Term
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Definition
absorbtion
distribution
metabolism
excretion |
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Term
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Definition
Huge for us, has to do with timing, when is this drug going to work.
Need to know how its moving when its going to start when its going to peak and when is it reasonable to re dose. |
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Term
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Definition
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Term
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Definition
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Term
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Definition
completely reversible
minimal side effects
effective
inexpensive
*doc wants it to work like a light switch.
rapid onset
cadaveric relaxation
rapid emergence |
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Term
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Definition
We prepare
We administer
We monitor |
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Term
How fast will it get there?
How fast will it work |
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Definition
blood flow-bypass absorbtion and put it right in the blood stream. blood flow to your organ tells you how fast it will get there.
concentration gradient
volume of distribution
Tissue capacity
Receptor/drug complex-affinity? How many receptors does it need to occupy before a change occurs, Simple ion channel or GPCR. |
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Term
| Effect site equilibration |
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Definition
| 1/2 life between administering bolus and onset of effect. Timing, not peak effect, its an onset. |
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Term
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Definition
everything goes down hill, simple concentration gradients. Steeper the hill, the faster it goes.
most Drugs we use are simply diffusing down a concentration gradient and always moving. |
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Term
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Definition
trans membrane proteins
Ligand gated receptors
-ion pore channel
-g coupled protein (inside cell)
*both work at the cells surface. |
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Term
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Definition
| don't use them as far as pharmacology. Our drugs dont work here! |
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Term
| Exception to drugs working at the cells surface |
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Definition
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Term
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Definition
Nicotinic Ach receptors
Serotonin
(cation selective and excitatory)
Gaba-inhibitory (primary inhibitory transmitter in the brain
Glycine- primary inhibitory transmitter in spinal cord, effects GABA receptors (anion selective and inhibitory)
Glutamate: main excitatory neurotransmitter |
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Term
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Definition
NMDA, AMPA, Kainate
primary excitatory transmitter |
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Term
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Definition
Margin of saftey
Nice fit for receptor
Has a high affinity for receptor
is an agonist then it only needs to occupy a few receptors to cause an effect. |
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Term
| Muscle relaxant receptor occupancy |
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Definition
| Needs to occupy almost >75% of receptors to even begin to interfere with muscle contraction. Due to body's wide margin of safety, muscle contraction can occur with 25% receptors free from from drug. Must overwhelm the receptor to get started. |
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Term
| Receptors.. How much drug do I need to get started? Availability?? |
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Definition
| not a static concept its constantly moving. |
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Term
| How much drug do I need to block that? |
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Definition
| may need a lot NMB or little depending on the drug |
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Term
| Constant Stimulation of Receptors |
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Definition
| makes cells diminish the number of available receptors. happens almost instantly. |
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Term
Volume of Distribution
(short bus) |
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Definition
| amount of drug /plasma concen=Vd |
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Term
Cool Aid Man
Volume of distribution |
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Definition
How much volume and how much sugar in each cool aid is different.
Concentration is the same..they taste exactly alike.
Little jar of cool aid is the blood stream/CO/ circulation volume. this is where we put our drugs.
Large jar: rest of your human outside the blood stream. |
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Term
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Definition
Humans come in different sizes so their big jars could be slightly altered.
Peripheral volume of distribution.
This is bigger=more adipose tissue=anesthetic drugs hang on longer. |
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Term
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Definition
Smaller circulating volumes=smaller little jar.
Central volume of distribution |
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Term
Cool Aid Jar example
Normal Guy not too big not too small..car wreck and left 1/2 his blood on the pavement. you are giving him anesthesia. What has happened to his central volume of distribution??
Will you need as much drug? |
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Definition
its depleted. Small cool aid jar is 1/2 empty.
Give less drug |
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Term
Ex #2 Volume of Distribution
Really long case, all drugs are lipid soluble, leave the blood system and store in tissues everywhere. Pt is 750 lbs. Which cool aid jar is changed?
Whats going to happen with your drugs? |
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Definition
Big jar.
Take them longer to wear off.
Pt has large storage vault. hang on to alot of stuff even into the PACU. |
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Term
Ex #3 Volume of Distribution
Pt is elderly and on 3 different BP meds. 1 Hydrochlorothiazide, and ACE inhibitor.What has happened to jars? |
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Definition
Small cool aid jar is going to be smaller (central Vd) Bc decreased circulating volume. BP med and Diuretic--> dec
Big cool aid jar is bigger.
Elderly have a smaller blood volume
Less muscle mass and more adipose tissue. (big cool aid jar bigger-->peripheral Vd |
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Term
Where do our drugs go?
