Pharm Test 1 Flashcards
Elimination is dependent on
which organ is eliminating the drug
The organ that is eliminating a drug is dependent on
- Whether or not the drug is a high-extraction drug
- what the blood flow is through that organ
If the blood flow through an elimination organ is normal, we call it
high
If the blood flow through an elimination organ is limited, we call it
low
Oral morphine doesn’t provide the full effect because
After the GI tract morphine goes into the liver and the liver removes a lot of it. It is a high extraction drug
What is the range for a high extraction drug?
> 0.7
What is the range for an intermediate extraction drug?
0.3-0.7
What is the range for a low extraction drug?
<0.3
What is Q in the extraction ratio?
The blood flow through an elimination organ.
What is the Clorgan formula?
Clorgan=QE
What is E in the extraction ratio?
the percentage of drug that comes out of an elimination organ
If you have a high E and a low Q, what is your Clorgan?
Low
If you have a low E and a high Q, what is your Clorgan?
Low
If you have a high E and a high Q, what is your Clorgan?
high
If you have a low E and a low Q, what is your Clorgan?
low
Why is the half life important?
It helps us determine how we should dose a patient and how much we should dose them
Define half life
the time it takes the body to get rid of half of the concentration of a drug in the blood
What is the half life formula?
T1/2=0.7XVd/CL
What is giving a drug in “steady state” mean?
Giving the drug at the same rate that the body is eliminating it.
What do we do to reach target concentration quickly?
Give a bolus of a drug
For a drug that has a 4 hour half life, how many half lives would it take for the drug given at steady state to reach target concentration in the blood?
16 hours
For a drug that has a 4 hour half life, how many half lives would it take for the drug to be completely eliminated from the blood after the infusion is stopped?
16 hours
What effects half life?
Many things, including disease state
A true half life will be _____ than the calculated half life
greater
If you don’t wait 4 half lives before taking another dose of the drug, what will happen?
The drug will accumulate in the plasma and can become toxic very quickly
How is bioavailability denoted?
F
What does bioavailability tell us?
How much of the drug reaches systemic circulation
What is the bioavailability of an IV drug?
100%
What factors effect bioavailability?
- Physical properties of the drug (hydrophylicity, PKA, solubility)
- Fomulation/route
- GI- diet, gastric emptying, transporters, health
- interactions with other drugs
- disease state
- circadian rhythm
What is first pass elimination?
The first system that the drug goes through that changes the concentration of the drug.
What are routes that bypass first pass elimination?
- IV
- IM
- SC
- Inhalation
*has it’s own first past effect - sublingual
- transdermal
- rectal
*suppositories might move upward, therefore only 50% bypass hepatic circulation
What is target concentration based on?
What we are trying to accomplish in the patient (pain relief, controlling afib)
What is the most important factor of the dosing ratess?
Clearance
How do you solve for dosing ratess?
CL X Target concentration
For bioavailability that is less than 100%, how is the formula changed?
Dosing rateoral=dosing rate (calc.)/Foral
The CL X Target concentration is divided by the bioavailability.
If your bioavailability is less, your are going to have to give _____ of the drug
more
What is an intermittent dose for oral drugs?
Giving a pill every few hours instead of constantly.
Dosing rate X dosing interval (in hours)
If you are given the target concentration, the clearance, and the time interval how do you solve for the intermittent dose?
- Dosing ratess=CL X Target Concentration
- Dosing rateoral=dosing cate (calc.)/ForalX dosing interval
Describe what is happening in this graph.
The black line is the drug being given in steady state. It is showing that after 4 half lives, the drug reaches 10mg/L and the patient is receiving the targeted effect of the drug.
The red line shows the drug being given every 8 hours. The patient has peaks and troughs that’s staying right around the target concentration.
The blue line is the drug being given every 24 hours. You can see that at the peaks the patient is receiving a much higher effect than the target concentration, but the troughs are also much lower. In the case of this siezure drug, you can see how the troughs would leave this patient open to having seizures.
How to calculate the loading dose?
