IV Uptake and Distribution Flashcards
1
Q
Absorption, distribution, metabolism and excretion describe: (pharmacokinetics or pharmacodynamics)?
A
Pharmacokinetics
2
Q
In very general terms, pharmacokinetics is basically:
A
What the body does to a drug
3
Q
Mechanism of effect, sensitivity, and responsiveness describe: (pharmacokinetics or pharmacodynamics)?
A
Pharmacodynamics
4
Q
In very general terms, pharmacodynamics is basically:
A
What a drug does to the body
5
Q
What are the 4 commonly measured pharmacokinetic parameters of injected drugs?
A
- Elimination half-time
- Bioavailability
- Clearance
- Volume of distribution
6
Q
What is meant by the compartmental model?
A
The body is divided into compartments that represent theoretical spaces with calculated volumes.
7
Q
The body is divided into __ compartments. The _____ and the ______ compartment.
A
2; central and peripheral
8
Q
Once in the body, a drug will follow one of 3 paths, they are:
A
- It will remain in the vascular system, body water
- Bind to proteins (drug is inactive if bound)
- Cross membranes and enter tissues
9
Q
Where does unbound drug go?
A
it enters organs, muscles, and fat and most importantly: acts at the receptor site.
10
Q
The transfer of drug to various sites depends on:
A
The intrinsic factors of the drug.
11
Q
What is meant by intrinsic factors when describing a drug?
A
molecular size, degree of ionization, lipid solubility and protein binding
12
Q
What 2 factors affect uptake of a drug?
A
- The amount of blood flow to a tissue
- The concentration gradient across the membrane
13
Q
What does a drugs molecular size have to do with crossing membranes?
A
the smaller the particle, the better it moves across the lipid bilayer.
14
Q
Molecular weights greater than ________ do not cross the cell membrane.
A
100-200
15
Q
Molecules cross membranes by _______ or _______ transport.
A
active or passive
16
Q
Name 4 characteristics of active transport.
A
- it requires energy
- it’s faster than passive
- uses carriers to form complexes
- can move against a concentration gradient
17
Q
Passive transport moves molecules from areas of _______ concentration to _________ concentration via _____________ or ___________.
A
from higher concentration to lower via water channels or straight through the lipid bilayer
18
Q
Many drugs are either weak _______ or ________ and may be charged at physiological pH.
A
acids or bases
19
Q
Ionized drug molecules are _______
A
charged
20
Q
Nonionized drug molecules are _________
A
uncharged
21
Q
Ionized drug molecules are _______ soluble and unable to _____________________.
A
water soluble and unable to cross cell membranes easily
22
Q
Charges on the molecule of the drug are repelled by _____________, and therefore, cannot cross into cells.
A
sections of the cell membrane with similar charge
23
Q
The higher the degree of ionization of a drug, the ________ (more or less) able the drug is to cross into the tissues.
A
Less ability to cross into tissues like the GI tract, blood-brain barrier, placental barrier and liver hepatocytes
24
Q
Are ionized drugs absorbed well orally?
A
No
25
How are ionized drugs excreted?
by the kidney. They are not metabolized by the liver
26
Non-ionized drugs are \_\_\_\_\_\_\_\_\_\_\_\_.
lipophilic
27
Because non-ionized drugs are lipophilic, they can:
cross the lipid bilayer. They easily enter the blood-brain barrier, the GI tract and the placenta
28
How is the degree of ionization determined?
by the disassociation constant (pKa) and by the pH gradient across the membrane.
29
When the pH is equal to the Pka, what kind of charge can we expect on the molecule?
There will be equal parts of charged and uncharged forms.
30
An acidic compound is charged when it is in its (protonated/ unprotonated) form.
unprotonated. Remember, acids are proton donors and become charged when they give up a proton.
31
A basic compound is charged when it is in its (protonated/ unprotonated) form.
Protonated. Remember, bases are proton acceptors.
32
The ionized form a drug (will/ will not) cross the cell membrane.
will not
33
The more (ionized/ unionized) a drug is the more active it is.
unionized
34
The higher the ratio of ionized to unionized drug, the (slower/ faster) the compound is to cross into tissues and exert its effect.
slower
35
When considering the ratio of ionized to unionized drug in the body, does the ionized form stay in the ionized form?
No, once the unionized form has moved across the cell membrane into cells, there will be an imbalance in the ionized: unionized ratio in the blood, so more ionized will convert to unionized to maintain the same UP/P ratio for the pH of the solution they are in.
36
Because ionized drug will eventually convert to unionized, we can assume what about the drug absorption?
That eventually the drug will be absorbed.
37
Challenge: Procaine has a pKa of 8.9. What does this tell us about the absorption of procaine.
