Drug dispostion/ADME Flashcards
1
Q
Drug Disposition
A
The study of movement of drugs across biological membranes in the body from the time of absorption until elimination.
2
Q
What does ADME stand for?
A
- Absorption
- Distribution
- Metabolism
- Elimination
3
Q
What are some mechanisms that substances can be transported across a cell membrane?
A
- Simple/Passive diffusion
- Facilitated diffusion
- Active transport
- Pinocytosis
4
Q
Passive diffusion is movement ____ (against/with) a concentration gradient.
A
With a concentration gradient.
5
Q
What kind of transport includes Paracellular movement and transmembrane movement?
A
Passive Diffusion
6
Q
What type of movement is through aqueous channels or specialized intercellular junctions?
A
Paracellular movment (a type of passive diffusion)
7
Q
What type of movement is diffusion through lipid membranes and aqeous protein channels in the cell membrane?
A
Transmembrane movement (a type of passive diffusion)
8
Q
What is the lipid/water partition coefficient?
A
The relative solubility in liquid of a substance
9
Q
The _____ (higher/lower) the lipid solubility the easier it can cross cell membranes.
A
higher
10
Q
What is the diffusion coefficient?
A
Measure of the diffusional mobility of a particular molecule.
11
Q
What three things does the diffusion coefficient depend on?
A
- Molecular size
- Molecular conformation
- Degree of ionization
12
Q
_____ (smaller/larger) molecules diffuse more easily
A
Smaller molecules
13
Q
______ (ionized/non-ionized) molecules cross lipid membranes more easily.
A
Non-ionized
14
Q
Facilitated diffusion is movement ____ (with/against) a concentration gradient
A
Movement with a concentration gradient
15
Q
Is energy required for facilitated diffusion?
A
No
16
Q
Facilitated diffusion is _____ and _____ mediated.
A
Carrier and channel mediated
17
Q
Is facilitated diffusion saturable?
A
Yes
18
Q
What is it when the transfer of substances across the membrane involves attachment to a specific macromolecular carrier?
A
Carrier-mediated
19
Q
What is it when the transport across the membrane involves opening of ion channel proteins?
A
Channel-mediated
20
Q
What two types of transport are carrier-mediated and are saturable?
A
Facilitated diffusion and Active transport
21
Q
What are three types of Active transport?
A
- Primary Active transport
- Secondary active transport
- Drug efflux (P-glycoprotein system)
22
Q
Active transport is movement _____ (with/against) the concentration gradient.
A
Against
23
Q
Does active transport require energy?
A
Yes
24
Q
What type of active transport is directly supplied by ATP?
A
Primary active transport
25
What type of transport uses ATP after it is used to create an electrochemical gradient (stored energy)?
Secondary active transport
- involves symporter and antiporter
26
What type of transport removes drugs after being absorbed into specific cells or tissue sites?
Drug Efflux
27
The P-glycoprotein system is an expression of what gene?
ABCB-1 gene
28
What are some examples of ways the P-Glycoprotein system works?
- Chemotherapy from cancer cells
- Antibiotics from bacterial cells
- Certain drugs from CNS endothelial cells as part of the blood-brain barrier
29
What transport is a type of endocytosis?
Pinocytosis
30
Does pinocytosis require energy?
Yes
31
What is the process of pinocytosis?
Drugs bind to the surface of the membrane then invaginates and interiorizes the drug
32
Membranes are more permeable to ____ (ionized/non-ionized) forms of drugs.
Non-ionized
33
What two things does ionization depend on?
pKa of the drug and the pH of the medium on either side of the membrane
34
When ___ = ____, the drug will be 50% ionized (N:I = 1:1)
pKa = pH
35
Acidic drugs are ionized _____ (acidic/basic) environments
basic environments (high pH)
36
_____ (acidic/basic) drugs ionize in acidic environments.
Basic drugs
37
Do y'all remember how to distinguish weak bases and weak acids on a graph?
