Additionally, since the drug skin to dilate blood vessels in the immediate area in- is not absorbed from the GI tract, it avoids first-pass creases the rate of absorption. Injection of a drug in a metabolism. Intranasal administration is of special nonaqueous solution such as peanut oil or implanta- interest because it causes local effects such as relieving tion of a drug pellet or delivery device further slows nasal congestion and treating allergies, but it can also the rate of absorption.
Subcutaneous implantation of have systemic effects, in which case the drug moves drug-containing pellets is most often used to adminis- very rapidly across a single epithelial cell layer into ter hormones. Implanon and Nexplanon are two con- the bloodstream, avoiding first-pass liver metabolism traceptive implants now available in the United States. The approach is noninvasive, painless, and easy to 40 mm 1. Even more import- small incision just under the skin of the upper arm.
A ant is the fact that intranasal administration allows the woman is protected from pregnancy for a 3-year period blood—brain barrier to be bypassed, perhaps by achiev- unless the device is removed. Absorption is very between neurons. A large number of drugs, hormones, rapid because the area of the pulmonary absorbing steroids, proteins, peptides, and other large molecules surfaces is large and rich with capillaries see Figure are available in nasal spray preparations for intranasal 1.
The effect on the brain is very rapid because blood delivery, although not all drugs can be atomized. Hence from the capillaries of the lungs travels only a short neuropeptides such as the hormone oxytocin can be distance back to the heart before it is pumped quickly administered by intranasal sprays to achieve significant to the brain via the carotid artery, which carries oxy- concentrations in the brain.
The psychoactive study that evaluated the effects of intranasal oxytocin effects of inhaled substances can occur within a matter administration on social behavior in autistic adults. Intranasal absorption can also be achieved without Inhalation is the method preferred for self-admin- dissolving the drug. Direct application of finely pow- istration in cases when oral absorption is too slow and dered cocaine to the nasal mucosa by sniffing leads to much of the active drug would be destroyed in the rapid absorption, which produces profound effects on GI tract before it reached the brain.
Nicotine released the CNS that peak in about 15 to 30 minutes. This damage occurs because cocaine a matter of minutes. Tetrahydrocannabinol THC , an is a potent vasoconstrictor. Reducing blood flow de- active ingredient of marijuana, and crack cocaine are prives the underlying cartilage of oxygen, leading to also rapidly absorbed after smoking.
In addition to the necrosis. This method provides to the diffusion of water-soluble drugs, certain lipid- the opportunity for painless vaccinations and drug in- soluble substances i. These and other capable of penetrating slowly. Accidental absorption of developing techniques have been described by Langer industrial and agricultural chemicals such as tetraethyl and Banga For great- the blood—brain barrier discussed later in the chapter , er detail on environmental toxins, see the online chap- prevents or slows passage of these drugs from the blood ter Environmental Neurotoxicants and Endocrine Dis- into neural tissue.
For example, epidural injection is ruptors on the Companion Website. Transdermal i. The method is convenient because barrier.
In animal experiments, a microsyringe or a can- the individual does not have to remember to take a pill, nula enables precise drug injection into discrete areas and it is painless without the need for injection. It also of brain tissue intracranial or into the cerebrospinal provides the advantage of avoiding the first-pass effect. In this way, experimenters can study the undertaken during pandemics, transdermal delivery electrophysiological, biochemical, or behavioral effects is much quicker than other methods, and it reduces of drugs on particular nerve cell groups.
This method the dangers of accidental needle sticks of health care is described in Chapter 4. Animal research has evolved workers and unsafe disposal of used needles. Patches into potentially important treatment methods for human consist of a polymer matrix embedded with the drug conditions such as cerebral meningitis inflammation of in high concentration. Transdermal delivery is now a one of the protective membranes covering the brain. An common way to prevent motion sickness with scopol- infusion pump implanted under the skin of the scalp amine, reduce cigarette craving with nicotine, relieve can be programmed to deliver a constant dose of antibi- angina pectoris with nitroglycerin, and provide hor- otic into the cerebral ventricles; this device permits treat- mones after menopause or for contraceptive purposes.
