Unit 4 - Pharmacokinetics & Pharmacodynamics Flashcards
(156 cards)
1
Q
what is volume of distribution
A
relationship between administrated dose and resulting plasmc concentration
theoretical measure of how a drug distributes through the body
2
Q
Vd =
A
amount of drug / desired plasma concentration
3
Q
Vd assumes what 2 things
A
- drug distributes instantaneously (equilibration at time = 0)
- drug isn’t subjected to biotransformation or elimination before full distribution
4
Q
distribution of body water in 70 kg patient:
A
5
Q
when is a drug assumed to be lipophilic in regards to Vd
A
Vd > TBW
> 0.6 L/kg or > 42 L
6
Q
when is a drug assumed to be hydrophilic in regards to Vd
A
Vd < TBW
< 0.6 L/kg or < 42 L
7
Q
which requires a higher dose to acheive a given plasma concentration - a lipophilic or hydrophilic drug?
A
lipophilic
8
Q
which requires a lower dose to achieve plasma concentration - lipophilic or hydrophilic drugs?
A
hydrophilic
9
Q
what is a loading dose
A
amount of drug that must be administered to achieve a therapeutic plasma concentration quickly
10
Q
loading dose =
A
(Vd x desired Cp) / bioavailability
11
Q
bioavailability for an IV medication
A
1
12
Q
what is clearance
A
volume of plasma cleared of drug per unit time
13
Q
most important clearing organs
A
liver
kidneys
organ independent (Hofmann, esterases)
14
Q
clearance is directly proportional to:
A
- blood flow to clearing organ
- extraction ratio
- drug dose
15
Q
clearance is indirectly proportional to:
A
- half-life
- drug concentration in central compartment
16
Q
what is steady state?
A
stable plasma concentration when the amount of drug entering the body is equivalent to the amount of drug eliminated from the body
17
Q
as a general rule, when is steady state acheived?
A
after 5 half-lives
18
Q
how to achieve steady state faster in a drug with a long half life
A
give a loading dose
19
Q
illustrates biphasic decrease of a drug’s plasma concentration after rapid IV bolus
A
2 compartment model
20
Q
what does the alpha portion of 2 compartment model represent
A
distribution (t ½ a)
21
Q
what does the beta portion of the 2 compartment model represent
A
elimination (t ½ B)
22
Q
what does line A represent in 2 compartment model
A
drug distributes to theoretical compartments
follows concentration gradient from central compartment to peripheral compartments
23
Q
what influences the slope of line A in 2 compartment model
A
Vd
more lipophilic = larger Vd = steeper slope
24
Q
what does line B in 2 compartment model represent
A
elimination
25
what determines drug redistribution
concentration gradient between plasma and tissues
26
what is A+B in 2 compartment model
plasma concentration over time
27
what is a rate constant
describes the speed at which a reaction occurs or how fast molecules move between compartments
28
k12
rate constant for drug transfer from central to peripheral compartment
29
k21
rate constant for drug transfer from peripheral to central compartment
30
ke
rate constant for drug elimination from the body
31
what does the 3 compartment model describe
different constants going to and from each compartment and central compartment
some compartments may saturate before others
32
what is elimination half time
time it takes for 50% of drug to be removed from plasma during elimination phase
33
when is a drug considered cleared from the body?
when 96.9% of the dose is eliminated from plasma
(~5 half times)
34
what does half time measure
a constant fraction, NOT a constant amount
35
what is context-sensitive half-time
time for plasma concentration to decrease by 50% after gtt stopped
36
exception to opioid CSHT
remifentanil
highly lipophilic but quickly metabolized by plasma esterases = similar CHST regardless of infusion duration
37
what is an acid
substance that donates a proton
38
what is a base
substance that accepts a proton
39
what happens to a strong acid or strong base in water
will dissolve completely
40
what happens to a weak acid or weak base in water
a fraction will ionize
remaining fraction will be non-ionized
41
is morphine a weak acid or a weak base
weak base
42
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)
43
how will a weak acid act in an acidic solution
more non-ionized and lipid soluble
44
how will a weak acid act in a basic solution
more ionized and water soluble
45
how will a weak base act in an acidic solution
more ionized and water soluble
46
how will a weak base act in a basic solution
more non-ionized and lipid-soluble
47
what has the greatest impact on degree of ionization in a drug with a pKa close to plasma pH
small changes in plasma pH
48
what is ionization
process where a molecule gains a positive or negative charge
49
ionization of weak acids and bases depends on what 2 factors
1. pH of solution
2. pKa of the drug
50
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
51
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
52
drug preparation for weak acids
paired with positive ion (Na+, Ca2+, Mg2+)
