(PM3B) Pharmacokinetics Flashcards
What is the therapeutic window of a drug?
The drug level in blood
Between toxicity & poor therapeutic activity
What is Cmax?
Maximum concentration of a drug in the blood
What is Cmin?
Minimum concentration of a drug in the blood
Define bioavailability.
The fraction of an administered dose that reaches the bloodstream
F - symbol in an equation
How is bioavailability determined?
(1) Blood sample taken from patient
(2) Blood cells are centrifuged out
(3) HPLC used to measure drug conc. in plasma
What is HPLC?
High performance liquid chromatography
What does a graph of drug plasma concentration over time indicate?
Absorption
How is absorption of a drug known?
Cp (plasma concentration) vs t (time)
Area under the curve
How can the absorption of IV and oral routes of a drug be compared?
Cp (plasma concentration) vs t (time)
Calculate and compare area under curve
What is the symbol representing bioavailability?
F
How is bioavailability of a route of administration calculated?
F(route) = AUC(route) / AUC(IV)
What does AUC refer to?
Area under curve
What does F refer to?
Bioavailability
What are the commonly used models for distribution?
(1) One compartment model
(2) Two compartment model
What is the one compartment model?
Model for distribution of a drug
Assumption that a drug is distributed in the body in a single homogenous department
Assumes perfusion to heart/ liver/ lungs from blood
What is the two compartment model?
Model for distribution of a drug
Central & peripheral compartments
Central: Blood/ heart/ lungs/ liver
Peripheral: Fat/ muscle/ skin
What does Vd refer to?
Volume of distribution
What is volume of distribution shortened to?
Vd
What is Vd?
Plasma drug concentrations related to total amount of drug present in the body
‘Apparent’ volume of distribution
How is blood plasma concentration calculated?
Cp = (Mass of drug in body) / Vd
Cp = (SxFxD) / Vd
How is Vd calculated?
Vd = (Mass of drug in body) / Cp
In a calculation, what is the mass of the drug in body for an IV injection?
Mass of the drug in the body = 1
How many litres of blood are there in the body?
Approx. 5L
What can be inferred from a volume of distribution (Vd) of greater than 5L? Why?
Drug has been distributed into tissues/ systems OTHER than the blood
How is IV loading dose calculated?
(Desired Cp) x Apparent volume of distribution
How is rate calculated?
Change in amount over time
What does K refer to?
Rate constant
What does n refer to, with regards to rate of reaction?
Order of the process
What is a zero order reaction?
When n=0
When is the rate of change constant?
When X^n = 1, because n=0
Is the rate constant negative or positive? Can that change?
Positive
Always positive
Is dX/dt negative or positive when X is diminishing?
Must be negative
(1) When is the rate constant accompanied by a minus symbol?
(2) Give an example.
(1) When X is diminishing
(2) When a drug is being eliminated from the body
(1) What can {Xt = X(0) - K(0)t} be written as?
(2) What does it mean?
(1) C(pt) = C(p0) - K(0)t
(2) For a zero order elimination, Cp at time t equals Cp at time 0, minus the zero order elimination rate constant multiplied by the time taken
What is the equation {Xt = X(0) - K(0)t} in the same format as?
y = mx + c
(1) If a Cp vs t graph is a straight line, what can be assumed?
(2) What information can be taken from this?
(1) Elimination is zero order
(2) Rate constant and Cp can be found at time zero
What does X represent?
Total amount of drug present in the body
If X is raised to the power of 1, what does this mean in terms of rate of reaction?
(2) What does this mean for the rate of reaction?
(1) First Order reaction
(2) Rate of reaction is not constant, because X is always changing
What does K(0) represent?
Zero order elimination rate
What does K(1) represent?
First order elimination rate
How is the drug concentration of the plasma at time (t) calculated?
Cp(t) = Cp(0)exp^{-K(1)t}
In an equation, what does ‘exp’ represent?
The exponential
(1) What does Cp(t) = Cp(0)exp^{-K(1)t} look like in logarithmic form?
(2) What is this equation used for?
(1)
lnCp(t) = lnCp(0) - K(1)t
(2) Calculating the drug concentration of the plasma at a time (t)
What assumption is made when a drug is injected IV, regarding a Cp vs t plot?
