Drug half-life Half-life is the amount of time necessary to alter the amount of drug in the body by one-half. In the simplest example, the human body is considered as a single compartment of a size equal to the volume of distribution (Vd). The time course of the drug in the body is proportional to both the volume of distribution and the clearance, or elimination, of the drug from the body. Drug metabolism and excretion dictate the drug’s half-life. Elimination half-life (signified by “t1/2”) is defined as the time taken for the concentration of the drug in the blood to fall to 50 percent of its original value (for the plasma drug concentration to reduce by 50 percent). Elimination is 94 percent complete after four half-lives. Dosage intervals are typically based on half-life estimations, and dosage regimes are developed to produce stable drug concentrations in the plasma, keeping the concentration at or above the minimum effective level and below toxic levels. In some circumstances, when an effective level of concentration in the plasma must be achieved quickly, a larger than normal dosage, called a loading dose , is given. Once the required plasma level of drug is reached, the normal recommended dose is repeated at regular intervals (called the maintenance dose ) to maintain a stable concentration of the drug in the plasma (plasma level). Drugs with a relatively narrow therapeutic span are typically prescribed according to the therapeutic index, which is the ratio of the drug’s toxic dose to its minimally effective dose. Plasma levels must be monitored to assess appropriate dosage. the initial drug. In many cases, a drug produces both desirable and negative effects by acting on a single type of receptor in a variety of different tissues or two different receptors. When drugs react with receptors to form a drug-receptor complex, the binding of the receptor to the drug molecule is called coupling . Coupling efficiency refers to the completeness of coupling. In many cases, spare receptors (which are not bound) will also exist on the macromolecule. Drugs interact with receptors by bonding, a chemical force classified in one of three main ways: Covalent; electrostatic; and hydrophobic. Covalent bonds are very strong and may be irreversible, while electrostatic bonds are weaker and hydrophobic bonds are quite weak. Drugs that bind through weak bonds to their receptors are typically more selective than drugs that bond very strongly. This is the case because weak bonds require a very close fit of the drug to its receptor in order for an interaction to occur. Only a small number of receptor types are likely to fit a particular drug structure precisely. Weaker noncovalent bonds require a better fit of drug to receptor binding site and are usually reversible. Very strong bonding (covalent bonds) usually involves less selectivity and irreversible reaction. Drug receptors function in the following ways: ● Receptors determine the quantity of a drug required for a specific response : Receptors tend to dictate the relationship between a dose or the concentration of a drug and its action or effects. The receptor’s affinity for binding a drug determines how much of the drug is necessary to form sufficient numbers of drug-receptor partnerships to produce specific effects, as well as to limit those effects. ● Receptors regulate chemical signaling in the body : Receptors are the reason drug action is selective: The size, shape and electrical charge of a drug determine whether and with what affinity it will bind to a specific receptor. There are many chemically different binding sites available in a cell, tissue or organism; changes in a drug’s chemical composition can significantly increase or decrease a drug’s affinities for different types of receptors, with each of these differences responsible for different therapeutic and toxic effects.
hydrophilic drugs, typically requiring adjusted dosages. The majority of drugs and metabolites are excreted by the kidneys. A number of factors influence at what rate the drug is excreted, including healthy condition or the presence of kidney disease, urine pH, renal blood flow, and the concentration and the molecular weight of the drug. Drugs that are not excreted are metabolized in the following manner. Metabolism, or enzymatic conversion, is a process that terminates the action of many drugs, particularly lipophilic compounds, which readily dissolve in lipids. In most cases, metabolism forms a more water-soluble compound that can more easily be excreted in urine. The majority of enzymes encountered by the drug are located in the gastrointestinal tract and liver. Drugs and metabolites that are secreted by the liver into bile enter the duodenum by the common bile duct, where they pass through the small intestine. Some drugs are reabsorbed back into the blood stream and return to the liver though the process of enterohepatic circulation. The drug is further metabolized or is secreted back into bile (referred to as enterohepatic cycling , which may extend drug action). Drugs secreted into bile move into the large intestine to be excreted as fecal matter. Drugs may enter breast milk through a network of capillaries surrounding milk-producing glands. While amounts are very small, they may affect the infant, who has reduced ability to metabolize or excrete the drug. Lipid-soluble drugs may also be excreted passively though perspiration, saliva and tears. Pharmacodynamics Pharmacodynamics describe how a drug affects the body, including its mode of action: ● Drug : A chemical substance that interacts with a biological system to produce a physiologic effect. ● Receptor : The part of the complex cell or macromolecule to which a drug binds to initiate drug action. ● Ligand : An ion, molecule or molecular group, including hormones and neurotransmitters, that binds to another chemical entity to form a larger complex. Receptors and selectivity Receptors are a primary focus of pharmacodynamics, in that the receptor is the part of the cell or organism that associates with or interacts with the drug, setting off a chain of biochemical events that are the drug’s effects. A receptor is commonly a protein molecule found on the surface of the cell or within the cell in the cytoplasm. Receptors are selective, in that they can only bind with certain complex molecules (ligands). In order for a drug to interact with a receptor, it must have a complementary chemical structure, fitting like a key into a lock. While most drugs will combine with more than one type of receptor, there are highly selective drugs that only bind to one particular receptor. Such a drug is said to be specific – that is, producing effects by specifically interacting with a single receptor. Most drugs interact with several receptors and thus have the capability to produce distinctly different pharmacologic effects. While drugs are classified according to a particular or primary function, no drugs cause only one single, specific effect. This is because drug molecules tend to bind to more than one type of receptor molecule. Even if a drug did bind to only one kind of receptor, the effects would vary because the subsequent biochemical processes would take place in different cell types with a range of biochemical functions. In the development and use of drugs, selectivity is measured by separating effects into either beneficial – or therapeutic – effects, versus toxic effects. In some case, a necessary drug (one that produces desired benefits) causes toxicity when given in dosages that produce the greatest benefits. In these cases, another drug may be prescribed that reduces the toxicity of
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Book Code: MTX1324B
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