Pharmacokinetics Flashcards
Define pharmacokinetics
What are the 4 categories of pharmacokinetics
Pharmacokinetics is the study of the way in which the body handles administered drugs.
Absorption
Distribution
Metabolism
Excretion
Draw the graphs on one set of axes that represent the relationship between drug concentration and time for any drug administered: Oral, IV and inhaled, Assuming first order kinetics.
X-axis - time
y- axis - [Drug]
- Oral
Gut –> Vein –> Liver –> Vein –> Heart –> Lungs –> Heart –> Aorta –> target organ - IV
Vein –> heart –> lungs –> heart –> aorta –> target organ - Inhaled
Lungs –> heart –> aorta –> target organ
Cmax 3 > 2 > 1 (highest to lowest)
Tmax 1 > 2 > 3 (slowest to fastest)
Differentiate first and zero order kinetics.
Draw the graph illustrating first and zero order kinetics
Give classic examples of drugs removed by first and zero order kinetics
FIRST order: a constant PROPORTION of drug is eliminated per unit time. E.g. Gentamicin
ZERO order: a constant AMOUNT of drug is eliminated per unit time. E.g. Alcohol
First order kinetics is a concentration-dependent process (higher the conc. the faster the clearance), whereas zero order kinetics is independent of concentration.
What is Michaelis Menten kinetics
Michaelis-Menten kinetics describes enzymatic reactions where a maximum rate of reaction is reached when drug concentration achieves 100% enzyme saturation
What is non-linear elimination kinetics. Give the classic example of a drug cleared by Non-linear elimination kinetics
This is the term which describes drug clearance by Michaelis-Menten processes, where a drug at low concentration is cleared by first order kinetics and at high concentrations by zero order kinetic. E.g. Phenytoin..
At low concentrations the more substrate you give the faster the reaction rate. At high concentrations, the rate of the reaction remains the same because all the enzyme molecules are “busy”, i.e. the system is saturated.
What is the Michaelis-Menton Equation
V = Vmax x S
_________
Km + S
V: Velocity of the reaction
Vmax: Maximum velocity of the reaction
S: Drub (Substrate) concentration
Km: Substance concentration at 50% of Vmax
See graph on deranged physiology website
Use a graph to apply Michaelis-Menton elimination kinetics to the concept of therapeutic index
See deranged physiology website
X - axis: Dose
Y - axis: Drug concentration at steady state
Define volume of distribution
The apparent volume of plasma into which a drug appears to distribute. It is a theoretical volume that can substantially exceed the total body volume or potentially be infinite in size.
Vd = Dose of drug / [ Measured Plasma concentration ]
Usually expressed in L/kg
What are the clinical uses of volume of distribution
- Loading dose calculations
- ? clearance by dialysis easily
- Used retrospectively to estimate the magnitude of a drug overdose
What are the drug properties that affect volume of distribution
The drug properties that influence protein binding and tissue binding
- Molecular size
- Charge
- pKa
- Lipid/water partition coefficient
What are the patient factors that affect volume of distribution
- Age
- Gender
- Body muscle/fat proportion
- level hydration
- Water distribution (oedema/effusions/ascites/pregnancy)
- Extracorporeal sites of distribution
(Circuit / filters / oxygenator etc.)
Define context sensitive half time
CSHT (Context sensitive half time) is the time required for the plasma concentration of an INFUSED drug to fall to half the concentration when the infusion was stopped.
