Sharon Phillips Andreoli, MD

• Professor of Pediatrics,
• James Whitcomb Riley Hospital for Children and Indiana
• University School of Medicine
• Byron P. and Frances D. Hollett
• Professor of Pediatrics,
• Director, Division of Pediatric Nephrology,
• Indiana University School of Medicine,
• Indianapolis, Indiana

Nitrous oxide is used to maintain surgical anaesthesia in combination with other anaesthetic agents allergy knoxville order clarinex on line amex. Entonox provides analgesia for obstetric practice and for emergency treatment of injuries allergy medicine zyrtec generic order 5mg clarinex with amex. Any closed allergy symptoms for ragweed buy clarinex 5 mg with mastercard, distensible allergy treatment essential oils order clarinex 5mg on line, air-filled space expands during administration of nitrous oxide allergy vanilla symptoms discount clarinex 5 mg line, which moves into it from the blood allergy treatment 5ths purchase discount clarinex. Nitrous oxide will cause pressure changes in closed, non-compliant spaces such as the middle ear, nasal sinuses and the eye. Continued administration of oxygen may be necessary during recovery, especially in elderly patients (see diffusion hypoxia, above). Exposure to nitrous oxide for more than 4 h can cause megaloblastic 298 Anaesthesia and neuromuscular block changes in the bone marrow. Because prolonged and repeated exposure of staff, as well as of patients, may be associated with bone marrow depression and teratogenic risk, scavenging systems are used to minimise ambient concentrations in operating theatres. Chapter 19 Halogenated anaesthetics Halothane was the first halogenated agent to be used widely, but in the developed world it has been largely superseded by isoflurane, sevoflurane and desflurane. A description of isoflurane is provided, and of the others in so far as they differ. The reaction with soda lime causes the formation of a vinyl ether (compound A), which may be nephrotoxic. Sevoflurane is less soluble than isoflurane and is very pleasant to breathe, which makes it an excellent choice for inhalational induction of anaesthesia, particularly in children. In many hospitals, despite its higher cost, sevoflurane is displacing isoflurane as the most commonly used volatile anaesthetic. Desflurane is extremely volatile and cannot be administered with conventional vaporisers. It has a very pungent odour and causes airway irritation to an extent that limits its rate of induction of anaesthesia. Despite this limitation, its very rapid recovery characteristics, even after very prolonged anaesthesia, make it an increasingly popular choice for major surgery. Isoflurane Isoflurane is a volatile colourless liquid that is not flammable at normal anaesthetic concentrations. It has a pungent odour and can cause bronchial irritation, making inhalational induction unpleasant. Halothane reduces cardiac output more than any of the other volatile anaesthetics. Halothane can trigger malignant hyperthermia in those who are genetically predisposed (see p. In more severe cases this is followed by transient jaundice or, very rarely, fatal hepatic necrosis. Severe hepatitis is a complication of repeatedly administered halothane anaesthesia (incidence of 1 in 50 000) and follows immune sensitisation to an oxidative metabolite of halothane in susceptible individuals. This serious complication, along with the other disadvantages of halothane and the popularity of sevoflurane for inhalational induction, has almost eliminated its use in the developed world. It remains in common use in other parts of the world because it is comparatively inexpensive. Isoflurane causes respiratory depression and diminishes the ventilatory response to carbon dioxide. Isoflurane is a potent coronary vasodilator and in the presence of a coronary artery stenosis it may cause redistribution of blood away from an area of inadequate perfusion to one of normal perfusion. Isoflurane relaxes voluntary muscles and potentiates the effects of non-depolarising muscle relaxants. Sevoflurane Sevoflurane is less chemically stable than the other volatile anaesthetics in current use. Use of unnecessarily high concentrations of oxygen in incubators causes retrolental fibroplasia and permanent blindness in premature infants. Some preparations of propofol cause pain on injection, but adding lidocaine 20 mg to the induction dose eliminates this. The recovery from propofol is rapid, and the incidence of nausea and vomiting is extremely low, particularly when propofol is used as the sole anaesthetic. Recovery from a continuous infusion of propofol is relatively rapid as the plasma concentration decreases by both redistribution and metabolic clearance (predominantly as the glucuronide). Special syringe pumps incorporating pharmacokinetic algorithms enable the anaesthetist to select a target plasma propofol concentration. It depresses laryngeal reflexes more than barbiturates, which