Pharmacokinetics Flashcards
What is a loading dose?
The amount of drug that must be delivered to achieve a therapeutic plasma concentration quickly
Volume of distribution is a theoretical measure of?
How a drug is distributed throughout the body
What is the loading dose formula
Loading Dose = Vd x (desired Cp / bioavailability)
What is the equation for Volume Distribution
Vd= amount of drug / desired plasma concentration
Vd descibes the relationship between?
administered dose of a drug and the plasma concentration that results
Volume distribution for IV administrations assumes what two things?
- drug distributes instantaneously (full equilibrium occurs at time = 0)
- drug is not subjected to biotransformation or elimination before fully distributed
Vd is affected by drug and patient characteristics. Name a few of each
molecular size, ionization, protein binding
pregnancy and burns
For an IV medication, bioavailability always equals?
- since its injected into bloodstream. other bioavailabilities will vary based on route of admin
How much water does each compartment contain in a 70kg patient?
TBW
ECF
ICF
Plasma Vol
Interstitial Fluid
TBW: 42L
ECF: 14L
ICF: 28L
Plasma Volume: 4L
Interstitial Fluid: 10L
A volume of distribution that exceeds total body water (42L or >0.6l/kg) is assumed to be? And will it require a higher or lower dose to achieve a given plasma concentration? Give an example
Lipophilic.
will need a higher dose to achieve plasma concentration due to passing through tissue membranes.
ex: propofol
A volume of distribution that is less than total body water (<42L or <0.6l/kg) is assumed to be? And will it require a higher or lower dose to achieve a given plasma concentration? Give an example
Hydrophilic
Require a lower dose, the drug will stay in plasma.
ex: Neuromuscular Blockers
What is drug clearance?
The volume of plasma that is cleared of drug per unit time.
Clearance is Directly proportional to?
Blood flow to cleaning organ,
Extraction Ratio,
Drug dose
Clearance is inversely proportional to?
**-Half-Life **
[If CL increases (faster drug elimination) → t₁/₂ decreases (shorter drug presence in body).
If CL decreases (slower elimination) → t₁/₂ increases (drug remains longer).]
-Drug concentration in the central compartment (plasma)
[High clearance → Low drug concentration (faster elimination).
Low clearance → High drug concentration (slower elimination)]
To maintain a steady-state concentration in the plasma, the infusion rate or dosing interval must?
EQUAL the rate of drug clearance by metabolism and elimination
SS Rate of Admin = Rate of Elim
As a general rule, steady state is achieved after how many half lives?
5
What describes the speed at which a reaction occurs (or how fast a molecule moves between compartments)
A rate constant
The half-time measures a constant _____ and NOT a constant ______
constant FRACTION and not a constant amount
it takes the same time for a Cp of a drug to fall from 200mg/L to 100mg/L as it does for the same drug to fall from 50mg/L to 25mg/L
What is different about context-sensitive half time?
Takes the duration of drug administration into account. Calculated with computer algorithms
what is the “context” in context-sensitive half-time?
duration of infusion (time)
which opioid has a similar context-sensitive half-time regardless of infusion duration?
remifentanil
An acid is a substance that _____ a proton
donates
A base is a substance that ____ a proton
Accepts
If you place a strong acid or strong base in water it will?
Completely dissociate
A drug that is a weak acid will ____ a proton to water (pH = 7).
donate
a drug that is a weak base will _____ a proton from water (pH=7)
accept
Ionization is dependent on what 2 factors?
- pH of the solution
- pKa of the drug
pKa is a _____ property of a molecule
pH is a _____ property of a solution
pKa is constant
pH is changeable
The pKa tells us how much a molecule wants to behave like an acid.
Low pKa =
High pKa =
Low pKa = Amazing Acid (wants to donate)
High pKa = Terrible Acid
When a basic drug (ex: Lidocaine) is placed in a relatively more acidic environment (ex: blood), the Henderson-Hasselbach equation predicts:
drug will be more ionized than nonionized
Will a weak base drug with a pKa < pH be more ionized or nonionized?
