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Pharmacokinetics Flashcards

1
Q

What are the parameters used to determine the volume of distribution? What are the units of measurement?

A

Volume of distribution measures the amount of drug in the body to the concentration of drug (C) in blood or plasma (unbound drug!!):

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2
Q

What are the main compartments in the body in which drugs can be distributed? What are examples of drugs that may be found within these compartments?

A
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3
Q

How is clearance of a drug determined?

A

Clearance is the factor that predicts the rate of elimination in relation to the drug concentration.

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4
Q

Describe what is meant by clearance having an additive character.

A

Elimination of the drug from the body may involve processes occuring in the kidney, the lung, the liver, and other organs. The total clearance will be an addition of all of the clearances in these organs.

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5
Q

Given an example of two drugs, atropine and warfarin, what would be their respective Vds? Wouuld they be high, low, etc? What is the reason for their respective Vd?

A

Warfarin: large, protein bound molecule and will have a small Vd

Atropine: little protein bound, and will have a large Vd

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6
Q

What is the difference between first and zero order elimination?

A

First-order elimination is proportional to the concetration of the drug. While zero-order elimination is independent of the concetration of the drug (ie the rate of drug elimnation is constant)

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7
Q

What factors are important in determining the clearance of zero order drugs?

A

Clearance, or the rate of elimination, is not dependent on the concentration:

  1. The concentration of the drug may have exceeded the maximum elimination capactiy.
  2. The elimination of the drug requires an endogenous factor that is limited
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8
Q

What are the two major sites of drug elimination?

A

Liver and kidneys

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9
Q

How is hepatic clearance measured?

A

Hepatic clearance is measured as the difference between total systemic clearance and renal clearance

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10
Q

What is meant by the concept that zero-order drugs are not elimination saturable?

A

Opposed to first order, wherein the eimination of the drug is dependent on the conentration of the drug; in zero-order clearance, elimination of the drug is independent of concentration and a factor that causes this may be a saturation of the elimination capacity.

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11
Q

What three main drugs exhibit zero-order elimination?

A
  • aspirin (anti-inflammatory)
  • Phenytoin (anticonvulsant)
  • Atropine (anesthetic, antiarrythmic- anticholinergic with action at muscarinic receptors)
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12
Q

T or F: For drugs that exhibit zero-order elimication, regarding capacity-limited elimination, clearance of the drug will vary with concentration?

A

True, and thus, the area under the curve should not be used to calculuate the clearance of such drugs.

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13
Q

Propranolol (beta blocker), opiates, and lignocaine (Antiarrhythmic and Anesthetic) are all examples of drugs with high hepatic extraction ratios. What is meant by a drug with high hepatic extraction ratio?

A

High extration ratio drugs are those that are highly extracted/eliminated from the body either by a particular organ, or are highly eliminated after first-pass

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14
Q

What factors are used to determine the half-life of a drug?

A
  • volume of distribution
  • clearance

The half-life indicates the time required to attain 50% of steady state- or to decay 50% from steady-state conditions.

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15
Q

What is the rule of thumb for how many half lives are required to reach 94% of the steady state (or 94% elimination of the drug)?

A

4 half-lives are required to reach 94% steady state concentration, or to eliminate 94% of the drug

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16
Q

What phenomenon will result if more doses are repeated and the dosage interval is shorter than 4 half-lives?

A

Accumulation: occurs when dosage rate > elimination rate

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17
Q

Regarding drug accumulation, how will you determine the amount of drug that is cleared per unit of time?

A

K = 0.7/half-life

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18
Q

What are the two main pharmokinetic parameters?

A
  1. Volume of distribution
  2. Clearance
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19
Q

How will you determine the accumulation factor?

A
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20
Q

Using the accumulation factor equation, what is the accumulation factor for a drug given once after every half-life?

A

Accumulation factor = 1/.5 = 2

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21
Q

What is the definition of bioavailability?

A

The fraction of unchanged drug reaching the systemic circulation following administration by any route.

