1
Q
Isomer? two main types
A
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.
2
Q
What is a chiral molecule
A
◦ Cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes
3
Q
What is a stereoisomer?
A
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
4
Q
Do stereoisomers share the same chemical properties? Exceptions? Physical properties?
A
◦ 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.
5
Q
Diastereoisomer
A
- Diastereomer - Diastereomers are stereoisomers not related through a reflection operation. They are not mirror images of each other
6
Q
Enantiomer
A
- 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
7
Q
Name 3 types of bonding between molecules
A
- 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
8
Q
Define a weak acid
A
neutral molecule that can reversible dissociate into an anion (neg charge) and a proton e.g. aspirin
9
Q
Define weak base
A
neutral molecule that can reversible for a. Cation (positively charged molecule) by combination with a proton
10
Q
Define the law of mass action
A
- 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
11
Q
When is a weak acid lipid soluble? When is a weak base lipid soluble?
A
◦ Protonated of weak acid is neutral (lipid soluble) –> in acidic environemnt
◦ Unprotonated base is lipid soluble –> in basic environment
12
Q
Use an equation to define pH
A
pH = pKa - log (protonated/unprotonated)
13
Q
If pH is < pKa then what effect does this have on the H + A <-> HA reaction
A
it is positive
pH = pKa - log (protonated/unprotonated)
Therefore if pH is less than pKa then log (protonated/unprotonated) is positive
14
Q
What is an amine compound? What does a primary/secondary/tertiary refer to
A
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
15
Q
Ficks law of diffusion
A
16
Q
What is the diffusion coefficient related to in ficks law of diffusion
A
17
Q
How thick is a cell membrane?
A
10nm
18
Q
What is the henderson hasselbach equation
A
19
Q
pKa is
A
pH at which 50% of the drug is ionised
20
Q
Compre unionised and ionised drugs
A
21
Q
Define ion trapping. E.g.
A
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
22
Q
Define absorption
A
the extent to which intact drug is absorbed from the gut lumen into portal circulation - expressed as a fraction fo the dose (f (g))
23
Q
Define diffusion
A
the movement of drug molecules down their concentration gradient across the cell membrane without using energy
24
Q
What is active transport
A
- Movement of drug molecules against their concentration gradient across the cell membrane using energy
25
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
26
Define endocytosis
vesicles containing drug molecules are moved across the cell membrane into the cell by invagination
27
Define exocytosis
vesicles continuing drug molecules are moved outside the cell by incorporation of vesicles back into the cell membrane expelling contents
28
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
29
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.
30
Rate of absorption across membranes is proportional to (5)
1. Molecular size - permeability coefficient (Grahams law)
2. Concentration gradient - directly proportional
3. Ionisation - pKa
4. Lipid solubility
5. Protein binding
31
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
32
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
33
Write a Henderson Hasselback equation for an acid and a base
34
Speed of onset of a drug is related to
* Concentration gradient - Potency and therefore dose
* Distribution volume
* Rate of absorption - see factors above
35
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
36
What stomach and intestinal factors play into drug absorption (4)
37
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
38
What is the fraction fo drug that escapes first pass metabolism called?
F(h)
1- hepatic extraction ratio
39
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)
40
What si the equation for bioavailability?
(F =f(g) x f(h)) [hepatic enzyme activity, hepatic blood flow, drug uptake by hepatocytes)
41
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
42
IM bioavailability usually?
75-100%
May be painful
43
SC bioavailability? Limiting factor to dosing?
75-100%
Smaller volumes than IM
May be painful
44
Rectal bioavailability
30-100%
Less first pass metabolism than PO
45
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
46
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
47
What would too hydrophilic be a problem for absorption
Cannot cross cell membrane
48
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
49
What is a reverse transporter reducing systemic absorption
P glycoprotein
50
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
51
How do you measure oral bioavailability?
Area under concentration time curve in comparison to IV if first order clearance
52
AUC of an IV curve =
Dose/clearance
53
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
54
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
55
What is the ratio of IV to PO morphien
3:1
56
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)
57
What factors determine extraction ratio
1. Liver blood flow
2. Uptake into hepatocytes
3. Enzyme capacity - Michaelis constant - concentration fo the substrate at which enzyme is working at 50% of capacity
58
What is Michaelis constant
Michaelis constant - concentration fo the substrate at which enzyme is working at 50% of capacity
59
What is the name of the term for when concentration fo the substrate at which enzyme is working at 50% of capacity
Michaelis constant -
60
Low hepatic extraction ratio drugs have what consequences
1. 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
61
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
62
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
63
What % of GTN is bioavailable?
1%
64
Which type of drugs are significantly effected in their bioavailability by enzyme activity
High extraction ratio drugs
65
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
66
What is the limiting layer to TD absorption
Stratum corneum
67
Factors affecting systemic absorption for TD dosing
Lipid solubility
MW
pH
Local histamine release
Reginoal blood flow
Skin thickness
68
Advantages 5 and disadvantages 5 to TD dosing
69
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
70
Benefits of intrathecal dosing
Rare systemic side effects as little reaches systemic circulation
71
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
72
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
73
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
74
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
75
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
76
Factors affecting Vd 8
* Drug factors
◦ MW
◦ Lipid solubility
◦ Ionisation
◦ Protein binding
◦ Tissue binding outside plasma
* Patient factors
◦ Age
◦ Pregnancy
◦ Disease
77
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
78
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
79
Loading dose calculation
It is worth noting that all A, B and D reach steady state at the same time
80
Drug distribution rate depends on
Blood flow to target tissue
81
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
82
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
83
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
84
Excretion vs elimination
Excretion is removal from the body
Elimination is removal from the plasma
85
What processes contribute to elimination
Distribution, metabolisma dn excretion
86
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
87
Elimination rate equation
Elimination rate (mg/hr) = clearance x concentration
88
Clearance = Equation
Rate of elimination / concentration
89
Rate of elimination/concentration =
Clearance
90
Rate of elimination / clearance =
Concentration
91
Clearance x concentration =
Rate of elimination
92
Extraction ratio = (equation)
1 - (concentration out/concentration in)
93
Clearance is determined by which 2 factors
Blood flow
Efficiency of irreversible extraction (extration ratio)
94
E(H) stands for?