is an advantage when inserting a laryngeal mask airway. Pharmacokinetics Intravenous anaesthetics enable an extremely rapid induction because the blood concentration can be raised quickly, establishing a steep concentration gradient and expediting diffusion into the brain. The rate of transfer depends on the lipid solubility and arterial concentration of the unbound, non-ionised fraction of the drug. After a single induction dose of an intravenous anaesthetic, recovery occurs quite rapidly as the drug is redistributed around the body and the plasma concentration reduces. Recovery from a single dose of intravenous anaesthetic is thus dependent on redistribution rather than rate of metabolic breakdown. With the exception of propofol, repeated doses or infusions of intravenous anaesthetics will cause considerable accumulation and prolong recovery. Attempts to use thiopental as the sole anaesthetic in war casualties led to it being described as an ideal form of euthanasia. When administration of a volatile anaesthetic is stopped, it is eliminated quickly through the lungs and the patient regains consciousness. This advantage, and others, has resulted in propofol displacing thiopental as the most popular intravenous anaesthetic. Propofol reduces vascular tone, which lowers systemic vascular resistance and central venous pressure. Unless it is undertaken very slowly, induction with propofol causes transient apnoea. On resumption of respiration there is a reduction in tidal volume and increase in rate. Thiopental Thiopental is a very short-acting barbiturate4 that induces anaesthesia smoothly, within one arm-to-brain circulation time. The incidence of nausea and vomiting after thiopental is slightly higher than that after propofol. Accidental intra-arterial injection will also cause serious injury distal to the injection site. Thiopental reduces vascular tone, causing hypotension and a slight compensatory increase in heart rate. Chapter 19 pharyngeal and laryngeal reflexes are only slightly impaired, the airway may be less at risk than with other general anaesthetic techniques. It is a potent bronchodilator and is sometimes used to treat severe bronchospasm in asthmatics requiring mechanical ventilation. Hallucinations with delirium can occur during recovery (the emergence reaction), but are minimised if ketamine is used solely as an induction drug and followed by a conventional inhalational anaesthetic. Their incidence is reduced by giving a benzodiazepine both as a premedication and after the procedure. Subanaesthetic doses of ketamine can be used to provide analgesia for painful procedures of short duration such as the dressing of burns, radiotherapeutic procedures, marrow sampling and minor orthopaedic procedures. Ketamine can be used for induction of anaesthesia before giving inhalational anaesthetics, or for both induction and maintenance of anaesthesia for short-lasting diagnostic and surgical interventions that do not require skeletal muscle relaxation. It causes pain on injection and excitatory muscle movements are common on induction of anaesthesia. Etomidate causes adrenocortical suppression by inhibiting 11b- and 17b-hydroxylase, and for this reason is not used for prolonged infusion. Even after a single dose of etomidate, adrenocortical suppression can last for as long as 72 h and in septic patients is associated with an increased incidence of organ failure. Despite all of these disadvantages it remains in common (although decreasing) use, particularly for emergency anaesthesia, because it causes less cardiovascular depression and hypotension than thiopental or propofol. Tonic and clonic movements resembling seizures occur in some patients but do not indicate a light plane of anaesthesia or a need for additional doses of the anaesthetic. Emergence reactions (above) are lessened by benzodiazepine premedication and by avoiding unnecessary disturbance of the patient during recovery. Anaesthesia persists for up to 15 min after a single intravenous injection and is characterised by profound analgesia. Ketamine may be used as the sole analgesic for diagnostic and minor surgical interventions. In contrast to most other anaesthetic drugs, ketamine usually causes a tachycardia and increases blood pressure and cardiac output, making it an increasingly popular choice for inducing anaesthesia in shocked patients. Ketamine is contraindicated in pregnancy before term, as it has oxytocic activity. In the past, misguided concerns about the effect of volatile anaesthetics on the newborn led many anaesthetists to use little, if any, volatile agent when giving general anaesthesia for caesarean section. Under these conditions some mothers were conscious and experienced pain while paralysed and therefore unable to move. Despite its extreme rarity nowadays,8 fear of awareness under anaesthesia is still a leading cause of anxiety in patients awaiting surgery. This could be attained by deep