ADME 1&2-HG Flashcards
1
Q
Drugs produce their desired therapeutic effects as a result of what?
A
their presence at appropriate concentration at their site of action
2
Q
Describe the therapeutic window
A
It is the range between maximum tolerable concentration/minimum toxic concentration
and minimum effective concentration
3
Q
The time when the drug begins or onset and termination is called what?
A
the drug’s duration
4
Q
Describe the rising phase and falling phase during duration
A
Rising phase: Abs > Met + Exc
Falling phase: Met + Exc > Abs
Abs=> absorption, Met => metabolism, Exc => excretion
5
Q
Describe the therapeutic index/ratio
A
MTC/MEC
minimum toxic [] / min effective []
6
Q
What is concerned with the disposition (fate) of the drug w/in the body? (how does it get in, where does it go, changes made to it, get out?)
A
pharmacokinetics
7
Q
What determines pharmacokinetics?
A
dynamics of drug…
- absorption
- distribution
- metabolism
- excretion
8
Q
Absorption, distribution, metabolism, excretion are processes that shape the [] vs time profile for drugs. So they govern what?
A
- onset
- intensity
- duration
govern drug action
9
Q
Describe why cell membranes represent a common barrier to drug movement
A
plasma membrane
- consists of phospholipid bilayer with hydrophobic center
- lipid phase contains small aqueous channels or pores
10
Q
What do membrane proteins embedded in the bilayer serve as? What do they elicit?
A
- receptors
- ion channels
- transporters
elicit an electrical and chemical signaling pathways and often targets for drugs
11
Q
Name the 4 characteristics of cell membranes
A
- water permeable
- low MW drugs may pass through pores
- relatively impermeable to proteins and peptides
- lipophilic and non polar and non ionized cmpds may pass through membrane
12
Q
When a drug is taken up into the cell via membrane invaginations, what is the term? (route for uptake of drug into cell)
A
pinocytosis or endocytosis
13
Q
What transports chemotherapeutic agents across the membrane?
A
P-glycoprotein (MDR-1)
14
Q
WRT solubility, describe how a drug passes through a membrane and gets out of it
A
- to cross membrane then it must be soluble in lipid material of the membrane
- soluble in the aqueous phase to get out of the membrane
15
Q
Describe ion trapping at steady state
A
- acidic drugs accumulate on more basic side
- basic drugs accumulate on more acidic side
represents important determinant for where, when, how much absorption, distribution, and excretion takes place for a given drug
16
Q
What factors modify absorption?
A
- route of administration
- circulation to site of absorption
- formulation factors that affect drug solubility
- area of absorbing surface
- membrane thickness
- drug concentration
- physicochemcial factors affecting membrane transport
- transport mechanisms
17
Q
What are the major routes of drug administration? Name specific and general
A
- Enteral - via GI tractoral
- ingestion, sublingual, rectal
Parenteral - not by GI
- IV,
- subQ,
- IM,
- intra-arterial,
- inhalation,
- topical
18
Q
What are the factors affecting the absorption from GI when taking a enteral drug?
A
- Acidic environment of stomach
- gastric emptying time
- intestinal motility and transit time
19
Q
Describe how the acidic environment of the stomach effects enteral drugs
A
- can cause inactivation and degradation of drug
- most acidic drugs will be nonionized in stomach and readily enter systemic circulation
- most basic drugs will be ionized and not absorbed until reached the small intestines
20
Q
Describe gastric emptying time effects of taking enteral drugs
A
generally drugs are better absorbed in small intestine due to surface area than stomach
- increasing gastric emptying will increase drug absorption
21
Q
What effects how much free drug can be found in systemic circulation?
A
- locus of action receptors
- tissue reservoirs
- bound drug
22
Q
What are the mechanisms of biotransport
A
passive diffusion
carrier-mediated biotransport => facilitated diffusion and active transport
23
Q
How do most drugs cross biologic membranes?
A
passive diffusion
24
Q
Rate of diffusion is governed by Fick’s law. What is it? Name the terms
A
-DAK (Cout-Cin) / (^X)
D=> diffusion ocefficient, K=> partition coefficient, A=>Surface area, ^X=>membrane thickness,
Cout-Cin=>concentration gradient, K=>ionization
25
What part of Ficks law is inversely related to the size of the drug?
diffusion coefficient =\> D
26
What part of Ficks law reflects the lipid solubility of the drug mainly through the oil:H20 ratio?
partition coefficient =\> K
27
What part of Ficks law uses a larger contact area that promotes diffusion?
surface area =\> A
28
What part of Ficks law maintains that the thinner the membrane the quicker the diffusion?
membrane thickness (^X)
29
The higher the Cout-Cin value is has what affect on diffusion?
larger gradients promote more drug diffusion
30
What is a major determinant of the ability of a drug to cross membranes? What dictates this?
ionization (K)
pH of environment of bodily fluid in which drug is dissolved in
31
Why are IM drugs generally absorbed well?
due to high blood flow in muscle and the lateral diffusion from the site of injection
32
What are the advantages/disadvantages of IM drugs?