These infusion pumps have important uses in tering the body, a limited number of drugs are able to delivering drugs systemically as well. With appropriate penetrate. However, techniques are continuing to be de- software, it is possible to provide pulsed administration veloped to increase skin permeability through a variety of an agent that mimics the normal biological rhythm, of methods.
For instance, handheld ultrasound devices for example, of hormones. An exciting development has that send low-intensity sound energy waves through been the addition of feedback regulation of these pumps, surrounding fluid in the tissue temporarily increase which includes a sensor element that monitors a sub- the size of the pores in the skin, allowing absorption of stance such as blood glucose in a diabetic individual and large molecules from a skin patch.
The downside to these pumps is the electrical current with tiny batteries to the reservoir or risk of infection and frequent clogging, which reduces the patch. The electrical charge repels drug molecules their usefulness in maintaining stable drug concentra- with a similar charge and forces them through the skin tions over prolonged periods. If the amount and duration of Many disorders of the CNS are characterized by current are changed, drug delivery can be restricted to abnormal changes in gene activity, which alter the man- the skin for local effects or can be forced more deeply ufacture of an essential protein such as an enzyme or into the blood.
This process is also capable of pulling a receptor. Gene therapy refers to the application of molecules out through the skin for monitoring. Such deoxyribonucleic acid DNA , which encodes a specific monitoring might be used by diabetic individuals to protein, to a particular target site. DNA can be used more frequently and painlessly evaluate levels of blood to increase or block expression of the gene product to glucose.
An additional approach uses mechanical dis- correct the clinical condition. One significant difficulty ruption of the skin. Such a delivery sys- Administering gene therapy is clearly more challenging IV. Vectors are usu- ally injected directly into the brain region targeted for 1.
Viral vectors are frequently considered 0. Because viruses vary in terms of binding, 0. Human trials have been increasing in number, but much research remains to be done before the safety 0. Nevertheless, Intravenous IV administration produces an instantaneous many animal studies are highly encouraging, and gene peak when the drug is placed in the blood, followed by a rapid decline.
Intramuscular IM administration pro- therapy is believed to have enormous potential for the duces rapid absorption and rapid decline, although IM treatment of debilitating disorders of the nervous sys- administration in oil IM-oil shows slower absorption and tem such as stroke-induced damage, spinal cord injury, gradual decline. After Levine, and Marsh, Keep in mind that the by metabolism or digestive processes, and the extent of peak level for each method reflects not only differences binding to food or inert complexes.
Absorption is also in absorption rate, but also the fact that slow absorption dependent on drug concentration, which is determined provides the opportunity for liver metabolism to act on in part by individual differences in age, sex, and body some of the drug molecules before absorption is com- size. Finally, absorption is dependent on the solubility Meyer Quenzer 3e plete. Advantages and disadvantages of selected meth- and ionization Sinauer Associatesof the drug.
To brain, which is the primary target site for psychoactive understand this process, we need to look more carefully drugs i. We have already shown that Cell membranes are made up primarily of complex the rate of absorption is dependent on several factors. TABLE 1. These molecules are arranged in a bilayer, with their and the aqueous extracellular fluid.
Proteins that are phosphate ends forming two almost continuous sheets found inserted into the phospholipid bilayer have func- filled with fatty material FIGURE 1. This configu- tions that will be described later see Chapter 3. The ration occurs because the polar heads are attracted to molecular characteristics of the cell membrane prevent the polar water molecules. Hence the charged heads most molecules from passing through unless they are are in contact with both the aqueous intracellular fluid soluble in fat.
A B Globular Phospholipid protein charged region Extracellular Negatively charged hydrophilic region. Uncharged hydrophobic region Intracellular Globular Fatty uncharged protein tails. The fatty tails of charged group PO4— at one end hydrophilic and the molecules are tucked within the two charged two fatty uncharged tails hydrophobic.