general anaesthesia (but with risk of cardiovascular depression, respiratory complications and slow recovery) or by regional nerve blockade (which may be difficult to do or contraindicated. Neuromuscular blocking drugs first attracted scientific notice because of their use as arrow poisons by the natives of South America, who used the most famous of all, curare, for killing food animals6 as well as enemies. Though he did not continue until complete recovery, he did suggest that the drug might be of use in tetanus. Despite attempts to use curare for a variety of diseases including epilepsy, chorea and rabies, the lack of pure and accurately standardised preparations, as well as the absence of convenient techniques of mechanical ventilation if overdose occurred, prevented it from gaining any firm place in medical practice until 1942, when these difficulties were removed. Drugs acting at the myoneural junction produce complete paralysis of all voluntary muscle so that movement is impossible and mechanical ventilation is needed. It is plainly important that a paralysed patient should be unconscious during surgery. Doubts were resolved in a single experiment: A normal subject was slowly paralysed (curarised) after arranging a detailed and complicated system of communication. Twelve minutes after beginning the slow infusion of curare, the subject, having artificial respiration, could move only his head. He indicated that the experience was not unpleasant, that he was mentally clear and did not want an endotracheal tube inserted. After 22 min, communication was possible only by slight movement of Mechanisms When an impulse passes down a motor nerve to voluntary muscle it causes release of acetylcholine from the nerve endings into the synaptic cleft. This activates receptors on the membrane of the motor endplate, a specialised area on the muscle fibre, opening ion channels for momentary passage of sodium, which depolarises the endplate and initiates muscle contraction. Neuromuscular blocking drugs used in clinical practice interfere with this process. Natural substances that prevent the release of acetylcholine at nerve endings exist. There are two principal mechanisms by which drugs used clinically interfere with neuromuscular transmission: 1. By competition with acetylcholine (atracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuronium). They do not cause depolarisation themselves but protect the endplate from depolarisation by acetylcholine. Reversal of this type of neuromuscular block can be achieved with anticholinesterase drugs, the left eyebrow, and after 35 min paralysis was complete and direct communication lost. The insertion of the tracheal tube had caused only minor discomfort, perhaps because of the prevention of reflex muscle spasm. Note: a randomised controlled trial is not required for this kind of investigation. Rocuronium and vecuronium can also be reversed with the modified g-cyclodextrin, sugammadex (see below). It might be expected that this prolonged depolarisation would cause muscles to remain contracted, but this is not so (except in chickens). With prolonged administration, a depolarisation block changes to a competitive block (dual block). Because of the uncertainty of this situation, a competitive blocking drug is preferred for anything other than short procedures. Chapter 19 Antagonism of competitive neuromuscular block Neostigmine the action of competitive acetylcholine blockers is antagonised by anticholinesterase drugs, which enable accumulation of acetylcholine. Too much neostigmine can cause neuromuscular block by depolarisation, which will cause confusion unless there have been some signs of recovery before neostigmine is given. This g-cyclodextrin was designed specifically to encapsulate rocuronium: the negatively charged hydrophilic outer core attracts the positively charged rocuronium and pulls the drug into its lipophilic core. A full neuromuscular block from rocuronium can be reversed with sugammadex in less than 3 min. Neostigmine can be used only when the block from rocuronium has started to recover spontaneously (perhaps 30 min after initial injection) and it has many unwanted effects that are not a feature of sugammadex. The relatively high cost of sugammadex is currently prohibiting its widespread adoption. It has very little direct effect on the cardiovascular system but at doses of greater than 0. Vecuronium is a synthetic steroid derivative that produces full neuromuscular blockade about 3 min after a dose of 0. Depolarising neuromuscular blocker Suxamethonium (succinylcholine) Paralysis is preceded by muscle fasciculation, and this may be the cause of the muscle pain experienced commonly after its use. Suxamethonium is the neuromuscular blocker with the most rapid onset and the shortest duration of action (although the onset of rocuronium is almost as fast and with sugammadex the recovery is faster than that of suxamethonium).

