Basic of Pharmacology: Pharmacokinetics Part II Flashcards
2nd part of PP
1
Q
What is the other name of Cytochrome P-450 system
A
Mixed Function oxidase (MFO) Enzyme system.
2
Q
CYP 450 enzymes definition? They are responsible for ________and _________ Phase _____metabolic reaction of drug.
A
Group of membrane bound microsomal enzymes responsible for OXIDATION and REDUCTION phase I metabolic reaction of drug
3
Q
What is the primary membrane bound organelle where CYP 450 is located? the membrane organelle of which specific organ _______; Other organ too.. Yes or NO?
A
Smooth ER in the LIVER; Yes
4
Q
CYP 450 system has more than ______individual CYP 450 Enzymes
A
50
5
Q
What is the most abundant CYP expressed in the liver?
A
CYP3A4 (most amount of drug metabolism)
6
Q
CYP 450 enzyme system, they have enzyme_______ or _________
A
Induction
Inhibition
7
Q
Enzyme induction means: (Enzyme induced)
A
Enzyme activity increased
8
Q
Enzyme inhibition means: (Enzyme reduced)
A
Enzyme activity decreased
9
Q
1 way to major source of drug-drug interactions
A
Enzymes Induction and inhibition
10
Q
All enzymes cannot be
A
induced or reduced.
11
Q
CYP 450 inducers are drugs
A
have to ability to stimulate/induce the activity of CYP450 microsomal enzymes
12
Q
CYP 450 inducers are drugs
A
have to ability to stimulate/induce the activity of CYP450 microsomal enzymes
13
Q
Classic examples of CYP 450 inducers (RPP-CSC)
A
Rifampin Phenobarbital Phenytoin Carbamazepine St John's Wort Cigarette smoking
14
Q
IMPORTANT: If you give a patient rifampin (inducer) and you give patient drug B what will happen to drug B
A
DECREASED level of Drug B SYSTEMICALLY because the rifampin induces CYP450 (more enzymes available) Drugs B will go under extensive metabolism, so systemic levels will decrease
15
Q
IMPORTANT: CYP 450 inhibitor are drugs
Know the reducers drug
A
Inhibit activity of CYP450 microsomal enzymes
16
Q
Non-MICROSOMAL ENZYMES responsible primarily for phase ____reactions : such as ______ and ______ and some ______ and _____
A
II ; conjugation, hydrolysis; oxidation and reduction
17
Q
Are non-microsomal enzymes CYP 450 enzymes
A
no
18
Q
NON-SPECIFIC ESTERASES enzymes responsible for
ANY ester bonds drugs and any ester local anesthetics
A
Hydrolysis of drugs;
19
Q
Non-microsomal enzymes such as ______ _____ _and ________ enzymes (Do/DO NOT) undergo enzyme induction
A
Plasma cholinesterase and acetylating enzymes
20
Q
Factors affecting metabolism (DAGPIE) : Which is the most important?
A
DAGPIE Disease state Age Gender PHARMACOGENETIC factors Induction or inhibition of enzyme Environmental factors
21
Q
What is EXCRETION
A
The irreversible removal of drug form the body
22
Q
What is the main organ responsible for the removal of drugs and drug metabolites
A
Kidney
23
Q
IMPORTANT: Primary excretory organ
A
Kidney
24
Q
What are the 2 major pathway of renal excretion?
A
Glomerular filtration
Tubular secretion
25
How does Biliary excretion occurs :
directly into the bile from the liver cells.
26
Where are gaseous and volatile anesthetics excreted_______
Excreted via the lungs
27
What is clearance (drug elimination other term)
the irreversible removal of drugs from the body FROM ALL ROUTES OF ELIMINATION
28
Drug elimination : clearance (Cl) combined with these two PHARMK...c phases
Metabolism and Excretion
29
IMPORTANT: Why do we care about clearance?