1. Compare procaine's pKa to the pH of blood
pH = pKa + log UP/ P
7. 4 = 8.9 + log UP/P
- 1.5 = log UP/P (antilog -1.5)
= 0.032 UP/P
this means there are 32 unprotonated molecules of procaine for every 1000 protonated. As the 32 unprotonated move into the cell, some of the protonated will convert to make the 32:1000 ratio again. This is going to be a long slow process, which is why procaine has a slow onset of action.
38
When the pKa is close to the pH, only ______ changes in pH are needed to create significant changes in the ionized: unionized ratio.
slight
39
For weak bases, if the pKa \< pH, which form predominates (ionized/ unionized)?
unionized predominates
40
For weak bases, if the pH is equal to the pKa, which form predominates (ionized/ unionized)?
they will exist in equal parts.
41
For weak bases, if the pKa is \> pH, which form predominates (ionized/ unionized)?
ionized form predominates
42
Most of the drugs we use in anesthesia are ______ (acids/ bases), except for _________ which are (acids/ bases).
we use basic drugs, except for barbiturates which are acids.
43
For weak acids, if the pKa \< pH, which form predominates, the ionized, or the unionized?
ionized form predominates
44
For weak acids, if the pKa is equal to the pH, which form predominates, the ionized or the unionized?
they will exist in equal parts.
45
For weak acids, if the pKa is \> the pH, which form predominates, the ionized or the unionized?
unionized form predominates.
46
If you have a basic drug, with a pKa of 7.2, and you place it in a pH of 7.4, will it be more ionized or unionized?
It is going to be more unionized because you are placing it in a basic medium compared to its pKa.
47
What is ion trapping?
Ion trapping occurs when there are 2 different pH values across a membrane (ex. placenta). The drug may exist in the ionized form on one side the membrane but can exist in an unionized form on the other side. This can cause a situation where the ionized form just sits, trapped.
48
Ion trapping influences what 3 things?
1. oral absorption of drugs
2. maternal- fetal transfer
3. central nervous system toxicity of local anesthetics.
49
To enter a cell and cross the hydrophobic but lipophilic lipid bilayer, a drug must be at least partially _________ \_\_\_\_\_\_\_.
lipid soluble
50
If a drug is too lipid soluble, what will happen to it as it crosses the cell membrane?
It will not be able to move out of the membrane into the cell.
51
What is the oil to water partition coefficient?
It is the ratio of a drugs lipid solubility to water solubility at equilibrium. It is based on the concentration of the agent in each component, the water vs. the oil.
52
Why do we care what a drug's water to oil partition coefficient is?
It is a predictor of how well a drug will cross a membrane and get to the target tissue.
53
The larger the value of the water-oil partition co-efficient, the ________ the lipid solubility of the drug.
greater
54
Some drugs will cross the membrane regardless of the oil-water partitiion coefficient, how do they cross?
By a receptor protein that will carry it
55
How do we get charged amino acids across our cell membranes?
Via carrier proteins. We cannot get charged molecules across the lipid bilayer without a carrier.
56
There are basically 2 ways a drug can get across a cell membrane, they are:
1. By simple diffusion (depending on the oil water partition coefficient)
2. By utilizing one of the cell membranes transport molecules.
57
What is the blood- gas partition coefficient?
-instead of oil/water partition coefficient, this one is used to describe the solubility of gases and volatile agents
58
For gases and volatile agents to cross the alveoli and enter the blood they must have some ________ and some \_\_\_\_\_\_\_\_\_\_\_\_.
some lipid solubility and some blood solubility
59
Do the drug concentrations have anything to do with how gases and volatile agents cross membranes?
No, not the concentrations, but the partial pressure of the drugs determine if they will cross the membrane.
60
Gases move from an area of ________ partial pressure to an area of ________ partial pressure.
higher to lower.
61
What is the driving force for the movement of inhaled molecules into the blood?
The higher the initial partial pressure (at the alveoli) of the gas being inhaled is the driving force for moving the molecules into the blood until equilibrium is reached.
62
What is the tissue to blood coefficient?
It describes the solubility of a drug in particular tissue. It is specific for that tissue. This can tell us which drugs enter a tissue and to what extent, but does not tell us the overall effect of the drug at that tissue.
63
# Define absorption
Movement of drug molecules across membranes and into the bloodstream.
64
Which route of drug delivery does not require absorption?
Anything you give IV. Absorption describes the phase of the drug where it enters the bloodstream to get to it's site of action.
65
The diffusion of drugs across a membrane by passive diffusion can be described by \_\_\_\_\_\_\_'s law.