* **Advantages:**
* Avoid first pass metabolism.
* Rapid absorption by simple diffusion through capillary membranes
**Disadvantages:**
* Trained personnel required.
* site of injection will influence the absorption, generally the deltoid muscle is the best site.
* Gender differences (gluteus maximus)
* Pain and tissue damage possible.
* Volume limited to 4-5 ml.
33
What type of drug administration can be used for delivery to specific target organs? What is the drawback of this method?
intraarterial
requires great care and reserved for experts
34
What drug admin involves Injection into the subarachnoid space? Why is this important?
intrathecal
To rapidly bypass the blood-brain barrier and blood-cerebrospinal fluid barrier.
35
For what reasons would intrathecal admin be done?
Can be used for local effects- spinal anesthesia
Also used for treatments of acute CNS infections.
Ex. meningitis
36
What drug admin is for gaseous and volatille compounds? Describe what is used for the different effects
inhalation
* **Local effect** - bronchodilators
* **Systemic effect** - general anesthesia
37
What are important characteristics of inhalation?
Rapid absorption =\> Absorption of gases is relatively efficient due to large alveolar surface area and extensive pulmonary circulation
Important route for certain drugs of abuse
Allergic reaction is a concern
38
What type of drug admin that is generally used for local effect but all can produce systemic effects as well?
topical
39
Describe the percutaneous effects and formulation of topical drug admin. give examples
* formulated as creams or ointments and applied to skin for local effect.
* useful in patches for other drugs that are highly lipid soluble and can pass through the epidermis.
Ex: in patches include, fentanyl (narcotic), nicotine, nitroglycerine, hormone (birth control) patches.
40
Give effect of topical drug admin on mucous membrane
Rapid absorption.
Can lead to systemic toxicity
41
Describe how topical drugs effect the eye
administered directly to the cornea for local effect.
42
Where can topical drugs be administered?
1. percutaneous
2. mucous membrane
3. eye
43
What are the 2 major factors affecting drug distribution?
rate of distribution
extent of distribution
44
What are the characteristics of rate of distribution?
* Cardiac output and regional blood flow
* Tissue Volume
* Capillary permeability
45
What are the characteristics of the extent of distribution?
* Physicochemical factors affecting transport across membranes
* Plasma protein binding
* Intracellular binding
* Permeability and or transport characteristics of specific tissue membranes
46
T/F The greater the blood perfusion rate the more drug is distributed to an organ.
true
47
Where is the total blood flow the greatest?
Where are the highest perfusion rates?
* Total blood flow is greatest to brain, kidneys, liver, and muscle
* highest perfusion rates to brain, kidney, liver, and heart.
48
Why are capillaries quite permeable and provides a large surface area for drugs to penetrate across?
Capillaries are typically lined by a single layer of endothelial cells which have fenestration (or spaces) between them
49
How do drugs cross the capillaries?
via filtration or passive diffusion
50
What are major factors controlling transcapillary movement of drugs and how are they transported wrt weight?
lipid solubility and molecular size
Transport of substances \> 25 kD is largely mediated by pinocytosis
51
There are two deviations to the typical capillary structure which result in variation from normal drug tissue permeability. Name and describe them
* **Permeability is greatly increased in the renal capillaries** by large spaces between endothelial cells. This results in more **extensive distribution of many drugs out of the capillary bed by filtration**.
* In contrast, **brain capillaries have tight junctions between cells which are relatively impermeable and therefore restrict the transfer of molecules from blood to brain tissue (Blood-brain barrier)**. Lipid soluble compounds can be readily transferred but the transfer of polar substances is severely restricted.
52
What can limit distribution of free drug to its site(s) of action?
Extensive binding to plasma protein will cause drugs to stay in the central blood compartment
53
Although drugs may be bound to many macromolecules, where is the most common? Which specifically is this normal for?
binding to plasma protein is the most common.
albumin
54
Acidic drugs commonly bind to what? basic drugs often bind to what?
albumin
globulins
55
T/F Drug binding to plasma proteins is generally specific.
false, it is nonspecific
56
T/F drug binding is a reversible process
How is this mediated?
true
dynamic equilibrium bw bound and unbound drug
57
What is the total fraction of drug bound is determined by what?