body elimination dose of a drug
***MAINTENANCE DOSE OF A DRUG requires to OBTAIN A GIVEN STEADY STATE SERUM CONCENTRATION
How much to give
potential drug-to-drug
30
Clearance (PHARMACOKINETICS definition)
The volume of plasma cleared of drugs from the body per unit of time (Volume of plasma drug -free /unit of time )
31
Formula of TOTAL CLEARANCE IN THE BODY; clearance
Cl total = Cl renal X Cl hepatic x Cl other (lungs)
32
MEMORIZE THIS (IMPORTANT) Body clearance ? VD is ______ __ _______ and K (el) _____________
Cl = Vd + K(el); Volume of distribution; Elimination rate constant K (el)
33
Clearance made up of 2 processes
Metabolism
| Excretion
34
Organ for clearance : primary route of drug metabolism ___________and _______ ______system is the primary system responsible for drug metabolism
Liver; CYP 450
35
a) If the drug infusion matches the clearance rate then the drug concentration _________(elevated, decreased, constant)
b) If the clearance rate exceeds the infusion rate then the drug concentration ________
a) will be constant
| b) Will fall
36
The most important to determine clearance of REGULAR DRUGS
Drug elimination half life
37
Hepatic Clearance
VOlume of blood that perfuses the liver that is cleared of drug per unit of time
38
Determinants of HEPATIC CLEARANCE
```
Liver blood flow (Q)
Extraction Ration (ER)
```
39
Hepatic clearance formula
Hepatic blood flow (Q) x Hepatic extraction rate
40
HWat does Extraction rate takes into consideration
Drug intrinsic clearance and protein binding
41
High hepatic Extraction Ratio (ER >0.7)
That particular drug is going to be cleared through the LIVER dependent SOLELY on HEPATIC BLOOD FLOW
42
Changes in liver enzyme activity have (lot/minimal ) ________influence on hepatic clearance. JUST ______
minimal; ______Hepatic
43
3 drugs with HIGH EXTRACTION RATIO and HEAVILY HEPATICALLY CLEARED
Lidocaine, propofol, and propanolol
44
If patient is on propanolol should __________
Take up until ready for surgery
45
LOW hepatic Extraction Ratio (ER <0.3); Hepatic clearance will/will not dependent on hepatic blood flow
Hepatic clearance will NOT depended on hepatic blood flow
46
Hepatic clearance is affected by _______ _____binding and _______ activity
Protein and enzyme binding
47
Protein binding ________ in binding will _______ hepatic clearance
Decreased: increased
48
Enzyme activity _________ in activity will ______hepatic clearance
increased ; increased
49
CLASSIC example of low hepatic Extraction ration drug
Alfentanil
50
Renal Clearance: 3 Processeses
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
51
Glomerular filtration what happens:
Free fraction of unbound drug filtered via the glomerulus
| Bromanc Capsule
52
Does highly protein bound readily filtered at the glomerulus?
No
53
What is GFR?
is the amount of glomerular filtration formed each minute by all nephrons.
54
The higher the number the ______ the clearance
Better
55
Active tubular secretion requires _______ and_____transport
active transport, requires energy
56
ACtive tubular secretion does what?
Move drug from the blood into tubular
57
The majority of drug tubular secretion takes place where
In the PROXIMAL TUBULE
58
****IMPORTANT the kidneys eliminate drug from plasma by both
Glomerular filtration
| Active Tubular secretion
59
***Able to give lasix to some patient because they may use
active tubular secretion although GFR may be not working
60
Passive tubular reabsorption definition
is the process by which solutes and water are removed from the tubular fluid and brought back to blood
61
What form is readily reabsorbed? where does it occur ?
NON-IONIZED; DISTAL TUBULE OF the NEPHRON
62
Example of a drug OCCURS primarily with highly lipid soluble compound
Sodium Thiopental
63
Factors affecting rate of reabsorption
pH
| pKa
64
*****IMPORTANT CONCEPT ANSWER THIS : A more acidic urine will do what to a basic drug and what to an acidic drug?
excrete faster
65
Cockcroft-Gault Equation (no need to know formula) : FDA approved
Calculate creatinine clearance, how well the kidney is doing the process of glomerular filtration
66
****IMPORTANT CONCEPT ANSWER THIS: A basic urine will do what to a basic drug and what to an acidic drug?
excrete faster
67
Biliary excretion definition
the transfer of drug or metabolites form the PLASMA to the BILE through hepatocytes
68
This transport is due to ______ secretion of drugs into the ______ by means of Transport protein systems
active' bile
69
_________ _______May prolong the pharmacological effect of certain drugs
ENTEROHEPATIC CIRCULATION
70
ENTEROHEPATIC CIRCULATION
A drug or metabolite secreted into bile will eventually into the duodenum via the gallbladder
71
Examples of drugs of enterohepatic circulation?
morphine
| Diazepam
72
ENTEROHEPATIC CIRCULATION.
The cycle in which the drug is absorbed, excreted into the bile and reabsorbed
73
Pharmacokinetic Models
Hypothetical structures used to describe the fate of a drug in the body following its administration.
74
The distribution of drugs in the body can be described by :_______, ______ or _________
one, two or three compartment models.
