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By N. Charles. Felician College.

It is used as a marker of Myeloid antigen is a surface epitope of myeloid leukocytes order discount levitra with dapoxetine online. It is restricted to mye- of a heterogeneous group of disorders characterized by neo- loid cells and is found on early progenitor cells buy levitra with dapoxetine with a visa, monocytes purchase 40/60mg levitra with dapoxetine otc, plastic transformation in a multipotential hematopoietic stem myeloid leukemias, and weakly on some granulocytes. Differentiation haematopoietic cells and endothelial cells as well as bone usually ends at the blast stage, causing myeloblasts to accu- marrow stromal cells. They develop as a consequence (a) of ineffective hematopoiesis marked by abnormal myeloid, erythroid and megakaryocytic precursors. The Bcr/Abl fusion gene that 101 101 results controls the synthesis of a 210-kDa fusion protein that has tyrosine kinase activity. There is a striking increase in neoplas- tic granulocytic precursors in the bone marrow. The target 100 101 102 103 100 101 102 103 of transformation is a pluripotent stem cell. It is marked 101 by elevated numbers of mature and immature granulocytes, 0 G3 G4 and may be clinically manifested as a chronic phase, acceler- 10 97. T(9;22)(q34;q11) reciprocal translocation leading to fusion of deposits, possibly representing debris from cells, are found. The Bcr-abl fusion gene encodes a chimeric pro- nopathy, weight loss, hemolytic anemia, polyclonal gammopa- tein that possesses constitutive Abl tyrosine kinase activity as thy, and skin rashes may characterize the disease in middle-aged a consequence of abnormal regulation and oligomerization to older subjects. Clinically, patients manifest rash, dyspnea, infltrate together with plasma cells in lymph nodes revealing architectural effacement. There is arborization of newly formed vessels and proliferating vessels with hyperplasia of endothelial cells. To induce an experimental plasmacytoma in laboratory mice or rats, par- Immunoblastic lymphadenopathy: See angioimmunoblas- affn oil is injected into the peritoneum. These tumors, comprised of neoplastic plasma cells, synthesize and secrete monoclonal immuno- Immunoblastic sarcoma is a lymphoma comprised of globulins yielding a homogenous product that forms a spike immunoblast-like cells that are divided into B and T cell in electrophoretic analysis of the serum. The Extramedullary plasmacytoma is a plasma cell dyscrasia tumor cells are large and have a clear cytoplasm containing in which the malignant plasma cells have moved beyond the round to oval nuclei with fne chromatin. Patients manifest a defciency of cell-mediated immunity which causes skin tests of the tuberculin type to be negative. Antigen-presenting cells resembling den- dritic cells apparently represent the transformed cell type. They are divided into low, intermediate, and high ated with transformed germinal center B cells. Tumor derived from a transformed peripheral B cell or, occasionally, a transformed peripheral T cell. A heterogenous group of neoplasms that include precur- Hodgkin disease, non-Hodgkin lymphoma, and Burkitt lym- sor B lymphoblastic leukemia/lymphoma, mantle cell phoma are examples. Lymphomas or lymphocyte tumors lymphoma, B cell chronic lymphocytic leukemia, follicu- grow in lymphoid or other tissues but fail to enter the blood in lar lymphoma, mucosa-associated lymphoid tissue lym- large numbers. The numerous types of lymphomas are char- phoma, diffuse large cell lymphoma, Burkitt lymphoma, acterized by various classes of transformed lymphoid cells. Castleman disease also called giant lymph node hyperpla- sia, is a disease of unknown etiology which involves both Non-classical Hodgkin lymphoma is a nodular lymphocyte- lymph nodes and extranodal tissues. Two histopathologic predominant Hodgkin lymphoma that comprises 5% of all Hodgkin lymphomas. The frst, termed hyaline- vascular angiofollicular lymph node hyperplasia, accounts for 90% of the cases. It usually affects young men who present with an asymptomatic mass in the mediastinum. Histopathologically it reveals numerous small, follicle- like structures, frequently with radially penetrating, thick- walled, hyalinized vessels; concentrically arranged small lymphocytes around the follicular structures called “onion skinning” and extensive proliferation of capillaries in the interfollicular areas. The second type of Castleman disease is plasma cell angiofollicular lymph node hyperplasia which comprises 10% of the cases. The mass may consist of multiple matted lymph nodes with histopathologic features Figure 17. A multicentric type of the plasma cell variant of portend development of lymphoma in the future, although it angiofollicular lymph node hyperplasia is more aggressive. Clinical features of plasma cell angiofollicular hyperplasia include Reticulosis: See lymphoma. Their immunoglobulin genes manifest which there is a uniform accumulation of lymphocytes. The architecture of the lymph node