Extraction ratio
95
Maximum extraction is
Blood flow that enters an organ
96
Clearance aggregate if multiple sites =
Clearance systemically = rate of elinination in that organ/ concentration + rate of elimination in next organ/concentraiton etc etc
97
How do you calculate rate of elimination?
Dose / AUC of a the concentration time curve (this is elimination)
Only if first order elimination
98
What is mixed order kinetics?
Saturatable
Dose or concentration dependent elimination
99
Rate of elimination related to Vmax is?
100
Km relationship to rate of elimination
101
Vmax x C / (Km + C) =
Rate of elimination
102
What is Km
Drug concentration at which rate of elimination is 50% of Vmax
103
VMax is
Maximum eliminiation capacity
104
Rate of elimination equation (not clearance x concentration)
105
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
106
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
107
Flow dependent elimination describes what type of drugs?
High extraction drugs
108
How do you achieve steady state drug concentration (Css)
Maintenance dose rate(mg/hr) / clearance (L/hr)
109
How is clearance related to steady state drug concentration
Maintenance dose rate = clearance x steady state drug concentration
110
What happens to clearance if steady state halves
doubles
111
Clearance equation
U X V / P
112
U X V / P =
113
Excretion has what relationship to clearance?
Excretion = clearance x concentration
114
What curve can be used to find clearance?
Clearance = dose / area under the curve
115
What is a blood plasma concentration ratio? Equation? Significance?
116
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
117
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
118
Liver extraction ratio =
Clearance liver/flow
119
What is hepatic blood flow
90L/hr for a 70kg person
1500ml/min
120
Systemic bioavailability =
Give the equation
121
What are some drugs with low hepatic extraction ratios
chlorpropamide, diazepam, phenytoin, theophylline, tolbutamide, warfarin
122
Equation for extraction ratio
123
Liver extraction ratio
124
How would you relate liver intrinsic clearance to bioavailability?
125
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
126
Define intrinsic clearance
◦ Intrinsic ability of the liver to metabolise the drug in the absence of restrictions imposed on drug delivery to the liver cell by blood flow and protein binding
127
Equation for intrinsic clearance =
Vmax/Km
◦ V (max) = maximal velocity of the reaction at the saturating substrate concentration i.e. the maximal rate at which the enzyme can convert the drug to a metabolite
◦ K (m) - Michaelis-Menten constant and expressed how tightly the enzyme binds the substrate
‣ The lower the Km the tighter the binding
‣ Dissociation constant
128
What is the Michaelis Menten constant? What signficance does it have to clearance?
◦ V (max) = maximal velocity of the reaction at the saturating substrate concentration i.e. the maximal rate at which the enzyme can convert the drug to a metabolite
◦ K (m) - Michaelis-Menten constant and expressed how tightly the enzyme binds the substrate
‣ The lower the Km the tighter the binding
‣ Dissociation constant
Clearance = Vmax/Km
129
Simplify the clearance equatino for a low enzyme activity case
130
Simplify the clearance for a high enzyme clearance case
131
Capacity dependent elimination refers to?
132
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
133
Perfusion dependent liver elimination depends on?
Liver blood flow
134
How does protein binding affect a high hepatic extraction ratio drug?
135
For each of the below five high clearance heptically or low
- Morphine
- Paracetamol
- Lignocaine
- Phenytoin
- Diazepam
- Propano9lol
- Theophylline
- Warfarin
- GTN
136
Enterohepatic recircultation is? Works how? example
Enterohepatic circulation
* Drugs excreted in the bile such as glucoronidation conjugatesmay be hydrolysed in the small bowel by glucoronidases by bacteria
* Lipid soluble active drugs may as a result be reabsorbed into portal circulation to the liver where the extracted fraction is reconjugated and re-excreted and the rest passes to systemic circulation
* Failure of this is why the OCP doesn’t work with some antibiotics as recirculation is lost
137
How to determine the relative importance of metabolism and renal excretion of unchanged drug
* Give dose of the drug —> collect all the urine —>measure out how much fo the drug comes out unchanged (the rest is metabolised)
◦ This is the fraction excreted unchanged and varies from close to 0 (all metabolised - morphine, propranolol, theophylline all pretty close) to close to 1 (penicillin, amoxicillin, gentamicin,digoxins)
138
If you have liver and renal clearanc eof a drug how are these related
additive
139
Fraction of a drug excreted unchanged has what relationship to renal clearance
Renal clearance/total clearance
140
Fraction metabolised =
1 - fraction excreted unchanged
141
What relationship does bioavailability have to hepatic extraction
* Then maximum oral bioavailability can be estimated based on
◦ F = f(g) x f(h)
◦ Where at maximum f(g) = 1
◦ F(h) = 1 - E(H)
142
Heptic extraction ratio
◦ Hepatic extraction ratio (E (H)) = hepatic clearance / hepatic blood flow
143
Renal clearance is made up of which 3 processes? What is the equation for renal clearance?
