How do drugs get into cells?

Published on 23/06/2015 by admin

Filed under Complementary Medicine

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 3298 times

Chapter 16 How do drugs get into cells?

Chapter contents

Absorption at the cellular level 123
Distribution of the drug 125

Absorption at the Cellular Level

• Cell membranes are effectively selective biological barriers that inhibit the passage of certain molecules.
• Cell membranes are largely made up of two layers of phospholipids.
• Globular proteins – of varying size and make-up – are embedded within the membrane. These tend to be for transport and regulatory functions.

Drugs or remedies cross cell membranes by the following methods:

• passive diffusion
• facilitated passive diffusion
• active transport
• pinocytosis.

Passive Diffusion (Absorption)

• Accounts for the greatest amount of chemical transport across the cell membrane.
• Uses no energy.
• Transfer occurs down a chemical gradient; in other words, chemicals move from an area of high concentration to an area of low concentration (osmosis) (Figure 16.1); This can be from the gastrointestinal tract to the bloodstream, where the concentration of the substance is lower.
• Chemicals absorbed this way tend to be fat soluble and non-polar, features that allow them to pass across the phospholipid membrane. Some polar molecules can pass through but they must be very small.
• Small molecules will penetrate the membrane more easily, and therefore more rapidly, than a large molecule.
• Because there is rapid removal of substrates due to the circulation flowing rapidly past the site, absorbed chemicals become distributed over a wide area of the body.
image

Figure 16.1 Passive diffusion into a cell.

As the pH varies through the digestive tract, so do the characteristic of many compounds (see Chapter 8 ‘Acids and bases’, p. 55). This leads to certain compounds being more non-polar than others. This then affects how easily they can pass through the membrane. The condition of the digestive tract is therefore an important factor in chemical absorption.

Facilitated Passive Diffusion

• Does not work against a concentration gradient but is a type of enhanced osmosis.
• There is possibly some type of carrier that combines reversibly with the molecules on one side of the membrane and transfers them over to the other side. Such carriers are specific for certain molecules.
• The whole process is limited by the number of carriers present, so it is possible for the system to reach saturation, at which point it will be unable to work any faster.
• The process seems to require no energy.

• Passive Diffusion Through Protein Channels and how these Channels are ‘Gated’

Sodium, potassium and calcium salts, which are vital to the function of cells, need to be able to pass through cell membranes down a concentration gradient. Such a mechanism is provided by proteins, which can be seen by electron microscopy across the cell membranes. These channels can be placed in an open position or closed because they are ‘gated’. In other words, a barrier can go across the channel when required to prevent the flow of the ions.

Various medications can affect the patency (openness) of these sodium, potassium and calcium channels, e.g. calcium-channel blockers (which, as the name suggests block the calcium channels and prevent the flow of calcium) and potassium channel activators (which keep the potassium channels open to allow the flow of potassium out) in heart medication.

Control of the opening and closing can be done in one of two ways:

• voltage gating
• chemical gating or ligand gating.

Voltage Gating

Usually found in neurons, in which a rapid change in voltage is responsible for the generation of an action potential being passed along the axon. Muscle tissue is also sensitive to voltage change. In this respect, the protein gates act like an electromagnet, opening and closing depending on the charge that is present.

Whether these gates are open or closed will dictate the quantity of chemical allowed through the membrane. In this situation, a massive influx of sodium creates an action potential; the opening of the potassium gates, changing the charge back again, stops the action potential.

Voltage gating is covered in more detail in Chapter 31 (see Figure 31.2, p. 237).

Chemical Gating or Ligand Gating

Some protein channels are opened when a specific chemical substance (a ligand) binds to them. This causes a change in shape of the protein, thus opening and closing the channel, depending on what shape they are. The neurotransmitter acetylcholine works in this way. This method of gating allows a nerve impulse to be transmitted from one neuron to the next until it reaches its target organ.

Note: this is not the same as active transport (see Figure 31.1, p. 236) or facilitated diffusion (see p. 124), as the substances pass down a concentration gradient. It is basically controlled osmosis.

Active Transport

Active transport requires a carrier mechanism, that uses energy to move a drug or remedy up a concentration gradient. The rate of movement does not depend on concentration but on the capacity of the carrier mechanism. The sodium–potassium pump is a form of active transport (see Figure 31.1, p. 236).

