Eileen M. Handberg, PhD

• Associate Professor of Medicine
• Director, Clinical Programs
• Division of Cardiovascular Medicine
• University of Florida
• Gainesville, Florida

As with sodium and calcium channels weight loss after mirena removal purchase 60mg xenical otc, potassium channels are formed from the assembly of pore-forming subunits along with various accessory -subunits weight loss vegan diet order 60mg xenical with mastercard. However weight loss pills for women purchase discount xenical online, -subunits of potassium channels include between two and six transmembrane domains weight loss 800 calorie diet purchase generic xenical pills, and the full channel is formed as a dimer or tetramer weight loss pills cheap effective purchase xenical 120 mg with visa, depending on the specific subfamily weight loss nutritionist order xenical online pills. Dysregulation of expression and function of potassium channels is quite common in many acquired forms of heart disease. Voltage-gated potassium channels, or Kv channels, are activated by membrane depolarization. Unlike sodium and calcium channels, functional potassium channels are formed by the assembly of four such subunits and various -subunits. The latter influence a range of channel properties including trafficking of the major subunit to the sarcolemmal membrane as well as regulation of channel biophysical properties, that is, the opening and closing of the channel in response to various factors such as membrane voltage, ligands, mechanical stimuli, second messengers, or post-translational modification. Voltage-gated sodium channels are responsible for the activation and propagation of the cardiac action potential. Not surprisingly, acquired and inherited syndromes that affect the function of voltage-gated sodium channels in the heart are responsible for a broad range of arrhythmic phenotypes. Cardiac sodium channels activate extremely rapidly, within 1 msec, and begin to inactivate almost completely within several milliseconds. The most abundant cardiac sodium channel comprises a pore-forming -subunit known as Nav1. Ito,fast is particularly prominent in the epicardial layer of the ventricles, especially in the right ventricle. This differential expression is thought to contribute to the pathology of J wave syndromes, including Brugada syndrome. The second major class of potassium currents in the heart are the Kir currents carried by inwardly rectifying potassium channels. Conductance through these channels is high at negative membrane potentials, so this current is critical for terminal repolarization (phase 3) and for setting the resting membrane potential (phase 4). The augmented outward current shortens action potential duration and abbreviates systole, thereby diminishing energetic requirements. Importantly, the resulting action potential duration shortening diminishes refractoriness, which may enhance the risk for re-entrant arrhythmias. The last major class of inward rectifiers includes the acetylcholine- and adenosineactivated potassium channels, which are encoded by Kir3. These channels, which are enriched in nodal and atrial cardiac myocytes, are activated when ligands bind to muscarinic or purinergic G protein-coupled receptors, which facilitate the uncoupling of G from G and the activation of the Kir channels by the released G. In the healthy heart, the sinus node, which is located at the junction of the right atrium and the superior vena cava, is the predominant pacemaker. Secondary pacemakers with intrinsically slower pacing rates are found further downstream in the specialized conduction system within the atrioventricular node and the His-Purkinje system. The firing rate of pacemaker cells is regulated primarily by autonomic tone: sympathetic stimulation increases the slope of phase 4 depolarization, whereas parasympathetic stimulation decreases the slope by augmenting repolarizing currents. Nodal suppression may result from pharmacologic agents, such as -adrenergic blockers, calcium channel blockers, or digitalis, as well as from fibrotic diseases. Conversely, under pathologic conditions, myocardial cells outside the specialized conduction system may exhibit spontaneous activity, a phenomenon termed abnormal automaticity. During cardiac repolarization, a number of inward and outward currents are active, and small changes in conductance of individual channels can markedly affect the trajectory of repolarization. Afterdepolarizations, which are abnormal oscillations in membrane potential, occur either during (early afterdepolarizations) or after (delayed afterdepolarizations) an action potential. Afterdepolarizations of sufficient magnitude to evoke an action potential produce triggered activity. Conversely, rapid pacing and drugs that shorten the action potential duration tend to suppress early afterdepolarizations. Early afterdepolarizations in the setting of action potential duration prolongation often trigger torsades de pointes (Chapter 65), a polymorphic ventricular tachycardia, especially when there is increased dispersion of repolarization. During each cardiac cycle, impulses must be generated in pacemaker cells within the sinus node, and a wave of excitation must propagate throughout the atria, travel down the specialized conduction system (including the atrioventricular node and His-Purkinje network), and then activate the ventricular myocardium. Processes that diminish intercellular coupling, such as fibrosis or calcification of the specialized conduction system, can diminish the safety factor for conduction and produce varying degrees of heart block. Conduction block may also be seen with the secondary electrical remodeling that is associated with structural heart disease and with many cardioactive drugs. Disorders of Impulse Formation Afterdepolarizations and Triggered Activity Gap Junction Channels Gap junction channels, which are responsible for the electrotonic coupling of cardiac myocytes, are essential for normal impulse propagation throughout the myocardium. The channels are formed by the hexameric assembly of connexin monomers, each of which is a tetramembrane spanning protein. Connexin 43 is the dominant isoform expressed in ventricular and atrial myocardium, whereas connexin 40 is also abundantly expressed in the atrium. Gap junctions in the node integrate the intrinsic beating rate of each nodal cell into a single functional unit. Abnormalities in connexin expression and function, a process known as pathologic gap junction remodeling, are observed in atrial and ventricular myocardium in many acquired forms of heart disease. The remodeling contributes to aberrant impulse propagation and predisposes to arrhythmic behavior. In addition, germline or somatic mutations in cardiac connexin genes are associated with arrhythmic syndromes, especially atrial fibrillation. Cardiac arrhythmias, which are disturbances in the rate or rhythm of the heartbeat, are a reflection of abnormal impulse formation or conduction. Inasmuch as cardiac myocytes reside within a complex multicellular environment and are electrotonically coupled by gap junction channels, arrhythmic syndromes almost always reflect a complex interplay of individual, or cell autonomous, properties within a multicellular network. However, many arrhythmic syndromes result from, or are exacerbated by, genetic variations, including disease-causing alterations in coding regions that directly affect the function of proteins, which regulate cardiac electrophysiology, as well as sequence variants in regulatory or other noncoding genome regions, which appear to regulate transcriptional and post-transcriptional behavior. Fundamentally, re-entry involves self-perpetuating waves of excitation that circulate around an inexcitable obstacle. Re-entry normally requires the presence of unidirectional block within a "fast" conducting pathway around an obstacle, combined with recirculation of the impulse from a second "slow" pathway in the retrograde direction, as might be the case at a bifurcating Purkinje-ventricular junction or around scar tissue of a healed myocardial infarction. However, the "obstacle" may also be viable myocardium that is inexcitable owing to its intrinsic electrophysiologic properties, such as cellular uncoupling or refractoriness, a phenomenon referred to as functional block. Because refractoriness is critically dependent on the action potential duration, areas of myocardium with prolongation of the action potential duration may form a suitable substrate for functional re-entry. Heterogeneity in action potential duration and the concomitant dispersion of refractoriness also play critical roles in the maintenance of arrhythmic behavior, especially through a phenomenon known as phase 2 re-entry. This term refers to the flow of current during phase 2 of the