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Foundation > Drug Absorption and Distribution > Flashcards

Drug Absorption and Distribution Flashcards

1
Q

In pharmacokinetics (what the body does to a drug) there are 4 parameters:

A
  1. Absorption
    From site of administration into the blood
  2. Distribution
    Drug can reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids of tissues
  3. Metabolism
    Body inactivates the drug through enzymatic modification
  4. Excretion
    Drug is eliminated from the body in urine, bile or faeces
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2
Q

Mention the 6 different routes of drug administration

A

1.Oral

  1. Parenteral (injection)
    Intravenous (IV)
    Intramuscular (IM)
    Subcutaneous (SC)
  2. Inhalation
  3. Topical
    creams, ointments, transdermal patches
  4. Sublingual
    (e. g. nitroglycerin)
  5. Rectal
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3
Q

ORAL route -

A

mostly absorption occurs primarily in the ileum

Advantages:
safe
convenient
economical

Disadvantages
irritant drugs cause sickness
not possible in vomiting patients
patient compliance necessary
some drugs (e.g. proteins) destroyed by gut acid/flora
intestinal absorption can be erratic
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4
Q

Explain 5 factors affecting gastrointestinal absorption.

These factors impact on a drugs BIOAVAILABILITY –> the proportion of the administered dose which enters the systemic circulation

A
  1. Gut motility
    (Increase GM, decrease A)
  2. Gut pH
    poor absorption of strong acids and bases
  3. Physico-chemical interactions eg with food, other drugs
  4. Competition for carriers/transporters
  5. Particle size and formulation:
    pharmaceutical preparations are formulated to produce the desired absorption characteristics
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5
Q

Define Absorption across physiological barriers

A

Absorption is the passage of drug from the site of administration to the plasma

main site of absorption of oral drugs is the small intestine

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6
Q

The most important ways in which drugs cross cell membranes are

A
  1. passive diffusion through lipid (SD)
  2. diffusion through aqueous channel (FD)
  3. carrier mediated transport (AT)
  • important for all routes of administration except i.v.
  • drug must cross cell membranes and be absorbed into bloodstream
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7
Q

Absorption across physiological barriers

  1. PASSIVE DIFFUSION
A
  • lipid solubility –> rate of absorption
  • non-polar/ un-ionised substances dissolve in lipid
  • ionised species have low lipid solubility
  • many drugs are weak acids or bases and therefore exist in both ionised and un-ionised forms
  • ratio of ionised : un-ionised determined by pH
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8
Q

Drug absorption – pH and pKa.

The proportion of a drug that is ionised depends on the pH of the solution and the pKa of drug. How?

A

Many drugs are weak acids (proton donator) or bases (proton acceptor)

pKa = measure of the strength of an acid/base

When pH of solution=pKa of drug, 50% of drug is ionised

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9
Q

50% of drug is ionised when ____________

A

When pH of solution=pKa of drug,

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10
Q

Acidic drug in acid solution is

A

LESS IONIZED - neutral

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11
Q

Basic drug in acid solution is

A

mostly ionized = base H+

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12
Q

Basic drug in basic solution is

A

LESS IONIZED - neutral

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13
Q

Acidic drug in basic solution is

A

mostly ionized = acid-

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14
Q

pH - pKa

relations to Approx % ionisation of acids vs of base

A 
if pH - pka = 
-3 ---->Ai=0.1, Bi = 99.9
-2 ------>-Ai=1, Bi = 99
-1 ---->Ai=10, Bi = 90
0 ---->Ai=50, Bi = 50
1 ---->Ai=90, Bi = 10
2 ---->Ai=99., Bi = 1
3 ---->Ai=99.9, Bi = 0.1

see table and practice drawing it

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15
Q

pH partitioning =

A

= acidic drugs accumulate in basic fluid compartments and visa versa

eg.
Aspirin is a weak acid. It has a pKa of ~3.5

→ In the stomach, it is mostly un-ionised (neutral), therefore can pass through the lipid membrane, into the plasma, but it gets trapped in the plasma as it becomes ionized.

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16
Q

Explain the distribution of drugs across body compartments

A

Once in the systemic circulation (following absorption or i.v. injection) drugs must be distributed to their target organ/tissue.

