By I. Peratur. Concordia University, Mequon Wisconsin.

As a result order 0.5 mg dutasteride with mastercard, genetic testing of the RYR1 gene be recognized even if they do have one or more surgeries order 0.5mg dutasteride mastercard. In addition discount 0.5mg dutasteride free shipping, genetic testing however generic dutasteride 0.5mg amex, it is important for his or her family members to for families may become more complex as knowledge know they also have a risk for MH susceptibility, since it about MH grows. The authors family member who has MH susceptibility should tell explained that although MH susceptibility has typically their doctor about their family history. Since MH may go been described as an autosomal dominant trait caused by unrecognized, it is important that anyone who has had a a single gene that is passed from one generation to the close relative die from anesthesia notify the anesthesiol- next, they believe MH susceptibility may actually depend ogist before any type of surgery is planned. People with upon various genetic changes that occur in more than one a family history of MH susceptibility may choose to meet gene. RYR1 and DHPR affected person may consider having a test to see if they alpha 1 subunit), not all changes in these genes lead also inherited MH susceptibility. For example, although Although there are many people who have the same at least 20 different genetic changes have been identified symptoms of MH when exposed to trigger drugs, genetic in the RYR1 gene that can lead to MH susceptibility, research has shown that there are probably many genes, some people who have certain types of these changes located on different chromosomes, that can all lead to actually have a different genetic condition that affects the MH susceptibility. This indicates that there is genetic het- muscles called central core disease (CCD). Infants with erogeneity among different families with MH suscepti- this autosomal dominant condition typically have very bility, meaning that different genes can lead to the same poor muscle tone (i. Among families who 2001, researchers identified six different types of MH have CCD, there are some individuals who do not have susceptibility. Although specific genes have been discov- the typical muscle changes, but have MH susceptibility ered for some of these types, others have been linked instead. Hopefully, future research will help scientists only to specific chromosomal regions. The exact number of individuals who are born with a genetic change that causes MH susceptibility is not • MHS3—Located on chromosome 7q21-22. However, it is estimated that internationally one in • MHS4—Located on chromosome 3q13. Specific 50,000 people who are exposed to anesthesia develop an gene and protein unknown. Symptoms such as rapid breath- Signs and symptoms ing, rapid heart rate, and high body temperature can usu- ally be detected with various machines or devices that Although the specific symptoms of malignant hyper- examine basic body functions during surgery. Muscle thermia can vary, the most common findings include: stiffness of the jaw, arms, legs, stomach and chest may be • stiffness/spasms of jaw muscles and other muscles noticed as well. If the diagnosis is made • rapid breathing, causing decreased oxygen and during or after surgery, immediate treatment is needed to increased carbon dioxide in the blood prevent damage to various parts of the body or death. If a • rapid or irregular heartbeat person has a suspicious reaction to anesthesia, he or she • high body temperature (over 110°F) may undergo a muscle biopsy to confirm MH suscepti- bility at a later date. As of March 2001, existing genetic testing identifies some The diagnosis of MH susceptibility can be made changes that have been seen among families with MHS1 before or during a reaction to a triggering drug. Research studies may provide information the diagnosis is made before a susceptible individual is for families with MHS2, MHS3, MHS4, and MHS5 as exposed and/or develops a reaction. Sometimes the testing requires DNA from only one people who learn they have an increased chance for MH affected person, but in other cases, many samples are because they have a relative with MH susceptibility. However, until Testing these individuals requires a surgical procedure genetic technology improves, the contracture test that is called a muscle biopsy, in which a piece of muscle tis- done on muscle tissue will likely remain the “gold stan- sue is removed from the body (usually from the thigh). The muscle is taken to a laboratory and is Treatment and management exposed to halothane (a triggering anesthetic) and caf- feine, both of which cause any muscle tissue to contract, The early identification of an MH episode allows for or tighten. Thus the test is called the caffeine halothane immediate treatment with an “antidote” called dantrolene contracture test (CHCT). This medication prevents the release of calcium viduals with MH susceptibility is more sensitive to caf- from the sarcoplasmic reticulum, which decreases mus- feine and halothane, causing it to contract more strongly cle stiffness and energy production in the cells. In addition, the anesthesiologist will change the whether a person has MH susceptibility or not.

