Unit 4 - Pharmacokinetics & Pharmacodynamics Flashcards
what is volume of distribution
relationship between administrated dose and resulting plasmc concentration
theoretical measure of how a drug distributes through the body
Vd =
amount of drug / desired plasma concentration
Vd assumes what 2 things
- drug distributes instantaneously (equilibration at time = 0)
- drug isn’t subjected to biotransformation or elimination before full distribution
distribution of body water in 70 kg patient:
when is a drug assumed to be lipophilic in regards to Vd
Vd > TBW
> 0.6 L/kg or > 42 L
when is a drug assumed to be hydrophilic in regards to Vd
Vd < TBW
< 0.6 L/kg or < 42 L
which requires a higher dose to acheive a given plasma concentration - a lipophilic or hydrophilic drug?
lipophilic
which requires a lower dose to achieve plasma concentration - lipophilic or hydrophilic drugs?
hydrophilic
what is a loading dose
amount of drug that must be administered to achieve a therapeutic plasma concentration quickly
loading dose =
(Vd x desired Cp) / bioavailability
bioavailability for an IV medication
1
what is clearance
volume of plasma cleared of drug per unit time
most important clearing organs
liver
kidneys
organ independent (Hofmann, esterases)
clearance is directly proportional to:
- blood flow to clearing organ
- extraction ratio
- drug dose
clearance is indirectly proportional to:
- half-life
- drug concentration in central compartment
what is steady state?
stable plasma concentration when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body
as a general rule, when is steady state acheived?
after 5 half-lives
how to achieve steady state faster in a drug with a long half life
give a loading dose
illustrates biphasic decrease of a drug’s plasma concentration after rapid IV bolus
2 compartment model
what does the alpha portion of 2 compartment model represent
distribution (t ½ a)
what does the beta portion of the 2 compartment model represent
elimination (t ½ B)
what does line A represent in 2 compartment model
drug distributes to theoretical compartments
follows concentration gradient from central compartment to peripheral compartments
what influences the slope of line A in 2 compartment model
Vd
more lipophilic = larger Vd = steeper slope
what does line B in 2 compartment model represent
elimination
what determines drug redistribution
concentration gradient between plasma and tissues
what is A+B in 2 compartment model
plasma concentration over time
what is a rate constant
describes the speed at which a reaction occurs or how fast molecules move between compartments
k12
rate constant for drug transfer from central to peripheral compartment
k21
rate constant for drug transfer from peripheral to central compartment
ke
rate constant for drug elimination from the body
what does the 3 compartment model describe
different constants going to and from each compartment and central compartment
some compartments may saturate before others
what is elimination half time
time it takes for 50% of drug to be removed from plasma during elimination phase
when is a drug considered cleared from the body?
when 96.9% of the dose is eliminated from plasma
(~5 half times)
what does half time measure
a constant fraction, NOT a constant amount
what is context-sensitive half-time
time for plasma concentration to decrease by 50% after gtt stopped
exception to opioid CSHT
remifentanil
highly lipophilic but quickly metabolized by plasma esterases = similar CHST regardless of infusion duration
what is an acid
substance that donates a proton
what is a base
substance that accepts a proton
what happens to a strong acid or strong base in water
will dissolve completely
what happens to a weak acid or weak base in water
a fraction will ionize
remaining fraction will be non-ionized
is morphine a weak acid or a weak base
weak base
how will weak acids and weak bases react in water
weak acid will donate a proton to water (pH = 7)
weak base will accept a proton from water (pH = 7)
how will a weak acid act in an acidic solution
more non-ionized and lipid soluble
how will a weak acid act in a basic solution
more ionized and water soluble
how will a weak base act in an acidic solution
more ionized and water soluble
how will a weak base act in a basic solution
more non-ionized and lipid-soluble
what has the greatest impact on degree of ionization in a drug with a pKa close to plasma pH
small changes in plasma pH
what is ionization
process where a molecule gains a positive or negative charge
ionization of weak acids and bases depends on what 2 factors