That 100% of the drug is present at t = 0
i.e. volume in body = volume injected
What format can the Cp vs t equations be rearranged to, to be used to calculate values given on the plot?
y = mx + c
What does it mean if a ln(Cp) vs t plot is a straight line?
Reaction (elimination) is first order
What does it mean if a Cp vs t plot is a straight line?
Reaction (elimination) is zero order
What assumption is made for Cp vs t plots of elimination rates?
Based on ONE compartment model
What order of elimination do most drugs undergo?
First order elimination
How are drugs eliminated from the body?
(1) Metabolism
(2) Excretion
What does KE represent?
Rate of elimination
What is the short-hand for rate of elimination?
KE
Is the rate of a zero order elimination dependent on Cp?
No, it is a constant.
When does zero order elimination most commonly occur?
When elimination pathways for a drug are saturated
Is the rate of a first order elimination dependent on Cp?
Yes. Proportional
What does a ln(Cp) vs t plot look like, using a TWO compartment model?
(1) 1st phase: Distribution and elimination
- ln(Cp) drops rapidly
(2) 2nd phase: Elimination ONLY
- ln(Cp) decreases at a slower rate
What occurs during the first phase of the curve of a ln(Cp) vs t plot?
- Drug is being distributed from central compartment to peripheral
- Drug is being eliminated from the central compartment
What occurs during the second phase of the curve of a ln(Cp) vs t plot?
- Central and peripheral compartments are at drug conc. equilibrium
- Drug is being eliminated from central compartment
What does ‘biliary’ mean?
Referring to bile or the bile duct
What are the main types of excretion?
(1) Kidneys -> Urine - primary route
(2) Biliary -> Faeces
What does ‘clearance’ refer to?
- Irreversible removal of a drug from systemic circulation by metabolism or excretion
- The volume of blood from which the drug is completely removed per unit of time
Where does clearance occur?
When blood flows through an organ of elimination
(1) Liver - metabolism
(2) Kidneys - excretion
Which organ is primarily associated with metabolism?
Liver
Which organ is primarily associated with excretion?
Kidney
How is the total clearance calculated?
CL(total) = CL(renal) - CL(non-renal)
Where does most non-renal clearance occur?
Metabolism in the liver
What is renal clearance?
Irreversible removal of a drug from the systemic circulation via excretion in the kidney
What is hepatic clearance?
Irreversible removal of a drug from the systemic circulation via metabolism in the liver
What are the units of clearance?
mL/ minute
OR
L/ hour
What equation is used to calculate first order clearance of a drug?
CL(s) = K(E)V(d)
Subscript (s) denotes systemic
Is drug clearance considered constant (first order)? Give a reason for your answer.
Yes.
Both K(E) and Vd are constants
In an equation, what does t(1/2) refer to?
Elimination half-life
What is elimination half-life {t(1/2)}?
Time taken for Cp to drop to Cp/2
e.g. 50mg/mL -> 25mg/mL
How is elimination half-life {t(1/2)} calculated?
t(1/2) = 0.693 / K(E)
What is the significance of 0.693 in an equation, relating to elimination?
It is the numerator for the equation used to calculate elimination half-life
What is the main reason a drug may be formulated as a salt or hydrate?
To increase solubility
What is the salt factor referred to as in short-hand?
S
What is the salt-factor?
The fraction of the administered dose that is the active pharmaceutical ingredient
How is the salt factor (S) calculated?
(Mr of API) / (Total Mr of drug)
How can blood plasma concentration be calculated?
Cp = (Total mass of drug in body) / Vd
Cp = (SxFxD) / Vd
What does ‘steady state’ refer to?
When the amount of drug administered in a given time is equal to amount of drug eliminated in the same given time
What is the steady state plasma concentration?
CpSS
How long does it take for a drug to reach steady state?
Depends on t(1/2), elimination half-life
When the amount of drug being absorbed = amount of drug being eliminated
(1) What is CpSS?
(2) How can it be calculated?
(1) Steady state plasma concentration
2
CpSS = (SxFxD) / (Clearance x dosing interval)
Define dosing interval.
The frequency of intermittent drug administration, based on elimination half-life {t(1/2)}
How does the time to steady state compare to the half-life?