In contrast discount 0.5 mg dutasteride mastercard, the time to reach steady widely throughout the body; in fact order dutasteride 0.5 mg with visa, it does distribute to state is affected by neither the dose amount nor dosing various tissues generic dutasteride 0.5mg visa, such as the liver purchase dutasteride 0.5mg on line, lungs, eyes, and adipose frequency. Since the total volume of the body does not equal fected by the elimination rate (which is reflected in the 4200 L, it can clearly be seen that this is not a “real” vol- t1/2). Giving a larger dose or giving the dose more often ume but one that relates the blood concentration to the will not change the time needed to reach steady state amount of drug in the body. Just as it takes approximately five half-lives for a Protein Binding drug to be essentially (97%) eliminated, it also requires five half-lives for a drug to reach steady state. This is ex- Most drugs bind to plasma proteins such as albumin and emplified in the concentration–time profiles of Figure 1-acid glycoprotein (AGP) to some degree. The hypothetical drug in this example has a half-life comes clinically important as it is assumed that only un- of 8 hours and is dosed every 8 hours. The graph shows bound (free) drug is available for binding to receptors, that at about 40 hours (five half-lives), the maximum being metabolized by enzymes, and eliminated from the and minimum concentrations become consistent, indi- body. For example, phenytoin is approximately 90% bound to plasma proteins, leaving 10% of the concentration in the blood as free drug and available for pharmacologi- 1000 cal action and metabolism. If the presence of renal dis- ease or a drug interaction were to alter the degree of protein binding to only 80%, this change could have substantial clinical consequences. Even though the total t1/2 = 8hr percent bound changes relatively little, the net result is to double the amount of free drug. However, for most drugs, displacement from protein binding sites re- sults in only a transient increase in free drug concentra- tion, since the drug is rapidly redistributed into other body water compartments. Thus, interactions or changes 10 in protein binding in most cases have little clinical effect 0 despite these theoretical considerations. This nonlinearity often occurs be- cause the drug-metabolizing enzymes for the drug be- NONLINEAR PHARMACOKINETICS come saturated at typical blood concentrations, such that despite increases in dose, drug is still metabolized The underlying assumption in the discussion of these at the same rate and blood concentrations go up unex- concepts is that the drug of interest follows linear phar- pectedly. In this case, following Michaelis-Menten en- macokinetic principles; that is, the concentrations zyme kinetics, the maximum velocity (Vmax) has been achieved are proportional to the dose given. For exam- reached and the rate of drug metabolism remains con- ple, a doubling of the dose will produce a doubling of stant. For some drugs, however, this is not the case: an increase in dose may produce a con- centration much greater than expected. For example, in- creases in dosage of the antiepileptic agent phenytoin 60 above approximately 300 mg daily usually produce a 50 180 40 160 30 140 120 20 Phenytoin Therapeutic Range 100 10 80 60 0 40 Bolus dose + Continuous Infusion 20 Continuous Infusion Only 0 100 200 300 400 500 600 Phenytoin Dose (mg) 0 FIGURE 5. Within the either an intravenous bolus dose immediately followed by therapeutic range, a relatively small increase in dose results initiation of a continuous intravenous infusion or initiation of in a greater than proportional increase in concentration, a continuous intravenous infusion only. Frequently it is useful to consider the overall expo- (A) Theoretical dose sure of a person to a drug during the dosing inter- (B) Cmax val. Which of the following pharmacokinetic param- (C) Bioavailability eters defines the exposure of a person to a drug? The AUC (area under the curve) best describes (D) Half-life the overall exposure of a person to a given drug (E) Clearance over the course of the dosing interval. Organs such as the liver remove exogenous chemi- the concentration of drug integrated over the pe- cals, such as drugs, from the body. A (Cmax) is phenytoin, for which the difference between the not correct, as Cmax gives the maximum concentra- minimum effective concentration and the minimum tion achieved but does not reveal how long measur- toxic concentration is small, clinicians must calcu- able concentrations of the drug were present or late the rate at which a given individual removes how long until this concentration was achieved. The volume of fluid from which (Tmax) only refers to the time until the maximum drug can be completely removed per unit of time concentration is achieved, again not giving a refer- (rate of drug removal) is termed: ence to overall exposure over time. D (half-life) (A) Distribution simply describes how much time is required for the (B) Clearance concentration to decrease by one-half. Finally, clear- (C) Metabolism ance (E) is the volume of fluid (usually plasma) (D) Excretion from which drug can be removed per unit of time 3. Clearance is defined as the volume of fluid from hours), steady state will be reached shortly follow- which drug is completely removed per unit of time ing which DOSE (not which half-life)? Distribution is the theoreti- (C) 5th dose cal volume to which the drug distributes and me- (D) 8th dose tabolism and excretion are simply methods of (E) 12th dose clearing drug.

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