LD=Vd X TC
The loading dose is assumed that it is given over
5 minutes
Why is rate of administrations critical for potentially toxic drugs?
Giving a bolus too fast doesn’t allow time for the drug to distribute into compartments and therefore reaches toxic levels in the plasma very quickly
How do we monitor for therapeutic dosing?
Peak and trough tests
When is the peak test taken?
5-10 minutes after drug administration
When is the trough test taken?
30 minutes before the next dose
What do the peak and trough tests tell us?
Assessment of individual response to standard population pharmacokinetic variables.
To be able to dose the drug to each individual patient based on their disease state, other drugs they’re on etc.
If you have a drug that preferentially stays in the fat, which weight do you use?
their actual weight
If you have a drug that preferentially stays in the blood stream, which weight do you use?
Their Ideal body weight
What test tells us how well the kidneys are functioning, and how does it work?
The creatinine clearance.
The muscles release a steady rate of creatine in the blood as waste which gets down to the kidneys for excretion. If creatinine starts to build up in the body then it is safe to assume that the kidneys are not functioning properly.
What is biotransformation?
The changing of a drug to either make it work better, or in most cases to decrease or stop the drug from working altogether.
What is the second largest organ in the body?
the liver, after the skin
Where does most, but not all, biotransformation happen?
The liver
What is in the hepatic portal system?
- oral
- gi
- local veins
- hepatic portal vein
- sinusoids very leaky
- hepatocytes
- hepatic vein
- vena cava
- systemic circulation
Where is a drug biotransformed?
Hepatocytes
What are the 2 different places that biotransformed drugs can go after the hepatocytes?
Back into the blood stream to be delivered to the body
Into the Bile duct to be eliminated through bile
What is the circulation for a drug given in a central line?
- Vena cava
- r atrium
- r ventricle
- l atrium
- l ventricle
- systemic cirulation
- hepatic artery
- sinusoids
- hepatic vein
- vena cava
- systemic circulation
Why are the sinusoids an area with fairly low oxygen concentration?
Because blood from the hepatic portal vein and the hepatic artery both mix here
What are the sinusoids in the liver very susceptible to?
Heart failure
Do sinusoids regenerate quickly?
yes
What are phase 1 reactions?
When we take an enzyme and either add or unmask a functional group (-OH, -NH, -SH et.) very small substances.
What are phase 2 reactions?
We’re tacking on larger molecules
In some way, phase 1 and phase 2 help with the ______ of a drug.
elimination
Is there a specific order phase 1 and phase 2 has to happen?
No, and they don’t have to go through both reactions.
Phase 1 turns the drug into a more _______ metabolite. Making it harder to cross into the cell and therefore easier to eliminate.
polar
Phase 2 reactions are ________ reactions.
conjugate
meaning to combine 2 things
Phase 1=
oxidation, reduction, hydrolysis
After phase 1 most drugs are
inactivated
Phase 2 results in drugs with a ________
higher molecular weight, essentially detoxifying the drug by making it harder to cross into the cell.
What are the 4 main groups of phase 1?
Oxidation
reduction
dehydrogenation
hydrolysis
What is oxidation?
Loss of an electron
What is reduction?
Gaining of an electron
What is dehydrogenation?
removing an OH group
What is hydrolysis?
breaking down of water in a reaction and that breaks a bond
Why are we focusing on oxidation reactions?
Because that is how vast majority of drugs are modified in phase 1 reactions.
What is used in the primary oxidation pathway?
an enzyme called Cytochrome P450. It’s a molecule
P450 cycle
- drug comes in lipophilic
- binds to CYP450
- loss of E-
* Flavoprotein oxidizes and becomes oxidized
* then goes through the compound NADPH
* NADPH is reduced turning into NADP+
* NADPH is recycled somewhere in the liver
* Now Favoprotein is recycled and is in it’s reduced form - P450 molecule is a holder for the drug
- 2 Oxygen molecules and electrons are added to the drug
- Oxygen detaches from the drug and attaches to 2 Hydrogen turning into water
- The other oxygen stays on the drug and becomes a hydroxyl group
- Drug is then more hydrophilic & is released into either the circulation to be excreted by the kidneys or the bile to be excreted through the intestines
What takes electrons from P450?
