Chapter 21- Intro to Pharmacology Drugs treated with an acid or a base are salts of the original drug, usually

y have the names mesylate, tartrate, citrate, or hydrochloride after the names. For example, Penicillin G potassium (pencillin G-K) is the potassium salt of penicillin. The Antibiotic erythromycin is available in several chemical forms, o Erythromycin gluceptate- parenteral route o Erythromycin succinate- orally o Erythromycin estolate- is highly absorbable form of erythromycin But the specification of the type of salt may not always be seen in practice -_drugs are normally referred to simply by name- trazadone, rather than trazadone hydrochloride. But the salt name is usually written if it necessary for an effective route of administration, that is the best choice for the patients condition. Penicillin G is the form of penicillin normally given by parenteral route while penicillin V is given orally. The letters after the drug mean something! Many drugs simply take part of the generic name as the trade name o Amoxil is amoxicillin o Buspar is busprione o Platinol is cisplatin o Pilocar is pilocarpine Most of the cephalosporin antibiotics have cef or kef in the name such as Keflex, biocef, and Keftab Pharmacokinetics is a study of the movement of and changes in the drug within the body. o Absorption- how the drug gets into the plasma o Distribution- where the drug goes in the body (fat storage, storage in the plasma, formation of drug protein complexes) o Metabolism- how the drug is changed in the body o Elimination- how the body gets rid of the drug By definition, drugs administered by intravenous injection are not absorbed, as they are injected directly into the blood Factors that determine the amount of drug absorbed o The pH of the compartment Drugs are absorbed only as intact molecules, not as dissolved salts or charged particles. A weak acid will ionize in a basic environment (the duodenum) but wont ionize in an acid environment (the stomach), therefore the drug is absorbed better in the stomach if the drug is a weak acid because less of the molecules are ionized (charged). Acetaminophen and Aspirin are examples of weak acids. (so absorbed in the stomach <3) Diazepam (valium) and chlordiazepoxide (Librium) are weak bases. (absorbed in the duodenum)

o Lipid solubility Cell membranes are made of fats (lipid bilayer) therefore, a drug that is lipid soluble will pass more easier through the cell membrane, and BYPASS the plasma(composed mostly of water). Drugs that are highly lipid soluble are CNS drugs and anesthetics (surgery medicine) o Vascularity of the administration site Since the drug is being absorbed into the blood, the more blood vessels there are at the absorption site, the more rapidly the drug will be absorbed. (sublingual administration provides rapid absorption, as the area underneath the tongue contains a larger number of blood vessels) o If the pH of a body compartment is altered, drug absorption will be altered as well For example, aspirin is absorbed well in the acid environment of the stomach. If an antacid is taken concurrently, the acidity of the stomach fluids will be reduced, and less of the aspirin will be absorbed. The distribution of the drug in the body o Part of the drug will be free in the plasma, meaning it is in the plasma running free (this is the drug that will actually be working in the body). The rest may be stored in some way, such as bound to plasma proteins, or stored in fat. How the drug is stored in the body o storage sites for drugs may be in fatty tissue (the liver, spleen, CNS, or stored fat) if the drug is highly lipid soluble, or protein-drug complexes. o These complexes are where the bound part of the drugs are attached to in the plasma, for example, an acidic drug may be bound to albumin (which is basic) and the bound portion is the inactive act, while the unbound portion does the work o Binding of the drug to plasma proteins stabilizes the drug (lets out the drug at a regular pace) and keeps it from being filtered out and broken down. o http://en.wikipedia.org/wiki/Plasma_protein_binding (read the first couple paragraphs) The volume of distribution and loading dose o The volume of distribution is larger if the drug is stored in many sites and a lower volume of distribution is smaller is it is just stored in one place (the blood plasma). Since it is the free drug in the plasma that determines the therapeutic effect, a relatively large amount of drug may have to be taken before the distribution sites fill up, allowing plasma level Metabolism