144
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
145
What properties increase drug filtration
* Ideal filtration substance is small, non protein bound, poorl lipid soluble but readily water soluble
146
What are the 2 secretion transport proteins in the PCT
Proximal tubule contains at least 2 active transport mechanisms (CL[S])
◦ Weak acid transporter - negatively charged
◦ Weak base transporter - positively charged
147
What is important for secretion mechanisms to work?
* Secretion mechanisms able to strip bound drug off plasma proteins similar to high hepatic extraction ratio drugs, most however have low intrinsic secretion clearance and this does not occur instead
◦ CL unbound [S] = fu x CLs
148
What agents are filtered but not secreted or reabsorbed
Creatinine (to an extent), inulin
149
What agents is ssecreted completeley with no reabsorption? Why is this useful?>
* Para-aminohippuric acid PAH is so actively secreted by acid secretion system that all is removed from the renal blood in one pass through the kidney; nil reabsorption. It’s clearance is therefore a measure of renal blood flow
150
What concentration would a substance be if complteley filtered then not secreted or reabsorbed?
* Most of 120mL/min is reabsorbed, so only 1-2mL/min urine produced
* Therefore if the drug is not secreted or reabsorbed it would be 100x concentrated in urine compared to unbound plasma
◦ Therefore there is a considerable concentration gradient
151
Overall renal clearance equation is
152
What are the agents whihc are well known for acid secretion competition? Base secretion competition?
◦ Give competitor to secretion i.e. probenecid (acid), cimetidine (base) and observe if renal clearance reduced
153
What type of molecules do not really get renally excreted at all?
High molecular weight compounds (>30 000 daltons) are not filtered or secreted by the kidney adn are therefore preferentially excreted in bile
154
What is the intact tubule hypothesis
* No matter the elimination mechanism renal clearance is reduced in proportion to reduction in creatinine clearance (intact tubule hypothesis)
◦ Kidney behaves as thought he number of tubules is reduced with remaining normally functioni
155
What theory do we base renal adjustment of medications on
* No matter the elimination mechanism renal clearance is reduced in proportion to reduction in creatinine clearance (intact tubule hypothesis)
◦ Kidney behaves as thought he number of tubules is reduced with remaining normally functioni
156
At what point does it become necessary to adjust for renal function
Clearance >50% by renal elimination and renal function itself is reduced to <50% of normal function
157
Dose rate is adjusted how for creatinien clearance?
Proportionally
Allownace of fraction of drug elininated unchanged
◦ Allowance of fraction of drug eliminated unchanged
◦ E.g. if fraction of drug eliminated unchanged is 0.5, and creatinine clearance is reduced to 10% of normal then dose rate should be 55% of normal
◦ This can be done by reducing size of dose or increasing interval - depends on whether effect or toxicity occurs at peak or trough concentrations
158
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
159
A constant proportion of drug elimination per unit of time reflects what process
first order kinetics
160
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
161
Define zero order kinetics?
* The rate of drug elimination is independent of the concentration of the drug
* Constant amount of drug is eliminated per unit of time
162
Draw a graph representing zero order kinetics
163
What does this graph represent
zero order kinetics
164
What is an example of a zero order kinetics agent
Phenytoin at high doses
Alcohol
165
Mathematically what describe a zero order kinetics elinination
linear process
Constant amoutn of drug eliminated per unit of time
166
Why is zero order kinetics difficult to manage
Narrow therapeutic index
167
Define a one compartment model? How does this process into elinination
* SIngle bolus of a drug is administered into a single compartment
* The drug distributes IV into the compartment
* Drug elimination an exponential process characterised by a. single constant rate of elimination
168
Concentration at any time in a singel compartment model is reflected by waht equation?
169
What relationship does time have to concentration in single compartment first order knietics models
170
Clearance is calculated as what in a single compartment model?
Cl = k x Vd
K is the rate constant of elimination, or the fraction eliminated per unit of time
171
Draw a single compartment model diagram
172
Draw a diagram demonstrating a 2 compartment model and label it
173
Draw a graph representing concentration vs time for a 2-compartment model?
174
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
175
If you were to describe the fall in plasma concentration in a 2 compartment model what would you call it
Biexponential fall in plasma concentration
- Phase alpha - distribution
- Phase beta - elimination
176
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
177
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
178
Draw a 3 compartment model diagram
179
How would express concentration at any time based on a 3 compartment model
180
What drugs do not follow compartment models?
Cannot be used if organ independent clearance as the assumption the drug is eliminated only formr the central compartemnt cannot be made
181
What does AUC reflect in a concentration time curve
Drug removal from plasma
182
What relationship does clearance have with AUC of the concentration time curve
Cl = dose/ AUC
183
What is half life
* The time taken for the amount of drug in the body (or plasma concentration) to fall by half during elimination or during constant infusion
184
What assumption must be made for half life to have relevance as a concept
The body must be a single compartment of a size equalt o the Vd
185
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.
186
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.
187
How would you make plasma concentration vs time a straight line?
Aconstant proportion of the drug is eliminated over each unit of time; such that a logarithm of plasma concentration versus time —> straight line! This is First order elimination
188
What is k
elimination rate constant
Expressed as a proportion of the drug eliminated per unit of time from the body
units = per hour
189
How does half life related to k
190
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:
191
K is related to Cl and Vd how?
192
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%
193
At what point is a drug said to have virtually been eliminated
5 half lifes = ~97% elimination
194
ASsumptions of half life
Single body compartment
First order kinetics with constant proportion of elimination per unit of time
195
How is half life related to Vd
Directly proportional
increased Vd = increased half life
Only the drug in the blood is exposed to hepatic and renal clearance
196
How is half life realted to Cl
Increased clearance, reduces time for elimination i.e. inversely realted
197
Define half life
time required for the plasma drug concentration to decrease by a factor of 2
198
How is half life different to elimination half life?
