Pharmacokinetics Flashcards
Isomer? two main types
isomers are molecules or polyatomic ions with identical molecular formulae — that is, same number of atoms of each element — but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
◦ Isomers do not necessarily share similar chemical or physical properties. Two main forms of isomerism are structural or constitutional isomerism, in which bonds between the atoms differ; and stereoisomerism or spatial isomerism, in which the bonds are the same but the relative positions of the atoms differ.
What is a chiral molecule
◦ Cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes
What is a stereoisomer?
is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space
Do stereoisomers share the same chemical properties? Exceptions? Physical properties?
◦ A chiral molecule or ion exists in two stereoisomers that are mirror images of each other, called enantiomers; they are often distinguished as either “right-handed” or “left-handed” by their absolute configuration or some other criterion. The two enantiomers have the same chemical properties, except when reacting with other chiral compounds. They also have the same physical properties, except that they often have opposite optical activities.
Diastereoisomer
- Diastereomer - Diastereomers are stereoisomers not related through a reflection operation. They are not mirror images of each other
Enantiomer
- Enantiomer - Enantiomers, also known as optical isomers, are two stereoisomers that are related to each other by a reflection: they are mirror images of each other that are non-superposable
Name 3 types of bonding between molecules
- Bonding - weak bonds re generally more selective as they require a precise fit for interaction
◦ Covalent
‣ Strong, not reversible under most biological conditions e.g. aspirin and cyclo-oxygenase therefore the effect persists after the agent is no longer detectable in the blood
‣ Only reversed by synthesis of new enzyme
◦ Electrostatic
‣ Common, vary from strong linkahges between permanently ionic molecuels to weaker hydrogen bonds and very weak induced dipole interactions e.g. Van der Waals forces
◦ Hydrophobic
‣ Weak and important for lipid soluble drugs with lipids on cell membranes
Define a weak acid
neutral molecule that can reversible dissociate into an anion (neg charge) and a proton e.g. aspirin
Define weak base
neutral molecule that can reversible for a. Cation (positively charged molecule) by combination with a proton
Define the law of mass action
- Rate of chemical reaction directly proportional to the product of the activities/concentration of the reactants
◦ Implies that for a chemical reaction mixture that is in equilibrium the ratio between concentration fo the reactants and products is constant
◦ Therefore the chemical potential of forward and backward reactions are equal
When is a weak acid lipid soluble? When is a weak base lipid soluble?
◦ Protonated of weak acid is neutral (lipid soluble) –> in acidic environemnt
◦ Unprotonated base is lipid soluble –> in basic environment
Use an equation to define pH
pH = pKa - log (protonated/unprotonated)
If pH is < pKa then what effect does this have on the H + A <-> HA reaction
it is positive
pH = pKa - log (protonated/unprotonated)
Therefore if pH is less than pKa then log (protonated/unprotonated) is positive
What is an amine compound? What does a primary/secondary/tertiary refer to
A large number of drugs are weak bases, most are aminecontinaing molecules
* the nitrogen of a neutral amine has 3 atoms associated with it plus a pair of unshared electrons
◦ Primary amine - 1 carbon + 2 H —> can bind a further proton
◦ Secondary amine - 2 carbons, 1 H —> can bind a further proton
◦ Tertiary amine - 3 carbons —> can bind a further proton
◦ Quaternary amine - 4th carbon nitrogen bond - permanently charged and no unshared electrons with which to bind a proton i.e. poorly lipid soluble
Ficks law of diffusion
What is the diffusion coefficient related to in ficks law of diffusion
How thick is a cell membrane?
10nm
What is the henderson hasselbach equation
pKa is
pH at which 50% of the drug is ionised
Compre unionised and ionised drugs
Define ion trapping. E.g.