It is not a number but rather a function of the duration of drug delivery, which is the ‘context’
For drugs described by 1 compartment models, the CSHT is the same as the half-life (e.g. there is no ‘context’ because the duration of the infusion is not relevant). However, all anaesthetic drugs are described by multiple compartments
Why is context sensitive half time clinically useful
CSHT provides clinically useful guidance of the expected increase in the time required to eliminate the drug as a function of the duration of the drug administration
Draw the graph that represents the context sensitive half times of
Diazepam: 200 minutes at 1 hour
Fentanyl: 200 minutes at 5 hours
Thiopental: 200 minutes at 7 hours
Dexmedetomidine: 80 minutes at 7 hours
Midazolam: 70 minutes at 7 hours
Alfentanil: 60 minutes at 7 hours
Ketamine: 25 minutes at 7 hours
Sufentanil: 25 minutes at 7 hours
Propofol: 25 minutes at 7 hours
Etomidate: 10 minutes at 7 hours
Remifentanil: 5 minutes at 7 hours
Define clearance
Clearance is the efficiency of irreversible elimination of drug
The volume of blood cleared of drug per unit time
It is the proportionality constant between plasma drug concentration and elimination rate
How does drug elimination rate differ from drug clearance. How do these to entities affect first order and zero order kinetics
DRUG ELIMINATION RATE is the amount of drug cleared from the blood per unit time
CLEARANCE is the volume of blood cleared of drug per unit time
In first order kinetics
- Drug elimination rate is proportional to dose
- Clearance remains independent of dose
In zero order kinetics
- Elimination rate is constant
How is clearance related to drug elimination rate
Clearance = Elimination rate / Concentration
Is effect site concentration the same as plasma concentration
Effect site concentration is the concentration of the drug at the site of its biological activity, i.e. its receptors
Plasma concentration is the concentration of the drug in plasma.
These two entities may not be the same.
What determines the rate of onset of a drug
The rate of effect onset of a drug is determined by the distribution of a drug from other compartments (e.g. central compartment) into the effect site.
What is Keo
What is t1/2 keo
Equilibration between the central and effect site compartments follows first order kinetics, and is described by the constant Keo.
When the plasma concentration is at steady state the t1/2keo is the time taken to achieve 50% effect sit concentration
Why does the equilibration between the effect site compartment and the plasma compartment follow first order kinetics?
Because the rate of movement of the drug from the plasma compartment to the effect site is dependent on the plasma concentration. This will follow first order kinetics and is defined by the constant Keo.
What is a simple way to explain the difference between plasma concentration and effect site concentration
Propofol infusion –> plot values over time
EEG (to measure sleepiness –> plot values over time
Observe delay in ‘sleepiness’ as Propofol infusion reaches a steady plasma concentration. This is because the plasma compartment must equilibrate with the effect site compartment
Why is the relationship between the peak onset time and the t1/2 keo important
The slower the t1/2 keo, the larger the bolus dose required
What is a the mathematical equation that describes a single compartment model.
Describe how the components of this equation define the graph.
C = Co . e^-kt
C: Concentration Co: Concentration at time = 0 e: e (2.716....) k: the rate constant for elimination t: time
It is a washout curve:
k –> determines the steepness of the descent of the washout curve
Co –> determines the starting point on the y-axis of the curve.
What is the time constant for an elimination curve. What is the time constant’s relationship to the elimination rate constant (k) and the half life t1/2
The time constant (tau) is the time taken for the concentration of the drug in plasma to reduce by a factor of ‘e’ (2.716).
If the inititial elimination rate of the washout curve graph is extrapolated using a straight line into the time (x) axis, this is the time constant.
time constant = 1/k
time constant = t1/2 / ln 2 (ln2 = 0.693)
This means that time constant is 44% longer than the half life.
What is the definition of an exponential function
The rate of change of the function is proportional to the dependent variable
Define half life
What is the formula for half life
Half life is the time taken for the plasma concentration of a drug in the blood to halve.