Fick's
66
A large difference in drug conentration (or in the case of gases, partial pressure) across a membrane ____________ diffusion rate.
increases
67
A large membrane area and a drug that is easily soluble _________ diffusion rate across a membrane.
increases
68
A thicker membrane and a large molecule ________ diffusion across a membrane.
decreases
69
Once broken down into smaller particles, an oral medication will cross cell membranes and enter the bloodstream by \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
passive diffusion
70
Passive diffusion of a drug requires it to be in a ________ form so the ionization state is important.
lipid
71
Most oral drugs are best absorbed in the \_\_\_\_\_\_\_\_\_\_\_\_.
small intestine
72
Oral drugs that are weak acids are better absorbed in the \_\_\_\_\_\_\_\_\_\_\_\_\_\_.
stomach
73
In the acidic environment of the stomach, weakly acid drugs tend to exist in their _________ forms and are therefore more easily absorbed.
unionized
74
In the small intestine, bicarbonate is excreted into the intestinal lumen, creating a more basic envirnoment, in which basic drugs will convert to:
their more unionized, more lipid- soluble form, making them more easily absorbed by the intestine
75
# Define distribution.
The drug distributed through the body and into the tissues where it can act.
76
Drugs bound to protein are: (active/ inactive).
inactive
77
The 3 most common binding proteins are:
albumin and alpha acid glycoproteins and lipoproteins
78
Protein structures are ________ with ________ binding sites.
large with multiple sites
79
The bond between drugs and proteins tend to be very (weak/ strong).
weak, they will detach easily
80
Do all drugs bind to protein?
no
81
For drugs that have a high affinity for protein, protein can act as a:
reservoir
82
Describe how protein acts as a reservoir for drugs.
If a drug is highly bound to protein, the unbound will cross into the cells. As the unbound leaves the blood, the ratio of bound to unbound changes and more becomes unbound. This is an example of a slow release of drug.
83
What is meant by redistribution?
1. The drug will be distributed until equilibrium occurs
2. As plasma levels of the drug decrease from metabolism, the drug will move back into the plasma to maintain equilibrium
3. Once it goes back into the plasma, some of it might go into the fat, depending on it's lipid solubility. This is why propofol has such a short duration of action.
84
What is metabolism or biotransformation?
The body converts drug molecules into other chemical compounds. Usually they are converted into polar molecules that are easy for the body to eliminate. Rarely drugs can convert into less polar molecules which can lead to toxicities, but these drugs rarely make it to market.
85
What is the primary site of drug metabolism?
the liver
86
Name 5 sites (other than the liver) where drug metabolism can take place.
1. Lung
2. Kidney
3. Skin
4. Epithelial cells of the GI tract
5. Plasma
87
There are 2 phases of metabolism. What happens in phase 1?
Primary Oxidation-Reduction reactions in the endoplasmic reticulum in hepatocytes.
88
What is the cytochrome P-450 system?
Found in the liver, consists of enzymes linked to heme proteins. This is a family of enzymes, each of which may be different for metabolizing a different drug.
89
There are more than ____ Cytochrome P-450 enzymes.
50
90
Only ____ cytochrome P-450 enzymes are resonsible for 90% of all drug metabolism.
6
91
Name the 6 Cytochrome P-450 enzymes that are resonsible for 90% of all drug metabolism.
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP3A4
CYP3A5
92
Name the 4 common chemical reactions in Phase 1 metabolism.
1. hydroxylation
2. oxidation
3. reduction
4. hydrolysis
93
As they are metabolized, some drugs undergo multiple conversions; some polar molecules just
enter the bloodstream to be excreted by the\_\_\_\_\_\_\_\_\_\_\_ or may enter the
biliary fluid to be excreted in \_\_\_\_.
kidneys; bile
94
Can Phase 1 metabolism reach saturation?
Yes. This is enzyme mediated metabolism so it is possible to saturate the system's ability to metabolize a compound.
95
What sorts of things cause a Phase 1 metabolism saturation?
1. Giving too much of a compound
2. When similar compounds are given that use the same enzyme for metabolism. The result is a build up of compound and an increased half-life
96
# Define induction in relation the enzymes of the Cytochrome P-450 system.
Induction is an increase in the number of active enzymes that can metabolize a drug, resulting in a shorter half-life. Drugs and environmental exposure, like smoking, can increase the number.
97
What happens if drugs inhibit the Cytochrome P-450 system?
The drug for the specific enzyme or another drug may actually inhibit the activity of the enzyme, prolonging the half-life of the administered drug.
98
What happens in Phase 2 metabolism?
Large, polar compounds are attached to the molecule being metabolized. Some drugs go through this in Phase 1 but most go through it in phase 2.
99
What does attaching a polar molecule to a drug do to it?
Makes it more water soluble. Polar molecules are more easily eliminated by biliary and renal routes.
100
What is first pass effect (first pass metabolism) ?