Pinocytosis

The mechanism by which white cells engulf bacteria and amoebae engulf their prey is well known. The engulfing process is usually by cells that are part of a cell membrane. In this case, the substance is much smaller than that engulfed by the white cells or amoeba and is dissolved in water. The process is often referred to as ‘cellular drinking’, which suggests that the substances that are taken in by the cell are dissolved in liquid.

Pinocytosis probably plays a minor role in drug transport, except for protein drugs (Figure 16.2):

(i) Solute (substance dissolved in water) outside the cell, at the cell surface.
(ii) ‘Pocket’ forms round solute.
(iii) ‘Pocket’ closes, trapping solute inside cell.
(iv) Solute is dispersed in cell.
image

Figure 16.2 Pinocytosis by a cell membrane (see text for explanation).

Distribution of the Drug

Three main factors that have to be considered in drug distribution:

• blood flow
• transport across the cell membrane
• extent of binding to plasma and tissue proteins.

The Importance of Blood Flow

The perfusion rate in different tissues varies as follows:

• High perfusion rates: hormone-producing glands and other tissues that secrete chemicals, the brain, lungs, heart, kidneys and liver, actively dividing cells.
• Moderate perfusion rates: skin, muscles and fatty tissues.
• Low perfusion rates, poorly supplied: teeth, bone, ligaments and tendons.

Other factors will also affect the drug or remedy distribution:

• Patient activity.
• The size of the organ (an enlarged organ will usually have a much higher blood flow).
• Actively dividing cells require a good blood supply (hence the order of perfusion rate listed above).
• Local tissue temperature.

Any tissue that is actively dividing or unusually enlarged will usually enjoy a higher rate of blood flow. This situation is taken advantage of in chemotherapy; actively dividing cells require a good blood supply, and following this logic will therefore receive more of the drug than elsewhere. Conversely, if the blood flow is disrupted in any way, the decreased perfusion rate will reduce the chances of the right amount of drug or remedy getting to the area where it is needed.

This principle is helpful when dispensing herbal remedies, where a herb is included to increase blood flow to an area requiring treatment.

Plasma Protein Binding

A drug or remedy can be bound to circulating plasma proteins (usually albumin) or it can move around freely in an unbound state. If the remedy is bound then it is not free to be used and is said to be inactive, therefore only the unbound remedy works. As these unbound molecules leave the circulation, molecules are released from the blood proteins because the concentration of free molecules is lower (see Figure 16.1, p. 124).

Note: plasma protein binding is extremely important for the effectiveness of a drug or remedy, and also for its potential toxicity.

The Practicalities of Blood–Protein Binding

Blood proteins are reasonably non-specific in their binding habits, which means they are not choosy as to what they bind to. Therefore, different drugs or remedies will compete for the same binding site. Displacement can be a problem if the protein prefers one molecule to another and throws off one chemical in favour of another. It is therefore a potential site for drug–herb interaction:

• Warfarin: is usually bound to plasma proteins and is very easily displaced, which is why patients on warfarin who receives other medication have to have their warfarin levels checked very carefully.
• Berberine (found in Huang Lian, Huang Bai): can increase bilirubin levels by displacement of bilirubin from albumin, by the berberine (Chan 1993).

Effect of Membrane Barriers on Absorption

Generally, small molecules up to a molecular weight of 500 kDa are absorbed through capillary walls even if they are ionized, because the cell junctions are not entirely sealed and are in fact a little ‘leaky’. However, other barriers are not so easy to get through.

• Blood–Brain Barrier

• A very well protected barrier: the glial cells are tightly packed, making a very effective barrier to prevent molecules seeping through (Figure 16.3).
• Lipid-soluble molecules can pass through the membrane relatively easily. Ionized (polar) molecules find this membrane difficult to pass through, because it is un-ionized (non-polar).
image

Figure 16.3 The blood–brain barrier.

• Blood–Placenta Barrier

• A complex structure.
• The fetal capillaries are enclosed by the chorionic villi (the tiny finger-like projections extending from the chorion to the uterine lining). They are separated from the maternal blood vessels by a large cavernous sinus (Figure 16.4).
• Permeability of this barrier is of great interest to both pharmacists and herbalists.
• Generally, the placental membranes offer very little resistance to chemical molecules and only act as a barrier to ionized molecules with a molecular weight greater than 50.
image

Figure 16.4 The blood–placenta barrier.

Reference

Chan (1993) Chan E. Displacement of bilirubin from albumin by berberine. Biology of the Neonate. 1993;63(4):201-208.

Related posts:

Default ThumbnailToxicology Respiratory diseases Problems with lipid metabolism Acids and bases Lipids Phenols