Half life = time required for the plasma drug concentration to decrease by a factor of 2
Elimination half life (T1/2 Beta) - The time required for the amount of drug in the body to fall by 50%
199
What flaws in half life are there?
If concentration and effect do not have a good relationship it is not useful
Requires first order elimination
Does not account for multicompartments models
* Half life is very plasma centric - plasma half life may have relevance to systemic toxicity but not to drug site concentration e.g. renally cleared gentamicin accumulating to massive levels in the urine killing bacteria well above its MIC
200
How does half life provide useful information about dosing?
* Physiological effect at a certain time - only applies where concentration has a reasonable relationship to drug effect. Assists in determining when doses can be expected to wear off
* Duration of action - As duration of action is a logarithmic scale as a function of the dose; increasing the dose is an inefficient way of prolonging duration of action. Doubling the dose increases the duration of action by 1 half life - risk of toxicity high
201
How many half lives does it take to achieve steady state
3-5
◦ Approach
‣ 1 half life at constant rate dosing —> 50% plasma concentration as a percentage of steady state
‣ 2 half lives “” —> 75%
‣ 3 half lives “” —> 87.5%
‣ 4 half lives “” —> 93.75%
‣ 5 half lives “” —> 96.875%
◦ I.E. 3-5 half lives to achieve target plasma concentration or approximate steady state
202
2 factors whihc determine fluctuations in intermittent dosing
Half life
Time between doses
203
When might an SR preparation be required?
f a drug is given every half life —> then the concentration varies between the peak and half the peak
◦ This can be relavent if the drug half life is short and the drug shows dose relatated toxicity as you cannot dose frequently enough to avoid these big swings in toxicity and sub therapeutic effect
‣ This means these drugs often need SR preparation —> where fluctuations in plasma concentration are determined by slow absorption rather than rapid elimination rate
204
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
205
Accumulation occurs in what context? Realistically what interval determines this? Accumulation is proportional to what? Therefore accumulation factor =
* Whenever drug doses are repeated the drug will accumulate until dosing stops because elimination completely takes an infinite amount of time
* Realistically this means if the dosing interval is shorter than 4 half lives accumulation will be detectable
* Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval
◦ Fraction lost = 1-fraction remaining
Accumulation factor = 1/ fraction lost in one dosing interval
206
Accumulation factor eequation?
* Whenever drug doses are repeated the drug will accumulate until dosing stops because elimination completely takes an infinite amount of time
* Realistically this means if the dosing interval is shorter than 4 half lives accumulation will be detectable
* Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval
◦ Fraction lost = 1-fraction remaining
Accumulation factor = 1/ fraction lost in one dosing interval
207
What benefit is there in using an accumulation factor or calculating it?
THus the peak concentration after intermittent doses at steady state will be qual to the peak concentration after the first dose x the accumalation factor
208
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213
Maintenance dose equation
Cl x Steady state concentration
214
Steady state plasma concentration dpeends on?
Maintenance dose rate/clearance
215
In a low hepatic clearance drug Clearance depends on?
Cl = Fraction unbound x internal clearance
216
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
217
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
218
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
219
What types fo drugs and in what administrations do liver enzyme inducers and inhibitors affect
* Enzymes inducers and inhibitors will alter steady state dur concentration of all metabolised drugs given orally, and low extraction ratio drugs given IV
220
What drugs are affected most markedly by circumstances affecting liver blood flow?
* Circumstances which alter liver blood flow e.g. cardiac failure will usually be of less importance unless also affecting drug metabolising enzymes in oral dosed medications
◦ Oral dosing steady state concentrations in high hepatic extraction drugs are not affected by hepatic blood flow as effects on first pass clearance and systemic clearance cancel each other out
◦ However steady state is changed by intrinsic clearance in oral dosing due to change in first pass clearance is not compensated by a change in systemic clearance which is determined by hepatic blood flow
221
What is the most important factors to steady state concentrations for high hepatic extraction ratio drugs (2)
* Where high clearance drugs are given IV for long enough to reach steady state hepatic blood flow and protein binding are important determinants of unbound drug concentrations
◦ Virtually all the drug delivered to the liver is extracted so the rate of delivery is the major factor
◦ Protein binding alters drug available for extraction by the liver
◦ This occurrence is rare but encountered in lignocaine infusions and morphine infusions
◦ When liver blood flow is altered e.g. cardiac failure steady state changes
222
How do you determine steady state for non linear pharmacokinetics
223
What is a Michaelis Menten equation?
1. Saturation of drug metabolism —> changing intrinsic clearance
* Michaelis-Menten equation
◦ V = velocity of reaction
◦ S = substrate concentration
◦ VMax is maximum velocity at high substrate concentrations
◦ Km is the substrate concentration at half Vmax - a measure of the affinity of the substrate for the enzyme
◦ Rate V is equivalent to the rate of elimination
◦ Rate of elimination = CL x concentration
* Therefore re-arranging
V = (Vmax x S) / (Km + S)
Cl (int) = V/C = Vmax/ (Km + C)
Usually plasma concentration in therapeutic range is small compared to Km so" Cl = Vmax / Km
Clearance becomes independent of drug concentration, however if drug concentration is close to or above Km the kinetics become non linear
224
Outline phenytoin as an example of saturated drug kinetics - therapeuytic range, typical Km, Vmax, , effect on half life of changing clearance, steady state therefore is faster or slower?
