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BIOM 3090 > Pharmacokinetics: distribution and elimination > Flashcards

Pharmacokinetics: distribution and elimination Flashcards

1
Q

Distribution of drug is achieved primarily thru the ________ circulation with minor contributions from the ________

A

Systemic, lymphatics

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2
Q

Once in the systemic circulation, a drug can

A
  • Remain in vascular (blood) space
  • Distribute to enter interstitial fluid
  • Further distribute to enter intracellular fluid
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3
Q

Distribution of drug in the body is affected by

A
  1. Physiochemical properties of the drug
  2. Anatomy and Physiology of Patient: Tissue Perfusion
  3. Non-target Binding of Drug
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4
Q

Physiochemical properties of the drug that affects drug distribution

A
  • Lipid solubility
  • Size (molecular weight)
  • Degree of ionization
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5
Q

Which tissues initially receive the drug distribution

A

vessel-rich tissues (liver, kidney, brain, heart) receive the greatest cardiac output and thus distribution of drug

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6
Q

Drug distribution to what tissues is slower

A

Distribution of drug to less well-perfused tissues (muscle, fat, skin, most
viscera) is slower, but accounts for most of the extravascular drug

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7
Q

Non target binding of drug refers to

A

Plasma protein binding and tissue binding

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8
Q

Plasma protein binding

A

Many drugs circulate in the blood bound to plasma
proteins; can show low to high affinity for proteins
-Cannot diffuse from vascular space to tissues

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9
Q

What binds drugs that are weak bases

A

α1-acid glycoproteins

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10
Q

Albumin

A

a major carrier for drugs that act as weak acids

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11
Q

Tissue binding

A

Many drugs accumulate in tissues at levels higher
than blood or interstitial fluid; can prolong drug action
-bind cellular proteins, phospholipids, etc that are not the target sites

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12
Q

The volume of distribution (Vd) describes

A

the extent to which a drug partitions between blood and tissue compartments

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13
Q

Volume of distribution equation

A

amount of drug in body (mg) / plasma drug concentration (ug/mL)

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14
Q

Drugs are eliminated (cleared) from the body either

A

-unchanged by the process of excretion or
-converted to metabolites by biotransformation

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15
Q

TRUE OR FALSE:
Although biotransformation (metabolism) and excretion are distinct processes, they have the same pharmocologic endpoint (reduction in circulating levels of active drug)

A

True

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16
Q

Rate of drug metabolism and excretion by an organ is generally limited
by

A

The rate of blood flow to the organ

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17
Q

“Kinetics of elimination of majority of drugs are first-order” meaning

A

constant fraction (%) of drug in blood (body) is eliminated per unit time

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18
Q

Units of clearance

A

(volume/unit time/kg body weight)

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19
Q

Clearance equation

A

Metabolism + Excretion / [Drug] plasma

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20
Q

What does the extraction ratio quantify

A

The extent to which an organ contributes to drug clearance

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21
Q

Extraction ratio equation

A

Extraction = [Drug]in - [Drug]out / [Drug]in

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22
Q

Do excretory organs eliminate polar (water soluble) or non-polar (lipid soluble) compounds more efficiently

A

Polar

23
Q

What is the most important excretory organ

A

The kidney

24
Q

Biliary tract excretion and reabsorption

A

-eliminated by feces
-reabsorption of excreted drug possible in small intestine –> enterohepatic recirculation of drug back to systemic circulation

25
Q

Are drug s bound by plasma proteins easily filtered

A

No

26
Q

Filtering of free (unbound) drug and metabolites

A

freely filtered at the glomerular capillaries (glomerulus); non-saturable and non-selective process

27
Q

Renal excretion: Active drug secretion

A

Active drug secretion in proximal convoluted tubule adds drug to urine; is saturable, selective and inhibitable by other drugs

28
Q

Renal excretion: reabsorption of drug

A

Reabsorption of drug back into blood from urine can be active in the distal
convoluted tubule but is mainly passive reabsorption of the nonionized form of the drug

