week 2 - pharmacokinetics and pharmacodynamics Flashcards
Pharmacokinetics is the study of concentration changes of drugs during _ _ _ ?
absorption
distribution
metabolism
elimination
PharmacoKINETICS is what the _ does to the _ once the drug enters.
body
drug
KB toys- kinetics/body
pharmacoKINETICS- the vascular system delivers drug to affected tissue, the drug can either be __ to plasma proteins and when __ can cross membrane to enter tissues. __ drug enters organs, muscle fat, and receptors
bound
unbound
unbound
PharmacoKINETICS affects a drug’s _ _ _ _ _?
onset time course offset patient variability of response amount of drug available to act on receptors
drug transfer to sites is dependent on six factors
molecular size degree of ionization lipid solubility protein binding perfusion concentration gradients
pharmacoDYNAMICS - what a __ does to our __
drug
body
Double D’s - drug/dynamic
pharmacoDYNAMICS deals with the __ of receptors to a drug, the __ by which a drug effects occur, what the __ does to the body, and receptor sensitivity is measured by the __ __ required to elicit responses
responsiveness
mechanisms
drug
plasma concentrations
the dose response curve depicts the relationship between the __ __ and the __ __
drug dose
pharmacologic effect
the dose response curve demonstrates the differences in four things
potency
slope
efficacy
individual responses
the potency of a drug is depicted by location along __ axis of dose response curve
dose
potency is influenced by __ and __ __
pharmacoKINETICS (ADME)
receptor affinity
ED is the dose required to produce an effect in a % of patients
ie- ED50, ED99
the slope is influenced by the __ of receptors __ before drug effects occur
number
occupied
a steep slope denotes that a __ of receptors are occupied before the drug effect occurs, an example of this are __
majority
neuromuscular blockers
with a steep slope a __ increase in drug concentration elicits a __ increase in drug effect
small
large
with a steep slope the difference between the __ dose and the __ dose is smaller
therapeutic
toxic
MAC is __
crap
drug interactions can cause alterations in pharmacoKINETICS, an example being
patients on highly protein bound agents such as phenytoin or aspirin have __ metabolism of NMBs due to less drug ACCEPTOR sites
Higher rate of
drug interactions can cause alterations in pharmacoDYNAMICS, an example being a __ in volatile agent MAC with patients receiving opioids
decrease
an example of a PHYSIOCHEMICAL drug interaction is when one drug causes a second drug to __ in an IV line
precipitate
What are some examples of beneficial drug interactions?
meperidine and promethazine
hydralazine and propranolol for HTN
adverse drug interactions impair the efficacy or enhance the toxicity of drugs through four ways
impair absorption compete with binding sites alter metabolism alter excretion Basically opposite of ADME
Plasma drug concentrations do not always indicate what?
clinical effects
Drugs are __ of weak acids or weak bases
salts
Salts are __ __ resulting from a neutralization reaction between an acid and a base
ionic compounds
Salts are electrically __ and have __ net charge
neutral
no
Ionized drugs are __ soluble and __ cross cell membranes due to electrical charge
water
CAN NOT
Non-ionized drugs are __ soluble and __ diffuse across cell membranes like the blood brain barrier
lipid
CAN
The __ the degree of ionization, the __ the ability to cross the blood brain barrier, the placental barrier, and hepatocytes
greater
LESS
the degree of drug ionization is determined by the drug’s dissociation constant or __ and the __ of the drug’s environment
pKa
pH
The __ the ionization, the __ the renal excretion
greater
easier
when pH equals pKa, the drug is __ parts ionized and non-ionized
equal
__ changes in environmental pH result in __ changes in degree of ionization / non-ionization
small
large
Say you went out drinking with Dr. Lancaster
all his available enzyme systems for metabolism are saturated after the eighth bottle of chardonay
the degree of ionization for drugs varies across membranes that separate fluids with different __ values
give three examples
pH
maternal fetal drug transfer, central nervous system toxicity of local anesthetics, absorption of drugs differs from gastric pH to blood
explain the concept of maternal fetal ion trapping
the maternal pH is 7.4, the fetal pH is 7.25, lidocaine has a pKa of 7.9 and easily crosses the placenta, but once in the more acidic environment it cannot cross back and concentrations become toxic for the fetus
the treatment for local anesthetic overdose must include __
hyperventilation
Changes in protein binding influence drug effect and some drugs are extensively bound to plasma proteins. what is the most common plasma protein and what pH of drug does it favor?
albumin
low pH/acidic drugs
what are two plasma proteins that favor high pH or basic drug binding?
alpha1 acid glycoprotein (AAG) &
beta-globulin
What are plasma proteins?
