(PM3B) Pharmacokinetics Flashcards
1
Q
What is the therapeutic window of a drug?
A
The drug level in blood
Between toxicity & poor therapeutic activity
2
Q
What is Cmax?
A
Maximum concentration of a drug in the blood
3
Q
What is Cmin?
A
Minimum concentration of a drug in the blood
4
Q
Define bioavailability.
A
The fraction of an administered dose that reaches the bloodstream
F - symbol in an equation
5
Q
How is bioavailability determined?
A
(1) Blood sample taken from patient
(2) Blood cells are centrifuged out
(3) HPLC used to measure drug conc. in plasma
6
Q
What is HPLC?
A
High performance liquid chromatography
7
Q
What does a graph of drug plasma concentration over time indicate?
A
Absorption
8
Q
How is absorption of a drug known?
A
Cp (plasma concentration) vs t (time)
Area under the curve
9
Q
How can the absorption of IV and oral routes of a drug be compared?
A
Cp (plasma concentration) vs t (time)
Calculate and compare area under curve
10
Q
What is the symbol representing bioavailability?
A
F
11
Q
How is bioavailability of a route of administration calculated?
A
F(route) = AUC(route) / AUC(IV)
12
Q
What does AUC refer to?
A
Area under curve
13
Q
What does F refer to?
A
Bioavailability
14
Q
What are the commonly used models for distribution?
A
(1) One compartment model
(2) Two compartment model
15
Q
What is the one compartment model?
A
Model for distribution of a drug
Assumption that a drug is distributed in the body in a single homogenous department
Assumes perfusion to heart/ liver/ lungs from blood
16
Q
What is the two compartment model?
A
Model for distribution of a drug
Central & peripheral compartments
Central: Blood/ heart/ lungs/ liver
Peripheral: Fat/ muscle/ skin
17
Q
What does Vd refer to?
A
Volume of distribution
18
Q
What is volume of distribution shortened to?
A
Vd
19
Q
What is Vd?
A
Plasma drug concentrations related to total amount of drug present in the body
‘Apparent’ volume of distribution
20
Q
How is blood plasma concentration calculated?
A
Cp = (Mass of drug in body) / Vd
Cp = (SxFxD) / Vd
21
Q
How is Vd calculated?
A
Vd = (Mass of drug in body) / Cp
22
Q
In a calculation, what is the mass of the drug in body for an IV injection?
A
Mass of the drug in the body = 1
23
Q
How many litres of blood are there in the body?
A
Approx. 5L
24
Q
What can be inferred from a volume of distribution (Vd) of greater than 5L? Why?
A
Drug has been distributed into tissues/ systems OTHER than the blood
25
How is IV loading dose calculated?
(Desired Cp) x Apparent volume of distribution
26
How is rate calculated?
Change in amount over time
27
What does K refer to?
Rate constant
28
What does n refer to, with regards to rate of reaction?
Order of the process
29
What is a zero order reaction?
When n=0
30
When is the rate of change constant?
When X^n = 1, because n=0
31
Is the rate constant negative or positive? Can that change?
Positive
Always positive
32
Is dX/dt negative or positive when X is diminishing?
Must be negative
33
(1) When is the rate constant accompanied by a minus symbol?
| (2) Give an example.
(1) When X is diminishing
| (2) When a drug is being eliminated from the body
34
(1) What can {Xt = X(0) - K(0)t} be written as?
| (2) What does it mean?
(1) C(pt) = C(p0) - K(0)t
(2) For a zero order elimination, Cp at time t equals Cp at time 0, minus the zero order elimination rate constant multiplied by the time taken
35
What is the equation {Xt = X(0) - K(0)t} in the same format as?
y = mx + c
36
(1) If a Cp vs t graph is a straight line, what can be assumed?
(2) What information can be taken from this?
(1) Elimination is zero order
| (2) Rate constant and Cp can be found at time zero
37
What does X represent?
Total amount of drug present in the body
38
If X is raised to the power of 1, what does this mean in terms of rate of reaction?
(2) What does this mean for the rate of reaction?
(1) First Order reaction
| (2) Rate of reaction is not constant, because X is always changing
39
What does K(0) represent?
Zero order elimination rate
40
What does K(1) represent?
First order elimination rate
41
How is the drug concentration of the plasma at time (t) calculated?
Cp(t) = Cp(0)exp^{-K(1)t}
42
In an equation, what does 'exp' represent?
The exponential
43
(1) What does Cp(t) = Cp(0)exp^{-K(1)t} look like in logarithmic form?