Weak base -> Drop that base
Weak acid -> High on acid
38
Weak acid formula for the Henderson-Hasselbalch equation:
Too difficult to type the whole thing out, but remember it is NON-ionized/ionized
39
Weak base formula for the Henderson-Hasslebalch equation:
Too difficult to type the whole thing out, but remember it is ionized/NON-ionized
40
What type of environment is a weak acid absorbed? Sequestered?
Absorbed in an acidic environment
Sequestered in an alkaline environment
41
What type of environment are weak bases absorbed? Sequestered?
Absorbed in an alkaline environment
Sequestered in an acidic environment
42
Don't forget to do some math problems!!
:)
43
What is the movement of the drug from the site of administration into the blood?
Absorption
44
What is the rate limiting step of Absorption?
Dissolution
45
What three things is the solubility determined by?
- Molecular structure
- Ionization
- Preparation
46
Once ____ occurs, then the drug can be absorbed.
Dissolution
47
Factors that can affect absorption that are related to the DRUG:
- Molecular size (small absorbs better)
- Rate of dissolution (liquids and powders dissolve faster than solids)
- Degree of ionization (less ionized -> more absorption)
- Concentration at the absorptive site (higher concentration -> more absorption)
- Route of administration
(IV> IM> SC> PO>topical, generally)
48
Factors that can affect absorption that that are related to the ANIMAL:
- Blood flow (more blood flow -> more absorption)
- Absorbing surface area (More surface area -> more absorption)
- Other: connective/scar tissue, species, fasted vs fed, individual variation
49
What is bioavailability?
The fraction of a given dose that ends up in systemic circulation
50
What type of administration technically does NOT have an absorption phase?
IV Route
51
IV route is considered to represent ____ (%) bioavailibility.
100 %
52
_____ use generally means that the drug is not intended to be absorbed systemically and is meant to exert an effect locally.
Topical
53
What are some areas that drugs can be used topically?
Skin, intramammary, intrauterine, conjunctival, nasal, inhaled, epidural, intravesicular, intraplueral
54
_____ use generally means that the drug is intended to reach the bloodstream.
Systemic
55
If a drug is not given IV, then it must undergo absorption to get from the site of administration to the blood stream. What are some routes that this occurs?
- Enteral
| - Parenteral
56
Enteral
GI tract
57
What are some factors that can affect the rate of absorption in the gut?
- Presence/absence of food
- Presence of bile
- interaction with gut microbes
- Location in the GI tract
58
Where does most absorption in the GI tract take place?
Small Intestine (thank you Reich)
59
When a drug enters the GI tract, how may it act?
- Interact with material already present
- Get into solution with gastric juice
- Be carried through the Gi tract
- Interact with microbes
- Traverse the enteric mucosa to each sub-mucosa capillaries and the systemic circulation
60
In what area of the body if a drug is given will it bypass the portal vein?
Oral cavity, sublingual absorption
61
Disintegration
Physical dispersion of a solid dosage form
62
Dissolution
Drug molecules enter the solution
**rate limiting step of absorption**
63
Where in the body are weak acids more non-ionized and therefore better absorbed?
In the stomach (acidic environment)
64
Where in the body are weak bases more non-ionized and therefore better absorbed?
Small intestine
65
What is the route for First-pass metabolism?
Drugs absorbed distal to the oral cavity and proximal to the rectum enter the portal vein and then into the liver wehre biotransformation may occur
66
A drug that undergoes first pass metabolism will have a _____ (higher/lower) bioavailability.
Lower
67
Pre-systemic metabolism
Any metabolism that occurs before the drug goes into systemic circulation
* Includes first pass metaboism
68
What is the route for Enterohepatic recycling?
Drug is absorbed into portal circulation, metabolized and excreted in bile, then reabsorbed in the small intestine again.