‣ Marked saturation of metabolism at therapeutic ranges 10-20mg/L
‣ Small increases in dose cause large increases in total and unbound steady state drug concentration
‣ Typical Km of 5mg/L (total drug) and Vmax of 450mg/day steady state concentrations at doses 300, 360 and 400mg/day would be 10, 20, 40mg/L respectively
‣ Because clearance decreases apparent half life increases from 12 hours at low doses to as long as a week at higher concentrations
‣ This means
* The time to achieve steady state cna take as long as 1-3 weeks at the top of the therapeutic range
* In the therapeutic range phenytoin concentration fluctuates little over a 24 hour period allowing foronce daily dosing and sampling for drug concentration at any time in the dosing interval
* If dosing is stopped due to toxicity it takes a long time for it to come down
225
When substrate velocity is low compared to Km for drug metabolising enzymes what occurs
Reaction velocity increases in a linear fashion with substrate concnetrtion
226
What is the reaction velocity at any particular substrate concentration?
V = Vmax x S/ Km +S
227
What is the Vmax of ethanol?
‣ Km is 0.01% (100mg/L) so concentrations causing pharmacological effect are well above Km
‣ Vmax is 10g/hour (12.8mL/hr)
‣ At the common driving limit 0.05% the rate of metabolism is 8.3G/hr
228
What si the Km of ethanol
‣ Km is 0.01% (100mg/L) so concentrations causing pharmacological effect are well above Km
‣ Vmax is 10g/hour (12.8mL/hr)
‣ At the common driving limit 0.05% the rate of metabolism is 8.3G/hr
229
What are examples of how first order kinetics can break down (4)
1. Saturation of enzyme responsible for drug metabolism changing intrinsic clearance
2. Saturation of first pass metabolism - large oral dose saturating enzyme and drugs with high hepatic extraction ratios this can occur decreasing intrinsic clearance/
3. Saturation of renal secretion clearance - although filtration clearance will continune to increase
4. Saturation of protein binding sites increasing fraction of unbound
230
Fraction unbound = (equation)
1/ (1+ KaPu)
Ka = affinity for binding protein
Pu = concentration of free unbound protein
231
For drug fraction unbound equation what factor is usually not a major part? How can it become more significant? What happens inthese circumstances?
* Usually as protein concentrations so far eclipse drug concentration Pu = total protein meaning Fu only depends on affinity constant; however in limited circumstances where albumin binding sites are saturated unbound protein concentration decreases and fraction unbound increases. Total drug concentration then increases less than proportionally, and can appear to plateau at a point where functionally the availability of unbound drug has increased
232
What is t1/2 k (eo)
Equation
Why is it important
Half time for equilibration between drug concentration in plasma and effect site
= 0.693 / k (eo)
Allows for appropriate titration against clinical effect
Determines dosing intervals
233
When does context sensitive half time = half life?
The closer an infusion comes to steady state the closer they come together
234
What is context sensitive half time?
Time required for the plasma drug concentration to fall by 50% after the cessation of an infusion designed to maintain a constant plasma concentration
235
Context in context sensitive half time refers to?
duration of infusion
236
What determines context sensitive half time
Distribution adn redistribution to/from central compartment
Clearance
Duration of infusion
237
When is context sensitive half time at its longest
Steady state
238
What pharmacological model is context sensitive half time not useful in?
1 compartment model
Then half life is always equal to context sensitive half time
239
What characteristics of Vd and clearance are more likely to have a longer context sensitive half time?
Drugs with a small central volume and rapid clearances are rapidly cleared regardless of peripheral compartment size -e.g.remifentanil. Large central volumes and slow systemic clearance are eliminated very slowly - and accumulation becomes more relevant. E.g. Amiodarone.
240
COmpare the context sensitive half time of remifentanyl, propofol, alfentanil, fentanyl and thiopental
241
What is the max propofol context sensitive half time
20-40 minutes
242
Why does propofol have a short context sensitive half time
Rapid clearance
Clearance faster than redistribution
243
Why is remifentanil not a drug of concern for context sensitive half time
Rapid metabolic clearance by plasma and tissue esterases, context insensitive
244
Fentanil max context sensitive half time?
300 minutes
245
Thiopental context sensitive half time at 8 hours
What is unique about it?
150 minutes
Continues to rise
Active metabolite pentobarbital
First order kinetics convert to zero order kinetics
246
What is decrement time? What is an example of a commonly used decrement time?
Decrement time is the time predicted ffor the plasma drug concentration to fall by a certain percentage after cessation of an infusion at steady state
Context sensitive half time is an example of a decrement time of 50%
247
What does EC50 denote?
Affinity of a drug for a receptor
The concentration of the drug required to give half maximal effect
248
What is therapeutic index
EC50 for adverse effect / therapeutic effect EC50
249
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
250
What equation denotes drug effect as a function of its concentration
251
Explain why drug effect falls linearly with time
* Drug concentration falls in an exponetial manner with time
◦ Logarithm of this is linear
* Logarithm of drug concentration is also linear with drug effect in the range 20-80%
◦ i.e. effect falls linearly with time
252
If you gave a massive dose of a drug, there were no adverse effects at hihg doses what would you observe with respect to effect over time
* If the dose of the drug is large enough to produce a concentration which causes a maximal effect rhe effect will change very little until the rug concentration falls to that producing 80% of maximal effect
* The duration of action can be prolonged in this manner
◦ The duration of action increases as a logarithmic function of the dose
◦ Risk of adverse effects
* Drug concentration falls in an exponetial manner with time
◦ Logarithm of this is linear
* Logarithm of drug concentration is also linear with drug effect in the range 20-80%
◦ i.e. effect falls linearly with time
253
ACEI have a half life of how long? How many times a day do you give them? How does this work?