Time constant = t1/2 / 0.693
Time constant = Vd/Clearance
t1/2 = (0.693 x Vd) / Clearance
How much of the drug is eliminated by: 1 x t 1/2 2 x t 1/2 3 x t 1/2 4 x t 1/2 5 x t 1/2
1 x t 1/2 - 50% 2 x t 1/2 - 75% 3 x t 1/2 - 87.5% 4 x t 1/2 - 93.75% 5 x t 1/2 - 96.875%
How will doubling the dose of a drug affect its duration of action
It should increase the duration by about 1 half life (because its clearance is a logarithmic function
How is the concept of half life applied to first order and zero order kinetics
In first order kinetics half life is constant regardless of drug concentration
In zero order kinetics half life becomes meaningless and one refers instead to a dose or concentration removed per unit time
Write down the equations for the following curves
Negative exponential curves
- Wash - out curve
- Washi - in curve
Positive exponential
1. bacterial colony growth
Wash-out curve
C = Co . e^-kt
C: Concentration Co: Concentration at time = 0 e: e (2.716....) k: the rate constant for elimination t: time
Wash-in curve
C = Css(1 - e^-kt)
Positive exponential –> bacterial colony growth
N = 2^t/d
N - number of organisms
t and d - time between consecutive cell divisions
How is the loading dose of a drug calculated
Loading dose = Vd x [Conc. Steady State]
____________________
Bioavailability
What factors influence bioavailability
- Route of administration
- Pharmaceutical preparation
- Physicochemical interactions
- Patient factors
- Pharmacokinetic factors
Which route of administration has the lowest bioavailability, in general?
Oral
How does pharmaceutical preparation influence bioavailability
Large particle size and significant protein binding –> delayed absorption
Small particle size and low protein binding –> faster absorption
What is an example of a patient factor that might influence absorption of drugs
Coeliac disease and other congenital and acquired malabsorption syndromes.
Trauma/Drugs could delay gastric transit time which will slow absorption of most orally administered drugs
Give an example of a pharmacokinetic factor that could reduce the bioavailability of a drug
First pass metabolism
What is the hepatic extraction ratio
The fraction of drug removed from the blood by the liver on each pass through the liver and it depends on 3 factors:
- Hepatic blood flow
- The uptake into hepatocyte
- The enzyme metabolic capacity
Give examples of drugs with a high hepatic extraction ratio
Propranolol
Opiates
Lignocaine
Which routes of administration avoid first pass metabolism
IV, IM, SC, Intranasal, transdermal, intrathecal, epidural, sublingual, buccal, nasal, rectal
Why are transdermal preparations of drugs produced? Give examples of drugs that are given by the transdermal route
Transdermal drugs are designed to produce slow, constant release of drug. This provides a steady plasma concentration without significant peaks and troughs. Also for when oral route not possible (e.g. non-compliant patient)
Topical effects
- EMLA
- Steroids
Avoid first pass metabolism
- Fentanyl
- Nitrates
- Hyoscine / scopolamine
- Oestrogen preparations
What factors influence transdermal absorption
lipid bilayers in the stratum corneum permit only highly lipid soluble substances
Lipid solubility
Blood supply
Surface area
Concentration of drug
What is the bioavailability of IM drug administration and what does this depend on
Approaches 100%
- regional blood supply
good areas: deltoid / gluteus and quadriceps
Describe the effect of particle size on the inhalational drug administration
Less than 1 micron –> reach alveoli –> systemic absorption and effects
More than 1 micron –> drug remains in upper airways and has local effects
What determines how a drug is distributed in the body?
Depends on:
ABILITY TO CROSS THE LIPID MEMBRANE BILAYER
- Lipid solubility
- Protein binding
- Ionisation
- Molecular size
Describe organs with high, medium and low blood flow
High (drugs distribute here first)
- brain
- heart
- lungs
- kidney
- thyroid
- adrenals
Medium (then here)
- Muscle
Low (lastly here)
- Fat
How does protein binding influence distribution in the body
Protein binding acts to hold the drug within the circulation to prevent movement into tissues.
Give examples of drugs that are extensively protein bound
Aspirin NSAIDS Sulphonamides Warfarin (97%) Anticoagulants Phenytoin (95%)
When are polar drugs able to cross the lipid bilayer
Only If there are fenestrations present.