Skin prick tests are helpful in specialist hands for diagnosing IgE-dependent drug reactions allergy shots quickly purchase generic clarinex pills, notably due to penicillin allergy home discount clarinex 5mg fast delivery, cephalosporins allergy testing geelong buy clarinex amex, muscle relaxants allergy medicine generic purchase discount clarinex on line, thiopental allergy medicine and pregnancy buy discount clarinex 5mg, streptokinase allergy testing labs purchase 5 mg clarinex, cisplatin, insulin and latex. If a patient claims to be allergic to a drug then that drug should not be given without careful enquiry that may include testing (above). Pseudo-allergic reactions these are effects that mimic allergic reactions but have no immunological basis and are largely genetically determined. A variety of mechanisms is probably involved, direct and indirect, including complement activation leading to formation of polypeptides that affect mast cells, as in true immunological reactions. Severe cases are treated as for true allergic anaphylactic shock (above), from which, at the time, they are not distinguishable. Desensitisation Once patients become allergic to a drug, it is better that they should never again receive it. Desensitisation may be considered (in hospital) where a patient has suffered an IgE-mediated reaction to penicillin and requires the drug for serious infection. Such people can be desensitised by giving very small amounts of allergen, which are than gradually increased (usually every few hours) until a normal dose is tolerated. The procedure may necessitate cover with a corticosteroid and a b-adrenoceptor agonist (both of which inhibit mediator synthesis and release), and an H1-receptor antihistamine may be added if an adverse reaction occurs. Lupus erythematosus due to drugs (procainamide, isoniazid, phenytoin) may be pseudo-allergic. Long-term use of oestrogen replacement in postmenopausal women induces endometrial cancer. Diethylstilbestrol caused vaginal adenosis and cancer in the offspring of mothers who took it during pregnancy in the hope of preventing miscarriage. It was used for this purpose for decades after its introduction in the 1940s, on purely theoretical grounds. Controlled therapeutic trials were not done and there was no valid evidence of therapeutic efficacy. There is a higher incidence of secondary cancers in patients treated for a primary cancer. Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines and alkylating agents. Retinal injury develops with thioridazine (particularly, of the antipsychotics), chloroquine and indometacin, and visual field defects with vigabatrin. It is not sufficient safeguard merely to ask a woman if she is, or may be, pregnant, for it is also necessary to consider the possibility that a woman who is not pregnant at the time of prescribing may become so while taking the drug. Testing of new drugs on animals for reproductive effects has been mandatory since the thalidomide disaster, even though the extrapolation of the findings to humans is 19 Nervous system. The suggestion that congenital cataract (due to denaturation of lens protein) might be due to drugs has some support in humans. As both can cause retinopathy, it would seem wise to avoid them in pregnancy if possible. Babies born to mothers dependent on opioids may show a physical withdrawal syndrome. The placental transfer of drugs from the mother to the fetus is considered on page 86. During the first week after fertilisation, exposure to antimetabolites, misoprostol, ergot alkaloids or diethylstilbestrol can cause abortion, which may not be recognised as such. Thus, the activity of a teratogen (teratos, monster) is most devastating soon after implantation, at doses that may not harm the mother and at a time when she may not know she is pregnant. Those subsequently found to be safe include diazepam (but see below), oral contraceptives, spermicides and salicylates. Diazepam (and other depressants) in high doses may cause hypotonia in the baby and possibly interfere with suckling. In this emotionally charged area it is indeed hard for the public, and especially for parents of an affected child, to grasp that: the concept of absolute safety of drugs needs to be demolished. In real life it can never be shown that a drug (or anything else) has no teratogenic activity at all, in the sense of never being a contributory factor in anybody under any circumstances. Let us suppose for example, that some agent doubles the incidence of a condition that has natural incidence of 1 in 10 000 births. If the hypothesis is true, then studying 20 000 pregnant women who have taken the Late pregnancy. Because the important organs are well formed, drugs will not cause the gross anatomical defects that can occur following exposure in early pregnancy. Inhibitors of prostaglandin synthesis (aspirin, indometacin) may delay onset of labour and, in the fetus, cause 120 Unwanted effects and adverse drug reactions drug and 20 000 who have not may yield respectively two cases and one case of the abnormality. It does not take a statistician to realise that this signifies nothing, and it may need ten times as many pregnant women (almost half a million) to produce a statistically significant result. This would involve such an extensive multicentre study that hundreds of doctors and hospitals have to participate. The participants then each tend to bend the protocol to fit in with their clinical customs and in the end it is difficult to assess the validity of the data. Alternatively, a limited geographical basis may be used, with the trial going on for many years. During this time other things in the environment change, so again the results would not command our confidence. If it were to be suggested that there was something slightly teratogenic in milk, the hypothesis would be virtually untestable. In practice we have to make up our minds which drugs may reasonably be given to pregnant women. If the former course is chosen then we cannot give any drugs to pregnant women because we can never prove that they are completely free of teratogenic influence. It therefore seems that we must start from a position of presumed innocence and then take all possible steps to find out if the presumption is correct. The problem of prescription in pregnancy cannot be considered from the point of view of only one side of the equation. Drugs are primarily designed to do good, Chapter 9 and if a pregnant woman is ill it is in the best interests of her baby and herself that she gets better as quickly as possible. What we must try to avoid is medication by the media or prescription by politicians. A public scare about a well-tried drug will lead to wider use of less-tried alternatives. We do not want to be forced to practise the kind of defensive medicine that is primarily designed to avoid litigation. Spermatogenesis is reduced by a number of drugs including sulfasalazine and mesalazine (reversible), cytotoxic anticancer drugs (reversible and irreversible) and nitrofurantoin. There has been a global decline in sperm concentration and an environmental cause. In particular, over half of these involve ingestion of paracetamol, with the associated risk of serious toxicity. The total number of deaths related to drug poisoning in England and Wales increased