Wk 1-2: Pharmacokinetics, Pharmacodynamics, Pharmacogenomics Flashcards
(180 cards)
1
Q
Affinity
A
Affinity: The attraction between a drug and a receptor.
2
Q
Allosteric site:
A
Allosteric site: A binding site for substrates not active in initiating a response; a substrate that binds to an allosteric site may induce a conformational change in the structure of the active site, rendering it more or less susceptible to response from a substrate.
3
Q
Bioavailability (F):
A
Bioavailability (F): The fraction or percentage of a drug that reaches the systemic circulation.
F = quantity of drug reaching systemic circulation / quantity of drug administered
4
Q
Biotransformation:
A
Biotransformation: Metabolism or degradation of a drug from an active form to an inactive form.
5
Q
Chirality:
A
Chirality: Special configuration or shape of a drug; most drugs exist in two shapes.
6
Q
Clearance:
A
Clearance: Removal of a drug from the plasma or organs.
7
Q
Downregulation:
A
Downregulation: Decreased availability of drug receptors.
8
Q
Enantiomer (also called isomer)
A
Enantiomer (also called isomer): A mirror-image spatial arrangement, or shape, of a drug that suits it for binding with a drug receptor.
9
Q
Enterohepatic recirculation:
A
Enterohepatic recirculation: The process by which a drug excreted in the bile flows into the gastrointestinal tract, where it is reabsorbed and returned to the general circulation.
10
Q
First-pass effect:
A
First-pass effect: The phenomenon by which a drug first passes through the liver where it may be degraded before distribution to the tissues.
11
Q
Half-life (t1⁄2):
A
Half-life (t1⁄2): The time required for half of a total drug amount to be eliminated from the body.
12
Q
Hepatic extraction ratio:
A
Hepatic extraction ratio: A comparison of the percentage of drug extracted and the percentage of drug remaining active after metabolism in the liver.
13
Q
Ligand:
A
Ligand: Any chemical, endogenous or exogenous, that interacts with a receptor.
14
Q
Pharmacodynamics:
A
Pharmacodynamics: Processes through which drugs affect the body.
15
Q
Pharmacokinetics:
A
Pharmacokinetics: Processes through which the body affects drugs.
16
Q
Prodrug:
A
Prodrug: A drug that is transformed from an inactive parent drug into an active metabolite; in effect, a precursor to the active drug.
17
Q
Receptor:
A
Receptor: The site of drug action.
18
Q
Second messenger:
A
Second messenger: A chemical produced intracellularly in response to a receptor signal; this second messenger initiates a change in the intracellular response.
19
Q
Therapeutic window:
A
Therapeutic window: The range of drug concentration in the blood between a minimally effective level and a toxic level.
20
Q
Threshold:
A
Threshold: The level below which a drug exerts little to no therapeutic effect and above which a drug produces a therapeutic effect at the site of action.
21
Q
Upregulation:
A
Upregulation: Increased availability of receptors.
22
Q
Volume of distribution (Vd):
A
Volume of distribution (Vd): The extent of distribution of a drug in the body.
23
Q
High hepatic extraction ratio = ___ oral bioavailability
A
High hepatic extraction ratio = low oral bioavailability
24
Q
Low hepatic extraction ratio = ___ oral bioavailability
A
Low hepatic extraction ratio = high oral bioavailability
25
Drugs w/ low hepatic extraction ratio <30%
```
Barbiturates
diazepam
warfarin
theophylline
tolbutamide
```
26
Drugs w/ high hepatic extraction ratio >70% include...
lidocaine
meperidine
imipramine
27
Apparent Volume of Distribution
Vd = Amt in body / Plasma drug concentration
28
Name a drug that is not metabolized at all
gentamicin (Garamycin)
29
Prodrug allopurinol metabolizes into
oxypurinol
30
Prodrug codeine metabolizes into
morphine
31
Prodrug enalapril metabolizes into
enalaprilat
32
Prodrug prednisone metabolizes into
Prednisolone
33
Prodrug valacyclovir metabolizes into
Acyclovir
34
first-order kinetics
the actual amount of drug eliminated is proportional to the concentration of the drug (the more drug there is, the faster it is eliminated). This applies to most drugs
35
zero-order kinetics
Fixed amounts of drugs, rather than a fractional proportion, are eliminated at a constant rate
Example: alcohol
This can be dangerous
36
Pharmacodynamics refers to:
the set of processes by which drugs produce specific biochemical or physiologic changes in the body
37
Four types of receptors:
gated ion channels
transmembranous receptors
G protein– coupled receptors (GPCR)
intracellular receptors
38
Foods with tyramine (fermented cheese, wine...) should not be taken with _____ to avoid _______.