Time to steady state is approximately equal to 5 half-lives
Does a higher dose affect the time taken to reach steady state?
No
What is steady state, with regard to a continuous IV infusion?
Rate of infusion is equal to rate of elimination
In an equation, what does ‘R’ refer to?
Rate of elimination
What is R / CL equal to?
CpSS (Blood plasma steady state)
How can time to steady state be decreased?
Administer a loading dose
What is the purpose of a loading dose?
To decrease time taken to achieve a steady state
What is the purpose of achieving a steady state quickly?
To achieve appropriate therapeutic effect faster
What is gentamicin?
Powerful antibiotic
Considered as last-resort
What is the oral bioavailability of gentamicin?
Approximately 0
(1) How is gentamicin administered?
(2) What dose is given?
(1) IV
(2) 5-10mg/ L
When is gentamicin indicated?
For serious bacterial infections
Define ototoxic.
Having a toxic effect on ear/ ear nerve supply
Define nephrotoxic.
Having a toxic effect on kidney - damaging or destructive
What are the adverse effects of an overdose of gentamicin?
(1) Ototoxicity - damaging ear/ ear nerve supply
(2) Nephrotoxic - damaging to kidney
What significance does 5 times the half-life have?
Time taken to reach steady state for a drug
What effect does increased dosing have on the peaks and troughs of plasma drug concentration?
Increases difference between peaks and troughs
Does NOT increase time taken to reach steady state
If a drugs half-life is 6.5hrs, how long can we assume it takes the drug the reach steady state in the blood plasma?
6.5 x 5 = 32.5hrs
What does TDM refer to?
Therapeutic drug monitoring
What is therapeutic drug monitoring written as in short-hand?
TDM
What is therapeutic drug monitoring (TDM)?
Optimising patient individual therapy using:
(1) Drug levels
(2) Pharmacokinetics
(3) Pharmacodynamics
What is TD50?
Median toxic dose
What is ED50?
Median effective dose
When is TDM used?
- Drugs with a narrow therapeutic range
- Drugs with a low therapeutic index
- Drugs where dose and effect are not strongly correlated
- Drugs with wide variance in patient clearance
What is LD50?
Median lethal dose
What should Cp be in practice?
Steady state
Takes about 5 times the half-life to reach this point
Do analytical methods distinguish between bound and unbound drug in blood plasma concentration? If so, which method(s)?
No.
Analytical methods give total Cp levels
Give no distinction
What is important when considering implementation of a second drug which interacts with the protein-binding of a strongly protein-bound first drug?
Increase in free (as opposed to protein-bound) will be PROPORTIONATELY significant
Likely to cause the patient a problem
What is important when considering implementation of a second drug which interacts with the protein-binding of a strongly protein-bound first drug?
Increase in free (as opposed to protein-bound) will be PROPORTIONATELY insignificant
Not likely to cause the patient a problem
What could cause a disproportionate rise/ increase in the blood plasma level of a highly protein-bound drug?
Saturation of protein binding sites
How are Vd and Clearance values determined?
From an average of the population
How do Vd and Clearance values differ for specific drugs in TDM?
(1) Begin with average population values
(2) Adjust for individual patients
How are Vd and Clearance values adjusted to be more specific for the patient?
(1) Patient CpSS (steady state) is measured
(2) Compare with expected average population values
(3) Adjust KE (rate of elimination) to better match drug clearance in individual patient
(4) Use patient-specific Clearance values for future dosing calculations
If the individual/ specific Clearance or Vd values vary significantly from the average values from the population, why could this be?
- Concurrent drug therapy (interaction)
- Compliance
- Medication error
- Malabsorption
- Incorrect assay results
Specific patient may be genuinely different from average population data
How can specific/ individual patient clearance be estimated PRIOR to waiting for steady state blood plasma concentration being achieved?
Blood sample taken
Measure of creatinine clearance
How is creatinine produced?
Creatinine is a breakdown product of creatine phosphate in muscles
Where is creatine phosphate broken down?
In muscles
What does creatine phosphate produce when broken down?
Creatinine
At what rate is creatinine produced?
Constant rate
Does creatinine protein-bind?
No
Is creatinine reabsorbed in the kidneys?
No, almost entirely not
What is creatinine clearance a useful measure of?