After a drug is absorbed it goes directly to the hepatic portal system and directly to the liver. Depending on the drug, some amount of metabolism takes place here, before it can enter the systemic circulation.
101
# Define bioavailabitly.
The amount of drug that makes it to systemic circulation after first pass metabolism.
102
What are esterases?
Esterases are enzymes that split ester molecules. Plasma esterase or pseudocholinesterase metabolize or inactivate many ester drugs. (like sux, etomidate, and procaine)
103
# Define elimination.
The removal of a drug molecule from the body.
104
Metabolizing a drug into a different form, whether active or inactive is one form of \_\_\_\_\_\_\_\_\_.
Excretion (the original drug has effectively been removed from the body)
105
What is meant by volume of distribution Vd?
The apparent volume of the amount of plasma in which the drug is dissolved. (it's theoretical since we never know the exact volume of the plasma)
106
If a drug stays in the plasma, like heparin, what can be said about the volume of distribution?
the volume of distribution is directly related to the plasma volume.
107
If the drug leaves the plasma, what can be said about the volume of distribution?
if a drug leaves the plasma and distributes to the tissue, the volume of distribution can be very large.
108
In what units is volume of distribution reported in?
liters/kg
109
Why would we care about volume of distribution?
Vd is good for quickly determining if a drug stays in the plasma, follows total body water, or concentrates in the tissues.
110
What is meant by clearance?
Clearance quantitates the rate by which a drug is removed from the body.
111
What makes up the central compartment?
Plasma, kidney, liver, lungs, heart, brain. All of the highly perfused tissues
112
The organs of the central compartment receive \_\_\_\_% of the cardiac output.
75
113
The organs of the central compartment make up only \_\_% of the body mass.
10
114
In the central compartment there is (rapid/ slow) uptake of a drug.
rapid
115
What is the pathway of the drug between compartments?
1. Drug first introduced into the central compartment
2. Drug distributes to the peripheral compartment
3. As concentration of drug in the central compartment falls, drug returns to the central compartment for clearance
116
What is the volume of the peripheral compartment?
It has a large calculated volume. There is extensive uptake of the drug in the peripheral compartment.
117
What parts of the body would be considered the peripheral compartment?
skin, muscle, hair, bones
118
As we age, the rate of drug transfer between our compartments:
decreases, leading to greater plasma concentrations of certain drugs.
119
Name a drug that tends to stay in the central compartment in the elderly.
Thiopental
120
When medicating elderly patients, and understanding that transfer between compartment may be delayed, how would you dose your medications?
You would want to increase your dosing interval. With narcotics, you could over narcotize your patient if you give too much before it can transfer over to the periphery.
121
The body mass of the vessel rich central compartment is \_% of the body, but gets \_\_% of the cardiac output.
10% but gets 75% of the CO
122
The muscle group of the body makes up \_\_% of the body mass but gets \_\_\_% of the cardiac output.
50% of the body mass and gets 19% of the blood flow.
123
The fat group of the body makes up \_\_\_% of the body mass but gets ___ % of the cardiac output.
20% of the body mass and gets 6% of the CO
124
The vessel poor group of body tissues make up \_\_\_% of the body mass and get \_\_\_% of the cardiac output.
20% of the body mass and get \<1% of the blood flow.
125
As people age, they ____ fat and ____ muscle.
gain fat and lose muscle. Remember the fat stores a lot of drugs that may come back
126
Drugs that are very lipophilic transfer very (slowly/ quickly) to fat and muscle.
quickly
127
Volume of distribution Vd is the sum of:
all of the volume of the compartments
128
Mathematically, Vd=
Dose of IV drug divided by the plasma concentration before elimination
129
Vd is influenced by the physiochemical characteristics of the drug, which are:
1. Lipid solubility
2. Binding to plasma proteins
3. Molecular size
130
The more lipid soluble a drug, the more it immediately goes to:
the second compartment
131
The higher the plasma binding of a drug, the \_\_\_\_\_\_\_\_\_ the distribution.
lower, drug bound to protein makes too large a molecule that cannot cross the cell membrane.
132
# Define elimination half-time.
The time necessary for the plasma concentration of a drug to fall 50% during the elimination phase.
133
Elimination half time is directly proportional to:
its Vd and inversely proportional to its clearance.
134
How is elimination half-time related to the dose of the drug given?
E1/2 time is independent of the dose of the drug given.
135
It doesn't matter if you give 500mcg of fentanyl or 200 mcg of fentanyl, elimination 1/2 time is:
the time it takes for the amount of drug in the plasma to be halved.
136
As soon as you give a drug IV, _________ begins right away.
elimination
137
The slower the drug is cleared, the ________ the half time is going to be.
slower
138
# Define elimination half-life.
The time necessary to eliminate 50% of the drug from the body altogether (not just from the plasma).