cardiac action potential from a depolarized cell to neighboring cells that are more fully repolarized and not refractory to reexcitation. Current can then flow into these cells from neighboring cells in which the action potential dome is maintained, thereby causing local reexcitation, a closely coupled extrasystole, and the initiation of re-entry. In Brugada syndrome, this process is thought to arise in the right ventricular outflow tract, where the transient outward current density is significantly greater in the epicardium compared with the endocardium. Insights into the biophysical basis of congenital arrhythmic syndromes and into the pathologic remodeling observed in acquired arrhythmic syndromes have already resulted in several targeted new therapies informed by the expression, function, and regulation of ion channels. Atrial remodeling and atrial fibrillation: recent advances and translational perspectives. The specific differential diagnosis, prognosis, and treatment of these symptoms are determined by the severity of the symptom. In general, the likelihood of a lifethreatening arrhythmia, such as ventricular tachycardia or ventricular fibrillation, in a patient with symptoms of palpitations or syncope is significantly greater in a patient who has structural heart disease. Therefore, the determination of whether structural heart disease is present is a key step in the diagnosis and prognosis of patients with suspected arrhythmias. A careful history can often distinguish benign palpitations from those that need further evaluation. It can be useful to have the patient tap out with a finger what the palpitations feel like. An irregularly irregular pattern suggests atrial fibrillation, whereas a more regular, rapid pattern suggests a sustained tachycardia. A reliable symptom suggesting that palpitations are caused by a tachyarrhythmia, particularly a supraventricular tachycardia, is the sensation of a regular, rapid-pounding sensation in the neck. If, however, the symptoms are not due to a single occasional extrasystole or are accompanied by presyncope or syncope, further evaluation is required. On occasion, arrhythmias can manifest more subtly as exercise intolerance, lethargy, and vague complaints of malaise or without any symptoms at all. Most tachyarrhythmias in patients without structural heart disease are due to supraventricular tachycardias (Chapter 64) that resolve spontaneously within several seconds. When the tachyarrhythmia is more prolonged, it often resolves with simple interventions. Patients themselves can cough several times, perform the Valsalva maneuver, exhale forcefully against a closed glottis for several seconds, or even rub gently on their eyeballs. A physician can use carotid sinus massage (Chapter 64), performed by pressing and rubbing the carotid pulse just below the angle of the mandible for 5 to 15 seconds. This maneuver should be avoided in elderly patients and in patients with a history of cerebrovascular accident, known carotid artery stenosis, or carotid bruit on auscultation. In patients with structural heart disease, palpitations may signify ventricular tachycardia (Chapter 65), particularly if they occur with syncope or presyncope. Syncope, defined as a sudden loss of consciousness, and presyncope, or lightheadedness, are caused by global impairment of blood flow to the brain (Table 62-1). Syncope can be a manifestation of tachyarrhythmias, bradyarrhythmias, or neurocardiogenic syncope, or it can be unrelated to any arrhythmia. A careful history and physical examination are necessary to exclude other cardiac causes. Important historical features that suggest an arrhythmic cause are an association with palpitations and the lack of any neurologic deficits preceding or following the event. Important differential diagnoses include conditions other than lightheadedness that may be termed dizziness by the patient. Vertigo (Chapter 428), a sense of imbalance or of the "room spinning," and ataxia (Chapter 410) can usually be distinguished by the history and physical examination. The most important distinguishing feature is that PresyncopeandSyncope postictal symptoms, a key feature of seizure disorders, are absent when syncope is the result of an arrhythmia. Patients with syncope from an arrhythmia usually awaken without any neurologic residual, unless the patient experienced a cardiac arrest with prolonged hypoxia and required resuscitation. Because most spells of episodic loss of consciousness occur outside medical observation, the history is the most critical part of the evaluation (Table 62-2). Each syncopal episode should be reviewed in detail, with special attention to symptoms preceding the episode, events during unconsciousness, and the symptoms and time course of regaining orientation after consciousness is restored. Seizures or cardiac arrhythmias can occur in any body position, but recumbent patients rarely develop neurocardiogenic (vasovagal) syncope and never have orthostatic hypotension. Prodromal lightheadedness, dizziness (but uncommonly vertigo), bilateral tinnitus, nausea, diffuse weakness, and dimming of vision are symptoms of cerebral hypoperfusion and support the diagnosis of syncope, which may be from a cardiac, orthostatic, or neurocardiogenic cause. Loss of consciousness so rapid that a prodrome is absent may occur with seizures and with some cardiac arrhythmias such as asystole, which typically causes loss of consciousness within 4 to 8 seconds in the upright position but usually requires 12 to 15 seconds in the recumbent position. The activity of the patient immediately before the onset of symptoms may also provide clues. Syncope associated with the cessation of exertion or with anxiety or pain suggests neurocardiogenic syncope, whereas symptoms during exertion suggest an arrhythmia. Syncope associated with a change in posture suggests orthostatic causes, whereas syncope while straining at urination suggests situational neurocardiogenic syncope. Although body stiffening and limb jerking occur with generalized seizures, similar movements can result from cerebral hypoperfusion, especially if perfusion is not restored rapidly. In contrast to epileptic seizures, which generally produce tonic-clonic activity for at least 1 to 2 minutes, muscle jerking in syncope rarely persists for longer than 30 seconds. If an arrhythmia continues or the patient is physically maintained upright, tonic stiffening of the body followed by jerking movements of the limbs can occur. Occasionally, motor movements identical to a tonic-clonic seizure occur, and a mistaken diagnosis of epilepsy can be made. The time frame over which consciousness and orientation are regained is perhaps the most important clue in differentiating seizures from syncope. Recovery of orientation after neurocardiogenic syncope occurs within seconds of regaining consciousness. Recovery of orientation after selfreversible arrhythmia-associated syncope is usually proportional to the duration of the unconsciousness and is usually rapid (0 to 10 seconds). By comparison, the period of confusion after seizures, often accompanied by agitation, continues for 2 to 20 minutes after recovery of consciousness. Although not a primary arrhythmia, neurocardiogenic syncope is a related diagnostic and management issue because its symptoms are frequently similar to those of arrhythmias and because neurocardiogenic syncope secondarily results in bradycardia (see later). If features of epilepsy are present, arrange for early review by an epilepsy specialist. Sinus bradycardia manifests as a slow atrial (sinus) rate and can occur at rest or as an inappropriately slow rate during exercise (chronotropic incompetence). The sinus rate and even the presence of sinus pauses are influenced by autonomic tone. Therefore, healthy individuals-particularly younger patients and well-trained athletes (with high vagal tone)-have occasional sinus slowing, often during sleep. A sinus pause of more than 3 seconds is considered pathologic if it is associated with symptoms while a patient is awake. Sinus bradycardia and sinus arrest can also be the result of medications, typically -blockers and calcium-channel blockers. When not "physiologic" or due to medications, sinus bradycardia and sinus arrest are the result of intrinsic conduction system disease. Sinus bradycardia, especially if it is intermittent, can also signify disease of the right coronary artery. The treatment of choice for patients with symptomatic bradyarrhythmias or those likely to progress to complete heart block is implantation of a permanent pacemaker (Chapter 66). Supraventricular tachyarrhythmias that may be associated with palpitations, presyncope, or syncope include atrial tachycardia. Ventricular tachyarrhythmias include the various forms of ventricular tachycardia.