How do they get out? |
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Definition
Central volume of distribution, and immediately diluted.
Gets out by diffusion from the central volume.
higher the concentration gradient the fast it gets out of capillary beds.
Non charged and lipid soluble and not bound to plasma proteins.
Bound to plasma proteins it cant get out of capillary beds. |
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Term
| Can a drug still get out of the capillary beds if its lipid soluble not charged and not bound to proteins?? |
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Definition
even if its water soluble it can get out of most capillary beds.
Limited exchange capacity are in the blood brain barrier. |
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Term
| When does metabolism start? |
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Definition
| Immediately, drug concentration can dec right away bc metabolism. |
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Term
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Definition
| some books use the 2 compartment model- only takes into account the "k" and something is always moving. As soon as the drug is in the central compartment it is taken to organs and excreted. Has to be moved back to the central circulating area to be excreted. |
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Term
| What the 2 compartment models doesn't cover?? |
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Definition
Re distribution
ex drug: pentathol
doesnt take into account how our immediate drugs are working. |
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Term
How large is your compartment?
How big is your bucket and how fast are you filling it? |
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Definition
How fast your drug gets there is related to the blood supply. Each compartment is a bucket.
Brain? not very big, lean tissue, not a lot of solublitiy issues. How much blood does it get?? Big load of CO. |
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Term
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Definition
| Small bucket and filling it with a hose. You are filling it fast! |
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Term
| Bones fat all storage places? |
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Definition
| Low blood supply, high solubility, large mass. Huge bucket and you are filling it with an eye dropper. |
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Term
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Definition
depends on the mass
solubility of the drug in the compartment
whether that drug, it binds to proteins or macromolecules in that compartment
just like our drugs bind to proteins in the plasma
Ph in the compartment |
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Term
| How fast are you filing it? |
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Definition
| Depends on CO or flow to the compartment. |
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Term
Where do our drugs go?
How do they get out? |
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Definition
Central volume of distribution, and immediately diluted.
Gets out by diffusion from the central volume.
higher the concentration gradient the fast it gets out of capillary beds.
Non charged and lipid soluble and not bound to plasma proteins.
Bound to plasma proteins it cant get out of capillary beds. |
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Term
| Can a drug still get out of the capillary beds if its lipid soluble not charged and not bound to proteins?? |
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Definition
even if its water soluble it can get out of most capillary beds.
Limited exchange capacity are in the blood brain barrier. |
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Term
| When does metabolism start? |
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Definition
| Immediately, drug concentration can dec right away bc metabolism. |
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Term
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Definition
| some books use the 2 compartment model- only takes into account the "k" and something is always moving. As soon as the drug is in the central compartment it is taken to organs and excreted. Has to be moved back to the central circulating area to be excreted. |
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Term
| What the 2 compartment models doesn't cover?? |
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Definition
Re distribution
ex drug: pentathol
doesnt take into account how our immediate drugs are working. |
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Term
How large is your compartment?
How big is your bucket and how fast are you filling it? |
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Definition
How fast your drug gets there is related to the blood supply. Each compartment is a bucket.
Brain? not very big, lean tissue, not a lot of solublitiy issues. How much blood does it get?? Big load of CO. |
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Term
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Definition
| Small bucket and filling it with a hose. You are filling it fast! |
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Term
| Bones fat all storage places? |
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Definition
| Low blood supply, high solubility, large mass. Huge bucket and you are filling it with an eye dropper. |
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Term
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Definition
depends on the mass
solubility of the drug in the compartment
whether that drug, it binds to proteins or macromolecules in that compartment
just like our drugs bind to proteins in the plasma
Ph in the compartment |
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Term
| How fast are you filing it? |
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Definition
| Depends on CO or flow to the compartment. |
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Term
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Definition
10% mass
75% of CO
Lungs, heart, brain, endocrine glands, kidney.
*heart and brain can be put into the central compartment because it equilibrates that quickly. |
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Term
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Definition
70% mass
25% cardiac output
muscle, skin, fat, bones |
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Term
| Which group fills faster? |
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Definition
| Small bucket with bigger hose |
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Term
| Which equilibrates slowly? |
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Definition
| larger bucket with smaller hose |
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Term
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Definition
how much is in different compartments
what you look for is what is it going to do at steady state and concentration is the same. |
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Term
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Definition
| Factors in redistribution. If you were to redose the patient bc they woke up you would be contributing to accumulation. Vessel poor group will act as a reservoir. |
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Term
| Why do patients wake up on sodium pentathol? |
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Definition
Redistribution, reaches the brain in 30-60 sec to cause unconsciousness. Brain is a vessel rich group so it gets a lot of blood and med immediately goes to vessel rich groups. In 30-60 secs the brain and the blood have the same concentration of substance. Same concentration in each compartment but the amount of drug is not the same. Also the vessel poor groups concentration is not enough. 8 min later the concentration in the brain falls because it goes back into the blood stream. PT doesn't wake up bc of metabolism but bc redistribution to another compartment.