(2) What is this equation used for?
(1)
lnCp(t) = lnCp(0) - K(1)t
(2) Calculating the drug concentration of the plasma at a time (t)
44
What assumption is made when a drug is injected IV, regarding a Cp vs t plot?
That 100% of the drug is present at t = 0
i.e. volume in body = volume injected
45
What format can the Cp vs t equations be rearranged to, to be used to calculate values given on the plot?
y = mx + c
46
What does it mean if a ln(Cp) vs t plot is a straight line?
Reaction (elimination) is first order
47
What does it mean if a Cp vs t plot is a straight line?
Reaction (elimination) is zero order
48
What assumption is made for Cp vs t plots of elimination rates?
Based on ONE compartment model
49
What order of elimination do most drugs undergo?
First order elimination
50
How are drugs eliminated from the body?
(1) Metabolism
| (2) Excretion
51
What does KE represent?
Rate of elimination
52
What is the short-hand for rate of elimination?
KE
53
Is the rate of a zero order elimination dependent on Cp?
No, it is a constant.
54
When does zero order elimination most commonly occur?
When elimination pathways for a drug are saturated
55
Is the rate of a first order elimination dependent on Cp?
Yes. Proportional
56
What does a ln(Cp) vs t plot look like, using a TWO compartment model?
(1) 1st phase: Distribution and elimination
- ln(Cp) drops rapidly
(2) 2nd phase: Elimination ONLY
- ln(Cp) decreases at a slower rate
57
What occurs during the first phase of the curve of a ln(Cp) vs t plot?
- Drug is being distributed from central compartment to peripheral
- Drug is being eliminated from the central compartment
58
What occurs during the second phase of the curve of a ln(Cp) vs t plot?
- Central and peripheral compartments are at drug conc. equilibrium
- Drug is being eliminated from central compartment
59
What does 'biliary' mean?
Referring to bile or the bile duct
60
What are the main types of excretion?
(1) Kidneys -> Urine - primary route
| (2) Biliary -> Faeces
61
What does 'clearance' refer to?
- Irreversible removal of a drug from systemic circulation by metabolism or excretion
- The volume of blood from which the drug is completely removed per unit of time
62
Where does clearance occur?
When blood flows through an organ of elimination
(1) Liver - metabolism
(2) Kidneys - excretion
63
Which organ is primarily associated with metabolism?
Liver
64
Which organ is primarily associated with excretion?
Kidney
65
How is the total clearance calculated?
CL(total) = CL(renal) - CL(non-renal)
66
Where does most non-renal clearance occur?
Metabolism in the liver
67
What is renal clearance?
Irreversible removal of a drug from the systemic circulation via excretion in the kidney
68
What is hepatic clearance?
Irreversible removal of a drug from the systemic circulation via metabolism in the liver
69
What are the units of clearance?
mL/ minute
OR
L/ hour
70
What equation is used to calculate first order clearance of a drug?
CL(s) = K(E)V(d)
Subscript (s) denotes systemic
71
Is drug clearance considered constant (first order)? Give a reason for your answer.
Yes.
Both K(E) and Vd are constants
72
In an equation, what does t(1/2) refer to?
Elimination half-life
73
What is elimination half-life {t(1/2)}?
Time taken for Cp to drop to Cp/2
e.g. 50mg/mL -> 25mg/mL
74
How is elimination half-life {t(1/2)} calculated?
t(1/2) = 0.693 / K(E)
75
What is the significance of 0.693 in an equation, relating to elimination?
It is the numerator for the equation used to calculate elimination half-life
76
What is the main reason a drug may be formulated as a salt or hydrate?
To increase solubility
77
What is the salt factor referred to as in short-hand?
S
78
What is the salt-factor?
The fraction of the administered dose that is the active pharmaceutical ingredient
79
How is the salt factor (S) calculated?
(Mr of API) / (Total Mr of drug)
80
How can blood plasma concentration be calculated?
Cp = (Total mass of drug in body) / Vd
Cp = (SxFxD) / Vd
81
What does 'steady state' refer to?
When the amount of drug administered in a given time is equal to amount of drug eliminated in the same given time
82
What is the steady state plasma concentration?
CpSS
83
How long does it take for a drug to reach steady state?
Depends on t(1/2), elimination half-life
When the amount of drug being absorbed = amount of drug being eliminated
84
(1) What is CpSS?
| (2) How can it be calculated?
(1) Steady state plasma concentration
| 2
CpSS = (SxFxD) / (Clearance x dosing interval)
85
Define dosing interval.