is well preserved with distinct cortical B symptoms are symptoms that often occur in lymphoma germinal centers with little or minimal capsular infltration patients. Infammatory cells are detectable between fever, and night sweats often associated with chest pain. It affects the jaws and be found in various locations such as gastrointestinal tract, abdominal viscera. Pseudolymphomas may occur in individuals reveal rearrangement between the c-myc-bearing chromo- who later develop lymphomas. Burkitt lymphoma patients have antibodies Lymphomatosis refers to numerous lymphomas occurring to the Epstein–Barr virus in their blood sera. The disease in different parts of the body, such as those occurring in occurs in geographic regions that are hot and humid and Hodgkin’s disease. It occurs in subjects with acquired immunodefciency and in other immunosuppressed individu- Biclonality: In contrast to uncontrolled proliferation of a als. There is an effective immune response against the lym- single clone of neoplastic cells which is usually associated phoma that may lead to remission. It is licular hyperplasia and loss of the distinct boundary between expressed in tonsils and secondary lymphoid organs, and the mantle zone and the germinal center. Most Burkitt lymphoma cell lines nal centers contain small lymphocytes with diffuse immuno- express the receptor. M y c is an oncogene designated v-myc when isolated from the avian myelocytomatosis retrovirus and designated c-myc when referring to the cellular homologue. The myc genes are activated by overexpression either by upregulation, caused by transcriptional regulatory signal mutations in the frst intron, or by gene amplifcation. When c-myc is in its normal position on chromo- some 8, it remains transcriptionally silent, but when it is translocated, as in Burkitt lymphoma, it may become acti- vated. The protooncogene c-myc is amplifed in early carci- noma of the uterine cervix, lung cancer, and promyelocytic Figure 17. There is a for this purpose to develop long-term B lymphocyte cul- generalized erythroderma, hyperpigmentation, and exfolia- tures. It causes infectious mononucleosis and ing in the epidermis forming Pautrier’s abscesses. Late in the establishes a latent infection of B cells that persists for life disease, T immunoblasts may appear. Epstein–Barr nuclear antigen is a molecule that occurs in B cells before virus-directed protein can be found in nuclei of Sezary cells are T lymphocytes that form E rosettes with infected cells.

Eur J Clin Phar- for measuring the serum carbamazepine concentration a few weeks macol 1975; 8: 337–341 purchase levitra with dapoxetine 40/60 mg without a prescription. Autoinduction and steady- has been established purchase levitra with dapoxetine with a mastercard, when seizure control is poor or deteriorated state pharmacokinetics of carbamazepine and its major metabolites discount levitra with dapoxetine 40/60mg on-line. Br J Clin (also as a check for compliance), when dose-related adverse efects Pharmacol 1992; 33: 611–615. Interdosage fuctuations in plasma carbamazepine concentration de- are suspected or when drug–drug interactions or other conditions termine intermittent side efects. In general, there is little value in measuring the unbound drugs in paediatric patients. Phenytoin, carbamazepine, sulthiame, lam- serum carbamazepine concentration, and the total concentra- otrigine, vigabatrin, oxcarbazepine and felbamate. Serum carbamazepine concentrations in el- carbamazepine-10,11-epoxide metabolite is usually not justifed. Seizure control and pharmacokinetics of antiepileptic drugs in pregnant women with epilepsy. Justus Liebig’s Annalen des Che- spective study of seizure control in relation to free and total plasma concentrations mie 1899; 305: 96–102. A common anticonvulsant binding site for phenytoin, carbamazepine, + blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and lamotrigine in neuronal Na channels. Relations between mechanisms of action and clinical Academy of Neurology and the American Epilepsy Society. The neurobiology of antiepileptic drugs for the treat- feeding in children of women taking antiepileptic drugs. An international multicenter randomized double-blind controlled trial of lamo- 41. Clinical signifcance of pharmacokinetic interactions between apy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for antiepileptic and psychotropic drugs. Antiepileptic drugs – best practice guide- monotherapy for epilepsy: a meta-analysis. Trigeminal neuralgia: its treatment with a new anticonvulsant drug (G- epine for the treatment of complex partial seizures and secondarily generalized 32883). A double-blind trial of gabapentin efcacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicen- monotherapy for newly diagnosed partial seizures. Carbamazepine in comparative trials: pharmacokinetic controlled-release carbamazepine in newly diagnosed epilepsy. Double-blind comparison of lamotrigine and carbamazepine: a multicentre, double-blind, cross-over study. Efcacy and tolerability of zonisamide