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SL12102 - The science of medicines Y1 > Lecture 7- Physiochemical properties of small drugs > Flashcards

Lecture 7- Physiochemical properties of small drugs Flashcards

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Biology 101 flashcards
1
Q

The body cannot absorb solids so for a drug to have biological effect it must be…

A

released/liberated from it’s dosage form at the site of administration and undergo dissolution.

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2
Q

Liberation can significantly effect drug’s bioavailability. What is bioavailability?

A

The quantity of drug that reaches its site of action and the rate at which it gets there.

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3
Q

What effects liberation?

A
  • the dosage form (excipients and manufacture)
  • the physiology of the site of administration (eg. pH at the site)
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4
Q

Slowest step effects…

A

OVERALL RATE

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5
Q

Compare (briefly) liberation/dissolution of tabs, caps, suspensions and solutions.

A
  • Tabs can be coated/uncoated- coatings can dissolve away in GI or coatings do not dissolve in stomach and so there is a delay in the release.
  • Capsule break open in the stomach and release the contents. Capsules are usually faster than tablets.
  • In suspensions the drug dissolves more rapidly.
  • Solutions don’t have to undergo the dissolution process (already in solution)
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6
Q

How do tabs with insoluble permeable coatings get drugs into solution?

A

Tablets with insoluble permeable coating allow water to penetrate without the coating dissolving. The water enters the tablet, and the drug dissolves within to form a solution. The drug reaches the GI tract, and the drug (in solution) leaves the tablet by diffusion.

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7
Q

How do standard coated tablets dissolve?

A

the coating dissolves leaving the simple tablet- drug dissolution of the simple tablet is very slow

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8
Q

Super disintegrants can be put into tablets. What do they do?

A

Swell and break up the tablet apart rapidly into coarse granules. These coarse granules have a bigger SA than simple tablets so have faster rate of drug dissolution

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9
Q

Coarse granules can disintegrate further into….

A

The coarse granules disintegrate into fine granules/primary particles. Dissolution of fine granules/particles is even faster.

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10
Q

Why is the rate of drug dissolution for drugs in suspension so fast?

A

Drugs in suspension don’t need to go through the dissolution process. The rate of drug dissolution when in suspension is even faster.

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11
Q

What is the definition of drug dissolution?

A

The process whereby the drug moves from a crystal to liquid state through two steps.

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12
Q

What are the two steps of drug dissolution?

A
  1. Solvation of drug molecules at the crystal surface generating a stagnant layer of drug solution (the diffusion layer)
  2. Drug molecules diffuse across the diffusion layer into the bulk dissolution medium
    Slowest of these two steps= decides the rate of the overall drug dissolution.
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13
Q

What does the Noyes- Whitney equation describe?

A

dissolution at a constant temperature and pressure.

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14
Q

Give the Noyes- Whitney Equation.
Label it and give units.

A
  • m = mass of drug release from the dosage form into solution (kg)
  • t = time (s)
  • dm/dt = dissolution rate of the drug (kg s-1)
  • D = diffusion coefficient of the solute in the dissolution medium (m s-1)
  • A = surface area of the drug particle (m2)
  • Cs = solubility of the drug (kg m3)
  • C = concentration of drug in bulk solution at time (kg m-3)
  • h = thickness of the boundary layer (m)
  • These units are a bit big, in practice, smaller units would be used.
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15
Q

Once the drug is in solution it must diffuse through the GI epithelium. The drug must diffuse through the mucus membrane and then from the apical to the basolateral of the epithelium. What are the two pathways that the drug molecule may take?

A

transcellular (through the epithelium) and paracellular (between adjacent cells in epithelium).
- The slowest of these steps= controls overall absorption rate of the drugs.

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16
Q

Which is the most common pathway- transcellular are paracellular?

A

transcellular.

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17
Q

In Paracellular absorption, small hydrophilic drugs must diffuse through three types of junctions…

A

tight junctions, adherents junctions and desmosomes.

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18
Q

Describe tight junctions

A

membranes of neighbouring cells fused by intimate connections between cell surface proteins, forming a band around the entire cell. The rate at which the drug molecule diffuses through the tight junctions is rate limiting for the paracellular pathway.

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19
Q

Describe adherents junctions

A

connect actin filaments in the cytoskeletons of neighbouring cells together. Crucial in transmitting mechanical signals and maintaining tissue structure. If a molecule gets past the tight junction, it will then pass through the adherents junctions.

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20
Q

Describe desmosomes

A

the most common cell junction. Fibrous proteins cross the gap between cells and anchor keratin filaments in the cytoskeletons together. Vital for tissue integrity.

21
Q

Transcellular pathway is the major pathway. Name the three ways drugs can cross the membrane through transcellular pathway…

A

passive diffusion, facilitated diffusion and active transport.

22
Q

Describe passive diffusion in transcellular pathway.

A

the main pathway of drug absorption. Solutes diffuse down a concentration gradient.