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This field slim9 weight loss pills order 120 mg xenical with mastercard, which has experienced a major boost from the completion of the human genome project, offers considerable promise for the development of novel therapeutics, optimized drug trials, and medicine tailored to your personal response. Over the next several decades, the knowledge emerging from pharmacological studies will have an immeasurable impact on society. A better understanding of the potential toxic effects of abused substances on the fetus and on the heart, brain, and other organ systems will evolve. The possibility of developing gene products that would alter the course of a disease will open new horizons in the effectiveness and the selectivity of therapeutic agents. The effect of the chemical substances in the environment and their possible causal relationship to cancer or birth defects will be an area of great social concern and one with which pharmacologists will be confronted. Finally, the discoveries in the area of pharmacogenetics will allow for a better understanding and avoidance of adverse drug reactions, as well as the development of individualized therapeutic regimens. Progress in areas of social concern and in aspects of health-related drug intervention will require pharmacologists who are not only schooled in scientific disciplines, but who possess a sense of ethics, a sense of logic, and a firm understanding of the philosophical overtones of their research. This brochure was prepared by the Graduate Recruitment and Education Committee of the American Society for Pharmacology and Experimental Therapeutics, September 2003. Carrico Art Director: Phillip Payette Thanks to the following who have contributed pictures, diagrams, and content: Araba Adjei Otabek Imamov Douglas A. Woosley Bethany Holycross Yuan Zhou Leaf Huang American Society for Pharmacology and Experimental Therapeutics 9650 Rockville Pike, Bethesda, Maryland 20814 Theoretical dose-response curves for different types of actions of drugs at receptors 1. For example, dopamine is used as a renal arteriolar vasodilator, diamorphine to relieve pain in the treatment of myocardial ischaemia, and nebulized salbutamol to reverse bronchoconstriction in the treatment of acute severe asthma. The receptors that are involved in the action of a range of receptors are listed in Table 4. A schematic representation of the two types of second messenger systems that mediate the effects of drugs acting at G-protein coupled receptors. In a second system (right-hand side), there is increased activity of the enzyme phospholipase C. Examples (Table 4) include corticosteroid, testosterone, thyroid hormone, vitamin D, and peroxisome proliferator activated receptors. Catalytic receptors Catalytic receptors are membrane-bound enzymes that have a ligand binding site and a catalytic site, which is activated or inhibited by the ligand. These effects are accompanied by either increases ("up-regulation") or decreases ("down-regulation") in receptor numbers during long-term therapy, and such changes can be responsible for both beneficial and adverse effects. Some soluble receptors arise as byproducts of receptor down-regulation, as receptors are downgraded. Some are produced as part of the normal function of the receptor and compete with the membrane-bound receptor for binding to the relevant ligand. Soluble receptors can be used to prevent an endogenous ligand from binding to its membranebound receptor, thus reducing its cellular effects. Drug action via indirect alteration of the effect of an endogenous agonist Just as an antagonist can produce a therapeutic effect by directly opposing the action of an endogenous agonist, so the effects of an endogenous agonist can be altered in indirect ways. For example, glucagon is a physiological antagonist of the actions of insulin and can be used to treat insulin-induced hypoglycaemia. For example, amphetamines increase the release of monoamines, such as dopamine, from nerve terminals. For example, some antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, inhibit the reuptake by neurons of neurotransmitters such as noradrenaline and 5-hydroxytryptamine. For example, one of the proposed mechanisms whereby the cromones, such as sodium cromoglicate, produce their therapeutic effects in asthma is by inhibiting the release of inflammatory mediators from mast cells in the lungs. Drug action via inhibition of transport processes Because the transport and disposition of cations (such as sodium, potassium, and calcium) and of other substances (such as organic acids in the kidneys and neurotransmitters in the nervous system) play so many important roles in the maintenance of normal cellular functions, inhibition of their transport is an important type of mechanism of drug action. The following are examples of the ways in which drugs may act through inhibition of transport processes. For example, the loop diuretics furosemide and bumetanide act at the luminal surface of the ascending limb of the loop of Henle by inhibiting the active transport system known as Na/K/Cl co-transport, which involves the transport of sodium, potassium, and chloride in the same direction across cell membranes. The potassium-sparing diuretic amiloride acts by inhibiting sodium channels in the distal segment of the distal convoluted tubule. The thiazide diuretics act by inhibiting the Na/Cl co-transport system in the proximal segment of the distal convoluted tubule. However, some diuretics act by mechanisms other than direct actions on transport processes. For example, spironolactone is a competitive antagonist at aldosterone receptors in the distal convoluted tubule, and acetazolamide is an enzyme inhibitor, inhibiting the action of carbonic anhydrase in the proximal convoluted tubule. The different drugs have different specificities for calcium channels in different tissues, and because calcium plays so many important roles in these tissues, the drugs have several different actions, principal among 10 which are an antiarrhythmic action in the heart (for example verapamil) and a vasodilator action on peripheral arterioles (for example nifedipine). A T-type calcium channel blocker, mibefradil, which did not cause a reflex tachycardia (unlike the L-type channel blockers) was used to treat hypertension, but had to be taken off the market because it was involved in so many adverse drug-drug interactions. In the treatment of hyperglycaemia in diabetes, the rapid fall in blood glucose produced by insulin is undoubtedly due to this action. For this reason, the fluids infused intravenously during emergency treatment with insulin of severe hyperglycaemia in diabetic ketoacidosis should usually contain potassium. It inhibits the transport of organic acids across epithelial barriers and not only blocks the active secretion of penicillin into the renal tubular lumen, but also blocks the active reabsorption of uric acid. It has been used as a uricosuric agent in the treatment of gout, and occasionally to reduce the renal clearance of the penicillin s or cephalosporins from the blood, although this is usually achieved without probenecid, simply by increasing the dosage of antibiotic. Drugs that open potassium channels therefore reduce the likelihood of activation of the cell, while drugs that close potassium channels increase the likelihood of