139
If dosing intervals are less than the elimination half time __________ occurs.
drug accumulation
140
Elimination half time and elimination half life are the same thing and the terms can be used interchangably. T or F.
False. They are not equal. The decrease in the drugs plasma concentration does not parallel its elimination from the body.
141
At each half time occurs, the drug concentration in the body is:
halved.
142
So by the 3rd half time, the amount of drug in the system is:
1st half time - 1/2
2nd half time- 1/4
3rd half time- 1/16, so by the 3rd half time only 1/16 of the original dose is left in the system.
143
By the 4th to 5th half time most of the drug is:
gone from the system.
144
What is the alpha phase of the distribution curve?
It is the distribution phase, where the drug is moving to the second compartment.
145
What is the beta phase of the distribution curve?
Where the drug is moving back into the central compartment where it will be metabolized by the liver and the kidneys.
146
What are the 3 steps of distribution:
1. Following system absorption of a drug, the highly perfused tissues, kidneys, heart, liver, brain) receive a large amount of the total drug
2. As the plasma concentration in the blood becomes lower than the concentration in these tissues, drug moves back into the plasma and is distributed to the less well perfused tissues: fat, muscle
3. With continuing elimination of the drug from the blood, the plasma concentration of the drug decreases, and drug will move from all of the sites back into the circulation
147
Tissues that accumulate drug act as a _____________ to maintain the plasma concentration and\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
act as a reservoir and prolong the drug's effect.
148
Large or repeated doses of drug __________ inactive tissue, negating redistribution and proloning duration of action, as now reduction of the drug depends on ____________ and not redistribution.
saturate inactive tissue; reduction depends on metabolism not redistribution
149
Systemic absorption, regardless of the route of drug administration, depends on the drug's\_\_\_\_\_\_\_\_\_\_\_.
solubility
150
Whare are 2 advantages of giving drugs orally.
1. most convenient
2. most economic
151
Name 4 disadvantages for giving drugs via the oral route.
1. Emesis
2. Destruction of drug by enzymes or acidic gastric fluid
3. Irregular absorption with food or other drugs
4. First pass effect
152
What is the major advantage of giving a drug via the sublingual route; submucosal?
It has a rapid onset and it bypasses the liver first pass effect.
153
Name one advantage of using the transdermal route of drug adminstration.
It provides a sustained plasma concentration of the drug
154
Name 4 disadvantages of using the transdermal route.
1. Absorption occurs around sweat ducts and hair follicles, these act as diffusion shunts.
2. The rate limiting step is diffusion across the strateum corneum of the epidermis
3. Thickness and blood flow are factors reflected in the skins permeability for drugs
4. Contact dermatitis can occur at the site
155
When giving a drug via the transdermal route, which side of the body gets more perfusion?
front
156
When choosing a place to place a transdermal medication patch, you would want to choose a place with the _________ layer of strateum corneum.
thinnest
157
When giving a drug via the rectal route, you must give it ( more proximal or more distal)
More distal. The distal rectum absorbs drugs directly into systemic circulation and is not subject to first pass effect.
158
Name 2 disadvantages to using the rectal route of drug administration.
1. If given too far, and into the proximal rectum, the drug will be transported to the portal system via the superior hemorrhoidal veins and be subjected to first pass effect
2. If you place it too distally, the drug could pop out, especially if your patient coughs. These factors explain the unpredictable responses when a drug is give rectally.
159
What is the major advantage of using the IV route in anesthesia?
You achieve therapeutic plasma concentrations precisely and rapidly.
160
Can the IM route be used for anesthesia?
Yes, for example, you can give ketamine IM to an uncooperative child to get them to fall asleep.
161
What is meant by lung uptake?
The lung uptakes basic lipophilic drugs (lidocaine, demerol, and fentanyl) and acts as a reservoir to release drug back into the systemic circulation.
162
Describe the lung first-pass effect with fentanyl.
When you give fentanyl IV, a lot of it will go to the lungs and the lungs will act as a reservoir. Fentanyl has a double peak in the blood. The plasma level will peak when you give it, then go down as drug shifts into the lungs, and then peaks again as it leaks back into the plasma.
163
Can ionized, water soluble drugs cross the blood-brain barrier?
No. Only lipophilic drugs can cross. However; if the blood-brain barrier has been compromised, as in massive head injury or severe hypoxia, ionized drugs will cross
164
Which drugs are more effective, drugs with pKa closer to the patient's pH or ones that are farther from it?
drugs whose pKas are closer to the body's pH.
165
Drugs that are ionized usually go straight to the:
kidney, where they will be excreted.