o Drugs undergo chemical changes in the body, this is called metabolism. Metabolism occurs in almost any organ, but most of the metabolism is done in the liver. The liver contains a larger number of metabolic enzymes. The most important of these enzymes, pharmacologically, is the cytochrome mixed function oxidase system, or cytochrome P450. o Cytochrome P450 metabolizes most drugs. (cimetidine, barbiturates alter the activity or levels of this enzyme which may result in changes in the rate of metabolism of other drugs)- the level of these enzymes may be influenced by age or gender. For example, neonates and geriatric (young and old people) may not have the necessary enzymes for metabolism of a certain drug. The antibiotic chloramphenicol causes a syndrome in neonates called grey baby syndrome. This occurs because the infants do not have the enzyme (glucuronidase) necessary to metabolize the drug Elimination o Elimination of a drug is the removal of the drug from the body, while clearance is removal of the drug from the plasma. o Clearance is done by the kidneys or liver (sometimes by the livers) o Drug is filtered out in the kidney(provided that it is not lipid soluble or protein boundw) or secreted from the liver into the bile and then made into feces (POOP!). If a drug is lipid soluble, the liver must eliminate it. Drug Half Life o Every drug has a limited amount of time in which it will remain active in the body. The half life is determined by the clearance rate which is influenced by: The rate of elimination of the drug How quickly the drug might be inactivated in the body (by enzymes) o For example, acetylcholine is not used therapeutically as a drug because it is rapidly inactivated by plasma enzymes called cholinesterases, its half life is only a couple of seconds. o Some lipid soluble drugs have very long half lives because they pass through the liver and are exerted into the bile. However, instead of being eliminated from the body, when the bile (containing the drug) is realized into the intestine from the liver and gall bladder, the drug is reabsorbed through the intestinal wall. This phenomenon is called enterohaptic recycling. (the half lives of these drugs can be as long as several days) o Alteration of Drug Half-Life Drugs excreted through the kidney will ionize in urine (pH various but naturally it is around neutral) that is of a different pH, or remain intact when the urine pH is favorable.

Rate of drug elimination may be changed if (ingesting acidic drinks, decreasing respiration rate, or taking bicarbonate for an upset stomach, which changes the balance of proteins in the blood, causing changes in the amount of free drug in the plasma and thus influencing the rate of elimination. Half life of a drug also depends on the ability of the patient to clear the drug. (poor renal functions, decreased liver function) The Adverse Effect Profile o Understand the mechanism of the drugs action and using knowledge of physiology, anticipate its physiological effects Drug-Drug Interactions o Compete to get absorbed <3 (the higher concentration of the drug wins ;] ) o Sucralfate, a drug used to promote healing of the stomach lining, binds to many drugs in the digestive tract and prevents or decreases their absorption; the tetracycline drugs (tetracycline, doxycycline, minocycline, etc), if taken with meals or mineral supplements (which contains iron, calcium, and magnesium), bind to these minerals in the intestine and cannot be absorbed into the body. o Changing the pH of the environment, such as antacids (which decrease the absorption of acidic drugs like aspirin) but in contrast, the decrease in acidity might increase the absorption of a drug that is more basic in nature (diazepam)(valium) o Changes in local blood flow Drugs are injected intramuscularly because they are absorbed more slowly than intravenous injection. Including a vasoconstrictor, such as norepinephrine, or local anesthetic (procaine) will decrease local blood flow and reduce the rate of absorption even further. This allows more drug to be injected, which is then absorbed over a long period of time. o Drug Distribution- Protein Binding interaction Many drug interactions occur because two or more drugs bind to the same plasma proteins. The one that binds the tightest and the fastest wins leaving the loser floating in the plasma. This results in too much of the loser drug as free drug in the plasma. The free drug (the one that does work) is greater in effect and greater in potential for toxicity. Since increased amounts of the free drug are available to work in the body, this drug may cause toxic effects. Remember that the free drug is more quickly metabolized or filtered out by the kidney, so it will be eliminated from the body faster as well. A good example of a drug that is highly plasma protein bound is warfarin (Coumadin). This drug has protein biding interactions with many drugs. The majority of protein binding interaction occur with drugs bound to the plasma protein

albumin. These drugs are many, and include carbamazepine, warfarin, propylthiouracil, oral hypoglycemic drug (tolazamide, chlorpropamide), and erythromycin. Drug-Drug interactions at the level of drug clearance o Whenever a patient takes a drug, that drug is designed to do its job and leave. The body eliminates the drug after a period of time, by expelling the drug through the lungs, urine, or bile. The drug may be broken down with enzymes (metabolism) in the liver or filtered out of the blood by kidneys. Drug-Drug interaction- Competition for Drug Clearance o Isoproterenol acts on the heart to increase heart rate and increae electrical conduction through the heart tissue. Too high of a dose can cause tachycardia and arrhythmias. Thyroid drugs sensitize the heart to the effects of norepinephrine and epinephrine, which are produced under stress. Taking both drugs together could increase the probability of a fatal arrhythmia. o Drugs such as furosemide and thiazide diuretics, cause a large amount of potassium loss. The heart is very sensitive to potassium levels and when other drugs that alter potassium are taken concurrently, severe arrhythmias may result. o Drug Agonism and Antagonism An agonist is a drug specially designed to mimic with the actions of an endogenous substance. The lining of the blood vessel (the vascular endothelium) normally produces a vasodilating (widens blood vessels) substance, nitric oxide (NO- also called endotheline). The NO is used to activate an enzyme, which makes cyclic GMP, a potent vasodilating agent. The antianginal drug nitroglycerin is a glycerol molecule with three nitro groups attached to the molecule (NO2). These nitro groups are removed from the molecule and converted to nitrous oxide. The nitrous oxide then inserts itself into the metabolic pathway and cyclic GMP is formed, just as with the endogenous substance. Basically there are drugs that can mimic certain enzymes. The drug edrophonium binds to an enzyme, acetylcholinesterase, and inhibits it. Acetylcholinesterase is used by the body to break down acetylcholine, a neurotransmitter. Edorophonium, by inhibiting the enzyme, increases the amount of acetylcholine available, and thus magnifies its effects. This drug does not increase the actions of acetylcholine directly, but it is an indirect agonist

