Lecture 2 - Pharmacodynamics and Pharmacokinetics (Test 1) Flashcards
What does TTE stand for?
Can we use this in our charting in the OR?
Titrate to Effect
YES! If you have a gtt on a roller-clamp, you can chart “TTE” and you’re covered :)
Slide 2
What type of study is Pharmacokinetics?
Quantitative- what we can measure (ADME)
(slide 12)
what does ADME stand for
Absorption, Distribution, Metabolism, Excretion
(slide 12)
Which four factors/disease processes would lead to decreased plasma proteins?
Age (Elderly)
Hepatic Disease
Renal Failure
Pregnancy
Burns (verbal)
Slide 17
If normal free fraction of a drug is 2% and the patient has lost 50% of plasma proteins, the free fraction of the drug would now be…
4% - It doubles
Slide 17
What is ED50?
The dose required to produce effect in 50% of patients
(Slide 37)
What does Pharmacokinetics study?
The study of Injected and inhaled drugs and their metabolites
(slide 12)
What is LD50?
The dose required to produce death in 50% of patients
(Slide 37)
Pharmacokinetics determines the concentration of the drug to what 3 factors?
- In the plasma
- At the effector site on the receptor
- The variety of significant effects from person to person
(slide 12)
Therapeutic index is?
The ratio between (LD50/ED50 )
(Slide 37)
Which disease processes/factors would result in a large volume of distribution?
Burns
Sepsis
Pregnancy
Age
Slide 18
Would you rather have a wide or narrow therapeutic index?
A wide therapeutic index because it makes the medication safer compared to a narrow one.
(Slide 37)
If a drug is lipophilic and has poor protein binding, the volume of distribution is…
Large
Slide 18
If a drug is highly protein bound to plasma proteins, the volume of distribution is…
Small
Slide 18
Which two drugs discussed in class have a high volume of distribution?
Thiopental (Barbiturate used to induce general anesthesia)
Diazepam/Valium
Slide 18
What is stereochemistry?
How drug molecules are structured in 3 dimensions.
(Slide 38)
What are chiral compounds?
Molecules with asymmetric centers
Usually related to way carbon molecules are bonded
(Slide 38)
Which drug, discussed in class, is highly bound to plasma proteins and therefore has a small volume of distribution?
Warfarin
Slide 18
What does 1 Compartment Model of distribution theorize?
That after immediate injection of a drug into the blood, it mixes with 5L of cardiac output then leaves the blood stream. (does not take CO % to tissues into consideration)
[Ka –> Vd –> Ke]
(slide 13)
What process converts active, lipid-soluble drugs into in-active water soluble drugs?
Metabolism
Slide 19
What is the structural basis of enantiomers?
Chemically identical
Mirror images
Can’t be superimposed
(Slide 38)
The rotation of light to the right is called?
Dextrorotatory
(Slide 39)
What are some examples of active metabolites?
Diazepam
Propranolol
Morphine
Codeine
Slide 19
What is another name for propranolol?
Inderal
Slide 19
Define Central Compartment distribution:
What dilutes the drug in the first minute following injection into the blood.
(slide 13)
How are most drugs metabolized?
Hepatic Microsomal Enzymes
(Slide 20)
The rotation of light to the left is called?
Levorotatory
(Slide 39)
Besides hepatic microsomal enzymes, what are three other ways drugs are metabolized?
Plasma - Hoffman Elimination and Ester Hydrolysis
Kidneys
Tissue Esterases (GI Tract, Placenta)
Slide 20
Drug rotation to the right is rectus or sinister?
Rectus
(Slide 39)
Drug rotation to the left is rectus or sinister?
Sinister
(Slide 39)
Phase I metabolism consists of…
Oxidation
Reduction
Hydrolysis
Slide 20
A 50/50 enantiomer mixture is called a what?
Racemic mixture!
(Slide 39)
What are the characteristic of a racemic mixture?
Equal Optical activity
Can exhibit different ADME
One enantiomer is active; other inactive or side effects
(Slide 39)
In phase II metabolism, this happens when drugs are covalently linked with a highly polar molecule to become water-soluble…
Conjugation
Slide 20
Define what a vessel rich group is when talking about Central Compartment.
It’s the low body mass % tissues that get the most cardiac output perfusion % than other tissues in the body.
(slide 13)
T/F: Are 1/3 of drugs racemic?
True
Slide 39
Large family, 10-isoforms
Membrane bound and contains a heme cofactor
Involves oxidation and reduction
CYP450 enzymes
Slide 21
What is the most common CYP450 enzyme for the metabolism of anesthetics, with up to 60% of CYP450 activity?