166
The non-ionized form of the drug is pharmacologically \_\_\_\_\_\_\_\_\_\_\_. It undergoes reabsorption across renal tubules, is absorbed from the GI tract, and is metabolized by the liver.
active
167
The ionized fraction of the drug is _______ lipid soluble. It ________ penetrate lipid membranes, and is repelled from portions of the cell membrane with similar charges. They are excreted by the kidneys \_\_\_\_\_\_\_\_\_\_\_.
poorly lipid soluble, cannot penetrate lipid membranes, and is excreted by the kidneys unchanged.
168
The degree of ionization of a drug depends on its ________ and the ________ of the fluid surrounding it.
on its pKa and the pH of the fluid surrounding it.
169
Changes in pH can result in a large degree of:
ionization
170
Acidic drugs are highly ionized at a _____ pH.
alkaline
171
Basic drugs are highly ionized at an _______ pH.
acidic
172
Most drugs are racemic, what does that mean?
They exist in equal parts: ionized and unionized.
173
So what happens if your patient is acidotic and you you give them a weak acid, like pentothal, what do you need to consider.
If you give a weak acid in an acidic environment, more of the unionized (active) form will exist and your patient will get more effect from a a lower dose of the drug.
174
Considering the phenomenon of ion trapping, giving narcotics and local anesthetics via epidural to a pregnant women could do what as it crosses the placenta?
As the drugs cross the placenta, and enter a different pH, they could convert to their unionized form and become more active, making the baby sleepy.
175
Do protein bound drugs stay inactive?
No, as plasma concentrations of a drug fall, the drugs will dissociate from protein and enter circulation.
176
Does a patients albumin level affect the way drugs will affect them?
Yes. If you have a drug that usually bound to protein, but the patient has very low protein, more of that drug will be unbound and active. For example, liver failure patients, have low protein stores, so drugs are more active. Use caution in dosing these patients.
177
Unbound drug in the plasma is more readily ________ and __________ as well.
metabolized and excreted
178
Warfarin, propanolol, phenytoin and diazepam are all examples of drugs that are\_\_\_\_\_\_\_\_ protein bound.
highly protein bound. These drugs are markedly affected by alterations in protein binding.
179
Clearance is defined as:
The volume of plasma cleared of a drug by metabolism and excretion. (the liver metabolizes and the kidney excretes)
180
Describe first order rate kinetics.
as the concentration of drug in the plasma decreases, less drug is available at the site for metabolism or excretion, therefore the amount being eliminated is also decreased. The change in the amount of drug being eliminated per unit time is a logarithmic decline.
181
Most drugs metabolized by humans are metabolized by (first rate order kinetics or zero order kinetics)
first rate order kinetics
182
First rate order kinetics means that almost all drugs adminstered in the therapeutic dose ranges are cleared at a rate ___________ to the amount of drug present in the plasma.
proportional
183
Are there drugs that can exceed the metabolism of the body?
Yes, even at therapeutic doses this can happen. Your body cannot handle these drugs. In this case only a constant amount of drug is metabolized per unit time. The body is working as quickly as it can but there are only so many sites of metabolism.
184
Describe zero order rate kinetics.
* the metabolism and excretion rate becomes saturated
* the concentration of the drug is unrelated to the amount of drug being metabolized.
* this happens when all available enzymes are metabolizing drug as much as they can
* this is not a logarithmic decline but a linear decline. There is a specific amount of drug being eliminated per unit time
* this seldom happens in humans
185
Why does zero order kinetics seldom happen in humans?
Because even if enough drug was given to saturate all of the enzymes, this would only last for a short time, then once the concentration fell it would go back to first order.
186
Why would alcoholics suck up more of our ansthetic?
Alcoholics develop an enzyme induction that can metabolize more alcohol. Ansthetics use a lot of the same pathways, so alcoholics will metabolize anesthetics quickly.
187
Why would people on dilantin suck up more of our anesthetic?
Dilantin is a drug that induces enzymes, similar to alcoholics, because anesthetics use a similar pathway, they would metabolize the anesthetic very quickly.
188
What is the hepatic extraction ratio:
How quickly your liver can metabolize drugs. It refers to enzymatic activity. A big part of how we metabolize is genetic.
189
Hepatic clearance depends on 2 factors:
1. Hepatic extraction ratio
2. Hepatic blood flow
190
If the hepatic extraction ratio of a drug is high (greater than 0.7), then clearance of the drug depends on:
the hepatic blood flow
191
When hepatic extraction is good (ratio 0.7 or greater) and the drug clearance is now solely dependent on blood flow to the organ, this is termed:
perfusion- dependent elimination
192
If the hepatic extraction ratio is low (less than 0.3) a decrease in protein binding or an _________ in enzymatic activity will increase hepatic clearance.
increase
193
In cases where there is a low hepatic extraction ratio and enzymatic activity is needed to improve drug clearance, what effect will changes in hepatic blood flow have on clearance?
changes in hepatic blood flow will have minimal changes on clearance.