MAOIs, hypertensive crisis
39
Pharmacogenomics
Role of genetic variation in drug response
40
Genetics may account for ___ to ___ % of variability in drug disposition and effects.
20 to 95%
41
Adverse Drug Related Events account for (% admissions, total deaths)...
3 to 10% of hospital admissions and prolonged hospital stays, and 100,000 deaths annually
42
___% DNA accounts for individual differences/variances in drug metabolism and response
0.1%
43
Allele:
any of the alternative forms of a gene occurring at a specific location on specific chromosome
44
Genotype:
internally coded, inheritable info in the organism; combination of 2 alleles at single locus
45
Phenotype:
a measurable trait or characteristic
46
SNP: Single nucleotide polymorphism...
Variation in a DNA sequence the occurs when single nucleotide (Adenine, Thymine, Cytosine, Guanine) differs among members of a population.
47
Polymorphisms
DNA variants that occur within a specific population at a frequency rate higher than 1%
48
The focus of pharmacogenomics are...
...SNPs/Polymorphisms
49
Substrate:
A drug that binds to and is metabolized by an enzyme
50
Enzyme:
catalysts that cause oxidation, reduction or hydrolysis of drug
51
Enzyme Inducer:
molecule (drug) that speeds up the production of an enzyme
52
Enzyme Inhibitor:
molecule (drug) that slows down or inhibits the production of an enzyme
53
Inducer/Inhibitor can include
...the drug itself, a second drug, food (grapefruit juice, kale)...
54
Genetic variants effect proteins how?
Genetic variants translate into functional changes in proteins
55
More than ___ families of drug metabolizing enzymes in humans
30
56
Pt without pseudocholinesterase will be unable to break down _______ and could face complications of _______ including ________ as a result.
succinylcholine, prolonged paralysis and apnea
57
Common efflux protein
P-glycoprotein
58
Transport proteins like P-glycoprotein are thought to be ______ against toxins in food, etc
Protective
59
P-gp controls ATP-dependent _____ _____ of ______
cellular efflux of substrates, anticancer drugs, immunosuppressive drugs, and other meds
60
A LOW expression of gene for P-gp will result in...
...higher drug levels. Less P-gp = more drug in circulation.
61
P-gp associated with lower ___ drug concentrations
HIV
62
Protease inhibitors for HIV (indinavir, nelfinavir, etc...) have ___ bioavailability due to P-glycoprotein
Variable or low
63
Pt's with low expression of P-gp have ______ plasma concentrations of HIV antivirals
2-5 times
64
P-gp is expressed in these places:
GI tract, CNS
65
___% of drugs marketed in US metabolized by cytochrome 450 / CYP450
70%
66
CYP450 inhibited by these types of foods
Grapefruit juice, charred foods, kale / cruciferous vegetables
67
CYP450 highest levels in this organ _____ but also found in this organ ____
liver, GI tract
68
P-gp is found in ______ and also in ____ and _____
intestine (transfers back to intestine), also in liver and kidney (transfers to bile and urine)
69
The drug ______ INHIBITS intestinal P-gp and renal P-gp, leading to ____ levels of digoxin
Quinidine; increases ABSORPTION of digoxin in intestine, and decreases ELIMINATION of digoxin at kidney
70
The antibiotic drug ________ has this effect on P-gp, and digoxin.
Rifampin induces intestinal P-gp, decreases digoxin absorption, lowering serum concentrations
71
Alcohol can _______ CYP enzymes leading to ____ serum levels of drug
inhibit, increase ...(hypoglycemia in pt's taking insulin
72
Metronidazole inhibits enzyme ______, which increases ____ and leads to ______-like reaction
inhibits aldehyde dihydrogenase
elevates acetaldehyde
causes disulfiram-like reaction (flushing, h/a, n/v, hypotension, blurred vision)
73
SMOKING can _______ CYP enzymes leading to ________ metabolism and _______ levels of certain drugs
Smoking can increase CYP metabolism leading to decreased levels of diazepam, propooxyphene, chlorpromazine, amitryptaline, theophylline...