The alpha 1 receptor for norepinephrine causes vasoconstriction, when stimulated. The drug prazosin binds to the same receptor and blocks the binding of norepinephrine in a competitive manner. Thus, the effects of norepinephrine are antagonized by the prazosin, as the NE cannot always bind to the receptor and exert its effects. Addictive, Synergistic, and Antagonistic Effects o Drugs that produce the same physiological effects may behave differently when taken together If two drugs both lower blood pressure by the same mechanism (blocking calcium channels) and both are seen to lower systolic pressure by 5%, then, by taking both drugs currently, we would expect a 10% decrease in systolic pressure. This is called an additive effect, the amount of effect of one drug is adding to that of another. Two drugs have the same therapeutic effect but do not work by the same mechanism, say, one drug blocks calcium channels, reducing systolic pressure by 5%, and the other blocks norepinephrine receptors (also reducing systolic pressure by 5%)- this time, taking both drugs concurrently produces a decrease in systolic pressure of 15%. This is called synergismtwo drugs taken together producing a physiological effect that is much greater than the effects of each drug added together (5%+5%=10% not 15%). A drug may also interfere with the actions of another drug, reducing the physiological effect. This is called antagonism. o Additive and Synergistic Drug Toxicity Many drugs have adverse effect that will be additive or synergistic with those of another drug, which produces toxicity to an organ or system. Furosemide and streptomycin both produce ototoxicityfurosemide lowers the fluid volume in the inner ear, reducing stimulation of the auditory nerve, and aminoglycoside antibiotics (streptomycin) are directly toxic to the auditory nerve. When these drugs are taken alone, the effects are manageable; however, when taken concurrently, the effect on the auditory system more than doubles. These drugs synergize and can produce significant damage to the ear, with much more ototoxicity than would be expected from either drug alone. The interaction between a central nervous system (CNS) depressant and an antihistamine. Antihistamines produce a small amount of CNS depression, some more

than others. However, when antihistamines are taken with another that produces a large amount of CNS depression, such as anticonvulsants, antipsychotics, or even alcohol, the effect can be lethal. The same is true with ethyl alcohol, which is an extremely potent CNS depressant. Effects of alcohol with CNS depressants If alcoholic beverages are taken with sedating drugs, such as antiseizure medications, antipsychotics, antidepressants, or barbiturates, the central and adutonomic nervous systems can be depressed to an extent that they are unable to function, and death could result. Since the depressant effet is so much greater when both drugs (alcohol and DNS depressants or certain antihistamines) are taken concurrently, this is a synergistic effect. Synergistic Therapeutic Effects- Too much of a good thing Some drugs may synergize to produce too much of a beneficial effect as well. The effects of aspirin and warfarin. Aspirin is an antithrombotic drug; it affects platelets in the blood, to make them less sticky reducing the formation of small thrombi (clots). The reduction in the stickiness of the platelets may decrease the activity of clotting factors on the platelets as well, thus reduce clotting. Warfarin is an anticoagulant that works by interfering with the recycling of vitamin K, which is required for many of these clotting factors to work properly. When aspirin and warfarin are taken together, the effect of the two drugs synergize and blood clotting is decreased to the extent that internal bleed may occur. Additive Therapeutic Effects The antithrombotic drugs aspirin and dipyridamole are drugs that have additive therapeutic effects. Since both drugs have the same physiological effect (inhibition of platelet function), the overall therapeutic effect of combination therapy will be predictable-approximately the sum of the effects from each drug. Concurrent therapy may be beneficial, as lower doses of each may be given, reducing the level of side effects from each drug, while the therapeutic effect is maintained. So if you take both drugs in lower doses, it will equal the sum of the therapeutic effect that the patient wants, while lower the side effects of both of the other drugs <3. Antagonism of Therapeutic Effects Some drugs may antagonize (block) the effects of others. This antagonism might be a direct antagonism, where one drug

