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Ganciclovir may cause severe neutropenia when been found to have alterations in thymidylate syn- used in combination with zidovudine discount diovan 160 mg otc pulse pressure wave. Because of its significant host cytotoxicity buy cheap diovan 80mg on line whats prehypertension mean, idoxuri- Adverse Effects purchase discount diovan on-line arterial, Contraindications, dine cannot be used to treat systemic viral infections. The most frequent adverse reactions to trifluridine ad- Absorption, Metabolism, and Excretion ministration are transient burning or stinging and palpebral edema. Other adverse reactions include su- Idoxuridine is marketed strictly for topical ophthalmic perficial punctate keratopathy, epithelial keratopathy, use, and systemic exposure is insignificant. However, af- hypersensitivity, stromal edema, irritation, keratitis ter oral dosing, the drug is rapidly metabolized and ex- sicca, hyperemia, and increased intraocular pressure. Trifluridine is mutagenic in vitro and carcinogenic and teratogenic when administered subcutaneously to Clinical Uses animals. Because it is applied topically in humans, treatment of herpes simplex infections of the eyelid, con- the likelihood of systemic effects is low. However, infection can occur in immunized nucleoside analogue containing arabinose in place of ri- persons, because influenza viruses mutate rapidly and bose. Amantadine (Symmetrel) is a synthetic tricyclic amine, Vidarabine triphosphate competes with deoxyadeno- and rimantadine (Flumadine) is its -methyl derivative. Vidarabine also inhibits ri- viral M2 protein, an integral membrane protein that acts bonucleoside reductase and other enzymes. In certain Absorption, Metabolism, and Excretion strains, the pH changes that result from M2 inhibition alter the conformation of hemagglutinin, hence inhibit Vidarabine is administered only as a topical ophthalmic viral assembly. It has relatively limited solubility and is not Viral resistance develops rapidly in approximately significantly absorbed after application to the eye. Resistant viruses are associated with the failure of pal metabolite, arabinosyl hypoxanthine, which retains drug prophylaxis in close contacts of infected individu- some degree of antiviral activity. Mutation in the transmembrane domain of the M2 pro- Clinical Uses tein is the most frequent cause of resistance to amanta- The principal use of vidarabine is in the treatment of dine and rimantadine. It is also used to treat super- ficial keratitis in patients unresponsive or hypersensi- Absorption, Metabolism, and Excretion tive to topical idoxuridine. Amantadine is rapidly and completely absorbed from the gastrointestinal tract, and peak blood levels are Adverse Effects, Contraindications, achieved in 2 to 5 hours. The serum half-life of amanta- and Drug Interactions dine averages 17 hours in young adults and 29 hours in The most commonly observed side effects associated the elderly. Most of the drug (90%) is eliminated un- with vidarabine are lacrimation, burning, irritation, changed by glomerular filtration and tubular secretion. Vidarabine has oncogenic and Rimantadine is well absorbed following oral admin- mutagenic potential; however, the risk of systemic ef- istration, with peak blood levels achieved in 5 to 7 fects is low because of its limited absorption. Its elimination half-life averages 25 hours in not be used in conjunction with ophthalmic cortico- young adults and 32 hours in the elderly. Individuals over the age of 65, residents of these agents are administered within 48 hours of the on- long-term care facilities, and patients with long-term set of symptoms, they reduce the duration of fever and health problems. However, when vaccination aminidase, like hemagglutinin, is a viral surface glyco- is contraindicated or early vaccination is not possible, protein that interacts with host cell receptors containing amantadine and rimantadine are effective prophylactic terminal neuraminic acid residues. The binding of agents that have been shown to protect approximately hemagglutinin to its cellular receptors initiates viral 70 to 90% of patients from influenza A infection. Since penetration and promotes the fusion of the viral enve- these drugs do not prevent the host immune response to lope to the plasma membrane. Neuraminidase then de- influenza A, they may be used to prevent infection during stroys these hemagglutinin receptors by breaking the the 2- to 4-week period required to develop immunity bond between the terminal neuraminic acid residue and following vaccination. The cleavage of hemagglu- unrelated to its antiviral activity, is in the therapy of tinin receptors is required for the release of progeny Parkinson’s disease (see Chapter 31). It also