Different degrees of ionisation fo the same substance on each side of a menbrane that separates fluids with a different pH –> basic drugs across the placenta
Define absorption
the extent to which intact drug is absorbed from the gut lumen into portal circulation - expressed as a fraction fo the dose (f (g))
Define diffusion
the movement of drug molecules down their concentration gradient across the cell membrane without using energy
What is active transport
- Movement of drug molecules against their concentration gradient across the cell membrane using energy
Give 3 key characteristics of facilitated diffusion
What is an example
facilitated diffusion
◦ Selective - although often not fully selective for the target agent so drugs can mimic these compounds to achieve transport
◦ Saturatable
◦ Inhibitible
example
- Amino acid or GLUT transporters in the gut or kidney
Define endocytosis
vesicles containing drug molecules are moved across the cell membrane into the cell by invagination
Define exocytosis
vesicles continuing drug molecules are moved outside the cell by incorporation of vesicles back into the cell membrane expelling contents
Give an example of endocytosis
- So large they can only enter cells by endocytosis which is trigger by a cell surface receptor —> engulfed by cell membrane, and carried into the cell by vesicle inside the membrane —> breakdown of the vesicle
- Responsible for B12 complexed with intrinsic factor
- SImilarly iron is absorbed this way with transferrin into Hb producing RBC precursors
What does zero order mean
- Absorption = zero order when rate is independent of the amount of the drug remaining in the gut e.g. when the rate is determined by the rate of gastric emptying or by a controlled release drug formulation.
Rate of absorption across membranes is proportional to (5)
- Molecular size - permeability coefficient (Grahams law)
- Concentration gradient - directly proportional
- Ionisation - pKa
- Lipid solubility
- Protein binding
Outline the effect protein bidning has on absorption across membranes
‣ Extent of protein binding only important if >90% protein bound, and small changes in bound fraction produce large changes in unbound drug
‣ In general the rate fo drug metabolism increases and amount of unbound drug is the same, however for a small amount of highly protein bound drugs where metabolic pathways are close to saturation the unbound drug concentration wil increase and possibly reach toxicity e.g. phenytoin
Outline the effect of lipid solubility on absorption
independent of pKa as it is quoted in the unionised for only
‣ Does not necessarily result in rapid onset of action e.g. alfentanilis 7x less lipid soluble than fentanyl yet more rapid onset of action owing to being less potent, small distribution volume and therefore initially greater concentration gradient between plasma and effect site
‣ Lipid solubility will affect the rate of absorption from the site of administration
Write a Henderson Hasselback equation for an acid and a base
Speed of onset of a drug is related to
- Concentration gradient - Potency and therefore dose
- Distribution volume
- Rate of absorption - see factors above
What drug pharmaceutic factors affect drug absorption
A. Physics chemical properties of the drug - solubility, molecular charge
B. Crystal size and form
C. Excipients
D. Special dosage forms - SR, enteric coated
E. pH - stomach and small intestine
What stomach and intestinal factors play into drug absorption (4)
What is first pass clearance
◦ First pass clearance - extent to which the drug is removed by the liver during its first passage into the portal blood through the liver to the systemic circulation
What is the fraction fo drug that escapes first pass metabolism called?
F(h)
1- hepatic extraction ratio
Bioavailability is
Mathematically
◦ Bio-availability = the fracrtion of unchanged drug reaching the system circulation following administration by any route in comparison to IV
‣ Dependent on absorption and first pass clearance (F =f(g) x f(h)) [hepatic enzyme activity, hepatic blood flow, drug uptake by hepatocytes)
What si the equation for bioavailability?
(F =f(g) x f(h)) [hepatic enzyme activity, hepatic blood flow, drug uptake by hepatocytes)
What is bioequivalence? What conditions must be met? Which type fo drugs are more likely to ahve this occur
‣ Two formulations of the same drug where extents and rates of absorption have no clinically important differences between effects either therapeutic or adverse
* Small differences can be important where low therapeutic ratio, or in instances of non linear kinetics
* Whereas large differences may not matter in high therapeutic ratios
* Generally requires 90% confidence interval of the AUC ratio is between 0.80 and 1.25
IM bioavailability usually?