They wouldnt wake up because we are going to add more drugs to this! |
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Term
If vessel rich group is smaller??
ex elderly |
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Definition
| We need to decrease our dose to limit redistribution. |
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Term
2nd rule
what is moving along the constant lines? |
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Definition
Drug that is non ionized
Lipid soluble and
not bound to protiens (plasma proteins)
Plasma proteins are recpetor sites, when the drug is bound its not being used/not active drug.
*the drug is moving down its concentration gradient at a constant rate for that drug. |
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Term
| Concentration at "steady state" |
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Definition
all equiliabration and all the movement has been accomplished. By looking at drugs in Steady state you are eliminating the kenetics, only looking at dynamics. You are shooting for this when a pt is on an infusion. As much going in is what is going out. Concentration the same in ALL compartments. IS the amount of drug the same?? NO! all taste the same but there are different amounts in each compartment.
This is when partition co efficents will be evaluated.
Concentration is the same amount of drug is different. |
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Term
| How do we compare compartment's concentrations to make sure they are equal at steady state? |
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Definition
| wait until they get up to steady state and then read plasma level. Its easily assayed. |
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Term
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Definition
PO medicine, usually a function of PO meds, you have to give a lot more than whats actually going to hit the blood stream.
How much cardiac output does the pulm circulation get? all the Cardiac output. Many of our drugs have significant uptake in the pulmonary tissue because if they are in the blood they are being passed through the lungs.
Lipid soluble drugs have significant uptake in pulm tissue.
Vessel rich group..little bucket lean tissue |
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Term
| Lipid soluble drugs significant for Pulmonary uptake by the lungs and acts as a storage compartment? |
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Definition
Fentanyl
Sufentanil
Alfentanil
Above drugs lose macromolecules in the lungs but then the macromolecules are able to be used later. Lungs are a storage compartment more than a 1st pass mechanism.
Reservoir NOT a First Pass
Its a vessel rich reservoir. |
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Term
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Definition
give a single bolus of a drug how long does it take for most of it to be removed from the person. Certain fraction of the drug will be eliminated every 1/2 time (5 usually is enough)
This is important to maintain steady state and you don't want accumulation. |
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Term
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Definition
5 1/2 lives to start
5 1/2 lives to go away |
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Term
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Definition
minimal alveolar concentration, whats in the lungs that will keep 1/2 the patients from doing something.
MAC awake 1/2 the patients respond to a verbal command, they may not recall but will respond to verbal command. |
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Term
| When will your patient wake up? |
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Definition
need to know how much is circulating and how long will it take to wear off
need to know which cause accumulation* |
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Term
| Contact sensitive 1/2 life |
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Definition
if contact sensitive, infusion of a drug when you shut it off, when will the concentration in the blood decrease by 1/2.
"contact sensitive" means that
after we turn off the infusion when is the blood level going to decrease by 1/2. Takes into account the properties of the drug (Chemical)and how long have you had to infusion going. USe it alot in anesthesia bc it compares drugs to each other. compares kenetics dynamics length of infusion. what it doesnt tell..When the patient will wake up.
**ONly telling you when the concentration of the drug will drop by 1/2. When the patient wakes up is totally depended on how far the concentration has to fall before they return to consciousness.
Measure in the plasma but nothing works in the plasma.
Does not tell you when the patient will wake up, but tells you WHEN THE CONCENTRATION IN THE PLASMA WILL DROP BY 50%. |
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Term
| Sevo contact sensitive 1/2 life |
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Definition
| asleep is 2% awake is .3% must fall greater than 50% and this is whats annoying about the MAC awake ratio, higher the ratio the shorter the thing has to fall before the patient wakes up. smaller the ratio..it has to drop a long way. 1/3 bigger than 1/5. if the levels have to drop a long way you can be sure your patient wont remember you for a long time. nice wide therapeutic window but will take a while to get off. |
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Term
Steady state
When does the patient go to sleep and when does the patient wake up? |
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Definition
Patient goes to sleep when first the plasma level is up to a concentration that will put them to sleep, has to get to a therapeutic dose, but they don't go to sleep with the drug in the plasma they go to sleep with drug in the brain.