Acceptors
Protein binding influences what?
Drug distribution
Protein bound drugs can’t act on what?
Receptors
The degree of protein binding is _____ to the degree of lipid solubility.
Proportional
Drug/protein binding is what?
Weak, broken easily by declining plasma concentrations or by plasma proteins binding to a different drug.
If drugs compete for a protein site, chronically given drugs may be displaced and do what?
Have a larger free fraction of the drug in circulation. Example: Warfarin/ASA - Warfarin is 98% plasma protein bound
-If ASA is then administered, it may displace warfarin from plasma proteins. Patient becomes hypercoagulable
Absorption does what?
Determines how much drug is delivered to circulation
What is an advantage of IV administration?
entire amount of drug is delivered to systemic circulation. Equals 100% bioavailability - most rapid onset (IV is the only route that does this)
Parenteral administration is what? What is it dependent on?
Injection via IM or SQ - is rapid & predictable, bioavailability is 75-100%.
dependent on capillary perfusion of tissue and the lipid solubility of the drug.
Pulmonary administration is the route for what?
Volatile Agents (iso, sevo, des)
Non-Volatile Agents (oxygen, nitrous)
Bronchodilators
is 5-100% bioavailable (largest range)
What is bioavailability?
Extent to which a drug reaches its effect site after introduction into circulation.
What is bioavailability dependent on?
Several things: LSMPPPP - Anyone got an acronym pneumonic? 1. Lipid solubility 2. Solvent solubility 3. Molecular weight 4. pH - ex lidocaine into acidic tissue - highly ionized, cannot penetrate nerves 5. pKa 6. Perfusion 7. Pathology
What are drug compartment models useful for?
Predicting serum & tissue concentrations.
BUT, they are theoretical spaces and volumes
What are the types of drug compartment models?
- Single Compartment - (not useful for lipid soluble anesthetics)
- Two compartment - central (10% of mass, 75% perfusion) and peripheral compartments (90% of mass, 25% of perfusion)
when you’re 10 years old you foolishly wish you were 75, and when you’re 90 years old you wisely wish you were 25 again
What are the physiologic compartments and their percentages?
Plasma - 5% Interstitial fluid - 16% Intracellular fluid - 35% Trans-cellular fluid - 2% Fat - 20%
What is the Volume of Distribution and how is it calculated?
It is the mathematical expression of amount of drug in body compared to the serum drug concentration.
It is calculated by dividing intravenous drug dose by plasma concentration before elimination occurs.
Volume of distribution (Vd) = drug dose/plasma concentration of drug.
Drugs with small Vd have __ plasma drug concentrations
High
Drugs with large Vd have __ plasma drug concentrations and ___ drug available to tissue
low, little
Vd is represented by what?
The area under plasma concentration curve.
What is stereochemistry?
Also known as “3D” chemistry”, looks primarily at how molecules are structured. The study of chirality is an important branch of stereochemistry.
Chirality
Molecule with center(s) of 3-D assymmetry
Is the basis of enantiomerism (3D structure of molecules)
QUIZ QUESTION: concerning enantiomerism… Pair of molecules that exist as mirror images but can’t be superimposed
Enantiomers are what?
Quiz question: They are pairs of molecules existing as mirror images of each other but can’t be superimposed. Importance? Drug receptors are stereo specific to elicit a conformational change.
What are the RULE in anesthesia?
Stereoisomers. Classifications are
(+) positive, (-) negative,
(L) left,(R) right
and many others!
Enantiomers “Lock & Key” hypothesis is what?
- Receptors are “keys” preferring one type of enantiomer over another.