B The layers and have no contact with aqueous fluid. Movement Stomach 1. The larger the concen- Blood 7. Lipid solubility increases the absorption Saliva 6. For example, the narcotic drug heroin is a simple modifi- cation of the parent compound morphine. Heroin, or diacetylmorphine, is more soluble in lipid than is mor- weak bases. If we put the weak acid aspirin acetylsali- phine, and it penetrates into brain tissue more readily, cylic acid into stomach acid, it will remain primarily in thus having a quicker onset of action and more potent a non-ionized form FIGURE 1.
The lack of electrical reinforcing properties. This occurs despite the fact that charge makes the drug more lipid soluble and hence before the psychotropic drug effects occur, the heroin readily absorbed from the stomach to the blood. In the must be converted to morphine by esterase enzymes intestine, where the pH is around 5. That property makes heroin a prodrug, increases and absorption through that membrane is re- that is, one that is dependent on metabolism to con- duced compared with that of the stomach.
This strategy is one used by pharma- do not move from the stomach to the blood and back ceutical companies that develop prodrugs that cross to the stomach again. In our example, aspirin in the the blood—brain barrier see later section if the active acidic gastric fluid is primarily in non-ionized form and drug cannot penetrate easily. In blood pH 7. Meanwhile, the circu- can become ionized when dissolved in water.
Hence, solved in water, many drugs form two charged ion- although passive diffusion would normally cease when ized particles when placed in water. Although NaCl is drug concentration approached a equilibrium, the a strong electrolyte, which causes it to almost entirely combination of ion trapping and blood circulation of dissociate in water, most drugs are only partially ion- the drug away from the absorbing surface means that ized when dissolved in water.
The extent of ionization absorption from oral administration can be quite high. Acidic solutions have a lower pH, and alkaline basic Drugs that are highly charged in both acidic and solutions have a pH greater than 7.
In a significant influence on absorption as well. For in- general, drugs that are weak acids ionize more readily in stance, the much larger surface area of the small in- an alkaline environment and become less ionized in an testine and the slower movement of material through acidic environment.
Once the intact aspirin molecules reach the blood pH 7. Its more ion- ized form reduces passage 5 through the Ionized Ionized cells to the blood, so absorption from the intestine is slower than from the stomach. Stomach pH 2. Non-ionized plays a part in determining plasma drug level: in women, adipose tissue, relative COOH to water, represents a larger proportion of OCOCH3 the total body weight. Overall, the total fluid volume, which contains the drug, is relatively smaller in women than in men, 4 producing a higher drug concentration 5 at the target site in women.
It should be obvious also that in the smaller fluid vol- COO— ume of a child, a standard dose of a drug OCOCH3 will be more concentrated and therefore will produce a greater drug effect. Ionized Drug distribution is limited by Intestine pH 5.
In the intestine very often is the significant rate-limiting general, those parts of the body in which blood flow factor. For this reason, medication is often prescribed is greatest will have the highest concentration of drug.
Quite rapidly, high concentrations of it should certainly be no surprise to you that the drug drugs will be found in the heart, brain, kidneys, and dosage required to achieve a desired effect is direct- liver. Other tissues with less vasculature will more ly related to the size of the individual. In general, the slowly continue to absorb the drug from the plasma, larger the individual, the more diluted the drug will causing plasma levels to fall gradually. As plasma lev- be in the larger fluid volume, and less drug will reach els fall, the concentration of drug in the highly vascu- target sites within a given unit of time.
The average larized organs will be greater than that in the blood, dose of a drug is typically based on the response of so the drug will move from those organs back into the individuals between the ages of 18 and 65 who weigh plasma to maintain equilibrium.
Hence those organs pounds. However, for people who are very lean or will have an initial high concentration of drug, and obese, the average dose may be inappropriate because then drug redistribution will reduce drug concen- of variations in the ratio of fat to water in the body. Ultimately drug concentration will be in For these individuals, body surface area, which reflects equilibrium in all tissues. Drug redistribution may be both size and weight, may serve as a better basis for responsible for terminating the action of a drug, as in determining drug dose.