- pH of solution
- pKa of the drug
what is pKa
constant property of a molecule that tells us how much it wants to behave like an acid
equals the pH where 50% of the drug exists as uncharged base & 50% exists as conjugate acid
low pKa = amazing acid
what is the Henderson-Hasselbalch equation
pH = pKa + log (base / conjugate acid)
a basic drug placed in a relatively more acidic environment - ionized fraction (conjugate acid) will predominate
drug preparation for weak acids
paired with positive ion (Na+, Ca2+, Mg2+)
ex: sodium thiopental
drug preparation for weak bases
paried with negative ion (Cl-, sulfur)
ex: lidocaine hydrochloride
which is more likely to undergo hepatic biotransformation - ionized or nonionized
nonionized
which is more likely to undergo renal elimination - ionized or nonionized
ionized
which diffuses across lipid bilayers into BBB, GI tract, and placenta: ionized or nonionized
nonionized
ionized fraction predominates if:
- molecule is a weak base and pH of solution < pKa of drug (base added to acidic solution)
- molecule is a weak acid and pH > pKa (acid added to basic solution)
non-ionized fraction predominates if:
- molecule is a weak base and pH of solution > pKa (base added to basic solution)
- molecule is a weak acid and pH of solution < pKa (acid added to acidic solution)
which portion of a drug freely diffuses across a cell membrane
only the lipophilic, non-ionized fraction
what causes fetal ion trapping
- fetal pH is a little lower than maternal pH
- if mom receives a more basic solution, the non-ionized fraction crosses the placenta, a weak base enters a more acidic environment, and there’s a greater degree of ionization inside the fetus
- ionized drug can’t freely cross placenta back to mother and is trapped in fetus
- fetal distress increases acidosis and trapping
strongest diffusion gradient for fetal ion trapping
maternal alkalosis + fetal acidosis
neuraxial LA most likely to undergo fetal ion trapping
lidocaine
neuraxial LA least likely to undergo fetal ion trapping
why
chloroprocaine
high pKa, rapid metabolism in mother’s blood
for most drugs, rate of metabolism depends on what 2 factors:
- Concentration of drug at site of metabolism - influenced by blood flow to site
- Intrinsic rate of metabolic process - influenced by genetics, enzyme induction/inhibition
what is zero order kinetics
- describes situation where there is more drug than enzyme
- constant amount metabolized per time
examples of drugs that follow zero order kinetics
aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
what is first order kinetics
- Describes situation where there is less drug than enzyme (no saturation)
- Enzyme will metabolize a constant fraction per unit time
nearly all drugs we adminsiter undergo what rate of metabolism
first order kinetics
what is metabolism
enzymatic process of altering a molecule’s chemical structure
primary organ of metabolism
liver
primary role of metabolism
change a lipid-soluble, pharmacologically active compound to water-soluble, pharmacologically inactive byproduct
how does creating molecules with greater water solubility lead to increased urine elimination
- increasing ionization and decreases Vd
- increased delivery to kidneys for elimination
if the body can’t change a lipid-soluble into a water-soluble drug, what happens?
- it will be continuously reabsorbed by renal tubules into pericapillary fluid - returned to plasma
- theoretically could remain in the body for a long time
what is a prodrug
examples?
body converts an inactive molecule into a pharmacologically active molecule
ex- codeine, oxycodone, hydrocodone, fospropofol
3 phases of metabolism
- modification
- conjugation
- elimination
result of phase 1 metabolism: modification
Result in small molecular changes that ↑ polarity of a molecule to prepare it for a phase 2 reaction
carries out most phase 1 metabolism reactions
CYP450 system
3 types of phase 1 metabolism reactions
- oxidation
- reduction
- hydrolysis
what is oxidation
removes electrons from a compound
what is reduction
adds electrons to a compound
what is hydrolysis
adds water to a compound to split it (usually ester)
what happens in phase 2 of metabolism
(conjugation)
Conjugates (adds on) an endogenous, highly polar, water-soluble substrate to the molecule
produces water-soluble, biologically inactive molecule ready for excretion
common phase 2 metabolism substrates
glucuronic acid, glycine, acetic acid, sulfuric acid, methyl group
what is enterohepatic circulation
examples?
