R. Marcus. Mountain State University.
Some scientists suspect that any perfor- mance enhancement experienced from anabolic steroids comes not from mus- cle power but from psychological effects 500mg paracetamol for sale, with the drugs increasing a user’s aggressiveness generic paracetamol 500 mg visa. Anabolic steroids can produce mania cheap paracetamol 500mg with mastercard, anger discount 500 mg paracetamol otc, impulsiveness, euphoria, and feelings of invincibility—a combination that may lead some users into harmful social interactions. The combination can produce other types of unwise behavior as well, such as extravagant expenditures of money and taking reckless physical risks. Reports exist of paranoia and hallucinations developing while using steroids and disappearing when steroid usage is stopped. Drug Types 25 Sports governing authorities banned the use of anabolic steroids by com- petitors. Various other drugs are prohibited as well, but in 1988 most of the failed drug tests ordered by the International Olympic Committee revealed anabolic steroids, the most common one being nandrolone. In the 1990s a study involving 58,625 college students found only 175 steroid takers to study. Similar association of steroids with other illicit drug usage is found at the high school level. The number of regular users will be much smaller than the number of “lifetime” users. A female who uses those drugs may develop facial hair and a deeper voice, along with unwanted changes in sexual organs. In a young person who is still growing, androgens can pre- maturely halt further growth and thereby cause a smaller adult stature. Among persons of either gender and any age, androgens may alter blood composition and increase the body’s retention of various minerals. For example, sodium retention promotes bloat- ing and can be inadvisable for persons with heart trouble. Extended use of the substance may worsen cholesterol levels, thereby narrowing blood ves- sels, and such narrowing promotes heart attack and stroke years later. Steroid abusers tend to take far higher doses than are considered medically safe, thus further increasing the risks. Oral and slow-release under-the-skin implant for- mats of anabolic steroids can be processed in ways that will physically permit them to be injected. Such a practice is highly dangerous, as noninjectable for- mats of drugs have components that are not designed for direct introduction into the bloodstream. Anabolic steroid dependence is reported with withdrawal symptoms that can include weariness and depression. For information about speciﬁc anabolic steroids, see alphabetical listings for: boldenone, ethylestrenol, ﬂuoxymesterone, methandriol, methandrosteno- lone, methyltestosterone, nandrolone, oxandrolone, oxymetholone, stano- zolol, testolactone, testosterone, and trenbolone. Is it something that goes away if 26 The Encyclopedia of Addictive Drugs someone’s eyes open? Specialists may quibble, but this book classiﬁes all such experiences as hal- lucinations. Many people dislike hallucinatory experiences, especially people who like to be in control of themselves and of situations around them. Such people often ﬁnd hallucinations not only unpleasant but downright frightening. Scientiﬁc interest in hallucinogens began to emerge in the 1800s, blossoming in the 1950s and 1960s. In those latter times hallucinogens were popularly identiﬁed with beatniks and hippies, and social disapproval of those lifestyles promoted legal restrictions on hallucinogens that terminated almost all sci- entiﬁc research regarding these substances. First, despite easy availability, inhalants are among the most dangerous of abused substances. There is no range of inhalants, some of which are benign and some of which are risky, as there is with stimulants or depressants. All inhalants are dangerous despite wide var- iations in their chemistry, and this sets them apart from other types of drugs. Second, inhalants are generally used by inhaling them in their gaseous state (which is not the same as smoking and also differs from eating a solid or drinking a liquid). Third, inhalants are used mainly by younger persons (typically teenage males), a usage pattern that also sets inhalants apart from other drugs. With some inhalants the amount needed to produce a recreational effect is close to a fatal dose, and deadly outcomes demonstrate that the difference was too close for some deceased users to handle. In addition, strenuous exercise seems related to inhalant death, troublesome for users at dance clubs. The products are often ﬂammable, sometimes producing serious physical injury unrelated to pharmacology. Some users act as