pharmacokinetics in practice and intro to pharmacogenomics

Question 1

what is Cmax and Tmax

Answer 1

Cmax= maximum plasma concentration

tmax= time taken to reach Cmax

Question 2

what is clearance?

Answer 2

Clearance (CL) = removal of drug by all eliminating organs

Question 3

whats a modified release drug

Answer 3

one that requires less frequent dosing because its effects last a lot longer

Question 4

what is the half life of a drug dependant on

Answer 4

• 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

Question 5

why is it relevant to understand drug half lives when prescribing

Answer 5

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)

Question 6

at what point do we consider a drug to be clinically cleared from the body?

Answer 6

after 5X the half life of the drug

Question 7

outline characteristics of STAT doses

Answer 7

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

Question 8

define steady state, Css and time to Css

Answer 8

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)

Question 9

what effects on Css and time to Css would a 50% reduction is dosage on continuous IV infusion have

Answer 9

50% dose reduction leads to 50% reduction in Css
Time to Css is unchanged (as the t1/2 remains the same)

Question 10

what is the therapeutic window?

Answer 10

Aim for Css which lies between the Maximum safe concentration (MSC) and minimum effective concentration (MEC)

Question 11

what is the difference between first-order kinetics and zero-order kinetics

Answer 11

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.

Question 12

give some examples of when continuous IV infusion would be used.

Answer 12

Critical care patients
Antibiotics
Unfractionated heparin
General anaesthetics

Question 13

how do the Cmax and Tmax differ between single oral dose and single modified release oral dose

Answer 13

• modified has a lower Cmax because there is less absorption from the GI tract
• increased Tmax because of this slower absorption

Question 14

what is T12

Answer 14

• the time taken for plasma drug conc to fall to 50%
• used mainly in IV administer

Question 15

define pharmacogenomics.

Answer 15

‘The use of genetic and genomic information to tailor pharmaceutical treatment to an individual.’

Question 16

how do genomic variations effect pharmacodynamics?

Answer 16

• variations in drug receptor
• variations in efficacy (‘on’ targets)
• increased incidence of adverse drug reactions (ADRs) (‘on’ and ‘off’ targets)

Question 17

how do genomic variations effect pharmacokinetics?

Answer 17

• 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

Question 18

what are the different routes that drugs can be excreted?

Answer 18

• 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.

Question 19

describe the graph of single dose IV administration

Answer 19

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.

Question 20

describe the graph of a single dose oral administered drug and name factors which effect this.

Answer 20

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.

Question 21

compare the difference in graphs with single oral dose and modified release dose.

Answer 21

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.

Question 22

outline the characteristics of a single IV dose

Answer 22

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.

Question 23

contrast single IV dose 100% with single IV dose 50%

Answer 23

• 50% Css reduction
• time to Css is the same

Question 24

contrast continuous IV infusion and reduced clearance continuous IV infusion

Answer 24

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

Question 25

what can be used to speed up the time to steady state and why would we want to do this?

Answer 25

Waiting to reach steady state may be detrimental
A loading dose will speed up time to steady state

Question 26

outline some key points about loading dose

Answer 26

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.

Question 27

Outline how pharmacogenomics can support safe and effective prescribing, for example with opioid use.

Answer 27

• 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

Question 28

outline the different effects that pharmacogenomics has on pharmacokinetics vs pharmacodynamics.

Answer 28

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.

Question 29

define half-life

Answer 29

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.