exam 1 Flashcards
(231 cards)
1
Q
Transfer of drug from site of administration to systemic circulation
A
Absorption
2
Q
Transfer of drug from systemic circulation
A
Distribution
3
Q
Enzymatic alteration of a drug
A
Metabolism
4
Q
Removal of a drug from the body
A
Excretion
5
Q
metabolism + excretion
A
Elimination
6
Q
Action of the drug on the body
The reason you take the drug
A
Pharmacodynamics
7
Q
Action of the body on the drug
Fate of the drug in the body
“ADME”
A
Pharmacokinetics
8
Q
The more _____________ the drug, the easier it is to cross the cell membrane
A
lipophilic
9
Q
Hydrophilic
A
heads
10
Q
lipophilic:
A
tails
11
Q
The extent of drug absorption
A
bioavailability (F)
12
Q
what is the primary area of absorption
A
duodenum
(dissolution + disintegration = stomach)
13
Q
reflects loss of drug due to hepatic (and intestinal) metabolism on the way to the systemic circulation
A
first pass effect
14
Q
what type of drug form diffuses across membrane
A
NON-ionized (lipid soluble)
15
Q
where does the majority of metabolism occur
A
plasma or central compartment (where the kidneys and the liver reside)
16
Q
true or false
IV (both infusion and single dose/bolus) are always 100% or 1
A
true
17
Q
what are the 3 steps of distribution
A
1st disintegration: drug leaves the capsule; optional step (e.g., suspensions)
2nd dissolution: drug molecules dissolve in gastric fluid
3rd absorption
18
Q
_____________ = metabolism + excretion
A
elimination
19
Q
The more ____________ the drug, the easier it is to cross the barrier
A
lipophilic
20
Q
the heads of the membrane are _______________
A
Hydrophilic
21
Q
the tails of the membrane are ________________
A
Lipophilic
22
Q
______hill Transport = Passive
A
DOWN
23
Q
What is an example of passive diffusion
A
facilitated diffusion
24
Q
particles that are transported by facilitated diffusion (passively) are (4):
A
o Small (monomers)
o Polar (water-soluble/hydrophilic)
o Charged ions (e.g., glucose, Ca, Cl, Na, K)
o Transport proteins (e.g., membrane transporters)
25
2 types of facilitated diffusion
pores/channels
carrier proteins
26
___hill Transport = Active
UP
27
factors that influence the GI tract
* GI motility
* Gastric emptying
* Intestinal motility
* Perfusion of the GI tract
* Presence of other drugs
* Presence or absence of food
28
second opportunity to be absorbed
enterohepatic recycling
29
which form is most easily absorbed
un-ionized form
30
Primary site for drug:
disintegration + dissolution
stomach
31
Primary site for oral drug:
absorption
duodenum
32
binding to tissue/protein components
ADsorption
33
water-soluble, high protein binding
small/low Vd
34
lipid-soluble, low protein binding
large/high Vd
35
>____% protein bound = highly protein bound
this IS clinically relevant for protein binding issues
>90%
36
what 3 things create DIFFICULT transport
tight junctions
astrocytes
pericytes
37
what 2 things create EASY transport
lipophilic/un-ionized
small molecular weight
38
If an efflux transporter is exposed to a drug inhibitor (preventing the efflux pump from working properly), it will ___________ the likelihood of absorption
ENHANCE
39
EFFLUX transporter example
ATP-Binding Cassette (ABC) Transporters
40
INFLUX transporter example
Solute Carrier Transporters (SCT)
41
Factors Impacting Drug Binding for HIGHLY Bound (>90%) Plasma Proteins
* Protein concentration
* Protein size (Da, kDa)
* Number of protein binding sites; bound (CB)
* Association binding constant
o Measure of the tightness of the binding (whether the drug can detach from a protein easily)
* Concentration of unbound drug (Cu) or free drug (Cf)
42
hydrostatic balance; keeps the blood volume intact
medium MW
large concentration
albumin
43
medium MW
VARIABLE concentration (goes up in times of stress; non-detectable in healthy people)
a1-acid glycoprotein (AAG)
44
protein carrier of fat