if they do not realize they need a continual supply of oxygen, and they administer inhalants in ways that cause suffocation. In addition to all these acute dangers, long-term use of many inhalants can produce nerve damage, impairing the ability to use arms and legs and hands and feet, damage veriﬁed scientiﬁcally. This conse- quence is harder to verify because inhalant users often take other potent drugs, so proving which mind-altering drug affected the mind can be very difﬁcult. Unquestionably, however, inhalant users can develop states of mind interfer- Drug Types 27 ing with—or even preventing—their ability to function in society. Admittedly, some users avoid serious outcomes, just as some car drivers run red lights without harm. Generally, adult drug users shun most inhalants except as a choice of des- peration if nothing else is available. Inhalant users tend to be teenagers or younger, perhaps because other drugs of abuse (even alcohol and tobacco) are harder for some young persons to obtain. Snifﬁng is often a social event with acquaintances rather than a solitary pastime. Another study found glue sniffers to have personalities matching those of alcoholics. Case studies of butane sniffers tell of lonely persons with difﬁculties at school or at home. A psychological test of 59 inhalant abusers47 found them to be impulsive persons with little respect for authority. Most research ﬁnds inhalant users to be unhappy persons mar- ginalized by society. Yet not all researchers ﬁnd that inhalant users are social misﬁts from dysfunctional families; some appear to be ordinary persons, though still youthful. That difference in ﬁndings—most researchers saying inhalant abusers are social misﬁts, with some researchers contending inhalant abusers are normal— deserves an attempt at explanation. Many inhalant researchers work where inhalant abuse has been publicized as a major community problem, and those places tend to have populations of socially marginalized people. Researchers commonly study persons receiving medical attention for inhalant abuse, and sometimes the medical attention is received involuntarily by court order. Such persons may be no more typical of inhalant users than hospitalized alcoholics receiving court-ordered treatment are typical of most alcohol users. A user who sniffs several times a day is not the same kind of user who sniffed with some friends once or twice over a period of several years. Although most research ﬁnds inhalant abusers to be troubled outcasts, it is possible that such typical ﬁndings are due to the demographics of the population being studied.
I Dihydrofolic Acid Dihydrofolate Trimethoprim and Reductase Pyrimethamine inhibit I Tetrahydrofolic Acid Figure V-1-3 buy discount paracetamol 500mg. Backup drugs include aminoglycosides (streptomycin paracetamol 500 mg on-line, amikacin paracetamol 500mg with mastercard, kanamycin) purchase paracetamol 500 mg overnight delivery, fluoroquinolones, • Prophylaxis: azithromycin capreomycin (marked hearing loss), and cycloserine (neurotoxic). In suspected multidrug resis- c1arithromycin (daily) tance, both drugs may be used in combination. Sununary of the Actions, Resistance, and Side Effects of the Antitubercular Drugs ;W"-""",,,,,. An antimicrobial agent should have maximal toxicity toward the infecting agent and minimal toxic~ for the host Table V-l-l summarizes the five basic antibacterial actions demonstrated by antibiotics and the agents working by each of these mechanisms. Microbial resistance can occur by the gradual selection of resistant mutants or more usually by R-factor transmission between bacteria. Table V-1-2 summarizes the common modes of resistance exhibited by microorganisms against the various classes of antimicrobial agents. Inhibitors of Bacterial Cell-Wall Synthesis The inhib~ors of bacterial cell-wall synthesis are the beta-Iactam antibiotics (the penicillins and cephalosporins; Figure V-l-l), the carbapenems, vancomycin, and aztreonam. The mechanisms of action of penicillins, the bacterial modes of resistance to penicillins, the penicillin subgroups, their biodisposition, and side effects are provided. The subgroups discussed are the penicillins that are ~-Iactamase susceptible with a narrow spectrum of activity; ~-Iactamase-resistant penicillins that have a very narrow spectrum of activity; and ~-Iactamase-susceptible penicillins that have a wider spectrum of activity. The common penicillins and their susceptible organisms are listed for each subgroup. These have the same mode of action as the penicillins and also require an intact ~-Iactam ring structure for activ~. Each is considered in terms of range of activity, susceptibility