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22
Q

What two factors may affect the decrease in bioavailability for a drug that is administered orally?

A
  1. Incomplete absorption across the gut wall
  2. First-pass elimination by the liver
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23
Q

What two factors are most important for determining bioavailability?

A
  • route of administration, drug chemistry
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24
Q

What is the extraction ratio? What organ usually has the highest extraction ratio?

A

Liver

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25
Q

If a drug has toxic metabolites, will it be given orally?

A

No

  • drugs given orally will be metabolized in the liver as a component of the first-pass effect.
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26
Q

How is systemic bioavailability determined?

A

F = absorption (f) x (1-ER)

ER= extration rate = CL/Q

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27
Q

Determine the systemic bioavailability for morphine given the following values:

f (absorption) = 100%

morphine blood clearance = 60 L/h/70 kg

hepatic blood flow = 90 L/h/70 kg

A

F=f x (1-ER)

ER= CL/Q

F = 100 x [1-(60/90)]

F= 33%

Morphine has a systemic bioavailability of 33%

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28
Q

How can a drug given orally be said to exhibit both first order and zero order elimination?

A

Drugs given orally must transverse the gut wall and get metabolized by the liver in order to make it to the bloodstream.

Drug absorption is zero-order when the rate is independent of the amount of drug remaining in the gut (for instance, when it is determined by the rate of gastric emptying or by a controlled-release drug formulation)

When the dose is dissolved in gastrointestinal fluids, the rate of absorption is usually proportional to the gastrointestinal fluid concentration and thus is first-order

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29
Q

What are examples of organs that may serve as locations of first-pass loss?

A

Liver (portal vein from the intestines entering liver)

Lungs (drugs administered by nongastrointestinal (“parenteral”) routes

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30
Q

IV dose adminiatration of drugs will exhibit 100 bioavailability. What are the pros and cons to IV dosages?

A
31
Q

Why is drug absorption always greater in the intestine than in the stomach, irregardless of ionization?

A

The extensive surface area of the intestines allow for greater drug absorption.

32
Q

Why does accelerating gastric emptying increase the rate of absorption?

A

THe stomach has a smaller surface area (along with a thick mucus layer) compared to the intestines, which has an extensive surface area. Thus, accelerating gastric emptying will allow for the drug to become available for absorption in the intestines at a faster rate.

33
Q

What equation can be used to compare the bioavailability of drugs given by different routes?

A

AUC (route)/AUC (iv)

AUC = Area under the curve

34
Q

Bioavailability can be determined by the AUC (area under the curve) on a plasma conc. vs. time graph. What factors greatly determine bioavailability?

A
  1. Route of administration
  2. length of time drug remains at site of action with minimal deleterious side effects.
  3. Clearance- for drugs with high extraction ratios, the ratio of clearance to blood flow will determine the extraction ratio, which determines bioavailability. A higher extraction ratio will result in a decreased bioavailability.
  4. Drug delivery rate to organ of elimination- if there is a high extraction ratio
35
Q

Explain why many drugs are highly extracted by hepatic metabolism. Include in your description information regarding the heaptic artery and portal vein. Explain enterhepatic recirculation.

A

Drugs can enter the liver under two mechanisms:

  • absored from the gut and enter the liver via the portal vein
  • enter liver through systemic circulation via the hepatic artery

Both mechanisms will cause the drug to become metabolized in the liver (and some is excreted into bile).

The additive effect of passage of a drug from GI reabsorption and systemic circulation is known as enterhepatic recirculation.

36
Q

What factor detemines extraction ratio, and therefore bioavailability?

A

Clearance

ER = Cl/Q

Q- rate of blood flow

37
Q

Rank the bioavailability of the four main routes of administration:

Oral, Intravenous, Subcutaneous, Intramuscular

Which route of administration has the greatest differnce in bioavailability depending on the drug.

A

Most: Intravenous (F=1)

Subcutaneous (0.75

Intramuscular (0.75 < F<1)

Least: Oral (0.5 < F < 1)

Thus, drugs that must be taken orally will exhibit the greatest difference in bioavailability, which can be dependent on their chemistry/interactions, clearance, location of extraction, etc.