physically blocks the binding or actions of another, or it might be more indirect in nature (blocking the activation of the second drug or creating an environment in which it is unfavorable for the other drug to work). Probenecid, a drug used for gout, must be transported into the kidney tubules in order to be effective. Aspirin uses the same transport system to enter the kidney tubules and be excreted. Concurrent therapy with aspirin would thus antagonize the effects of probenecid, as it would inhibit transport of the drug to its site of action. A patient with Parkinsons disease might be taking Sinamet, which is a combination of L-dopa and the enzyme inhibitor carbidopa. The carbidopa inhibits the actions of the enzyme drop decarboxylase, which normally converts L-dopa into dopamine. The same patient might also be prescribed amethyl dopa, for hypertension. In order to be effective, this drug must be converted to a methyl dopamine in the sympathetic neuron, using the same enzyme pathway as L-dopa. By inhibiting the actions of dopa decarboxylase, the Sinamet would also inhibit the actions of the a-methyl dopa, by inhibiting its activation. o Drug-Food Interactions In addition to interactions between drugs in the body, there are also many drugs that interact with chemicals found in certain foods that should be avoided during therapy. It is the responsibility of the pharmacy, as well as the prescriber, to be sure that the patient knows to avoids these types of foods. The anticoagulant warfarin works by decreasing vitamin K, which decreases the activity of the vitamin Kdependent clotting factors. Vitamin K is present in foods such as green leafy vegetables. Vitamin K absorbed from the green vegetables replaces the vitamin K lost through the action of the drug and reduces the efficacy of the drug (a drug food antagonism). Monoamine oxidase (MAO) inhibitors inhibit the breakdown of norepinephrine and elevate mood. A chemical called tyramine (present in foods such as cheese, chocolate, wine, and other types of food and drink) is normally metabolized by MAO. Tyramine can cause norepinephrine to be released in large quantities. If these foods are eaten during therapy with a MAO inhibitor, large amounts of norepinephrine will be produced that now cannot be broken down, as

breakdown of norepinephrine has been substantially inhibited by the drug. This rapid and large increase in norepinephrine levels can cause a hypertensive crisis, which could be fatal (a drug food synergism). Blood Laboratory Values- For the exam, you may be required to be familiar with basic laboratory tests, what they refer to, and general normal values. You might especially be aware of common laboratory tests for renal clearance, respiratory function, and liver function. Some commonly used blood test include o Test for renal function: These include blood urea nitrogen (BUN) and creatinine levels. The rate at which the kidney clear creatinine (a produce of muscle breakdown) is an indicator of kidney function. A high rate of creatinine clearance indicates proper kidney function, while a low rate indicates that the patient may have renal impairment. A high level of urea (BUN) may also be an indicator of poor renal function. Too high of a level of urea may also be indicative of gout. The ratio of blood urea nitrogen to vreatinine is also an indicator of renal function. o Liver function: Liver function is measured by means of the activity and levels of serum enzymes. In general, the lower the levels of liver enzymes, the better. Test for liver function include the serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Elevated of SGOT may be seen in various conditions, such as rheumatoid arthritis, pancreatitis, muscular dystrophy, and asthma. Falseley elevated SGOT levels may be seen in certain conditions (inhalation of calcium dust or therapy with opiates and certain antibiotics). An elevated AST/ALT ratio may indicate liver damage due to alcohol (cirrhosis), or hepatitis. o Blood glucose levels: blood glucose is normally measured in either the fasting state (the patient has had no food in 12 hours) or the postprandial state (the patient has eaten recently). A high level of blood glucose may indicate that the patient is an uncontrolled diabetic, while low levels may indicate hypoglycemia. A diagnosis of either condition is not made on the basis of one serum glucose determination, but requires a long and involved test called the glucose tolerance test, where serum levels of glucose are measured at intervals after the patient drinks a concentrated solution of glucose (Glucola). o Serum blood gasses: A determination of respiratory function may be made by analyzing the partial pressures of oxygen and carbon dioxide in the blood. A low oxygen level or high level of carbon dioxide may indicate depressed respiratory function. o Electrolyte levels: These are often assessed in a hospital setting, to be sure that the serum levels of sodium, potassium and calcium are

within normal levels. The most important of these is the potassium level, which may need to be supplemented to protect heart function, particularly before a surgical procedure.