1. the drug concentration
2. its affinity for binding sites
3. the number of binding sites
58
What is the major determinant of the fraction of drug bound at low drug concentrations?
The affinity of binding sites
59
What happens to the number of binding sites become at high drug concentrations?
limiting variable
60
Drug binding to plasma proteins is what type of process?
saturable and nonlinear process
61
The higher the oil:H2O ratio then what does it have to do with the diffusion?
easier to diffuse
62
If a drug is too large and/or too polar to diffuse across a lipid membrane, then how will it enter the cell?
These molecules enter cells by means of a carrier that facilitates their movement down a concentration gradient across the membrane.
63
Tell yes/no if facilitated diffusion uses movement against a [] gradient, utilization of energy, exhibits saturation
movement against a [] gradient =\> no
utilization of energy =\> no
exhibits saturation =\> yes
64
Tell yes/no if active transport uses movement against a [] gradient, utilization of energy, exhibits saturation
movement against a [] gradient =\> yes
## Footnote
utilization of energy =\> yes
exhibits saturation =\> yes
65
Carrier-mediated transport is often coupled to the transport of other substances (most notably ions). What are the 2 types of this?
cotransported
countertransported.
66
What is a means to explain the influence of pH and the pKa on the extent of the ability for a drug to cross the plasma membrane?
What does this assume?
pH - parition theory
assumes that drugs are absorbed only when they are non ionized and therefore have a higher lipid solubility
67
The driving force for drug movement across a membrane is what?
the concentration gradient that exist for the nonionized form of the drug
drug will move to diminish the concentration gradient until the nonionized drug concentrations on 2 sides are equal
68
Most drugs are what? Why is this important?
weak electrolytes
exists in charged and uncharged forms in solution
69
The presence of free functional groups such as carboxyl and amino groups in general determines what?
whether they are acids or bases
70
Describe the equilibrium for acids and bases
HA \<=\> A- + H+
BH+ \<=\> B + H+
71
What is the Henderson-Hasselbalch equation?
Ka = [A-] [H+] / [HA]
72
What is the pH equation for acids and bases
pH = pKa + log ([A-] / [HA])
pH = pKa + log {[B] / [BH+] }
73
T/F weak acids must be nonionized to cross the membrane
true
74
T/F Weak bases must be ionized to cross the membrane
75
What describes the rate at which a drug leaves its site of administration and the extent to which that occurs?
absorption
76
Describe bioavailability
fractional extent to which a given dose of a drug reaches either its site of action or a biological compartment from which the drug has free access to its site of action
value ranges from 0-1
77
Describe the path to circulation of oral drugs. What role does the liver have on the drug? How does it affect bioavailability?
Drugs administered orally, pass through the GI tract. Where they are directed to the liver via portal circulation.
Because most drugs are primarily metabolized (and inactivated) in the liver, this tends to reduce the free concentration of drug available to the systemic circulation.
**This phenomenon is known as first pass metabolism and severely limits bioavailability.**
78
Since many drugs are given in solid form, they must be dissolved before absorption takes place. Describe this process from solid to blood
**Solid**
dissolution in GI tract
**solution**
absorption
**Blood**
79
If absorption is slow relative dissolution then all we are concerned with is what?
absorption.
80
if dissolution is the slow, rate determining step (the step controlling the overall rate) then what controls the overall process? When is this a common problem?
factors affecting dissolution will control the overall process.
common which have low solubilty or given at high dose
81
In many instances drug formulation is manipulated to modify absorption for therapeutic advantage. Give 4 examples
1. Delayed or sustained release tablets (enteric coatings)
2. Depot preparations
3. Rapid release formulations (gel caps)
4. Transdermal patches
82
Of the GI tract, give the order starting with smallest pH
stomach \< esophagus \< duodenum \< buccal \< small/large intestine
83
Of the GI tract, which have membranes other than normal
Buccal is thin
esophagus is very thick
84
T/F Of the GI tract, Blood supply is good in all area
85
Of the GI tract, which organs have small surface area or large surface area
Small =\> buccal, esophagus, stomach
very large =\> duodenum, small intestine
86
Of the GI tract, give the order starting with shortest transit time
duodenum \< buccal = esophagus \< stomach \< small intestine \< large intestine
87
Of the GI tract, which are by-passed
buccal and large intestine
88
What are the factors affecting gastric emptying?
* volume of ingested material
* type of meal
* body position
* drugs
89
The contractions of the small intestine regulate the time the food is in contact with the reabsorptive epithelium. Describe the ratio
Faster contraction, faster transit time.
