Metabolism Of Drugs Flashcards
1
Q
Decreased Vd
A
Increased plasma cxn
2
Q
Decreased Vd
A
Increased plasma concentration
3
Q
Vd=100
A
Decreased plasma
4
Q
What is considered normal Vd
A
Anything that sounds physiologic
- 60% BW water
- 40L of water in body
- less than that is low
5
Q
What is considered a high Vd
A
100, 1000L, higher than physiologic
6
Q
Vd calculation
A
Amount in body/cxn in plasma
7
Q
What does Vd refer to
A
Not necessarily to an identifiable physiological bioluminescent, but merely to the volume that would be required to contain all of the. Drug in the body at the same concentration as in the plasma
8
Q
What is Vd often referred to
A
As the apparent Vd
9
Q
Two scenarios of distribution
A
- drugs are distributed throughout the body but not eliminated
- drugs are distributed throughout the body and are eleiminated
Reality is that drugs are eliminated
-plasma cxn is always going down
10
Q
What does a classic IV distribution slope look like
A
Starts out high and with a steep slope, and then taping off to a less steep slope, going down. Starts at its highest cxn then falls.
11
Q
Steep slope in the IV distribution curve
A
Changes plasma cxn fast
12
Q
Flatter slope in the IV distribution slope
A
Elimination
13
Q
What does the shape of a distribution curve tell us
A
How the drug was given
14
Q
When you get a question about Vd, and it asks amount, what should you be careful not to do
A
If it asks amount, looking for mg, not liters. If L are involved, it is a cxn, not amount
15
Q
What are two ways in which we should know how to calculate Vd
A
Know how much you would give
Know how much MORE you would give to reach a certain amount if there was already some of the drug in the body.
Vd(C2-C1)
16
Q
What does a large Vd tell us
A
That most of the drug is in the extra plastic space (tissue)
17
Q
Vd and half life
A
A factor that increases Vd can increase the half life and extend the duration of action of that drug
18
Q
Drug reservoirs
A
There are a lot of them. Drugs can be in all kinds of tissues
19
Q
And 80kg person has a Vd of 18L/kg of a drug in his body. Is hemodialysis a good option to rid him of this drug?
A
Vd=18x80=very high Vd!!
Hemodialysis best for low vD, when doing Vd cases, always look at units
20
Q
Placental transfer of drugs
A
- not a barrier to drugs, most drugs cross by simple diffusion
- can cause congenital abnormalities
- fetus is exposed to some extent to essentially all drugs taken by the mother
- any drug that can get to the CNS can get to the fetus
21
Q
3 types of drug metabolism
A
- mechanism of termination of drug action
- mechanism of drug activation
- drug elimination without metabolism
22
Q
Drug metabolism as a mechanism of termination of drug action
A
Active to inactive. The action of many drugs is terminated before that are excreted because they are metabolized to biologically inactive derivatives
23
Q
Drug metabolism as a mechanism of drug activation
A
Inactive to active
Prodrugs
Active to more active
Liver metabolizes most drugs, that’s why liver damaged with acetaminophen
24
Q
Prodrugs
A
Inactive as administered, these drugs must be metabolized in the body to become active
25
Drug elimination without metabolism
Some drugs such as lithium are not modified by the body, act until they are excreted
26
What are the two types of metabolism
Phase I
| Phase II
27
Phase I metabolism
Making minor changes to drug to make more water soluble
| -accomplished by enzymes (cytochrome P450) found in smooth ER
28
Phase II metabolism
Involve conjugation reactions where an endogenous substrate is conjugated to the drug via the actions of a transferase enzyme
-attach another substance in body to the drug to make it heavy and hard to move in the body
29
What type of metabolism involves making minor chemical changes to the drug to make more water soluble
Phase I
30
What type of metabolism involves transferase enzymes
Phase II
31
What type of metabolism is lacking in neonate
Phase II
| -makes them susceptible to drugs metabolized in this manner
32
For phase I and phase II metabolism, what order do they occur in
This is not a sequence and they can occur in any order
33
Top two sites for metabolism
Liver and kidney
34
What is the most important organ for metabolism
Liver
35
Metabolism occurs via enzymes located in or on:
- smooth ER (phase I)
| - cytoplasm (phase II)
36
What is in the center of a cytochrome P450?