CYP3A4
Slide 21
In this CYP family, things are 40% homologous.
(Ex. All the guys in our class)
CYP3
SLIDE 21
In this CYP family, the group is 55% homologous.
(Ex. The guys in our class from Texas)
CYP3A
Slide 21
The individual enzyme from a group.
(Ex. Just Andrew :) )
CYP3A4
SLIDE 21
What does 2 Compartment Model theorize?
That SOME of the drug that is immediately injected into the blood stream and the central compartment with distribute to peripheral compartments (like the kidney, liver, tissues) but will then return back to the central compartment of the blood to get eliminated.
(Does NOT take into account different levels and rate of distribution with CO% and metabolism to these peripheral compartments)
(slide 15)
S-enantiomer of ketamine is more potent with less delirium?
T/F?
True
(Slide 40)
Why do people like L-bupivicaine?
Because of less cardiac toxicity
(Slide 40)
Why do people like Cisatracurium, the isomer of atracurium?
Lacks the histamine effects
(Slide 40)
Why is Xopenex preferred over Albuterol?
Because Xopenex causes less cardiac side effects (tachycardia)
(Slide 40)
What is Pharmacogenetics?
How a single gene or all genes (genome) influences responses to drugs!
*Why do some patients respond to the 1st antidepressant and some trial/error?
*Why does a dose of chemotherapy work or kill?
(Slide 41)
Acid drugs primarily like to bind to what type of protein in the blood?
Albumin
(slide 16)
What is Pharmacogenetic testing?
Looks for variants in genes that code for:
1. Drug-metabolizing enzymes
2. Drug targets
3. Immune proteins
(Slide 41)
Alkalotic drugs primarily like to bind to what type of protein in the blood?
A1-Acid Glycoprotein
(slide 16)
You give a drug that progressively inhibits the agonist drugs effect, what type of antagonism is happening?
a. inverse antagonism
b. competitive antagonism
c. non-competitive antagonism
b. competitive antagonism
Slide 6
Which type: free (unbound) or bounded drug able to cross the cell membrane during distribution?
only Free (unbound) drugs
(slide 16)
What can only determine the concentration available to receptor? (Potency)
Only free/unbound drugs
(slide 16)
I keep giving a drug to overcome an antagonistic drug my patient overdosed on but I cannot cause the desired effect. What type of antagonism is happening?
a. inverse antagonism
b. competitive antagonism
c. non-competitive antagonism
Non-competitive antagonism
Slide 6
In a patient who is given a high protein-bound drug whose blood Albumin is low, will the effected result of that drug in the body be more or less?
More- because there will be more unbound drug readily available to cross the membrane to illicit it’s desired effects.
(slide 16)
An _______ drug binds to a receptor but does not activate it and instead blocks the agonist (or endogenous ligand) effect.
Antagonist
Slide 5
What are the 3 reversible bonds agonist and antagonist use to bind to their receptor(s).
What is the one irreversible bond?
Reversible: Ion, Hydrogen, Van Der Waals
Irreversible: Covalent
Slides 4 & 5
An ______ activates the receptor by binding to it and produces the same effects as the endogenous ligand.
agonist
Slide 4
Describe an ionic bond.
What is the alternative name for this bond?
Ionic - bonds between oppositely charged ions.
Electrocovalent :)
Slide 4
Describe a hydrogen bond.
Binds to a very electronegative atom.
Slide 4
The sum of attractive or repulsive forces between atoms that can’t change orbits easily is describing a _______ bond.
Van Der Waals
Slide 4
Why do we care about pharmacokinetics and pharmacodynamics?
We need to know the drug’s onset & offset and the T.I. (therapeutic index) so we can adequately titrate drug levels and avoid over or under-dosing our patients.
Slide 2
Receptors are typically made of a _______.
Drug effect relates to the _______ of bound receptors.
The greatest effect happens when _____ receptors are bound.
Protein, number/amount, all/100%
Slide 3
Receptors go through a ______ ______ when bound to. This changes the shape of the receptor to make it more or less active.
conformational change
Slide 3
What is context sensitive half-time?
Amount of time it takes to drop the level of the drug in plasma by 50% after the discontinuation of the infusion.
slide 27
Why is it important to know context sensitive half-time of a drug?
To know when to turn off the drug to awaken our patients for extubation.
Slide 27
(fentanyl has a longer context-sensitive half-life, so we need to turn it off early as opposed to propofol and sufentanil have shorter context-half life, so they can be turned off 20-25 minutes prior to extubation.)
When do we do infusions on patients during surgery instead of using volatiles?