75-100%
May be painful
SC bioavailability? Limiting factor to dosing?
75-100%
Smaller volumes than IM
May be painful
Rectal bioavailability
30-100%
Less first pass metabolism than PO
If a drug has first order elimination what graph can be used to calculate bioavailability
Area under the curve of the concentration vs time cruve
What can the area under the cruve of the concentration vs time curve be used to calcualte?
Bioavailability
Only if the drug has first order kinetics
What would too hydrophilic be a problem for absorption
Cannot cross cell membrane
Why would too lipohilic be an issue for absorption
Cannot cross the water layer adjacent to the cell to be absorbed into the blood stream
What is a reverse transporter reducing systemic absorption
P glycoprotein
Bioavailability fraction is an outcome of the multiplication fo which 3 factors
Fraction absorbed x fraction remaining after mucosal metabolism x fraction remaining after liver metabolism
How do you measure oral bioavailability?
Area under concentration time curve in comparison to IV if first order clearance
AUC of an IV curve =
Dose/clearance
If a drug doesn;t have first order clearance how else might you figure out bioavailability?
◦ Compare urinary recoveries of the drug or metabolite after IV or oral doses
◦ Measuring steady state concentrations during IV and oral dosing
Define first pass clearance
- Definition: the extent to which the concentration of a drug is reduced after its first passage through an organ typically the liver before reaching systemic circulation
◦ Organs include: GIT, lungs, vascular endothelium
What is the ratio of IV to PO morphien
3:1
What is the extraction ratio?
Mathematically
◦ The fraction of drug removed from systemic circulation by an organ during each pass through the organ
◦ Bioavailability = fraction absorbed x (1 - ER)
What factors determine extraction ratio
- Liver blood flow
- Uptake into hepatocytes
- Enzyme capacity - Michaelis constant - concentration fo the substrate at which enzyme is working at 50% of capacity
What is Michaelis constant
Michaelis constant - concentration fo the substrate at which enzyme is working at 50% of capacity
What is the name of the term for when concentration fo the substrate at which enzyme is working at 50% of capacity
Michaelis constant -
Low hepatic extraction ratio drugs have what consequences
- Bioavailability = absorption. Therefore as long as well absorbed all good e.g. theophylline
Even doubling or halving the minor proportion has little impact on bioavailability
High hepatic extraction ratio drugs include e.g.?
What effect does inhibiting or inducing enzymes have?
verapamil
Has only a small effect on hepatic extraction ratio and on systemic clearance but has a mjaor effect on proportion escaping extraction and thus a major effect on bioavailability
Bioavailability of high hepatic extraction ratio drugs is highly dependent on?
‣ Bioavailability - highly dependent o enzyme activity; changes in hepatic blood flow do alter first pass clearance and bioavailability however also alter the systemic clearance the the two effects are in opposite directions therefore cancelling each other out
‣ Systemic clearance - mostly dependent on hepatic blood flow
What % of GTN is bioavailable?
1%
Which type of drugs are significantly effected in their bioavailability by enzyme activity
High extraction ratio drugs
ADv (3) Disadvantages (5) of oral routes of administration
- advantages
◦ Cheap, convenient,no pain on administration - Disadvantages
◦ EMesis, drug destruction by digestive enzymes, drug destruction by gastric acid, metabolism by GI bacteria, lowest bioavailability
What is the limiting layer to TD absorption
Stratum corneum
Factors affecting systemic absorption for TD dosing
Lipid solubility
MW
pH
Local histamine release
Reginoal blood flow
Skin thickness
Advantages 5 and disadvantages 5 to TD dosing
Epidural dosing
- SPeed of onset related to?
- What increases unionised fraction for LA
- Duration of block depends on?