74
Warfarin is metabolized mainly by CYP___
CYP2C9
75
Warfarin tends to be poorly metabolized by ______ due to ________ of CYP2C19
Asians, due to poor expression of CYP2C19
76
Variant alleles of CYP2C9 occur in ____% of white population, affecting warfarin metabolism
18%
77
Warfarin response is also impacted by gene ______
VKORC1, which encodes synthesis of vit K
78
Lecture slide shows that average required warfarin dose is highest for this population; lowest for this population
Highest doses for African-American; lowest doses for Asian-American
79
Clopidogrel is this type of drug ______ which when metabolized by CYP____ results in its active metabolite
prodrug, CYP2C19
80
Deficiency of CYP2C19 among clopidogrel patients can result in recurrent ______, and are most commonly seen among _______ (50%) and then _______ (33%)
....higher rates of recurrent CV events, Asians, African Americans
81
CYP2C19*1 is the "wild type" which means ______
Normal enzyme activity
82
CYP2C19*2 is predominantly carried by _______ and are considered ________, and when on Plavix, they face higher rates of _______
Asians, poor-metabolizers, higher recurrent rates of CV events
83
Warfarin works when _______ inhibits VKORC1 which encodes synthesis of ______
S-warfarin
| vitamin K
84
S-warfarin is metabolized by _____
CYP2C9
85
Mutations to CYP2C9 can lead to ______ in warfarin patients (CYP2C9*2, CYP2C9*3)
Bleeding, due to decreased metabolism of S-warfarin, higher serum levels of S-warfarin, subsequent lower levels of VKORC1, and decreased production of vit K and decreased coagulation activity.
86
VKORC1 mutation known as "________" can lead to ______ and thus require lower doses of _______; common among _______
VKORC1 "A haptotype" inactivating mutation can lead to less VKORC1 and thus require lower doses of warfarin; common among _______
87
Codeine is a _______ and requires ______ to convert to active form _____
Prodrug, requires CYP2D6 to convert to morphine
88
CYP2D6 poor metabolizers can lead to _______ effect of codeine and ultra-rapid metabolizers can lead to ______ effect from taking codeine leading to symptoms related to ______
CYP2D6 poor metabolizers can lead to poor pain relief effects of codeine (since poor metabolism to morphine), and ultra-rapid metabolizers can lead to toxic effect from taking codeine due to rapid increase in morphine levels - respiratory depression / apnea
89
Cough and cold medications are not recommended for use in children younger than ____.
Opioids (codeine etc) not recommended in children younger than ______.
18 years
6 years
warning for use of tramadol for tonsillectomy etc for ages 12-16.
90
Anti-depressant treatments are successful in ____ (fraction) of patients, which can be related to ______ status of patients
2/3 patients, metabolizer status
91
Poor-metabolizers of anti-depressants can have this electrolyte imbalance.
Hyponatremia, related to SSRs and tricyclic antidepressants
92
Poor metabolizer may have _______ level of drug in system, with potential _______ problems
higher, toxicity
93
Ultra-metabolizer may have _____ level of drug in system, and may be ______ to achieve therapeutic drug levels
lower; unable
94
This drug _____ can interfere with Tamoxifen (BRCA cancer med) leading to cancer recurrence
Paxil (SSRI)
95
New drug applications are required to be screened for KCNH2 blocking activity, which can lead to ________.
QTc-prolongation
96
Variations to ________ receptors may lead to ________ effects of albuterol and beta-blockers like metoprolol
beta-adrenergic receptors; pronounced effects, or no effect at all
97
Antidepressants of this type have more pharmacogenomic problems and drug response issues
tricyclic antidepressants (e.g. noritriptaline) vs SSRI
98
Swedish and Middle-Eastern patients tend to be _________ metabolizers of CYP_____
Swedish and Middle-Eastern patients tend to be ultra-metabolizers of CYP2D6.