some conjugated compounds excreted in bile, reactivated in intestine, then reabsorbed into systemic circulation (diazepam, warfarin)
what happens in phase 3 of metabolism
(elimination)
Involves ATP-dependent carrier proteins that transport drugs across cell membranes
Present in kidneys, liver, GI tract
hepatic clearance is a product of what 2 things
- Liver blood flow: how much drug is delivered to liver
- Hepatic extraction ratio: how much drug is removed by liver
what is an extraction ratio
measure of how much drug delivered to clearing organ (Q) vs. how much drug is eliminated by that organ
what does an ER of 1.0 mean
100% of the drug delivered is removed
what does an ER of 0.5 mean
50% of drug delivered is removed
how is hepatic clearance categorized
perfusion-dependent elimination or capacity-dependent elimination
hepatic extraction ratio associated with perfusion-dependent clearance
examples
high ratio (> 0.7)
fentanyl, lidocaine, propofol, sufentanil, morphine, meperidine, ketamine, metoprolol, nifedpine, diltiazem, verapamil
how do alterations in hepatic enzyme activity affect drugs with a high hepatic extraction ratio
little effect
what increases or decreases clearance in drugs with a high hepatic ER
increased or decreased liver blood flow
hepatic extraction ratio associated with capacity-dependent clearance
examples
low ER (<0.3)
rocuronium, diazepam, lorazepam, methadone, thiopental, theophylline, phenytoin
examples of intermediate hepatic ER
midazolam
vecuronium
alfentanil
methohexital
what affects clearance in drugs with a low hepatic ER
alterations in hepatic enzyme activity
induction = increased clearance
inhibition = decreased clearance
when are drugs subjected to first-pass metabolism
PO drugs with high ER
what is first-pass metabolism
After drug is absorbed from GI tract, delivered to portal circulation - portion is metabolized before drug reaches biophase
what is enterohepatic circulation
a process where liver excretes a substance into bile, then that substance is reabsorbed from small intestine and transported back to liver
examples of drugs that undergo enterohepatic circulation
diazepam, warfarin
most important mechanism of drug biotransformation
CYP 450 system
carries out most of body’s phase 1 biotransformations
CYP 450 system
unique feature of CYP 450 system
exogenous chemicals can influence enzyme expression
where are P450 enzymes located
smooth ER of hepatocyte
extrahepatic tissue (lungs, kidneys, skin, adrenal gland, GI tract)
Most important CYP450 enzyme
CYP 3A4
metabolizes 50% of drugs we administer
how do enzyme inducers affect drug clerance
stimulates enzyme synthesis
increases drug clearance, decreases t ½
how does enzyme inhibition affect drug clearance
competes for binding sites on enzyme
decreased drug clearance, increased t ½
CYP 3A4 inhibitors
- grapefruit juice
- cimetidine
- erythromycin
- azole antifungals
- SSRIs
CYP3A4 inducers
- ethanol
- rifampin
- barbiturates
- tamoxifen
- carbamazepine
- St John’s wort
CYP 3A4 substrates
- opioids: fentanyl, alfentanil, sufentanil, methadone
- benzos: midazolam, diazepam
- LAs: lidocaine, bupivacaine, ropivacaine
how does CYP 2D6 inhibition affect codeine
codeine is a prodrug metabolized to active metabolite via CYP 2D6
inhibition reduces metabolism to morphine and decreases potency
CYP 2D6 substrates
codeine
oxycodone
hydrocodone
CYP 2D6 inducers
disulfiram
CYP 2D6 inhibitors
isoniazid
SSRIs
quinidine
CYP 1A2 substrates, inducers, and inhibitors
- substrate: theophylline
- inducers: tobacco, cannabis, ethanol
- inhibitors: erythromycin, cipro
what determines renal elimination
polarity & pH of glomerular fluid
how are most hydrophilic vs. lipophilic drugs excreted
- hydrophilic: excreted unchanged