The sex of the individual also the case of the rapid-acting CNS depressant thiopental. Thiopental, a barbiturate used for intravenous anes- contrast to the wide fluctuations that occur in the blood thesia, is highly lipid soluble; therefore, rapid onset of plasma, the contents of the CSF remain quite stable. Many substances that diffuse out of the blood and affect Deep sedation does not last very long, because the other organs in the body do not seem to enter the CSF, blood level falls rapidly as a result of redistribution of nor do they affect brain tissue.
However, within 5 minutes, blood vessels and the CSF. In this way, thiopental induces sleep is the distinct morphology of brain capillaries. Figure almost instantaneously but is effective for only about 1. Because that leaves the heart, lipid-soluble drugs are readily the job of blood vessels is to deliver nutrients to cells distributed to brain tissue.
However, the blood—brain while removing waste, the walls of typical capillaries barrier limits the movement of ionized molecules from the blood to the brain. This sys- Aqueduct tem supplies brain cells with oxygen, glu- Lateral of Sylvius cose, and amino acids, and it carries away ventricle carbon dioxide and other waste products.
CSF is B manufactured by cells of the choroid plex- Dura mater us, which line the cerebral ventricles. In addition to artery filling the ventricles and their connecting aqueducts, CSF fills the space between the Cerebral arachnoid membrane and the pia mater vein subarachnoid space to cushion the brain against trauma. B The enlarged diagram shows Brain capillary detail of CSF-filled subarachnoid space and its Cerebral with tight junctions relationship to cerebral blood vessels.
Note how cortex the blood vessels penetrate the brain tissue. Blood plasma Tight Lipid-soluble transport junction Intercellular cleft Carrier-mediated transport Pinocytotic vesicle Blood plasma. Endothelial End foot cell of astrocyte.
There is more discussion molecules through the blood vessel wall because there of the many functions of astrocytes in Chapter 2. Before we go on, we should emphasize that the After Oldendorf, Although the barrier does reduce diffusion are made up of endothelial cells that have both small of water-soluble i. In ad- Finally, the blood—brain barrier is not complete.
Sev- dition, general capillaries have pinocytotic vesicles eral brain areas are not isolated from materials in the that envelop and transport larger molecules through blood and a limited blood—brain barrier exists in other the capillary wall.
In contrast, in brain capillaries, the regions of the brain wherever a functional interaction Meyer Quenzer 3e intercellular clefts are closed because adjoining edges Sinauer Associates e. Also, fenestrations are absent and pinocytotic cal trigger zone, is a cluster of cells in the brainstem that vesicles are rare.
Although lipid-soluble materials can responds to toxins in the blood and induces vomiting. Surrounding brain capillaries are to know which drugs remain non-ionized at plasma pH numerous glial feet—extensions of the glial cells called and readily enter the CNS, and which drugs only circu- astrocytes or astroglia. It is becoming apparent that late throughout the rest of the body.
Minor differences in these astrocytic glial feet contribute to both postnatal drug molecules are responsible for the relative selectiv- formation and maintenance of the blood—brain barrier ity of drug action. For example, physostigmine readily throughout adulthood. It has been shown that blood— crosses the blood-brain barrier and is useful for treating brain barrier characteristics depend on the CNS envi- the intoxication caused by some agricultural pesticides.
In contrast, the structurally related function. Conversely blood—brain barrier characteris- but highly ionized drug neostigmine is excluded from tics can be induced in non-CNS endothelial cells that the brain and increases acetylcholine only peripheral- are cultured with astrocytes see Alvarez et al.
By ly. Its restriction by the blood—brain barrier means that filling in the extracellular space around capillaries and neostigmine can be used to treat the muscle disease my- releasing secretion factors, these astroglia apparently asthenia gravis without significant CNS side effects, but help maintain the endothelial tight junctions.
