How the Body Handles Drugs USING Kidney and Liver-INTERESTING FACT

Concentrations of Drugs in the Blood are a Balance Between Input and Output

• The concentrations of all chemicals in your body are the result of a balance between input and output.
• For drugs the input is usually a steady injection through an intravenous (IV) line or a periodic uptake through pills taken at regular intervals.
• The output of drugs is mainly through 2 organs, the liver and kidney.
• When the output equals the input a steady-state is attained and the concentration will no longer change:

• Graph above shows a drug given as a pill every 8 hours. When the pill is given the serum concentration shoots up. The concentration falls between pills

Graphs are from a Madonna computer simulation.

• The second graph shows the serum concentration rising steadily when a drug is given by IV infusion. When the rate of excretion exactly equals the rate of infusion the concentration levels out.

Role of the Liver

• The liver takes up drugs and oxidizes them using cytochrome P450 enzymes. There are many of these iron-containing enzymes and each type is specialized for oxidizing certain types of chemicals.
• Here are some features of the system:
  • Oxidation of the drugs usually makes them more water soluble or hydrophilic. Hydrophilic compounds are filtered more easily into the kidney tubules than hydrophobic ones.
  • Many of the P450 enzymes are adaptive- that is, exposure to a certain drug will cause greater production of the enzyme that attacks the drug.
  • The P450 enzymes have side reactions that produce compounds that are toxic to the liver. Thus prolonged high level use of any drug may damage the liver.
• The liver has other methods of detoxifying drugs in addition to the P450 system. For example, many drugs are conjugated by attaching various molecules to their side chains.

Role of the Kidney:

• Most drugs are small and if they are hydrophilic they will be filtered across the glomerular membranes into the kidney tubules. If a drug is bound to a plasma protein less of it will be filtered and it may stay in the body for a long time.
• Many things can happen to the filtered drug:
  • Since drugs are foreign substances, most are not reabsorbed actively and often they are rapidly eliminated in the urine. If a drug is reabsorbed it will be eliminated slower.
  • Some drugs are actively secreted into the tubules. There are transporters for secreting both organic acids and organic bases (many drugs fit one of these categories). A secreted drug will be eliminated faster than a similar one which is not secreted.
  • Sometimes we can manipulate the kidney to get faster elimination. In aspirin poisoning, for example, bicarbonate is sometimes given to make the blood more alkaline. This ionizes the aspirin and the ionized aspirin is reabsorbed more slowly from the kidney tubule– it stays in the tubule and is eliminated.

Some Medical Consequences:

• Whenever you use a therapeutic drug you are trying to get its blood concentration above a therapeutic level- if the concentration is below this level it will not produce the desired result.
  • The difference between toxic and therapeutic concentrations is called the therapeutic window
  • But all drugs are toxic at high concentrations and you must also keep the drug below the toxic level.
  • For many drugs this is easy- the 2 levels are far apart (wide therapeutic window), but for others (such as digitalis) the 2 levels are close together (narrow therapeutic window) and the concentration in the blood must be closely monitored.
• If a patient is taking multiple drugs there may be cross reactions involving the P450 enzymes.
  • Drug B may inhibit the P450 enzyme for drug A for example.
  • Drug C may induce a P450 enzyme that eliminates drug A faster, etc..
• There is a tendency to over-dose older persons.
  • As we get older both the liver and the kidney decline, making it harder to eliminate drugs from the blood.
  • The aging kidney loses nephrons. If half the nephrons are lost this will approximately double the half time of elimination for drugs filtered by the kidney
  • This will cause the blood concentration to rise. If we take the same dose as a younger person we may be over-dosed and this can result in a toxic level.
  • It is easy to prevent this for drugs eliminated mainly through the kidney. The filtration rate (GFR) is easily checked and if it is low dosage should be reduced for many drugs.

• Properly dosed younger person: dose is high enough to be therapeutic, but low enough to avoid toxicity

• Same dose given to an older person causes serum concentration to rise to above the toxic level because of reduced kidney function
  • The reduced kidney function produces a longer elimination half time (16 hours in this example)