99
SNF on gene TCL1A can cause side effects of patients taking ______ including symptoms of _______; implication is _______
Tamoxifen; joint pain, stiffness, myalgias, decreased bone density; decreased medication adherence
100
Metformin can result in _____ side effects if pt has certain gene
GI side effects
101
Therapeutic drug monitoring is common among the ___
narrow therapeutic drugs, like aminoglycosides (gentamicin, other -mycin drugs)
102
Enteric coating medications dissolve in:
intestine
103
Rectal drugs are limited by ____ but have less _____ effect than oral drugs
erratic absorption, less hepatic first-pass effect than oral
104
Sublingual, buccal meds bypass ___ and have ____ onset
first-pass
| rapid
105
IV meds have toxicity related to
peak concentrations
106
Inhalation meds have ____ onset
rapid
107
Topical meds offer the benefit of ______
less systemic exposure
108
Fick's Law predicts
how well a drug will passively diffuse across a membrane
109
Passive diffusion is most common, and is facilitated by
larger surface area
larger concentration gradient
higher permeability
lower membrane thickness
110
P-glycoprotein is an example of ____
carrier mediated, active transport
111
Non-ionized > less polar are...
more lipid soluble > crosses membrane
112
Ionized > more polar are...
less lipid soluble > does not cross membrane
113
Drug trapping: Weak base: ionized form predominates in
acidic environments (stomach)
114
Drug trapping: Weak acid: ionized form predominates in
basic environments (urine)
115
P-gp is an efflux transporter also known as
MDR1, ABCB1
116
P-gp is ______ for substrate
nonselective
117
P-gp serves a protective function such as
protecting fetus, blood brain barrier, etc
118
P-gp is found here:
tumor, intestine, blood brain barrier, kidney, placenta...
119
P-gp is inhibited by many drugs including:
Amiodarone, captopril, carvedilol, ketoconazole, quinidine, verapamil, grapefruit juice
120
P-gp is induced by...
St Johns Wort
Tipranavir/ritonavir (HIV med)
Phenytoin
Carbamazepine
121
Basic / alkaline drugs are absorbed in the...
...duodenum (alkaline environment, remain non-ionized, and able to pass membrane into portal circulation)
122
Acidic drugs are absorbed in the...
...stomach (acidic environment, remain non-ionized, and able to pass membrane into portal circulaton)
123
P-gp is inhibited by...
...grapefruit juice, cyclosporine, verapamil, amiodarone
124
Distribution is
drug movement from systemic circulation to tissues
125
Which organ has the highest normalized blood flow?
Kidneys (3333 ml/min/kg)
126
Drug binding proteins include
albumin
| alpha1-acid glycoprotein
127
Plasma protein binding remains ______
constant
128
Vd =
Amt drug in body / drug concentration (plasma)
129
Smaller Vd will remain in _____
Vascular compartment (more hydrophilic, large molecule, high PPB.... aspirin
130
Larger Vd will remain
outside of plasma compartment (More lipophilic, small molecule, low PPB) ...fluoxetine
131
Elimination =
removal of drug from body, includes metabolism and excretion
132
Purpose of metabolism:
To facilitate excretion
133
Metabolism phases: Phase 1 and 2
```
Phase 1 (makes molecule polar, oxidation, hydrolysis
Phase 2 (conjugation (glucuronide)
```
134
CYP450 uses this type of metabolism:
Phase 1 (oxidation, more polar/H2O soluble molecule)
135
Enzyme is a
catalyst
136
Metabolites can be active, such as metabolites of
diazepam
137
Metabolites can be toxic, such as with
hepatotoxic acetaminophen metabolite
138
Pro-drugs are metabolized into their active form such as:
Fosphenytoin, capecitabine, enalopril, codeine
139
CYP450 constitute _____% of drug metabolism
70-80%
140
CYP INDUCERS include
Barbituates, rifampin, anti-seizure meds, dexamethasone, phenytoin, St Johns Wort, char-grilled meat, cigarette smoke
141
CYP INHIBITORS include
Grapefruit juice, antiretrovirals, -azoles, SSRIs, PPIs, CCBs, -mycins
142
A person who takes codeine who has a duplicate allele of CYP2D6 will be ____ and have ______ effect
ultra-metabolizer, increased morphine level
143
Phenobarbitol is acidic, therefore administering sodium bicarb will ________
alkalinize the urine and trap the drug to excrete it in case of an overdose
144
Alcohol follows _______ kinetics
Zero-order (constant amount over time)
145
Half-life equation
Half-life = 0.693 x Vd / Cl
146
Half life is prolonged by:
increase in Vd, OR by decrease in rate of clearance
147
Zero-order elimination drugs have no true...