facilitates the spread of infection by allowing viral particles to penetrate the Adverse Effects, Contraindications, neuraminic acid–rich respiratory mucus and by pre- and Drug Interactions venting the clumping of virus that results from the bind- ing of hemagglutinins to neuraminic acid residues on The most frequently reported side effects of amanta- neighboring viral particles. Inhibition of neuraminidase dine and rimantadine are nausea, anorexia, dizziness, activity prevents the release of progeny virus and inhibits and insomnia. High doses of Influenza virus resistant to oseltamivir has not been amantadine may produce cardiac arrhythmias, delirium, found in naturally acquired isolates but has been iso- hallucinations, and suicidal ideation; long-term treat- lated from influenza patients who have undergone ment may cause peripheral edema, orthostatic hypoten- treatment with this drug. Abrupt with- mutations in the active site of neuraminidase and are drawal of amantadine may produce a neuroleptic generally less virulent and infective than nonresistant malignant syndrome. Animal studies of oseltamivir carboxylate can produce mutations in have shown that amantadine is teratogenic and riman- hemagglutinin that decrease the overall dependence of tadine may be embryotoxic. Individuals with congestive heart failure, edema, orthostatic hypotension, seizure disorders, or uncontrolled psychosis should be closely monitored Absorption, Metabolism, and Excretion during therapy with amantadine. The dosage of riman- Orally administered oseltamivir phosphate is rapidly ab- tadine must be decreased in cases of renal or hepatic sorbed and converted by hepatic esterases to oseltamivir impairment, whereas amantadine requires dosage ad- carboxylate. The the systemic circulation as oseltamivir carboxylate, with elderly are more susceptible to the central nervous sys- peak plasma concentrations achieved within 2. The plasma elimination half-life of oseltamivir rimantadine is generally better tolerated in this popula- carboxylate is 7 to 9 hours. Individuals over age 65 require half the dose of ei- drug and its active metabolite occurs primarily by active ther drug given to younger adults. Thiazide–triamterene, trimethoprim–sulfamethoxazole, Oseltamivir is approved for the treatment of uncompli- quinine, and quinidine increase plasma amantadine levels. Cimetidine decreases rimantadine clearance, and aspirin It decreases the duration of illness by 1 to 1. Oseltamivir is also indicated for the prophy- that delivers the drug as an aerosol in a lactose carrier. It re- The lactose particles are large, and about 78% deposit in duces infection rates to approximately 10 to 25% of that the oropharynx. Following oral inhalation, zanamivir has found in untreated populations; however, it is not in- a bioavailability of 12 to 17%, with peak plasma concen- tended to substitute for the early vaccination recom- trations being reached within 1. Oseltamivir can be used as post- inated by the kidneys without significant metabolism and exposure prophylaxis in household contacts of infected has a plasma elimination half-life of 2. Clinical Uses Zanamivir is indicated for treatment of uncomplicated Adverse Effects, Contraindications, acute influenza A and B virus in patients aged 7 and and Drug Interactions older. Treatment should be initiated no later than 2 days The most frequently reported adverse effects of os- after the onset of symptoms. Its efficacy in patients with chronic cardiac and Drug Interactions or respiratory disease has not been established. Bronchospasm ical trials, no difference in the incidence of complica- and impaired lung function have been reported in some tions was seen between treatment and control groups. Allergic re- justment is recommended for individuals with renal in- actions, including angioedema, have been rarely sufficiency; the drug’s safety in patients with hepatic in- reported. No formal drug interaction studies of oseltamivir Zanamivir is contraindicated in individuals with se- have been performed. Oseltamivir and its carboxylate vere or decompensated chronic obstructive lung disease metabolite do not interact with the cytochrome P450 or asthma because it has not been shown to be effective system. Although probenecid decreases the elimination in these individuals and can cause serious adverse pul- of oseltamivir, dosage adjustment is not required during monary reactions. Individuals with mild to moderate coadministration of these drugs because of oseltamivir’s asthma may have a decline in lung function when taking margin of safety. Absorption, Metabolism, and Excretion Immune Globulin Zanamivir has a bioavailability of less than 5% when ab- Immune globulin ( -globulin, immunoglobulin [Ig] G) sorbed through the gastrointestinal tract.