Half life 3 hours, once daily dosing i..e 7 half lives between dosing intervals
C50 for 50% of maximal effect is 1ng/L (peak concentration after 19mg dose after 3 hours is 64ng/mL)
EMax = 100%
In the first 4 half lives the effect after peak concentration has only decreased by 20% despite a much larger decrease in dose --> as above the 80% mark
After 24 hours 33% is still inhibited
* Drug concentration falls in an exponetial manner with time
◦ Logarithm of this is linear
* Logarithm of drug concentration is also linear with drug effect in the range 20-80%
◦ i.e. effect falls linearly with time
* If the dose of the drug is large enough to produce a concentration which causes a maximal effect rhe effect will change very little until the rug concentration falls to that producing 80% of maximal effect
* The duration of action can be prolonged in this manner
◦ The duration of action increases as a logarithmic function of the dose
◦ Risk of adverse effects
254
Over what range of doses is effect change linear to time?
HOw long does it take to get from the highest time of linearity to the lowest? What happens once it is below this value?
* When concentrations are 4x the C50 and 1/4 of the C50 the effect change is close to linear over time
* It takes 4 half lives for concentrations to drop from effect of 80% to 20% of Emax
* Once concentrations are <1/4 of C50 the effect is proportional to concentration i.e. exponential decline
255
At what blood concentrations is half life useful?
When concentration is low relative to c50
256
How would you draw a graph depicting a therapeutic window/
257
When is drug concentration not a good measure of effect(7)
* Drugs used at concentrations giving maximal effect
◦ For part of the dose interval there is no change in effect as concentration decreases
◦ Increasing the dose does not increase response but may cause adverse events with separate concentration-effect relationships with higher EC50
* Hit and run drugs
◦ Act irreversibly e.g. MAO or aspirin
◦ Termination requires synthesis of new platelets or enzymes so no direct relationship between drug concentration and effect
* Delayed distribution
◦ Site of action is an area slowly distributed to, therefore different to where the drug is measured in plasma e.g. digoxin
◦ The effect increases as drug concentration falls due to redistribution
◦ Drug concentration soon after dose less effect than later
* Acute tolerance - tachyphylaxis
◦ Rapid tolerance after a dose, e.g. ephedrine, amphetamines
◦ Act by releasing noradrenaline from sympathetic nerve ending which rapidly become depleted of neurotransmitter and resistant to further effect
◦ Drug concentrations soon after a single dose cause a greater effect than the same concentrations at a later time
* Wrong effect measured
◦ e.g. after warfarin
◦ INR is measured where instead production of new clotting factors is the effect, you need to wait for the old ones to disappear before seeing INR change
* Active metabolites
◦ If not measured by the analytical method used
◦ Dissociation between concentration and effect
◦ If high hepatic extraction —> different oral and IV concentration/effect relationship
◦ Seen in beta adrenoreceptors antagonists
* Enantiomeric drugs
◦ Many drugs are marketed as racemic mixtures of enantiomers (optical isomers)
◦ Identical physics-chemical characteristics, different pharmacokinetic and dynamic profiles
◦ Drug monitoring measures both
◦ The enantiomers are often eliminated at different rates and the ratio therefore changes, leading to change in concentration effect relationship
* Saturable protein binding
◦ Fraction unbound changing with concentration there will be dissociation between concentration and effect
Shortcut to memory
- Drug effects immediate and prolonged - hit and run, acute tolerance
- Drug concentration inaccurate - enantiomers, active metabolites
- Pharmacodynamics - wrong effect measured, drug side effects less so drugs used at doses above maximum effect
- Drug distribution -0 protein binding, redistribution delayed to effect site
258
Draw a drug concentration vs effect graph representing delayed redistribution
259
Draw a drug concentration vs effect graph for acute tolerance/tachyphylaxis
260
Why might effects of a drug be delayed
◦ Time required to distribute to site of action
‣ Lag of effects after IV infusion
◦ Slow turnover of physiological substance involved in expression of drug effect e.g. warfarin
261
Target concentration = equation
maintenance dose rate / clearance
262
What is the loading dose calculation
Vd x target concentration
263
How would you get from maintenance dose to peak dose?
multiply by the accumulation factor
264
When is the dosign intervl of a half life appropriate? Why does it make things easy (4)
* A dosing interval of a half life has some benefits
◦ Plasma concentration fluctuates 2 fold over dosing interval
◦ Amount of the drug shortly before each dose is equivalent to the maintenance dose
◦ Steady state plasma concentration averaged over dosing interval same as steady state infusion at the same dose rat e
◦ Loading dose - twice the maintenance
* Dosing interval of a half life is appropriate if the half life is 8-24 hours
265
Why is dosing intervals of a half life inappropriate if the half life is too short? What is the range at which a singel half life per dose is appropriate
* Dosing interval of a half life is appropriate if the half life is 8-24 hours
◦ Not practical if shorter - as >3x daily not convenient. Ways of getting around this can include
‣ If large therapeutic index then massive doses can be used
‣ Slow release - low therapeutic index, narrow therapeutic range
◦ Longer half lives
‣ Once daily may be appropriate
‣ It will take an extended period to achieve steady state
‣ Can use a loading dose where tolerant but for some medications it becomes lethal
266
How do you related Cmax at steady state to Cmax at first dose?
267
How do you determine extend of fluctuation in dosing over a dosing period
268
How do you compare dosing interval with half life?