29
Q

Drug biotransformation or metabolism definition

A

change in the chemical structure of an absorbed drug within a living organism, usually by enzyme-catalyzed biochemical reactions

29
Q

What is the main metabolizing organ

A

The liver

30
Q

All orally administered drugs or other substances are first taken to

A

the liver

31
Q

First pass effect

A

Where orally administered substances are first taken to the liver and extensively metabolized before reaching systemic circulation

32
Q

What does the first pass effect do

A
  • Reduces bioavailability of drug for target site
  • Prevents some drugs from being given orally eg. lidocaine, many opioids (morphine, fentanyl)
33
Q

Why is drug metabolism important

A

Enzymes play a pivotal role in metabolism by making drugs more excretable and terminating their action (inactivate)

34
Q

Many _____________drugs must be metabolized to
more __________metabolites

A

lipid-soluble, water-soluble

35
Q

Metabolism often results in _____ of the parent drug

A

inactivation

36
Q

How are some drugs activated by metabolism

A

Administered as inactive “prodrugs”, gets converted into active metabolite

37
Q

How many phases does drug metabolism occur in

A

2 phases

38
Q

Phase I reaction of drug metabolism

A

Drugs are converted to more polar (hydrophilic) metabolites –> either excreted or –> undergo phase II reactions

39
Q

Phase II reaction of drug metabolism

A

Substance from the diet is attached usually to the functional group derived from phase I reactions –> more polar, excretable product

40
Q

What reactions are involved in phase I and II of drug metabolism

A

Phase I:(oxidation/reduction/
hydrolysis reactions)

Phase II: (conjugation reactions)

41
Q

Characteristics of phase I reactions

A

-Processes usually involve one or more cytochrome P-450 (CYP) enzymes found in smooth ER
-Approximately 12 CYP450’s are known to be important for the metabolism of drugs; mainly the CYP2C, CYP2D, CYP3A subfamilies

42
Q

Most common and least common phase I reactions

A

Most common: oxidation
Least common: Reduction and hydrolysis

43
Q

What do phase I reactions do in terms of functional groups

A

Introduce or unmask

44
Q

Oxidation in phase I reactions involves

A

Addition of oxygen or removal of hydrogen from drug

45
Q

What percent of oxidative reactions involve CYP450 enzymes

A

95%

46
Q

Characteristics of phase II reactions

A

Couple drug (or phase I metabolite) with substrates from diet to produce conjugates

47
Q

Conjugates

A

Generally more polar, inactive and readily excretable

48
Q

Types of phase II reactions (4)

A

1.Glucuronic acid conjugation (UDP
glucuronosyl transferase)
- conjugation of morphine, acetaminophen, salicylic acid, chloramphenicol, etc. to glucuronic acid

2.Sulphate conjugation (sulfotransferases)
-Phenols and alcohols conjugated to sulphate (SO4)
3.Acetylation (N-acetyltransferases)
-Occurs in drugs with -NH2 group conjugated to COCH3
4.Glutathione conjugation
(glutathione-S-transferases)
-Epoxides, arene oxides conjugated to glutathione (GSH)

49
Q

Phase II: enterohepatic recirculation

A

Some phase II metabolites can be excreted into bile for elimination in feces, but glucuronidases in gut bacteria can hydrolyze the
conjugate off, and free the drug, which can be reabsorbed –> enterohepatic recirculation; prolongs drug elimination half life

50
Q

Individuals deficient in glucuronide synthesis are slow to

A

Metabolism certain drugs

51
Q

Examples of specific drugs involved in each phase II reaction

A
  1. Glucuronic acid conjugation
    -conjugation of morphine, acetaminophen, salicylic acid, chloramphenicol, etc. to glucuronic acid

2.Sulphate conjugation
-acetaminophen, morphine

  1. Acetylation
    -most sulfonamide antimicrobial drugs

4.Glutathione conjugation
-some anticancer drugs (alkylating agents)

52
Q

Review metabolism summary

A

ya

BIOM 3090 (12 decks)

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