Also, it it would not be effective in treating pesticide-induced is likely that the close interface of astrocytes with both intoxication. A second approach is to develop a prodrug that is lipid Organ system Days after fertilization soluble and becomes bioactivated by brain enzymes.
As is true for other cell membranes, lipid- of any drug known to be teratogenic in animals should soluble substances diffuse easily, and water-soluble be avoided by women of childbearing age. The potential for transfer of drugs from mother to fetus has very important impli- Depot binding alters the magnitude and cations for the health and well-being of the developing duration of drug action child.
Potentially damaging effects on the fetus can be We already know that after a drug has been absorbed divided into two categories: acute toxicity and terato- into the blood from its site of administration, it circulates genic effects.
Thus high concentrations of drug The fetus may experience acute toxicity in utero after may be found in all organs that are well supplied with exposure to the disproportionately high drug blood level blood until the drug gradually redistributes to all tissues of its mother.
In addition, after birth, any drug remaining in the body. Such and prolonged action because of slow and incomplete sites, called drug depots or silent receptors, include metabolism. It is well known that opiates such as hero- several plasma proteins, with albumin being most im- in readily reach the fetal circulation and that newborn portant. Any drug molecules bound to these depots can- infants of heroin- or methadone-addicted mothers expe- not reach active sites, nor can they be metabolized by the rience many of the signs of opiate withdrawal.
Certain liver. However, the drug binding is reversible, so the drug tranquilizers, gaseous anesthetics, alcohol, many barbi- remains bound only until the blood level drops, causing turates, and cocaine all readily pass into the fetal circula- it to unbind gradually and circulate in the plasma. In addition, alcohol, cocaine, The binding of a drug to inactive sites—called and the carbon monoxide in cigarette smoke all deprive depot binding—has significant effects on the magni- the fetus of oxygen.
Such drugs pose special problems tude and duration of drug action. Some of these effects because they are readily accessible and are widely used. First, depot binding re- Teratogens are agents that induce developmen- duces the concentration of drug at its sites of action be- tal abnormalities in the fetus.
The effects of teratogens cause only freely circulating unbound drug can pass such as drugs both therapeutic and illicit , exposure across membranes. Onset of action of a drug that binds to X-rays, and some maternal infections e. The reduced because the number of drug molecules reach- fetus is most susceptible to damaging effects during the ing the target tissue is dependent on its release from first trimester of pregnancy, because it is during this inactive sites.
Individual differences in the amount of period that many of the fetal organ systems are formed. Second, because binding to albumin, fat, and muscle Many drugs can have damaging effects on the fetus de- is rather nonselective, many drugs with similar phys- spite minimal adverse effects in the mother. For exam- iochemical characteristics compete with each other for ple, the vitamin A—related substance isotretinoin, which these sites. Such competition may lead to much-high- is a popular prescription acne medication Accutane , er-than-expected free drug blood level of the displaced produces serious birth defects and must be avoided by drug, producing a drug overdose.
For example, the an- sexually active young women. Experience has taught us tiseizure drug phenytoin is highly protein bound, but that evaluation of drug safety must consider potential aspirin can displace some of the phenytoin molecules fetal effects, as well as effects on adults. Furthermore, from the binding sites because aspirin binds more read- because teratogenic effects are most severe during the ily. Low binding means more free drug, so these individuals seem more sensitive. Competition among drugs for depot-binding sites Higher-than-expected blood levels of the displaced drug, possibly causing greater side effects, even toxicity Unmetabolized bound drug Drug remaining in the body for prolonged action Redistribution of drug to less vascularized tissues Termination of drug action and inactive sites.
The exponen- Third, bound drug molecules cannot be altered by tial function occurs because very few clearance sites liver enzymes, because the drug is not free to leave are occupied, so the rate is concentration dependent.
For this Hence when blood levels are high, clearance occurs reason, depot binding frequently prolongs the time that more rapidly, and as blood levels drop, the rate of the drug remains in the body. This phenomenon ex- clearance is reduced. Such slow release half-life determination for the stimulant dextroam- means that an individual could test positive for urinary phetamine Dexedrine , a drug used to treat attention THC one active ingredient in marijuana without ex- deficit hyperactivity disorder.