versus phenobarbital, phenytoin, and primidone. Efect of valproate on cognitive func- randomised, double-blind, non-inferiority trial. Long-term safety and efcacy of zonisamide versus Epilepsy Cooperative Study 264 Group. Epilep- cation in children – efects on cognitive function: the Multicenter Holmfrid Study. Phenobarbitone, phenytoin, carbamaze- partial epilepsy: pooled analysis of two long-term, randomized, follow-up studies. Risk of serious cutaneous disorders afer initiation of use of vetiracetam with controlled-release carbamazepine and extended-release sodium phenytoin, carbamazepine, or sodium valproate: a record linkage study. Multicentre, double-blind, randomised com- son syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neu- parison between lamotrigine and carbamazepine in elderly patients with newly rology 2005; 64: 1134–1138. Real-world efciency of pharmacogenetic screening for drugs: use of an International Database on Malformations and Drug Exposure carbamazepine-induced severe cutaneous adverse reactions. The efect of antiepileptic drugs on thyroid ed quality of life as an outcome measure. Disorders of reproduction in patients with epilepsy: antiepileptic drug the elderly: results from a randomized double-blind trial of carbamazepine and related mechanisms. Clinical features in 28 consecutive cases of lab- epilepsy on antiepileptic drug monotherapy. Bloom Center for Pharmacy, Jerusalem, Israel 2University of Bonn, Bonn, Germany Primary indication Adjunctive therapy of focal seizures Usual preparation Tablets: 400, 600 and 800 mg Usual dosage 800–1200 mg/day Dosing frequency Once daily Signifcant drug interactions Enzyme inducing antiepileptic drugs decrease plasma eslicarbazepine levels. Eslicarbazepine acetate decreases the plasma levels of steroid oral contraceptives, simvastatin and rosuvastatin Serum level monitoring Routine monitoring of serum eslicarbazepine levels is not recommended Reference range Not established as yet Common/important adverse effects Dizziness, blurred vision, diplopia, visual disturbances, nausea and vomiting, fatigue, incoordination, headache, somnolence, hyponatraemia Main advantages Usually well tolerated, once daily dosing Main disadvantages Efcacy spectrum probably restricted to focal epilepsies Mechanism of action Blockade of voltage-gated sodium and calcium channelsa Oral bioavailability Almost complete (in terms of the active metabolite eslicarbazepine) Time to peak levels 2–3 ha Elimination Hydrolysed rapidly to eslicarbazepine, which is excreted in urine in free and conjugated form. Minor metabolites include (R)-licarbazepine, oxcarbazepine and their conjugates Volume of distribution About 2. Minor active metabolites include oxcarbazepine and (R)-licarbazepine Comment A useful antiepileptic drug for the treatment of focal seizures in adults, with a favourable tolerability profle a Mechanism of action and pharmacokinetic parameters refer to eslicarbazepine, for which eslicarbazepine acetate can be considered a pro-drug. Tus, eslicarbazepine reduces the availability Mechanisms of action and activity in experimental of voltage-gated sodium channels through enhancement of slow in- models [6] activation and is a potent blocker of Cav3. Other distinctive properties of eslicarbazepine Eslicarbazepine Acetate 449 (a) (b) (c) 12 1. An increase in plasma cholesterol the rotarod test, and showed distinguishing anticonvulsant prop- was reported in rats and dogs but not in other species, including erties, characterized by a wider (1. Its clinical pharmacokinetics has been studied following oral administration to healthy young and elderly adults, Toxicology adults and paediatric patients with epilepsy, and patients with renal Tere have been no fndings considered to be of concern for human and hepatic impairment. Mice were stimulated twice daily (inter-stimulation interval 6–7 h) on 12 consecutive days. Eslicarbazepine binding to plasma proteins was unafect- licarbazepine, less (R)-licarbazepine and less oxcarbazepine in plas- ed by warfarin, diazepam, digoxin, phenytoin and tolbutamide. Oxcarbazepine was shown to be a minor metabolite also linear and dose-proportional [30]. In a population pharmacokinetic analysis of data obtained in these The mean observed accumulation ratio (Rac) or accumulation index patients, eslicarbazepine pharmacokinetics was best described of licarbazepine was 1. The minor metabolites in plasma – (R)-licarbaze- (R)-licarbazepine and oxcarbazepine. Analysis of nytoin levels was seen in the analysis of patients with epilepsy [23]. A study in healthy subjects showed no and to healthy subjects (n = 8) who served as a control group [20]. Tus, moderate liver impairment has no relevant efect once daily to women dose-dependently decreased the systemic on glucuronidation or on the formation of (R)-licarbazepine and exposure to levonorgestrel and ethinyloestradiol from combined oxcarbazepine [20]. No data are available for patients with severe oral contraceptives, which was most likely caused by induction of liver impairment.

