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Pharm Exam 1 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Define pharmacokinetics

A

The fate of substances introduced to the body

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2
Q

What are the 3 facets of pharmacokinetics?

A
  • Absorption
  • Distribution
  • Elimination
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3
Q

What does the journey of an oral drug look like in the body before being measured from the venous system at time 0?

A
  • Goes through GI tract, needs to dissolve to get across GI endothelium
  • Drug transported immediately to the liver
  • Drug then goes to heart and lungs (both sites of metabolic activity
  • Drug gets delivered to tissues
    _ THEN drug goes to venous system where we are able to measure it
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4
Q

Explain plasma drug concentration as a function of time when administered orally

A
  • There is a lag time between when a drug enters the mouth to when it reaches the intestines
  • Then there is an upward spike as drug is being absorbed
  • Both rates of absorption and elimination are proportional to amount of drug in plasma
  • Peak concentration, Cmax, is when rates of absorption and elimination are equal
  • After Cmax, run out of drug to absorb, so mostly elimination
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5
Q

What does the area under the curve (AUC) of the plasma drug concentration as a function of time graph represent?

A

Total exposure to drug

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6
Q

Explain plasma drug concentration as a function of time when administered intravenously

A
  • At time 0, we are at Cmax because drug is immediately absorbed and distributed
  • C0 = Cmax
  • Decreases at a monoexponential decay
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7
Q

Define bioavailability

A

The fraction (F) of an administered dose of a drug that reaches the systemic circulation unchanged

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8
Q

How is bioavailability measured?

A

F = (AUC from time 0 –> infinity of administered drug)/(AUC from time 0 –> infinity of drug given intravenously)

  • If drug can get into circulation without any elimination, unscathed, F=1 (100% absorbed)
  • If drug is not soluble or destroyed completely by intestinal epithelium, F=0
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9
Q

How can you deal with the problem of bioavailability?

A

Proper dosing!

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10
Q

What governs bioavailability of an orally administered drug?

A
  • Solubility and the ability of the drug to resist decomposition in the GI lumen
  • The ability of the drug to permeate, and resist metabolism within, the GI epithelium
  • The ability of the drug to resist metabolism in the portal circulation
  • The ability of the drug to resist metabolism within the liver, hepatic vein, lungs, etc. prior to first measurement
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11
Q

What are some properties of drugs that interfere with bioavailability?

A
  • Drugs like insulin that are proteins are totally degraded by pancreatic secretions of taken orally
  • Drugs that are too big, greater than 1000, or too highly charged will have a hard time getting across epithelium
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12
Q

Name the different routes of drug aministration

A
  • Enteral: oral, sublingual, buccal, rectal
  • Parenteral: intravenous, intra-arterial, intradermal, subcutaneous, intramuscular, intrathecal, intra-articular
  • Other: transdermal, inhalational, ophthalmic, urogenital
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13
Q

Describe the absorption, advantages, and disadvantages of IV bolus route (IV)

A
  • Absorption: Complete, instantaneous
  • Advantages: Bioavailability, speed
  • Disadvantages: Increased chance of the adverse reaction, possible anaphylaxis
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14
Q

Describe the absorption, advantages, and disadvantages of oral route (PO)

A
  • Absorption: Slower absorption then IV bolus and IM injection, bioavailability varies according to drug
  • Advantages: Safest and easiest route of administration, lends itself to immediate and modified-release formulas
  • Disadvantages: Some drugs have erratic absorption, unstable in GI tract, or are highly metabolized by GI and liver
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15
Q

Describe the absorption, advantages, and disadvantages of buccal or sublingual route (SL)

A
  • Absorption: Rapid absorption for lipid soluble drugs
  • Advantages: No first-pass affects
  • Disadvantages: Some drugs maybe accidentally swallowed, not for most drugs (taste, poor absorption), can damage or mucosa or teeth
    ~Good for drugs that are degraded by the liver~
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16
Q

Describe the absorption, advantages, and disadvantages of intramuscular route (IM)

A
  • Absorption: Rapid from aqueous solution, slow from nonaqueous solutions
  • Advantages: Easier to inject than IV
  • Disadvantages: Irritating drugs may be very painful, differing rates of absorption depending on muscle group
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17
Q

Describe the absorption, advantages, and disadvantages of rectal route (PR)

A
  • Absorption: More reliable absorption from solution (enema) than suppository
  • Advantages: Useful when patient cannot swallow medication, avoids some liver metabolism
  • Disadvantages: Absorption maybe erratic, some patient discomfort
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18
Q

Describe the absorption, advantages, and disadvantages of transdermal route

A
  • Absorption: Slow or none, rates vary, can increase with occlusive dressing
  • Advantages: Minimization of systemic effects, ease-of-use, lends itself to transdermal delivery system
  • Disadvantages: Some irritation by patch or drug, permeability varies with skin condition and anatomic site, type of creams/appointment base affects release absorption
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19
Q

What are some factors affecting distribution of drug from plasma?