Flavoprotein
What is the most common flavoprotein?
Flavin mononucleotide
FMN
By oxidizing P450, Flavoproteins become
oxidized themselves
CYP3A4 synthesize what percent of oxidation reduction reactions?
50%
CYP2D6 synthesize what percent of oxidation reduction reactions?
20%
CYP2B6 synthesize what percent of oxidation reduction reactions?
8%
What does CYP short for?
Cytochrome P450
What is the most important CYP450?
CYP3A4
Where does the oxidation reaction happen inside of the hepatocyte?
Sarcoplasmic reticulum
CYP384*1 means
this is a wild type
what does the wild type mean?
it is the variant that is most commonly seen in the population.
CYP3A4*2
is a mutant of the CYP3A4*1 and may have different activity.
What is a polymorphic variant?
A deviation from the wild type that may have a greater, lesser, or same effect as the wild type.
What produces variants?
Genetic mutations
What is a P450 induction?
a drug(medicine, food, charbroiled) that increases the number of cytochrome P450 enzymes which increases the CYP3A4 enzyme which effects the drug
What is a P450 Inhibition?
A drug(medicine, food, charbroiled) that decreases the number of cytochrome P450 enzymes which decreases the CYP3A4 enzyme which effects the drug
If a drug is inactivated by CYP3A4, and we take an inducer, what will happen?
The drug will become inactivated at a much faster rate.
Less drug effect
What is a prodrug?
something that has to be activated by CYP3A4
If a drug is activated by CYP3A4, and we take an inducer, what will happen?
The drug will be become active much more quickly and may reach toxic effects quickly.
more drug effect
If a drug is inactivated by CYP3A4, and we take an inhibitor, what will happen?
Less of the drug is being inactivated, meaning more of the drug is being released into the body and you may reach toxic effects faster.
more drug effect
If a drug is activated by CYP3A4, and we take an inhibitor, what will happen?
Less of the drug will become activated, meaning that less of the active drug will be available in the plasma.
Less drug effect
What is glucuronidation?
attaching a glucose
What is the acetylation?
attaching an Acetyl-CoA
What is Glutathione conjugation?
attaching a glutathione (GSH)
What is Glycine conjugation?
attaching a Glycine
What is sulfation?
attaching a Phosphoadenosyl phosphosulfate
What is Methylation
attaching a S-Adenosylmethionine
What is water conjugation?
attaching a water
What is a UGT?
Uridine diphosphate glucuronyltransferases
a type of glucuronidation reaction
They attach a glucuronic acid to molecules
A carrier molecule with the Glucuron transferase (which transfers a glucose molecule from UDP to the drug itself)
What do UGT’s attach a glucuronic acid to?
Phenols, alcohols, carboxyl, and sufhydryl groups
Where are UGT’s primarily found?
in the liver
What is uridine diphosphate?
the carrier molecule
What do the glucuronyltranferases do?
Transfers a glucose molecule from UDP to the drug itself
What is the response of a drug undergoing glucuronidation?
It becomes more aqueous soluble, and is excreted via the urine more easily
What is a Glutathione-S-transferase? GST
attach a glutathione
Glutathione characteristics
ubiquitous
Critically important in detoxification
Increases water solubility to get rid of toxins
Where are glutathiones found?
Everywhere. Really high in RBC’s because they can build up high amounts of oxidants in them because they carry oxygen.
What is a xenobiotic?
something that is foreign in the body
What happens to xenobiotics when a glutathione binds to it?
It forms a glutathione conjugate which makes it more likely to be excreted in the urine
What does overdosing do?
It overwhelms the normal detox pathways
What are extrahepatic metabolism examples?
Brain
Lung
Intestine
Plasma
Kidney
What are things that change the way we metabolize drugs?
diet
environment
age and sex
disease state
genetics
DEAD Genetics