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Polyglucans in the systemic deposits of myoclonus epilepsy and in cor- 2008; 40: 782–788 40/60 mg levitra with dapoxetine mastercard. Mutations in a gene encoding a novel syndrome but also West syndrome: result of Japanese cohort study buy levitra with dapoxetine no prescription. Epilepsia 2010; protein tyrosine phosphatase cause progressive myoclonus epilepsy buy levitra with dapoxetine with mastercard. Mutational spec- presenting as infantile spasms and generalized tremor in three patients. Association of mutations in a lysosomal in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 2007; protein with classical late-infantile neuronal ceroid lipofuscinosis. Early-juvenile Batten’s disease: a recognisable sub- phosphate as a cause for Lafora disease. Isolation of a novel gene underlying inherited mitochondrial myopathy and myoclonic epilepsy. A homozygous mutation in human in combined β-galactosidase and neuroaminidase defciency in man. Moreover, as epilepsy is a chronic condition, tabolite(s) afer the addition of another xenobiotic. Tese interac- many patients will develop related or unrelated diseases thereby tions are associated with a modifcation in plasma concentration of increasing the probability of co-administration with other drugs. Pharmacodynamic interactions occur at disorders such as bipolar disorder, migraine and chronic pain, fur- the site of pharmacological action between drugs that have either ther enhancing the possibility of combination therapy. Tese interactions are increasing use of over-the-counter medications, herbal remedies not usually associated with changes in plasma drug concentrations and supplements represents a further source of potential clinically and therefore are less well recognized and documented. This can lead to interactions with other drugs that are metabolized Pharmacokinetic interactions by the same enzymes. The most prominent pharmacoki- fect of other drugs with inducing or inhibiting properties. In P-glycoprotein is highly expressed in the intestine, brain, liver and addition, valproic acid is a common displacer from protein binding kidney, where it acts as a natural defence mechanism against several sites. However, for highly attributed to other mechanisms are in fact mediated by modulation protein-bound drugs eliminated by low extraction hepatic metab- of P-glycoprotein function at level of drug absorption, distribution olism, like phenytoin, the initial displacement may result in tran- or excretion. In this respect, the co-administration the pharmacologically active component [14]. In this situation, the of antacids containing magnesium hydroxide or aluminium hy- monitoring of free rather than total drug concentrations can be droxide may impair the absorption of phenytoin and gabapentin, more clinically useful, but in practice is seldom needed. Moreover, the absorption of phenytoin is is the displacement of phenytoin by valproic acid [15]. The efect reduced when the drug is given to epileptic patients receiving con- of valproic acid on phenytoin pharmacokinetics is complex, being tinuous nasogastric feeds. In both examples, reduced drug absorb- a combination of a protein binding displacement and enzyme in- tion has been attributed to formation of insoluble–non-absorbable hibition. As a result of this interaction, in patients While drug transporters, notably P-glycoprotein, may have an co-prescribed valproic acid, therapeutic and toxic efects occur at important role in the gastrointestinal absorption of many drugs, total plasma phenytoin concentrations lower than usual. Within the intestinal epithelium, P-glycoprotein is found in a successful therapeutic outcome. This interplay between transporters and drug-metabolizing or be a substrate, and it has been shown that carbamazepine, enzymes makes it difcult to defne transporter-mediated drug phenytoin and phenobarbital are both substrates and inducers of interactions. Metabolic pro- Drug interactions during the distribution phase are usually caused cesses are necessary to convert a drug into one or more metabo- by competition between two drugs for binding sites on plasma pro- lites which are more water-soluble than the parent drug, facilitating teins [3]. The chemical reactions involved in the biotrans- rise in the fraction of unbound drug in plasma or tissue, thereby formation of drugs are catalysed by various enzyme systems and potentially increasing the pharmacological efect of the displaced are