(1) Kidney function
(2) Predicted patient-specific drug clearance
(3) Approximation of actual glomerular filtration rate
How can actual glomerular filtration rate be approximated?
Measurement of creatinine clearance
mg/mL
What is C(urine)?
Creatinine concentration in the urine
What is V(urine)?
Volume of urine collected in mL/min
What is C(plasma)?
Creatinine concentration in the plasma
mg/mL
What are the units for creatinine clearance?
mL/minute
Clearance has units of volume per time
What equation is used to measure creatinine clearance definitively?
CLcr = {C(urine) x V(urine)} / C(plasma)
What equation is used to measure creatinine clearance approximately?
Cockcroft-Gault equation
CLcr(est) = {(140-age) x Weight x Constant} / C(s)
In an equation, what does C(s) represent?
Serum creatinine
What is the constant used, for men, to calculate estimated creatinine clearance?
1.23
What is the constant used, for women, to calculate estimated creatinine clearance?
1.04
What is the significance of 1.23, regarding elimination?
Creatinine clearance
Constant (numerator) for MEN
What is the significance of 1.04, regarding elimination?
Creatinine clearance
Constant (numerator) for WOMEN
What is the Cockcroft-Gault equation?
CLcr(est) = {(140-age) x Weight x Constant} / C(s)
What is the Cockcroft-Gault equation used for?
Estimation of creatinine clearance for an individual
What happens to serum creatinine concentration as GFR decreases?
Increases
Less creatinine is being cleared
What drug categories is TDM used for?
(1) Antiepileptics
(2) Aminoglycoside antibiotics
(3) Cardiac drugs - e.g. digoxin, lidocaine
(4) Others - theophylline, lithium, methotrexate
What are anti-epileptics used for?
Treating/ prophylaxis of seizures
What are example(s) of the ‘old-style’ anti-epileptic drugs?
- Phenytoin
- Carbamazepin
- Sodium valproate/ valproic acid
What are example(s) of the ‘new-style’ anti-epileptic drugs?
Gabapentin
What is phenytoin?
An old-style anti-epileptic drug
(1) What is the therapeutic range of phenytoin?
(2) What happens if there is an overdose?
(1) 10-20mg/L
2
- Blurred vision
- Drowsiness
How significantly is phenytoin metabolised?
Heavily metabolised
Is phenytoin protein bound?
Yes. Highly protein bound
What is Vmax?
Reaction rate when binding site is fully saturated
Maximum rate of reaction
In an equation, what does V refer to?
Rate of reaction
In an equation, what does K(m) stand for?
Michaelis-Menten constant
How is the daily dose of a drug, such as phenytoin, calculated?
Daily dose = (Vmax x CpSS) / (Km + CpSS)
How is Vmax for a drug derived?
Calculated from population data
Population average for that specific drug
How is Km for a drug derived?
Calculated from population data
Population average for that specific drug
What is Km?
The substrate concentration when the rate of reaction is 1/2 of Vmax
What is the equation used to calculate steady state blood plasma (CpSS), with regard to daily dose?
CpSS = (Daily dose x Km) / (Vmax - Daily dose)
What is lithium indicated for?
- Acute mania
- Prophylaxis of manic depression
Describe the therapeutic window of lithium.
Narrow
0.4-1.2mmol/L
What is the effective dose for lithium?
Varies significantly from patient to patient
What are the effects of toxicity/ overdose of lithium?
- Blurred vision
- Drowsiness
- Confusion
- Palpitations
Define teratogen.
A factor which causes malformation of an embryo
Does lithium require therapeutic drug monitoring (TDM)?
Yes.
Because the therapeutic dose varies SIGNIFICANTLY in patients
Describe metabolism of lithium.
Not metabolised
Describe the excretion of lithium, relating to rate clearance.
First order elimination
Clearance approximates to 25% of creatinine clearance
How does the clearance of lithium compare to the clearance of creatinine?
Approximates to 25% of creatinine clearance
What can decrease the elimination of lithium?
- Decreased renal function
- Diuretics
- most NSAIDs
What can increase the elimination of lithium?
- Aminophylline
- OTC antacids
What is aminophylline?
A compound of theophylline
A bronchodilator
What formulations are available for lithium?