Although this drug is periencing cognitive effects at that time. A list of the half-lives of some common drugs is a drug from highly vascularized organs e. Keep in mind that clearance tissues with less blood flow will reduce drug concen- trations in those organs. Cocaine Coke, big C, 0. Drug clearance reduces blood levels and in large part determines the intensity Acetylsalicylic Aspirin 3—4 hours acid and duration of drug effects.
The easiest way to assess the rate of elimination consists of intravenously adminis- Ibuprofen Advil 3—4 hours tering a drug to establish a peak plasma drug level, then Naproxen Aleve 12 hours collecting repeated blood samples. The decline in plasma Sertraline Zoloft 2—3 days drug concentration provides a direct measure of the clear- Fluoxetine Prozac 7—9 days ance rate without complication by absorption kinetics.
For example, the half-life of orally administered dextroamphetamine Dexedrine is approximately 10 hours. Therefore, 10 hours 1 half-life 75 Amount of drug remaining. After 20 and 30 hours i. After six half-lives, the drug is 50 essentially eliminated, with 1. The curve rep- resenting the rate of clearance is steeper early on, when the rate is more rapid, and becomes more shallow as the rate of clearance decreases.
For any given daily dose Time in half-lives of a drug, the steady state plasma level is approached after a period of time equal to five half-lives time C. Hence, for a given dosing interval, the shorter the half- from the blood is also dependent on biotransformation life of a drug, the more rapidly the therapeutic level rate as well as depot binding and storage in reservoirs of the drug will be achieved. Drugs with longer half- such as fat.
Half-life is an important characteristic of a drug be- For example, if we needed the blood level of drug X cause it determines the time interval between doses. After 4 hours, the three half-lives, a drug given once a day should ideally blood level would have dropped to mg, at which have a half-life of 8 hours. A shorter half-life would mean time we could administer another mg, raising the that effective blood levels would not be maintained over blood level to mg.
Four hours later, another mg 24 hours with once-a-day dosing, and this would di- could be added to the current blood level of mg, minish the effectiveness of the drug. Such a drug would bringing the new value to mg, and so forth. The require multiple administrations in one day or use of a sustained-release product. A half-life significantly longer than 8 hours would lead to drug accumulation because there would be drug remaining in the body when the Desired blood drug level steady state plasma level next Meyer dose 3e Quenzer was taken.
Drug accumulation increases the potential Sinauer for side effects and toxicity. Associates Peak 1 Blood drug level. The therapeu- tic window is the range of plasma drug levels that are high enough to be effective, but not so high that they cause toxic effects. However, the target thera- peutic concentration is achieved only after multiple administrations.
The arrows represent the times of administration. The shape of drug biotransformation, elimination, or storage at of the scallop is dependent on both the rate of absorption inactive sites. If first-order kinetics is assumed, after and the rate of elimination. The smooth line represents one half-life time B , the plasma drug level has fallen drug accumulation in the blood during continuous intrave- to one-half its peak value. Half-life determines the time nous infusion of the same drug.
Although zero-order biotransfor- mum of mg was reached because more drug was mation occurs at high levels of alcohol, the biotransfor- given than was metabolized. However, as we reached mation rate shifts to first-order kinetics as blood levels the steady state level after approximately five half- are reduced see Figure 1.
These chemical changes drugs are eliminated according to the zero-order are catalyzed by enzymes and can occur in many tis- model. Zero-order kinetics means that drug mole- sues and organs, including the stomach, intestine, cules are cleared at a constant rate regardless of drug blood plasma, kidney, and brain. However, the great- concentration; this is graphically represented as a est number of chemical changes, which we call drug straight line FIGURE 1. It happens when drug metabolism or biotransformation, occur in the liver.
