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Biochemistry > Absorption & Distribution > Flashcards

Absorption & Distribution Flashcards

1
Q

What is absorption?

A

The process by which a drug move from its site of administration to the systemic circulation

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2
Q

What is distribution?

A

The reversible transfer of a drug to and from the systemic circulation

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3
Q

What is metabolism?

A

Any chemical alteration of a drug by the living system to enhance water solubility and hence excretion

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4
Q

What is excretion/elimination?

A
  • The irreversible transfer of a drug from the systemic circulation
  • E.g renal excretion or sweat
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5
Q

What result does metabolism usually have?

A

Increased solubility

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6
Q

Biologically active compounds must reach the site of action…

A

Biologically active compounds must reach the site of action:
- In sufficient quantity
- For suitable duration otherwise not clinically useful

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7
Q

An oral drug must be able to…

A

An oral drug must be able to:
- dissolve
- survive a range of pHs (1.5 to 8.0)
- survive intestinal bacteria
- cross membranes
- survive liver metabolism
- avoid active transport to bile
- avoid excretion by kidneys
- partition into target organ
- avoid partition into undesired places

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8
Q

What is the green area of the plasma concentration called?

A

Therapeutic

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9
Q

Factors affecting absorption…

A

Factors Affecting Drug Absorption:
- Acid stability
- Solubility
- Permeability
- Lipophilicity
- Metabolism

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10
Q

Acid stability…

A

Acid stability:
- Tablet - pass through the stomach (pH ~ 2) before it gets into the systemic circulation.
- Drug needs to be stable to these acidic conditions at body temperature.
- The pH of the small intestine is ~ 7

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11
Q

Where does the majority of absorption happen?

A
  • Small intestine
  • Majority of absorption often takes place here, due to the comparatively large surface area
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12
Q

Solubility

A

The drug requires sufficient aqueous solubility for dissolution, as only dissolved compound can be absorbed. Fat globules – low surface area – poor surface contact.

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13
Q

Permeability

A

Poor permeability, gut wall metabolism and/or efflux can all lead to poor absorption across the intestinal wall.

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14
Q

Lipophilicity

A

Drugs which are absorbed passively through the gut wall also need to be sufficiently lipophilic to cross cell membranes but polar enough to be sufficiently water soluble

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15
Q

Octanol/water partition coefficient

A

Measure of the extent of ionization as well as intrinsic lipophilicity

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16
Q

Metabolism - Gut wall / first-pass metabolism

A
  • All blood from the stomach, small and large intestines passes to the liver via the hepatic portal vein.
  • Some of the compounds may be metabolised (first-pass metabolism) before the compound reaches the systemic circulation
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17
Q

pH of blood

A

7.4

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18
Q

pH of small intestine

A

6.5

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19
Q

pH of stomach (empty)

A

1.4-2.1

20
Q

Ph of stomach (full)

A

3-7

21
Q

pH of urine

A

5.5-7

22
Q

It is the ? form of compounds

A

It is the neutral form of compounds that is absorbed passively

23
Q

What happens to an acidic group in basic or neutral pH?

A

Acidic group in basic or neutral ph the acidic group will be deprotonated and negatively charged and less likely to pass through the membrane

24
Q

What happens to an acidic group in acidic conditions?

A

In acidic conditions it will be protonated and it will be neutral and more likely to pass through the membrane.

25
Q

What happens to a basic group under acidic conditions?

A

A basic unit like an amine, under acidic conditions will be protonated and it will be charged so less likely to pass through the membrane

26
Q

What happens to a basic group under basic conditions?

A

A basic group under basic conditions will be deprotonated and neutral so it can easily pass through the membrane.

27
Q

If you want a compound to be absorbed into the small intestine…

A

If you want a compound to be absorbed into the small intestine you need something that will be neutral under the conditions of pH 6.5.

28
Q

When the drug gets to its desired site it needs to be…

A

When the drug gets to it’s desired site it needs to be unionised and neutral to be absorbed.

29
Q

Why are unionised drugs passively absorbed?

A
  • It has to pass through a lipophilic membrane which is unfavourable for charged molecules
  • In more acidic meiums, the percentage of an acidic compound ionised is less at pH 7.4 so more compound will have the capacity to be passively absorbed.
  • A basic compound in acidic medium will be more ionised so there will be less in the neutral form and therefore less absorbed passively.
30
Q

Why will charged drugs struggle to be soluble in the membrane?

A

Charged drugs will struggle to be soluble in the membrane as there will be good hydrogen interactions between the drug and the water, have to break them for it to get into the mebrane.

31
Q

What is the main route for most oral drugs?

A

Transcellular absorption

32
Q

What is transcellular absorption?

A
  • The drug must be in solution at the cell surface
  • Drug is in the gut and diffuses through one membrane and diffuses out the other membrane at the other side of the cell.
  • This is done passively.
  • Most you can ever get is an equal distribution of the drug either side
33
Q

What is paracellular absorption?

A
  • Drug passes through gaps between cells which presents fewer barriers then going through one side and then the other side of the cell.
  • Inefficient as pores have a smaller surface area than cellular surface
  • Restricted to low molecule weight hydrophilic molecules
34
Q

What is active transport?

A
  • Drugs carried through the membrane by a transporter
  • Requires energy
  • Against concentration gradient
35
Q

What is eflux?

A
  • Endosomes and lysosomes can take things up and spit them ou
  • Want to avoid this
  • Can avoid this by making sure the drug isn’t recognised or by doing something which neutralises the efflux mechanisms
36
Q

What are the main factors influencing distribution?

A
  • pKa
  • lipophilicity
  • plasma protein binding
37
Q

Tissue pH is slightly less than plasma (blood) pH…

A

Tissue pH is slightly less than plasma (blood) pH therefore basic compounds tend to distribute out of plasma into tissue more than acidic compounds.

38
Q

What is plasma protein binding?

A

When drugs can bind to macromolecules in the blood.

39
Q

Compounds with high plasma protein binding…

A

Compounds with high plasma protein binding are retained in the plasma and cannot therefore distribute into the tissues.

40
Q

What are oligonucleotide drugs?

A

Oligonucleotide drugs are readily degraded by nucleases which are present in the blood.

41
Q

If you want to give someone a drug which is an oligonucleotide…

A

If you want to give someone a drug which is an oligonucleotide you need to do special stuff that these enzymes don’t get to it and easily degrade your drugs.

42
Q

What is the most abundant protein in drugs?

A

Serum albumin

43
Q

What does serum albumin do?

A

It binds various hydrophobic molecules in a non-specific fashion, with a preference for acids (e.g. fatty acids in nature) and steroids

44
Q

Basic drugs tend to bind to…

A

Basic drugs tend to bind to alpha-1-acid glycoprotein

45
Q

What is serum albumins’ main job?

A
  • It’s main job is to transport fatty acids so it’s got pockets which are fairly long and greasy and has space for an acidic unit at the end.
  • It transports these fatty acids into the blood and they’re going to go where they need.
  • Because there are many fatty acids the protein is not very specific and it will also accept long fairly non-polar compounds perhaps ones which have something ionisable to give a negative charge at the end.
46
Q

What is drug-drug interactions?

A
  • Effects which arise when multiple drugs are given to a patient.
  • These can arise when the drugs compete for binding of blood proteins, changing their baseline binding levels and usually increasing the bioavailability of one or both of them.
47
Q

What can albumin binding also be used for?

A

Albumin binding can also be used to increase the long-term solubility and release of hydrophobic drugs

Biochemistry (18 decks)

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