large MW
small concentration
lipoprotein
45
Factors that Decrease Albumin Concentrations
decreased protein synthesis
liver dx
46
Factors that Decrease Albumin Concentrations
excess elimination of protein
kidney dx
47
Factors that Decrease Albumin Concentrations
increased protein catabolism
trauma, surgery
48
Factors that Decrease Albumin Concentrations
decreased protein synthesis and increased protein catabolism
malnutrition
49
Factors that Decrease Albumin Concentrations
distribution of albumin into extravascular space
burns
50
Metabolism =
Biotransformation
* Enzymatic (usually) or non-enzymatic
51
what 3 things impact the liver metabolism
blood flow
enzyme activity
protein binding
52
the liver makes the drug more ______________, _____________ the polarity (so that the kidneys can eliminate it)
HYDROphilic
INCREASED polarity
so that it can be eliminated
53
* Drugs are transported into hepatocytes by
o 1) Passive diffusion
o 2) Carrier-mediated transport
54
4 Major Consequence of Drug Biotransformation/Metabolism
* Increase in water solubility
* Increase in rate of elimination
* Termination of biologic activity
* Bioactivation (desired or undesired)
55
Something that is not pharmacologically activated until the body does something to activate it
Normally metabolized to their active form, and then can be metabolized further
prodrug/desired drug
codeine
56
Instead of being inactive, it is __________, and could be transformed into an active metabolite, same effect, or different effect from a drug
active drug
demerol (normeperidine)
57
superfamily of monooxygenases
Heme-containing enzymes, catalyze the oxidation of organic substances
CYP450
phase 1
of hepatic metabolism
58
o Conjugation reactions
o Glucuronide
phase 2
of hepatic metabolism
59
P-Glycoprotein (P-gp) or ABC-B1
ABC transporters
efflux
60
Proposed to predict the kinetics of drugs such as
digoxin,
cyclosporine
and fexofenadine
P-Glycoprotein (P-gp) or ABC-B1
61
transporters: influx
SLC transporters (solute carrier)
62
Located on both the basolateral/blood/plasma side and the apical/lumen/organ side
SLC (influx) + ABC (efflux)
63
plasma/blood
side
basolateral
64
lumen/organ
side
apical
65
most important factor for excretion
nephron
66
transporters actively making the drug more concentrated in the urine
secretion
(example: abx)
67
drug gets placed back into the plasma/blood from the urine; GIVE EXAMPLE
reabsorption
lithium is example
68
If clearance of a drug is LESS than < 120 ml/min, then we know the drug is filtered + net ___________________
reabsorption
69
If clearance of a drug is MORE than > 120 ml/min, then we know the drug is filtered + net ______________
secretion
70
taken back up through the portal vein into the liver
enterohepatic recycling
71
Excretes drug by emptying into the duodenum
bile
72
_______________ ____________ is why some drugs have a long half-life
enterohepatic recycling
73
Primary drug of
biliary extraction (intact or as metabolites)
diazepam
74
Primary drug of
enterohepatic circulation:
morphine
75
Determinants in the Selection of Drug Route
* Type of desired effect
* Physiochemical properties
* Rapidity of effect
* Quality of effect
* Condition of patient
76
Pharmacokinetic Parameters:
Assessment of ________________
Bioavailability
77
Max concentration
Cmax
78
Time to max concentration
Tmax
79
the % of the drug available to systemic circulation
fraction absorbed from gut
The rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action
Bioavailability (F)
80
rate + extent of drug exposure in the body
Area Under the Curve (AUC)
81
RATE of ELIMINATION, per unit of time
K
hr-1, min-1, sec-1
82
Rate of elimination, per unit of time (K)
o Linear vs. non-linear (____________-________)
Michaelis-Menten
83
VOLUME of drug eliminated per unit of time
clearance (Cl)
ml/hr, L/min
only ml or L!