Heme complex
37
How are cytochrome P450 enzymes names
With a root CYP followed by a number designating the family, a letter denoting the subfamily, and another number designating the CYP form.
-CYP3A4 is family 3, subfamily A, gene number 4
38
How many CYPs that metabolize drugs in humans
12
39
The mast active CYPs for drug metabolism re
CYP2C, CYP2D, CYP3A
40
Which CYP does most of the metabolism
CYP3A metabolizes 50% of all drugs
41
What are the phase I reactions (CYP450)
1. Cytochrome P450-dependent oxidation
2. Reduction
3. Hydrolysis
42
Drugs that increase the expression of p450 enzymes
CYP inducers
These ultimately increase metabolism, and decrease affect of the drug
43
Drugs which will reduce the plasma level and therefore the effectiveness of the substrate drug.
CYP inducers
44
What CYP gets most affected from CYP inducers
3A, it metabolizes 50% of drugs
45
List of CYP inducers
- benzopyrenes from cigs
- ethanol (chronic)
- carbamazepine
- rifampin
46
What is this an example of: in a patient taking oral contraceptives who is later Rxed rifampin for a bacterial infection, she becomes pregnant
CYP inducers
Increased enzymes, decreased plasma cxn of BC
47
Drugs which decrease the expression of p450 enzymes, causing an increase in the plasma level and therefore increase the toxicity risk of the substrate drug
CYP inhibitors
48
List of CYP inhibitors
- cimetidine (ulcer meds)
- erythromycin
- Grapefruit juice (NOT GRAPE JUICE)
49
What is this an example of: in a patient taking warfarin as an anticoagulant who is later Rxed cimetidine for peptic ulcers, he bruises and bleeds easily
```
CYP inhibitor (cimetidine)
-increased plasma warfarin which increase risk of bleeding
```
50
Phase II metabolism reactions
1. Glucuronidation
2. Sulfate on
3. Acetlyation
51
Enzyme associated with glucuronidation
Glucuronosyl transferase
52
Enzyme associated with sulfation
Sulfotransferase
53
Enzyme associated with acetylation
Acetyltransferase
54
What is something to take into consideration when talking about acetylation in phase II metabolism reactions
Some people are slow or fast acetylators (genetic variation)
- if fast, you rapidly metabolize drugs by acetyltransferase
- slow=drug induced lupus
55
Slow acetlators
Longer half life, can get lupus if you take certain drugs
56
Difference between drug elimination and drug excretion
A drug may be eliminated by metabolism long before the modified molecules are excreted from the body
57
What are the two ways drugs are terminated
Metabolism
Renal excretion
(Liver and kidneys!)
58
What are the three steps to renal excretion of drugs
1. Glomerular filtration
2. Proximal tubular secretion
3. Distal tubular reabsoprtion
59
Glomerular filtration of drugs
- Only free, unbound drug is filtered
| - lipid solubility and pH DO NOT influence passage of drugs into the glomerular filtrate
60
Do lipid solubility and pH influence passage of drugs into the glomerular filtrate?
No
61
Proximal tubular secretion in renal exretion of drugs
Secretion occurs by active transport
- OAT
- OBT
Competition between drugs for certain carriers can occur
62
This part of renal excretion of drugs requires ATP
Proximal tubular secretion
63
What are the two energy require transport systems of proximal tubular secretion
OAT and OBT
64
Where can there be competition between drugs for carriers within each transport system (OAT and OBT)
Proximal tubular secretion
65
What part of the renal excretion of drugs is incomplete in premature infants and neonate
Proximal tubular secretion
| -may retain certain drugs
66
Distal tubular reabsorption in the renal excretion of drugs
- distal convoluted tubule
- if uncharged, the drug may diffuse out of the tubular and back into the systemic circulation
- manipulating the pH of urine increases elimination of drugs
67
What is the exception for charged/uncharged ions and getting across membranes
In the glomerulus.