69
A drug that undergoes enterhepatic recycling will have a _____ (longer/shorter) half-life
Longer
70
When bile emulsifies fat soluble drugs, what does it form?
Micelles
- otherwise, these drugs could not diffuse in the aqueous intestinal environment.
- Good to give these drugs with a MEAL to stimulate bile secretion
71
What drug administration will often avoid first-pass metabolism?
Buccal/sublingual (different than oral)
72
Rectal drug administration
- used in animals who are unable to take oral meds
- First- pass metabolims may or may not be redcued
- Absorption may be erratic
73
Parenteral
Basically any route other than enteral
Commonly used for IV, IM, SC, IP
74
Drugs given parenteral are expected to get into the systemic circulation _____ (faster/slower) than oral and topical use.
Faster
Generally the barriers to absorption via these routes is less than with oral and topical use
75
Which methods of parenteral administration generally involve and invasive procedure to inject a drug?
IM
SC
IP
76
Generally SC is ____ (faster/slower) than IM
slower
77
Other (non-injectable parenteral routes)
Transdermal/percutaneous
| Respiratory
78
Which parenteral route is relatively impermeable to aqueous solutions?
Skin
- if drug is inteded to be given this way, then it may need to be manipulated to increase lipphilicity, increase local humidity, or provide a very high local concentration
79
What layer of skin is the rate- limiting barrier for transdermal absorption?
Stratum corneum
80
____ (upper/lower) respiratory tract is less useful for absoprtion
Upper respiratory tract
81
Drugs used topically are generally intended to have _____ (high/low) absorption into systemic circulation.
Minimal/low absorption
82
Distribution
Transfer of drugs from the bloodstream to tissues around the body
83
Compartments
Groups of tissues/fluids for which the rates of update/clearance of a drug are similar
84
Factors affecting distribution:
- Physiochemical properties of the drug (pKa, Solubility, molecular weight)
- Concentration gradeitns between blood and tissue
- Ratio of blood flow to tissue mass (lower blood flow, lower surface area, less influx of drugs)
- Affinity of the drug
85
The _____ properties of the drug will determine how much and how fast it will cross membranes
physiochemical
86
Apparent Vd (L/kg)
The apparent volume necessary to contain the entire amount of a drug if it were evenly distributed throughout the body at the concentration present in plasma
87
Specialized barriers:
```
BBB
ocular
prostatic
testicular
synovial
mammary
placenta
```
88
Which organs have high blood flow and therefore have a potential for greater drug distribution?
Brain, heart, kidneys
Intermediate: liver, skin
Low: Muscles, fat, bone
89
What kind of drugs are more likely to get into the CNS?
Lipophillic drugs
90
While the drug is bound to plasma protein, is the drug active or inactive?
Drugs are inactive when bound
91
What do acidic drugs typically bind to?
Albumin
92
What do basic drugs typically bind to?
beta-globulins and glycoproteins
93
Is binding a saturable process?
Yes
94
When does drug displacement occur?
When two highly protein bound drugs are given at the same time. This leads to an increased amount of active (free) drug in circulation and possible toxicity
The drug displaced will depend on the relative affinity of each of the drugs
95
Is binding generally reversible?
Yes
96
T/F: the more highly protein bound a drug is, the more significant even minor changes in protein binding can be.
T
97
Metabolism
Chemical alteration of the durg by different body tissues (biotransformation)
98
Why are drugs typically changed (metabolized)?
So they can be eliminated more easily by the kidney
99
What is the process of making a drug inactive and easier to excrete?
Bioinactivation
100
What is the main organ for drug biotransofrmation?
The liver
101
What is bioactivation?
When an inactive substance (prodrug) is converted to an active metabolite
102
What are the three ways of bioactivation?
- Inactive drug (prodrug) is converted to an active metabolite
- Active drug is converted to active metabolite
- Non- toxic substance can be converted to a toxic metabolite (lethal synthesis)
103
What are the two phases of liver metabolism?