23
Q

Describe facilitated diffusion in the transcellular pathway

A

selective- if the solutes aren’t recognised by the carrier proteins they wont be taken in this way. This carrier-mediated transport of a drug goes down the concentration gradient.

24
Q

Describe active transport in transcellular pathway

A

selective- if the solutes aren’t recognised by the carrier proteins, they won’t be taken in this way. This carrier mediated transport of a drug goes down or against the concentration gradient. If it goes against the concentration gradient it requires energy input from ATP.

25
Q

Describe the relationship between drug concentration at absorption site, and rate of absorption for both passive and active absorption.

A

Passive absorption has a linear relationship between drug concentration at absorption site and rate of absorption. Active has a positive relationship but it plateaus. Eventually, the specific sites on carrier proteins which specific drug molecules attach to will all be filled by other drug molecules- a point of saturation is reached

26
Q

Endocytosis is a very minor pathway. Describe.

A
  • Internalization of the plasma membrane, engulfing extracellular fluid and therefore some dissolved drug molecules from in the extracellular fluid.
  • Endosomes containing the extracellular fluid and dissolved drug molecules may fuse with lysosomes and contents are degraded by lysosomal enzymes.
  • Some drugs may escape lysosomal degradation and be released through basolateral membrane.
27
Q

Describe passive diffusion.

A
  • A system not in equilibrium moves towards equilibrium which means that flow/flux must occur.
  • Start off with low entropy ordered systems. Over time, due to the random movement of molecules entropy increases and a disordered system is formed and equilibrium is reached.
  • This is a passive process, no energy required.
28
Q

Passive diffusion can be explained through the equation for flux. Give the equation.

A
29
Q

Passive diffusion can also be described using Fick’s first law of diffusion. Give the equation and describe it.

A
  • The flux is directly proportional to the concentration gradient (dc/dx). The further a system is from equilibrium (higher dc/dx), the faster it moves towards equilibrium.
  • Negative sign for the diffusion coefficient indicates flow from high to low concentration.
30
Q

What is the Stoke-Einstein equation used to do?

A

Relates diffusivity to local environmental conditions (temp), properties of medium through which molecule is dissolving (viscosity), properties of the diffusing molecule (bigger drug= lower diffusivity it will have)

31
Q

Give the Stokes- Einstein equation

A
32
Q

Molecules move really quickly but they are blind. Explain.

A

Molecules move really quickly but are blind- they move randomly and collide with other molecules. They don’t move really quickly from A-B. it is not that simple.

33
Q

In a collection of diffusing molecules, the mean distance moved (X) in a specific direction is proportional to the square root of time. Give the equation for speed of diffusion.

A
34
Q

Frick’s law can be used to explain the diffusion of drugs getting through the membrane. Give the equation.

A
35
Q

How is the concentration gradient maintained across the membrane. Surely an equilibrium would eventually be reached?

A

You might think that once the drug has diffused into the membrane equilibrium would be reached and there would be a constant concentration gradient. However, the concentration gradient is maintained by drug absorption into the blood.

36
Q

In Fick’s law equation is flux described as inversely proportional or proportional to h, thickness of membrane?

A

inversely. As epithelium thickness increases, rate of diffusion decreases.

37
Q

In Fick’s law equation is flux described as inversely proportional or proportional to A, area of membrane?

A

proportional

38
Q

How is the SA of the GI epithelium increased?

A

There are folds within the walls of the GI tract which increase surface area. The villi on the surface of these folds increases SA. The microvillus on the villi increases SA once again

39
Q

In Fick’s law equation is flux described as inversely proportional or proportional to D, diffusivity of the drug in the membrane?

A

proportional

40
Q

In Fick’s law, what does the partition coefficient K quantify?

A

The distribution of a drug between the aqueous and liquid phase.

41
Q

If we measure the partitioning of a drug in oil and water we will have an understanding of how ………. a drug is.

A

lipophilic

42
Q

P is the oil/water partition coefficient. Give equation.

A
43
Q

How can we work out P, the oil/water partition coefficient, in a lab?

A
  1. see how soluble the drug is in oil and water and divide the values.
  2. The shake flask method= add equal volumes of water and oil. Shake for extended period. Allow phases to separate. Determine the concentration of drug in each phase using equation.
44
Q

The partition coefficient, P is usually expressed as….

A

LogP

45
Q

If a drug is more soluble in octanol than water, what is the value of P and LogP?

A

P is bigger than one
LogP is bigger than zero

46
Q

If a drug is more soluble in water than octanol, then what is the value of P and LogP?

A

P is less than one and LogP is less than 0

47
Q

Oil phase is usually octanol, so P is often described as the ….

A

octanol/water partition coefficient.

48
Q

We want a balance between a drug being soluble in octanol and water. What are the effects of being too water soluble? Too lipophilic?

A

Hinders permeability of membrane. Too lipophilic= not soluble enough.

SL12102 - The science of medicines Y1 (19 decks)

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