(1) Oral solids:
- e.g. lithium carbonate
(2) Oral liquids:
- e.g. lithium citrate
What is the therapeutic range of lithium, in mmol per litre?
0.4-1.2mmol/L
How much does 1mmol of lithium weigh?
Mr of lithium = 7
Therefore, 1mol = 7g, so 1 mmol = 7mg
What is the therapeutic range of lithium, in mg per litre?
2.8-8.4 mg/L
What is the salt factor for lithium carbonate?
Lithium carbonate = Li2CO3
0.19
Describe the therapeutic range of theophylline.
Narrow therapeutic range
5-15 mg/L
When is toxicity reached in theophylline?
> 20 mg/L
What are the symptoms of theophylline toxicity?
- Arrhythmias
- Seizures
Describe the inter-patient variability of theophylline?
Significant inter-patient variability
What was theophylline previously indicated for?
COPD
Why is theophylline no longer widely used for treatment of COPD?
There are now longer-acting inhaled agonists available
What is the most common formulation of theophylline?
Sustained-release
Describe the rate of elimination of theophylline?
First order elimination
What causes the significant variation in clearance of theophylline?
(1) Age
(2) Liver cirrhosis - decreases clearance/ elimination
(3) Cystic fibrosis - increases clearance/ elimination
(4) Co-medication
Describe the effect of liver cirrhosis on clearance/ elimination of theophylline.
Decreases clearance/ elimination
Due to reduced hepatic clearance - metabolism
Decreased by 40%
Describe the effect of cystic fibrosis on clearance/ elimination of theophylline.
Increases clearance/ elimination
Describe the effect of phenytoin on clearance/ elimination of theophylline.
Increases clearance/ elimination
Increased by 75%
Describe the effect of oral contraceptives on theophylline clearance/ elimination.
Decreases clearance/ elimination
Decreased by 30%
Describe the effect of acute pulmonary oedema on clearance/ elimination.
Decreased by 50%
Describe the effect of congestive heart failure on clearance/ elimination.
Decreased by 40%
Define congestive heart failure.
Fluid build up in the heart
Creates inefficiency of heart pumping
Describe the effect of liver cirrhosis on clearance/ elimination.
Decreased by 40%
Describe the effect of mild smoking on clearance/ elimination.
Increased by 50%
Describe the effect of heavy smoking on clearance/ elimination.
Increased by 100%
How do the effects of heavy smoking and mild smoking on clearance/ elimination compare?
Mild - Increase by 50%
Heavy - Increase by 100%
Define cystic fibrosis.
Condition where the lungs become filled with thick, sticky mucous
Describe the effect of propranolol on clearance/ elimination.
Decreased by 30%
Describe the effect of oral contraceptives on clearance/ elimination.
Decreased by 30%
Describe the effect of cimetidine on clearance/ elimination.
Decreased by 40%
What is cimetidine?
H2 receptor antagonist
Reduces stomach acid production
Describe the effect of carbamazepine on clearance/ elimination.
Increased by 50%
Describe the effect of phenytoin on clearance/ elimination.
Increased by 50%
Describe the effect of rifampicin on clearance/ elimination.
Increased by 50%
Why are biologics/ biomacromolecules not suitable for oral administration?
Broken down by proteases in the GIT
How are biologics/ biomacromolecules administered?
(1) IV - most common
(2) SC - leads to lymphatic system
(3) IM
How are biologics/ biomacromolecules distributed in the body?
Vascular space -> Lymphatic system
via interstitial tissue space
How does the volume of distribution (Vd) vary in biologics/ biomacromolecules?
8-20L
Define catabolism.
Metabolic pathway which breaks down molecule into smaller sub-components
Describe the elimination of biologics/ biomacromolecules.
Too large to be filtered by the kidneys
Usually reabsorbed in the kidney
Mostly eliminated via intracellular catabolism
(1) What are biologics/ biomacromolecules broken down into?
(2) How are they broken down?
(1) Constituent amino acids
(2) Intracellular catabolism
Describe the t(1/2) of a biologic/ biomacromolecule.
Typically very long half-life
Measured in days
What effect does the long half-life of biologics/ biomacromolecules have on dosing?
Long dosing intervals
What does ‘MAB’ refer to?
Monoclonal antibody
How is a monoclonal antibody abbreviated?
MAb