Absorption of most oral penicillins (amoxicillin being an exception) is impaired by food cheap diovan on line heart attack 22, and the drugs should be administered at least 1–2 hours before or after a meal purchase diovan 80 mg amex blood pressure chart poster. Intravenous administration of penicillin G is preferred to the intramuscular route because of irritation and local pain from intramuscular injection of large doses diovan 160mg online blood pressure home remedies. Serum concentrations 30 minutes after an intravenous injection of 1 g of penicillin G (equivalent to approximately 1. Only a fraction of the total drug in serum is present as free drug, the concentration of which is determined by protein binding. Highly protein-bound penicillins (eg, nafcillin) generally achieve lower free-drug concentrations in serum than less protein-bound penicillins (eg, penicillin G or ampicillin). Protein binding becomes clinically relevant when the protein-bound percentage is approximately 95% or more. They are polar molecules, so intracellular concentrations are well below those found in extracellular fluids. Benzathine and procaine penicillins are formulated to delay absorption, resulting in prolonged blood and tissue concentrations. A 600,000 unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection. However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily parenteral dose of 18–24 million units. Tubular secretion accounts for about 90% of renal excretion, and glomerular filtration accounts for the remainder. The normal half-life of penicillin G is approximately 30 minutes; in renal failure, it may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one fourth to one third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43–1). Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion; no dosage adjustment is required for these drugs in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher systemic concentrations for longer periods than in the adult. Clinical Uses Except for amoxicillin, oral penicillins should be given 1–2 hours before or after a meal; they should not be given with food to minimize binding to food proteins and acid inactivation. Penicillins should never be used for viral infections and should be prescribed only when there is reasonable suspicion of, or documented infection with, susceptible organisms. Penicillin Penicillin G is a drug of choice for infections caused by streptococci, meningococci, some enterococci, penicillin- susceptible pneumococci, non-β-lactamase-producing staphylococci, Treponema pallidum and certain other spirochetes, some Clostridium species, Actinomyces and certain other gram-positive rods, and non-β-lactamase-producing gram- negative anaerobic organisms. Depending on the organism, the site, and the severity of infection, effective doses range between 4 and 24 million units per day administered intravenously in four to six divided doses. Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Benzathine penicillin and procaine penicillin G for intramuscular injection yield low but prolonged drug levels. Procaine penicillin G was once a commonly used treatment for uncomplicated pneumococcal pneumonia and gonorrhea; however, it is rarely used now because many gonococcal strains are penicillin-resistant, and many pneumococci require higher doses of penicillin G or the use of more potent β-lactams. Penicillins Resistant to Staphylococcal Beta Lactamase (Methicillin, Nafcillin, and Isoxazolyl Penicillins) These semisynthetic penicillins are indicated for infections caused by β-lactamase-producing staphylococci, although penicillin susceptible strains of streptococci and pneumococci are also susceptible to these agents. Listeria monocytogenes, enterococci, and methicillin-resistant strains of staphylococci are resistant. In recent years the empirical use of these drugs has decreased substantially because of increasing rates of methicillin-resistance in staphylococci. However, for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci, these are considered the drugs of choice. However, food interferes with absorption, and the drugs should be administered 1 hour before or after meals. Methicillin, the first antistaphylococcal penicillin to be developed, is no longer used clinically due to high rates of adverse effects. Oxacillin and nafcillin, 8–12 g/d, given by intermittent intravenous infusion of 1–2 g every 4–6 hours (50– 100 mg/kg/d for children), are considered the drugs of choice for serious systemic staphylococcal infections. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypenicillins, and Ureidopenicillins) These drugs have greater activity than penicillin against gram-negative bacteria because of their enhanced ability to penetrate the gram-negative outer membrane. The aminopenicillins, ampicillin and amoxicillin, have very similar spectrums of activity, but amoxicillin is better absorbed orally. Amoxicillin, 250–500 mg three times daily, is equivalent to the same amount of ampicillin given four times daily. Amoxicillin is given orally to treat urinary tract infections, sinusitis, otitis, and lower respiratory tract infections. Ampicillin, at dosages of 4–12 g/d intravenously, is useful for treating serious infections caused by susceptible organisms, including anaerobes, enterococci, L monocytogenes, and β-lactamase-negative strains of gram-negative cocci and bacilli such as E coli, and Salmonella sp. Due to production of β lactamases by gram-negative bacilli, ampicillin can no longer be used for empirical therapy of urinary tract infections and typhoid fever. Ampicillin is not active against Klebsiella sp, Enterobacter sp, P aeruginosa, Citrobacter sp, Serratia marcescens, indole-positive proteus species, and other gram- negative aerobes that are commonly encountered in hospital-acquired infections. The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are also active against selected gram-negative bacilli, such as Klebsiella pneumoniae. Although supportive clinical data are lacking for superiority of combination therapy over single-drug therapy, because of the propensity of P aeruginosa to develop resistance during treatment, an antipseudomonal penicillin is sometimes used in combination with an aminoglycoside or fluoroquinolone for pseudomonal infections outside the urinary tract. Ampicillin, amoxicillin, ticarcillin, and piperacillin are also available in combination with one of several β-lactamase inhibitors: clavulanic acid, sulbactam, or tazobactam. The addition of a β-lactamase inhibitor extends the activity of these penicillins to include β-lactamase-producing strains of S aureus as well as some β-lactamase-producing gram-negative bacteria (see Beta-Lactamase Inhibitors). Adverse Reactions The penicillins are generally well tolerated, and, unfortunately, this may encourage inappropriate use. The antigenic determinants are degradation products of penicillins, particularly penicilloic acid and products of alkaline hydrolysis bound to host protein. A history of a penicillin reaction is not reliable; about 5–8% of people claim such a history, but only a small number of these will have a serious reaction when given penicillin. Less than 1% of persons who previously received penicillin without incident will have an allergic reaction when given penicillin. Because of the potential for anaphylaxis, however, penicillin should be administered with caution or a substitute drug given if the person has a history of serious penicillin allergy. Oral lesions, fever, interstitial nephritis (an autoimmune reaction to a penicillin-protein complex), eosinophilia, hemolytic anemia and other hematologic disturbances, and vasculitis may also occur. However, if necessary (eg, treatment of enterococcal endocarditis or neurosyphilis in a patient with serious penicillin allergy), desensitization can be accomplished with gradually increasing doses of penicillin. Nafcillin is associated with neutropenia; oxacillin can cause hepatitis; and methicillin causes interstitial nephritis (and is no longer used for this reason).

Toxic-confusional states may occur with very high doses of drugs that have prominent antimuscarinic actions buy diovan with mastercard pulse pressure 93. Neurologic Effects Extrapyramidal reactions occurring early during treatment with older agents include typical Parkinson’s syndrome generic diovan 40mg with visa ulterior motive, akathisia (uncontrollable restlessness) buy on line diovan pulse pressure factors, and acute dystonic reactions (spastic retrocollis or torticollis). Parkinsonism can be treated, when necessary, with conventional antiparkinsonism drugs of the antimuscarinic type or, in rare cases, with amantadine. Akathisia and dystonic reactions also respond to such treatment, but many clinicians prefer to use a sedative antihistamine with anticholinergic properties, eg, diphenhydramine, which can be given either parenterally or orally. Tardive dyskinesia, as the name implies, is a late-occurring syndrome of abnormal choreoathetoid movements. It has been proposed that it is caused by a relative cholinergic deficiency secondary to supersensitivity of dopamine receptors in the caudate-putamen. The prevalence varies enormously, but tardive dyskinesia is estimated to have occurred in 20–40% of chronically treated patients before the introduction of the newer atypical antipsychotics. Any patient with tardive dyskinesia treated with a typical antipsychotic drug or possibly risperidone or paliperidone should be switched to quetiapine or clozapine, the atypical agents with the least likelihood of causing tardive dyskinesia. Many treatments have been proposed, but their evaluation is confounded by the fact that the course of the disorder is variable and sometimes self-limited. Most authorities agree that the first step should be to discontinue or reduce the dose of the current antipsychotic agent or switch to one of the newer atypical agents. A logical second step would be to eliminate all drugs with central anticholinergic action, particularly antiparkinsonism drugs and tricyclic antidepressants. Seizures, though recognized as a complication of chlorpromazine treatment, were so rare with the high-potency older drugs as to merit little consideration. Autonomic Nervous System Effects Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine—should be managed by switching to drugs with less marked adrenoceptor-blocking actions. Metabolic and Endocrine Effects Weight gain is very common, especially with clozapine and olanzapine, and requires monitoring of food intake, especially carbohydrates. Hyperglycemia may develop, but whether secondary to weight