A
  1. Capacity of drug to cross cell membrane
  2. Endothelial cell layer fenestration
    - High degree of fenestration (liver and kidney) vs low degree (most tissues) vs almost no degree (brain)
    - Degree of frustration can change with location within the tissue and as a function of pathological state
  3. Blood flow: High blood flow (major organ systems) vs low blood flow (adipose tissue, bone, synovia)
  4. Binding of drugs to plasma proteins, i.e. albumin
  5. Partitioning of drugs into body fat or binding to tissue components
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20
Q

How do drugs get through a cell membrane?

A

They need some intrinsic permeability or a transporter

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21
Q

Diffusion of a drug through a lipid

For an uncharged molecule:

Flux of molecules across membrane per unit time =

A

(C1-C2) x ((Area x Permeability)/Thickness)

Permeability (P) is proportional to lipophilicity/molecular weight

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22
Q

What factors affect the ability of a drug to diffuse through a lipid membrane?

A
  1. Lipophilicity = How well a drug can dissolve in a lipid
    - Greater the lipophilicity, greater ability to pass through membrane
  2. Molecular weight = size
    - The bigger the molecule, the harder to get across
    - Molecular weight is to the 4th power, small differences in molecular weight have a huge impact on permeability
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23
Q

Describe the blood brain barrier

A
  • Endothelial layer (inside layer) is contiguous, strengthened by adhesive cell-cell contacts (drugs need to be small to cross(
  • That’s of are encapsulated in astrocyte foot processes
  • Apical surface of endothelial cells (facing lumen/blood) contain the P-glycoprotein transporter (wide drug recognition, grabs drug as it’s trying to cross and spits it back out into the bloodstream, important for drugs that would be dangerous if they crossed the BBB)
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24
Q

Why are drugs WEAK acids or basis?

A

This keeps reasonably soluble in the bloodstream so they don’t precipitate out

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25
Q

Describe ion trapping

A
  • Acids prefer more basic environments
  • Bases prefer more acidic environments
  • When there is a membrane separating differentials in pH, ions will be trapped on the side they prefer most
  • i.e. aspirin is acidic, so it prefers plasma to the stomach because the plasma is more basic
  • The extent of partitioning depends on the difference in pH
  • This is a form of distribution
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26
Q

Volume of distribution (Vd) formula

A

Amount in body at equilibrium/concentration in plasma (A/Cp)

In a reservoir, concentration = amount/volume

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27
Q

Why is volume of distribution important?

A
  • Vd is a proportionality constant. Relates AMOUNT of drug to CONCENTRATION of drug
    For IV bolus, Vd permits a direct calculation of initial concentration in plasma (Cp)0 for any given dose
    (For any other form of administration, Vd provides a sense of concentration that will be achieved)
    Vd gives you an idea of whether drug is doing anything weird in distributional sense
28
Q

How does concentration related to dose?

A

C0 = Amount0/Volume = Dose!/Volume

After time 0, an extractor like the liver eliminates the drug and concentration goes down

29
Q

Why are volumes of distribution different for different drugs?

A

Drugs that love fat high have high volumes of distribution because not much stays in blood

Drugs that bind to albumin have low volumes of distribution because it stays contained in plasma

30
Q

Realities of volume of distribution

A
  • Vd is inferred, hypothetical
  • You’re constrained to plasma for measurement of drug concentration
  • Plasma contains proteins like albumin to which some drugs bind
  • Tissues can contain protein (beyond targets) to which some drugs bind or fat into which some drugs partition
31
Q

Factors that affect volume of distribution

A
  • Albumin binds drugs making Vd appear small

- Proteins in tissues bind drugs and fat sequesters drugs making Vd appear large

32
Q

Why can binding of drugs to plasma protein matter?

A
  • Plasma proteins, through binding of a drug, can restrict access of the drug to its site of action
  • Plasma proteins can vary with disease or physiological status, hence concentrations of a drug at the drug’s site can vary
  • Displacement of a drug by another drug at plasma proteins can result in troublesome elevations of the drug with regard to adverse effects
33
Q

What is drug elimination?

