)
what is the difference between first-order kinetics and zero-order kinetics
first order kinetics:Definition: The rate of drug elimination is proportional to the concentration of the drug in the plasma.
Zero-Order Kinetics:
Definition: The rate of drug elimination is constant and independent of the plasma drug concentration.
give some examples of when continuous IV infusion would be used.
Critical care patients
Antibiotics
Unfractionated heparin
General anaesthetics
how do the Cmax and Tmax differ between single oral dose and single modified release oral dose
- modified has a lower Cmax because there is less absorption from the GI tract
- increased Tmax because of this slower absorption
what is T12
- the time taken for plasma drug conc to fall to 50%
- used mainly in IV administer
define pharmacogenomics.
‘The use of genetic and genomic information to tailor pharmaceutical treatment to an individual.’
how do genomic variations effect pharmacodynamics?
- variations in drug receptor
- variations in efficacy (‘on’ targets)
- increased incidence of adverse drug reactions (ADRs) (‘on’ and ‘off’ targets)
how do genomic variations effect pharmacokinetics?
- variations in drug metabolism (eg CYP450 enzymes)
- genetic mutations in drug receptor cause for inefficient binding - variations in efficacy
- increased incidence in adverse drug reactions due to lack of CYP enzymes and HLA-B variants causing hypersensitivit reactions
what are the different routes that drugs can be excreted?
- Renal (Kidneys):
Through urine via glomerular filtration, tubular secretion, and tubular reabsorption. - Hepatic (Bile and Feces):
Excreted into bile or directly into feces.
May undergo enterohepatic recycling. - Pulmonary (Lungs):
Exhalation of gaseous or volatile substances. - Sweat:
Excreted through sweat glands. - Saliva:
Diffusion into salivary secretions. - Breast Milk:
Secretion during lactation.
Other Minor Routes:
Tears.
Hair.
Skin.
describe the graph of single dose IV administration
Key Characteristics:
Immediate peak concentration: Drug enters directly into the bloodstream, bypassing the absorption phase.
No lag time: Rapid onset of action as the drug is immediately available for distribution.
Exponential decline: The plasma concentration decreases over time due to distribution to tissues and elimination (metabolism and excretion).
Phases:
Distribution Phase: Initially, the drug rapidly moves from the bloodstream to tissues.
Elimination Phase: A slower decline in plasma concentration as the drug is metabolized and excreted.
Graph Shape:
A sharp spike at the time of administration, followed by a biexponential or monoexponential decline depending on the drug’s pharmacokinetics.
describe the graph of a single dose oral administered drug and name factors which effect this.
Lag phase: A delay before the drug appears in the plasma due to absorption from the gastrointestinal tract.
Gradual rise to peak concentration: The rate of drug absorption exceeds the rate of elimination during this phase.
Peak plasma concentration (Cmax)
Reached when absorption rate equals elimination rate.
Decline phase: Plasma concentration decreases as elimination exceeds absorption.
Factors Influencing the Curve:
Absorption rate: Slower absorption results in a delayed and lower Cmax
.
Bioavailability: The fraction of the oral dose that reaches systemic circulation affects the overall plasma concentration.
First-pass metabolism: Oral drugs may undergo significant metabolism in the liver before reaching the bloodstream, reducing plasma levels.
Graph Shape:
An ascending curve leading to Cmax, followed by a descending curve as elimination predominates.
compare the difference in graphs with single oral dose and modified release dose.
Key Characteristics:
Slower absorption phase: Drug release is controlled over an extended period, leading to gradual absorption into the bloodstream.
Reduced peak concentration: The peak plasma concentration is lower than with a single oral dose, minimizing the risk of toxicity.
Prolonged therapeutic effect: Maintains plasma levels within the therapeutic window for a longer duration, reducing the need for frequent dosing.
Smoother curve: Avoids the “peaks and troughs” associated with single oral dosing.
Graph Features:
A gradual rise in plasma concentration with a lower Cmax
-increased Tmax
.
A plateau-like phase where plasma concentration is maintained within the therapeutic range for an extended period.
A slower decline as the drug is released and eliminated gradually.
outline the characteristics of a single IV dose
Key Characteristics:
Immediate peak concentration: Drug enters the bloodstream directly, achieving 100% bioavailability instantly.
No absorption phase: Bypasses the gastrointestinal tract and first-pass metabolism.
Rapid decline: Plasma concentration decreases exponentially due to distribution into tissues and elimination.
Short duration of action: Drug levels quickly fall below the therapeutic range, requiring frequent dosing for sustained effects.
Graph Features:
Instantaneous spike in plasma concentration (C
m
a
x
max
).
Rapid, exponential decline due to distribution and elimination.
No lag or absorption phase.
contrast single IV dose 100% with single IV dose 50%
- 50% Css reduction
- time to Css is the same
contrast continuous IV infusion and reduced clearance continuous IV infusion
Continuous IV Infusion (Standard Clearance):
Gradual increase in plasma concentration over time, reaching steady-state after several half-lives.
Plasma levels remain at a normal steady-state concentration.
After stopping the infusion, plasma concentration declines exponentially based on normal clearance.
Reduced Clearance Continuous IV Infusion:
Slower rise to steady-state due to slower drug elimination.
Reaches a higher steady-state concentration.
After stopping the infusion, the plasma concentration declines more slowly due to the reduced clearance rate.
- reduced cl - increased time to cl
- time to css inc
- css inc
- dose reduction required
what can be used to speed up the time to steady state and why would we want to do this?
Waiting to reach steady state may be detrimental
A loading dose will speed up time to steady state
outline some key points about loading dose
Purpose: To reach the therapeutic plasma concentration quickly.
Administration: Often much larger than the regular maintenance dose.
Time to Reach Steady State: Reduces the time it takes for the drug to reach therapeutic levels, especially when the drug has a long elimination half-life.
Maintenance Dosing: After the loading dose, smaller, regular doses are given to maintain steady-state levels.
Outline how pharmacogenomics can support safe and effective prescribing, for example with opioid use.
- variations in CYP enzymes effect metabolizers
- can be used to see peoples levels of metabolism so we can alter dosage
- if it means unsafe or ineffective administration, can administer different drug
- reduce side effects
- reduce dependancy
outline the different effects that pharmacogenomics has on pharmacokinetics vs pharmacodynamics.
pharmacokinetics - ADME
- genetic differences in the transporters and enzymes can all effect how the drug is absorped, distributed, metabolised and excreted
pharmacodynamics
- Genetic polymorphisms in drug targets or downstream signaling pathways affect the drug’s ability to elicit its intended effect.
define half-life
The half-life (t1/2) of a drug is the time it takes for the concentration of the drug in the bloodstream to decrease by half.