75
One COMPARTMENT MODEL means:
| EX
Entire body as single compartment, evenly distributed; Single volume and clearance;
Example is : SINGLE BOLUS of a drug
76
Assumption of the one compartment model
Drug distribution and equilibration to all tissues and fluids occurs instantly (not really true)
77
Elimination occurs via (1 compartmnt) in ______ order kinetics.
FIRST ORDER KINETICS
78
Once equilibration is reached in 1 compartment
the drug concentration at the site of action is approximately the same as in plasma
79
IMPORTANT : If we know the concentration we want to achievee and know the _____ _________ then we can calculation using the dose required to achieve that concentration. State formula: substitute variables as needed
Volume of distribution
Vd= Dose/Concentration
CONCENTRATION= Dose/ Vd
80
Plasma concentration vs. Time curves for drugs
A graphical way to show what is happening to the drug concentration overtime after you give an IV bolus.
81
Time is on the ____ axis
| Plasma is on the ___axis
x axis
| y axis
82
NOT IMPORTANT : THE STRAIGHTER CURVE
BETTER AT PREDICTING
83
MOST ANESTHETICS undergo________Model
Multicompartment
84
Two-compartment model pharmacokinetics design
CENTRAL
| PERIPHERAL compartments
85
What happens during 2 compartment model ; List 5 organs.
Drugs is introducedDistribuated rapidly and UNIFORMY inthe bloodsteram and the highly perfused ORGANS (Heart, lung, kidney, liver, Brain)
86
What is the central compartment
lungs, brain, liver, kidney and heart
87
During the 2 compartment model has defined
Distribution and Elimination phase
88
Distribution phase is ________During the distribution, changes in the concentration of the drug______What happens?
Rapid movement of drugs from the plasma to the rapidly equilibration tissues. Reflect the concentration of drug in the plasma reflect primarily movement of drusg within, rathe than loss from the body. NOT INSTANTANEOUS
89
Explain the elimination phase as it relates to drug in plasma and volume of distribution? What happens when the drug has reached equilibration in plasma and tissue?
The relative proportion of drug in the plasma and peripheral volumes of distribution remains constant. Once the drug in the plasma and tissues has
reached equilibrium, the decline of plasma concentration is driven by elimination of the drug from the body from the central compartment be metabolism OR excretion
90
Peripheral compartment"
Fat , muscle, skin, CSF
91
*****ANESTHETIC DRUGS distribute extensive into ________ -____
peripheral tissues
92
Does drugs elimination occur from peripheral Tissues? They have to go back to the blood stream?
NO
93
Some anesthetics should be tailored from patient who are
morbidly obese.
94
INTERCOMPARMENTAL CLEARANCE is
the movement of the drug from the central to the periperal compartment .
95
Peripheral compartment decline wih
Aging.
96
Any residual drug present in the peripheral compartment at the time of repeat IV dosing may result in (increased/diminished)________ effect of distributive process on the reduction of the plasma concentration and lead to exaggerated effects
The degree of cumulative effect can be predicted by several factors such as dosing interval and knowledge of the elimination half-life
diminished
97
As you increase time, concentration ________
Decreases
98
Vd should be drawn in what phase
elimination phase
99
Distribution half life; calculated in ____
| Tells you the plasma concentration is declining because moving from PLASMA to the tisses
Distribution phase
100
Shorter half life, the faster the plasma
decreasing.
101
MOST ANESTHETICS follow a ______compartments model
3
102
Such as propofol
1 central , 2 peripheral compartments.
103
Drugs like propofol uses : 3 compartments
1 central , 2 peripheral compartments.
104
VERY IMPORTANT IN ANESTHESIA: Following the administration of an IV anesthetic drug, the immediate distribution phase causes a brisk decrease in plasma levels as the drug is transported to the rapidly equilibrating vessel-rich group of tissues where the drug can cause their effect
From brain to other peripheral compartments.
105
MOST SITE OF ACTION FOR ANESTHESIA meds
BRAIN
106
Redistribution is _____________
Drug effect is terminated when the drug leaves the vessel-rich group and redistributes to other less well perfused tissues such as muscle and fat
107
Describe redistribution pathway once you give an IV medication ...
Give IV---> Majority in blood _--> Brain--> Blood concentration decreases --> Brain concentration increased- --> once brain concentration decreased--> tissues and fat concentration increases.
108
Pt wakes up after anethesia
Because of redistribution
109
Determinant of tissue uptake of drugs
Blood flow
Concentration gradient
BBB
Physiochemical properties of drug (solubility, ionization and protein binding
110
Determinants of the capacity of tissue to store drugs (KEEP IT )
lipid solubiltiy (the greater > the more able to keep)
tissue mass
Binding to macromolecules
pH of the tissue.