38
Q

What three structures can metabolize drugs, decreasing the bioavailability of drugs given orally?

A
  1. Liver
  2. Kidneys
  3. intestinal cells /microbiota in the GI
39
Q

What are the effects of a drug being too hydrophilic or too lipophilic?

A

too hydrophilic- may be unable to cross lipid cell membrane

too lipophilic- not soluble enough to cross water layer that is adjacent to the cell

40
Q

What are the ideal locations for the absorption of weak acids and bases?

A

Weak acids- best absorbed in the stomach

Weak bases- best absorbed in the intestines

41
Q

T or F: While enteric coated drugs can prevent dissolution in gastric acid, they may also resist dissolution in the intestine and thereofre absorption?

A

True

42
Q

Controlled release preparations are best for drugs with a long or short half-life?

A

short half life (<4 hrs)

  • beneficial in reducing likelihood of accumulation
43
Q

Why will accelerating the rate of gastric emptying increase the rate of absorption?

A

The rate of drug absorption is markedly increased in the intestines due to the large surface area available for absorption compared to the stomach.

44
Q

Describe what happens when a drug is capacity limited.

A

For drugs that bind to proteins, when the binding of that protein approaches capacity, more of the drug becomes available for elimination. Because more drug is available for elimination, the concentration of the the total plasma drug increases less rapidly.

45
Q

What plasma proteins are involved in bind weak acids and bases respectively. How can this binding be influenced by systemic changes?

A

Weak acids are bound by albumin (which means albumin must be slightly basic). Note that in diseased states when albumin is decreased, weak acid drugs may be less bound and thus have a great Vd, as more of the drug can move into the extravascular compartment of the body. This also means that toxicity from the drug can be increased.

alpha-acidic glycoprotein binds to basic drugs. This glycoprotein can be increased in acute inflammatory states. Thus, in acute inflammation, more basic drug can bind to this glycoprotein. Ultimately, this will decrease Vd, as less drug is in the peripheral tissues and more remains in the vasculature. Doses may not be able to reach therapeutic levels.

46
Q

T or F: Protein binding is usually reversible and the fraction of drug bound is dependent on the concentration of the drug?

A

True

47
Q

T or F: Assays to measure concentrations of most drugs in plasma do not distinguish between free and bound drug?

A

True.

Importance? If a drug is more bound to plasma proteins that normal, assays may show a high level of the drug. However, because of increased binding, the drug is actually not available to site of action. Thus, therapeutic effects may not be achieved.

48
Q

Explain the dynamics between bound and unbound drug.

A

Bound drug is in equilibrium. As free drug is eliminated, more drug comes off of protein to re-establish equilibrium.

49
Q

What are the two factors that can change the steady-state concentration of unbound drug? Why is this important?

A
  1. change in the administration rate of the drug
  2. change in the clearance of the unbound drug

Importance: If you change the conc. of unbound, equilibrium must re-established. This occurs by additional drug being removed from the bound plasma protein and entering the extravascular tissues. This can affect the Vd of the drug. Assays may not accurately estimate drug conc. and therapeutic response may not be seen.

In cases where the drug has a small therapeutic index, this can be dangerous, as more drug can be removed from the plasma and enter the tissues, causing deleterious effects.

50
Q

Under what circumstances is plasma protein binding a significant factor? Why?

A

Drugs that have a narrow therapeutic index and drugs that may be displaced by competing drugs.

Unbound drug is in equilibrium with plasma protein bounded drug. Thus, if a drug has a narrow therapeutic index, it is important to ensure that unbound drug does not accumulate, because toxic effects may ensue. If protein binding is not normal, more unbound drug may be present and present deleterious effects.

MAybe if a competing drug is supposed to be bound, but it is not bound in adequate concentration due to a lack of binding proteins, the competing drug can then compete with intended drug and exhibit delterious effects.