activation of the cell. Drugs that open potassium channels include vascular smooth muscle relaxants, such as minoxidil and hydralazine (used in the treatment of hypertension), and nicorandil (used in the treatment of angina pectoris). Drugs that block potassium channels include the sulfonylureas, which thereby increase the release of insulin from beta cells in the pancreas (used in the treatment of type 2 diabetes). Drug action via enzyme inhibition Many types of drug action can be produced by inhibition of enzymes, and the precise action will depend on the role that the inhibited enzyme plays in normal function. The following are illustrative examples of the ways in which drugs may act by inhibiting enzymes. It is used in the treatment of myasthenia gravis because of its effect in increasing the concentration of acetylcholine at the muscle motor end-plate, thereby alleviating the block in neuromuscular transmission that occurs in this condition. This effect is produced mainly by its active metabolite, alloxanthine (or oxypurinol), which is a noncompetitive inhibitor of xanthine oxidase. The reduction in uric acid production reduces the risks 11 of attacks of acute gouty arthritis, reduces the incidence of chronic gouty arthritis, and prevents the occurrence of uric acid stones (gouty nephropathy). Xanthine and hypoxanthine are considerably more water-soluble than uric acid, and their urinary excretion is rapid. This inhibition is thought to mediate the positive inotropic and chronotropic effects of cardiac glycosides, perhaps through a resultant rise in calcium concentrations within cardiac cells. However, it is not certain whether that is the mechanism whereby lithium produces its therapeutic effects in the treatment of manicdepressive illness. The xanthines (for example theophylline) inhibit phosphodiesterase in the lung, causing bronchodilatation. However, this may not be their main mode of action as they also have actions at purine receptors. Milrinone and related compounds, such as enoximone, inhibit phosphodiesterase type 3, and have a positive inotropic effect on the heart; however, they increase mortality in heart failure and are used only in short-term therapy. Sildenafil and related compounds, such as avanafil, tadalafil, and vardenafil, inhibits phosphodiesterase type 5 in the corpus cavernosum in the penis, causing vasodilatation and hence penile erection. For example, procaine inhibits pseudocholinesterase and can enhance the actions of the depolarizing muscle relaxant succinylcholine. Metronidazole inhibits aldehyde dehydrogenase and can cause a disulfiram-like reaction to alcohol. Drug action via direct enzymatic activity or the activation of enzymes Just as some drugs act by inhibiting enzymes, so some drugs activate enzymes or themselves act as enzymes. However, gene replacement therapy has so far proved disappointing and enzyme replacement therapy is limited by the difficulty of delivering enzymes to their sites of action. Another example is the oral use of pancreatic enzymes in treating malabsorption in patients with chronic pancreatic insufficiency, using specially coated formulations plus antacids to reduce inactivation by gastric acid. Examples of enzymes that are used to treat or prevent illnesses or diseases associated with deficiencies are listed in Table 5. Streptokinase, urokinase, alteplase, and anistreplase are activators of plasminogen and thus cause clot lysis. Snake venoms, such as ancrod (Malayan pit viper venom), have thrombin-like activity and thus activate clotting. It is freely filtered at the renal glomerulus but is reabsorbed to only a small extent by the renal tubules. It therefore increases the concentration of osmotically active particles in the tubular fluid and takes water with it, thus increasing urine volume. Mannitol has been used to produce a diuresis in the treatment of some types of acute poisoning and in cerebral oedema. It has sometimes been used to restore renal tubular function and urinary output in shock. Urea has a similar action to mannitol and has been used similarly in the treatment of cerebral oedema. For example, the -melanocyte-stimulating hormone analogue afamelanotide has been used to treat erythropoietic protoporphyria. Epoetins, which are analogues of the naturally 14 occurring hormone erythropoietin, are used to treat the anaemia of chronic renal insufficiency. They form a diverse group of agents, such as the halogenated hydrocarbons (for example, halothane, desflurane, enflurane, and trichloroethylene), and non-halogenated agents (for example nitrous oxide and cyclopropane), which produce similar effects on the brain. The usual models of drug action do not readily accommodate this group of compounds. It is generally thought that their primary action is on the lipid matrix of the biological membrane, that the biophysical properties of the membrane are thereby changed, and that this results in changes in ion fluxes or other functions that are crucial for the normal operation of neuronal excitability. The best examples are oral and parenteral use of ferrous salts in the treatment of anaemia due to iron deficiency and intramuscular use of hydroxocobalamin (vitamin B12) in the treatment of vitamin B12 deficiency, particularly as associated with pernicious anaemia. The use of hormones as replacement therapy (for example, thyroxine to replace natural thyroid hormone in hypothyroidism) could also be included under this heading, but is better included under the heading of drugs acting via a direct action on receptors, which is how hormones act. Examples of normal constituents of the diet used as dietary supplements to treat or prevent illnesses or diseases associated with deficiencies Compound Deficiency disease Carnitine Primary deficiency; valproate toxicity Cereal starch Glycogen storage disease Cobalamins Pernicious anaemia Ferrous salts Iron deficiency anaemia Folic acid* Folate deficiency Vitamin C Scurvy Vitamin D analolgues Osteomalacia and rickets Zinc Acrodermatitis enteropathica *Also used in pregnancy to prevent neural tube defects, a use that is not relevant to this table 2. Pasteur showed that tartaric acid exists in two forms with different optical activities: one form rotates polarized light to the left and the other rotates it to the right. He did this after he had observed that tartaric acid crystals had two different shapes when viewed microscopically and separated the two types of crystals. The two stereoisomers of the amino acid alanine the terminology used to describe stereoisomers is complex. If a substance rotates polarized light to the right, it is called dextrorotatory and is designated by the letter d or by the symbol (+). However, these designations do not tell you anything about the actual spatial configuration of the molecules themselves, which is designated by other symbols: absolute configurations of chiral centres are designated by R and S (from the Latin "rectus" = right and "sinister" = left) and D and L (from the Latin "dexter" = right and "laevus" = left); relative configurations are designated by cis and trans (Latin words meaning "on this side" and "on the other side"), Z and E (German zusammen, together, and entgegen, opposite), and and. In enantiomers, asymmetry occurs either at a single centre of potential asymmetry (or "chiral" centre) if only one such centre exists in the molecule, or at more than one if more than