- Volatiles causes significant N/V in patients, so we do not use volatiles on them. ( we can give propofol instead)
- With craniotomies and back fusion surgeries, you do not want to paralyze patients because you need to check sensory and motor pathways.
slide 27
Local anesthetics and opioids are _________.
Weak bases.
slide 28
What is the percentage of the ionized and non-ionized drug when Pk and pH are identical?
50% of drug ionized and 50% of drug non-ionized
slide 28
Barbituates (thiopental) are _______.
Weak acids
slide 28
Acids are ionized in _____ environment and bases are ionized in _______environment.
Alkaline pH, Acidic pH
slide 28
What are the characteristics of Non-Ionized drug?
Pharmacologically active, crosses lipid barriers (GI, BBB), has no renal excretion, & undergoes hepatic metabolism.
Slide 29
What are the characteristics of an Ionized drug?
Pharmacologically inactive, does not cross lipid barriers (GI, BBB), undergoes renal excretion, does not undergo hepatic metabolism, and is water soluble.
slide 29
If a weak acid (PK 7.6) is put in a basic pH (Blood 7.8), will it ionize?
For Weak Acids: Pk After pH
7.8 (pH) - 7.6 (Pk) = +0.2
Yes, the weak acid drug will ionize at basic pH.
(Nicely Negative Numbers are non-ionized)
slide 30
If a weak base (Pk 8.0) is put in an acid pH (blood 7.2), will it ionize?
For Weak Bases: Pk Before pH
8.0 (Pk) - 7.2 (pH) = +0.8
Yes, the weak base drug will ionize at acidic pH.
Slide 30
Do we want ionized drug or non-ionized drug?
Non-ionized drug.
Slide 29.
What happens to the pregnant lady (pH 7.4) and distressed baby (pH 6.8) who gets a spinal anesthetic with LA and opioid (weak base PK 7.3)?
For pregnant lady,
The drug crosses lipid bilayer and spinal anesthetic work. 7.3 - 7.4 = -0.1 (small amount of non-ionized form cross lipid bilayer)
For baby,
Non-ionized form of the drug cross the lipid bilayer to the baby, and once it gets in the baby’s system, the drug ionizes, drug cannot go back to mom due to its ionization. This is called “ion trapping.”
7.3 - 6.8 = +0.5 (ionized in fetus blood)
slide 31
The effect of a partial agonist is _____ of a response than a full agonist.
Less of a response, even at max dose. (Slide 7)
Where on a receptor does a partial agonist bind to?
At the agonist site. (Slide 7)
Compared to a full agonist, what is the effect of an inverse agonist?
An inverse agonist produces the OPPOSITE effect of a full agonist. (Slide 7)
Where on a receptor does an inverse agonist bind to?
At the same site as the agonist. (Slide 7)
The number of receptors we have can increase or decrease depending on ________ and ________.
comorbidity and drug therapy (slide 10)
Ephedrine is given in the OR at 5 mg to great effect. You give another 5 mg to no effect. You then have to give 10 mg to achieve the same effect as before. What is this phenomenon an example of?
Tolerance/tachyphylaxis. This is a very quick tolerance, leading to a decreasing number of working receptors. (Slide 10)
*ephedrine is an indirect sympathomimetic ;)
You give repeated doses of albuterol for asthma in quick succession. However the effect of albuterol is not as effective as the first dose. What is occurring to the receptors that is causing the decreased effectiveness of albuterol?
Repetitive activation of the receptors causes downregulation of the receptors. (Slide 10)
Pheochromocytoma will ____ the amount of beta receptors in response to the excess catecholamine release.
Decrease (slide 10)
The lipid bilayer has receptors for many drugs. Per lecture, these 5 types of anesthesia drugs have receptor sites here. (Hint: ouch, sleepy, slow down, speed up, don’t move)
Opioids, Benzodiazepines, beta blockers, catecholamines, neuromuscular blockers (slide 11)
These 3 drugs mentioned in lecture have proteins/receptors that get activated inside the cell. (Hint: one is used when you’re too sweet, one is used by mimaw with arthritis and bodybuilders, one is a PDE inhibitor)
Insulin, steroids, milrinone (slide 11)
Anticoagulants bind to receptors on _____ proteins.
Circulating proteins (slide 11)
The effect of bleeding and bruising is usually due to the (bound or unbound/free) form of the anticoagulant.
The free form. (Slide 11)
What drug can induce more enzymes and what effect could it have on other drugs given?
Phenobarbital.
induces enzymes and can increase metabolism of other drugs. Drugs are metabolized faster and have less effect.
(slide 22)
What common item is known for decreasing activity of enzymes and what effect would this have on drugs given.