to resistance, clinical usage, and specific antibiotics in that class. Imipenem and meropenem have the same mode of antibacterial action as the penicillins and cephalosporins but structurally are carbapenems that have the ~-Iactam ring. Inhibitors of Bacterial Protein Synthesis Figure V-1-2 illustrates the mechanisms of bacterial protein synthesis, and Table V-1-3 summarizes the places in the translatory sequence, as well as the mechanisms by which antibiotics operate to disrupt protein synthesis. Streptomycin is particularly useful in the treatment of tuberculosis and is the drug of choice for treating bubonic plague and tularemia. They are broad-spectrum drugs with good activity against chlamydial and mycoplasmal species, as well as against other indicated bacteria. Chloramphenicol inhibits the activity of peptidyltransferase and is currently used primarily as a backup drug. Their spectrums of activity, clinical uses, biodisposition, and side effects are considered. The methods bacteria use to develop resistance to the sulfonamides, their activity and clinical uses, biodisposition, and side effects are considered. The simultaneous inhibition of the tetrahydrofolate synthesis pathway at two steps has a synergistic effect and prevents the rapid generation of resistance. Their clinical use, the relevant drugs in this class, their biodisposition, and side effects are reported. Its use as an antiprotozoal and antibacterial drug is discussed, as are its side effects. Antitubercular Drugs Infections caused by Mycobacterium tuberculosis are treated with combination therapy. Backup drugs include streptomycin, fluoroquinolones, capreomycin, and cycloserine. Table V-1-4 summarizes the actions, resistance, and side effects of the antitubercular drugs. Thus, most bacterial antibiotics are ineffective, and many otherwise potentially effective drugs are also toxic to their human hosts. A difference between fungi and humans susceptible to exploitation by antibiotics is the high concentration of ergosterol in their membranes. The polyenes amphotericin (amp B) are amphoteric compounds that bind to ergosterol, forming pores, which results in the leakage of intracellular contents. The activity, clinical uses, biodisposition, and side effects of these polyenes are discussed. The azoles (ketoconazole, fluconazole, c1otrimazole, miconazole, and itraconazole) kill fungi by interfering with ergosterol synthesis. The mechanisms of action, clinical uses, biodisposition, and side effects are considered. Griseofulvin interferes with microtubule function; terbinafine blocks ergosterol synthesis. Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes-eommonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. Saquinavir, one of the least toxic, has very low (and variable) oral bioavailability that predisposes to resistance development. The steps in viral replication and the main sites of action of such antiviral drugs are illustrated in Figure V-3-1. The mechanisms of action, activities, clinical uses, and adverse effects are discussed. Other Antivirals Amantadine blocks the attachment, penetration, and uncoating of influenza virus A; zanamivir and oseltamivir inhibit influenza viruses A and B neuraminidase, promoting viral clumping and decreasing the chance of penetration. It is used to treat respiratory syncytial virus, influenza A and B, Lassafever, Hantavirus, and as an adjunct to alpha-interferons in hepatitis C. TableV-4-2 lists the drugs of choice used against the various forms of malaria, and information is given about treatment and prophylaxis of malaria. The drugs used to treat helminthic infections are listed, and their mechanisms of action are noted. An 82-year-old hospitalized patient with creatinine clearance of 25 mL/min has a micro- bial infection requiring treatment with antibiotics. Which of the following drugs is least likely to require a dosage adjustment, either a smaller dose than usual or an increased inter- val between doses? Past history includes a severe allergic reaction to amoxicillin when used for an ear infection. The physician needs to treat this infection, but prefers not to use a drug that needs parenteral administration. Which one of the following agents is most likely to be appropriate in terms of both effectiveness and safety? A woman has pelvic inflammatory disease, and the decision is made to treat her with anti- biotics as an outpatient. One of the drugs to be used is a cell-wall synthesis inhibitor with activity against anaerobic gram-negative rods, including Bacteroides fragilis. She is warned that unpleasant reactions may occur if she consumes alcoholic beverages while taking this drug.