ex: sodium thiopental
53
drug preparation for weak bases
paried with negative ion (Cl-, sulfur)
ex: lidocaine hydrochloride
54
which is more likely to undergo hepatic biotransformation - ionized or nonionized
nonionized
55
which is more likely to undergo renal elimination - ionized or nonionized
ionized
56
which diffuses across lipid bilayers into BBB, GI tract, and placenta: ionized or nonionized
nonionized
57
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)
58
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)
59
which portion of a drug freely diffuses across a cell membrane
only the lipophilic, non-ionized fraction
60
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
61
strongest diffusion gradient for fetal ion trapping
maternal alkalosis + fetal acidosis
62
neuraxial LA most likely to undergo fetal ion trapping
lidocaine
63
neuraxial LA least likely to undergo fetal ion trapping
why
chloroprocaine
high pKa, rapid metabolism in mother's blood
64
for most drugs, rate of metabolism depends on what 2 factors:
1. Concentration of drug at site of metabolism - influenced by blood flow to site
2. Intrinsic rate of metabolic process - influenced by genetics, enzyme induction/inhibition
65
what is zero order kinetics
* describes situation where there is more drug than enzyme
* constant amount metabolized per time
66
examples of drugs that follow zero order kinetics
aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
67
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
68
nearly all drugs we adminsiter undergo what rate of metabolism
first order kinetics
69
what is metabolism
enzymatic process of altering a molecule’s chemical structure
70
primary organ of metabolism
liver
71
primary role of metabolism
change a lipid-soluble, pharmacologically active compound to water-soluble, pharmacologically inactive byproduct
72
how does creating molecules with greater water solubility lead to increased urine elimination
* increasing ionization and decreases Vd
* increased delivery to kidneys for elimination
73
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
74
what is a prodrug
examples?
body converts an inactive molecule into a pharmacologically active molecule
ex- codeine, oxycodone, hydrocodone, fospropofol
75
3 phases of metabolism
1. modification
2. conjugation
3. elimination
76
result of phase 1 metabolism: modification
Result in small molecular changes that **↑ polarity** of a molecule to prepare it for a phase 2 reaction
77
carries out most phase 1 metabolism reactions
CYP450 system
78
3 types of phase 1 metabolism reactions
1. oxidation
2. reduction
3. hydrolysis
79
what is oxidation
removes electrons from a compound
80
what is reduction
adds electrons to a compound
81
what is hydrolysis
adds water to a compound to split it (usually ester)
82
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
83
common phase 2 metabolism substrates
glucuronic acid, glycine, acetic acid, sulfuric acid, methyl group
84
what is enterohepatic circulation
examples?
some conjugated compounds excreted in bile, reactivated in intestine, then reabsorbed into systemic circulation (**diazepam**, **warfarin**)
85
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**
86
hepatic clearance is a product of what 2 things
1. **Liver blood flow**: how much drug is delivered to liver
2. **Hepatic extraction ratio**: how much drug is removed by liver
87
what is an extraction ratio
measure of how much drug delivered to clearing organ (Q) vs. how much drug is eliminated by that organ
88
what does an ER of 1.0 mean
100% of the drug delivered is removed
89
what does an ER of 0.5 mean
50% of drug delivered is removed
90
how is hepatic clearance categorized
perfusion-dependent elimination or capacity-dependent elimination
91
hepatic extraction ratio associated with perfusion-dependent clearance
examples
high ratio (\> 0.7)
fentanyl, lidocaine, propofol, sufentanil, morphine, meperidine, ketamine, metoprolol, nifedpine, diltiazem, verapamil
92
how do alterations in hepatic enzyme activity affect drugs with a high hepatic extraction ratio
little effect
93
what increases or decreases clearance in drugs with a high hepatic ER
increased or decreased liver blood flow
94
hepatic extraction ratio associated with capacity-dependent clearance
examples
low ER (\<0.3)
rocuronium, diazepam, lorazepam, methadone, thiopental, theophylline, phenytoin
95
examples of intermediate hepatic ER
midazolam
vecuronium
alfentanil
methohexital
96
what affects clearance in drugs with a low hepatic ER
alterations in hepatic enzyme activity
induction = increased clearance
inhibition = decreased clearance
97
when are drugs subjected to first-pass metabolism
PO drugs with high ER
98
what is first-pass metabolism
After drug is absorbed from GI tract, delivered to portal circulation - portion is metabolized before drug reaches biophase
99
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
100
examples of drugs that undergo enterohepatic circulation
diazepam, warfarin