gain-associated insulin resistance or to other potential mechanisms remains to be clarified. The management of weight gain, insulin resistance, and increased lipids should include monitoring of weight at each visit and measurement of fasting blood sugar and lipids at 3- to 6-month intervals. Measurement of hemoglobin A1C may be useful when it is impossible to be sure of obtaining a fasting blood sugar. Hyperprolactinemia in women results in the amenorrhea-galactorrhea syndrome and infertility; in men, loss of libido, impotence, and infertility may result. If dose reduction is not indicated, or ineffective in controlling this pattern, switching to one of the atypical agents that do not raise prolactin levels, eg, aripiprazole, may be indicated. Toxic or Allergic Reactions Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-potency antipsychotic drugs currently used. In contrast to other antipsychotic agents, clozapine causes agranulocytosis in a small but significant number of patients —approximately 1–2% of those treated. This serious, potentially fatal effect can develop rapidly, usually between the 6th and 18th weeks of therapy. It is not known whether it represents an immune reaction, but it appears to be reversible upon discontinuance of the drug. Because of the risk of agranulocytosis, patients receiving clozapine must have weekly blood counts for the first 6 months of treatment and every 3 weeks thereafter. Ocular Complications Deposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy. Thioridazine is the only antipsychotic drug that causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa. The maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication. Cardiac Toxicity Thioridazine in doses exceeding 300 mg daily is almost always associated with minor abnormalities of T waves that are easily reversible. Overdoses of thioridazine are associated with major ventricular arrhythmias, eg, torsades de pointes, cardiac conduction block, and sudden death; it is not certain whether thioridazine can cause these same disorders when used in therapeutic doses. In view of possible additive antimuscarinic and quinidine-like actions with various tricyclic antidepressants, thioridazine should be combined with the latter drugs only with great care. It is not always drug-related, and there are no studies that definitively show increased risk with particular drugs. A 20,000-patient study of ziprasidone versus olanzapine showed minimal or no increased risk of torsades de pointes or sudden death in patients who were randomized to ziprasidone. Use in Pregnancy; Dysmorphogenesis Although antipsychotic drugs appear to be relatively safe in pregnancy, a small increase in teratogenic risk could be missed. Questions about whether to use these drugs during pregnancy and whether to abort a pregnancy in which the fetus has already been exposed must be decided individually. If a pregnant woman could manage to be free of antipsychotic drugs during pregnancy, this would be desirable because of their effects on the neurotransmitters involved in neurodevelopment. Neuroleptic Malignant Syndrome This life-threatening disorder occurs in patients who are extremely sensitive to the extrapyramidal effects of antipsychotic agents (see also Chapter 16). If sweating is impaired, as it often is during treatment with anticholinergic drugs, fever may ensue, often reaching dangerous levels. The stress leukocytosis and high fever associated with this syndrome may erroneously suggest an infectious process. This syndrome is believed to result from an excessively rapid blockade of postsynaptic dopamine receptors. Early in the course, vigorous treatment of the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile. Other muscle relaxants, such as dantrolene, or dopamine agonists, such as bromocriptine, have been reported to be helpful. Drug Interactions Antipsychotics produce more important pharmacodynamic than pharmacokinetic interactions because of their multiple effects. Additive effects may occur when these drugs are combined with others that have sedative effects, α-adrenoceptor- blocking action, anticholinergic effects, and—for thioridazine and ziprasidone—quinidine-like action. A variety of pharmacokinetic interactions have been reported, but none are of major clinical significance. Overdoses Poisonings with antipsychotic agents (unlike tricyclic antidepressants) are rarely fatal, with the exception of those due to mesoridazine and thioridazine. The lethal effects of mesoridazine and thioridazine are related to induction of ventricular tachyarrhythmias. Management of overdoses of thioridazine and mesoridazine, which are complicated by cardiac arrhythmias, is similar to that for tricyclic antidepressants (see Chapter 30). Psychosocial Treatment & Cognitive Remediation Patients with schizophrenia need psychosocial support based around activities of daily living, including housing, social activities, returning to school, obtaining the optimal level of work they may be capable of, and restoring social interactions. Case management and therapy services are a vital part of the treatment program that should be provided to patients with schizophrenia. First- episode patients are particularly needful of this support because they often deny their illness and are noncompliant with medication.