each year from 1993 to a peak in 1999, and then began to decline. In India, deliberate self harm is seen with similar prescribed agents, together with frequent deliberate self harm with the antimalarial chloroquine and accidental or deliberate injury from pesticides such as the organophosphates or aluminium phosphide. In Sri Lanka deliberate pesticide ingestion is also a serious public health issue. Accidental self-poisoning, causing admission to hospital, occurs predominantly among children under 5 years of age, usually from medicines left within their reach or with commonly available domestic chemicals. Poisoning may also occur as a result of accidental ingestion, occupational exposure and in the context of recreational substance use. Poisoning by non-drug chemicals: heavy metals, cyanide, methanol, ethylene glycol, hydrocarbons, volatile solvents, heavy metals, herbicides and pesticides. Deliberate self-harm involves intentional selfpoisoning or self-injury irrespective of the intended purpose of that act. Self-poisoning is the commonest form of deliberate self-harm after self-mutilation. Poisoning, usually by medicines taken in overdose, is currently responsible for over 150 000 hospital attendances per annum in Most patients who die from deliberate ingestion of drugs do so before reaching medical assistance. Adults may be sufficiently conscious to give some indication of the poison or may have referred to it in a suicide note, or there may be other circumstantial evidence. The ambulance crew attending to the patient at home may have very valuable information and should be questioned for any clues to the ingested drug. Many substances used in accidental or self-poisoning produce recognisable symptoms and signs. In addition, sedatives, opioids and ethanol cause signs that may include respiratory depression, miosis, hyporeflexia, coma, hypotension and hypothermia. Other drugs and non-drug chemicals that produce characteristic effects include: salicylates, methanol and ethylene glycol, iron, selective serotonin reuptake inhibitors. Effects of overdose (and treatment) with other individual drugs or drug groups appear in the relevant accounts throughout the book. Maintenance of an adequate oxygen supply is the first priority and the airway must be sucked clear of oropharyngeal secretions or regurgitated matter. Shock in acute poisoning is usually due to expansion of the venous capacitance bed and placing the patient in the head-down position to encourage venous return to the heart, or a colloid plasma expander administered intravenously restores blood pressure. External cardiac compression may be necessary and should be continued until the cardiac output is self-sustaining, which may be a long time when the patient is hypothermic or poisoned with a cardiodepressant drug. External cardiac compression may be required for prolonged periods of cardiac arrest, up to several hours. In young patients the heart is anatomically and physiologically normal and will recover when the poison has been eliminated from the body. Mechanical ventilation is necessary if adequate oxygenation cannot be obtained or hypercapnia ensues. Hypotension: this is common in poisoning and, in addition to the resuscitative measures indicated above, conventional inotropic support may be required. In addition: there is recent interest in the use of high dose insulin infusions with euglycaemic clamping as a positive inotrope in the context of overdose with myocardial depressant agents. Many of these are in the context of overdosage with non-dihydropyridine calcium channel blockers that are often resistant to conventional inotropic agents. Acidosis, hypoxia and electrolyte disturbance are often important contributory factors and it is preferable to observe the effect of correcting these before considering resort to an antiarrhythmic drug. If arrhythmia does lead to persistent peripheral circulatory failure, an appropriate drug may be cautiously justified. Immobility may lead to pressure lesions of peripheral nerves, cutaneous blisters, necrosis over bony prominences, and increased risk of thromboembolism warrants prophylaxis. Particular treatments such as haemodialysis or urine alkalinisation may be indicated for overdose with salicylate, lithium and some sedative drugs. Some will require specific measures to reduce absorption or to increase elimination. Most patients recover from acute poisonings provided they are adequately oxygenated, hydrated and perfused. The procedure may be considered in very extraordinary circumstances for the hospitalised adult who is believed to have ingested a potentially life-threatening amount of a poison within the previous hour, and provided the airways are protected by a cuffed endotracheal tube. It is contraindicated for corrosive substances, hydrocarbons with high aspiration potential and where there is risk of haemorrhage from an underlying gastrointestinal condition. Emesis using syrup of ipecacuanha is no longer practised in hospital, as there is no clinical trial evidence that the procedure improves outcome. To be most effective, five to ten times as much charcoal as poison, weight for weight, is needed. Unless a patient has an intact or protected airway its administration is contraindicated. Activated charcoal is most effective when given soon after ingestion of a potentially toxic amount of a poison and while a significant amount remains yet unabsorbed. There are no satisfactorily designed clinical trials in patients to assess the benefit of single dose activated charcoal. Charcoal in repeated doses accelerates the elimination of poison that has been absorbed (see later). Activated charcoal, although unpalatable, appears to be relatively safe but constipation or mechanical bowel obstruction may follow repeated use. In the drowsy or comatose patient there is particular risk of aspiration into the lungs causing hypoxia through obstruction and arteriovenous shunting. Activated charcoal (Carbomix) consists of a very fine black powder prepared from vegetable matter. Indeed, 1 Joint position statements and guidelines agreed by the American Academy of Clinical Toxicology and the European Association of Poison Centres and Clinical Toxicologists review the therapeutic usefulness of various procedures for gut decontamination. These appear in the Journal of Toxicology, Clinical Toxicology from 1997 onwards, the latest position statements being in 2004 and 2005. Whole-bowel irrigation3 should not be used routinely in the management of the poisoned patient. While volunteer studies have shown marked reductions in the bioavailability of ingested drugs, there is no evidence from 2 For centuries it was supposed not only that there could be, but that there actually was, a single antidote to all poisons. This was Theriaca Andromachi, a formulation of 72 (a magical number) ingredients among which particular importance was attached to the flesh of a snake (viper). Klean-Prep, by mouth causes minimal fluid and electrolyte disturbance (it was developed for preparation for colonoscopy). Vomiting should be treated with an antiemetic drug because it reduces the efficacy of charcoal treatment. It should be used for the removal of sustained-release or enteric-coated formulations from patients who present more than 2 h after ingestion.