What is the definition of a prodrug and give two examples
A prodrug is a drug that has no inherent activity but can be converted by the body into an active drug:
- Enalapril (–> enalaprilat active)
- Diamorphine (heroin… –> morphine + MAM - 6 active)
How are drugs metablised
Phase 1 - non-synthetic phase (Cytochrome P450)
- Oxidation
- Reduction
- Hydrolysis
Phase 2 - synthetic phase (Increases H2O solubility)
- Glucuronidation
- Sulphation
- Acetylation
- Methylation
- Glycination
List the important examples of drugs that do not undergo normal phase 1 metabolism by the cytochrome P450 system in the liver
- Adrenalin | Noradrenalin | Dopamine –> MAO
- Alcohol –> alcohol dehydrogenase
- Atracurium | Cisatracurium –> Hoffman degradation
- Esters –> Non-specific plasma esterases
- GTN –> Inactivated by gastric mucosa
- ACE:I –> metabolised in the lung
What is the difference between elimination and excretion?
Elimination: Amount of drug removed from the plasma per unit time and therefore includes both distribution and metabolism
Excretion: Amount of drug removed from the body per unit time.
Which substances are excreted in bile versus urine and describe the mechanisms for this excretion
Bile –> larger MW
Mechanism: secreted by hepatocyte into bile cannaliculi against concentration gradient. Requires ATP.
Urine –> smaller MW
Mechanisms:
1. Filtered at glomerulus (small, lipid insoluble, non-PB)
2. PCT secretion against conc. gradient (ATP)
3. DCT secretion down conc gradient (no-ATP)
What consideration would you need to take in a patient with renal disease with regards to drug dosing
Renally cleared drugs will last longer
Renal disease affects Vd (peripheral oedema) –> increasing Vd for hydrophilic drugs
So in renal disease might need to increase loading dose AND increase dosing interval.
What is meant by a ‘one-compartment’ model for drug distribution
Makes the assumption that when a drug is administered, it is all evenly dispersed within one body compartment in an exponential manner. Never occurs in clinical practice
Define an exponential function
A condition where the rate of change of a variable at any point in time is proportional to the value of the variable at that time.
Or
A function where the x variable becomes the exponent of the equation y = e^x
What is Euler’s number
Denoted ‘e’
Represents the numerical value 2.71828 and is the base of natural logarithms
Define drug clearance vs. drug elimination rate. how are these concepts related
Clearance is the volume of blood cleared of drug per unit time
Clearance is the proportionality constant between plasma drug concentration and elimination rate.
Drug elimination rate is the amount of drug cleared from the blood per unit time.
Elimination rate = Clearance (L/hour) x [Drug] (mg/L)
Clearance = Elimination rate (mg/hour)
___________________
[Drug] (mg/L)
How do Clearance and elimination vary between first order and zero order kinetics
Elimination rate
- In 1st order kinetics: Elimination rate is proportional to dose
- In 0 order kinetics: Elimination rate is constant
Clearance
- In 1st order kinetics: Clearance is dose independent
What is the extraction ratio
The clearance performance of an organ
Dimensionless term that describes the proportion of the substance removed from the blood by the act of being filtered through abovementioned organ.
E = 1 - Cv / Ca
If you know blood flow to the organ and extraction ratio you can estimate the contribution it makes to the total drug elimination from the body
How would you calculate the clearance of the drug if you do not want to collect buckets of urine
Collect blood samples at known intervals and relate (on a graph) the drug concentration to the administered dose.
Clearance = Dose / AUC Conc-time graph
How can clearance be used clinically for maintenance dose calculations?
Elimination rate = Clearance x [Drug]
(do a dimensional analysis)
Therefore, to maintain a specific [drug] then:
Elimination rate = Maintenance rate
Drug out = Drug in
From above,
Maintenance rate = Clearance x [Drug}
What is the elimination half life?
Elimination half describes the relationship between plasma concentration and time.
The half life is the time required to reduce the concentration of a drug by half
1 half life - 50% original value 2 half lives - 75% original value 3 half lives - 87.5% original value 4 half lives - 93.75% original value 5 half lives - 96.875% original value
What is the formula for half life
t1/2 = 0.693 x Vd / Clearance
When is the concept of half life applicable: 1st order or 0 order kinetics
1st order only
0 order –> concept of half life becomes meaningless as the drug is eliminated at a constant rate not a constant proportion
how is half life different to the time constant?
