IV Uptake and Distribution Flashcards
Absorption, distribution, metabolism and excretion describe: (pharmacokinetics or pharmacodynamics)?
Pharmacokinetics
In very general terms, pharmacokinetics is basically:
What the body does to a drug
Mechanism of effect, sensitivity, and responsiveness describe: (pharmacokinetics or pharmacodynamics)?
Pharmacodynamics
In very general terms, pharmacodynamics is basically:
What a drug does to the body
What are the 4 commonly measured pharmacokinetic parameters of injected drugs?
- Elimination half-time
- Bioavailability
- Clearance
- Volume of distribution
What is meant by the compartmental model?
The body is divided into compartments that represent theoretical spaces with calculated volumes.
The body is divided into __ compartments. The _____ and the ______ compartment.
2; central and peripheral
Once in the body, a drug will follow one of 3 paths, they are:
- It will remain in the vascular system, body water
- Bind to proteins (drug is inactive if bound)
- Cross membranes and enter tissues
Where does unbound drug go?
it enters organs, muscles, and fat and most importantly: acts at the receptor site.
The transfer of drug to various sites depends on:
The intrinsic factors of the drug.
What is meant by intrinsic factors when describing a drug?
molecular size, degree of ionization, lipid solubility and protein binding
What 2 factors affect uptake of a drug?
- The amount of blood flow to a tissue
- The concentration gradient across the membrane
What does a drugs molecular size have to do with crossing membranes?
the smaller the particle, the better it moves across the lipid bilayer.
Molecular weights greater than ________ do not cross the cell membrane.
100-200
Molecules cross membranes by _______ or _______ transport.
active or passive
Name 4 characteristics of active transport.
- it requires energy
- it’s faster than passive
- uses carriers to form complexes
- can move against a concentration gradient
Passive transport moves molecules from areas of _______ concentration to _________ concentration via _____________ or ___________.
from higher concentration to lower via water channels or straight through the lipid bilayer
Many drugs are either weak _______ or ________ and may be charged at physiological pH.
acids or bases
Ionized drug molecules are _______
charged
Nonionized drug molecules are _________
uncharged
Ionized drug molecules are _______ soluble and unable to _____________________.
water soluble and unable to cross cell membranes easily
Charges on the molecule of the drug are repelled by _____________, and therefore, cannot cross into cells.
sections of the cell membrane with similar charge
The higher the degree of ionization of a drug, the ________ (more or less) able the drug is to cross into the tissues.
Less ability to cross into tissues like the GI tract, blood-brain barrier, placental barrier and liver hepatocytes
Are ionized drugs absorbed well orally?
No
How are ionized drugs excreted?
by the kidney. They are not metabolized by the liver
Non-ionized drugs are ____________.
lipophilic
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
How is the degree of ionization determined?
by the disassociation constant (pKa) and by the pH gradient across the membrane.
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.
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.
A basic compound is charged when it is in its (protonated/ unprotonated) form.
Protonated. Remember, bases are proton acceptors.
The ionized form a drug (will/ will not) cross the cell membrane.
will not
The more (ionized/ unionized) a drug is the more active it is.
unionized
The higher the ratio of ionized to unionized drug, the (slower/ faster) the compound is to cross into tissues and exert its effect.
slower
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.
Because ionized drug will eventually convert to unionized, we can assume what about the drug absorption?
That eventually the drug will be absorbed.
Challenge: Procaine has a pKa of 8.9. What does this tell us about the absorption of procaine.
- Compare procaine’s pKa to the pH of blood
pH = pKa + log UP/ P
- 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.
When the pKa is close to the pH, only ______ changes in pH are needed to create significant changes in the ionized: unionized ratio.
slight
For weak bases, if the pKa < pH, which form predominates (ionized/ unionized)?
unionized predominates
For weak bases, if the pH is equal to the pKa, which form predominates (ionized/ unionized)?
they will exist in equal parts.
For weak bases, if the pKa is > pH, which form predominates (ionized/ unionized)?
ionized form predominates
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.
For weak acids, if the pKa < pH, which form predominates, the ionized, or the unionized?
ionized form predominates
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.
For weak acids, if the pKa is > the pH, which form predominates, the ionized or the unionized?
unionized form predominates.
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.
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.
Ion trapping influences what 3 things?
- oral absorption of drugs
- maternal- fetal transfer
- central nervous system toxicity of local anesthetics.
To enter a cell and cross the hydrophobic but lipophilic lipid bilayer, a drug must be at least partially _________ _______.
lipid soluble
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.
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.
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.
