Pharm 100 - Lesson A.5
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Drug Absorption By Inhalation
Drugs which are in the form of a gas may be inhaled and enter the bloodstream through the lungs. This is the way that the general anesthetics work. They are absorbed by the bloodstream in the lungs and distributed throughout the body. When the concentration of the anesthetic in the brain reaches a critical level, the patient will be anesthetized. Bronchodilator and anti-inflammatory drugs used to treat asthma and other respiratory diseases are administered by inhalation in order to produce a direct effect on therespiratory effect and to minimize effects of the drug(s) on other organs.
Drug Absorption Rectal Administration
This method of administering a drug is sometimes used when a patient who is nauseous or vomiting cannot take a drug by mouth. The drug will be absorbed from the rectum into the bloodstream. Drugs are also sometimes administered by this route for their local effect; for example, for the relief of hemorrhoids.
Drug Absorption Oral Administration
This is the most convenient route for the administration of drugs. It is also the only practical route for the self administration of drugs. Let us consider now the steps which a tablet must undergo before it is able to exert an effect. First of all, the tablet must disintegrate into small particles in the fluids of the stomach and/or intestine. Next, these small particles must dissolve in the fluids of the stomach and/or intestine.Once the drug has dissolved, it may be absorbed through the stomach wall into blood vessels and carried in these blood vessels to its site of action. The absorption of a drug into the blood stream is favoured when the stomach is empty since this allows more ready access of the drug to the stomach wall. Some drugs are absorbed through the intestinal wall into blood vessels and carried in these blood vesselsto their site of action. The intestinal surface is a surface of very large area and the intestine is in general the major site of drug absorption. In the case of the vast majority of drugs, it is only the drug that is absorbed into the blood that is available to exert a therapeutic effect. If a drug is not absorbed into the blood stream, it will pass through the intestines and leave the body in the feces. Moreover, only that portion of the drug that goes into solution in the fluids of the stomach and intestines can be absorbed intothe blood. Consequently, it is vital to know how a drug is made into a tablet. The tablet must be made insuch a way that it will disintegrate into small particles and then dissolve in the stomach and intestinal fluids. If the tablet is not correctly made, it will not disintegrate and dissolve and will not be absorbed into the blood.
In order to ensure that tablets are properly made, the government requires the following tests to beperformed:
(1) the tablet must be shown to contain adequate amounts of the chemical responsible for the activity of the drug; and (2) the tablet must disintegrate in a test-tube test. These tests, however, are insufficient to insure that the drug will be effective. The reasons for this are the following: (1) the disintegration time measured in a test-tube may not in fact correspond to the disintegration time in bodyfluids; and (2) tablets are made in different ways by different companies and contain different additives. For this reason, the tablets made by different companies will have different properties.
What we require to know is the blood level of the drug at different time intervals after administration. This information tells us how much drug gets into the blood and is available to exert a therapeutic effect. Bioavailability is defined as the percentage of a drug contained in a drug product that enters the systemic (general) circulation in an unchanged form after administration of the product. The concept also includes the rate at which this entry occurs.
How are drugs named?
Every potential drug has a formal chemical name. However, this name is generally a complex one and not satisfactory for general use. If a drug is promising and a manufacturer wishes to place it on the market, then a special name is selected by a nomenclature committee sponsored by the American Medical Association, the PharmaceuticalAssociation, and the U.S. Pharmacopeial convention. This name which is a non-proprietary name is alsoreferred to as the generic name of the drug. Subsequently, a drug will be assigned a proprietary name ora brand name by the company that will market the drug. If a drug is marketed by more than onecompany, it may have several brand names. The Ontario government now publishes a Drug Benefit Formulary/Comparative Drug Index. This book is prepared by a medical committee and lists only drug products which it believes to be of good quality. The quality of the drugs is determined by inspection of drug factories, by analysis, and by data made available by the Manufacturer, Drug Administration in theUnited States and by the Health Protection Branch in Canada.
Diazepams 5 names
- DrugBenefit Formulary:
- Valium Hoffman LaRoche Limited
- Vivol Frank W. Horner Inc.