conventionally divided into phase I (functionalization) and drug. Phase I reactions involve the addition of a only if the displaced drug is highly protein bound (usually greater polar functional group (e. N-demethylation) by oxidation, re- placed drug is not highly bound, the amount displaced (which is duction or hydrolysis. Tere is a large interindividual of these enzyme systems is essential to understand the mechanisms variability in the expression and activity of these isoenzymes deriv- of metabolically based drug interactions. Mitochondrial β-oxidation is one of the major pathways of chemical modifcation of the protein [31]. Enzymatic activity can licarzepine, by a non-inducible cytosol arylketone reductase. Valproic acid is considered to be a inducers of various drug-metabolizing systems or because they broad-spectrum inhibitor of various drug-metabolizing enzymes are substrates for the same enzymes. Enzyme inhibition can be reversible or irre- Enzyme induction versible [28,29,30]. Enzyme induction consists of an increased synthesis of enzyme Reversible enzyme inhibition is probably the most common protein caused by prolonged administration of several xenobiot- type of enzyme inhibition and can be subdivided further into com- ics including drugs, industrial contaminants, dietary substances, petitive and non-competitive inhibition [28]. The inducing process tion refers to a mutually exclusive competition between two drugs results in an increased capacity for drug metabolism and may be as- (the substrate and the inhibitor) for the binding to the catalytic site sociated with a proliferation of the smooth endoplasmic reticulum of the enzyme. The extent of induction is generally prevents the substrate from binding to the active site of the en- proportional to the dose of the inducing agent. As the inducing pro- zyme with the result that the substrate cannot be metabolized. The cess requires synthesis of new enzyme, it occurs with some delay amount of enzyme inhibition depends upon the concentration of afer the exposure to the inducing agent and may take days or weeks the inhibitor and substrate and their relative afnities for the ac- before it is completed. Competitive inhibition is typically a rapid, transient and depends on both the time to reach the steady-state of the inducing dose-dependent process [14]. The initial efect usually occurs with- agent (approximately fve elimination half-lives) and the rate of syn- in 24 hours from the addition of the inhibitor, although the time to thesis of new enzymes. Similarly, the time course of de-induction is reach maximal inhibition will depend on the elimination half-lives also gradual and depends on the rate of degradation of the enzyme of the afected drug and of the inhibiting agent. Enzyme in- tor is withdrawn, the time course of deinhibition is also dependent duction may have important clinical implications as it increases the on the rate of the elimination of the inhibitor. Non-competitive rate of metabolism thereby leading to lower plasma drug concen- inhibition involves the strong, covalent binding of the inhibitor to trations and possibly decreased efcacy. Terefore, the substrate can still bind afected drug gives rise to a pharmacologically active metabolite, to the active site, but the basic structure of the enzyme is modifed induction may result in increased metabolite concentrations and and formation of the enzyme–substrate–inhibitor complex results possibly enhanced toxicity. With non-competitive inhibition, the The molecular mechanisms responsible for the process of enzyme time course of the interaction may be more complex, and a sig- induction have been at least partially elucidated. In most cases, en- nifcant part may be played by the turnover (resynthesis) rate of zyme induction is the consequence of an increase in gene transcrip- the enzyme. Drug Interactions 351 hydrocarbon receptor (AhR), the constitutive androstane receptor use. Tese methodologies include enzyme-based tech- With carbamazepine, induction starts in 1 week, maximal induc- niques, such as purifed enzymes, recombinant human enzymes tion and de-induction occur in 3 weeks. Carbamazepine signif- and human liver microsomes, and cell-based techniques, such as cantly induces its own metabolism (autoinduction) and, as a result liver slices, immortalized cell lines and primary hepatocytes. Each of this, its plasma clearance more than doubles during the initial method has its advantage and disadvantage, and the readers are re- weeks of therapy.