84
hour, min, seconds
t 1/2 life
85
5 x t1/2 =
steady state
86
ml or L only
Vd
87
The comparison of bioavailability of different formulations, drug products, doses, or batches of the SAME drug product
Example: tablet vs solution
bioequivalence
88
example of drug with narrow therapeutic index/range
phenytoin
89
most drugs have a _______ therapeutic index
WIDE
90
peak (tied to _________) and a trough (tied to _________)
efficacy
toxicity
91
AUC:MIC
AUC: minimum inhibitory concentration (MIC) needed to kill off bacteria
92
amount= changes
fraction= constant
first order
93
most common route of elimination
follows natural log
K= h-1, sec-1, min-1
first order
94
amount=constant
fraction=changes
example: ethanol/beer
zero order
95
least common
K0 = amount/time (mg/h, g/h, mcg/min)
“Saturation Kinetics”
zero order
96
1st: First-order elimination
at low amounts
2nd: Zero-order elimination at high amounts/saturation
Mixed order (Michaelis-Menten)
97
example of mixed order
phenytoin
98
2 phases:
1st: Alpha=distribution phase
2nd: Beta=elimination phase
TWO-compartment model
99
Hydrophilic
Bound drug
Example: digoxin
(not in the heart right away, takes time to equilibrate between plasma and heart tissue)
TWO-compartment model
100
Instantaneous
Lipophilic
Unbound drug
ONE-Compartment model
101
1st: central/plasma
2nd: rapidly goes into CNS
3rd: slowly goes into fat or adipose tissue (leading to drug accumulation and side effects)
Example: general anesthetics
THREE-compartment model
102
4 main hepatic enzymes
* CYP3A4
* CYP2C9
* CYP2C19
* CYP2D6
103
fraction not bound to protein
fu
104
innate ability of liver enzymes to metabolize (intrinsic clearance)
Cl int
105
well-stirred model
hepatic clearance
impacted by:
1) QH: liver blood flow
2) Clint: innate ability of liver enzymes to metabolize (intrinsic clearance)
3) fu: fraction NOT bound to protein
106
bioavailability provides evidence by understanding how much of a drug is metabolized*
first pass effect
Absolute: AUCPO x DoseIV/ AUCIV x DosePO
107
Basis for determining GFR in the clinical setting
This is because it is almost exclusively filtered by the kidneys
Creatinine Clearance (CrCl)
108
equation that utilizes serum creatinine for GFR estimation
Cockcroft and Gault Equation
109
fraction excreted unchanged in the urine
fe
110
Assumptions/True Statements:
Bioavailability (F) = 1 or 100% is available at time zero (0)
C0 (initial concentration), Tmax, Vd = 100% of drug delivery
Not effected by the “first pass effect”
IV bolus
111
One Compartment Model = ___________ Compartment
CENTRAL
primarily hydrophilic drugs
112
Assumptions/True Statements:
Vd is complete at time = 0 (Tmax)
Distribution equilibrium is instantaneous
IV BOLUS + ONE comparment model
113
mcg/ml, mg/L, etc
AUC
114
concentration at a given time
Ct
115
initial concentration at time=0
Co
116
RATE of elimination between Co and Ct
K
117
time between Co and Ct
T
118
Assumptions/True Statements:
Bioavailability (F) = 1 or 100%
You CANNOT assume that 100% of the drug is there at time = 0 (Co = 0)
Cmax, Tmax, Vd = 100% of drug delivery
Enters the body: zero order
Leaves the body: first order elimination
IV INFUSION
119
C0 (initial concentration), Tmax, Vd = 100% of drug delivery
Tmax = time 0
bolus
120
Cmax, Tmax, Vd = 100% of drug delivery
infusion
121
true or false
amount/concentration eliminated is HIGHER at the beginning in FIRST order
true
122
takes into account ln, NOT evenly spaced on the Y axis
semi-log paper (first order)
123
The more the drug-to-enzyme interactions, the ____________ the binding
stronger
124
The degree to which a drug acts on a given site relative to other sites
selectivity
125
The dose range of a drug that provides safe and effective therapy with minimal adverse effects
therapeutic window
126