A weak base drug with a pKa< pH will be more non-ionized.
Bases like being in more basic (high pH) environments compared to their pKa so they can cross membranes.
Will a weak base drug with a pKa > pH be more ionized or nonionized?
A weak base drug with a pKa>pH will be more ionized.
Bases don’t like acidic environments (pH less than their pKa) because they cant cross membranes as well.
Will a weak acid drug with a pKa<pH be more ionized or nonionized?
A weak acid drug with a pKa<pH it will be mostly ionized.
Acids don’t like when (pH is greater than pKa) because they cant cross membranes.
Will a weak acid drug with a pKa>pH be more ionized or nonionized?
A weak acid with a pKa>pH will be more NON-ionized.
Acids like to remain nonionized when the pH is less than it’s pka.
Drugs are usually prepared as a salt that dissociates in solution. A weak acid is paired with?
A positive ion, such as sodium, calcium, or magnesium
ex: sodium thiopental
Drugs are usually prepared as a salt that dissociates in solution. A weak base is paired with?
A negative ion, such as chloride or sulfate
ex: lidocaine hydrochloride
Is an ionized molecule more likely or less likely to experience hepatic biotransformation
Less Likely
Is a non-ionized molecule more likely or less likely to experience hepatic biotransformation
More likely
Is an ionized molecule more likely or less likely to experience renal elimination
more likely
Is a non-ionized molecule more likely or less likely to experience renal elimination
less likely
Is an ionized molecule likely going to diffuse across the lipid bilayers of the Blood Brain Barrier, GI tract, or Placenta
No, No, No
Is a non-ionized molecule likely going to diffuse across the lipid bilayers of the Blood Brain Barrier, GI tract, or Placenta
Yes, Yes, Yes
The ionized fraction of a drug predominates if:
the molecule is weak base and the pH of the solution < the pKa of the drug (base is added to an acidic solution)
The molecular is a weak acid and the pH of solution > the pKa of the drug (acid is added to basic solution)
The non-ionized form of a drug predominates if:
The molecule is a weak base, and the pH of the solution is > the pKa of the drug (a base is added to a basic solution)
The molecule is weak acid, and the pH of the solution is < the pKa of the drug (an acid is added to an acidic solution)
Which circumstance creates the STRONGEST gradient for the passage of local anesthetic from the mother to the fetus?
a. maternal acidosis and fetal acidosis
b. maternal acidosis and fetal alkalosis
c. maternal alkalosis and fetal acidosis
d. maternal alkalosis and fetal alkalosis
c. maternal alkalosis and fetal acidosis
maternal alkalosis increases non-ionized fraction in the maternal circulation, more local anesthetic available to diffuse across the placenta.
Fetal acidosis increases the ionized fraction inside the fetus. prevents local anesthetic from crossing the placenta back to the mother, thus “trapping” it inside fetus
How does fetal pH compare to maternal pH?
Fetal pH is a little lower than the mother’s pH
What happens when lidocaine enters the fetal circulation?
A more acidic environment increases lidocaine’s ionized fraction
How does uncontrolled maternal pain affect local anesthetic concentration in the fetus?
Pain causes the mother’s minute ventilation to increase (resp alkalosis), increasing lidocaine transfer across the placenta.
What are three plasma proteins to know
Albumin
Alpha1-Acid Glycoprotein
Beta-Globulin
Albumin primarily binds with basic or acidic drugs?
Primarily acidic but can bind neutral and basic
Alpha1-Acid Glycoprotein and Beta-Globulin primarily binds with basic or acidic drugs?
both bind with basic drugs
Albumin plasma concentration decreases by?
Liver disease, renal disease, old age, malnutrition, and pregnancy
Alpha1-Acid Glycoprotein plasma concentrations are increased by? decreased by?
increased: Surgical stress, MI, Chronic pain, RA, advanced age
decreased: neonates and pregnancy
What is the percent change formula?
