ADME Flashcards
(99 cards)
1
Q
absorbtion
A
A: How a drug moves from its site of administration into the bloodstream
2
Q
distribution
A
Movement of the drug between blood and tissues
3
Q
metabolism
A
Conversion of drugs into more hydrophilic metabolites
4
Q
excretion
A
Removal of drugs and/or metabolites from the body
5
Q
where are a majority of drugs absorbed
A
intestines due to increasaed SA
can be affetced with coloectomy or gastroparaesis
6
Q
cell membranes
A
act as a barrier for drugs to cross, many ways to cross (active vs passive transport, majority passive)
7
Q
drugs must be what to cross membrane
A
unbound
8
Q
molecular features predicting drug movement (features of drug), 4
A
Molecular size
Degree of ionization
Lipid solubility
Protein binding
9
Q
ionization of drugs to cross cell mem
A
must be non-ionized
10
Q
to be water soluble drugs must be:
A
ionized
11
Q
strong vs weak acids
A
strong with lower pKa, weak wither higher pKa
12
Q
most drugs are either a?
A
weak acid or base
13
Q
weak acids and bases
A
14
Q
acids, bases: ionization/protonation in basic/acidic pH
A
15
Q
pKa and pH relations in regards to protonation
A
pH = pKa: Protonated equals non-protonated
pH < pKa: Protonated form predominates
pH > pKa: Non-protonated form predominates
16
Q
only what form of a drug can cross the cell mem
A
non-ionized
17
Q
ratio of ionized to non-ionized drug influences what?
A
rate of absorption
18
Q
A
handerson hasselbach, can be used to determine ratio
19
Q
Ion Trapping
A
Because ionized molecules (drugs) can’t cross the membrane, can effectively trap them and enhance excretion
Principle is very useful in toxicology cases
20
Q
acidic vs alkaline urine
A
acidic: can be used to secrete weak basic compounds
alkaline: secretion of weak acidic compounds (ASA)
21
Q
abcesses and LA
A
Acidic environments of abscesses will affect ionization state of local anesthetics
Local anesthetics = basic, high pKA
Abscess = low(er) pH
When a basic drug is in an acidic pH, the protonated and ionized form predominates meaning lesser effect
22
Q
dif permability at dif tissues
A
can vary throughout body, for example: liver and brain
23
Q
Absorption
process of?
what is more important?
directly related factors?
A
Movement of a drug from its site of administration into the central compartment
Process of dissolution and diffusion
Bioavailability more important
SA and concentration both directly related to absorption
24
Q
bioavailabilty (F)
IV?
affected by?
A
Fraction of drug that reaches the systemic circulation intact
Bioavailability of IV = 100%
Affected by route of administration
25
dosage forms of drugs
immeadiate release
extended release
delayed release
26
hepatic extraction ratio
Fraction of drug in blood that is irreversibly removed during one pass through the liver
27
first pass clearence
Extent to which a drug is removed by the liver during its first pass in the portal blood through the liver to systemic circulation
28
result of hepatic clearence and first pass
decreased drug concentration
29
Drugs with low hepatic extraction, first pass clearance?
Drugs with low hepatic extraction will have low first pass clearance, and vice versa
30
First pass effect occurs due to metabolism by/in
Gut bacteria
Intestinal brush border enzymes
Portal blood
Liver enzymes
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low hepatic extraction
Low first pass clearance
Change in hepatic enzymes won’t have significant effect on first pass clearance
32
high hepatic extraction
Hight first pass clearance
Changes in enzyme function will have large effect on first pass effect
can be important for drugs with narrow therapeutic indexes (danger for toxicity with inhibited enzymes)
33
First Pass Effect and Enterohepatic Recirculation
drug recirculates between hepatic and enteroheptic circulation
prolongs half life=kept in system longer
34
basic routes of administration
enteral (GI tract invovled) and parenteral (GI not involved)
35
parenteral drugs avoid what?
first pass metabolism.
36
enteral administration advantages
Most common route
Safest
Easiest
Most economical
37
enteral administration cons
Limited absorption
Emetogenic potential
Subject to first pass
Absorption may be affected by food or other drugs
Irregularities in absorption or propulsion
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parenteral admin pros
Not subject to first pass
Most rapid onset
Ability to titrate
Doesn’t require cooperation
39
parenteral cons
Greater patient discomfort
Requires additional training to administer
Concern for bacterial contamination
Injection-associated risks: Extravasation, Intra-arterial injection, Limb loss
40
oral administration absorption governed by:
Surface area for absorption
Blood flow to site of absorption
Dosage form administered
Ionization status (lipo- vs. hydrophilic)
Concentration at site of absorption
41
enteric coatings
Drugs destroyed by gastric secretions, low pH, or that cause gastric irritation may have these to prevent these actions
Risk of bezoar formation
allows for delayed release of drug
42
parenteral routes
IV
IM
SQ
ID
inhalation
intranasal
epidural
topical
subg
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Intravenous (IV)
F = 100%
Immediate onset, Bypasses GI absorption
Best for emergencies
44
Intramuscular (IM):
F?
what drugs often given this way?