The frequency of intermittent drug administration, based on elimination half-life {t(1/2)}
86
How does the time to steady state compare to the half-life?
Time to steady state is approximately equal to 5 half-lives
87
Does a higher dose affect the time taken to reach steady state?
No
88
What is steady state, with regard to a continuous IV infusion?
Rate of infusion is equal to rate of elimination
89
In an equation, what does 'R' refer to?
Rate of elimination
90
What is R / CL equal to?
CpSS (Blood plasma steady state)
91
How can time to steady state be decreased?
Administer a loading dose
92
What is the purpose of a loading dose?
To decrease time taken to achieve a steady state
93
What is the purpose of achieving a steady state quickly?
To achieve appropriate therapeutic effect faster
94
What is gentamicin?
Powerful antibiotic
Considered as last-resort
95
What is the oral bioavailability of gentamicin?
Approximately 0
96
(1) How is gentamicin administered?
| (2) What dose is given?
(1) IV
| (2) 5-10mg/ L
97
When is gentamicin indicated?
For serious bacterial infections
98
Define ototoxic.
Having a toxic effect on ear/ ear nerve supply
99
Define nephrotoxic.
Having a toxic effect on kidney - damaging or destructive
100
What are the adverse effects of an overdose of gentamicin?
(1) Ototoxicity - damaging ear/ ear nerve supply
| (2) Nephrotoxic - damaging to kidney
101
What significance does 5 times the half-life have?
Time taken to reach steady state for a drug
102
What effect does increased dosing have on the peaks and troughs of plasma drug concentration?
Increases difference between peaks and troughs
Does NOT increase time taken to reach steady state
103
If a drugs half-life is 6.5hrs, how long can we assume it takes the drug the reach steady state in the blood plasma?
6.5 x 5 = 32.5hrs
104
What does TDM refer to?
Therapeutic drug monitoring
105
What is therapeutic drug monitoring written as in short-hand?
TDM
106
What is therapeutic drug monitoring (TDM)?
Optimising patient individual therapy using:
(1) Drug levels
(2) Pharmacokinetics
(3) Pharmacodynamics
107
What is TD50?
Median toxic dose
108
What is ED50?
Median effective dose
109
When is TDM used?
- Drugs with a narrow therapeutic range
- Drugs with a low therapeutic index
- Drugs where dose and effect are not strongly correlated
- Drugs with wide variance in patient clearance
110
What is LD50?
Median lethal dose
111
What should Cp be in practice?
Steady state
| Takes about 5 times the half-life to reach this point
112
Do analytical methods distinguish between bound and unbound drug in blood plasma concentration? If so, which method(s)?
No.
Analytical methods give total Cp levels
Give no distinction
113
What is important when considering implementation of a second drug which interacts with the protein-binding of a strongly protein-bound first drug?
Increase in free (as opposed to protein-bound) will be PROPORTIONATELY significant
Likely to cause the patient a problem
114
What is important when considering implementation of a second drug which interacts with the protein-binding of a strongly protein-bound first drug?
Increase in free (as opposed to protein-bound) will be PROPORTIONATELY insignificant
Not likely to cause the patient a problem
115
What could cause a disproportionate rise/ increase in the blood plasma level of a highly protein-bound drug?
Saturation of protein binding sites
116
How are Vd and Clearance values determined?
From an average of the population
117
How do Vd and Clearance values differ for specific drugs in TDM?
(1) Begin with average population values
| (2) Adjust for individual patients
118
How are Vd and Clearance values adjusted to be more specific for the patient?
(1) Patient CpSS (steady state) is measured
(2) Compare with expected average population values
(3) Adjust KE (rate of elimination) to better match drug clearance in individual patient
(4) Use patient-specific Clearance values for future dosing calculations
119
If the individual/ specific Clearance or Vd values vary significantly from the average values from the population, why could this be?
- Concurrent drug therapy (interaction)
- Compliance
- Medication error
- Malabsorption
- Incorrect assay results
Specific patient may be genuinely different from average population data
120
How can specific/ individual patient clearance be estimated PRIOR to waiting for steady state blood plasma concentration being achieved?
Blood sample taken
Measure of creatinine clearance
121
How is creatinine produced?
Creatinine is a breakdown product of creatine phosphate in muscles
122
Where is creatine phosphate broken down?
In muscles
123
What does creatine phosphate produce when broken down?
Creatinine
124
At what rate is creatinine produced?
Constant rate
125
Does creatinine protein-bind?
No
126
Is creatinine reabsorbed in the kidneys?