- Speed of onset determined by proportion of unionised drug available to penetrate the cell membrane
- Local anaesthetics are bases - pKa >7.4 therefore predominantly ionised at physiological pH; those e.g.lidocaine with a low pKa are less ionised and onset of block faster
- Adding sodium bicarbonate increases the unionised faction reducing the onset time
- Duration of block depends on tissue binding - bupivocaine longer
- Adding vasoconstrictor reduces loss of LA from epidural space prolongingin duration of action
Benefits of intrathecal dosing
Rare systemic side effects as little reaches systemic circulation
Factors affectingdistribution and tissue uptake of drugs
- Usual 5) + 3
- Molecular weight
- Lipid solubility
- Ionisation
◦ PKa of drug
◦ PH of tissue - Concentration gradient
- Protein binding
- Regional blood flow
◦ Vessel rich group - Brain, heart, kidney, liver, endocrine organs
◦ Muscle group
◦ Fat group
◦ Vessel poor group - hair, bones, teeth, cartilage - Tissue mass
Volume of distrbiution definition
the theoretical volume into which a drug would need to be distributed following its administration to produce a desired plasm concentration
Main determinant of volume of distrbiution
Strength of bdining of the drug to tissue compartments as compared with plasma proteins
Molecular seize - large molecules excluded from cells
Equation for Vd
Vd = amount of drug in the body/ concentration in the plasma
V = plasma volume + [(fraction unbound in plasma)/fraction unbound in tissue] x tissue volume
Main determinant being frction unbound in tissue
Can Vd be greater than the body composition volume
V is an apparent volume, it can vastly exceed any physical volume in the body because it is the volume necessary t the contain the amount of the drug homogenously at the concentration found in the blood, plasma or water - therefore if higher than body composition it is led tightly in tissues
Factors affecting Vd 8
- Drug factors
◦ MW
◦ Lipid solubility
◦ Ionisation
◦ Protein binding
◦ Tissue binding outside plasma - Patient factors
◦ Age
◦ Pregnancy
◦ Disease
How is Vd calculated
Measurement
* Using a one compartment model a known dose of a drug is given at time 0
* Blood samples collected and concentrations measured
* Semi logarithmic plot is draw and plasma concentration at time 0 is extrapolated back to the y axis
* Then using Vd = dose/concentration at time 0
What is a loading dose? Explain using a diagram why this might be useful? What is the equation for calculation?
◦ If we just start with maintenance dosing it takes time for drug concentration to accumulate to steady state —> V determines loading dose
◦ E.g. if you want 10mg/mL in blood but the volume of distribution is 20L then you need 200mg loading dose
Loading dose calculation
It is worth noting that all A, B and D reach steady state at the same time
Drug distribution rate depends on
Blood flow to target tissue
Using a drug as an example explain drug redistribution and onset of action to a taregt tissue
‣ E.g. digoxin takes a long time to diffuse into the muscle of the heart (at least 4-6 hours until full effect i.e. oral and IV dose equivalence, and concentrations during this period have no relationship to effect, instead measure concentrations >6 hours after), however diazepam very quickly reaches the brain. Where extended duration between dose and redistribution the effect can be increasing as blood concentration is decreasing
‣ Diazepam and digoxin however have the same redistribution characteristics(over 4-6 hours) however because the target organ is better perfused in diazepams case the redistribution to effect site results in quicker onset of action
‣ They even have similar half lives of 1-2 days
What problems can you face with a loading dose
◦ Concentrations are high initially following initial dose or loading dose in compartments exposed to high blood flow —> this may produce toxic effects temporarily. This may require a slower loading dose or a intermittent loading dose schedule
Where redistribution is slower than the onset of significant side effects at unintended tissues
What are key factors with penetrating the BBB
- Methods of molecular transfer
◦ Passive diffusion - lipid soluble, low molecular weight, uncharged drugs e.g. Inhaled and IV anaesthetics
◦ Facilitated diffusion
◦ Active transport - glucose and hormones - Methods of preventing transition
◦ ABC transport protein - protect the brain from toxins, antibiotics and cytotoxic
◦ Enzymes e.g. monoamine oxidase
Excretion vs elimination
Excretion is removal from the body
Elimination is removal from the plasma
What processes contribute to elimination
Distribution, metabolisma dn excretion
Define clearance
- Describes the rate/efficiency of irreversible elimination from systemic circulation
The volume of drug cleared per unit of time
Volume used can be blood, plasma (convention) and unbound in water
Elimination rate equation
Elimination rate (mg/hr) = clearance x concentration
Clearance = Equation
Rate of elimination / concentration
Rate of elimination/concentration =
Clearance
Rate of elimination / clearance =
Concentration
Clearance x concentration =
Rate of elimination
Extraction ratio = (equation)
1 - (concentration out/concentration in)
Clearance is determined by which 2 factors
Blood flow
Efficiency of irreversible extraction (extration ratio)
E(H) stands for?