269
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
270
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
271
Outline factors contributing to variation in dosing requirements between people
Non modifiable
- Genetic polymorphism
- Age - neonate, children, eldely
- Gender, pregnant
/Drug interactions
Disease
Environm,ental influences
Adherence
272
Why might you monitor drug concentration measurements? 5
◦ Marked pharmacokinetic variability
◦ Therapeutic and adverse effects are related to drug concentration
◦ Narrow therapeutic index
◦ Defined concentration range
◦ Desired therapeutic effect difficult to monitor e.g. if HR is the target this is easy to monitor however if this cannot be done
‣ Drugs used prophylactically to stop a condition e.g. arrthymia, seizure mania, asthma prevention
‣ Avoid serious toxicity with narrow therapeutic range
273
What sort of factors need to be met to interpret a drug concentration?
* Age, gender
* Clearance
◦ Single most important factor
◦ Interpreting measurement therefore requires
‣ Dose
‣ Organ blood flow
‣ intrinsic function
* Dosing history
◦ Duration of treatment with current dose
◦ ADherence
* Timing of samples - in relation to starting drug and timing of last dose
◦ Oral peak measurements at least 2hours post
‣ In digoxinscase 6 hours after last dose
‣ Lithium- just enforce the next dose
‣ Aminoglycoside 1 hour as rapid
◦ Steady state
‣ At least 3.5 half lives of steady dosing
‣ Midpoint of dosing interval for collection
* Other drug therapy
* Relevant other disease states
* Reason for request
* Clinical status
* Are there active metabolites unmeasured
274
When should you generally measure peak measurements
Oral 2 hours post
(unless digoxin 6 hours post, aminoglycoside 1 hour post)
275
When should you measure steady state drug levels
3.5 half lives of steadydosing and midpoint of interval
276
When is the least variable time to measure dosing
Trough
277
For long half life drugs when do you monitor drug levels
Doesn;t matter, little variance
278
When do you measure plasma concentrations for short half lives drugs
trough
279
What determines fraction of drug unbound? 4
‣ Affinity of the drug for the protein - lipid solubility being high predicts high protein bindings, ionised drugs don’t bind to proteins
‣ Concentration of the binding protein and number of available binding sites
‣ Concentration of the drug relative to the binding protein
* In almost all therapeutic instances the drug dose is well below the binding protein saturation,meaning fraction unbound is constant
* The one caveat is alpha 1 acid glycoprotein - concentration relatively low,unbound concentration of some drugs associated increase linearly with dose but less than proportionate increase in total concentration as saturation occurs causing the unbound fraction to increase; in acute phase conditions its concentration rises
* Salicylates are the only albumin bound drug with which this occurs; unless albumin levels are markedly low
‣ Availability of binding sites
* Dependent on number of binding sites on the protein
* Competition from endogenous and other drugs
280
High lipid solubility usually equates to what in reference to protein binding?
high protein binding
281
Ionised drugs bind well to proteins true or false
False
282
Is fraction unbound constant? When is the answer incorrect?
* In almost all therapeutic instances the drug dose is well below the binding protein saturation,meaning fraction unbound is constant
* The one caveat is alpha 1 acid glycoprotein - concentration relatively low,unbound concentration of some drugs associated increase linearly with dose but less than proportionate increase in total concentration as saturation occurs causing the unbound fraction to increase; in acute phase conditions its concentration rises
* Salicylates are the only albumin bound drug with which this occurs; unless albumin levels are markedly low
283
How many drug binding sites on albumin? What binds to them
At least 6
2 of these tightly bind long chian fatty acids, 1x biulirubin., 2 major acidic drug binding sites
* Site 1 - warfarin
* Site 2 - ibuprofen, diazepam
* Drugs binding at the same site displace each other competitively;readily reversible reactions
* Additional binding sites can induce confirmational change affecting binding at site 1 and 2
284
Give 2 examples of drugs bound to albumin
phenytoin
Salicylates
285
How would you describe drug binding to albumin
Structurally selective
High capacity
286
Name the sites that albumin has to bind to
* Site 1 - warfarin
* Site 2 - ibuprofen, diazepam
* Drugs binding at the same site displace each other competitively;readily reversible reactions
* Additional binding sites can induce confirmational change affecting binding at site 1 and 2
287
Albumin binds acidic or basic drugs?
Acidic
288
Alpha 1 acid glycoprotein binds what
lidocaine, propanolol
289
What is a non albumin binder of drugs? 3
Alpha 1 acid glycoprotein
Alpha 2 globulin - copper
Beta 1 globulin - iron
Lipoproteins of red cells - amphotericin
290
Alpha 1 acid glycoprotein binding is variable due to?