Additional information Common and serious Infusion-related: Local: reddening of the infusion site and phlebitis cheap 500mg paracetamol mastercard. Counselling Photosensitivity may develop on exposure to strong sunlight and ultraviolet rays buy paracetamol 500mg on-line, e discount 500 mg paracetamol free shipping. This assessment is based on the full range of preparation and administration options described in the monograph discount paracetamol 500 mg amex. Levomepromazine | 515 Levom eprom azine (m ethotrim eprazine) 25mg/mL solution in 1-mL ampoules * Levomepromazine hydrochloride is a phenothiazine derivative. Pre-treatment checks * Avoid or use with caution in patients with liver dysfunction or cardiac disease. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Technical information Incompatible with Heparin sodium Compatible with Flush: NaCl 0. On exposure to light, levomepromazine rapidly discolours; such solutions should be discarded. Lidocaine (lignocaine) hydrochloride -- intravenous adm inistration 10mg/mL (1%) in 10-mL pre-filled syringes; 20mg/mL (2%) in 5-mL pre-filled syringes 10mg/mL (1%) solution and 20mg/mL (2%) solution in 2-mL, 5-mL, 10-mL and 20-mL ampoules 1mg/mL (0. Reduce the rate further if infusion is continued beyond 24 hours (rarely required). Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Alternatively, withdraw the required dose of 1% or 2% injection and add to a suitable volume (usually 500mL) of Gluc 5% to give a solution contain- ing between 1mg/mL and 4mg/mL. Inspect visually for particulate matter or discolor- ation prior to administration and discard if present. Stability after Fromamicrobiologicalpointofview,shouldbeusedimmediately;however,prepared preparation infusions may be stored at 2--8 C and infused (at room temperature) within 24 hours. Lidocaine hydrochloride -- intravenous administration | 519 Additional information Common and serious Immediate: Anaphylaxis and other hypersensitivity reactions have rarely been undesirable effects reported. Other: Apprehension, nervousness, euphoria, tinnitus, blurred or double vision, nystagmus, vomiting, sensations of heat, cold or numbness, twitching, tremors. Elimination half-life is 1--2 hours but may be prolonged if infusions are given for longer than 24 hours or if hepatic blood flow is reduced. Significant * The following may "lidocaine levels or effect (or "side-effects): interactions antiarrhythmics ("risk of myocardial depression), antipsychotics ("risk of ventricular arrhythmias), atazanavir, beta-blockers ("risk of myocardial depression), cimetidine ("risk of toxicity), fosamprenavir (avoid combination), quinupristin with dalfopristin ("risk of ventricular arrhythmias). Action in case of Symptoms to watch for: Medullary depression, seizures, cardiovascular overdose collapse. This assessment is based on the full range of preparation and administration options described in the monograph. Important: When lidocaine is used for local anaesthesia, rapid and extensive absorption may occur resulting in systemic side-effects. Infiltration anaesthesia: dose is determined by patient’s weight and the site and nature of the procedure: * Maximum dose without adrenaline: 200mg. Technical information Incompatible with Not relevant Compatible with Not relevant pH 5--7 Sodium content Negligible (continued) Lidocaine hydrochloride -- local anaesthetic use | Linezolid | 521 Technical information (continued) Excipients Some products contain preservatives. If it is accidentally given intravenously, see the separate monograph on intravenous administration for monitoring requirements. Pharmacokinetics Serum lidocaine concentrations are usually insignificant following local use. Action in case of Symptoms to watch for: Cardiovascular collapse, seizure, medullary overdose depression. This assessment is based on the full range of preparation and administration options described in the monograph. Linezolid 2mg/mL solution in 300-mL infusion bags * Linezolid is an oxazolidinone antibacterial. Dose in renal impairment: adjusted according to creatinine clearance:1 * CrCl 10--50mL/minute: dose as in normal renal function * CrCl <10mL/minute: dose as in normal renal function. If platelet count drops on a dose of 600mg twice daily, consider reducing to 600mg once daily. Check for minute leaks by squeezing the bag firmly -- if the bag leaks, do not use. Inspect visually for particulate matter or discoloration prior to administration and discard if present. Technical information Incompatible with Amphotericin, ceftriaxone, co-trimoxazole, diazepam, erythromycin, pentamidine isetionate, phenytoin sodium. Signs of metabolic Throughout * Symptoms include recurrent nausea, vomiting, acidosis treatment abdominal pain, low bicarbonate level or hyperventilation. Signs of supra- * May result in the overgrowth of non-susceptible infection or organisms -- appropriate therapy should be superinfection commenced; treatment may need to be interrupted. Signs of visual * Can cause peripheral and optic neuropathy: monitor impairment for blurred vision,visualfielddefects, changes in visual acuityandcolourvision. Development of Throughout and * Development of severe, persistent diarrhoea may be diarrhoea up to 2 months suggestive ofClostridiumdifficile-associated diarrhoea after treatment and colitis (pseudomembranous colitis). This assessment is based on the full range of preparation and administration options described in the monograph. Liothyronine sodium | 525 Liothyronine sodium (L-tri-iodothyronine) 20 micrograms dry powder ampoules * Liothyroninesodiumhasasimilaractiontolevothyroxinebutismore rapidlymetabolisedandhas a faster effect. Doses below are expressed in terms of liothyronine sodium: Liothyronine 10 micrograms 10. Pre-treatment checks * Caution in myxoedema coma as a large dose can precipitate heart failure, especially in elderly patients and those with ischaemic heart disease. When thyroid replacement therapy is started, metabolism is raised at a greater rate than adrenocortical activity; this can result in adrenocortical insufficiency so that additional corticosteroid therapy may be required. No more than 12 hours should elapse between doses to avoid fluctuations in hormone levels. Administration more frequently than every 4 hours does not allow for assessment of therapeutic response between doses. Inspect visually for particulate matter or discolor- ation prior to administration. Additional information Common and serious The following are indicative of overdosage, and disappear after reduction of undesirable effects dosage or stopping treatment for a day or more: anginal pain, cardiac arrhythmias, palpitations, "pulse, cramps, diarrhoea, muscular weakness, flushing, sweating, restlessness, excitability, headache. Pharmacokinetics Liothyronine has a plasma half-life in euthyroidism of about 1--2 days; the half- life is prolonged in hypothyroidism and reduced in hyperthyroidism. Action in case of Symptoms of overdosage disappear after reduction in dose or stopping overdose treatment for a day or more. This assessment is based on the full range of preparation and administration options described in the monograph. Lorazepam 4mg/mL solution in 1-mL ampoules * Lorazepam is a short-acting benzodiazepine with anxiolytic, anticonvulsant and central muscle relaxant properties.
Because central noradrenergic pathways are so diffuse purchase paracetamol 500 mg online, and the synaptic effects of noradrenaline have a comparatively slow time-course proven paracetamol 500mg, these neurons could have a wide range of functions generic paracetamol 500 mg otc, depending on the brain region being targeted and the neurobiological status of the individual cheap paracetamol 500 mg visa. In general terms, however, it is agreed that noradrenergic neurons influence arousal. This encompasses not only the sleep/waking cycle (see Chapter 22) but also more specific activities, such as selective attention and vigilance (Aston-Jones et al. Indeed, depression and anxiety, both of which are relieved by drugs that modify noradrenergic transmission, can be regarded as arousal disorders. Yet, despite nearly 40 years of research, it is still uncertain whether an increase in noradrenergic transmission contributes to unpleasant emotional responses to environmental stimuli (e. Many electrophysiological studies have shown that single-unit activity of noradrenergic neurons in the locus coeruleus is increased by sensory stimuli. This would be consistent with the attenuation of the neuronal response on repeated presentation of the test stimulus, the presumption being that this change underlies behavioural habituation. Even if this turns out to be the case, it is likely that noradrenergic neurons in different brain regions make different contributions to this process. This complication is suggested by the results of a recent microdialysis study in which release of noradrenaline in response to the sound of a buzzer alone was provoked after repeated Figure 8. This adaptive change occurred in the frontal cortex but not the hypothalamus suggesting that only noradrenergic neurons innervating the former brain region (i. Another concept is that noradrenergic transmission influences the emotional impact of a given stimulus, i. One obvious possibility is that inadequate noradrenergic transmission explains depression, whereas moderate activity provokes attentive interest that is vital for appropriate cognitive function, and excessive noradrenergic activation culminates in anxiety or agitation. Evidence supporting this single axis for central noradrenergic function/dysfunction is discussed in Chapters 19 and 20. It is equally possible that the role and consequences of central noradrenergic transmission depend on the type or severity of the stimulus and individual differences in the neurobiological coding of behaviour. This would mean that the optimal behavioural response to a given environmental stimulus requires a specific increase in noradrenergic transmission. However, it is also possible to envisage