The larger the value of the water-oil partition co-efficient, the ________ the lipid solubility of the drug.
greater
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
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.
There are basically 2 ways a drug can get across a cell membrane, they are:
- By simple diffusion (depending on the oil water partition coefficient)
- By utilizing one of the cell membranes transport molecules.
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
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
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.
Gases move from an area of ________ partial pressure to an area of ________ partial pressure.
higher to lower.
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.
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.
Define absorption
Movement of drug molecules across membranes and into the bloodstream.
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.
The diffusion of drugs across a membrane by passive diffusion can be described by _______’s law.
Fick’s
A large difference in drug conentration (or in the case of gases, partial pressure) across a membrane ____________ diffusion rate.
increases
A large membrane area and a drug that is easily soluble _________ diffusion rate across a membrane.
increases
A thicker membrane and a large molecule ________ diffusion across a membrane.
decreases
Once broken down into smaller particles, an oral medication will cross cell membranes and enter the bloodstream by ______________.
passive diffusion
Passive diffusion of a drug requires it to be in a ________ form so the ionization state is important.
lipid
Most oral drugs are best absorbed in the ____________.
small intestine
Oral drugs that are weak acids are better absorbed in the ______________.
stomach
In the acidic environment of the stomach, weakly acid drugs tend to exist in their _________ forms and are therefore more easily absorbed.
unionized
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
Define distribution.
The drug distributed through the body and into the tissues where it can act.
Drugs bound to protein are: (active/ inactive).
inactive
The 3 most common binding proteins are:
albumin and alpha acid glycoproteins and lipoproteins
Protein structures are ________ with ________ binding sites.
large with multiple sites
The bond between drugs and proteins tend to be very (weak/ strong).
weak, they will detach easily
Do all drugs bind to protein?
no
For drugs that have a high affinity for protein, protein can act as a:
reservoir
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.
What is meant by redistribution?
- The drug will be distributed until equilibrium occurs
- As plasma levels of the drug decrease from metabolism, the drug will move back into the plasma to maintain equilibrium
- 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.
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.
What is the primary site of drug metabolism?
the liver
Name 5 sites (other than the liver) where drug metabolism can take place.
- Lung
- Kidney
- Skin
- Epithelial cells of the GI tract
- Plasma
There are 2 phases of metabolism. What happens in phase 1?
Primary Oxidation-Reduction reactions in the endoplasmic reticulum in hepatocytes.
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.
There are more than ____ Cytochrome P-450 enzymes.
50
Only ____ cytochrome P-450 enzymes are resonsible for 90% of all drug metabolism.
6
Name the 6 Cytochrome P-450 enzymes that are resonsible for 90% of all drug metabolism.
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP3A4
CYP3A5
Name the 4 common chemical reactions in Phase 1 metabolism.
- hydroxylation
- oxidation
- reduction
- hydrolysis
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
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.
What sorts of things cause a Phase 1 metabolism saturation?
- Giving too much of a compound
- 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
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.
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.
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.
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.
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.
Define bioavailabitly.
The amount of drug that makes it to systemic circulation after first pass metabolism.
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)
Define elimination.
The removal of a drug molecule from the body.
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)
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)
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.
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.
In what units is volume of distribution reported in?
liters/kg
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.
What is meant by clearance?
Clearance quantitates the rate by which a drug is removed from the body.
What makes up the central compartment?
Plasma, kidney, liver, lungs, heart, brain. All of the highly perfused tissues
The organs of the central compartment receive ____% of the cardiac output.
75
The organs of the central compartment make up only __% of the body mass.
10
In the central compartment there is (rapid/ slow) uptake of a drug.
rapid
What is the pathway of the drug between compartments?
- Drug first introduced into the central compartment
- Drug distributes to the peripheral compartment
- As concentration of drug in the central compartment falls, drug returns to the central compartment for clearance
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.
What parts of the body would be considered the peripheral compartment?
skin, muscle, hair, bones
As we age, the rate of drug transfer between our compartments:
decreases, leading to greater plasma concentrations of certain drugs.
Name a drug that tends to stay in the central compartment in the elderly.
Thiopental
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.
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
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.
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
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.
As people age, they ____ fat and ____ muscle.
gain fat and lose muscle. Remember the fat stores a lot of drugs that may come back
Drugs that are very lipophilic transfer very (slowly/ quickly) to fat and muscle.
quickly
Volume of distribution Vd is the sum of:
all of the volume of the compartments
Mathematically, Vd=
Dose of IV drug divided by the plasma concentration before elimination
Vd is influenced by the physiochemical characteristics of the drug, which are:
- Lipid solubility
- Binding to plasma proteins
- Molecular size
The more lipid soluble a drug, the more it immediately goes to:
the second compartment
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.