111
VERY IMPORTANT for non-anesthetics drugs
Elimination half life
112
MEMORIZE This DEFINITION
Time necessary for the serum (plasma) concentration to decrease by 50% AFTER absorption and distribution phase
113
Half life is directly proportional to ____ ___ _____
| as half life increases, _____increases
Volume of distribution
114
Half life is _______ _________ to CLEARANCE
AS clearance decreases the half life __________
As clearance increases the half life
INVERSELY PROPORTIONAL As clearance decreases, the elmination half-life increases; decreases
115
Elimination half life useful for
Estimating the time needed to reach steady state
Dosing interval
Time required for drug removal from the body after the drug is no longer being administered.
116
Elimination half life useful for
- Estimating the time needed to reach steady state
- Dosing interval
- Time required for drug removal from the body after the drug is no longer being administered.
117
KNOW THIS FORMULA: ELimination
t 1/2 = 0.693 / K (el)
OR
t1/2 = 0.693 * Vd / Cl
118
As you decrease CL, half life ________
increases
119
Know The GRAPHS and SCALES
know if values are in log or non-log
120
How many half times in takes to remove the drugs
4-5 half lives
121
What is Steady state
when the rate of drug administration = rate of drug elimination /clearance, so that the serum concentration and amount of drug in the body are constant.
122
Steady-State is achieved at approximately ___________from the time the dosage regimen was initiated for first-order kinetic drugs
4 to 5 t1/2
123
MEMORIZED: IMPORTANT FOR ANESTHETIC DRUGS: CONTECT SENSITIVE HALF TIME
Time necessary for the plasma drug concentration to decrease by 50% after discontinuing a CONTINUOUS infusion of a specific duration
124
In "context sensitive half life" Context describes the combined effects of
DISTRIBUTION , METABOLISM and the DURATION OF THE IV CONTINUOUS RATE
125
Drugs can have (one/multiple) context sensitive half tiem
MULTIPLE
126
Primary factors affecting CONTEXT SENSITIVE HALF TIME
INFUSION time.
127
Depending on the lipid solubility and the efficiency of the
drugs clearance mechanisms, the context-sensitive half-time (decreases/Increases)__________ in parallel with the duration of the continuous IV infusion, because
it takes longer for the concentrations to fall if the drug has accumulated in peripheral tissues. An exception to this rule is ____________
Increases; Remifentanil
128
Is the context-sensitive half life related to Half time
NO
129
What is the definition of zero-order kinetics?
Refers to the elimination (removal) of a constant AMOUNT OF DRUG PER UNIT OF TIME (i.e.: 2 mg/min), regardless of the amount of drug or drug concentration in the body
130
IMPORTANT Short definition of zero order kinetics? ______ is independent
Elimination is INDEPENDENT OF TIME OR DRUG concentration
131
For drugs that undergo ZERO -ORDER KINETICS (think Z-A) small increases in drug dose produces ________ _____ in drug concentration
DRASTIC INCREASE in plasma concentration (disproportionate)
132
How does the process of zero order kinetics
Enzymes or transporters responsbile for metabolizing the drug become SATURATED
133
Term interchangeable: zero-order kinetics or ________
non-linear pharmacokinetics
134
Classic EXAMPLES of ZERO order kinetics DRUGS (PEA)
Phenytoin
Ethanol
Aspirin
135
First ORDER KINETICS, what is it?
Refers to the elimination of a constant FRACTION or PERCENTAGE of DRUG PER UNIT OF TIME
136
In first order kinetics, the rate of drug elimination is directly proportion to the drug concentration and are ________ on the concentration
DEPENDENT
137
ZERO ORDER KINETICS is half life helpful
half life is useless, because removal in nonlinear
138
TRUE or FALSE In first order kinetics, serum concentration either increase or decrease proportionally with the dose
True
139
In first order kinetic, if you increase the dose of the drug
| concentration will increase.
concentration will increase
140
FYI: FIRST ORDER kinetic drug, can go into _____ ______when there is a severe __________
Zero order kinetic; overdose
141
With a first order reaction, if the y-axis is in linear units, the process will be ____.
exponential
142
With first order reactions, if the y-axis is in log form, the process will be ___.
linear
143
In context sensitive half time, the "context" represent the
Duration of the drug infusion.