No, almost entirely not
127
What is creatinine clearance a useful measure of?
(1) Kidney function
(2) Predicted patient-specific drug clearance
(3) Approximation of actual glomerular filtration rate
128
How can actual glomerular filtration rate be approximated?
Measurement of creatinine clearance
mg/mL
129
What is C(urine)?
Creatinine concentration in the urine
130
What is V(urine)?
Volume of urine collected in mL/min
131
What is C(plasma)?
Creatinine concentration in the plasma
mg/mL
132
What are the units for creatinine clearance?
mL/minute
Clearance has units of volume per time
133
What equation is used to measure creatinine clearance definitively?
CLcr = {C(urine) x V(urine)} / C(plasma)
134
What equation is used to measure creatinine clearance approximately?
Cockcroft-Gault equation
CLcr(est) = {(140-age) x Weight x Constant} / C(s)
135
In an equation, what does C(s) represent?
Serum creatinine
136
What is the constant used, for men, to calculate estimated creatinine clearance?
1.23
137
What is the constant used, for women, to calculate estimated creatinine clearance?
1.04
138
What is the significance of 1.23, regarding elimination?
Creatinine clearance
Constant (numerator) for MEN
139
What is the significance of 1.04, regarding elimination?
Creatinine clearance
Constant (numerator) for WOMEN
140
What is the Cockcroft-Gault equation?
CLcr(est) = {(140-age) x Weight x Constant} / C(s)
141
What is the Cockcroft-Gault equation used for?
Estimation of creatinine clearance for an individual
142
What happens to serum creatinine concentration as GFR decreases?
Increases
Less creatinine is being cleared
143
What drug categories is TDM used for?
(1) Antiepileptics
(2) Aminoglycoside antibiotics
(3) Cardiac drugs - e.g. digoxin, lidocaine
(4) Others - theophylline, lithium, methotrexate
144
What are anti-epileptics used for?
Treating/ prophylaxis of seizures
145
What are example(s) of the 'old-style' anti-epileptic drugs?
- Phenytoin
- Carbamazepin
- Sodium valproate/ valproic acid
146
What are example(s) of the 'new-style' anti-epileptic drugs?
Gabapentin
147
What is phenytoin?
An old-style anti-epileptic drug
148
(1) What is the therapeutic range of phenytoin?
| (2) What happens if there is an overdose?
(1) 10-20mg/L
| 2
- Blurred vision
- Drowsiness
149
How significantly is phenytoin metabolised?
Heavily metabolised
150
Is phenytoin protein bound?
Yes. Highly protein bound
151
What is Vmax?
Reaction rate when binding site is fully saturated
Maximum rate of reaction
152
In an equation, what does V refer to?
Rate of reaction
153
In an equation, what does K(m) stand for?
Michaelis-Menten constant
154
How is the daily dose of a drug, such as phenytoin, calculated?
Daily dose = (Vmax x CpSS) / (Km + CpSS)
155
How is Vmax for a drug derived?
Calculated from population data
Population average for that specific drug
156
How is Km for a drug derived?
Calculated from population data
Population average for that specific drug
157
What is Km?
The substrate concentration when the rate of reaction is 1/2 of Vmax
158
What is the equation used to calculate steady state blood plasma (CpSS), with regard to daily dose?
CpSS = (Daily dose x Km) / (Vmax - Daily dose)
159
What is lithium indicated for?
- Acute mania
| - Prophylaxis of manic depression
160
Describe the therapeutic window of lithium.
Narrow
0.4-1.2mmol/L
161
What is the effective dose for lithium?
Varies significantly from patient to patient
162
What are the effects of toxicity/ overdose of lithium?
- Blurred vision
- Drowsiness
- Confusion
- Palpitations
163
Define teratogen.
A factor which causes malformation of an embryo
164
Does lithium require therapeutic drug monitoring (TDM)?
Yes.
Because the therapeutic dose varies SIGNIFICANTLY in patients
165
Describe metabolism of lithium.
Not metabolised
166
Describe the excretion of lithium, relating to rate clearance.
First order elimination
Clearance approximates to 25% of creatinine clearance
167
How does the clearance of lithium compare to the clearance of creatinine?
Approximates to 25% of creatinine clearance
168
What can decrease the elimination of lithium?
- Decreased renal function
- Diuretics
- most NSAIDs
169
What can increase the elimination of lithium?
- Aminophylline
| - OTC antacids
170
What is aminophylline?
A compound of theophylline
A bronchodilator
171
What formulations are available for lithium?