It may cause gastrointestinal discomfort allergy symptoms 8dpo cheap clarinex 5 mg on-line, headaches allergy symptoms red bumps discount 5 mg clarinex, reversible alopecia allergy forecast elgin tx order clarinex 5 mg line, increased levels of liver enzymes and allergic rash allergy testing your dog cheap 5 mg clarinex mastercard, but is generally well tolerated allergy symptoms in dogs buy cheap clarinex 5mg on line. It is more effective than conventional amphotericin in invasive aspergillosis allergy symptoms to zoloft buy clarinex 5mg, and probably equivalent to lipid-associated formulations. High doses increase the effects of phenytoin, ciclosporin, zidovudine and warfarin. It is improved by ingestion with food, but decreased by fatty meals and therapies that reduce gastric acidity. Plasma concentrations should be monitored during prolonged use for critical indications. The oral suspension formulation has significantly improved bioavailability compared to the capsule formulation and is much less affected by gastric hypoacidity. Itraconazole is used for a variety of superficial mycoses, as a prophylactic agent for aspergillosis and candidiasis in the immunocompromised, and i. It appears to be an effective adjunct treatment for allergic bronchopulmonary aspergillosis. These often resolve after the first week of therapy, and almost all of those affected are able to continue with the course of treatment. Accumulation of the cyclodextrin vehicle (see above) may cause sodium retention in renally impaired patients with i. Patients with hepatic cirrhosis should receive a standard loading, but only half of the daily maintenance dose. Rashes and photosensitivity appear to be more common than with the other triazoles. It provides effective prophylaxis against invasive fungal infection in leukaemia and bone marrow transplant patients. Prolonged use may lead to cardiac failure, especially in those with pre-existing cardiac disease. Allylamine Terbinafine Terbinafine interferes with ergosterol biosynthesis, and thereby with the formation of the fungal cell membrane. Terbinafine is used topically for dermatophyte infections of the skin and orally for infections of hair and nails where the site. It is as active as the other 226 Viral, fungal, protozoal and helminthic infections inappropriate (see pp. Terbinafine may cause nausea, diarrhoea, dyspepsia, abdominal pain, headaches and cutaneous reactions. The therapeutic efficacy of griseofulvin depends on its capacity to bind to keratin as it is being formed in the cells of the nail bed, hair follicles and skin, for dermatophytes specifically infect keratinous tissues. Treatment must continue for a few weeks after both visual and microscopic evidence has disappeared. Griseofulvin is effective against all superficial ringworm (dermatophyte) infections, but ineffective against pityriasis versicolor, superficial candidiasis and all systemic mycoses. In vitro and in vivo, the echinocandins are rapidly fungicidal against most Candida spp. Caspofungin retains activity against most triazole- and polyene-resistant yeasts, and is also active against Pneumocystis jirovecii. Caspofungin is generally well tolerated, but headache, fever, raised liver function tests and hypokalaemia occur. Patients might experience histamineinduced reactions when the drug is infused too rapidly. Flucytosine Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil, which inhibits nucleic acid synthesis. The dose should be reduced for patients with impaired renal function, and the plasma concentration monitored. Micafungin has similar activity to caspofungin and is licensed for the treatment of invasive candida infections (oesophagitis, peritonitis and candidaemia) and for prophylaxis of Candida spp. It is highly protein bound and, unlike caspofungin and anidulafungin, does not require a loading dose. It has a much longer elimination half-life than the other echinocandins (27 h) and is not metabolised by the liver, but undergoes slow chemical degradation to inactive metabolites. Anidulafungin is approved for the treatment of invasive candidiasis in adult nonneutropenic patients. In terms of socioeconomic impact, malaria is the most important of the transmissible parasitic diseases. Female anopheles mosquitoes require a blood meal for egg production, and in the process of feeding they inject salivary fluid containing sporozoites into humans. As no drugs are effective against sporozoites, infection with the malaria parasite cannot be prevented. Chloroquine, quinine, mefloquine, halofantrine, proguanil, pyrimethamine and tetracyclines (blood schizontocides) kill these asexual forms. Drugs that act at this stage in the cycle of the parasite may be used for: Chapter 15 position. Because prevalence and resistance rates are so variable, advice on therapy and prophylaxis in this section is given for general