- Stereoselectivity (only bind to one type)
- Not all enantiomers are created equal, in anesthesia usually one type of enantiomer works better than another, example atracurium vs cisatracurium
Racemic mixtures are what? (THIS WILL BE ON QUIZ)
A mix where enantiomers (mirror images) present in a drug are in a 50/50 proportion. (cannot be 3 enantiomers in a racemic mixture)
1/3 of all drugs are racemic mixtures
Examples- morphine, methohexital, ketamine, all inhaled except sevo,
Examples : morphine, methohexital, ketamine (S + more potent than R - )
All inhaled agents except sevoflurane
Local anesthetics - ropivacaine - S enantiomer of bupivacaine, R bupivacaine cardiotoxic
Plasma concentration curve
Y axis = plasma concentration
X axis = time after drug administration
Plasma concentration β phase
β phase - elimination phase, is plateau shaped.
α phase + β phase = biphasic fall in drug concentrations.
Plasma concentration α phase
α phase - distribution phase, drug dispersed from central compartment to tissue
α phase - parabolic, curvilinear (contained by curved lines)
Steep with lipophilic drugs which easily cross cell membranes.
Bi-exponential decay curve
α steep slope - distribution
β phase - plateau slope - elimination
First Order Kinetics refers to what?
Definitely a test question
Most drugs undergo first order metabolism.
Drugs cleared at a rate proportional to plasma concentrations.
CONSTANT FRACTION of drug cleared in a set time period, ie - 30% of drug present in plasma cleared each hour.
Zero Order Kinetics refers to what?
Definitely a test question
Drug concentrations exceed the body’s ability to metabolize them.
Available enzyme systems for metabolism are completely saturated.
Constant amount (NOT FRACTION) of drug metabolized per time unit.
Ex: Say you went out drinking with Dr. Lancaster…
Zero PLUS First Order (Test question)
Some drugs undergo zero order kinetics at high plasma concentrations and first order kinetics when plasma concentrations fall.
Ex: Phenytoin
Known as Michaelis-Menton kinetic model
Phase 1 Reactions (3 of them)
Phase 1:
Transforms lipids soluble molecules to water soluble. Also increases polarity of molecules
1-Oxidation reactions:
Oxygen introduced into molecule, cytochrome P- 450 catalyzed.
2-Reduction reactions:
Electrons transferred for a net gain
-Also cytochrome p-450 catalyzed
3-Hydrolysis reactions:
Addition of water to an ester or amide to form two smaller molecules
ORH - Oregon regional hospital is in it’s first phase of reacting to the influx of 450 new graduate nurses by adding more oxygen tanks, transferring elective surgeries for a net GAIN, and adding water fountains.
Drug Metabolism Phase 2
Phase II:
-Conjugation reactions (no pharmacologic activity here)
-Drug of metabolite joined (conjugated) with endogenous substrate.
Endogenous substrates include:
1. Glucuronic acid
2. Sulfonic acid
3. Acetic acid
Phase II reactions
Phase II reaction products - no pharmacologic activity.
- Conjugation leads to more polar molecules
- Molecules highly ionized at physiologic pH
- Ionized molecules easily extracted by glomerular filtration.
Intracellular drug metabolism sites are what?
- Endoplasmic reticulum
- Mitochondria
- Cytosols
- Lysosomes
- Plasma membranes
Smooth hepatic endoplasmic reticulum is the site of hepatic microsomal enzymes
- Microsomes - fragments of endopasmic reticulum derived via centrifuge making up a distinct layer.
Microsomal fractions include iron containing hemoproteins called cytochrome P-450s
P-450’s makes me think of world war 2 airplanes which were made of iron and flown by hemoprotein
Elimination half-time is what? (Test Question)!
Most common method of describing a drug’s pharmacokinetic behavior!
5 elimination 1/2 times required for near total (97%) elimination of a drug.
-Cpss - concentration of plasma steady state with intermittent dosing also required 5 elimination 1/2 times
Elimination 1/2 time is defined as….
The time necessary for plasma concentration to decrease by 1/2.
It is directly related to Vd (Volume of distribution) - ie larger Vd drugs have longer elimination 1/2 times.