one exists (in which case there will be more than two enantiomers). In diastereomers, asymmetry occurs at only one of the chiral centres, although the molecule has more than one chiral centre, and in such 16 cases the isomers are not mirror images of each other. Enantiomers have similar physicochemical properties to each other, while diastereomers do not. Chiral asymmetry is usually due to a carbon atom, but not in all cases, the asymmetrical phosphorus atom in cyclophosphamide being a case in point. Examples of drug enantiomers are d-propranolol and 1-propranolol, R-warfarin and Swarfarin, L-glucose (laevulose) and D-glucose (dextrose), and cis-retinoic acid and all-transretinoic acid. Of all synthetic drugs used in clinical practice, about 40 per cent are chiral and about 90 per cent of those are marketed in the racemic form. Naproxen, esomeprazole, and escitalopram are examples of synthetic compounds that are marketed as single stereoisomers. In contrast, naturally occurring and semi-synthetic com pounds are almost all chiral and almost all are marketed as a single isomer. Examples include the naturally occurring amino acids (for example L-dopa) and D-glucose (dextrose). The centre of asymmetry of a compound need not be in a part of the molecule that is important for the action of the drug, but if it is there will be pharmacological differences between the different stereoisomers, and these differences may be of clinical relevance. Pharmacokinetic differences between stereoisomers (a) Absorption Both D-methotrexate and L-methotrexate are passively absorbed, but only to a small extent. However, L-methotrexate is also transported actively across the gut, while D-methotrexate is not. The binding of S-disopyramide to 1-acid glycoprotein is more extensive than that of Rdisopyramide. S-warfarin is more highly bound to albumin than R-warfarin, but R-warfarin is more highly protein bound overall than S-warfarin. These differences lead to differences in the distribution and rates of clearance of the different stereoisomers. For example, the first-pass hepatic metabolism of S-metoprolol is less than that of R-metoprolol. However, this is only the case in extensive hydroxylators of the debrisoquine type; in poor metabolizers, the firstpass metabolism of metoprolol is not affected by stereoisomerism. Both the rates and the routes of metabolism of the stereoisomers of warfarin are different: the half-lives of S-warfarin and R-warfarin are 32 and 54 hours respectively, and the routes of metabolism are to 7-hydroxywarfarin for S-warfarin and to warfarin alcohols for R-warfarin. The secretion of tocainide into the saliva is greater for R-tocainide than for S-tocainide.

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Streptococcus "~ti#e (group B streptococci) is the most common cause of neonatal meningitis weight loss green store tea buy xenical 60 mg with visa. It is most prevalent in young women who have had multiple partners and is most likely to infect the baby during a protracted delivery weight loss pills you can take while breastfeeding order genuine xenical online. Listeria is a less frequent cause of neonatal meningitis and other severe diseases in newborns weight loss 6 months discount 60mg xenical amex. HtUmophilus influenzae and Neisseria meningitidis rarely cause neonatal meningitis weight loss pills 901 purchase xenical. Transposons are incapable of independent replication but may contain antibiotic resistance genes as well as insertion sequences that provide for transfer of genetic information to bacterial chromosomes or plasmids weight loss pills side effects effective xenical 120 mg. The most serious consequences following infection occur in those individuals over 50 years of age who can develop a life-threatening encephalitis weight loss pills recalled cheap xenical 60 mg free shipping. Choice B is also incorrect; it is the mechanism of Shiga toxin and the 0157 shiga-like toxin, also known as verotoxin. But because the last thing to be transferred would be the rest of the fertility factor, the cell almost never becomes Hfr. Serum hepatitis is the oDly disease listed in which the causative agent has a reverse transcriptase involved in replication. Chloroquine kills only the erythrocytic schizonts/merozoites, so you must take the chloroquine for 4 weeks after leaving the malarial area to allow all stages to continue past the liver stages into the sensitive forms. Ketoacidotic diabetes is a major predisposing condition for zygomycosis, although lymphoma and leukemia also predispose the patient to zygomycosis. The capsular polysaccharide on the bacteria in the body inhibit phagocytic uptake until opsonized. The killing of Neisseria meningitidis organisms is primarily dependent on complement-mediated cell lysis. Patients with genetic deficiencies in C5 to C8 cannot carry out complement-mediated lysis of bacterial cells and have repeated septicemias with N. Pseudomonas is a Gram-negative organism; therefore, the patient has a Gram-negative septicemia. No toxicity is associated with the 0 polysaccharides, the flagella from Gram-negative bacteria, or catalase. If it had been a Gram-positive bacterium, teichoic acid-peptidoglycan fragments can trigger a similar process. Myasthenia gravis is associated with an antiacetylcholine receptor antibody, resulting in muscle weakness. Bordetella pertussis is unusual among bacterial infections in that it causes a lymphocytosis. A mononucleosis-like presentation may occur during the first year of human immunodeficiency virus infection. Although lymphocytes are severely depressed, myeloid cells are present in normal numbers. Scarring and permanent hair loss are most likely to occur with faws (tinea favosa). Neisseria are diplococci, vibrios are comma shaped, and campylobacteria are spiral shaped. Because campylobacter is grown under unique conditions and tempemture, it is identified by just growing under those conditions. Common pili of Escherichia coli bind to the colonic mucosa but not to the urn epithelium; therefore, in order to cause ascending urinary tract infections and not just be washed out by periodic urine flow, the E. Ulcemtive colitis is the only syndrome listed whose chronic inflammation is confined to the rectum. The California and LaCrosse viruses, which have mosquito vectors, are both bunyaviruses. Since the male is heterozygous for the Rh + gene and Rh + is dominant, the possibility exists for Rh + offspring. Although groups A and B streptococci and Staphylococcus aureus are beta-hemolytic, only the streptococci are catalase negative. The virulence of Yersinia pestis in humans depends on a variety of factors, the most important of which is its ability to proliferate intracellularly. Associated with this ability and virulence are Ca2 + dependence; V and W antigens; Yersinia outer membrane proteins; Fl envelope antigen; coagulase and fibrinolysin production; and pigment absorption. This condition was probably picked up in the Midwest, most likely along the Mississippi. Genes for drug resistance may reside individually on the bacterial chromosome or on plasmids. Clusters of multiple drug resistance genes are occasionally on chromosomes but are more commonly on plasmids. R-factors are like those p+ cells with just a few extra, closely linked drug resistance genes. So the conjugal transfer of an R-factor is the process that is most likely to transfer multiple