- it is a poor charge filter but a good size filter
- lets charged and uncharged in
68
Transporters for weak acids and bases
OAT and OBT
69
What part of renal excretion of drugs is affected by manipulating the pH of urine
Distal tubular reabsorption (distal convoluted tubules)
70
What is the only type of drug that can get filtered into the glomerulus
Free drugs
71
What does adding a weak acid to eliminate the overdose of a weka base have to do with
Reabsoprtion
72
Other modes of excretion other than renal
- GI
- pulmonary
- milk
73
Relates the rate of elimination to the plasma concentration
Clearance
74
high clearance, ____plasma cxn
Low
75
Low clearance, _____plasma concentration
High
76
Clearance equations
CL=(rate of elimination of drug)/(plasma drug concentration [Cp])
Rate of elimination=Cl x Cp
77
What are the two types of elimination kinetics
First order
| Zero order
78
First order kinetics
- constant fraction of drug eliminated
- half life is constant
- non-saturating kinetics (enzymes working at less than Vmax)
79
What kind of kinetics are most drugs
Most are eliminated by 1st order kinetics, all drugs are this except PEA, even overdoses
80
Zero order kinetics
- constant amount of drug eliminated
- half life not constant
- saturating kinetics (enzymes are at Vmax)
- HIGH DOSES of aspirin, ethanol, phenytoin (ZERO PEAs)
81
This is the type of elmination seen in very high doses of phenytoin, ethanol, and aspirin
Zero order kinetics
82
If the Vd increases, what happens to the half life
Increases
83
If the clearance increases, what happens to half life
Decreases
84
Time it takes to cut level of drug in half
Half life
85
Maintenance dose
Drug you are taking every day
| Chronic
86
Loading dose
Don't do it often
| Acute
87
Proper dosing regimen
Achievement of therapeutic window in blood without exceeding minimum toxic concentration of falling below the MEC
88
When do you not need to check a patients plasma levels when they are taking a drug
If easily measured, such as in reading blood pressure. You can take their blood pressure and see if it is working as opposed to checking their plasma levels
89
When do you need to check a patients plasma levels when they are taking a drug
When you cannot measure the effectiveness by any other means.
- drugs for prophylaxis
- must be titrated carefully
1. Pick desired dose (steady state) plasma level for drug
2. Compute dose to achieve value
3. Measure plasma level of drug
4. Adjust as necessary
90
Maintenance dose
MD=Css x CL/F
Css=cxn at stead state (what we want to achieve)
F=bioavailability (F=1 for IV)
CL=clearance
91
What is the maintenance dose for someone with a steady state of 10mg/L, clearance of 1mL/min, and bioavailability of 1 (IV)
(10mg/L x 1 mL/min)/1
10mg/min=maintenance dose
92
A patient with an asthma attack was relieved with 40mg/h of theophylline but the clinical wants to maintain the plasma concentration of theophylline at 15mg/L by oral dosing. What would be the calculated oral doses be at 6, 6, and 12 hour intervals?
6 hour intervals= 40mg/h x 6hr=240mg
8 hour intervals=40mg/hr x 6hr=320mg
12 hr intervals=40mg/hr x 12h= 480mg
We chose one of these based on the therapeutic window
93
One or series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly
Loading dose
94
Equation for loading dosage
Loading dose Css x Vd/F
95
If the problem says "Single IV bolts" what kind of dosing is it
Loading dose
96
Dose that achieves cxn above MEC immediately, used in life threatening situations
Loading dose
97
What is the main difference between maintenance dose and loading dose
Maintenance factors in CL, loading dose doesn't care about that. Loading dose cares about Vd, getting drug to target tissue
98
If the clinician is giving a loading dose to the asthma patient above (15mg/L), how would you calculate the dose given that the volume of distribution of theophylline is 0.5L/kg.
15mg/L X (0.5L/kg X 68Kg)
510mg
99
When would you want to give a loading dose
-time required too reach steady state is long, such as in ventricular arrhythmias
100
What is the goal of maintenance dose
Steady state is the goal
101
Steady state in maintenance dose
Curve will plateau, plateau principle. Want to stay at plateau
102
To ensure the appropriate response to a drug given for long term therapy, it is necessary to achieve a ________ of the drug in the plasma
Steady state
103
Equation for maintenance dose
MD=Css x CL/F
104
The time it takes for reach steady state for a drug is eliminated by _______ kinetics
First order
| The half life remains constant
105
Half life and steady state
Remains constant.
