DRUG METABOLISM

Introduction:  Metabolism, also called biotransformation, is the process of chemically converting a drug to a form that is usually more easily removed from the body. Metabolism involves complex biochemical pathways and reactions that alter drugs, nutrients, vitamins, and minerals. The liver is the primary site of drug metabolism, although the kidneys and cells of the intestinal tract also have high metabolic rates. Medications undergo many types of biochemical reactions as they pass through the liver, including hydrolysis, oxidation, and reduction.

Microsomal enzyme systems:  During metabolism, the addition of side chains, known as conjugates, makes drugs more water soluble and more easily excreted by the kidneys. Most metabolism in the liver is accomplished by the hepatic microsomal enzyme system. This enzyme complex is sometimes called the P-450 system, named after cytochrome P-450 (CYP-450), which is a key component of the system. The cytochrome P450 enzyme system

Enzyme induction and the role of prodrugs:  As they relate to pharmacotherapy, the primary actions of the hepatic microsomal enzymes are to inactivate drugs and accelerate their excretion. In some cases, however, metabolism can produce a chemical alteration that makes the resulting molecule more active than the original. For example, the narcotic analgesic codeine undergoes biotransformation to morphine, which has significantly greater ability to relieve pain. In fact, some agents, known as prodrugs, have no pharmacologic activity unless they are first metabolized to their active form by the body. Examples of prodrugs include benazepril and, proinsulin and losartan. Changes in the function of the hepatic microsomal enzymes can significantly affect drug metabolism. A few drugs have the ability to increase metabolic activity in the liver, a process called enzyme induction. For example, phenobarbital causes the liver to synthesize more microsomal enzymes. By doing so, phenobarbital increases the rate of its own metabolism as well as that of other drugs metabolized in the liver. In these patients, higher doses of medication may be required to achieve the optimum therapeutic effect. 

Considerations for liver functioning states:  Certain patients have decreased hepatic metabolic activity, which may alter drug action. Hepatic enzyme activity is generally reduced in infants and elderly patients; therefore, pediatric and geriatric patients are more sensitive to drug therapy than middle-age patients. Patients with severe liver damage, such as that caused by cirrhosis, will require reductions in drug dosage because of the decreased metabolic activity. Certain genetic disorders have been recognized in which patients lack specific metabolic enzymes; drug dosages in these patients must be adjusted accordingly. Metabolism has a number of additional therapeutic consequences.  

The roles of fast-pass effect:  For example, drugs absorbed after oral administration cross directly into the hepatic portal circulation, which carries blood to the liver before it is distributed to other body tissues. Thus, as blood passes through the liver circulation, some drugs can be completely metabolized to an inactive form before they ever reach the general circulation. This first-pass effect is an important mechanism, since a large number of oral drugs are rendered inactive by hepatic metabolic reactions. Alternative routes of delivery that bypass the first-pass effect (e.g., sublingual, rectal, or parenteral routes) may need consideration for these drugs. 

RELATED;

1.  ABSORPTION  

2.  PHARMACOKINETICS

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