drug resistance. Pernicious anemia patients give rise to antibodies against intrinsic factor that inhibit the transfer of vitamin B12 from the stomach to the bloodstream. Diphtheria toxin and Pseudomonas exotoxin A are both adenosine diphosphate-ribosylating toxins that irreversibly inactivate elongation factor 2 and inhibit protein synthesis. Although they have similar modes of action, they differ in their cellular targets and antigenicity. Swimming/diving/jumping in warm contaminated waters may cause infection with Naegleria, which rapidly develops into primary amebic meningoencephalitis, which is generally fatal. Repeated infections with depressed superoxide activity characterize chronic granulomatous disease. It is common that when bacteria invade the gastrointestinal tract tissue, inflammation and prostaglandins are triggered, causing higher fever, abdominal pain, and diarrhea. Choice D is type I Shigella dysenteriae, which is both invasive and produces the Shiga toxin. Cervical carcinoma is caused by oncogenic strains ofthe human papillomavirus (most commonly 16, 18, and 31). The early protein E6 is associated with the oncogenic potential of human papillomavirus. Therefore, based on the serologic data, this patient could have very early primary syphilis or untreated tertiary syphilis. The most common mechanism of resistance to antivirals is a genetic mutation in the viral gene coding for the viral protein that interacts with the antiviral so that the antiviral no longer interacts and is effective. Although several of the organisms could result in these clinical signs and symptoms, the intemctions of the patient in an old hunting shack containing rodent feces point toward the Hantavirus, Sin Nombre, as the cause. In which of the following phases of growth is a Gram-positive bacterium most susceptible to the action of penicillin Autopsy reveals disseminated granulomatous lesions throughout; some are caseating, but they are not calcified. The genetic mechanism responsible for the conversion of a nonto:xigenic strain of Corynebacterium diphtheriae to a toxigenic strain. What respiratory infection is known to increase susceptibility to pneumonia caused by Streptoooccus pneumoniae A patient with sickle cell anemia is most likely to have repeated septicemias and possible osteomyelitis with which agent The mother of a 9-year-old who is in the same school as another child just diagnosed with meningitis (even though the child did not know nor had any direct contact with the infected child) called the pediatrician, demanding her son be prophylactically treated. The physician suggests vaccinating the boy, doing surveillance cultures, and watching the child for symptoms. An 18-year-old Iowan dirt bike racer, who raced for the first time in the desert southwest 3 weeks ago, presents in September with cough, malaise, low-grade fever, myalgias, and chest pain. Sputum stained with calcofluor white and viewed on an ultraviolet microscope shows large blue-white fluorescing spherical structures (with a wall) and with numerous small round cells inside. A 26-year-old man presents with an infected foot from stepping on a nail2 days ago. He sprayed some antiseptic on it and did not seek medical help because he had his last tetanus booster about 1 year ago and he thought that would take care of the wound. The foot is quite inflamed around the wound with a little blue-green pus on the bandage. The organism isolated is a Gram-negative rod that is oxidase positive and does not ferment any carbohydrates. A Brazilian who left poverty and moved to Los Angeles lD years ago has died suddenly of heart failure. An autoimmune disease characterized by absence ofT cells, hypocalcemia, and tetany with lowered cell-mediated immunity is (A) Ulcerative colitis 18. A Peace Corps volunteer who recently returned from rural Africa develops symptoms of liver damage and a blocked bile duct after general anesthesia for a knee replacement. When complement is fixed by antigen-antibody complexes, what chemotactic factor for neutrophils is released Several workers in a turkey processing plant develop a mild conjunctivitis without corneal involvement. A 15-year-old boy on antibiotics to clear up a community-acquired methicillin-resistant Staphylococcus aureus has clindamycin added to his treatment regimen to slow the production of the various toxins including Panton-Valentine leukocidin. A 30-year-old woman presents with an inflamed, itchy, expanding cutaneous lesion on her side. She suspects she might have picked it up from her dog because it is where the dog 24. She has not been home for 2 days and has had the current pair of contacts continuously in her eyes for 6 weeks. Anti-A isohemagglutinins are present in persons with which one of the following blood types A patient presents with explosive, watery, noninflammatory diarrhea along with headache, abdominal cramps, nausea, vomiting, and fever. Bacterial surface polysaccharide plays a critical role in Gonorrhea Meningitis with no underlying trauma Mycoplasma pneumonia tO) Pyelonephritis tEl Urinary tract infection 42. A 10-year-old boy presents with an itchy scalp with the underlying hair becoming lighter. A 36-year-old female drug abuser has an abscess on her jaw where she lost a tooth from being struck in the face 2 weeks ago. You lance the lesion, express some lumpy material with difficulty, and send a swab of the organism to the lab for Gram stain, culture, and susceptibilities. The predominant organism in the Gram stain is a filamentous bacterium that is Gram positive, yet nothing grows in the lab. A 1-year-old girl who has received no vaccines because of parental fear of autism develops Streptococcal pneumoniae meningitis. A 65-year-old female Peace Corps worker is sent back to the states from East Africa because she had had a very high fever and African sleeping sickness is suspected. Which of his serum values (mg%) would indicate he had an immunodeficiency disease What organism (besides Trypanosoma brucei) is noted for its antigenic variation that leads to its ability to repeatedly reinfect the same person and cause disease and has led to difficulty in vaccine development The lab cultures on a special medium incubated at 42aC under microaerophilic conditions grow a Gram-negative spiral-shaped organism that is isolated. A preschool day care has reported that the majority ofthe children are complaining of very sore throats. A closer examination of the situation indicates that they also have slight fevers and vesicular lesions (some of which have ulcerated) on their tonsillar and pharyngeal mucosa. An otherwise healthy23-year-old woman presents with urinary urgency and frequency Comprehensive Examination: Block3 Answers and Explanations 1. The Gram stain suggests Haemophil:us influenzae is the causative agent, which is confinned by latex. The vaccine is a conjugate polysaccharide-protein vaccine as described in choice C. In utero Listeria infections are generally severe and are characterized by caseating, granulomatous lesions. Except for 1bxoplasma and parvovirus, the other organisms listed cause infections acquired during birth. Toxoplasma usually manifests with calcified central nervous system lesions in the baby. The v-src oncogene associated with the Rous sarcoma virus codes for a tyrosine protein kinase with a biologic activity that results in cellular transformation. Gram-positive bacteria