```
Phase I (non- synthetic)
Phase II (synthetic)
```
104
What are the three types of Phase I (nonsynthetic) liver metabolism?
Oxidative (most common)
Reductive (rare)
Hydrolytic
105
Where in the liver do phase I and phase II liver metabolism occur?
Microsomal (Smooth ER)
| Non-microsomal (cytoplasm or mitochondria)
106
Where do most phase I reactions take place?
in hepatocytes
107
What is the most important enzyme attach to the Smooth ER and occurs in phase I reactions?
Cytochrome P450 (mixed function oxidase system)
some non-microsomal enzymes may also contribute to some phase I reactions
108
What happens to a drug that undergoes a phase I reaction?
- inactivated
- converted to active metabolite
- converted to a toxic metabolite (lethal synthesis)
- produce a product that undergoes a phase II reaction
109
What happens during a phase II reaction?
Combination of a molecule with a reactive group conjugates with a substituent group rendering a final metabolite that is typically inactive and water soluble.
110
What is the most common reaction in Phase II?
Glucuronidation
*** Cats are deficient in glucuronidation
111
Is conjugation reversible?
Yes
112
What are some factors that affect liver metabolism?
- Age
- Individual/breed
- Body temperature
- Liver disease
- Hepatic blood flow
- plasma protein binding
- Route of administration
113
What are the only kind of enzymes that are induced?
microsomal
114
Enzyme induction
Drugs that increase synthesis, decrease degradation, active pre-existing compounds.
115
Enzyme inhibition
Drugs that decrease the capaccity of metabolic enzymes
116
Excretion
Removal of the drug (and metabolites) from the body
117
What organ does excretion primarily occur?
Kidney
118
What comprises renal excretion?
Glomerular filtration, active tubular secretion. tubular re-absorption
** Combined these are the TOTAL RENAL EXCRETION
119
GFR
Glomerular filtration rate
- a passive process that depends on systemic blood pressure and renal blood flow
* Hopefully y'all remember your Reich
120
What three factors can significantly affect GFR?
Electric charge (large, negative charged drugs are repelled)
plasma protein binding (only unbound molecules can be filtered)
Molecular size (smaller are more filterable)
121
Where does active tubular secretion occur?
REICH FOR THE WIN
proximal convoluted tubule.. duh
122
Are drugs moved against a concentration gradient in active tubular secretion?
Yes, yes they are. This uses energy dependent transporters.
123
Active tubular secretion allows what kind of molecules to be transported?
Ionized
124
Is active tubular secretion sensitive to protein binding?
Nope
125
What kind of transporters exist to move organic bases? Organic acids?
Organic cation transporters move bases
Organic anion transporters move acids
126
Where does tubular reabsorption occur?
In the proximal and distal convoluted tubules, of course
127
What kinds of drugs are reabsorbed?
Lipid soluble, non-ionized drugs
128
Acidification or urine (ammonium chloride or methionine) will cause ____ (weak acid/weak base) drugs to be inionized and ENHANCE their excretion.
Weak basic
129
Alkalinization of urine (sodium bicarbonate or potassium citrate) will cause ______ (weak acid/weak base) drugs to be ionized and ENHANCE their excretion.
weak acids
130
Factors affecting renal excretion:
- Age of patient
- heart/kidney/liver disease
- urine pH
- Drug factors such as: MW, charge, protein binding, lipid solubility, pKa, concentration of drug
131
Hepatic excretion
active transport of drugs and/or conjugates from the hepatic sinusoids to the bile canaliculi
132
What kind of drugs are more easily excreted in bile?
MW > 300 and a polar group attached
133
Fecal excretion
any drugs excreted into bile and not reabsorbed
134
What is the most significant impact of drug excretion in milk or eggs?
Drug residues when these are food products
- for this reason there are withholding times for drug therapy
135
What kind of drugs suffer ion trapping in milk?
Weak basic drugs