% change = (new value - old value / old value) x 100
How is the volume of distribution affected when plasma protein binding increases?
Vd will decrease (inverse relationship)
Describe Zero Order Kinetics
There is more drug than enzymes to metabolize. Enzymes will metabolize a constant amount per unit time. (negative linear curve)
What are some drugs that follow zero order kinetics ?
Aspirin, heparin, warfarin, alcohol, phenytoin, and theophylline
Describe First Order Kinetics
Less drug than enzymes available to metabolize, no saturation of enzymes. Enzymes metabolize drug at a constant fraction per unit time. Most drugs follow first order kinetics. (negative exponential curve)
How many phases are there in drug metabolism? what are they?
3.
Phase 1: Modification
Phase 2: Conjugation
Phase 3: Elimination
What are 3 types of phase 1 reactions?
Oxidation: removes electrons from a compound
Reduction: adds electrons to a compound
Hydrolysis: adds water to a compound to split it apart (usually an ester)
What is the purpose of phase 1 reactions in metabolism?
Reactions result in small molecular changes that increase the polarity (water solubility) of a molecule to prepare it for phase 2 reaction.
Most phase 1 biotransformations are carried out by what system?
P450 system
What is the purpose of phase 2 reactions in metabolism?
Conjugate (add on) endogenous, highly polar, water soluble substrates to the molecule. Produces a water soluble, bio inactive molecule ready for excretion.
What is enterohepatic circulation?
some conjugated compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into the systemic circulation.
What are 2 drugs that undergo enterohepatic circulation?
Diazepam and Warfarin
What is needed for phase 3 elimination?
ATP! ATP-dependent carrier proteins that transport drugs across cell membranes. Present in kidneys, liver, and GI tract
Name 3 drugs that undergo perfusion-dependent hepatic elimination
fentanyl, lidocaine, and propofol
Name 3 drugs that undergo capacity-dependent hepatic elimination
diazepam and rocuronium
Hepatic Clearance is the product of?
- Liver Blood Flow - how much drug is delivered to the liver
- Hepatic extraction ration - how much drug is removed by the liver
A drug with a high hepatic extraction ratio (>0.7), clearance is dependent on?
Liver blood flow
A drug with a low hepatic extraction ratio (<0.3) clearance is dependent on?
The ability of the liver to extract the drug from the blood.
Changes in hepatic enzyme activity or protein binding have a profound impact on which drugs?
Drugs with a low hepatic extraction ration, clearance dependent of the liver to extract drug from blood.
since only a small amount of drug is removed per unit time, alterations in liver blood flow, (greatly or minimally), affect clearance
Minimally
What does the hepatic extraction ratio measure?
measures how much drug is delivered to the liver vs. how much drug is eliminated by the liver
What does a hepatic extraction ratio of 0.5 mean?
50% of a drug delivered to the liver is eliminated
Enzymatic drug metabolism in the plasma tends to occur via one of three pathways, which are?
Pseudocholinesterase: succinylcholine, cocaine (+hepatic)
Nonspecific esterases: Esmolol, remifentanil, atracurium (+Hofmann)
Alkaline phosphatase: fospropofol
Drugs with an ester linkage are most susceptible to which type of metabolism?
Hydrolysis
Which local anesthetic is least likely to accumulate in a hypoxic fetus?
Chloroprocaine
What drugs are metabolized by pseudocholinesterase?
Succinylcholine
Mivacurium
Ester Local Anesthetics
-tetracaine
-procaine
-chloroprocaine
-cocaine (+hepatic)
What drugs are metabolized by non-specific esterases?
Remifentanil
Remimazolam
Esmolol (rbc esterases)
Etomidate (+ hepatic)
Atracurium (+Hofmann)
Clevidipine
What drug is metabolized by Alkaline Phosphatase?
Fospropofol
What drugs are metabolized by Hoffman elimination?
Cisatracurium
Atracurium (+ nonspecific esterases)