A

Elimination is the irreversible loss of a drug. It occurs by metabolism and/or excretion

  • Metabolism (biotransformation): the enzymatic conversion of one chemical entity (the drug) to another (the drug metabolite, usually inactive but sometimes active)
  • Excretion: the removal of unmodified drug from the body (usually by the kidneys)
34
Q

What are the major chemical reactions in drug metabolism?

A
  • Oxidation
  • Reduction
  • Hydrolysis
    (Phase I reactions, small chemical reactions)
  • Conjugation
    (Phase II reaction, big chemical reaction)
35
Q

T/F: Drugs can only enter stage I or stage II reactions, but not both.

A

False! Drugs can either

  1. Enter phase I reaction, yield inactive drug metabolite, then excreted
  2. Enter phase I reaction, yield inactive metabolite, enter phase II reaction, conjugated, then excreted
  3. Enter phase I reaction, yield active metabolite, then excreted
  4. Enter phase I reaction, yield active metabolite, enter phase II reaction, conjugated, then excreted
  5. Enter phase II reaction, conjugated, then excreted
  6. Excreted unchanged
36
Q

What is the liver’s role in drug metabolism?

A
  • Blood flow to (and from) liver is 1.35 L/min (LARGE BLOOD FLOW); most is splanchnic via portal vein
  • Endothelium of liver vasculature is fenestrated, i.e. highly permeable to small molecules
  • Endoplasmic reticulum of hepatocytes is laden with cytochrome P450 enzymes
37
Q

With what kind of reactions do cytochrome P450 enzymes assist, and where do they assist?

A

Phase I reactions, hepatocytes in the liver

38
Q

What are the 3 most important cytochrome P450 families in relation to drug clearance?

A
  1. CYP3A4
  2. CYP2D6
  3. CYP2C9
    Triumvirate of drug clearance!
39
Q

What are some examples of phase II reactions?

A
  • Glucuronidation (attach a sugar)
  • Sulfation (attach a sulfa)
  • Acetylation (attach 2Cs and O)
  • Peptide conjugation (attach amino acids)
  • Glutathione conjugation (attach tripeptide)
40
Q

What is the purpose of prodrugs in pharmacokinetics?

A

Can help with absorption or distribution before it is metabolized and excreted

41
Q

Describe the relationship between active an toxic metabolites in excretion

A

Phase I and II reactions can yield both active and toxic metabolites

42
Q

Describe the metabolism of acetaminophen and acetaminophen toxicity

A

Acetaminophen undergoes many phase I (monooxygenase hydroxylation –> 5% processed this way, yields toxic metabolites) and phase II reactions (glucuronidation, sulfation) in the liver

  • Liver has a detoxifier, GSH (phase II glutathione reaction) that detoxifies the metabolite in appropriate doses
  • In acetaminophen overdoses, unable to detoxify all the toxic metabolites –> hepatic and renal toxicity
43
Q

What organs play the biggest roles in excretion of drugs?

A
  1. Kidney –> urine
  2. Liver –> bile
    (2 biggest ones)
  3. Skin –> sweat
  4. Lungs –> expired air
44
Q

What are the 2 ways in which the kidneys excrete drugs?

A
  1. Glomerular filtration (20% of plasma)
  2. Peritubular filtration (80% of plasma)
    Filter in succession
45
Q

Describe glomerular filtration in relation to renal excretion of drug and drug metabolites

A
  • About 20% of renal plasma flow is filtered by the glomerulus into Bowman’s capsule
  • Anything below a molecular weight of 20,000 can pass together with the plasma into (as) the filtrate
  • Effect of binding plasma proteins - makes it too large to filter out
  • Reabsorption - acidity/basic nature of plasma effects reabsorption
46
Q

Describe carrier-mediated transport & peritubular filtration in relation to renal excretion of drug and drug metabolites

A
  • Filters weak acids and organic bases
  • Extremely effective and not impeded by drug binding to plasma proteins
  • Carrier-mediated transport helps bring drug back into blood, whether bound to albumin or not
  • MORE IMPORTANT THAN GLOMERULAR FILTRATION in terms of drug filtering*
47
Q

T?F: Transporters are only relevant to pharmacodynamics.

A

False! Transporters are invaluable in terms of elimination, so they are also important to pharmacokinetics.

48
Q

Why is there renal toxicity too (besides just liver toxicity) in acetaminophen overdose?

A

Cytochrome P450s are overwhelmed in the kidneys as well

49
Q

How do you determine rate of elimination?

A
  • Rate of elimination of a drug following first order elimination is proportional to the amount of drug in the volume characterized by Vd:

rate of elimination = k x A

50
Q

How does drug concentration relate to drug half life?

A

The half life of a drug will be the same no matter what its concentration!