Binds to a receptor and turns it “on”; causing activation of signaling cascades within the cell
agonist
127
Binds to a receptor and turns it “on”; LESS EFFICACY than full agonists
PARTIAL agonist
128
Binds to a receptor and does not activate it
antagonist
129
Most drugs bind to ____ type of receptor
This can result in “non-discriminatory” negative effects
>1
example: antipsychotics and antidepressants
130
receptors are STILL THERE, by constantly stimulating it, you keep the G-proteins from interacting with the receptor (the drug binds and no response occurs)
desensitization
131
Over time, the receptor is physically REMOVED from the membrane, it is not there anymore
down-regulation
132
true or false
down-regulation occurs with AGONISTS
true
tolerance develops
albuterol, insulin
133
When a constant stimulus (agonist) is applied to a receptor, the cell’s response will diminish over time
tolerance
134
RAPID development of tolerance
To achieve the same response: must increase the dose
tachyphylaxis
135
at the drug/receptor level:
the observed response is not the %, but rather the ___________
number/amount
1,000 receptors at 50% is > 10 receptors at 50%
136
Over time, more receptors appear on the membrane
Antagonists: constant blockade of a receptor
Sensitivity occurs if meds abruptly stopped
up-regulation
"BUS"
137
fastest "receptor"
LIGAND-gated ion channels (milliseconds)
138
example of ion channels
o Examples: nicotinic; Ach
o Drug: Lidocaine, NMBs, Lorazepam
139
2nd fastest "receptor"
G-protein coupled receptors (GPCRs)
140
example of G-protein coupled receptors (GPCRs)
o Examples: muscarinic; Ach
o Drug: epi, opioids
141
6 main types of "receptors"
* 1) Ion channels
* 2) G-protein coupled receptors (GPCRs)
* 3) Transmembrane receptors
* 4) Intracellular receptors
* 5) Extracellular enzymes
* 6) Cell surface adhesion receptors
142
Shift the dose-response curve to the ______ (more SENSITIVE)
LEFT
lorazepam + GABA
143
Receptor activated ion channel
example
Muscarinic M2 in the nodal cardiac tissue w/ vagal nerve stimulation; the channel is being altered by a receptor
144
VOLTAGE Gated
Some drugs bind to the:
Inactivated state (propafenone)
Activated state
Local anesthetics
145
Neuromuscular, nicotinic
LIGAND GATED ion channels
146
comprised of abY subunits
heterotrimeric
147
Alpha a subunit gives up ______, takes on GTP
GDP
GTP is activated
148
How can closely related GPCRs cause completely OPPOSING cellular responses
TYPE of ALPHA subunit; G PROTEIN types are different
149
How can UNrelated GPCRs cause a similar cellular response
similar G-protein pathways
150
What are the 2 steps for drug-receptor binding
1) binding = receptor occupancy
2) activating = tissue response
151
Numerator=_____________=K off
dissociation
152
Denominator=______________= K on
association
153
Kd
the lower the value, the _________ the affinity of the drug
higher
154
Reflects the ligand concentration at which 50% (half) of all available receptors will be BOUND with ligand
Kd
155
only _________ can cause a tissue response/activate a receptor
agonists
156
lower affinity = _________ shift
lower=RIGHT (you need a HIGHER concentration to achieve the % bound)
157
higher affinity = _________ shift
higher=LEFT
158
receptor occupancy, % bound
Kd
Bmax
159
tissue response, % effect
EC50
Emax
160
effective concentration for 50% (half) of max EFFECT
EC50
161
the response/effect elicited by a drug
efficacy
162
efficacy is determined by 2 things
Related to the NUMBER of ligand-receptor complexes formed
Related to the EFFICIENCY in which the ligand-receptor complex can produce a response
163
How is efficacy assessed from the dose-response graph
How high the Emax plateaus
* Antagonist= 0 efficacy
* Partial agonist= halfway
* Full agonist= all the way at the top (100%)
164
