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Clinically: therapeutic agent; used in the prevention, diagnosis, alleviation, treatment, or cure of disease in man or animals Generally: a substance other than food intended to affect the structure or function of a physiological system (i.e. human body) Popularly: a chemical or plant-derived substances that affect psychological, behavioral or physical functions and lead to varying degrees of dependence or addiction Often what determines whether a substance is a drug is its manner of use E.g. alcohol is a beverage – may be considered a drug if used for relaxation or to remove inhibitions or to stimulate appetite Ancient Greeks believed drugs are both poisons and medicine. In modern society, a drug is whatever is ingested to treat any medical or psychological condition
Side Effects Extensions of the administered drugs Often undesirable PHARMACODYNAMICS
Steady State Concentration Serum drug levels at which the input of the administered drug equals the output or elimination of the same drug Wherein the plasma drug concentration is constant Therapeutic Window The well-defined range at which the desired effect occurs between the minimum effective drug concentration and maximum effective drug concentration or minimum toxic concentration Area under the Curve Reflects the actual body exposure to drug after administration of a dose of the drug Unit: in mg*h/L Dependent on the rate of elimination of the drug from the body and the dose administered Total amount of drug eliminated by the body may be assured by adding up The AUC is directly proportional to the dose when the drug follows linear kinetics and inversely proportional to the clearance of the drug The higher the clearance, the less time the drug spends in the systemic circulation and the faster the decline in the plasma drug concentration Half-Life (t½) The amount of time it takes for a drug to be reduced by one-half its original steady of its pharmacologic, physiologic and radiological activity Volume of Distribution (Vd) Also known as apparent volume of distribution A calculated theoretical value Used clinically when trying to determine the leading dose necessary for a desired blood concentration of a drug May also be used for estimating a blood concentration in the treatment of overdose
Indication Disease, symptom or condition for which a drug is intended The therapeutic use of a drug Contraindication A condition which makes a particular treatment or procedure inadvisable because it may be harmful to the patient Relative contraindication Caution should be used when two drugs or procedures are used together Benefits should outweigh the risk Absolute contraindication Could result in a lifethreatening situation A procedure or medication that falls under this category should be avoided Mechanism of Action Mechanism by which a pharmacologically active substance produces an effect on a living organism or in a biochemical system
through a semi-permeable membrane (usually through intestinal absorption). forming a complex Metabolism Compounds begin to break down as soon as they enter the body The majority of small-molecule drug metabolism is carried out in the liver by redox enzymes called cytochrome P450 Wherein the parent compound is converted to new compounds called metabolites Metabolites may also be pharmacologically active. accumulation of foreign substances can adversely affect normal metabolism Three (3) sites of drug excretion Kidney – most important site Biliary excretion or fecal excretion – initiates in the liver Through the lungs – e. the drug is subjected to numerous distribution processes that tend to lower its plasma concentration Some factors affecting drug distribution: Regional blood flow rates Molecular size Polarity Binding to serum proteins. either by intravascular injection or by absorption from any of the various extracellular sites. most often via the bloodstream After entry into the systemic circulation. sometimes more so than the parent drug Excretion/Elimination Compounds and metabolites are removed from the body Usually through the kidneys (urine) or in the lever (feces) Unless excretion is complete. anesthetic gases Response to Therapy Can be measured quantitatively or qualitatively Antibiotics and anticonvulsants Trough levels Toxicokinetics Computational chemists try to predict the ADME-Tox qualities of compounds through methods like QSPR or QSAR The Receptor Theory Most drugs exert their effects by interacting with specialized target macromolecules Receptors bind drug particles. Volume of plasma necessary to account for the total amount of drug in the patient’s body. if that drug were present throughout the body at the same concentration as found in the plasma Unit: in terms of L/kg First-Pass Effect The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes. before being taken up by target cells Route of administration is an important consideration Bioavailability A subcategory of absorption used to describe the extent and rate of an administered dose of unchanged drug that reaches the systemic circulation Must be considered when calculating dosages for non-IV route of administration Distribution When the drug compound is reversibly carried to its effector site. resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation Liberation Occurs when the drug particles are released or broken down from their dosage form and their excipients Absorption Occurs when a drug compound goes into the blood stream.g. initiating events leading to alterations in the biochemical activity of a cell Receptor Functions 1) Receptors largely determined the quantitative relations between the dose or concentration of the drug and their pharmacologic effects Drug action is dependent on receptor affinity and/or the total number of receptors available 2) Receptors are responsible for selectivity of drug action .
plateletderived growth factor.Determinants: molecular size. o Nicotine receptors (by acetylcholine) Sodium influx Generation of action potential Activation of contraction of skeletal muscles o GABA receptors (by benzodiazepines) Increased chloride influx Hyperpolarization of the respective cell 2) G protein-coupled receptors Comprised of a single peptide that has 7 membrane-spanning regions Linked to a G protein having 3 subunits: Alpha subunit that binds guanosine triphosphate (GTP) Beta gamma subunit Response: several seconds to minutes 3) Enzyme-linked receptors Consists of cytosolic enzyme activity as an integral component of their structure or function Also have tyrosinekinase activity as part of their structure Upon binding to ligand: receptor undergoes conformational change (from inactive form to active kinase form) Response: minutes to hours E.g. steroid hormone . epidermal growth factor. atrial natriuretic peptide and insulin 4) Intracellular receptors The ligand must diffuse into the cell to interact with the receptor (must have sufficient lipid solubility) The ligand is transported in the body attached to plasma proteins (i. shape and electrical charge of the drug Changes in the chemical structure of a drug can dramatically increase or decrease a new drug’s affinities for different classes of receptors.e. they interfere with the ability of an agonist to activate a receptor “Pure” antagonist: prevent the binding of agonist molecules to receptors to block their biologic actions “Constitutive” antagonist: in addition to prevention of agonist binding. they suppress the basal signaling activity of receptors Chemistry of Receptors and Ligands Involves formation of chemical bonds: Electrostatic bonds Hydrogen bonds Weak interactions involving van der Waals forces The strength of these noncovalent bonds is inversely related to the distance between the interacting atoms The successful binding of the drug requires an exact fit of the ligand atoms with complementary receptor atoms The bonds are usually reversible.g. albumin) Response: much longer than other receptor families (hours to days) Onset: at least 30 minutes E.g. with resulting alterations in therapeutic and toxic effects 3) Receptors medicates the actions of both pharmacologic agonists and antagonists Agonist: activate receptors to signal as a direct result of binding to it Antagonist: bind to receptors but do not induce the generation of signals. except in Nonselective -blocker phenoxybenzamine Acetylcholinesterase inhibitors in the organophosphate class Lock and Key Theory Ligand: key Activation of receptor: lock Induced Fit Model The receptor is flexible It undergoes a conformational change to bind the ligand Receptor Families 1) Ligand-gated ion channels Responsible for regulation of the flow of ions across cell membranes Response: rapid Duration: a few millisecond E.
Effects of Disease on Drug Concentration and Response 1) Renal disease Excretion is generally accomplished by glomerular filtration Dosages must be reduced based on renal function tests 2) Liver disease Drug clearance is unpredictable Liver function tests are not useful for dose adjustments 3) Heart failure and shock Exposure of brain and heart to higher drug concentration Decreased perfusion to the kidneys and liver impairs drug clearance 4) Elderly patients Prone to more drug interactions and adverse drug reactions Aging causes decrease in organ function Altered drug sensitivity .
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