The man asked discount diovan 160 mg free shipping heart attack high dead end counterpart, ‘Doctor order cheap diovan online hypertension and obesity, could a drunk man stand up in the middle of this room buy diovan with american express hypertension nursing assessment, jump into the air, turn a complete somersault, and land down on his feet? The introduction of the breathalyser, which has a statutory role only in road traffic situations, Fig. There is a decline through all the stages of general anaesthesia and may die in attentiveness and ability to assimilate, sort and take from respiratory depression. Loss of consciousness occurs quick decisions on continuously changing information at blood concentrations around 300 mg/100 mL, death at input; an example is inattentiveness to the periphery of about 400 mg/100 mL. All of these are clearly highly undesirable effects when a Innumerable tests of physical and mental performance person is in a position where failure to perform well may be have been used to demonstrate the effects of alcohol. Some other important physiological and meta- Results show that alcohol reduces visual acuity and delays bolic effects of acute alcohol ingestion are described in recovery from visual dazzle, impairs taste, smell and hear- Table 11. It com- changes, excitement, mental confusion (including ‘black- monly increases subjects’ confidence in their ability to outs’), incoordination and even coma. Numerous other perform well when tested and tendency to underestimate conditions can mimic this presentation and diagnosis Table 11. Alcohol can cause severe hypoglycae- For this reason, the compulsory use of a roadside breath mia; measurement of blood alcohol may clarify the situa- test is acknowledged to be in the public interest. Chronic consumption Where blood or breath analysis is not immediately avail- able after an accident, it may be measured hours later and Tolerance to alcohol can be acquired and the point has ‘back calculated’ to what it would have been at the time of been made that it costs the regular heavy drinker 2. It is usual to assume that the blood concentra- as much to get visibly drunk as it would cost the average tion falls at about 15 mg/100 mL/h. When wine rationing was introduced in Paris during the Second World Alcohol dependence is a complex disorder with environ- War, deaths from hepatic cirrhosis dropped to about one- mental, drug-induced and genetic components with sixth of the previous level; 5 years after the war they had multiple genes probably contributing to vulnerability to regained their former level. In practice, prosecutions are undertaken only when the concentration is significantly higher to avoid arguments about biological variability and instrumental error. Urine The effects of alcohol and psychotropic drugs on motor car concentrations are little used as the urine is accumulated over time and does not provide the immediacy of blood and breath. Due to 146 Drug dependence Chapter | 11 | the risk of over- or under-prescribing, increasingly symp- a test dose of alcohol under supervision (after the 5th day tom-triggered prescribing is used to facilitate the inpatient of taking), so that patients can be taught what to expect, detoxification. This remains an extremely active area of It is usual to administer vitamins, especially thiamine, in research. But both patients use, but it carries significant risk of dependence and should and non-patients justifiably expect some guidance, and not be given if the patient is likely to persist in drinking doctors and government departments will wish to be alcohol. In other societies recom- needs to be recognised early due to very high mortality mended maxima are higher or lower. The type of drink (beer, wine, spirits) is not particularly Treatment of alcohol dependence relevant to the adverse health consequences; a standard Psychosocial support is more important than drugs, which bottle of spirits (750 mL) contains 300 mL (240 g) of al- nevertheless may help. Iftakenfor1 year(accompanied of cognitive decline,11and light-to-moderate alcohol con- by counselling and psychosocial support), acamprosate in- sumption may reduce risk of dementia in people aged creases the number of alcohol-free days and also the chance 55 years or more. The benefit may last for The curve that relates mortality (vertical axis) to alcoholic 1 year after stopping treatment. As con- Acamprosate may cause diarrhoea, and cutaneous sumption rises above zero the all-cause mortality declines, eruptions. The benefit is largely a reduction of deaths due to cardiovascular and Disulfiram (Antabuse) discourages drinking by inducing cerebrovascular disease for