Define elimination half-time.
The time necessary for the plasma concentration of a drug to fall 50% during the elimination phase.
Elimination half time is directly proportional to:
its Vd and inversely proportional to its clearance.
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.
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.
As soon as you give a drug IV, _________ begins right away.
elimination
The slower the drug is cleared, the ________ the half time is going to be.
slower
Define elimination half-life.
The time necessary to eliminate 50% of the drug from the body altogether (not just from the plasma).
If dosing intervals are less than the elimination half time __________ occurs.
drug accumulation
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.
At each half time occurs, the drug concentration in the body is:
halved.
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.
By the 4th to 5th half time most of the drug is:
gone from the system.
What is the alpha phase of the distribution curve?
It is the distribution phase, where the drug is moving to the second compartment.
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.
What are the 3 steps of distribution:
- Following system absorption of a drug, the highly perfused tissues, kidneys, heart, liver, brain) receive a large amount of the total drug
- 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
- 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
Tissues that accumulate drug act as a _____________ to maintain the plasma concentration and______________________.
act as a reservoir and prolong the drug’s effect.
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
Systemic absorption, regardless of the route of drug administration, depends on the drug’s___________.
solubility
Whare are 2 advantages of giving drugs orally.
- most convenient
- most economic
Name 4 disadvantages for giving drugs via the oral route.
- Emesis
- Destruction of drug by enzymes or acidic gastric fluid
- Irregular absorption with food or other drugs
- First pass effect
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.
Name one advantage of using the transdermal route of drug adminstration.
It provides a sustained plasma concentration of the drug
Name 4 disadvantages of using the transdermal route.
- Absorption occurs around sweat ducts and hair follicles, these act as diffusion shunts.
- The rate limiting step is diffusion across the strateum corneum of the epidermis
- Thickness and blood flow are factors reflected in the skins permeability for drugs
- Contact dermatitis can occur at the site
When giving a drug via the transdermal route, which side of the body gets more perfusion?
front
When choosing a place to place a transdermal medication patch, you would want to choose a place with the _________ layer of strateum corneum.
thinnest
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.
Name 2 disadvantages to using the rectal route of drug administration.
- 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
- 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.
What is the major advantage of using the IV route in anesthesia?
You achieve therapeutic plasma concentrations precisely and rapidly.
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.
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.
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.
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
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.
Drugs that are ionized usually go straight to the:
kidney, where they will be excreted.
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
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.
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.
Changes in pH can result in a large degree of:
ionization
Acidic drugs are highly ionized at a _____ pH.
alkaline
Basic drugs are highly ionized at an _______ pH.
acidic
Most drugs are racemic, what does that mean?
They exist in equal parts: ionized and unionized.
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.
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.
Do protein bound drugs stay inactive?
No, as plasma concentrations of a drug fall, the drugs will dissociate from protein and enter circulation.
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.
Unbound drug in the plasma is more readily ________ and __________ as well.
metabolized and excreted
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.
Clearance is defined as:
The volume of plasma cleared of a drug by metabolism and excretion. (the liver metabolizes and the kidney excretes)
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.
Most drugs metabolized by humans are metabolized by (first rate order kinetics or zero order kinetics)
first rate order kinetics
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
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.
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
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.
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.
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.
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.
Hepatic clearance depends on 2 factors:
- Hepatic extraction ratio
- Hepatic blood flow
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
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
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
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.
What is the term for clearance that requires enzymatic activity to increase, and not necessarily blood flow to the liver.
Capacity dependent elimination
Once metabolized by the liver, drugs are cleared by the _________.
kidneys
The most important organ for the elimination of unchanged drugs and their metabolites is:
the kidneys
__________ compounds are eliminated more efficiently by the kidneys than _________ ones.
water soluble are more efficiently eliminated than lipid soluble drugs.
Lipid soluble drugs have to be converted to _________ soluble forms so the kidneys can eliminate them.
water soluble
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.
What is biotransformation?
Biotransformation converts pharmacologically active, lipid soluble drugs, into water soluble and often inactive drugs.
How does water solubility affect volume of distribution?
increased water solubility reduces volume of distribution and increases renal excretion
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.
In first order kinetics, a constant fraction of available drug is _________ in a given time period.
metabolized
In zero order kinetics, plasma concentration of a drug ____________ the capacity of metabolizing enzymes.
exceeds
In zero order kinetics, metabolism of a ________ amount of drug occurs per unit time.
constant
Give 3 examples of drugs that exceed enzyme metabolism capacity and are metabolized by zero order kinetics.