51
Q

Compare and contrast drugs that are highly bound to plasma proteins and those are not. Compare/contrast on the basis of binding, availability at site of action and elimination rate.

A

Highly bound drug:

  • Drug remains in plasma
  • less drug is available at site of action
  • because the conc. is less, elimination also decreases (elimination is proportional to concentration)

Slightly bound drug:

  • more drug is released into extravascular tissues
  • more drug available at active sites
  • Higher concentration = higher elimination

Therefore, for highly bound drugs, the concetration must be increased to account for the overbinding of the drug and its stasis in the plasma compartment. The conc. must be increased to ensure that an appropriate concentration of free drug is present at the site of action.

52
Q

How does tissue binding affect Vd, Cl, and half-life?

A

Half-life:

Increased; drug has limited elimination due to accumulation/stroage in tissue. This can lead to a prolonged drug action.

Clearance:

Decreased- drug’s elimination is limited

Vd:

Increased; more drug is in the periphery, less in the vascular. Also note equilibrium, the more a drug is bound in the tissues, the less free drug in the tissue. Equilibrium is re-established and more drug unbinds from the protein in plasma and enters tissue. Therefore, more drug is now in the tissue.

Note: accumulation can cause local toxicity. Also, a drug can be strored in tissue and will not have its effect at the site of action.

53
Q

Differentiate between therapeutic window and therapeutic index:

A

Therapeutic window: Difference between MEC (minimum effective concentration) for desired response and the MEC for an adverse response.

Therapeutic index: LD/ED - ratio of the concentration where drug becomes toxic, over the concentration where it is most effective.

54
Q

What is the most important pharmokinetic parameter to determine steady state drug dosage? Why?

A

Clearance;

Dosage rate = Clearance x target concentration

Maintenance dosage, which is determined by using the dosing rate, is therefore used in an attempt to maintain steady state drug concentrations within the therapeutic window. This dosage is just enough to replace elimination. Maintenance dose considers the parameters of of the dosage rate, dosage interval, and bioavialability.

Maintenance dose = dosage rate x dose interval/bioavialability

Future thoughts… factors that affect clearance will therefore affect steady state concentrations.

55
Q

Explain the relationship between dosing frequency and plasma concentrations in reaching steady-state plasma drug concentrations:

A

Even though the dosing frequency may differ, the same amount of drug is being given. thus, plasma concentration of the drug remains constant. (Recall that for the maintenance dose, used to maintain steady-state concentrations, when you increased/lengthen the dosing interval, the maintenance dose concentration increased to account for the new increased dosing interval, and vice versa)

Becase the same steady-state concetration can be maintained using different dosing intervals, the average concentration depends ONLY on clearance!

C = rate of elimination / CL

Dosing rate = Clearance x target conc.

Maintenance rate = dosing rate/bioavailability x dosing interval

56
Q

Note the pros and cons to taking a drug less frequently:

A

Pros:

patient is more compliant = more convenient

Cons:

If therapeutic window is small, drug may become dangerous due to the larger dose, which is given with a longer dosage interval.

Therefore, small doses are more efficacious, but less convenient and may show decreased patient compliance.

57
Q

Explain the concept of loading dose. Include why it is used and what problems arise with using loading dose. Explain how these problems are alleviated:

A

Loading dose is used when the drug has a long half-life, but the goal is still to get the drug into the body and allow it to reach steady state concentrations as quickly as possible.

Loading dose = Vd x TC

Problem:

If the drug distributes into the system very quickly (i.e. the drug is a small, water-soluble/lipophilic molecule) initially, the drug concentration may reach toxic levels.

Solution:

Given the drug over a longer period of time/decrease the rate of administration (i.e. a drug is infused over a 20 minute period)

Also, connect the factors which can affect Vd, including: protein binding, tissue/bone binding

58
Q

Use the example of a drug with a short half-life, but has sustained action to describe the relationship of concentration and effect:

A

While the concentration of a drug can fall after dosage, the effects of the drug may outlast the actual presence of the drug. This is important because for drugs with short half-lives, the drug does not need to be excessively given because the effects of the drug will remain for the portion of time where the drug’s concentration is negligible.