Tells us how long to reach steady state
106
What kind of kinetics must be used for steady state
First order kinetics
107
For the graph of steady state (maintenance) and for elimination
They are the same, just inverted
- plasma cxn of drug on the Y axis
- time on the X axis
108
When looking at a graph with plasma concentration (steady state) on the Y and time on the X, and there is a plateau, what kind of dose is it
Maintenance dose
109
Do we care more about clinical steady state or mathematical
Clinical
110
Does clinical steady state = mathematical steady state?
No
111
It is generally accepted that drugs will reach "clinical" steady state in _______ half lives
4-5 half lives
112
Mathematical steady state is approximately ______ half lives
10
113
In clinical steady state, do we ever reach 100%
No, clinically, 93% and up is considered close enough
114
How do you find the clinical steady state of a drug with a given half life?
Since clinical steady state is 4-5 half lives, just multiple the half life times 4 or 5. So a drug with a 2 hour half life would have a steady state of 8-10 hours
115
Theophylline is infused at a rate of 20mg per hour and steady state plasma levels of 7.5 micrograms are reached in 32 hours. If the infusion rate is doubled, how long will it take to reach steady state?
32 hours
| -depends on half life, infusion rate does not matter, and doesn't depend on amount of drug
116
What is the steady state level of theophylline at the infusion rate of 40mg/hour? Previously, it was infused at a rate of 20mg per hour at a plasma steady state of 7.5 micrograms/ml
20= 7.5xCL/F
40=X x CL/F
If CL and F are constant, then it would have had to have doubled
X=15ug/ml
117
If you have a drug with two different steady states, do they reach the steady state at the same time?
Yes, infusion rate doesn't matter for this, amounts are different but time is the same
118
A single IV injection of 100mg of a drug is given and it takes 8 hours to eliminate 1/2 the drug from the body. How long would it take to eliminate 1/2 the drug if only 50mg were given in a single injection
8 hours
- same drugs, same half life
- 1/2 life unaffected by amount of drug
119
Half life and amount of drug
Half life is unaffected by the amount of drug given either by constant infusion, single injection,or orally, as long as the drug is eliminated by first order kinetics
120
Which of the following dosage regimens would be appropriate for a drug with a half life of 12 hours; a continuous infusion of two units of drug per day, injection of two units of drug once a day, or injection of one unit of drug twice a day?
Not enough info
- need MEC
- need MTC
- having these gives us the therapeutic window which is where the steady state needs to stay
- once a day dosing good with wide window
- narrow window will work best with 1 unit of drug twice a day, because it doesn't oscillate as much
121
Where do we want the peaks and troughs of a drugs steady state to stay
Within the therapeutic window
122
When it asks for drug concentration after 5 half lives after the dose given
Count the peaks over 5
123
When it asks for the drug concentration of a drug before the dose and its asking after a certain number of half lives
Count troughs
What is the plasma level before the 3rd dose. Count over 3, including the 0 as your first one
124
The ___________ will usually determine the desired trough levels of a drug given intermittently
MEC
125
The _______ determined the permissible peak of a drug given intermittently
MTC
126
Drugs you take once a day have a ______ therapeutic window
Wide
127
Drugs you take many times a day have a ______ therapeutic window
Narrow
128
What is the normal creatinine clearance
100mL/min
129
What is the dosage adjustment calculation for patients with renal failure
Corrected dose = average dose x (pts creatnine clearance/100mL/min)
130
A dose of 100mg Celebrex is ordered for RA treatment. The patient is found to have a createnine clearance of 50mL/min. What does of Celebrex should be administered to this patient
Corrected dose=100mg x (50mL/min/100mL/min)
50mg
If kidney function is half, going to give them half the dose
131
Non renal routes of clearance
For example, if a drug is cleared 50% by the kidney, and 50% by the liver, you would have to calculate the dosing according to that
132
What 4 equations WILL be on the test
Vd= (amount in body)/(plasma cxn)
Maintenance dose=Css x CL/F
Loading dose= Css x Vd/F
Renal dysfunction= dose x (pts renal/100)
1/2 life = .693 x Vd/Cl (only know relationship)