half-life
148
Zero-order elimination drugs can have dangerous...
accumulation
149
Zero-order drugs include...
alcohol, phenytoin
150
After about 5 half-lives, _____
97% of drug is eliminated
151
Steady-state =
equilibrium (rate in = rate out)
152
Endogenous ligands are
...ligands produced in the body (not drugs).
153
Intrinsic activity of a drug is...
...ability of a drug to activate a receptor
154
ACEI utilize this kind of receptor
enzymes
155
These drugs use intracellular receptors...
sex hormones, steroids
156
These drugs use circulating protein receptors...
...anticoagulants
157
Irreversible inhibitor example
Omeprazole (PPIs)
158
Allosteric interactions
Drug attaches to binding site OTHER than the active site to change conformational form of receptor, changing effect (increasing or decreasing)
159
Benzodiazepines are blocked by _____ which is a ______
Flumazenil, competitive antagonist, can reverse the binding of benzodiazepines
160
cAMP and cGMP and Ca++ are...
...second messenger molecules in the transduction pathway that cause cellular response
161
PDE5 inhibitors (sildenafil, etc) work at _____ level
second messenger, increasing cGMP response
162
Quantal Dose-Effect Curve
Measures how a population responds to a drug
163
________ Index = TD50 / ED50
Therapeutic Index = TD50 / ED50 (median toxic dose / median effective dose)
164
On-target toxicity
Intended receptor (improper dose, same receptor but wrong tissue); these are "class effects"
165
Off-target toxicity
Unintended target; enantiomers; binds different receptors; immune-related effects; binds different receptor sub-type
166
Tachyphylaxis =
Tolerance
167
PK related toxicity involves
CYP450, transporters, PPB related
168
PD related toxicity
Method of action interaction (PDE5 inhibitor + NTG)
169
Most frequent reason for drug withdrawal in US
hepatotoxicity
170
Hepatic function impairment marker
Bilirubin
171
Hepatocellular injury markers
AST, ALT, ALP
172
Renal injury marker
Creatinine (drugs: NSAIDS, gentamicin)
173
Pulmonary toxicity can be caused by...
amiodarone
174
Gentamicin has a narrow therapeutic index and requires _______ monitoring, specifically ____ and ____ monitoring. It causes ______ toxicity.
Therapeutic Drug Monitoring
Peak (toxicity >10-12mcg/mL)
Trough (>2mcg/mL)
Renal toxicity
175
NSAIDs can cause _______ toxicity
Renal
176
Narrow therapeutic drugs include
```
warfarin
digoxin
gentamicin
lithium
phenytoin
carbamazepine
Cytotoxic drugs (including anti-epileptic and chemotherapy drugs)
```
177
Drug distribution to various compartments (compartment / molecule type)
Total body water: small, hydrophilic (ethanol)
Extracellular water: Larger, hydrophilic (mannitol)
Blood plasma: Large, plasma-bound, ionized (heparin)
Adipose tissue: Lipophilic (diazepam)
Bone / teeth: Certain ions (fluoride, strontium)
178
Higher Vd typically means ______ half-life due to ______ availability to organs of elimination
longer
| decreased
179
Vd and compartments:
Plasma compartment:
Extracellular fluid:
Total body water:
Plasma compartment:
Low Vd [4L/70kg] (large, protein bound)
heparin
Extracellular fluid:
Medium Vd [20% body wt] (small, hydrophilic) Aminoglycoside abx
Total body water:
High Vd [60% body wt, 42L/70kg] (small, lipophilic) ETHANOL, ASPIRIN
180
Quinidine is metabolized by receptor ______ but works through noncompetitive inhibition to block receptor ________
CYP3A4
| CYP2D6