The time constant is the time that it would have taken for the plasma concentration to reach zero if the intial rate of elimination continued i.e. a straight line with the initial elimination gradient extrapolated down to the horizontal (or time) axis.
So the half time is the time taken for the plasma concentration to fall TO 36.8% of its original value
The half life is the time taken for the plasma drug concentration to drop by 50%
Half life = 0.693 x time constant
If no loading dose is given, how long will it take an infusion to reach steady state?
5 half lives
3 time constants
Why can some drugs be given as repeated doses when others must be given as an infusion
Drugs with wide therapeutic windows can be given as repeated doses.
some drugs have narrow therapeutic windows with the risk for toxicity high –> must be given as infusion.
When can the half life be used as the dose frequency
For drugs with a wide therapeutic range, as long as 50% drug concentration is still within the therapeutic window, then the half life can be used as the dose frequency
Draw tri-exponential decline characteristic of a three compartment model and label the graph
X-axis: Time
Y-Axis: Log e concentration
Phase 1 - steepest - distribution into C2 from C1
Phase 2 - less steep - distribution into C3 from C1
Phase 3 - Least steep - terminal elimination phase
Draw tangential line a (phase 1) intercepting y axis at A
Draw tangential line b (phase 2) intercepting y axis at B
Draw tangential line c (phase 3) intercepting y axis at C
tangential lines represent the rate constants (e.g. K12)
Rate constant = 1 / time constant
What is context sensitive half time?
When an infusion is given into the central compartment, it quickly moves into the second and then more slowly into the third compartment. When the infusion is stopped the drug will continue to move down its concentration gradient into these compartments. When equilibrium is reached, the only way of removing the drug from plasma is by metabolism and excretion (not distribution) i.e. the drug cannot move against its concentration gradient into the tissues.
Metabolism and excretion from the central compartment –> reduction in plasma concentration in the central compartment setting up a re-distribution concentration gradient from the peripheral compartments into the central compartment. This maintains the plasma concentration well beyond the end of the infusion.
The time taken for the drug concentration to fall by half at the end of the infusion which was designed to maintain a constant concentration is called the context-sensitive half life. The context is the length of the infusion
How do the plasma and effect site concentrations change during an infusion
Induction: [plasma] > {Cet]
Maintenance: [plasma] = [Cet]
Emergence: [plasma] < [Cet]
What are the specific indications for TIVA
- Hx severe PONV
- Long QT syndrome (QTc > 500 ms)
- Malignant hyperthermia risk
- ‘Tubeless’ ENT surgery
- Neurosurgery (limit intracranial volume)
- NMB disadvantageous (Myasthenia gravis)
- Anaesthesia in non-theatre environments
- Transfer of anaesthetised patients
- Day case surgery
- Trainee teaching
- Patient choice
What is TCI
Target Controlled Infusions
Computer controlled infusion pump that allows the anaesthetist set target plasma concentrations required for a certain effect: such as sedation or anaesthesia.
Microprocessor is pre-programmed with the 3 compartment model of propofol pharmacokinetics.
The pump continuously calculates the distribution and elimination of the intravenous anaesthetic agent - and successfully adjusts the infusion rate to maintain a predicted plasma drug concentration.
What is first order kinetics and why are the majority of drugs eliminated in this way?
In first-order kinetics a constant proportion of drug is eliminated per unit time, the the rate of elimination is proportional to the amount of drug present in the body.
That system cannot be saturated
The majority of drugs are eliminated like this because there is usually a relative EXCESS of enzymes compared with the substrate
What is zero order kinetics and give examples of drugs that undergo zero order kinetics at higher doses.
In zero order kinetics, a constant amount of drug is eliminated per unit time, so despite the plasma concentration of the drug, the same amount is eliminated per unit time.
The system can be saturated (enzymes)
So the enzymes become saturated and cannot be influenced by substrate concentration.
Several drugs at high doses will convert to zero order kinetics
- Phenytoin
- Thiopentone
- Salicylates
- Theophylline