- Novo-Dipam Novopharm Ltd.
- Apo-Diazepam Apotex Inc.
- Diazepam Drug Trading Company Ltd.
products from different companies differ in what ways?
It has been shown that drug products made by different companies can result in markedly different blood levels and that this can be of considerable therapeutic importance. The drug digoxin is usedwidely for the treatment of congestive heart failure. It is a very efficacious drug but has considerable toxic potential. It was, therefore, alarming to find that digoxin tablets made by different companies produced markedly different blood levels. In other words, the bioavailability of products made by different companies were different. When drugs are manufactured, additives are used together with the drug in order to ensure appropriate disintegration and dissolution of a drug. Approximately 30 years ago,a paper was published entitled “Outbreak of anticonvulsant intoxication by phenytoin”. Investigation of the cause of this intoxication revealed the following cause. The manufacturer had changed the normal additive in the phenytoin tablets from calcium sulfate to lactose. This change had increased thebioavailability of the tablets, resulting in blood levels of phenytoin rising to toxic levels.
problems with the Therapeutic Jungle
- The first problem: is that, although there is only one generic name for a drug, different companiesselling the drug can sell it using different brand names as seen above with diazepam. The way we handlethis problem in this course is by using the generic name of drugs rather than brand names.
- A second problem: is the overwhelming number of drugs introduced. Why does this occur? Once asuccessful new drug is marketed, a large number of similar drugs with minor changes in chemicalstructure and minor changes in therapeutic activity will appear. This is dictated by the needs ofcommerce. Each drug company feels that it has to capture a share of the market in many types of drugs ifit is to survive economically. A good example is the large number of drugs marketed for the treatment ofthe various forms of arthritis. Many of these new drugs are hailed as panaceas and it is only after severalyears of use that it is realized that a new drug is no better than an old drug.
- A third problem: is the large amount of advertising directed to marketing new and older drugs. Howshould one determine the quality of a new drug that is introduced onto the market? In my view, thisshould be done by reading an unbiased, critical assessment of the drug by a group of experts. Apublication which carries out such assessments is known as the “Medical Letter on Drugs andTherapeutics”. For anyone seeking unbiased information on the value of a new drug, this is the bestperiodical to consult.
Mechanisms for Termination of Drug Action- Redistribution/distribution
The pharmacological action of thiopental, an ultra short-acting barbiturate anesthetic, is terminatedby redistribution. When thiopental is injected intravenously, the patient falls asleep immediately and wakens after approximately 15-30 minutes. The brain is perfused with blood at a high rate while muscle and fat are perfused by blood at a slow rate. After intravenous injection of the drug, the concentration of the drug in the blood is high. The concentration of thiopental in the brain will be elevated and the patientwill fall asleep. At this time, the concentration of thiopental in muscle and fat is low. After a fewminutes have elapsed, the concentration of the drug in muscle and fat increases and the concentration inblood decreases. With the concentration of drug in the blood falling, the drug will leave the brain and move into the blood. As the concentration of the drug in the brain decreases, the patient will awaken. Thus, the action of the drug has been terminated by the drug redistributing from the brain into muscle and fat, but the drug has not been removed from the body.
Mechanisms for Termination of Drug Action - Excretion
Most drugs are excreted through the kidney. Some drugs are very poorly water soluble and cannot be excreted by the kidney. If there was no mechanism in the body to convert these drugs to more water soluble products, they might remain in the body for one's whole lifetime. Let us then consider how the body manages to convert drugs to water soluble substances so that they may be eliminated in the kidney.( Excretion removes the drug from the body.)
