Definition: the intestinal, then hepatic degradation or alteration of an ingested medication before it enters the general circulation All blood that circulates to the small intestines must travel through the liver on its way to the systemic circulation. The HEPATIC PORTAL SYSTEM conducts blood from the intestines to the liver where the contents from the intestines can have toxins and other substances removed before reaching the systemic circulation. Some drugs are considered foreign or a xenobiotic by the liver and never reach systemic circulation. First-pass effect

Effect of perfusion on absorption of parenterally administered drugs PERFUSION: the extent to which a tissue is supplied with blood Tissues that are well perfused with blood absorb injected drugs much quicker than tissues that are poorly perfused. Injecting a drug in an area that is far away from the blood stream will slow absorption as the drug will have to diffuse over a long distance. Injecting a drug in an area that has a blood supply, but only very few capillaries will slow absorption. Muscle is well perfused compared to fat so IM medications should be absorbed faster than SQ. Cold temps cause vasoconstriction in SQ capillaries, decreasing the rate of absorption.

Barriers to drug distribution DISTRIBUTION: the movement of a drug from the systemic circulation into tissues Drugs enter and exit the circulation at the capillaries Capillaries have FENESTRATIONS that allow fluid and molecules to enter and exit the circulation. Both hydrophilic and lipophilic molecules can fit through fenestrations. In the brain, the anatomy of capillaries is different. There are no fenestrations and there are glial cells and astrocytes surrounding the capillaries. This is called the BLOOD BRAIN BARRIER. The only type of drugs that can pass through the BBB are lipophilic molecules who pass through the cell membranes Other areas of the body that have similar capillary anatomy are the globe of the eye and the prostate. Capillaries of the placenta have fenestrations, so one should assume that drugs administered to a pregnant female may have an effect on the fetus.

Effect of tissue perfusion on drug distribution Drugs are distributed faster and in larger amounts to tissues that are well-perfused (active skeletal muscle, liver, kidneys, brain. Drug delivery is delayed to poorly perfused areas of the body such as fat and inactive skeletal muscle. REDISTRIBUTION is when drug molecules move back and between the blood and tissues due to diffusion. Redistribution continues until there is equilibrium between the blood and tissues.

Effect of plasma protein binding on drug distribution Plasma is filled with large proteins (album, globulins, etc) that are too large to leave the circulation. Many drugs are made so that a percentage of their molecules bind to these proteins. When bound to a protein, the drug is considered inactive as the drug/protein compound is stuck in the bloodstream. Only the “free form” of the drug is small enough to leave the capillaries and have an effect on the tissues. There is a balance between the bound drug molecules and free drug molecules. When a free molecule leaves circulation, a protein releases its bound molecule to replace the one that left.

Volume of distribution Vd: a value that indicates the extent to which a drug is distributed throughout the body. It assumes that the drug is equally distributed throughout each compartment of the body and that the concentration on the blood is in equilibrium with the concentration in the rest of the body. The larger the Vd, the more tissues the drug is able to penetrate, the lower the drug concentration will be in the blood. Vd are different between animals of the same size but different percentages of body fat. Actual Vd is not known. Apparent Vd is an estimate. Apparent Vd can be determined by knowing the dose of administered drug and the blood concentration of the drug.

Pharmacodynamics: the way drugs exert their effects Even if a drug is well absorbed and well distributed throughout the body, it won’t have an effect on all the tissues that it is distributed to. In order for a drug molecule to have an effect on a cell, the cell must have a receptor that is specific for that drug molecule. The drug molecule and receptor fit together like a lock and key. Every cell does not have a receptor for every drug molecule. A cell with many receptors for a drug will be more sensitive to the drug than a cell with few receptors.

Antagonists and agonists When a drug molecule combines with its specific receptor, it has a specific effect on a cell. The specific effect is the drug’s INTRINSIC ACTIVITY. Molecules with a similar shape to the drug molecule may be able to sit on the receptor site intended for the drug molecule. When it sits in the site, it blocks the action of the drug, or ANTAGONIZES it. The molecule that does the antagonizing is called the ANTAGONIST.

Antagonists and agonists An antagonist’s activity is further classified as competitive or noncompetitive. Competitive antagonism exists when two different drugs fit in the same receptor site and their intrinsic activities are opposite of one another. The effect that is seen depends on which drug is present in greater quantities. This exists with drugs that have reversal agents. This type of antagonism is also known as reversible or surmountable antagonism. Noncompetitive antagonism exists when two drugs fit in the same receptor site but their intrinsic activities are not opposite of one another and the two drugs do not reverse each other. In this case one drug either combines better with the receptor or one drug alters the shape of the receptor when it binds to it. The latter would prevent the noncompetitive antagonist from binding. This type of antagonism is also known as irreversible or insurmountable antagonism.

Antagonists and agonists Drugs are partial agonists if they attach to the same receptor and cause different levels of the same intrinsic activity. Example: if drug A increases the heart rate by 50% and drug B also increases the heart rate, but only by 25%, drug B is a partial agonist. Drugs are partial antagonists if one drug reduces the effect of the other without completely reversing it. Example: if drug A increases the heart rate by 50% and drug B decreases the heart rate by 25%, drug B is a partial antagonist.

Non-receptor-mediated reactions Some drugs produce their effects without binding to a receptor. Example 1: the diuretic Mannitol has the effect of being a diuretic. The molecules of Mannitol are excreted into the urine where they cause additional water to be excreted in the urine via osmosis. Example 2: chelators combine with ions or other compounds to produce their effects. EDTA is anticoagulant found in purple top blood tubes. It combines with calcium in the blood sample to prevent the clotting mechanism of the blood. Example 3: some antacid medications work by binding to HCl in the stomach to weaken the acid and reduce stomach irritation.