51
Q

How does half life relate to speed of elimination?

A

Longer half life means slower elimination

52
Q

Why is half life important?

A
  1. Elimination half life is an easily measured constant that provides an intuitive feel for the speed with which a rug is eliminated
  2. Various dosing regimens are predicated on knowledge of half life
    - Time to steady-state (constant infusion, rate of concentration is equal to rate of elimination): 4 half-lives
    - Drug accumulation in repeated dosing can be calculated via formulas incorporating half life
53
Q

What is clearance (CL)?

A

Clearance is a factor that relates the rate of elimination of a drug to the concentration of the drug in the plasma

rate of elimination (amount/time) = CL (volume/time) x C (amount/volume)

Clearance is the volume cleared per unit time

54
Q

Why is clearance important?

A

Clearance is a crucial concept in designing a rational regimen for long-term, steady-state drug administration

dosing rate = CL x Css

Clearance, when applied to tissues such as the liver or kidney, provides an index of tissue functionality

55
Q

Name some practicalities of clearance (CL)

A
  • In considerations of clearance, the fluid containing the drug has an apparent volume of distribution, Vd
  • Clearance can refer to drug cleared by the body (‘total body clearance’) or by single extractors, i.e. kidney (‘renal clearance’), liver (‘hepatic clearance’), etc.
  • Total body clearance is often normalized on a per kilogram basis
56
Q

Describe renal clearance, CLr

A
  • CLr is the sum of CLfiltration and CL secretion assuming no reabsorption
  • CLfiltration is linked to GFR (CLfiltration is linked to GFR x fraction of unbound drug to albumin)
  • Extraction ratio for filtration is at best 0.2, yet the renal extraction ratio for some drugs can be upwards of 1
57
Q

Why can the extraction ratio for CLfiltration be at best only 0.2?

A
  • Only 20% max of drug can be extracted through glomerular filtration because only 20% of plasma is filtered this way
  • Of this 20%, some may be reabsorbed
58
Q

Describe hepatic clearance, CLh

A
  1. Drugs can be divided into those having low (<0.3), intermediate (0.3-0.7), and high (>0.7) extraction ratios
  2. Drugs with high extraction ratios:
    - Good substrates for metabolism
    - Tend not to bind to plasma protein
    - Extraction for these drugs is perfusion limited
59
Q

What is an extraction ratio?

A

How much drug is extracted relative to how much drug is presented

60
Q

What are pharmacokinetic drug-drug interactions?

A

Effects at any level of absorption, distribution, and elimination

61
Q

What are some drug-drug interactions affecting/affected by absorption?

A
  1. GI absorption is slowed by drugs that inhibit gastric emptying, i.e. atropine or opiates
  2. GI absorption is accelerated by those that hasten gastric emptying, i.e. metoclopramide
  3. GI absorption is slowed or completed inhibited by physical complexation between drugs
    - Ca and Fe form insoluble complexes with tetracycline
    - Bile acid binding resins bind numerous acidic or amphoteric drugs
    - Omeprazole binding to protein
62
Q

What are some drug-drug interactions affecting/affected by distribution?

A

Alterations in Vd in the context of drug-drug interactions are almost always due to displacement of one drug by another from albumin

63
Q

Why is displacement of one drug by another from albumin not usually a clinical issue?

A
  • The degree of displacement is often modest
  • The increase in concentration of free (displaced) drug is often counterbalanced by increased clearance
  • Most drugs don’t have sufficiently narrow therapeutic ranges for this to be a concern
64
Q

What are some drug-drug interactions affecting/affected by metabolism?

A
  1. Alterations in (hepatic) metabolism are a highly important cause of drug-drug interactions
  2. The bases of interaction-induced alterations are:
    - Enzyme induction: Drug A metabolized by CP450, Drug B induces/increases CP450, more Drug A metabolized, Css increases
    - Enzyme inhibition: Drug A metabolized by CP450, Drug B inhibits/reduces CP450, either a) Drug A competes for metabolism by CP450 so less drug A metabolized or b) Drug B reacts with Drug A and deactivates it
    - Hemodynamic effects: high extraction ratio, more rapidly excreted
65
Q

What are some drug-drug interactions affecting/affected by transporters?

A
  1. Liver
    - Inhibition by one drug of transport of other drugs into hepatocytes would limit metabolism, hence increase plasma AUC, of the latter
    - This form of drug-drug interaction exists, but is poorly characterized
  2. Kidney
    - Inhibition by one drug of transport of other drugs into lumen of the tubule would limit excretion, hence increase plasma AUC, of the latter

Pharm Exam 1 (4 decks)

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