- This is INVERSELY proportional to CLEARANCE
- Greather clearance rates have shorter elimination half-times
Remember: Elimination 1/2 times are INDEPENDENT OF DOSE!
Context Sensitive half-times are what?
Provides a more clinically relevant measure of drug concentrations.
It is the time to halve serum concentrations (central compartment) of a drug after termination of drug delivery by infusion that has reached a steady state.
Context Sensitive half-times
Increase with duration of infusion due to less capacity available in inactive tissues for redistribution.
NO CONSTANT RELATIONSHIP to elimination half-times.
Time to Recovery is what?
How long it takes to wake up (is dependent on depth of anesthesia)
note - This is NOT accurately predicted by context sensitive half-times, NOT elimination half-times, but IS accurately depicted by CRNA SKILL LEVEL!
The time from IV administration to the onset of clinical effects is called what?
Effect site equilibration time.
This reflects drug distribution from plasma to brain.
Some drugs with short effect site equilibration times:
- remifentanil
- alfentanil
- thiopental
- propofol
What drugs have Short effect site equilibration times?
- remifentanil
- alfentanil
- thiopental
- propofol
What drugs have Long effect equilibration times?
- Fentanyl
- Sufentanil
- Midazolam
So what? - Long effect equilibration time drugs should be spaced at sufficient intervals to permit peak drug effects.
What is the definition of Clearance?
The volume of plasma completely cleared of drug by metabolism and excretion per unit of time.
Clearance is proportional to dose, large doses = greater clearance. Is inversely proportional to drug half-life, the smaller the half-life, the larger the clearance.
Clearance rates are goverened by what?
Drug properties and body capacity for clearance.
What is total clearance?
The sum of all organ’s clearance.
(clearance formula is blood flow or perfusion (Q) x extraction ratio (E))
Similar to a VQ ration, but this one is QE
What are the organs for clearance?
Liver & Kidneys
Drugs with smaller molecular size work faster or slower?
Faster
Which crosses the cell membrane easier, non ionized or ionized?
NONionized
Will increased lipid solubility hinder or improve the ability of a drug to cross the cell membrane?
Improve
Versed/Midazolam is very water soluble outside the body but following injection becomes very LIPID soluble because the __ __ OPENS at physiologic pH.
Imidazole ring
McCarver stated that the ring is closed then opens, but Stoetling notes the ring is closed at pH > 4, and thus highly lipid soluble, so opposite of the lecture. I made the card to follow the lecture for test purposes.
Which is more potent- a volatile with a MAC of 1.36 (halothane) or MAC of 6.78 (des)?
Halothane, the lower MAC indicates less drug is required, thus more potent
There is a direct relationship between drug dose, plasma drug __, and intensity of drug effects
Concentration
Respiratory acidosis may trap a local anesthetic in the CNS, what is the treatment?
Hyperventilation
IV percent bioavailability, TEST QUESTION- IV is the only route with 100% bioav
100%
Intramuscular percent bioavailability
75-100%
Inhalation percent bioavailability
5-100%
An example of solvent solubility affecting a drug’s bioavailability would be_
Diazepam/Valium is prepared in ethylene glycol
Why can you not give local anesthetic to a gangrenous toe?
The tissue is so acidic that the ionized drug cannot penetrate to the nerve
Volume of distribution Vd=
Dose / plasma concentration
If it’s binding to an acid- it’s a phase _ reaction
Two
For intermittently dosed drugs, how many half times are required to achieve steady state plasma concentration?
5 half times
Elimination half times use a __ compartment model
Context sensitive half times use a __ compartment model
One
Two or “distribution process”
The longer the effect site equilibration time, the slower the __ of the drug
Onset
Since clearance is proportional to the dose, the larger the dose means the more drug available to be cleared, so the clearance is __
Greater
Clearance is __ proportional to half life.
Inversely
Plasma percentage of physiological compartment
5%
Interstitial fluid percentage of physiological compartment
16%
Intracellular fluid percentage of physiological compartment
35%
Trans cellular fluid percentage of physiological compartment
2%
Fat percentage of physiological compartment
20%