Mechanisms for Termination of Drug Action - Liver
In the liver, there are enzymes available for converting drugs to more water soluble products which may be excreted by the kidney. The main enzyme or rather a series of enzymes are the cytochromes P450. These enzymes demonstrate genetic variability and as many drugs are substrates for these enzymes a number of drug interactions occur through two drugs competing for the same enzyme. In general, the mechanisms in the liver which convert drugs to water soluble products also result in the inactivation of drugs. Some chemicals, such as the PCBs and the insecticide DDT, are only very slowly converted tomore soluble water soluble products by the liver. As a result, chemicals of this type persist and accumulate in the body. For this reason, chemicals of this type have been banned in many countries
Drug Interactions - Absorption
One drug may combine with a second drug in the stomach or intestine to form a complex which cannot be absorbed into the blood. An example is the tetracycline group of antibiotics and antacids containing either calcium, magnesium or aluminum. For this reason, tetracyclines should not be taken at the same time as antacids. A drug which increases the movements of the intestine may speed the passage of a second drug through the intestine. For this reason, prolonged contact of the second drug with the intestinal wall is not possible and the absorption of the second drug may be hindered. A further mechanism whereby one drug may retard the absorption of a second is the following: some drugs seriously hinder the movements of the intestine. By so doing, they prevent the mixing of the intestinal contents which normally brings a drug into contact with the absorbing surface of the intestinal wall
Drug Interactions - Displacement
In the blood, the drug is present in two forms; namely, bound to a blood protein and in the free form. Only the free drug can move out of the blood into the tissues to exert its effect. A second drug may displace the first drug from its binding site on the blood protein. This will result in more of the free drug being present in the blood. If the mechanisms in the liver responsible for converting the free drug to its inactive form are saturated and cannot cope with additional drug, then more of the free drug will moveout of the bloodstream into the tissues to exert its pharmacological effect.
Drug Interactions - Changes in Liver Handling of Drug
Drug B may block the mechanisms in the liver responsible for the inactivation of Drug A.Consequently, the amount of Drug A in the body will be greater than usual and one will get a greater pharmacological effect than anticipated. Alternatively, Drug B may speed up the inactivation of Drug A in the liver resulting in less of Drug A in the body than anticipated. An example of the first type is the combined use of the anti ulcer drug, cimetidine, and the antiasthmatic drug, theophylline. Cimetidine blocks the mechanisms in the liver responsible for inactivation of theophylline, allowing theophylline levels in the blood to rise to potentially toxic levels. An example of the second type is the combined use of the antiepileptic drug, phenobarbital, and the anticoagulant, warfarin. Phenobarbital speeds up themechanisms in the liver responsible for the inactivation of warfarin, resulting in a drop in warfarin levelsin the blood and a diminished anticoagulant effect of warfarin.
Drug Interactions - Changes in Excretion
Drug B may hinder the excretion of Drug A by the kidney, thus prolonging the effects of Drug A inthe body. An example is the ability of probenecid to hinder the excretion of penicillin G by the kidney. Alternatively, Drug B may facilitate the excretion of Drug A by the kidney, thus decreasing the bloodlevel of Drug A. An example is the administration of the alkaline substance, sodium bicarbonate, tofacilitate the excretion of aspirin by the kidney when it is taken in overdose.
Drug Interactions - Interactions of Drugs with Potentially Toxic Substances in Food
Well matured cheeses and a variety of other foods contain a substance, related in structure toadrenaline, called tyramine. Tyramine, which is capable of raising blood pressure, is broken down in theliver by an enzyme known as monoamine oxidase (MAO). Thus, under normal circumstances, thetyramine present in foods is not a problem. One class of drugs used for treatment of certain types ofdepression are inhibitors of MAO. Thus, a patient receiving an MAO inhibitor for treatment ofdepression will have diminished levels of the enzyme MAO. If a patient is being treated with an MAOinhibitor and consumes a food containing tyramine, the tyramine will not be broken down to inactiveproducts and the blood pressure raising effects of tyramine will be greatly intensified. Thus, a patienttaking an MAO inhibitor for treatment of depression must receive information on which foods containtyramine and tyramine-like chemicals and avoid such foods. There is also a list of drugs that can causeproblems when taken in conjunction with MAO inhibitors and which must be avoided, e.g. meperidine(Demerol). It is worth noting that the effects of MAO inhibitors persist for a considerable number ofdays after ceasing to take this class of drugs. The bottom-line, take-home message when taking MAOinhibitors is to exert great caution when eating and when taking other drugs.
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