90
What type of drug admin is Formulated in a rapidly dissolving tablet, may be placed under the tongue where the rich blood supply promotes a rapid absorption? Give advantages/disadvantages
sublingual
**Advantages:**
* First pass- portal vein is bypassed. thus bioavailability is higher.
* Rapid absorption-Because of the good blood supply in the mouth.
* Drug stability- pH in mouth is relatively neutral.
**Disadvantages:**
* Holding the dose in the mouth is inconvenient.
* Useful when the drug dosage is small.
91
What type of drug admin is useful when drugs are not well tolerated via oral administration, and can be formulated in suppository form?
## Footnote
rectal
**Advantages:**
* useful in children, unconscious or vomiting patients.
* First pass metabolism does not occur.
**Disadvantages:**
* Absorption is erratic
* Not well accepted
92
If speed of drug delivery is an issue, as it may be in emergency medicine, this is the most rapid drug delivery method. What are the advantages/disadvantages?
IV
* **Advantages:** Patient compliance
* Rapid and complete delivery (high bioavailability)
* No first pass effect
* Flexible rate of administration
* Veins relatively insensitive -to irritation by drugs
* **Disadvantages:**Expensive -
* Sterility, pyrogen testing and larger volume of solvent means greater cost for preparation, transport and storage.
* Requires trained personnel.
* No Recall- once administered drug can not be removed.
* Risk of infection.
* Dangerous- toxicity can be a problem with rapid drug administrations
93
What drug admin involves administration of the drug dose just under the skin? Name advantages/disadvantages
Sub Q
* **Advantages:**Bypass first pass metabolism
* Absorption can be varied.
* Rapid from aqueous solution.
* Slow and sustained from repository or insoluble preps
* Can be given by patient. e.g. insulin.
* **Disadvantages: **Can be painful
* Irritant drugs can cause local tissue damage
* Not suitable for large volumes. Maximum of 2 ml injection thus often small doses limit use.
94
Slight changes in the binding of highly bound drugs can result in significant changes in clinical response or cause a toxic response. Why?
free drug in plasma which equilibrates with the site of pharmacological or toxic response, a slight change in the extent of binding, such as 99 to 98 % bound, which can result in an almost 100% change in free concentration, can cause very significant alteration in response
95
What tends to be of greatest concern for drugs with a narrow therapeutic window and when dosing regimens or elimination is altered?
slight changes in the binding of highly bound drugs
96
Many drugs accumulate in tissues at higher concentration than those found in extracellular fluids and blood. What is the cause of this?
cause of drug accumulation in tissues is often arises from active transport or binding.
97
Tissue binding usually arises through interactions with what?
proteins &/or phospholipids
(either extracellular or intracellular).
98
T/F Binding to proteins and/or phospholipids is generally reversible and saturable.
What is it dependent on?
true
dependent on the concentration, affinity, and binding capacity of the tissue
as well as the physicochemical properties of the drug.
99
T/F bound and ion trapped drugs represent a reservoir of drug that can serve to prolong the duration of response.
true
100
What are relevant drug reservoirs? give a short description
1**. stomach- traps basic drugs due to ionization **
2. **Albumin- limits the availability of free drug and thus alters kinetics**
3. **Tissue**- Liver concentrates drugs such as quinacrine (active transport)
- Thyroid concentrates iodine - Bone- tetracycline and other divalent chelating compounds can accumulate in bone. Additionally. Heavy metals may accumulate in bone.
4. **Fat**- lipid soluble compounds can readily partition into fat tissue which then acts as a storage depot for compound prolonging its action. This represents an i**mportant source of interpatient variability.**
101
Termination of a drugs effect usually occur by what?
metabolism and excretion
also result from redistribution from the site of action to other tissues or to bound proteins
102
How does redistribution terminate the effect of a drug?
blood flow differences between tissues or organs that see the drug initially
103
What are the drug distrubtion patterns?
1. The drug may remain largely within the vascular system.
2. The drug may become uniformly distributed throughout the body water,
3. concentrated specifically in one or more tissues that may or may not be the site of action
4. exhibit a non-uniform distribution in the body with variations that are largely determined by the ability to pass through membranes and their lipid/water solubility.
104
What is the most common drug distribution pattern?
pattern 4: non-uniform distribution in the body
105
What is a clinically relevant parameter that indicates the apparent body volume that a given drug is located within and is generally indicative of the compartment to which it distributes? What is the formula for it?
Volume of distribution (Vd)
it is a diagnostic tool
Vd = amount of drug administered / plasma drug concentration