guidance only and readers are referred to specialist sources for up-to-date information. This is called suppressive prophylaxis as it does not cure the hepatic cycle (above). Chemotherapy of an acute attack of malaria3 Successful management demands attention to the following points of principle: Sexual forms (site 3 in. Quinine, mefloquine, chloroquine, artesunate, artemether and primaquine (gametocytocides) act on sexual forms and prevent transmission of the infection because the patient becomes non-infective and the parasite fails to develop in the mosquito (site 4). When the infecting organism is not known or infection is mixed, treatment should begin as for Plasmodium falciparum (below). Drugs used to treat Plasmodium falciparum malaria must always be selected with regard to the prevalence of local patterns of drug resistance. Patients not at risk of re-infection should be reexamined several weeks after treatment for signs of recrudescence, which may result from inadequate chemotherapy or survival of persistent hepatic forms. Plasmodium falciparum is now resistant to chloroquine and sulfadoxine-pyrimethamine in many parts of the world. Areas of high risk for resistant parasites include sub-Saharan Africa, Latin America, Oceania (Papua New Guinea, Solomon Islands, Vanuatu) and some parts of South-East Asia. There are concerns with emerging artesunate resistance in western Cambodia due to monotherapy. Hyperparasitaemia and inappropriate or low dosing of antimalarials are important drivers of resistance. This additional therapy is necessary as quinine alone tends to be associated with a higher rate of relapse. Clindamycin (450 mg four times daily for 7 days) may be given as an alternative follow-on therapy instead of doxycycline, and is particularly suitable for pregnant women. Malarone (atovaquone and proguanil hydrochloride): 4 tablets once daily for 3 days. Mefloquine is also effective, but resistance has been reported in several regions, including South-East Asia. It is not necessary to use follow-on therapy after Riamet, mefloquine or Malarone. Doxycycline or clindamycin should be given subsequently, as above (mefloquine is an alternative, but this must begin at least 12 h after parenteral quinine has ceased). Intravenous artesunate showed a clear benefit when compared to quinine in patients with severe falciparum malaria. Jones K L, Donegan S, Lalloo D G 2007 Artesunate versus quinine for treating severe malaria. Mefloquine, doxycycline and atovaquone-proguanil (Malarone) are the most commonly advised prophylactic regimens, and are particularly recommended for areas of chloroquine-resistant falciparum malaria. Chloroquine, alone or in combination with proguanil, may be considered in areas of the world where the risk of acquiring chloroquine resistant falciparum malaria is low, although there is considerable concern regarding the protective efficacy of this regimen. Effective chemoprophylaxis requires that there be a plasmodicidal concentration of drug in the blood when the first infected mosquito bites, and that it be sustained safely for long periods. Thus, it is advised that prophylaxis begin long enough before travel to reveal acute intolerance and to impress on the subject the importance of compliance (to relate drug-taking to a specific daily or weekly event). Prophylaxis should continue for at least 4 weeks after leaving an endemic area to kill parasites that are acquired about the time of departure, are still incubating in the liver and will develop into the erythrocyte phase. The traveller should be aware that any illness occurring within a year, and especially within 3 months, of return, may be malaria. The World Health Organization gives advice in its annually revised booklet Vaccination Certificate Requirements and Health Advice for International Travel, and national bodies publish recommendations. Where there may be variation, therefore, the amount of drug prescribed is expressed as the weight of the active component, in the case of chloroquine, the base. Quinine is the only widely available drug that is acceptable as suitable for treating chloroquine-resistant infections during pregnancy. Mefloquine is teratogenic in animals and a woman should avoid pregnancy while taking it, and for 3 months afterwards (although evidence is accruing that it may be safe for use in chloroquine-resistant areas). Doxycycline is contraindicated throughout pregnancy, and Malarone (proguanil plus atovaquone) should be avoided unless there is no suitable alternative. Repeated attacks of malaria confer partial immunity and the disease often becomes no more than an occasional inconvenience. The reasoning is that immunity is sustained by the red cell cycle, loss of which through prophylaxis diminishes their resistance and leaves them highly vulnerable to the disease. There are, however, exceptions to this general