So the time it takes to get into the therapeutic window to the patient actually going to sleep is the time it takes for the drug to get across the biological membranes get to the receptor and function. It has to move to the right compartment and attach to the receptor and get to work.
Now when we shut off the infusion,and it wears off pretty fast, it doesnt accumulate. Giving it at a lever where it was excreted. Blood level falls and now its the same, why is the patient still asleep? The drug has to move out of the brain..when does it do this?
When the plasma concentration is lower so the drug concentration gradient is going in the other direction. They arent awake yet because it has to move out of the brain.
**concentration in the brain is what we are concerned about. |
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Term
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Definition
tells you the amount of drug in each compartment in relation to each other. When the concentration is at steady state there are different amounts of drug in each compartment. usually given in ratios/relationships.
All the cool aid jars taste the same, how big is the jar and how much sugar is it holding.
Also used to see how lipid soluble your drug is. lipid solubility is a chemical property of a compound.The more lipid soluble it is the easier it crosses biologic membranes.
Ex Morphine is 1= if there is one in the water there is one in the lipid. Not very lipid soluble. |
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Term
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Definition
| Incredibly lipid soluble based on their partition co efficient s, the higher the number is the more lipid soluble the drug is. this is just one factor involved volume of distribution, just tells you how fast it will cross biological membranes. |
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Term
| Short bus method to ionized vs non ionized |
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Definition
need to know if your drug is an acid or a base (most of ours are a base)
Drug Pka and ambiet ph (our humans ph 7.4 is norm)
Acid+base=salt+water (Co-->soltalime and Co2 goes away pt doesnt reabsorb it) salts are water not lipid soluble. |
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Term
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Definition
| Going to tell you if the drug has a charge or if its neutral.nuertal non charged drugs cross biological membranes easier. Where the drug is 50 50 1/2 ionized 1/2 unionized. |
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Term
| Method on if your drug will move |
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Definition
Acid drug: Pka After the ph (acid after)
Basic drug: Pka Before the Ph(base before)
__-__=___
-Nice Negative Numbers give Nice Non ionized drug.
*will tell you will your drug be more or less 50% ionized. |
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Term
| Some Simple Rules Acids and Bases |
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Definition
acids bind with Na K Mg and Ca
bases bind with Cl SO4
Acids accumulate in plasma
Bases accumulate in tissue |
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Term
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Definition
Correlates with lipid solubility. More lipid solubility a drug is it usually has higher protein binding.
Albumin-abundant and prefers acidic drugs
Alpha 1-likes bases (acid glycoprotien)
Alpha 1 tends to go up during stress states.
Also called acceptor sites, they bind but not active, they dont preform their function.
Remember there are proteins in the tissue also. |
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Term
| Protein binding competition |
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Definition
they can increases or decrease on or the others free fraction.
Saturatable
low protein states cause drug concentrations to low at steady state because the "free drug is available for metabolism.
total drug concentration is lowered
If our patient doesn't have many circulating proteins and we are giving a highly protein bound drug..we should decrease the dose. (acute admin is different then steady state) |
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Term
| Free drug (free fraction drug) |
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Definition
| active bioavaliable stuff. |
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Term
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Definition
Phase 1 Reactions
Oxidation and reduction
Hydrolysis
Conjugation: phase 2
-change a lipid soluble to a water soluble compound. |
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Term
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Definition
hepatic blood flow
intrinsic ability to eliminate the drug
protein binding
Liver has a very high capacity to handle most of these foreign substances so rate of elimination is limited only by the blood supply to the liver. Very high intrinistic ability to get rid of drugs. Gets drugs from circulation.
Unbound uniomized lipid soluble drugs are whats moving in. |
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Term
| First order/first order motion |
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Definition
| Liver can handle all you bring to it. chew up constant fraction of drugs. bring in 1000 mg it will chew up 1/2 of that. |
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Term
| Zero Order/zero order motion |
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Definition
Metabolism or transport mechanism is saturatable. If Dm glucose is 200 transport mechanisms are saturated and glucose will show up in urine.
Alcohol is like this.
Saturatable and the constant amount of drug will be metabolized.Bring all you want to the liver but it will only metabolize X amount. Will only metabolize 10mg whether you bring it 40 mg or 400 mg. |
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Term
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Definition
Pro drugs:(propofol example)
Active Metabolites: will it cleave it into something that works,watch out for this bc it will increase duration of action , can also have toxic ones ex nipride
Competition for enzymes: tagament-slows down metabolism to viagra
Enzyme deficiencies:
Enzyme induction:change the metabolism of the drug. Ex 3 martini lunch..their liver is ready and they will eat through your nmb. May have to give them more meds more frequently. |
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