Drug excretion

Published on 23/06/2015 by admin

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Chapter 18 Drug excretion

Chapter contents

Kidneys 133

Bile 136

Lungs 136

Saliva, tears and perspiration 136

Breast milk 136

Drug excretion can occur by several means:

• via the kidneys

• in the bile

• through the lungs

• in saliva, tears, perspiration

• in breast milk.

Kidneys

• The greatest proportion of drug excretion occurs through the kidneys.

• The liver makes most drugs and remedies water soluble for removal via the kidneys (see Figure 17.1, p. 131).

• One-fifth of the plasma reaching the kidney glomerulus is filtered through the pores in the glomerular cell membrane. The rest passes through the blood vessels around the renal tubules (Figure 18.1).

• Substances with a low molecular weight and not bound to plasma proteins can easily pass through the cell membranes into the tubules.

• Active secretion against a concentration gradient also takes place in the tubules.

Figure 18.1 A nephron: the functional unit of the kidney.

The factors affecting the rate at which the drug or remedy is excreted by the kidneys are:

• kidney disease

• pH of urine

• change in renal blood flow

• concentration of drug or remedy in plasma

• its molecular weight.

Kidney Disease

Useful complexes such as plasma proteins (see Chapter 16 ‘How do drugs get into cells?’, p. 126) can be lost, increasing the amount of unbound remedy in the body, with resulting toxicity. Other compounds may be lost in the urine as the reuptake is reduced.

pH of Urine

The pHs of the urine and blood are interrelated. Tubular secretion, which takes place in the kidneys, is an active process whereby certain molecules and ions are removed from the blood and actively secreted into the tubules. From the buffering equation (Figure 18.2), it is possible to see that:

• When the pH of the blood decreases, more hydrogen ions need to be secreted (thus removing them) to maintain the balance.

• If the pH increases, fewer hydrogen ions need to be secreted (they need to be retained).

Figure 18.2 The buffering equation.

The kidneys are capable of absorbing fluctuations in pH and will adjust the removal or retention of hydrogen ions as necessary. This is why the pH of the urine can vary so widely but the blood pH is maintained within very narrow limits.

Any reduction in tubular secretion due to disease may result in serious ion imbalances in the body. Blood is buffered through a balance between carbon dioxide (CO₂) and bicarbonate concentrations (HCO₃⁻).

The kidneys act when the blood becomes too acidic (right-hand side of the equation) or too basic (left-hand side of the equation) by altering the amount of water lost through urination. The buffering mechanism is associated with sodium balance, which is also controlled by the kidneys (Figure 18.3) and involves an enzyme called carbonic anhydrase (CA; see Chapter 26 ‘Cardiovascular disorders’, p. 198).

Figure 18.3 Reactions in the kidney involving the enzyme carbonic anhydrase (CA).

The erythrocytes also contain carbonic anhydrase, which acts as described above to enable them to carry carbon dioxide in the form of the bicarbonate ion (see Chapter 28 ‘Blood disorders’, p. 209).

There are also other buffers in the blood, such as the plasma proteins, but the kidneys have the most dramatic effect as regards pH balance in the blood.

• How Does pH Affect Drug Excretion?

The filtrate passing into the first part of the renal tubule has the same pH as plasma, roughly neutral. As the pH of urine can be anything from 4.5 to 8.0, this will affect the rate of drug excretion (see Chapter 8 ‘Acids and bases’, p. 55).

Take, for example, a drug that is weakly acidic: the lower the pH (e.g. 4.5), the more free hydrogen ions will be available and the weakly acidic drug molecules will be unlikely to give up their hydrogen molecules. They will therefore remain non-polar (uncharged) and be reabsorbed, through the non-polar cell membranes.

In very alkaline urine (e.g. 8.0), the acidic drug molecules will tend to be removed as they will have more readily given up their hydrogen molecule and become polar (charged), making their reabsorption through the non-polar (uncharged) cell membranes more difficult. They are also more easily removed by the ionic active process.

For a more alkaline drug the converse will occur.

Meat eaters tend to have slightly acidic urine (due to the type and amount of protein in their diet) and vegetarians have slightly alkaline urine. A patient’s diet might therefore be a consideration in the treatment plan.

Change in Renal Blood Flow

Perfusion rates are as important for removal as the distribution of a drug or remedy (see Chapter 16 ‘How do drugs get into cells?’, p. 125). Any change in renal blood flow due to kidney (or another) disease will increase the time it takes for a substance to leave the body.

Concentration of Drug or Remedy in Plasma

Normally, a high concentration of unbound substance will ensure its removal if it is small and water soluble. Many drugs are bound to plasma proteins (see Chapter 16 ‘How do drugs get into cells?’, p. 126). How tightly they are bound then affects how easily they can be removed when they reach the kidneys. This can be controlled by pH or the amount of free substance in the plasma.

Kidney disease affects the degree to which a substance is removed from the body. Changes in pH affect polarity and the abnormal exit of plasma proteins from the kidneys to which these substances might be attached.

Molecular Weight

The larger the chemical, the more difficulty it has passing through a cell membrane even if it is lipid soluble.

Bile

Drugs can be actively removed into the bile for removal from the body. Because this is done against a concentration gradient, and requires an active process, there might be competition for receptors. The drugs in question will be conjugated to achieve their removal, but might then take part in the enterohepatic cycle (see Chapter 17 ‘Metabolism’, p. 131). However, this process is not 100% effective and some substance is removed from the body in the faeces.

Lungs

These account for very little excretion, although small amounts of alcohol will undergo pulmonary excretion.

Saliva, Tears and Perspiration

All will excrete some chemicals, particularly if the drugs are lipid soluble.

Breast Milk

Some chemicals are excreted through breast milk, particularly volatile oils. Although the amounts are likely to be small this process is worth noting because the baby’s digestive system might be affected.

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