101
most important mechanism of drug biotransformation
CYP 450 system
102
carries out most of body's phase 1 biotransformations
CYP 450 system
103
unique feature of CYP 450 system
exogenous chemicals can influence enzyme expression
104
where are P450 enzymes located
smooth ER of hepatocyte
extrahepatic tissue (lungs, kidneys, skin, adrenal gland, GI tract)
105
Most important CYP450 enzyme
CYP 3A4
metabolizes 50% of drugs we administer
106
how do enzyme inducers affect drug clerance
stimulates enzyme synthesis
increases drug clearance, decreases t ½
107
how does enzyme inhibition affect drug clearance
competes for binding sites on enzyme
decreased drug clearance, increased t ½
108
CYP 3A4 inhibitors
* grapefruit juice
* cimetidine
* erythromycin
* azole antifungals
* SSRIs
109
CYP3A4 inducers
* ethanol
* rifampin
* barbiturates
* tamoxifen
* carbamazepine
* St John's wort
110
CYP 3A4 substrates
* opioids: fentanyl, alfentanil, sufentanil, methadone
* benzos: midazolam, diazepam
* LAs: lidocaine, bupivacaine, ropivacaine
111
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
112
CYP 2D6 substrates
codeine
oxycodone
hydrocodone
113
CYP 2D6 inducers
disulfiram
114
CYP 2D6 inhibitors
isoniazid
SSRIs
quinidine
115
CYP 1A2 substrates, inducers, and inhibitors
* substrate: theophylline
* inducers: tobacco, cannabis, ethanol
* inhibitors: erythromycin, cipro
116
what determines renal elimination
polarity & pH of glomerular fluid
117
how are most hydrophilic vs. lipophilic drugs excreted
* hydrophilic: excreted unchanged
* lipophilic: must undergo biotransformation reactions to increase water solubility before excretion by kidneys
118
what happens to lipophilic drugs that don't undergo biotransformation
will be reabsorbed into peritubular fluid by **diffusion**
119
2 processes to deliver a drug to urine
GFR
organic ion transporters
120
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
121
what are organic anion and cation transporters
transport proteins in proximal tubules actively secrete organic acids & bases into urine
122
examples of OAT (organic anion transporters)
furosemide, thiazide diuretics, PCN
123
examples of organic cation transporters (OCT)
morphine, meperidine, dopamine
124
what influences whether drugs are excreted into urine or reabsorbed into peritubular capillaries
urine pH
125
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
126
how do ammonium chloride or cranberry juice affect urine drug excretion
acidifies - helps eliminate basic drugs
127
how do sodium bicarb or acetazolamide affect urine drug elimination
will **alkalinize** urine - helps eliminate acidic drugs
128
uses water to cleave an ester linkage
hydrolysis
129
drugs metabolized by pseudocholinesterases
* Succinylcholine
* Mivacurium
* Ester LAs
* Tetracaine
* Procaine
* Chloroprocaine
* Cocaine (+ hepatic)
130
drugs metabolized by nonspecific esterases
* Remifentanil
* Remimazolam
* Esmolol (RBC)
* Etomidate (+ hepatic)
* Atracurium
* Clevidipine
131
drugs metabolized by alkaline phosphatase
fospropofol
132
drugs metabolized via Hofmann elimination
* Cisatracurium
* Atracurium
133
2 factors that affect Hofmann elimination
pH
temp
134
pseudocholinesterase deficiency extends duration of what drugs
succinylcholine, mivacurium, cocaine, ester LAs
135
which is hydrophilic vs. lipophilic - nonionized vs ionized
ionized - hydrophilic
nonionized - lipophilic
136
what percent of CO do these tissues receive:
vessel rich group
fat
muscle
VRG = 75%
muscle = 19%
fat = 6%
137
how much drug is eliminated after 2 half lives
75%
138
how much drug is eliminated after 3 half lives
87.5%
139
how much drug is remaining in the plasma after 5 half lives
3.125%
140
where are plasma proteins synthesized
liver
141
bond formed by drugs and proteins
weak bond (ionic, hydrogen, or van der Waals)
142
extent of plasma binding affects:
intensity of drug effects
drug's duration of action
143
most plentiful plasma protein
albumin
144
primary determinant of oncotic pressure
albumin
145
T½ of albumin
3 weeks
146
which plasma protein primarily binds with acidic drugs
albumin
147
what decreases Cp of albumin
liver and renal disease, old age, malnutrition, pregnancy
148
plasma protein that primarily binds with basic drugs
a1-Acid glycoprotein
149
increases Cp of a1-Acid glycoprotein
* surgical stimulation
* MI
* chronic pain
* RA
* advanced age
150
decreases Cp of a1-acid glycoprotein
* neonates
* pregnancy
151
percent change =
(new value - old value / old value) \* 100
152
causes of decreased plasma proteins
* reduced synthetic function (liver disease, malnutrition)
* increased protein excretion (renal disease)
* altered distribution (3rd trimester pregnancy)
153
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
154
how does increased protein binding affect potency
increased unbound fraction = increased potency
155
relationship between Vd and degree of protein binding
inversely related
156
metabolism and elimination of highly protein bound drugs
typically slower
