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IDIT > Drug Distribution -Dr Issar > Flashcards

Drug Distribution -Dr Issar Flashcards

1
Q

What is distribution

A

back and forth movement of drug in various tissues of the body and relative proportion of drugs in tissues

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2
Q

Where are the regions the drugs can go

A
  1. ECF (1/3 TBW)
  2. ICF (2/3 TBW)
  3. Interstitial fluid (3/4 ECF)
  4. plasma (1/4 ECF)
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3
Q

Maximum volume that your body has is

A

42 liters
(Total body water x 70kg)
.60 x 70 kg

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4
Q

VD = 3 L
Plasma distribution = 3.5
so..confined to _____

A

vasculature

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5
Q

what are the drug distribution patterns

A
  1. drugs confined to blood have high plasma protein binding. high mw (dextran)
  2. Low mw water soluble compounds uniformly distributed in body water (ethanol)
  3. concentrate in specific tissues
  4. non uniform distribution: ability to penetrate membranes and lipid/water solubility
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6
Q

What is volume of distribution

A

a proportionality factor (Vd) that relates the amount of drug in the body (Db) to the corresponding plasma concentration (Cp)
*not a true volume! apparent volume

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7
Q

what does concentration of drug in body after distribution depends upon

A
  1. dose

2. extent of distribution

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8
Q

The larger the Vd, the ____is the fraction of drug in the plasma

A

smaller

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9
Q

Why is the volume of distribution terms of some drugs much greater than the total body water?

A

Bc for some tissues the value of Kp is large.

Kp = tissue to plasma equilibrium distribution ratio

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10
Q

which factors can determine the fraction of drug in body within and outside of plasma

A
  1. volume of plasma (Vp)

2. volume of distribution (Vd)

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11
Q

which factors affect rate of drug distribution

A
  1. perfusion rate limited distribution:
  2. permeability limited distribution
  3. blood flow/tissue perfusion
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12
Q

describe perfusion rate limited distribution

A

in special hepatic capillaries, they lack a complete lining which results in more extensive distribution of drugs out of the capillary beds in which they dont act as anatomical barriers

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13
Q

describe permeability limited distribution

A

the distribution of polar compounds across the biological barrier is slow and is governed by the rate of diffusion that occurs across this barrier

  • drugs hydrophilic in nature
  • brain capillary
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14
Q

in which organs is total blood flow the greatest

A
  1. brain
  2. kidneys
  3. liver
  4. muscle
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15
Q

which organs have the highest perfusion rate

A
  1. brain
  2. kidney
  3. heart
  4. liver
    * total drug conc’s would rise most rapidly in these organs
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16
Q

which factors alter the extent of distribution

A
  1. lipid solubility;
  2. pH- pKa
  3. plasma protein binding
  4. intracellular binding
  5. extent of elimination that continuosly competes with the distribution phenomenon by removing the drug from the system
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17
Q

the faster the rate of perfusion the buildup of concentrations is gont to be ____in those tissues

A

faster

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18
Q

higher lipophilicity, buildup of concentrations is going to be much ______

A

higher

19
Q

High perfussion in brain allows drugs to get in and out easily. Characteristics include:

A
  1. small
  2. lipophilic
  3. remain in unionized form in plasma bc of pka
20
Q

Describe a drug in free form

A

Drug in free form which has abilty to move around in different compartments bind to proteins and keep them loosely bound to them.

21
Q

Drug protein binding may be a ___ or an irreversible process

A

reversible

22
Q

What is a protein bound drug

A
  1. pharmacologically inactive
  2. has restricted distribution
  3. can’t be metabolized
  4. cant be excreted.
23
Q

what is irreversible drug protein binding a result of?

A

chemical activation of the drug which attaches strongly to the protein/macromolecule by covalent chemical bonding. The affinity of the drug to the protein is very strong and stable and very difficult to break.

24
Q

describe reversible drug protein binding

A

implies that the drug binds the protein with weaker chemical bonds, such as H bonds or Van der Waals forces.

25
Q

what is the most common binding protein to which drugs bind

A

albumin

26
Q

albumin binds ___ drugs. alpha 1-acid glycoprotein binds ____ drugs and lipoproteins bind ___ drugs like steroids

A

acidic; basic; neutral

27
Q

High drug protein binding has a low ___ fraction which means you will have a ___Vd because most of drug is bound to protein and not enough drug to distribute to tissues

A

free; lower

28
Q

Low drug protein binding, means high ___ form interaction which leads to ___volume of distribution

A

free; high

29
Q

what is an ex of drug-drug interaction

A

warfarin and phenylbutazone (PBZ)

30
Q

when a highly protein bound drug is displaced from binding by a second drug/agent, a sharp increase in the ____ concentration in the plasma may occur, leading to toxicity.

A

free

31
Q

Albumin has ___ known binding sites that share the binding of many drugs. When does displacement occur?

A

two; when a second drug is taken that competes for the same binding site in the protein as the initial drug.

32
Q

what is the clinical concern with warfarin-PBZ interaction due to?

A

inhibition of CYP2C9 which metabolizes warfarin

33
Q

____ can displace bilirubin from their protein binding sites. As a consequence, less bilirubin is bound and is available in the free form which causes adverse effects in the newborn

A

Sulfonamides

34
Q

The accumulation of drug into tissues is dependent on both the ___ ____ and the _____ of the drug for the tissue.

A

blood flow; affinity

35
Q

what are characteristics of drugs going in and out of blood brain barrier

A
  1. diffusion dependent on lipid solubility & molecular mass
  2. pH and pKa
  3. P-glycoprotein efflux transporters (PGP)
  4. Channels and ion transporters - nutrients
36
Q

what role does Thiopental play in fat

A

blood concentraitons in brain decline. As drug gets eliminated it distributes to brain and adipose tissue. Go in and out of brain easily. It gets redistributed into various organs. In adipose it takes more until it satures. Have to saturate reservoir fat first in order to have sustained amounts

37
Q

what role does DDT play

A

even though pesticide was removed…has high affinity to adipose tissue

38
Q

what are physiological barriers to drug distribution

A
  1. blood brain barrier

2. placental barrier

39
Q

what are other routes of entry into the brain

A
  1. choroid plexus and other circumventricular organs

2. choroid plexus P-gp: pumps out penicillin out of brain

40
Q

what is permeable through the BBB

A
  1. carbon dioxide
  2. oxygen
  3. most lipid soluble substances such as alcohol and anesthetics
  4. water
41
Q

what is impermeable through BBB

A
  1. electrolytes
  2. plasma proteins
  3. non lipid soluble large organic molecules
42
Q

In placenta, Lipid soluble materials readily diffuse from maternal to fetal circulation according to their _______partition coefficients and degree of _____. ____ soluble drugs move much more slowly and _____ to their molecular size

A

lipid/water; ionization

Water; inversely

43
Q

The placental barrier is not perfect. It has ___ and efflux transporters that are relevant to drug distribution across the maternal- fetal interface that can allow ___ to pass through the placental barrier

A

influx; xenobiotics

IDIT (44 decks)

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