59
Q

T or F: The half-life measures the duration of the drug’s effect?

A

False, the half-life only measures the time that it takes for the drug’s concentration to decrease by 50%

60
Q

What pharmacokinetic measure is used to determine dosing frequency?

A

Half-life; 4 half-lives are required for steady-state conc.

61
Q

Describe the relationship between pka, pH and ionization for weak acids and bases:

A

The lower the pka, the more the drug will remain in is protonated form:

For weak acids, the protonated form is lipid soluble (HA), while for weak bases the protonated form is not lipid soluble as it is charges (BH+)

62
Q

Relate the Henderson-Hasselbalch equation for determining the concentration of weak acids/bases in their ionized/nonionized forms

A
63
Q

In terms of ion-trapping with weak acids and bases, what is the expected location of the acid or base at steady state?

A

At steady state…

Weak acids will be trapped in the plasma, more more basic environment where the ionized [A-] form of the drug is most present.

Weak bases will be trapped in the urine, a more acidic environment, where the ionized [HB+] form of the drug predominates.

64
Q

What drugs can be used to increase clearance of weak acids and bases? Explain their mechanism of action:

A

Weak acids:

Alkalinizing the urine with sodium bicarbonate will increase its clearance from the body.

Weak bases:

Acidifying the urine with ammonium chloride will increase its clearance from the body.

If you wanted to keep these drugs in the body, use the acid for weak acids and the base for weak bases.

65
Q

Explain why the kidney’s reabsorption is based on pH:

A

Polar = ionized

The tubules allow passive reabsoprtion of non-polar/non-ionized, lipid-soluble substances. The tubules are less permeable to ionized forms.

Polar compounds are more readily excreted than lipid-soluble.

66
Q

T or F: Unbound drug can be filtered in the glomerulus?

A

False

67
Q

What two factors will determine the amount of drug entering the tubular lumen of the kidneys for excretion?

A
  • Glomerular filtration rate (dependent on blood pressure- RAAS system, Starling forces- changes in hydrostatic pressure)
  • plasma protein binding (the more bound drug, the less eliminated). Also, in pathological states, the inadequate presence of plasma proteins, such as albumin, means that more drug is excreted.
68
Q

Explain enterohepatic cycling in terms of metabolite accumulation and polarity.

A

Lipid-soluble drugs can be absorbed in the GI, and altered to become more polar/water-soluble, allowing their excretion through the liver. However, activation of metabolites, which can be produced from drugs in the liver, may actually increase the activity of the drug and limit its excretion.

69
Q

Sweat, saliva and tears allow for the excretion of what types of substances?

A

non-ionized lipid-soluble

70
Q

Differentiate between the type of drug transport mechanisms including:

  • aqueous diffusion
  • lipid diffusion
  • endocytosis and exocytosis
  • carrier molecules

Include whether the transport is passive or active

A

Note that carrier molecules are the most efficient type of drug transporter.

71
Q

What are three determinants of xenobiotic exposure?

Explain how the body provides a protective barrie against xenobiotics. Include the action of efflux transporter, like P-glycoprotein transporter:

A

liver transporter + kidney transporters + metabolic enzymes

Efflux proteins, like P-glycoprotein which is present on the luminal, blood-facing side of the membrane, can secrete anions and conjugated metabolites which can act as multidrug resistance molecules and help to control exposure to xenbiotics.

72
Q

Lipophilic drugs are more likely to cross the blood-brain barrier. Explain what type of transport is used when transporting lipid-soluble molecules:

A

Paracellular (between the cells) transport is utilized opposed to transcellular (through the cell) for passage through the blood-brain barrier.

73
Q

What is the most effecient way to predict bioavailability?

A

AUC (Area under the curve)

74
Q

In what way, and using what equation, can you calculate the differences in bioavailability of a drug that is not given intravenously?

A

AUC (route)/ AUC (iv)

Pathology Cellular morphology (9 decks)

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