Drugs and Poisons Chapter 4 - 1 hapter 4: The Actions And Effects Of Drugs And Poisons - Pharmacodynamics Up to this point we have been discussing pharmacokinetics, that is, the way in which the body acts upon a drug. In order to consider the data gathered in phamacokinetics, we should look at some essential concepts in pharmacodynamics or how a drug acts upon the body. Keep in mind that drugs do not "cure" diseases or conditions. They alleviate symptoms or maintain life until the body can recover by compensating for a deficiency or excess. Sometimes a body cannot recover and medication must be given for the course of a lifetime. Poisons cause temporary or permanent damage to the body that can result in partial incompacitation or fatality. When considering how drugs and poisons "do their thing" one must be careful to discriminate between the action of the material in question and its effect. A. Terms 1. Drug Action - The action of a drug or poison refers to its biochemical mechanism. How does it act on a molecular level? A drug may interfere with membrane permeability, for example. Or it may be an enzyme inhibitor, hormone analogue and competitor, or DNA intercalator. Let us consider some specific drug action examples. Penicillin is an antibiotic that leads to the destruction of bacteria by covalently bonding to a transpeptidase enzyme which closes up the cell wall during biosynthesis. This is its biochemical mechanism of action. See Figure 4.1. Acetylsalicylic acid, aspirin, as well as acetaminophen, naproxen, ibuprofen, Celebrex®, and Vioxx®, inhibit different forms of the enzyme cyclooxygenase (abbreviated as C OONSCH3CH3COOHORCNHONSCH3CH3COOHOCNHO+ glycopeptide transpeptidaseR'~D-Ala~D-AlaH2NGly~RR'~D-AlaCEnzyme+ D-AlaR'~D-AlaCNHGly~Rpieces ofcell wall+ EnzymeEnzymea penicillinstable enzyme-penicillin complexFigure 4.1 - The Action of PenicillinsDrugs and Poisons Chapter 4 - 2 COX). This enzyme catalyzes first step in the biosynthesis of prostaglandins, prostacyclins and thromboxanes (eicosanoids). Certain eicosanoids are responsible for the inflammatory and pyretic effects of infection. It is believed that the chemical inhibition reaction involves the acetylation and inactivation of the enzyme by aspirin. A mode of action need not involve enzyme inhibition. It could be a simple physical action. Cholestyramine resins are used to form nonpolar aggregates with lipophilic substances. They can be used to interact with nonpolar lipids, fats and cholesterol, in the intestine and limit their absorption in the gut. Cholestyramine can also be used to treat pesticide poisoning. Nonpolar pesticides are stored in fat tissue. As the molecules of pesticide in the intestines are sequestered into the cholestyramine resin more molecules will move from the fat depots in order to reestablish disturbed equilibria in the blood and other body fluids. The resin itself is not absorbed by the intestine but is excreted in the feces. 2. Drug Effects The effects of a drug or poison refer to the observable biological responses such as bacteria dying when the host is treated with penicillin; fever and inflammation subsiding after aspirin therapy; or the reversal of toxicity due to pesticide poisoning after a cholestyramine antidote is given. A primary effect is that sought by the drug discoverer (or poisoner). Secondary effects are side effects, not usually desirable. Sometimes the side effects can be serendipitous such as those seen with sulfinpyrazone which was introduced for another ailment and ended up being used for gout. Aspirin, used for its analgesic effect, lengthens the time it takes for blood to clot and is now prescribed in low doses to prevent heart attacks. General anesthetics can cause vomiting. Sometimes secondary effects can be used therapeutically. Antihistamines, for example, have as their primary effect the alleviation of an immune response. Secondarily, they cause drowsiness and reduce nausea associated with motion. Over-the-counter sleep aides and antinausea preparations contain antihistamines such as dimenhydrinate (Dramamine®), meclizine (Antivert®) and doxylamine (Unisom®). B. Sites of Action The sites of action for drugs and poisons generally are either extracellular, on or within a membrane, or intracellular. Extracellular refers to the GI tract and blood stream which is physically separated from tissues and organs. Extracellular drug activity may be purely physical such as the cholestyramine sequestration of lipophilic materials mentioned above. The action of laxatives can also be physical. Laxatives loosen the stool by absorbing large quantities of intestinal water and stimulating peristaltic action. Cellothyl® and Colgel® contain methylcellulose, a good water absorbant. Metamucil® is psyllium from the Plantago seed. When mixed with an equal volume of water it forms a mucillaginous mass. Caphulac® and CHCH2CH CH2CH2CHCH2N(CH3)3Cl(Questran®)cholestyramine-+Drugs and Poisons Chapter 4 - 3 -OCCH2NCH2CH2N-OCCH2CH2CO-CH2CO-OOOOEDTAethylene diamine tetraacetateNormase® contain lactulose which is poorly absorbed in the intestines and becomes extensively hydrated. Extracellular events may also be chemical in nature. Recall that antacids work by the reaction of bicarbonate with stomach acid. See the ASIDE on antacids, laxatives and antidiarrheals. stomach acidH+ + HCO3-H2CO3H2O + CO2Alka Seltzerbelch The anticoagulant heparin is a polysaccharide sulfate which can form an electrostatic complex with blood-clotting factors (see ASIDE on blood clotting) and prevent the clotting cascade from progressing. Chelating agents such as EDTA tie up heavy metal ions with electrostatic interactions and are used as antidotes in heavy metal poisoning (and I though all I had to do was turn off the radio!). The membrane of the cell can be disrupted by a variety of nonpolar substances. It is currently believed that this may be the site and mechanism of action of anesthesia gases such as diethyl ether and halothane. If the orderly arrangement of protein receptors and channels is disturbed nerve signal transmission will also be disrupted and unconsciousness can occur. Many fungicides are bacterial membrane disruptors. And recall that antibiotics like penicillin prevent the cell wall from being completed. The possibilities for intracellular sites