Drug distribution is the reversible transfer of drug from one location to another within the body.

For most drugs this occurs as passive diffusion of the un-ionised form across cell membranes until equilibrium is reached.

17
Q

Distribution is a reversible process – drugs travel from the systemic circulation to the tissue as the concentration in the blood increases, and from the tissues into the blood when the blood concentration decreases.

Tissues that are well perfused e.g. lung liver get the drug ____________.

A

rapidly. Poorly perfused tissues such as fat, muscle and skin the distribution rate into these tissues is slower

18
Q

Factors affecting distribution
can affect in two ways:
1. RATE OF DISTRIBUTION
2. EXTENT OF DISTRIBUTION

A
  1. RATE:
    a. Membrane permeability e.g. Drugs perfuse faster through the highly permeable renal capillaries
    b. Blood perfusion e.g. Drug reaches highly vascularised tissues more rapidly e.g. lung/liver
  2. EXTENT OF DISTRIBUTION
    a. Lipid solubility
    e. g. Ionised lipid insoluble drugs cannot easily enter cells

b. pH-pKa
- -> plasma protein binding
- -> tissue binding

19
Q

Distribution – plasma protein binding drugs

A

Drugs can bind reversibly to plasma proteins in the blood (ppb)

20
Q

__________ is the most important plasma protein (for many acidic and some basic drugs)

Acid-glycoprotein and beta-globulin plasma proteins bind basic drugs

A

Albumin.

21
Q

Only _________ is pharmacologically active

A

FREE DRUG.

Free drug + Plasma protein
<=> Drug-Plasma protein complex

22
Q

Extensive ppb SLOWS drug action and elimination - slower acting BUT prolonged therapeutic effects

A

-

23
Q

Distribution – tissue binding of drugs

A

Drugs diffuse, or are transported, from the plasma into tissues.

Tissue can bind drugs:

  • either due to their composition – lipid soluble drugs will accumulate in fat
  • via binding to cellular components (proteins, pigments, minerals)
    e. g. Tetracyclines (antibiotics) accumulate slowly in bones and teeth, because they have a high affinity for calcium, and should not be used in children for this reason.
    e. g. Chloroquine (an antimalarial drug) has a high affinity for melanin and is taken up by the retina, which is rich in melanin granules, accounting for its ocular toxicity.
24
Q

Distribution – volume of distribution

A

Vd = pharmacological term used to quantify the distribution of a drug between plasma and the rest of the body.

If drugs are confined to the plasma compartment the Vd will be small/low

If drugs accumulate outside the plasma e.g. by being stored in fat, the Vd will be large/high

25
Q

Vd =

A

Vd= amount drug in body/[drug]plasma

Vd = drug in body / drug in plasma

26
Q

Distribution – important compartments

A

Total body water = ICV+ECV = 42L

Extracellular fluid = plasma + ISV

Plasma

Fat

27
Q

Drug distribution

1. Total body water

A

Drugs distributed throughout body water: - are lipid soluble drugs which readily cross cell membranes e.g. ethanol - Vd of ~41.5L

28
Q

Drug distribution

2. Extracellular fluid

A

Drugs distributed in the extracellular compartment:

- cannot easily enter cells because of their low lipid solubility e.g. gentamicin- Vd of ~16L

29
Q
  1. Plasma
A

Drugs confined to the plasma compartment:

- are too large to cross the capillary wall easily e.g. heparin - Vd of ~3.5L

30
Q
  1. Fat
A

Drugs that accumulate outside the plasma compartment e.g. in fat or bound to tissues e.g. Chloroquine - Vd of ~15,000L

31
Q

TRUE OR FALSE?
A low plasma binding protein level which may occur in old age or malnutrition will result in a higher proportion of unbound drug

A

TRUE

32
Q

SUMMARY

A

An acidic drug will be mainly un-ionised in an acidic fluid compartment, and mainly ionised in a basic fluid compartment

When the pKa of a drug = pH of the solution, 50% of the drug will be ionised

Drugs can be bound to plasma binding proteins such as albumin. Only the unbound drug is pharmacologically active

Binding of drugs to plasma binding proteins is reversible and competitive

Foundation (26 decks)

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