194
What is the term for clearance that requires enzymatic activity to increase, and not necessarily blood flow to the liver.
Capacity dependent elimination
195
Once metabolized by the liver, drugs are cleared by the \_\_\_\_\_\_\_\_\_.
kidneys
196
The most important organ for the elimination of unchanged drugs and their metabolites is:
the kidneys
197
\_\_\_\_\_\_\_\_\_\_ compounds are eliminated more efficiently by the kidneys than _________ ones.
water soluble are more efficiently eliminated than lipid soluble drugs.
198
Lipid soluble drugs have to be converted to _________ soluble forms so the kidneys can eliminate them.
water soluble
199
Are lipid soluble drugs excreted in the urine?
Highly lipid soluble drugs are reabsorbed such that little or no unchanged drug is excreted in the urine.
200
What is biotransformation?
Biotransformation converts pharmacologically active, lipid soluble drugs, into water soluble and often inactive drugs.
201
How does water solubility affect volume of distribution?
increased water solubility reduces volume of distribution and increases renal excretion
202
Does drug metabolism always render an inactive, detoxified drug?
No, metabolites of certain drugs remain active. Metabolites tend to be less strong than the parent compound but that is not always true.
203
In first order kinetics, a constant fraction of available drug is _________ in a given time period.
metabolized
204
In zero order kinetics, plasma concentration of a drug ____________ the capacity of metabolizing enzymes.
exceeds
205
In zero order kinetics, metabolism of a ________ amount of drug occurs per unit time.
constant
206
Give 3 examples of drugs that exceed enzyme metabolism capacity and are metabolized by zero order kinetics.
ETOH, ASA, Dilantin
207
What are the 4 pathways of metabolism?
1. Oxidation
2. Reduction
3. Hydrolysis
4. Conjugation
208
In phase 1 metabolism the drug goes through \_\_\_\_\_\_\_\_, \_\_\_\_\_\_\_\_\_, and/or \_\_\_\_\_\_\_\_\_\_\_.
oxidation, reduction and hydrolysis
209
In phase 2 metabolism, the parent or metabolite drug reacts with an endogenous substrate to form:
water-soluble conjugates
210
Phase ___ describes how the drug is metabolized.
2
211
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ are responsible for metabolism of most drugs in the liver.
Hepatic microsomal enzymes, they are located on the smooth endoplasmic reticulum of the hepatocye.
212
Plasma ________ metabolize drugs in the plasma.
esterases
213
The cytochrome P-450 system is a large number of different protein enzymes involved in \_\_\_\_\_\_\_\_\_\_\_\_\_, __________ and ____________ of a large number of drugs.
oxidation, reduction, and conjugation
214
They CYP stands for _____________ in the nomenclature for the hepatic enzyme metabolic system.
Cytochrome P-450
215
The first number on the CYP nomenclature denotes\_\_\_\_\_\_\_\_\_\_.
the genetic family
216
The second letter of the CYP nomenclature denotes \_\_\_\_\_\_\_\_\_\_\_\_.
genetic subfamily
217
The second number of the CYP nomenclature decribes:
the specific gene or isoenzyme
218
When drugs and chemicals stimulate the P-450 enzymes, what is this called?
Enzyme induction. People who smoke, do drugs, or are exposed to chemicals will eat up your anesthetic quicker because their enzymes are already in hyper mode.
219
Do smokers get nauseated with surgery?
They seldom do, because their CYP system is in hyper mode and the metabolize the anesthetic quick enough to avoid the side effects.
220
99% of drugs are broken down by:
liver enzymes
221
The 1% of drugs not metabolized by CYP are metabolized by:
nonmicrosomal enzymes
222
Nonmicrosomal enzymes metabolize drugs mostly by ____________ and \_\_\_\_\_\_\_\_\_\_\_\_.
conjugation and hydrolysis. To a lesser degree they metabolize by oxidation-reduction.
223
Nonmicrosomal enzymes are present in what 3 areas:
liver mostly, plasma, and GI tract
224
nonmicrosomal enzymes are responsible for hydrolysis of drugs that contain ________ bonds.
ester bonds. Like sux.
225
nonmicrosomal enzymes are not affected by or undergo \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
enzyme induction
226
nonmicrosomal enymes are determined \_\_\_\_\_\_\_\_\_\_.
genetically
227
Plasma esterases (are/ are not) affected by enzyme induction.
not affected
228
The most common mechanism by which drugs exert pharmacological effect is by their interaction with specific _____________ in the lipid bilayer of cell membranes, called \_\_\_\_\_\_\_\_\_\_.
macromolecules in the lipid bilayer. These are called receptors. This is pharmacodynamics.