Grapefruit Juice
Can increase concentration of drugs possibly to toxic levels.
Less enzymes = less metabolism of drugs.
(Slide 22)
What is a substance mentioned in lecture that effects hepatic microsomal enzymes?
Alcohol
(Slide 23)
An acutely drunk patient may require ______ anesthetic than normal.
Less
(Slide 23)
A chronic user of Marijuana may require _____ anesthetic than normal.
more
(Slide 23)
For most anesthetic drugs clearance is _______.
Constant
(Slide 23)
Up to a certain point, hepatic clearance is proportional to ________.
Concentration
(Slide 23)
Rate of hepatic drug metabolism equation:
R = Q( C inflow - C Outflow)
Slide 23
What can affect hepatic metabolic rate?
Cardiac output flow (Q)
Slide 23
Renal Clearance involves what 3 factors?
GFR
Active Tubular Secretion
Passive Tubular Reabsorption
Slide 24
The time necessary to eliminate 50% of drug from PLASMA after bolus dose
Elimination half-time
Slide 25
Why is it important to understand half-times?
To prevent drug stacking when giving drug boluses.
Slide 26
Are opioids weak acids or weak bases?
Weak bases; in this particulary example the pK is 8.0
(slide 32)
If we inject an opioid (weak base) into ischemic tissue (acidotic), will ion trapping occur? If so, then where will the ion trapping take place and why?
Yes, ion trapping will occur in the ischemic tissue because the pK of a weak base minus the pH of the ischemic tissue will result in a remarkably positive ionization which means you’re basically giving the pain med to dead tissue
(slide 32)
If a surgeon wants to perform a local block on a tissue that’s adjacent to and/or including ischemic tissue, what’s an alternative that Dr. Kane mentioned that might be more effective?
Spinal or epidural
( -Dr. Kane)
Define Pharmacodynamics
“The sensitivity of the body to the drug”
OR
“What the drug does to the body”
(slide 33)
What is a way we can quantitatively evaluate pharmacodynamics on the body after giving a desired drug?
Measuring plasma concentrations at different pharmacological responses
(slide 33)
What’s a good example of a drug that has remarkably different effects on the body at different titrations?
Dopamine: 1-2 mcg/kg/min = renal; 5-10 mcg/kg/min = increased SV and CO; >10 mcg/kg/min = vasoconstriction and increased SVR
( - Kane; slide 33)
Do we as CRNA’s (future selves) have the ability to check at any given time how many receptors a patient will have on any given tissue?
No
( - Kane)
Effects of drugs can vary. What ways in the Elderly cause this increased variability response to drugs? (3 things given on slide)
- Decreased CO (specifically to Brain and Liver)
- Decreased Protein Binding
- Increased Body Fat (this is confirmed and Kane rationalizes that this is d/t the increased loss of vessel-rich muscle tissues so in proportion their body fat becomes more relevant)
(slide 34)
Acute Alcoholism will require more or less anesthesia?
Less - if your patient comes in drunk, they require less anesthetic. (Updated 1/31 from her announcement)
( - Kane)
What comorbidity often leads to altered enzymatic activity that results in individual variability of medication responsiveness?
Acute vs Chronic Alcoholism
(slide 34)
Atypical Cholinesterase activity and Malignant Hyperthermia are both results of what?
Genetic Disorders
(Kane also mentions how natural redheads require more anesthesia)
( - Kane, slide 34)
What genetic disorder has been linked to higher incidences of Malignant Hyperthermia?
Ryanodine receptor alterations
( - Kane and Schmidty)
What is: “The ability of a drug to produce a clinical effect”
Kane also described this as: “How much of the effect can I get?”
Efficacy
(slide 35)
Define Potency
The dose required to produce a therapeutic response
AKA concentration vs. response (less drug + more effect = more potent)
(slide 35)
Does increased potency always equate to increased efficacy?
No
( - Kane)
Define Relative Potency
Relative Potency is basically how quickly do we see effects of the drug compared to its plasma concentration
An easier way to think is how much time lag will occur from the time the med is given to when the desired effects are achieved.
Remember the Fentanyl vs Alfentanil discussion where there was virtually no lag with Alfentanil, but Fentanyl took several minutes to reach it’s desired effect. Ie. Alfentanil has a GREATER relative potency
(slide 36)
Why is Relative Potency important to keep in mind when we give drugs?
Helpful to know when giving a drug that will have a time lag before reaching effects so we don’t give a second dose because we mistakenly believe the first dose wasn’t enough, which leads quickly to OVERDOSING
( - Kane, slide 36)