would be most susceptible to penicillin in the exponential phase, because this is the phase in which cell-wall synthesis is greatest. Atoxigenic strain of Corynebacterium diphtheriae is produced as a result of lysogenic phage conversion after a temperate bacteriophage infects a nontoxigenic strain of the organism. Herpes simplex viruses have the ability to become latent in neurons and reactivate (replicate) under certain conditions that are not well understood. Pneumococcal pneumonia is most frequent in patients with some damage to mucociliary elevators in the upper respiratory tracts. Antecedent measles, influenza virus infections, and alcoholism predispose patients to pneumococcal pneumonia. Sickle cell anemia patients have problems with septicemias with encapsulated organisms, such as pneumococcus and Klebsiella. Of those listed, Salmonella enteritidis has a prominent capsule and it is noted for causing repeated infections in sickle cell carriers. A selective medium permits growth in the presence of agents that inhibit other bacteri-. A minimal medium contains the minimum quantity and number of nutrients capable of sustaining growth of the organism. A differential medium differentiates among organisms on the basis of color due to different fermentation or pH. Congenital thymic aplasia is caused by an unknown intrauterine injury to the third and fourth pharyngeal pouches around the 12th week of gestation. The causative agent can only be Coccidioides immitis from the description of the spherules and endospores in the sputum. Without the results of the microscopic examination it possibly could have been Histoplasma capsulatum or Blastomyces pneumonia. The patient is also the right age group for Mycoplasma pneumonia, but again the microscopic data point instead to Coccidioides. From both the genus description and the epidemiology, it is most likely Pseudomonas aeruginosa.

Stimulation of nociceptive endings in the periphery is predominantly chemically mediated weight loss pills effects on the body buy 60mg xenical. Capsaicin weight loss pills volcano buy discount xenical 120 mg line, the active principle of red peppers weight loss 4 reviews best order for xenical, potently stimulates and then desensitizes nociceptors weight loss zephyrhills fl xenical 60 mg cheap. Pain differs from nociception because of central mechanisms weight loss pills stars use xenical 120mg discount, including an emotional component weight loss jewelry discount 120 mg xenical visa. It has no irritant effect on the gastric mucosa and can be used safely and effectively in most individuals who are intolerant of aspirin. Mechanism of action Paracetamol inhibits prostaglandin biosynthesis under some circumstances. There is no convincing evidence that paracetamol causes chronic liver disease when used regularly in therapeutic doses (4 g/24 hours). Paracetamol is structurally closely related to phenacetin (now withdrawn because of its association with analgesic nephropathy) raising the question of whether long-term abuse of paracetamol also causes analgesic nephropathy, an issue which is as yet unresolved. Pharmacokinetics, metabolism and interactions Absorption of paracetamol following oral administration is increased by metoclopramide, and there is a significant relationship between gastric emptying and absorption. The major sulphate and glucuronide conjugates (which account for approximately 95% of a paracetamol dose) are excreted in the urine. However, unlike paracetamol it also has antiinflammatory properties when used in high doses. Various preparations are available, including regular as well as buffered, soluble and enteric-coated forms. Enteric coating is intended to reduce local gastric irritation, but much of the gastric toxicity is due to inhibition of gastric mucosal prostaglandin biosynthesis (see below), rather than to direct gastric irritation. Consequently, slow-release preparations do not eliminate the adverse effects of aspirin on the gastric mucosa. In addition, aspirin and similar drugs can directly activate eosinophils and mast cells in these patients through IgE-independent mechanisms. Some of the selectivity of aspirin for platelet cyclo-oxygenase is probably due to exposure of platelets to high concentrations of aspirin in portal blood, whereas tissues are exposed to the lower concentrations present in the systemic circulation. Michaelis-Menten Salicyl phenolic glucuronide (20%) salicylate has dose-dependent (non-linear) kinetics (Chapter 3) at high therapeutic doses or after overdose. Urinary elimination of salicylate is considerably influenced by pH, being more rapid in alkaline urine, which favours the charged (polar) anionic form that is not reabsorbed, rather than the free acid (Chapter 6). This property is utilized in the treatment of salicylate overdose by urine alkalinization and demonstrates the principle of ion trapping. They occasionally cause local irritation of the skin, but adverse effects are otherwise uncommon. It is less of a respiratory depressant than the opioids and does not cause dependence. Drug interactions Aspirin increases the risk of bleeding in patients receiving anticoagulants via effects on platelets, gastrotoxicity and, in overdose, by a hypoprothrombinaemic effect. Aspirin should not be given to neonates with hyperbilirubinaemia because of the risk of kernicterus as a result of displacement of bilirubin from its binding site on plasma albumin (Chapter 13). It reduces the efficacy of antihypertensive medication and of diuretics by blocking formation of vasodilator and natriuretic prostaglandins in the kidney. Mechanism of action Nefopam is a potent inhibitor of amine uptake and potentiates descending pathways that operate the gate mechanism described above. Adverse effects and contraindications Nefopam has few severe (life-threatening) effects, although convulsions, cerebral oedema and fatality can result from massive overdose. It is contraindicated in patients with epilepsy, and also in patients receiving monoamine oxidase inhibitors (see below). It should not be used in acute myocardial infarction, as it increases myocardial oxygen demand and may be pro-dysrhythmogenic. Nefopam causes a high incidence of minor adverse effects, especially after parenteral use. These include sweating, nausea, headache, dry mouth, insomnia, dizziness and anorexia. Nefopam is contraindicated in glaucoma, and can cause urinary retention in men with prostatic hypertrophy. It is extensively metabolized by the liver to inactive compounds excreted in the urine. These work by inhibiting prostaglandin synthesis, and are available over the counter. Some anaesthetists give synthetic high potency opioids, such as fentanyl, either intravenously or epidurally, for obstetric surgery. Several endogenous peptides with analgesic properties are widely distributed throughout the nervous system. A fourth category, is now not classified as an opioid receptor because they bind non-opioid psychotomimetic drugs of abuse, such as phencyclidine and the only opioids that bind appreciably to them are drugs like pentazocine that have psychotomimetic adverse effects. Blocking opioid receptors with naloxone (see below) has little effect in normal individuals, but in patients suffering from chronic pain it produces hyperalgesia. A number of notably discreditable events, including the Opium Wars, ensued from the commercial, social, moral and