229
Receptors can _________ or ___________ in response to certain stimuli.
upregulate or downregulate
230
If someone is on a beta blocker, and you just take them off, what will happen with their receptors?
While on the beta blocker, the body recognizes that epi and norepi aren't having as much of an effect anymore, so it ramps up the number of receptors. If you stop the beta blocker and then expose the sites to epi and norepi you will get a massive response and a massive hypertensive issue
231
If receptors are constantly bombarded with more molecule then they need or want, they can __________ the number of receptors.
down regulate
232
What does the State of Receptor Activation Theory say?
Non-activated receptors convert to active by the drug.
233
Stress can actually _______ receptors.
upregulate
234
State the Receptor Occupancy Theory.
The more receptors occupied by the drug, the more effect.
235
Can drugs act without receptors?
Yes. ex. chelating drugs form bonds with metallic cations that may be found in the body. Antacids neutralize acid by direct cation.
236
What do agonist drugs do?
They mimic cell signalling molecules by activating the same receptor sites and causing similar effects.
237
What do antagonist drugs do?
These bind to receptors and change the configuration of the agonist site or bind to it, preventing effect from cell signalling molecules.
238
The affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
chemical structure
239
The relationship between drug and receptor is usually quite \_\_\_\_\_\_\_\_\_\_. Even slight modifications to a drugs molecular structure, even as slight as stereochemistry may result in major changes in pharmacological properties.
stringent
240
The structure of the drug molecule is what determines if it is ________ or \_\_\_\_\_\_\_\_\_.
lipophilic or hydrophilic
241
Interaction with biological receptors can differ greatly between two enantomers, even to the point of \_\_\_\_\_\_\_\_\_\_\_\_.
no binding
242
Some isomers may cause __________ or ___________ compared to its mirror image.
side effects or entirely different effects
243
Do all isomers have effect at the receptor site?
No, some will have no effect at all.
244
Ephedrine has ___ chiral centers and ____ isomers.
2 chiral centers, 4 isomers.
245
Synergistic effect: 1+1=
3
246
What is additive effect?
A second drug, acting with the first, will equal the sum of both. 1+1=2
247
Hypersensitivity occurs in people who are:
allergic to the drug. It actually creates an immune response to the drug.
248
Hypersensitivity is not just an itchy feeling. It is an actual immune response. Demerol causes itching, but why?
Demerol is a histamine releaseer, so it causes itching. You should not give demerol in asthmatics.
249
What is meant by a hyper-reactive resonse a drug?
people in whom an unusally low dose of drug produces its expected pharmacological effect.
250
The 4 different isomers of ephedrine all have pretty much the same potency. T or F.
False. Even slight changes change the drugs activity. The isomers of ephedrine range in potency from 1 to 36!
251
What is sp3 hybridization?
the concept of mixing atomic orbitals into new hybrid orbitals suitable for the pairing of electrons to form chemical bonds in valence bond theory.
252
# Define enantiomer.
A pair of molecules that are mirror images of each other.
253
# Define chiral carbon.
An assymetric carbon that is attached to 4 different types of atoms or 4 different groups of atoms.
254
Free rotation around the chiral carbon is (possible/ not possible)
not possible. but 2 stable forms of the molecule can exist.
255
Name this isomer of ephedrine and give its potency.
D- (-) ephedrine. Potency= 36
256
Name this isomer of ephedrine and give its potency.
L- (+) ephedrine. Potency= 11
257
Name this isomer of ephedrine and give its potency.
D- (-) pseudoephedrine. Potency = 1
258
Name this isomer of ephedrine and give its potency.
L- (+) pseudoephrine. Potency = 7
259
What is tachyplaxis?
rapidly diminishing reponse to successive doses of a drug rendering it less effective. The effect is common with drugs acting on the nervous system.
260
What is meant by therapeutic window?
the concentration of drug at the site of action where the desired therapeutic effect is produced.
261
True or False. The site of desired therapeutic effect is also the same site that produces undesirable effects.
It may or may not be.
262
What is the only measurable level of a drug when trying to determine the therapeutic window?
the plasma level, it does not give a good reflection of the amount of drug in the tissue for some drugs.
263
The goal is to have a plasma concentration that is above the ___________ and below the \_\_\_\_\_\_\_\_\_\_\_\_.
above the minimum therpeutic concentration and below the plasma concentration level associated with toxicity.
264
# Define therapeutic index.
ratio of toxic dose to therapeutic dose.
265
Drugs with a large therapeutic index are __________ (safer/ more risky) than drugs with smaller values.
safer