Extraction ratio
Maximum extraction is
Blood flow that enters an organ
Clearance aggregate if multiple sites =
Clearance systemically = rate of elinination in that organ/ concentration + rate of elimination in next organ/concentraiton etc etc
How do you calculate rate of elimination?
Dose / AUC of a the concentration time curve (this is elimination)
Only if first order elimination
What is mixed order kinetics?
Saturatable
Dose or concentration dependent elimination
Rate of elimination related to Vmax is?
Km relationship to rate of elimination
Vmax x C / (Km + C) =
Rate of elimination
What is Km
Drug concentration at which rate of elimination is 50% of Vmax
VMax is
Maximum eliminiation capacity
Rate of elimination equation (not clearance x concentration)
What drugs have important capacity limited elimination
At concentrations high relative to Km the elimination rate is almost independent of concentration - pseudo-zero order elimination. This problem of capacity limited elimination is important for aspirin,phenytoin and ethanol. CLearance has no real meaning for these and AUC should not be used to describe the elimination of these drugs
At hihg concentrations relative to Km what occurs to elimination?
At concentrations high relative to Km the elimination rate is almost independent of concentration - pseudo-zero order elimination. This problem of capacity limited elimination is important for aspirin,phenytoin and ethanol. CLearance has no real meaning for these and AUC should not be used to describe the elimination of these drugs
Flow dependent elimination describes what type of drugs?
High extraction drugs
How do you achieve steady state drug concentration (Css)
Maintenance dose rate(mg/hr) / clearance (L/hr)
How is clearance related to steady state drug concentration
Maintenance dose rate = clearance x steady state drug concentration
What happens to clearance if steady state halves
doubles
Clearance equation
U X V / P
U X V / P =
Excretion has what relationship to clearance?
Excretion = clearance x concentration
What curve can be used to find clearance?
Clearance = dose / area under the curve
What is a blood plasma concentration ratio? Equation? Significance?
What is the main risk of just giving increased oral doses if someone has high first pass clearanace?
- Adequate oral administration can overcome first pass clearance
◦ The risk being increased metabolites
◦ In some drugs e.g. lidocaine they are toxic
◦ Metabolite concentration will therefore be much higher than if given IV
What are some drugs with very high hepatic extraction ratios? What other characteristic do you have to be mindful of in high hepatic extraction ratio drugs?
lidocaine, isoniazid, morphine, propranolol, TCAs
◦ This leads to marker variation between individuals as well
◦ Bypassing hepatic sites of elimination e.g. in hepatic cirrhosis with portosystemic shunting will result in substantial increases in drug availability whereas there is less variation in drugs with low extraction ratios
Liver extraction ratio =
Clearance liver/flow
What is hepatic blood flow
90L/hr for a 70kg person
1500ml/min
Systemic bioavailability =
Give the equation
What are some drugs with low hepatic extraction ratios
chlorpropamide, diazepam, phenytoin, theophylline, tolbutamide, warfarin
Equation for extraction ratio
Liver extraction ratio
How would you relate liver intrinsic clearance to bioavailability?