regular drinkers of 1–2 units immediate unpleasantness. It is an aldehyde dehydroge- per day for men aged over 40 years and postmenopausal nase inhibitor, so that acetaldehyde (a toxic metabolite women. These features may result from even small 11Stampfer M J, Kang J H, Chen J et al 2005 Effects of moderate alcohol amounts of alcohol (such as may be present in some oral consumption on cognitive function in women. It has euphoric and seda- fetal/embryonic growth retardation (1% for every 10 g tive effects and is popular at dance parties where it has alcohol per day) and this is not ‘caught up’ later. It is highly addic- Fetal alcohol syndrome is a term that covers a spectrum tive and frequent ingestion may induce dependency and a of disorders;14 it includes the following characteristics: mi- severe withdrawal state. Even small amounts of alcohol taken by the mother delay motor development in the child; an effect Tobacco on mental development is uncertain. In 1492, the explorer Christopher Columbus observed Native Americans using the dried leaves of the tobacco There is no ‘safe’ level of alcohol consumption in 16) plant (later named Nicotiana for pleasure and also to pregnancy. Journal of the Royal Society 15For pictures see Streissguth A P, Clarren S K, Jones K L 1985 Natural of Medicine 97:292–296. Chronic consumptionmay increaserisk ofliver damagefromhalothane and enflurane Tricyclic amitriptyline Acute and chronic ingestion can increase availability and worse antidepressants sedation and side effects In 1990 there were 3 million smoking-related deaths per inhale (and have a high rate of death from tar-induced lung year, projected to reach 10 million by 2030. The amount of nicotine absorbed from tobacco smoke varies from 90% in those who inhale to 10% in those who do not. Smoke drawn through the tobacco Composition and taken in by the smoker is known as main-stream Tobacco smoke is complex (over 4000 compounds have smoke; smoke that arises from smouldering tobacco and been identified) and varies with the type of tobacco and passes directly into the surrounding air is known as side- the way it is smoked. These differ in composition, partly because ingredients are nicotine, responsible for acute effects of the different temperatures at which they are produced. Nicotine Although the risks of passive smoking are naturally smaller, is relatively un-ionised at this pH, and is readily absorbed the number of people affected is large. Cigar and pipe smokers thus obtain nicotine that breathing other people’s smoke increases a person’s riskofischaemicheartdiseasebyaquarter. Nicotine is rela- have3–7%(heavysmokersasmuchas15%)oftheirhaemo- tively ionised and insoluble in lipids. Polycyclic hydrocarbons are responsible for the concentration comparable to that reached in smoking hepatic enzyme induction that occurs in smokers. Nicotine pharmacology But under the psychosocial pressures the subject continues, learns to limit and adjust nicotine intake, so that the pleas- Pharmacokinetics ant pharmacological effects of nicotine develop and toler- ance to the adverse effects occurs. Thus to the psychosocial Nicotine is absorbed through mucous membranes in a pressure is now added pharmacological pleasure. Cotinine is • It modulates dopamine activity in the midbrain, used as a marker for nicotine intake in smoking surveys particularly in the mesolimbic system, which promotes because of its conveniently long t½ (20 h). Nicotine is an agonist to receptors at the • Short elimination t½ requires regular smoking to maintain the effect. The effects of nicotine on viscera are probably largely reflex, from stimulation of sen- sory receptors (chemoreceptors) in the carotid and aortic Nicotine shows all the characteristics of a drug of bodies, pulmonary circulation and left ventricle. On the fourth day he was deemed well enough to leave hospital and was given his • Increased airways resistance occurs due to the non- clothes, which had been kept in a paper bag. Within 1 h of leaving hospital he had to be readmitted, suffering again from poisoning due to nicotine absorbed transdermally from his still contaminated trousers. He recovered over 22Tobacco Advisory Group, Royal College of Physicians 2000 Nicotine 3 weeks, apart from persistent ventricular extrasystoles (Faulkner J M Addiction in Britain. There is vasoconstriction the mouth, throat and oesophagus is 5–10 times greater in the skin and vasodilatation in the muscles, tachycardia than that of non-smokers. It is as great for pipe and cigar and a rise in blood pressure of about 15 mmHg systolic smokers as it is for cigarette smokers.

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