- lipophilic: must undergo biotransformation reactions to increase water solubility before excretion by kidneys
what happens to lipophilic drugs that don’t undergo biotransformation
will be reabsorbed into peritubular fluid by diffusion
2 processes to deliver a drug to urine
GFR
organic ion transporters
how does plasma protein binding affect glomerular filtration of drugs
- drugs not bound to plasma proteins freely filtered by glomerulus
- Highly protein-bound drugs resistant to glomerular filtration - only free fraction will be filtered
what are organic anion and cation transporters
transport proteins in proximal tubules actively secrete organic acids & bases into urine
examples of OAT (organic anion transporters)
furosemide, thiazide diuretics, PCN
examples of organic cation transporters (OCT)
morphine, meperidine, dopamine
what influences whether drugs are excreted into urine or reabsorbed into peritubular capillaries
urine pH
what does acidic vs. basic urine favor in terms of drug excretion
- Acidic urine favors: reabsorption of acidic drugs, excretion of basic drugs
- Basic urine favors: reabsorption of basic drugs, excretion of acidic drugs
how do ammonium chloride or cranberry juice affect urine drug excretion
acidifies - helps eliminate basic drugs
how do sodium bicarb or acetazolamide affect urine drug elimination
will alkalinize urine - helps eliminate acidic drugs
uses water to cleave an ester linkage
hydrolysis
drugs metabolized by pseudocholinesterases
- Succinylcholine
- Mivacurium
- Ester LAs
- Tetracaine
- Procaine
- Chloroprocaine
- Cocaine (+ hepatic)
drugs metabolized by nonspecific esterases
- Remifentanil
- Remimazolam
- Esmolol (RBC)
- Etomidate (+ hepatic)
- Atracurium
- Clevidipine
drugs metabolized by alkaline phosphatase
fospropofol
drugs metabolized via Hofmann elimination
- Cisatracurium
- Atracurium
2 factors that affect Hofmann elimination
pH
temp
pseudocholinesterase deficiency extends duration of what drugs
succinylcholine, mivacurium, cocaine, ester LAs
which is hydrophilic vs. lipophilic - nonionized vs ionized
ionized - hydrophilic
nonionized - lipophilic
what percent of CO do these tissues receive:
vessel rich group
fat
muscle
VRG = 75%
muscle = 19%
fat = 6%
how much drug is eliminated after 2 half lives
75%
how much drug is eliminated after 3 half lives
87.5%
how much drug is remaining in the plasma after 5 half lives
3.125%
where are plasma proteins synthesized
liver
bond formed by drugs and proteins
weak bond (ionic, hydrogen, or van der Waals)
extent of plasma binding affects:
intensity of drug effects
drug’s duration of action
most plentiful plasma protein
albumin
primary determinant of oncotic pressure
albumin
T½ of albumin
3 weeks
which plasma protein primarily binds with acidic drugs
albumin
what decreases Cp of albumin
liver and renal disease, old age, malnutrition, pregnancy
plasma protein that primarily binds with basic drugs
a1-Acid glycoprotein
increases Cp of a1-Acid glycoprotein
- surgical stimulation
- MI
- chronic pain
- RA
- advanced age
decreases Cp of a1-acid glycoprotein
- neonates
- pregnancy
percent change =
(new value - old value / old value) * 100
causes of decreased plasma proteins
- reduced synthetic function (liver disease, malnutrition)
- increased protein excretion (renal disease)
- altered distribution (3rd trimester pregnancy)
when can alterations in protein binding be a problem
- CPB: hemodilution & heparinization
- ECMO circuits: ceftriaxone, fentanyl, midazolam
- Bilirubin & thyroxine can displace drugs from protein binding
how does increased protein binding affect potency
increased unbound fraction = increased potency
relationship between Vd and degree of protein binding
inversely related
metabolism and elimination of highly protein bound drugs
typically slower