What significance does protein binding have to extraction ratio
◦ The ability fo the drug to be removed in most cases dependent on the amount of drug free and therefore how tightly it is bound to proteins and cells
◦ In general only the drug free is available to diffuse into liver cells
◦ The exception being drugs very highly extracted from the liver
Simplify the clearance equatino for a low enzyme activity case
Simplify the clearance for a high enzyme clearance case
Capacity dependent elimination refers to?
In very low enzyme activity cases clearanace becomes proportional to only?
Degree of protein binding AND actviity of drug metabolism enzymes
No relationship really to liver blood flow, capacity limited
Perfusion dependent liver elimination depends on?
Liver blood flow
How does protein binding affect a high hepatic extraction ratio drug?
For each of the below five high clearance heptically or low
- Morphine
- Paracetamol
- Lignocaine
- Phenytoin
- Diazepam
- Propano9lol
- Theophylline
- Warfarin
- GTN
Renal clearance is made up of which 3 processes? What is the equation for renal clearance?
Glomerular blod flow per minute is? Filtration fraction?
How do you therefore relate filtration of a drug to this?
1200mL/min
10% –> GFR 120mL/min
Overall renal clearance equation is
What does first order kinetics mean? Draw a diagram? mathematically how is this graph described? How would you describe elimination over time? e.g.? Common?
- The rate of drug elimination at any given time is directly proportional to its plasma concentration at that time
- Creates a negative exponential process
- Constant PROPORTION of drug is eliminated per unit of time
- Most drugs undergo this pores
◦ Elimination system exceeds the substrate
◦ Examples - propofol, opioids - If elimination becomes saturated first order kinetics may convert to zero order kinetics
◦ E.g. phenytoin, thiopental
What does this graph express
- The rate of drug elimination at any given time is directly proportional to its plasma concentration at that time
- Creates a negative exponential process
- Constant PROPORTION of drug is eliminated per unit of time
Draw a graph representing zero order kinetics
What does this graph represent
zero order kinetics
Concentration at any time in a singel compartment model is reflected by waht equation?
What relationship does time have to concentration in single compartment first order knietics models
Draw a single compartment model diagram
Draw a diagram demonstrating a 2 compartment model and label it
Draw a graph representing concentration vs time for a 2-compartment model?
In a two compartment model there are two phases, what are they denoted as and what do they represent? What is point A, B and AB on a concentration vs time graph??
A = the y interceptor line a, can be used to determine half life of alpha
◦ Distribution half life
◦ Represents mostly rapid distribution
B - the y intercept of line b
◦ Can be used to determine half life of Beta
‣ Elimination half life
‣ Represents mostly elimination from the body
What equation descirbes concentration in a two compartment model?
C = drug concentration in central compartment
A = the y interceptor line a, can be used to determine half life of alpha
◦ Distribution half life
◦ Represents mostly rapid distribution
B - the y intercept of line b
◦ Can be used to determine half life of Beta
‣ Elimination half life
‣ Represents mostly elimination from the body
alpha - the slope of line a
Beta - the slope of line b
Alpha and beta are rate constants for these processes
Describe the meaning and significance of each point on the graph
C = drug concentration in central compartment
A = the y interceptor line a, can be used to determine half life of alpha
◦ Distribution half life
◦ Represents mostly rapid distribution
B - the y intercept of line b
◦ Can be used to determine half life of Beta
‣ Elimination half life
‣ Represents mostly elimination from the body
alpha - the slope of line a and the distribution phase, a rapid exponential phase
Beta - the slope of line b - slow exponenital phase with rate constant beta representing terminal eliminiation from the centrla compartment
Alpha and beta are rate constants for these processes
Draw a 3 compartment model diagram
How would express concentration at any time based on a 3 compartment model
What is the half life quation
Because this is an exponential (logarithmic) process the time taken or a twofold decrease would be proportional to the natural logarithm of 2. The constant 0.7 is an approximation of this.