advice, and the partially immune may or should use a prophylactic: n if it is virtually certain that they will never abandon its use n if they go to another malarial area where the strains of parasite may differ n during the last few months of pregnancy in areas where Plasmodium falciparum is prevalent (to avert the risk of miscarriage). Chloroquine is readily absorbed from the gastrointestinal tract and is concentrated severalfold in various tissues. A priming dose is used in order to achieve adequate free plasma concentration (see acute attack, above). Chloroquine is partly inactivated by metabolism and the remainder is excreted unchanged in the urine. The standard regimens normally provide immediate protection, but it will be sensible to avoid mefloquine (if an alternative antimalarial is available) in the last minute traveller with no history of previous mefloquine exposure or who is intolerant of the drug. Antimalarial drugs and pregnancy Women living in endemic areas in which Plasmodium falciparum remains sensitive to chloroquine should take chloroquine prophylactically throughout pregnancy. Corneal deposits of chloroquine may be asymptomatic or may cause halos around lights or photophobia. The functional defect can take the form of scotomas, photophobia, defective colour vision and decreased visual acuity resulting, in the extreme case, in blindness. Other reactions include pruritus, which may be intolerable and is common in Africans, headaches, gastrointestinal disturbance, precipitation of acute intermittent porphyria in susceptible individuals, mental disturbances and interference with cardiac rhythm, the latter especially if the drug is given i. Long-term use is associated with reversible bleaching of the hair and pigmentation of the hard palate. These effects are principally due to the profound negative inotropic action of chloroquine. Chapter 15 Adverse effects include nausea, dizziness, disturbance of balance, vomiting, abdominal pain, diarrhoea and loss of appetite. Neuropsychiatric events, including seizures and psychoses, occur after high-dose therapy in about 1 in 10 000 of those using the drug for prophylaxis. Less severe reactions including headache, dizziness, depression and insomnia have been reported but there is uncertainty as to whether these can be ascribed to mefloquine. The drug should not be used in travellers with a history of neuropsychiatric disease including convulsions and depression, and in those whose activities require fine coordination or spatial performance. It is converted to an active metabolite and no unchanged drug is recovered in the urine. It is no longer recommended for the treatment of drug-resistant Plasmodium vivax malaria and should also not be used for prophylaxis. Its unique effect is to eliminate the hepatic forms of Plasmodium vivax and Plasmodium ovale after standard chloroquine therapy, but only when the risk of re-infection is absent or slight. Primaquine is well absorbed from the gastrointestinal tract, is only moderately concentrated in the tissues, and is rapidly metabolised. It is only available as a fixed drug combination with artemether (Riamet or Co-artem). Unlike halofantrine, there are no cardiotoxicity concerns and it is well tolerated. It is used for malaria chemoprophylaxis, and occasionally to treat uncomplicated Plasmodium falciparum (both chloroquine-sensitive and chloroquine-resistant) and chloroquine-resistant Plasmodium vivax malaria. Mefloquine is rapidly absorbed from the gastrointestinal tract and its action is terminated by metabolism. Plasmodia, like most bacteria but unlike humans, cannot make use of preformed folic acid. Their plasmodicidal action is markedly enhanced by combination with sulfonamides or Report 1993 Chloroquine poisoning. Due to toxicity concerns (agranulocytosis) and increasing resistance to pyrimethamine, this regimen is no longer recommended for prophylaxis, although it continues to be available in parts of Africa, in particular Zimbabwe and neighbouring countries. It is used alone (usually with chloroquine) for malaria prophylaxis, and is also available with atovaquone (as Malarone: proguanil hydrochloride 100 mg plus atovaquone 250 mg) for prophylaxis and treatment. Proguanil is moderately well absorbed from the gut and is excreted in the urine either unchanged or as an active metabolite. Being little stored in the tissues, proguanil must be used daily when given for prophylaxis. The drug should be avoided or used in reduced dose for patients with impaired renal function. It is used to treat Plasmodium falciparum malaria in areas of multiple drug resistance. Apart from its antiplasmodial effect, quinine is used for myotonia and muscle cramps because it prolongs the muscle refractory period.

Generic clarinex 5mg amex. Celiac Disease and Non-Celiac Gluten Sensitivity | Michael Albertson MD - UCLA Health.