INVERSELY related to drug concentration required to produce a defined effect or response
potency
Potency is a comparable thing
165
morphine and fentanyl have the same _________, but different potency
efficacy
166
HIGHER EC50=*
requires MORE to obtain the same effect
"weaker drug"
167
surmountable antagonist
Reversible/Surmountable/Competitive
168
full agonist + reversible antagonist
would cause a ___________ shift
RIGHTward shift (would require additional agonists to achieve the same response)
169
full agonist + IRreversible antagonist
would cause a ___________ shift
DOWNward shift
because you would have less max attainable effect
170
example of physiologic antagonists
counteracts each other
glucagon and insulin
171
example of chemical antagonists
interacts directly with the drug
protamine and heparin
172
example of a
Partial Agonist + Full Agonist
Abilify
Schizophrenia drug (D2 partial agonist)
173
Partial Agonist + Full Agonist
EXCESS dopamine
DOWNward shift
174
Partial Agonist + Full Agonist
DEFICIENT dopamine
UPward shift
175
* Considered the safety factor of a drug
* The relationship between the amount of drug that causes a specific adverse effect and the amount that causes the desired effect
Therapeutic Index/Range
176
You want the toxic dose to be __________ than the dose that causes the desired effect*
higher
this causes a wide TR
177
examples of mismatch between:
Drug Level and Drug Effect
(3)
Irreversible/pseudo-irreversible binding to a receptor
Clotting factors (half-lives of 2-3 days)
Exceptionally high therapeutic index (“very safe” drugs with high doses)
178
examples of
irreversible/pseudo-irreversible binding to a receptor
* Omeprazole, Plavix, Exelon
Half-life and duration do NOT match up
179
true or false
Even beta1 selective drugs (like metoprolol) still have some effect on beta2 receptors (CAUTION with asthma)
true
180
* Once activated, they initiate a phosphorylation cascade
* Similar to G-protein coupled receptor, but uses a different second messenger
* Changes gene transcription, takes hours
* Example: insulin receptor
Kinase Linked Receptors
181
often in anesthesia; can use lower doses to achieve the same effect
synergistic
1+1=3
182
usually the drugs act on the same site
additive
183
effect of one drug with known effect is increased by a 2nd drug that does not have that effect
o Levodopa + carbidopa
potentiation
184
4 types of CNS depressants that work on GABA
Benzos (versed)
Barbiturates (phenobarbital)
Ethanol
most IV + volatile anesthetics
185
positive allosteric modulators
increase the (2)
FREQUENCY of the chloride channel opening
or
DURATION of chloride channel opening
186
Opioids + inhaled anesthetics
Majority effect: ____________
analgesia
187
Opioids + benzos
effect: ____________
Sedation
188
is sweating common with PNS symptoms
yes
189
anti-muscarinics should be cautioned with ____________
elderly
190
6 examples of anti-muscarinics
Benztropine: treats Parkinson’s
Prochlorperazine: anti-emetic
Diphenhydramine: blocks histamine + muscarinic, motion sickness
Atropine: dries secretions, bradycardia
Glycopyrrolate: dries secretions, bradycardia
Scopolamine: motion sickness, N/V
191
o Hyperkalemia can cause (6)
Bradycardia
Heart block
Muscle weakness
Flaccid paralysis
Metabolic acidosis
Death
192
DILATE the AFferent arteriole
(Increase blood flow into glomerulus)
prostagladins
193
CONSTRICT the EFferent arteriole
(Decreases outflow from glomerulus)
ATII
194
NSAIDS inhibit _________________
prostaglandins
195
ACEi/ARBs decrease production of ______
ATII
think "A&A"
196
long-acting; opioid treatment therapy
naltrexone
197
With naltrexone levels decreased (at the end of dosing interval), the body has upregulated the opioid receptors, leading to an ________________ response to opioids
exaggerated response!