F= 75-100%
Irritating drugs given this route
Not as rapid response as IV
Depot preparations (sustained release) ie., suspensions, ethylene glycol, peanut oil- all slow down absorption.
45
subcutaneous (SQ)
F?
little risk for?
absorption compared to IV/IM
examples?
F=75-100%
Slower absorption than IV or IM
Little risk of intravascular injection
Examples: Insulin, Mechanical pumps, heparin (DVT prophylaxis)
46
Intradermal (ID):
amount of drug?
examples?
Small amounts of drug
Tuberculosis skin test, Local anesthetics
47
Inhalation:
F?
onset?
selectivity/side affects?
examples?
F= 5-100%
Almost as rapid as IV. (Method of abuse)
Delivered directly to lung (good selectivity)- minimal systemic side-effects.
Gases, aerosols of solutions & powders -good for respiratory conditions.
48
Intranasal:
F?
examples?
[]?/V?
F= 5-100%
Vasopressin for tx of diabetes insipidus, calcitonin (osteoporosis).
Method of drug abuse.
must be high [], not much V can be used (1mL)
49
Intrathecal/Epidural:
Subarachnoid space of spinal cord – into CSF (Lumbar puncture- Baclofen in MS, regional anesthetic in delivery, morphine drip)
50
topical
locations?
local or systemic?
avoids/bypasses?
F?
examples?
Skin, oral mucosa, sublingual, rectal (avoids 50% of 1st pass metab)
When local effect is desired-but can provide systemic effects.
Sublingual (100%), rectal (50%) bypasses liver- good bioavailability.
Transdermal Controlled Release- Scopolamine, nitroglycerin, nicotine, estrogens (BCP), fentanyl.
51
subgingival
Perio specific uses: doxycycline(Atridox); minocycline(Arestin)
52
Distribution out of the bloodstream depends on what CV factors?
The administered drug leaves the blood stream and enters other “compartments”
Dependent upon:
Cardiac output
Capillary permeability
Blood flow
53
organ blood flow levels
Kidney: 360 mL/min/100gm
Liver: 95 mL/min/100gm
Heart: 70 mL/min/100gm
Brain: 55 mL/min/100gm
54
compartments of distribution
central: Well perfused organs and tissues (heart, blood, liver, brain, kidney). Drug equilibrates rapidly.
peripheral: Less well perfused organs/tissues (adipose, skeletal muscle, etc.)
special:CSF, CNS, pericardial fluid, bronchial secretions, middle ear
55
factors of drug distribution
Proteins?
concentrations?
Competition?
dx?
levels?
Protein binding: Albumin – acidic drugs, α-glycoprotein – basic
Free vs. bound concentrations
Competition
Disease impact
Drug levels
56
distribution accumulation in tissues
can occur in various locations:Organs, Muscle, Adipose, Bone
could be used for therapeutic advantage
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redistribution of drugs
| example drug?
From site of action into other tissues or sites
propofol: will diffuse across BBB (very lipophilic), redistributes out when [ ] is high (moves back out to low)= short onset/duration
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BBB
Blood brain barrier key to cross:
Lipid solubility
Efflux transporters present
Inflammatory processes can alter structure
59
inflammation at the BBB
occurs with meningitis, will open tight junctions and allow tx with vancomyocin (large molecule unable to get through tight junctions)
60
benadryl at BBB
very lipophilic, can cross easily causing drowsiness
newer forumlas of anit-histamines are less lipophilic and less sedative (zyrtec)
61
Volume of Distribution (Vd)
Volume of fluid in which a drug would need to be dissolved to have the same concentration in plasma.
Doesn’t represent “real” volume
Relationship between dose and resulting Cp
Lipophilic drugs tend to have a larger Vd
Protein bound drugs have lower Vd
62
Drugs with a Vd of:
< 5L:
5-15L:
> 42L:
< 5L: Confined to plasma
5-15L: Distributed to extracellular fluid (RBCs + plasma)
> 42L: Distributed to all tissues in the body, especially adipose
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⬆ Vd = ⬆ likelihood that
drug is in the tissue
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lower Vd= increased likelihood drug is:
confined to the circulatory system
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Metabolism: removal of drug properties?