How does 0.7 factor into a half life equation?
Because this is an exponential (logarithmic) process the time taken or a twofold decrease would be proportional to the natural logarithm of 2. The constant 0.7 is an approximation of this.
What is k
elimination rate constant
Expressed as a proportion of the drug eliminated per unit of time from the body
units = per hour
How does half life related to k
What is the concentration vs time equation
- Ct = concentration at various times (t)
- C0 = initial concentration at time 0
- K is the elimination rate constant
◦ Expresses the proportion of the drug in the body eliminated per unit of time
◦ Units = per hour
◦ This relates to half life as such:
K is related to Cl and Vd how?
What is the equation for T1/1 beta? What does this represent
The time required for the amount of drug in the body to fall by 50%
Draw a concentration vs time graph representing 1 hlaf life dosing at steady state, same amount of drug but given over 2 half lives (i.e. double the dose half as often), SR preparation with double the half life doses at 2 half lives
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Show the proof for the determinants of steady state concentration in Low hepatic clearance drugs being given IV
Low hepatic extraction - dependent on intrinsic clearance via systemic clearance for unbound drug concentration, and additionally fraction unbound for total concentration
Show the proof for the determinants of steady state concentration in High hepatic clearance drugs being given IV
High hepatic extraction - dependent on hepatic blood flow only for unbound drug concentrations, and hepatic blood flow and fraction unbound for total concentration
Demonstrate how the determinants of steady state are related to hepatic extraction ratio for oral drugs
- What determines low hepatic extraction ratio drugs
- What determines high hepatic extraction ratio drugs
Low and high hepatic extraction - dependent on intrinsic clearance via systemic clearance for unbound drug concentration, and additionally fraction unbound for total concentration
How do you determine steady state for non linear pharmacokinetics
COmpare the context sensitive half time of remifentanyl, propofol, alfentanil, fentanyl and thiopental
Why would you plot percent of maximal effect vs drug concentration gloraithmically?
- Curves are often replotted on a logarithmic axis because the part of the curve between 20-80% of maximum effect is linear and this most often applies to the action fo the drug at therapeutic concentrations
◦ Increasing drug concentration above 80% maximal effect achieves very little in terms of extra therapeutic effects
◦ This curve is produced by measuring a continuous variable e.e.g BP, exercise induced tachycardia
◦ The curve is called a graded concentrations effect curve
What equation denotes drug effect as a function of its concentration
How would you draw a graph depicting a therapeutic window/
Draw a drug concentration vs effect graph representing delayed redistribution
Draw a drug concentration vs effect graph for acute tolerance/tachyphylaxis
How do you related Cmax at steady state to Cmax at first dose?
How do you determine extend of fluctuation in dosing over a dosing period
How do you compare dosing interval with half life?
How is oral dosing regimes different to IV dosing regimes?
- Slower absorption of oral doses smoothies the plasma concentration profile - fluctuations become less
- Dose reaching systemic circulation affected by bioavailability so steady state calculations need to take this into account
Talk through how you would determine a dosing regime for a substance? What values do you need?
All you need is clearance, target concentration
The Vd and half life aren’t really needed unless peak values cause toxicity or their is a floor of effect that is important as the mean concentration will be the same regardless of frequency
Explain single dose studies
Short time, less exposure to volunteeers
Clearance, Vd, half life the key factros
‣ Single dose to a group of subjects and take samples adequate to fully define the plasma concentration versus time curve * Clearance - AUC from zero to infinite measured, and dose vs AUC the only values required ◦ Clearance = IV dose / AUC ◦ AUC units = mg x hr /L ◦ The AUC is determined using a number of trapezoids and the area from the last data point C (last) to infinite time is calculated as C (last)/k where k is the elimination rate constant of the lowest elimination phase * Elimination rate constant ◦ The slope of -k of the terminal portion of the natural log (1n) transformed concentration versus time plot and the half life as 0.693/k * Volume of distribution can be calculated by:
