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CMOD Week 5 > ADME 1 > Flashcards

ADME 1 Flashcards

1
Q

What size drugs can pass through the pores of cell membranes?

A

100-200 Da, however they are relatively impermeable to proteins and peptides.

Lipophilic and nonpolar and non ionized compounds may also pass through the membrane

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2
Q

Drugs can cross biological membranes via what two processes?

A

A. Passive Diffusion

B. Carrier-Mediated Biotransport

  1. Facilitated diffusion
  2. Active transport
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3
Q

How do most drugs cross biological membranes?

A

By passive diffusion. Diffusion occurs when the drug concentration on one side of the membrane is higher than that on the other side. Drug diffuses across the membrane in an attempt to equalize the drug concentration on both sides of the membrane.

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4
Q

What is Fick’s Law of diffusion?

A

Diffusion= -DAK(Cout-Cin)/deltaX,
where,

D= diffusion coefficient (inversely proportional to drug size, i.e. large drugs have small D, small drugs have large D)

A= surface area

K= lipid solubility of drug (oil:H2O) (high K= more transport because it will be soluble in the membrane)

deltaX= membrane thickness

Ionization (affects K): is a major determinant of the ability of a drug to cross membranes. It is dictated by the environment (pH) of the bodily fluid in which the drug is dissolved in.

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5
Q

T or F. Both facilitated and active diffusion are saturable

A

T. Both involve enzymes

NOTE: Carrier-mediated transport is often coupled to the transport of other substances (most notably ions). These may be either co- transported or counter-transported

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6
Q

What is an example of a molecules that is transported via facilitated transport?

A

riboflavin, vitamin B12

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7
Q

What is an example of a molecules that is transported via active transport?

A

5-flurouracil

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8
Q

What is the pH - partition theory?

A

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. This theory assumes that drugs are absorbed only when they are non ionized and therefore have a higher lipid solubility.

The driving force for drug movement across a membrane is the concentration gradient that exist for the nonionized form of the drug. Therefore, the drug will move to diminish the concentration gradient until the nonionized drug concentrations on the two sides are equal.

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9
Q

T or F. Most drugs are weak electrolytes.

A

T. Thus, they can exists in charged and uncharged forms in solution. The presence of free functional groups such as carboxyl and amino groups in general determines whether they are acids or bases.

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10
Q

What is ion trapping?

A

Based on the Henderson-Hasselbach Equation:

At steady-state-
1) acidic drugs will accumulate on the more basic side of the membrane.

2) basic drugs will accumulate on the more acidic side of the membrane.

This phenomenon is known as ion trapping and represents an important determinant for where, when, and how much absorption, distribution, and excretion takes place for a given drug.

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11
Q

What is Absorption?

A

Describes the rate at which a drug leaves it site of administration and the extent to which that occurs.

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12
Q

What is Bioavailability?

A

Clinically relevant parameter which refers to the 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. Bioavailability values range from 0 to 1.

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13
Q

What is first pass metabolism?

A

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

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14
Q

What are some factors that modify absorption?

A
  1. Route of administration
  2. Circulation to the site of absorption.
  3. Formulation factors that affect drug solubility
  4. Area of the absorbing surface
  5. Membrane thickness
  6. Drug concentration
  7. Physicochemical factors affecting membrane transport.
  8. Transport mechanisms
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15
Q

Whata re the major routes of administration?

A

External-via the GI tract and

parenteral- not via the GI tract

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16
Q

What are some enteral routes?

A

oral ingestion, sublingual, rectal

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17
Q

What are some parenteral routes?

A
  1. intravenous (IV)
  2. subcutaneous
  3. intamuscular
  4. intraarterial
  5. inhalation
  6. topical
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18
Q

Many drugs are given in solid form. Therefore, they must be dissolved before absorption takes place. If absorption is slow relative dissolution then all we are concerned with is absorption. However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process. This is a more common problem with drugs which have low solubility (below 1g/100 ml) or which are given at a high dose, e.g. griseofulvin.

A

Many drugs are given in solid form. Therefore, they must be dissolved before absorption takes place. If absorption is slow relative dissolution then all we are concerned with is absorption. However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process. This is a more common problem with drugs which have low solubility (below 1g/100 ml) or which are given at a high dose, e.g. griseofulvin.

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19
Q

In many instances drug formulation is manipulated to modify absorption for therapeutic advantage.

A

These include:
Delayed or sustained release tablets (enteric coatings)
Depot preparations
Rapid release formulations (gel caps) Transdermal patches

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20
Q

What are the main advantages of oral ingestion?

A

Safe- generally considered painless, easy to take.

Cheap - no need to sterilize (but must be hygienic), compact, multi-dose bottles, automated machines produce tablets in large quantities.

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21
Q

What are the main disadvantages of oral ingestion?

A

Slow onset- generally > 1 hr.
Not useful for emergencies.
Patient noncompliance
Low bioavailablity- due to first pass metabolism

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22
Q

Describe the pH of the main parts of the GI tract and the preferred drug acidity for absorption at these points?

A 
Buccal- 7; neutral
Esophagus- 5-6; weakly acidic
Stomach- 1-3; weakly acidic
Duodenum- 5-6.5; weakly acidic
Small intestine- 8; basic
Large intestine- 8; basic
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23
Q

Which parts of the GI tract can bypass the first effect metabolism?

A

buccal and large intestine

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24
Q

What are some factors that affect absorption from the GI tract?

A
  1. Acidic environment of stomach:
    - can cause inactivation and degradation of drug. Ex: Penicillin G
    - most acidic drugs will be nonionized in the stomach and thus will readily enter the systemic circulation, while basic drugs will be ionized and not absorbed until they reach the small intestines.
  2. Gastric emptying time:
    - Generally drugs are better absorbed in the small intestine (because of the larger surface area) than in the stomach, therefore increasing gastric emptying will increase drug absorption.

Factors affecting gastric emptying:
Volume of ingested material: Bulky materials tend to empty more slowly than liquids.
Type of meal: Fatty foods decrease gastric emptying
Body position: Lying on the left side decreases gastric emptying.
Drugs: Anticholinergics, Narcotics and Analgesics, reduce gastric emptying.

  1. Intestinal motility and transit time. The contractions of the small intestine regulate the time the food is in contact with the reabsorptive epithelium. Faster contraction, faster transit time
25
Q

How does sublingual administration work?

A

Formulated in a rapidly dissolving tablet, may be placed under the tongue where the rich blood supply promotes a rapid absorption.

26
Q

What are the main advantages of sublingual administration?

A

First pass- portal vein is bypassed. thus bioavailability is higher. Ex: Nitroglycerin
Rapid absorption-Because of the good blood supply in the mouth. Drug stability- pH in mouth is relatively neutral.

27
Q

What are the main disadvantages of sublingual administration?

A

Holding the dose in the mouth is inconvenient. Useful only when the drug dosage is small.

28
Q

How does subrectal administration work?

A

This route is useful when drugs are not well tolerated via oral administration, and can be formulated in suppository form.

29
Q

What are the main advantages of subrectal administration?

A

useful in children, unconscious or vomiting patients. First pass metabolism does not occur.

30
Q

What are the main disadvantages of subrectal administration?

A

Absorption is erratic Not well accepted

31
Q

What are the main advantages of IV administration?

A

If speed of drug delivery is an issue, as it may be in emergency medicine, this is the most rapid drug delivery method. Good for patients with seizures, life or death.

Patient compliance
Rapid and complete delivery (high bioavailability) No first pass effect
Flexible rate of administration
Veins relatively insensitive -to irritation by drugs

32
Q

What are the main disadvantages of IV administration?

A

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

33
Q

What are the main advantages of subcutaneous administration?

A

Bypass first pass metabolism
Absorption can be varied.
Rapid from aqueous solution.
Slow and sustained from repository or insoluble preps
Can be administered by patient. e.g. insulin.

34
Q

What are the main disadvantages of subcutaneous administration?

A

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.

35
Q

What are the main advantages of intramuscular administration?

A

Drugs are generally absorbed well due to high blood flow in muscle and the lateral diffusion from the site of injection.

Avoid first pass metabolism.
Rapid absorption by simple diffusion through capillary membranes

36
Q

What are the main disadvantages of intramuscular administration?

A

Trained personnel required.
The site of injection will influence the absorption, (generally the deltoid muscle is the best site.)
Gender differences in absorption (gluteus maximus)
Pain and tissue damage possible.
Volume limited to 4-5 ml.

37
Q

When is an intraarterial administration appropriate?

A

Can be used for delivery to specific target organs. However, this route requires great care and is reserved for experts.

38
Q

When is an intrathecal administration appropriate?

A

Injection into the subarachnoid space.
To rapidly bypass the blood-brain barrier and blood-cerebrospinal fluid barrier.
Can be used for local effects- spinal anesthesia
Also used for treatments of acute CNS infections.
Ex. Meningitis

39
Q

Inhalation drugs

A

Not done at home

For administration of gaseous and volatile compounds.

Local effect - bronchodilators
Systemic effect - general anesthesia

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

best route for a general anesthetic

40
Q

Topical drugs

A

generally used for local effect but all can produce systemic effects as well.

Percutaneous: Drugs may be formulated as creams or ointments and applied to skin for local effect. Also, may be useful in patches for other drugs that are highly lipid soluble and can pass through the epidermis. Examples of drug formulations in patches include, fentanyl (narcotic), nicotine, nitroglycerine, hormone (birth control) patches. All systemic

Mucous membrane: Rapid absorption. Can lead to systemic toxicity

Eye: Many drugs are administered directly to the cornea for local effect.

41
Q

What factors affect the rate of drug distribution?

A

Cardiac output and regional blood flow
Tissue Volume
Capillary permeability

42
Q

T or F. The greater the blood perfusion rate the more drug is distributed to an organ.

A

T.

43
Q

Where is blood flow greatest to? Impact as far as drugs?

A

Total blood flow is greatest to brain (14%), kidneys (22%), liver (27%), and muscle (15%). It would be expected that total drug concentration would rise most rapidly in these organs.

44
Q

Capillary permeability.

A

Capillaries are typically lined by a single layer of endothelial cells which have fenestration (or spaces) between them which make them quite permeable and provides a large surface area for drugs to penetrate across. Drugs may cross through via filtration or passive diffusion. Thus, lipid solubility and molecular size are major factors controlling transcapillary movement of drugs. Transport of substances > 25 kD is largely mediated by pinocytosis

There are two deviations to the typical capillary structure which result in variation from normal drug tissue permeability:

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.

45
Q

What does drug binding to plasma protein do to distribution?

A

Extensive binding to plasma protein will cause drugs to stay in the central blood compartment and thus can limit distribution of free drug to its site(s) of action.

46
Q

What is the most common plasma protein that drugs bind to?

A

Although drugs may be bound to many macromolecules, binding to plasma protein is the most common. Albumin, which comprises 50 % of the total plasma proteins binds the widest range of drugs.

47
Q

What kinds of drugs typically bind to albumin?

A

Acidic drugs commonly bind to albumin

Bilirubin, Bile acids, Fatty Acids,Vitamin C, Salicylates, Sulfonamides, Barbiturates, Phenylbutazone, Penicillins, Tetracyclines, Probenecid bind preferentially to Albumin.

48
Q

What do basic drugs typically bind to?

A

basic drugs often bind to globulins (ex. alpha1-acid glycoprotein).

Many endogenous substances, steroids, vitamins, and metal ions are bound to globulins.

Adenosine, Quinacrine, Quinine,Streptomycin, Chloramphenicol, Digitoxin, Ouabain, Coumarin bind preferentially to Globulins.

49
Q

Is drug binding to plasma proteins reversible?

A

Yes, Drug binding is a reversible process. A dynamic equilibrium exists between bound and unbound drug.

This tends to be of greatest concern for drugs with a narrow therapeutic window and when dosing regimens or elimination is altered.

Percent Unbound for Selected Drugs Caffeine-90
Gentamicin-77
Warfarin-0.8

50
Q

The total fraction of drug bound to plasma protein is determined by what?

A
  1. the drug concentration
  2. its affinity for binding sites
  3. the number of binding sites

Therefore:
The affinity of binding sites is the major determinant of the fraction of drug bound at low drug concentrations.

In contrast, at high drug concentrations the number of binding sites become the limiting variable

This entails that drug binding to plasma proteins is a saturable and nonlinear process.

51
Q

Theoretically, slight changes in the binding of highly bound drugs can result in significant changes in clinical response or cause a toxic response.
Since it is the 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.

A

Theoretically, slight changes in the binding of highly bound drugs can result in significant changes in clinical response or cause a toxic response.
Since it is the 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.

52
Q

T or F. Many drugs accumulate in tissues at higher concentration than those found in extracellular fluids and blood.

A

T.

The cause of drug accumulation in tissues is often arises from active
transport or binding.

Tissue binding usually arises through interactions with proteins and/or
phospholipids (either extracellular or intracellular).

Binding to such cellular constituents is generally reversible and saturable. This is dependent on the concentration, affinity, and binding capacity of the tissue as well as the physicochemical properties of the drug.

53
Q

As a result of the previously described factors that can affect membrane transport (i.e. lipid solubility) and distribution of drugs (binding), the free, nonionized form of the drug can become relatively inaccessible to the systemic circulation or the site of action. However, there is an equilibrium between free and bound forms of the drug, as well as between non ionized and charged forms. Thus, bound and ion trapped drugs represent a reservoir of drug that can serve to prolong the duration of response

A

As a result of the previously described factors that can affect membrane transport (i.e. lipid solubility) and distribution of drugs (binding), the free, nonionized form of the drug can become relatively inaccessible to the systemic circulation or the site of action. However, there is an equilibrium between free and bound forms of the drug, as well as between non ionized and charged forms. Thus, bound and ion trapped drugs represent a reservoir of drug that can serve to prolong the duration of response

54
Q

Relevant drug reservoirs

A
  1. stomach- traps basic drugs due to ionization (Ex. Codeine)
  2. Albumin- limits the availability of free drug and thus alters kinetics
    (Ex. Warfarin ~99% bound).
  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 important source of interpatient variability. (Ex. Thiopental)
55
Q

How does termination of a drug effect occur?

A

usually occur by metabolism and excretion. However, it may also result from redistribution from the site of action to other tissues or to bound proteins.

One reason for this is blood flow differences between tissues or organs that see the drug initially.

Ex. Thiopental is a rapid acting anesthetic and delivered efficiently to brain following IV administration because it is a highly perfused tissue. However, the distribution to the brain is not exclusive and the plasma concentration falls rapidly as it is readily delivered to other tissues. The concentration in the brain will mirror that in the plasma and fall, as well, thus terminating its action. In contrast, fat tissue will gradually accumulate the drug because of its high lipid solubility.

56
Q

Distribution can be thought of as following one of four types of patterns:

A

1) The drug may remain largely within the vascular system. Plasma substitutes such as dextran are an example of this type, but drugs which are strongly bound to plasma protein may also approach this pattern.
2) The drug may become uniformly distributed throughout the body water, such as the case of some low molecular weight water soluble compounds such as ethanol
3) A few drugs are concentrated specifically in one or more tissues that may or may not be the site of action. Iodine is concentrated by the thyroid gland. Tetracycline is almost irreversibly bound to bone and developing teeth. Another type of specific concentration may occur with highly lipid soluble compounds which distribute into fat tissue.
4) Most drugs 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. The highest concentrations are often present in the kidney, liver, and intestine usually reflecting the amount of drug being excreted.

Pattern 4 is the most common being a combination of patterns 1, 2 and 3.

57
Q

What is volume of distribution?

A

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. It is often used as a diagnostic tool

Vd = amount of drug administered / plasma drug concentration

58
Q

Volumes of fluid in compartments in the body

A 
Extracellular fluid- 13-16l
Plasma- 4l
Interstitial fluid- 10-13l
Intracellular fluid- 25-28l
Total body water- 40l
59
Q

What is the difference pharmacodynamics and pharmacokinetics?

A

pharmacodynamics- mechanism of action on the body

pharmacokinetics- set of properties that characterize how the drug is metabolized, where it goes in the body, etc.

CMOD Week 5 (16 decks)

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