A classic example of a drug that is elimi- I because these reactions often occur before a second nated by zero-order kinetics is high-dose ethyl alcohol. Phase I changes involve nonsynthetic When two or more drinks of alcohol are consumed modification of the drug molecule by oxidation, reduc- in a relatively short time, alcohol molecules saturate tion, or hydrolysis.
Oxidation is by far the most com- the enzyme-binding sites i. Type II, or phase II, modifications per hour regardless of concentration. The rate here is are synthetic reactions that require the combination determined by the number of enzyme molecules.
Any called conjugation of the drug with some small mol- alcohol consumption that occurs after saturation of the ecule such as glucuronide, sulfate, or methyl groups.
These metabolic products are less lipid soluble because they are highly 0. In summary, the two phases of drug biotransformation 0. Metabolites formed in the liver are returned to the circulation and are sub- 0. Me- tabolites that are active return to the circulation and 0.
TABLE 0. The sedative drug 0. In contrast, aspirin is converted at first to an 0 active metabolite by phase I metabolism, but phase 20 21 22 23 24 Time h II action produces an inactive compound. Finally, diazepam Valium , curve shows the decline of ethanol content in blood after a long-lasting antianxiety drug, has several active intravenous administration of a large dose to laboratory metabolites before phase II inactivation.
Further, as animals. The x-axis represents the time beginning 19 hours after administration. Plotted data show the change from mentioned previously, some drugs are inactive until zero-order to first-order kinetics when low concentrations they are metabolized.
For example, the inactive drug are reached between 23 and 24 hours after administration. The liver enzymes primarily responsible for Many psychoactive drugs, when used repeatedly, metabolizing psychoactive drugs are located on the cause an increase in a particular liver enzyme called smooth endoplasmic reticulum, which is a network enzyme induction.
Increased numbers of enzyme of tubules within the liver cell cytoplasm. These en- molecules not only cause the drugs to speed up their zymes are often called microsomal enzymes because own rate of biotransformation two- to threefold, but also they exhibit particular characteristics on biochemical can increase the rate of metabolism of all other drugs analysis.
Microsomal enzymes lack strict specifici- modified by the same enzyme. For example, repeated ty and can metabolize a wide variety of xenobiotics use of the antiseizure drug carbamazepine Tegretol i. Among many other drugs, producing a lower blood level and a the most important liver microsomal enzymes is the reduced biological effect.
Among the drugs metabolized cytochrome P CYP enzyme family. Mem- by the same enzyme are oral contraceptives.
For this bers of this class of enzyme, which number more than reason, if carbamazepine is prescribed to a woman who 50, are responsible for oxidizing most psychoactive is taking oral contraceptives, she will need an increased drugs, including antidepressants, morphine, and am- hormone dose or an alternative means of birth control phetamines. Although they are primarily found in the Zajecka, When drug use is terminated, there is a liver, cytochrome enzymes are also located in the in- gradual return to normal levels of metabolism.
Enzymes are classified into which increases CYP 1A2 enzymes. People who are families and subfamilies by their amino acid sequenc- heavy smokers may need higher doses of drugs such es, as well as by the genes encoding them, and they as antidepressants and caffeine that are metabolized by are designated by a number-letter-number sequence the same enzyme.
Such changes in drug metabolism such as 2D6. Among the cytochrome enzymes that are and elimination explain in part why some drugs lose particularly important for psychotropic drug metab- their effectiveness with repeated use—a phenomenon olism are CYP 1A2, 3A4, 2D6, and several in the known as tolerance see the discussion on tolerance later 2C subfamily.
Clearly, drug-taking history zymes of the liver are of particular interest to psycho- can have a major impact on the effectiveness of the pharmacologists because several factors significantly drugs that an individual currently takes. These factors In contrast to drug-induced induction of liver en- alter the magnitude and duration of drug effects and zymes, some drugs directly inhibit the action of enzymes are responsible for significant drug interactions.
These enzyme inhibition ; this reduces the metabolism of drug interactions can either increase bioavailability, other drugs taken at the same time that are metabo- causing adverse effects, or reduce blood levels, which lized by the same enzyme.
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