political interests involved in its world-wide trade and use. Opium is a complex mixture of alkaloids, the principal components being morphine, codeine and papaverine. Much work has gone into synthesizing morphine analogues in the hope of producing a drug with the therapeutic actions of morphine, but without its disadvantages. Synthetic drugs such as pethidine, dextropropoxyphene and pentazocine were originally incorrectly thought to lack potential for abuse. Pain relief by acupuncture may also be mediated by encephalin release, because it is antagonized by naloxone. The resulting pattern of pharmacological activity depends on their affinity for the various receptors and whether they are full or partial agonists. The affinity of narcotic analgesics for -receptors parallels their analgesic potency. In addition to their involvement in brain function, the opioid peptides play a neuroendocrine role. High concentrations of opioid peptides are also present in sympathetic ganglia and the adrenal medulla. Their function at these sites has not been elucidated, but they may play an inhibitory role in the sympathetic system. On withdrawal of the drug, endogenous opioids are not sufficient to stimulate the insensitive receptors, resulting in a withdrawal state characterized by autonomic disturbances. Mechanism of action Morphine relieves both the perception of pain and the emotional response to it. Adverse effects Certain patients are particularly sensitive to the pharmacological actions of morphine. These include the very young, the elderly and those with chronic lung disease, untreated hypothyroidism, chronic liver disease and chronic renal failure. Morphine depresses the sensitivity of the respiratory centre to carbon dioxide, thus causing a progressively decreased respiratory rate. Patients with decreased respiratory reserve due to asthma, bronchitis, emphysema or hypoxaemia of any cause are more sensitive to the respiratory depressant effect of opioids. Bronchoconstriction occurs via histamine release, but is usually mild and clinically important only in asthmatics, in whom morphine should be used with care and only for severe pain. Dopamine receptors are important and opioidinduced emesis is responsive to dopamine-receptor antagonists. Morphine increases smooth muscle tone throughout the gastro-intestinal tract, which is combined with decreased peristalsis. The increase in muscle tone also involves the sphincter of Oddi and morphine increases intrabiliary pressure. Dependence (both physical and psychological) is particularly likely to occur if morphine is used for the pleasurable feeling it produces, rather than in a therapeutic context. Patients with prostatic hypertrophy may suffer acute retention of urine, as morphine increases the tone in the sphincter of the bladder neck. Previous analgesic requirements (if known) should be taken into account when selecting a dose. Once the dose requirement is established, sustained-release morphine (12-hourly) is substituted, which should still be supplemented by immediate release morphine, for breakthrough pain. It is useful in those few patients with opioidresponsive pain who experience intolerable side effects when morphine is administered by other routes. There is an advantage in using diamorphine rather than morphine for this purpose, since its greater solubility permits smaller volumes of more concentrated solution to be used. Pharmacokinetics Morphine can be given orally or by subcutaneous, intramuscular or intravenous injection. Metabolism occurs in the liver and gut wall, with extensive presystemic metabolism. Morphine-6-glucuronide has analgesic properties and contributes substantially to the analgesic action of morphine. Only low concentrations of this active metabolite appear in the blood after a single oral dose. Morphine-6-glucuronide is eliminated in the urine, so patients with renal impairment may experience severe and prolonged respiratory depression. The birth of opiatedependent babies born to addicted mothers demonstrates the ability of morphine and its glucuronide to cross the placenta. This is exacerbated by the prolonged elimination t1/2 in neonates of about 22 hours. They are more potent but shorter-acting and are used to treat severe pain or as an adjunct to anaesthesia. Its actions are similar to those of morphine, although it is more potent as an analgesic when given by injection. It is more soluble than morphine, and this may be relevant to limit injection volume. Use Tramadol is widely used for moderate to severe pain, including post-operative pain. Adverse effects the adverse effects of diamorphine are the same as those for morphine. Pharmacokinetics Diamorphine is hydrolysed (deacetylated) rapidly to form 6-acetylmorphine and morphine, and if given by mouth owes its effect entirely to morphine. This accounts for its rapid effect when administered intravenously and hence increased abuse potential compared with morphine. Diarrhoea, abdominal pain, hypotension, psychiatric reactions, as well as seizures and withdrawal syndromes have been reported. Its main use is by mouth to replace morphine or diamorphine when these drugs are being withdrawn in the treatment of drug dependence. Methadone given once daily under supervision is preferable to leaving addicts to seek diamorphine illicitly. Many of the adverse effects of opioid abuse are related to parenteral administration, with its attendant risks of infection. The slower onset following oral administration reduces the reward and reinforcement of dependence. The relatively long half-life reduces the intensity of withdrawal and permits once-daily dosing under supervision. It causes similar respiratory depression, vomiting and gastrointestinal smooth muscle contraction to morphine, but does not constrict the pupil, release histamine or suppress cough. Pethidine is sometimes used in obstetrics because it does not reduce the activity of the pregnant uterus, but morphine is often preferred. Delayed gastric emptying (common to all opioids) is of particular concern in obstetrics, as gastric aspiration is a leading cause of maternal morbidity. Its effect has a rapid onset and if a satisfactory response has not been obtained within three minutes, the dose may be repeated. The action of many opioids outlasts that of naloxone, which has a t1/2 of one hour, and a constant-rate infusion of naloxone may be needed in these circumstances. Naloxone is used in the management of the apnoeic infant after birth when the mother has received opioid analgesia during labour. Such patients who are receiving naltrexone in addition to supportive therapy, are less likely to resume illicit opiate use (detected by urine measurements) than those receiving placebo plus supportive therapy. Naltrexone has weak agonist activity, but this is not clinically important, and withdrawal symptoms do not follow abrupt cessation of treatment. Treatment should not be started until the addict has been opioid-free for at least seven days for short-acting drugs. Naltrexone has not been extensively studied in non-addicts, and most of the symptoms that have been attributed to it are those that arise from opioid withdrawal. Use Codeine is the methyl ether of morphine, but has only about 10% of its analgesic potency. As a result, it has been used for many years as an analgesic for moderate pain, as a cough suppressant and for symptomatic relief of diarrhoea.