198
INCREASE in transporters or metabolizing enzymes
induction
199
INHIBITION of transporters or metabolizing enzymes
inhibition
200
with a drug that INHIBITS P-gp activity, ________ digoxin will stay in the body
MORE will stay
201
with a drug that INDUCES P-gp activity, ________ digoxin will stay in the body
LESS will stay
202
what are the 4 INDUCERS for CYP3A4*
Carbamazepine
Rifampin
Phenobarbital
Phenytoin
“CRPP”
203
what are the 8 INHIBITORS for CYP3A4:
macrolide abx (clarithromycin)
verapamil
diltiazem
grapefruit juice
HIV protease inhibitors (ritonavir)
cyclosporines
amiodarone
azoles (antifungals)
“My sons, Vera and Dilt are grapeful to navigate their cycles amid the Azoles.”
204
with INHIBITORS, it will lead to toxicity, except with ____-_______
pro-drugs
opposite effect (fewer active metabolites are occurring due to inhibition of metabolism; so, there is LESS therapeutic effect; example: codeine)
205
major types of inhibitors
1) Reversible: temporary
2) Irreversible: permanent
Example: clarithromycin
206
Which type of drug is more absorbed
non-ionized
207
Chelation is a type of ____________
absorption
208
examples of di-valent and tri-valent cations
minerals
Calcium, Iron, Zinc, Magnesium, Aluminum
(Antacids, dietary/vitamin supplements, dairy products)
they DECREASE absorption of some drugs when taken together
209
when taking minerals, wait at least 2-4 hours for these 3 types of drugs
* TetraCYCLINES (doxycycline, minocycline)
* Quinolones (levofloxacin, moxifloxacin)
* Osteoporosis drugs
210
INHIBITION leads to
toxicity (except with prodrugs)
211
INDUCTION leads to
decreased drug effects
212
Any drug that is ____ protein bound can be passively filtered
NOT protein bound = passive
213
true or false
URINE filtration is passive and does NOT use transporters
true
it is passive
214
ligand gated*
how long?
milliseconds
215
g-protein*
how long?
seconds
216
kinase-linked*
how long?
hours
217
nuclear*
how long?
hours
218
alterations in DNA inherited from a parent and are found in the DNA of virtually all cells
hereditary/germline
219
alterations in DNA that develop throughout a person’s life
acquired/somatic
220
examples of pharmacoDYNAMICS
drug-receptor,
agonists/antagonists
therapuetic effect vs toxic effects
downregulation vs upregulation
the reason you take the drug
221
examples of pharmacoKINETICS
ADME
first pass effect
Vd
Cmax, tmax, bioavailability
222
human genome started
year
1990
223
sequencing center
year
2001
224
finished version of human genome sequence completed
year
2003
225
laboratory (one illumina sequencer)
year
2017
226
rare, single gene, several mutations, large phenotypic effect
o Example: down syndrome
mendelian/simple
227
2 different versions/alleles
polymorphic
228
DNA variants for which we know the location in the genome and can easily determine a person’s genotype
marker loci
229
* Tailoring medical prevention and treatment therapies to the characteristics of each patient, improving their quality of life and health outcome
o "The right medicine to the right person at the right dosage at the right time”
precision medicine
230
Example of Pharmacogenomics (gene)
CYP2D6: codeine
231
true or false
IV infusion is F=1
true
anything IV, whether infusion or bolus