disruption of this neurochemical coding of behaviour in the ways illustrated in Figs 8. If there is a shift of the curve to either the right or the left, then the noradrenergic response that would be optimal in normal subjects now produces a suboptimal coping response. In the case of a shift to the left, a reduction in noradrenergic transmission would be required to restore optimal coping whereas for a shift to the right, an increase would be required. One is that the underlying coding is correct but it is the noradrenergic response evoked by the stimulus that is inappropriate. A second is that the amplitude of the noradrenergic response to arousing stimuli is normal but the underlying coding is not. For instance, an early report suggested that there is a positive correlation between the density of (postsynaptic) b-adrenoceptors in rat cortex and behavioural resistance to a mild environmental stress (novelty and frustration) but a negative correlation between these parameters when the stress is intensified (Stanford and Salmon 1992). Evidence suggests that the relationship between these two parameters is described by a bell-shaped curve and so an optimal phasic response is manifest only at intermediate levels of tonic activity (Rajkowski et al. Obviously, it is extremely unlikely that noradrenergic transmission is the sole factor to determine the behavioural response to even simple environmental stimuli. Indeed, a bell-shaped dose±response curve immediately suggests the intervention of one or more additional factors (neurotransmitters? Such interactions with other neurotransmitters could well define the relationship between noradrenergic transmission and the coding of the coping response. Either a reduction or an increase in noradrenergic transmission produces a functional mismatch and diminishes coping. In these normal subjects, optimal coping is attained when the noradrenergic response to a specific stimulus corresponds to that marked (^). If there is a leftward shift of the curve that describes the neurochemical coding of coping, then the (predetermined) noradrenergic response that would be optimal in normal individuals now produces suboptimal coping (*). One remedy for such a dysfunction is to reduce noradrenergic transmission so as to restore optimal coping. Similarly, in the case of a rightward shift of the coping curve (c), a predetermined noradrenergic response to a specific stimulus, that would be optimal in normal individuals, will again produce suboptimal coping (*). In both (b) and (c) an alternative way to restore optimal coping would be to reverse the shift in the noradrenergic transmission/coping curve. Aston-Jones, G, Rajkowski, J, Kubiak, P and Alexinsky, T (1994) Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. Bonisch, H, Hammermann, R and Bruss, M (1998) Role of protein kinase C and second messengers in regulation of the norepinephrine transporter. Fassio, A, Bonanno, G, Fontana, G, Usai, C, Marchi, M and Raiteri, M (1996) Role of external and internal calcium on heterocarrier-mediated transmitter release. Fillenz, M (1993) Short-term control of transmitter synthesis in central catecholaminergic neurones. Rajkowski, J, Kubiak, P, Ivanova, S and Aston-Jones, G (1998) State-related activity, reactivity of locus coeruleus neurons in behaving monkeys. Russ, H, Staust, K, Martel, R, Gliess, M and Schomig, E (1996) The extracellular transporter for monoamine transmitters exists in cells derived from human central nervous system glia. All these processes, together with some well-known drugs that affect them, are summarised in Fig. Yet, despite this relatively restricted distribution of cell bodies, their processes project more or less throughout the whole neuraxis. For a detailed review of this topic, see Jacobs and Azmitia (1992) but an outline of key features is given here. Despite these changes, all these nuclei are still regarded as forming two major groups. This means that these neurons are well placed for serving a key role in regulation of motor activity, autonomic function and nociception. In addition, there are numerous interconnections between the different Neurotransmitters, Drugs and Brain Function. Although extensive branching of the neuronal processes results in a considerable overlap in the terminal axonal fields of the different nuclei, there is evidence for some topographical organisation of the areas to which different nuclei project (Fig. In any case, species differences in the distribution of co-transmitters is a confounding factor. First, it has an absolute requirement for O2 and the reduced pterin co-factor, tetrahydrobiopterin. Second, hydroxylation of trypto- phan, like that of tyrosine, is the rate-limiting step for the whole pathway (reviewed by Boadle-Biber 1993) (see Chapter 8). Indeed, the activated form of tryptophan hydroxylase has an extremely high Km for tryptophan (50 mM), which is much greater than the concentration of tryptophan in the brain (10±30 mM).
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