(1) Oral solids:
- e.g. lithium carbonate
(2) Oral liquids:
- e.g. lithium citrate
172
What is the therapeutic range of lithium, in mmol per litre?
0.4-1.2mmol/L
173
How much does 1mmol of lithium weigh?
Mr of lithium = 7
Therefore, 1mol = 7g, so 1 mmol = 7mg
174
What is the therapeutic range of lithium, in mg per litre?
2.8-8.4 mg/L
175
What is the salt factor for lithium carbonate?
Lithium carbonate = Li2CO3
0.19
176
Describe the therapeutic range of theophylline.
Narrow therapeutic range
5-15 mg/L
177
When is toxicity reached in theophylline?
>20 mg/L
178
What are the symptoms of theophylline toxicity?
- Arrhythmias
| - Seizures
179
Describe the inter-patient variability of theophylline?
Significant inter-patient variability
180
What was theophylline previously indicated for?
COPD
181
Why is theophylline no longer widely used for treatment of COPD?
There are now longer-acting inhaled agonists available
182
What is the most common formulation of theophylline?
Sustained-release
183
Describe the rate of elimination of theophylline?
First order elimination
184
What causes the significant variation in clearance of theophylline?
(1) Age
(2) Liver cirrhosis - decreases clearance/ elimination
(3) Cystic fibrosis - increases clearance/ elimination
(4) Co-medication
185
Describe the effect of liver cirrhosis on clearance/ elimination of theophylline.
Decreases clearance/ elimination
Due to reduced hepatic clearance - metabolism
Decreased by 40%
186
Describe the effect of cystic fibrosis on clearance/ elimination of theophylline.
Increases clearance/ elimination
187
Describe the effect of phenytoin on clearance/ elimination of theophylline.
Increases clearance/ elimination
Increased by 75%
188
Describe the effect of oral contraceptives on theophylline clearance/ elimination.
Decreases clearance/ elimination
Decreased by 30%
189
Describe the effect of acute pulmonary oedema on clearance/ elimination.
Decreased by 50%
190
Describe the effect of congestive heart failure on clearance/ elimination.
Decreased by 40%
191
Define congestive heart failure.
Fluid build up in the heart
Creates inefficiency of heart pumping
192
Describe the effect of liver cirrhosis on clearance/ elimination.
Decreased by 40%
193
Describe the effect of mild smoking on clearance/ elimination.
Increased by 50%
194
Describe the effect of heavy smoking on clearance/ elimination.
Increased by 100%
195
How do the effects of heavy smoking and mild smoking on clearance/ elimination compare?
Mild - Increase by 50%
| Heavy - Increase by 100%
196
Define cystic fibrosis.
Condition where the lungs become filled with thick, sticky mucous
197
Describe the effect of propranolol on clearance/ elimination.
Decreased by 30%
198
Describe the effect of oral contraceptives on clearance/ elimination.
Decreased by 30%
199
Describe the effect of cimetidine on clearance/ elimination.
Decreased by 40%
200
What is cimetidine?
H2 receptor antagonist
Reduces stomach acid production
201
Describe the effect of carbamazepine on clearance/ elimination.
Increased by 50%
202
Describe the effect of phenytoin on clearance/ elimination.
Increased by 50%
203
Describe the effect of rifampicin on clearance/ elimination.
Increased by 50%
204
Why are biologics/ biomacromolecules not suitable for oral administration?
Broken down by proteases in the GIT
205
How are biologics/ biomacromolecules administered?
(1) IV - most common
(2) SC - leads to lymphatic system
(3) IM
206
How are biologics/ biomacromolecules distributed in the body?
Vascular space -> Lymphatic system
via interstitial tissue space
207
How does the volume of distribution (Vd) vary in biologics/ biomacromolecules?
8-20L
208
Define catabolism.
Metabolic pathway which breaks down molecule into smaller sub-components
209
Describe the elimination of biologics/ biomacromolecules.
Too large to be filtered by the kidneys
Usually reabsorbed in the kidney
Mostly eliminated via intracellular catabolism
210
(1) What are biologics/ biomacromolecules broken down into?
| (2) How are they broken down?
(1) Constituent amino acids
| (2) Intracellular catabolism
211
Describe the t(1/2) of a biologic/ biomacromolecule.
Typically very long half-life
Measured in days
212
What effect does the long half-life of biologics/ biomacromolecules have on dosing?
Long dosing intervals
213
What does 'MAB' refer to?
Monoclonal antibody
214
How is a monoclonal antibody abbreviated?
MAb