144
Why does the context sensitive half time increase with longer infusion duration ?
because it takes longer with for the concentrations to fall if drug has accumulated in PERIPHERAL TISSUES>
145
When an CYP450 inducing agent is prescribed with another medication What will happen ? What should be done to the dosage of the other medication?
The rate of metabolism is increased; may need to be adjusted and the effect of the medication reduced.
146
When a drug that (reduces CYP 450) Inhibiter/reducer, if a medication is taken with an agent that inhibits its metabolism?
then the drug level can rise and possibly result in a harmful or adverse effect.
147
Classic example of drug A (warfarin) given with an enzyme CYP 450 inducer Drug B (Rifampin), what will happen to drug A?
If warfarin is given with an enzyme inducer, Such as rifampin, the metabolism activity of CYP450 will increased, so warfarin metabolism increased, and SYSTEMICALLY warfarin is decreased because it is metabolism extensively
148
Inhibitors _______Drug substrate level systemically
INCREASE drug B systemically
149
Inducers _________Drugs substrate level systemically
INCREASE drug B systemically
150
Classic example of drug A (warfarin) given with an enzyme CYP 450 INHIBITOR Drug B (AMIODARONE), what will happen to drug A?
INR will increase and patient will be at risk for bleeding because the enzyme to metabolize the warfarin is inhibited.
151
What is the formula for rate of elimination
Cl * Concentration
152
Unit for RofE
Mass/ time
153
The faster the rate of clearance
The shorter the half life
154
The half-life of any drugs is _________ _______ to its rate of clearance
Inversely proportional
155
After 1 half-life, you will have reached ____ of steady state. After 2 half-lives, you will have reached _____ of steady state, and after 3 half-lives you will have reached ______of steady state. The rule of thumb is that steady state will be achieved __________ half lives.
50%; 75%; 87.5% ; that steady state will be achieved after 5 half-lives (97% of steady state achieved)
156
Does P450 enzyme induction has an effect on volume of distribution?
P450 enzyme induction has no effect on volume of distribution.
157
Hepatic extraction, the first-pass effect, and clearance for CYP3A4 substrates will be _______(inc/dec) by inducers
increased
158
If the extraction rate of verapamil is already equal to the hepatic blood flow, Does a further increase in metabolism increase clearance?
so further increase in metabolism will not increase clearance of this drug.
159
Graded dose-response curves used to determine
The maximal efficacy of the drug
160
______ used to determine potency between 2 drugs
ED 50;
161
______ used to determine potency between 2 drugs; the less of it the ______ (more/less) potent; The more of it the _____(more/less) potent
ED 50; more; less
162
For decreased or increased ph when using the Henderson Hasselbach equation, ______at 1 pH unit more alkaline than the pKa and_____ at 2 pH units more alkaline.
1/10 ______; 1/100
163
Well-documented Cyp450 Innhibitor is
AMIODARONE
164
What is called when the drug is excreted in the bile and reabsorbed in the intestine
Enterohepatic Circulation
165
What is enterohepatic circulation?
when the drugs is excreted into bile and reabsorbed in the small intestine.
166
2 drugs that undergo ESTER HYDROLYSIS
SUCCYNYLCHOLINE
| MIVACURIUM
167
The majority of drug tubular REABSORPTION takes place where
DISTAL TUBULE
168
Example, _____ ______ is a highly lipid soluble agent and is completely reabsorbed from the nephron MINIMALLY CHANGED
SODIUM THIOPENTAL.
169
Log from Vd is a ______Line
straight
170
Anesthetics drugs are best described by
MULTICOMPARTMENT
171
2 compartment model : Drugs distributes into 2 compartments________ and ________ . distributes first to ________ organs and then SLOWLY to _______. drugs moves _____ and _____between these 2 compartments to maintain equillibrium and then returns to_____ when _______occurs
central and peripheral; vessel rich group/; peripheral. Back and forth; CENTRAL; ELIMINATION
172
In the 2 compartment, changes in the concentration of drug in the plasma reflect
movement of drug within, rather than lost out of the body.
173
In adults, highly perfused make up ___% of body mass but receive ___ of cardiac output
10%; 75%
174
Distribute extensively into the PERIPHERAL TISSUES
Anesthetics
175
If K (el) is 0.25
25% of the amount of drug will be eliminated at any given moment in time.
176
What does K(el) means
elimination rate constant is the fractional rate of drug administration from the body.
177
What is morphine ? Wa or wb
| Lipid soluble? How does it travel to CNS?
Weak base; low ; slowly
178
At higher pH for weak bases, comparing two drugs , the one with higher pH has ________ actions
Higher