‣ Increased concentration in acute inflammation leading to changes in total plasma concentration even if elimination is unchanged (acute phase reactant)
‣ Structurally selective binding site - basic drugs
‣ Low capacity and more specific than albumin
291
How does alpha 1 acid glycoprotein binding compare to albumin
‣ Low capacity and more specific than albumin
292
Outline the only instance when unbound drug concentratino at steady state is dependent on drug binding to proteins
◦ The only instance where unbound drug concentration at steady state is dependent on drug binding to proteins is a high hepatic clearance drug given IV
‣ Except in very rare instances protein binding displacement in Vito does not result in increased drug effect
293
Why does drug binding not affect drug effect for the most part (2)
◦ Volume of distribution dependent on ratio of fraction unbound in blood and tissues
‣ If the fraction unbound in blood increases because fo competitive displacement without a change in tissue binding the volume fo distribution increases as the displaced drug spreads out and is bound to tissues happening over minutes to hours
◦ Fraction unbound is a factor in the clearance of the total drug
‣ Clearance = fraction unbound x intrinsic clearance
‣ Clearance of unbound drug is only determined by intrinsic clearance and not on protein binding, therefore when fraction unbound increases due to displacement drug is eliminated more rapidly until the unbound steady state returns to the starting point
* End result - increase in unbound fraction, decrease in total drug concentration at steady state in proportion to the increase in fraction unbound, no change in steady state unbound concentration
* It takes 3-5 half lives to occur
294
How do they figure out drug pharmacokinetics
1. Single dose studies
2. Multiple dose studies - steady state
3. Population pharmacokinetics
295
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:
296
How is population pharmacokinetics done
* Uses patient populations being treated with the drug
* It is not possible to carry out intensive sampling but generally you have more patients and build a picture from a few samples from each patient
* Uses modelling mixed effects approach
◦ Fixed effects -
‣ CL, volume of distribution, absorption constant etc
‣ Variable effects - age, weight, gender, renal or hepatic disease, smoking etc
◦ Random effects
‣ Intersubject variaability
◦ Global model developed and then subgroups analysed within to see if improved model fit to data can be established
297
Describe the epidural space
- Boundaries 5
Brief anatomical interlude
* Superiorly the epidural space extends to the foremen magnum
◦ Terminates at the fusion of the spinal and periosteal layers of the Dural mater —> i.e. cranial extension of epidural infused drugs is impossible
* Inferiority - epidural space extends to the sacrococcygeal membrane
* Posteirorly - vertebral lamina, capsules of facet joints and ligamentum flavum
* Laterally - Pedicles of vertebral arches and intervertebral foremen (communicates freely with paravertebral space)
* Anteriorly - vertebral bodies, IV discs, posterior longitudinal ligament
298
Describe the epidural space
- Contents 5
Contents
* Fat
* nerve roots
* BV
* Lymphatics
* Various fibrous connections
299
Describe the epidural space
Arterial and veinous supply
Arterial supply - anterior and posterior spinal arterial arcades arising from spinal arteries entering the space through every IV foremen. Anastomose with anterior spinal artery
Venous drainage - plexus of valveless veins, Bateson’s plexus which is in the anterior epidural space . Also posterior veins which are most prominent in the cervical epidural space.Received blood from thoracic and pelvic veins therefore straining and coughing can engorge them
300
How much can you inject into the epidural space theoretically
40mL
301
Epidural absorption into CSF depends on?
◦ Volume of drug administered - reflects surface area coated of available meninges
◦ Concentration difference
◦ Lipid solubility —> Lipophilicity - pH,pKa (affects speed of onset)
◦ Protein binding and free fraction
◦ CSF flow rate and turbulence - 500mL of fluid may 3wash over the site over a day
302
Once adminsitered epidurally a drug goes where 4
◦ Exits IV foramina to paraspinous muscles
◦ Distributes into the epidural fat - accounts for the 5-10x dosing difference between Intrathecal and epidural but the more prolonged effect
◦ Diffuse into ligaments
◦ Diffuse across spinal meninges and into CSF - the arachnoid mater is the main barrier to diffusion.
303
Distribution of epidural drugs based on what model? Characteristics
* Epidural spaces are irregular, segmental and the injected material encircles the Dural sac
* Two compartment model —> fast initial rise in concentration in plasma and fast initial drop representing metabolism, then slow release reflecting epidural fat pad release of drug
* Rapid early distribution into the epidural fat pad, and then slowly back out
304
Metabolism and excretion of epidurally injected drugs
Metabolism and excretion
* Normal mechanisms of metabolism and elimination, because of the haemodynamic effects of spinal anaesthetic drugs the perfusion of liver and kidneys may be decreased reducing clearance mechanisms
305
SAH space is where? Contains? Extends to what point?
* Space between arachnoid mater and Pia mater
* Contains CSF and communicates with CSF spaces in the skull
* The subarachnoid space extends along the vessel walls as they penetrate the spinal cord - there it interfaces with series of tiny Pia lined fluid pockets associated with at least all arterioles and venules in the CNS
◦ The spaces are called perivascular space/virchow-Robin
* CSF is always within 5mm from any area in the spinal cord
306
Intrathecal absorption to effect site dependent on? How does dose compare with epidural? Effect onset? Systemic toxicity? What unique factor does it allow you to do in comparison to systemic dosing? Duration
* Rate of diffusion into target tissue is rapid - high CSF concentration, short diffusion distance 2-4mm
◦ So lower doses and rapid effect, reduced chance of systemic toxicity
◦ Allows for administration of drugs that do not cross the BBB - hydrophilic e.g. methotrexate
* Systemic absorption slower than epidural as no rapid distribution phase (lack of highly vascular structures)
307
Distirbution of intrathecal dosing depends on?
* Local distribution —> Depends on baricity - density of injectate in comparison to CSF
◦ Density of solution / density of CSF
◦ Usually 1.003 g/mL for CSF
◦ Compared at 37 degrees
◦ Isobaric - stay put wherever injected
◦ Hyperbaric = heavy, sink —> affecting sacral nerve roots when upright
308
Intrathecal absorption into systemic system vs epidural
* Slow absorption with increased half life into systemic circulation
* The more lipophilic the drug the faster it is cleared from the CSF
309
Metabolism of intrathecal drugs?
* Normal mechanisms of metabolism and elimination, because of the haemodynamic effects of spinal anaesthetic drugs the perfusion of liver and kidneys may be decreased reducing clearance mechanisms
* No CSF based metabolism which means drugs which usually redistribute quickly and are metabolised quickly may have extended MOA esp. hydrophilic drugs
310
What things other than anaesthetic injectables are put intrathecally 5
* Baclofen
* Clonidine
* Analgesics - pall care,cancer pain
* Anti neo plastics - methotrexate
* Antibiotics - ventriculitis
Primary Pharmacology
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