ETOH, ASA, Dilantin
What are the 4 pathways of metabolism?
- Oxidation
- Reduction
- Hydrolysis
- Conjugation
In phase 1 metabolism the drug goes through ________, _________, and/or ___________.
oxidation, reduction and hydrolysis
In phase 2 metabolism, the parent or metabolite drug reacts with an endogenous substrate to form:
water-soluble conjugates
Phase ___ describes how the drug is metabolized.
2
________________ are responsible for metabolism of most drugs in the liver.
Hepatic microsomal enzymes, they are located on the smooth endoplasmic reticulum of the hepatocye.
Plasma ________ metabolize drugs in the plasma.
esterases
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
They CYP stands for _____________ in the nomenclature for the hepatic enzyme metabolic system.
Cytochrome P-450
The first number on the CYP nomenclature denotes__________.
the genetic family
The second letter of the CYP nomenclature denotes ____________.
genetic subfamily
The second number of the CYP nomenclature decribes:
the specific gene or isoenzyme
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.
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.
99% of drugs are broken down by:
liver enzymes
The 1% of drugs not metabolized by CYP are metabolized by:
nonmicrosomal enzymes
Nonmicrosomal enzymes metabolize drugs mostly by ____________ and ____________.
conjugation and hydrolysis. To a lesser degree they metabolize by oxidation-reduction.
Nonmicrosomal enzymes are present in what 3 areas:
liver mostly, plasma, and GI tract
nonmicrosomal enzymes are responsible for hydrolysis of drugs that contain ________ bonds.
ester bonds. Like sux.
nonmicrosomal enzymes are not affected by or undergo _______________.
enzyme induction
nonmicrosomal enymes are determined __________.
genetically
Plasma esterases (are/ are not) affected by enzyme induction.
not affected
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.
Receptors can _________ or ___________ in response to certain stimuli.
upregulate or downregulate
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
If receptors are constantly bombarded with more molecule then they need or want, they can __________ the number of receptors.
down regulate
What does the State of Receptor Activation Theory say?
Non-activated receptors convert to active by the drug.
Stress can actually _______ receptors.
upregulate
State the Receptor Occupancy Theory.
The more receptors occupied by the drug, the more effect.
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.
What do agonist drugs do?
They mimic cell signalling molecules by activating the same receptor sites and causing similar effects.
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.
The affinity of a drug for a specific macromolecular component of the cell and its intrinsic activity are intimately related to its ___________________.
chemical structure
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
The structure of the drug molecule is what determines if it is ________ or _________.
lipophilic or hydrophilic
Interaction with biological receptors can differ greatly between two enantomers, even to the point of ____________.
no binding
Some isomers may cause __________ or ___________ compared to its mirror image.
side effects or entirely different effects
Do all isomers have effect at the receptor site?
No, some will have no effect at all.
Ephedrine has ___ chiral centers and ____ isomers.
2 chiral centers, 4 isomers.
Synergistic effect: 1+1=
3
What is additive effect?
A second drug, acting with the first, will equal the sum of both. 1+1=2
Hypersensitivity occurs in people who are:
allergic to the drug. It actually creates an immune response to the drug.
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.
What is meant by a hyper-reactive resonse a drug?
people in whom an unusally low dose of drug produces its expected pharmacological effect.
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!
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.
Define enantiomer.
A pair of molecules that are mirror images of each other.
Define chiral carbon.
An assymetric carbon that is attached to 4 different types of atoms or 4 different groups of atoms.
Free rotation around the chiral carbon is (possible/ not possible)
not possible. but 2 stable forms of the molecule can exist.
Name this isomer of ephedrine and give its potency.
D- (-) ephedrine. Potency= 36
Name this isomer of ephedrine and give its potency.
L- (+) ephedrine. Potency= 11
Name this isomer of ephedrine and give its potency.
D- (-) pseudoephedrine. Potency = 1
Name this isomer of ephedrine and give its potency.
L- (+) pseudoephrine. Potency = 7
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.
What is meant by therapeutic window?
the concentration of drug at the site of action where the desired therapeutic effect is produced.
True or False. The site of desired therapeutic effect is also the same site that produces undesirable effects.
It may or may not be.
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.
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.
Define therapeutic index.
ratio of toxic dose to therapeutic dose.
Drugs with a large therapeutic index are __________ (safer/ more risky) than drugs with smaller values.
safer