Removal of drug: Either metabolized/biotransformed and eliminated or excreted unchanged
Must be water-soluble to be removed
Lipid solubility good for absorption and distribution, bad for excretion
66
Process of biotransformation
part of?
Conversion?
where/what does the heavy lifting?
part of metabolism
Converts drugs into polar metabolites
Lipophilic into hydrophilic
Liver does the heavy lifting via P-450
67
which of the CYP big 3 is majority
CYP3A4
68
big 3 of P450 system
CYP3A4
CYP2D6
CYP2C9
69
Cytochrome P-450 system
how many forms?
where?
important ones to know?
70+ forms
Liver, kidney, intestines
Big 3: CYP3A4, CYP2D6, CYP2C9
70
Metabolism – Phase I
Catabolic
Exposes functional group on parent compound
Usually results in loss of pharmacologic activity
Activation of prodrugs occurs this way
71
activation of phenytoin
occurs with phase I metabolism, prodrug
72
kinetics of metabolic P450 Interaction
Substrates, Inhibitors, and Inducers
73
Warfarin (Coumadin®)
+
Sulfamethoxazole/trimethoprim (Bactrim®)
affect with P450
bactrim acts as an inhibitor of P450, which allows increased warfarin meaning increased bleeding possible
74
P450 inducer example
75
Genetic Polymorphisms and CYP
Genetic variability in function of CYP isoenzymes
May be poor metabolizers (PM) or rapid metabolizers (RM), leading to:
Subtherapeutic effect: CYP2D6 PM – codeine, tramadol
Toxicity: CYP3A4 – diazepam, alprazolam (insufficient activity in some Asian populations)
76
Phase II metabolism
occurs when?
interpts variability?
example rxn?
Occurs after functional groups are exposed
Anabolic: adds water soluble molecules to structure
Much less interpatient variability
Major reactions:
Glucuronidation
Glutathione conjugation
Sulfate conjugation
Acetylation
77
can drugs go directly th phase 2? example?
yes, morphine does this
78
morphine metabolism
79
excretion
what? where? what kind of compounds?
Removal of unchanged drug
Kidney, lung, feces – primary routes
Polar compounds > lipid soluble compounds
80
excretion mechanisms at kidney
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
81
excretion at kidney
Dependent upon?
Only what is filtered?
passively reabsorbed?
Alkaline urine and acidic molecules?
Dependent upon renal function
Only unbound drug filtered
Non-ionized weak acids and bases passively reabsorbed
Alkaline urine “traps” ionized, acidic molecules, increases excretion
82
excretion at lungs
primarily what drugs?
affected by?
is drug changed?
Primarily inhaled anesthesia or volatile liquid
Affected by respiratory rate and blood flow
mainly excreted unchanged
83
2nd most common excretion route?
intestines
84
intestinal excretion
what meds?
Unabsorbed orally administered meds
Metabolites excreted in the bile
Un-reabsorbed metabolites secreted into the intestinal tract
85
main factor that determines rate of passive transport
lipid solubility
86
Partition
acids get trapped in basic environments, vice versa
87
Albumin binding
most prominent re: protein binding; binds acidic drugs (~2 molecules/albumin)
88
Extensive protein binding can slow:
Extensive protein binding can slow drug elimination
89
Competition for protein binding can sometimes lead to:
Competition for protein binding can sometimes lead to interactions
90
Drugs with low lipid solubility absorbtion at gut
Drugs with low lipid solubility are not well absorbed from the gut
91
Gut absorption depends on factors such as:
GI motility, GI pH, particle size, interaction w/ gut contents
92
Phase I reactions are:
catabolic; involves oxidation, reduction, and hydrolysis
93
Phase I prepares the drug for:
Phase I prepares the drug for Phase II, can result in more active products; often involves P450 system
94
Phase II reactions are:
Phase II reactions are anabolic, conjugated, leaving inactive and polar product for excretion
95
most drugs filtered where? unless they are?
Unless they’re protein bound, most drugs are filtered through the glomerulus
96
Weak acids and bases are actively secreted into:
Weak acids and bases are actively secreted into the renal tubule
97
Lipid soluble drugs excretion?
Lipid soluble drugs are passively reabsorbed, not efficiently excreted
98
Can use pH partition concept to:
Can use pH partition concept to facilitate excretion of certain drugs
99
which of the CYP big 3 is majority
CYP3A4