With cellular injury or ischemia generic levitra with dapoxetine 40/60 mg online, spontaneous diastolic depolarization develops in non-pacemaker cells causing arrhythmia buy 40/60mg levitra with dapoxetine visa. Unlike reentry order levitra with dapoxetine now, this arrhythmia cannot be started or stopped by stimulation, and is not responsive to cardioversion. The clinical significance of triggered activity is not clear, but it is used to explain a few ventricular tachyarrhythmias such as “torsades de pointes” and digitalis toxic arrhythmia. These are frequently seen in children with large stretched atria resulting from diseases or surgical repair such as Ebstein anomaly, mitral regurgitation, or following Fontan procedure. In atrial fibrillation, the atrial excitement is irregularly irregular with an atrial rate of 300-500/ min and a ventricular rate of 120-180/min. In addition, nonparoxysmal junctional tachycardia, which is a related but rare pattern of arrhythmia, can be observed in the setting of digoxin toxicity. A pediatric cardiologist needs to evaluate many children with rhythm disturbances but this consultation should not delay initial emergency treatment. As mentioned previously that for management point of view in an acute care setting, the rhythm disturbances can be divided into: i) Tachyarrhythmias with hemodynamic instability, ii) Tachyarrhythmias with hemodynamic stability), iii) Slow pulse rate (bradyarrthymias), and iv) Absent pulse (collapse rhythm). Tachycardia with Hemodynamic Instability Treatment of arrhythmias in emergency situation depends on the effect of arrhythmia on hemodynamic instability. For probable supraventricular tachycardia, the rhythm should be monitored during therapy to evaluate effect. In infants and young children, apply ice to the face without occluding the airway. One method of a Valsalva maneuver is to make the child blow through an obstructed straw. If a second shock is unsuccessful or the tachycardia recurs quickly, consider antiarrhythmic therapy (amiodarone or procainamide) before a third shock. If there is no effect and there are no signs of toxicity, give additional doses if required. Do not use verapamil in infants because it may cause refractory hypotension and cardiac arrest and use with caution in children because it may cause hypotension and myocardial depression. If a second shock (2 J/kg) is unsuccessful or if the tachycardia recurs quickly, consider antiarrhythmic therapy (amiodarone or procainamide) before a third shock. Atrial Fibrillation or Flutter For stable patients the treatment options are: • Beta-blocker (e. Administer cardioversion earlier if signs of severe cardiac failure manifest or if deterioration occurs during medical treatment. If patient is stable and presenting with >48 hours of signs of atrial dysrhythmia, consider anticoagulation prior to cardioversion. Tachycardia with Hemodynamic Stability Because all anti-arrhythmia therapies have the potential for serious adverse effects, consider consulting an expert in pediatric arrhythmias before treating children who are hemodynamically stable. Do not administer amiodarone and procainamide together without expert consultation. Impulse Conduction Disturbances Impulse conduction can be disturbed at any level of the conduction system. Causes include myocarditis, endocarditis, increased vagal tone, drugs (digitalis, β-blockers, Ca++ blockers), surgical injury, and atrial enlargement secondary to cardiac diseases. No specific treatment is necessary for type of block except for treating the underlying cause. Second degree Mobitz type I block (Wenckebach) usually results from a conduction delay involving conduction tissue above the His bundle. Electrocardiographically, the atrial and ventricular complexes are disassociated with a more rapid atrial rate. Compatibility with life depends upon the function of subsidiary pacemakers distal to the block. In this situation patient should be continuously monitored and proceed with evaluation to treat the underlying cause. So for all the slow rhythms that result in shock or life threatening hemodynamic instability, the priority is to support airway, breathing, and circulation as needed, administer oxygen, and attach a monitor/ defibrillator. Reassess the patient after these initial steps to determine if bradycardia is still causing cardiorespiratory symptoms. If heart rate is <60 beats per minute with poor perfusion start chest compressions. If signs of hemodynamic compromise persist despite the support of adequate oxygenation ventilation and compressions, give epinephrine. If bradycardia persists or responds only transiently, consider a continuous infusion of epinephrine or isoproterenol. Emergency transcutaneous pacing may be lifesaving if the bradycardia is due to complete heart block or sinus nodal dysfunction unresponsive to ventilation, oxygenation, chest compressions, and medications, especially if it is associated with congenital or acquired heart disease. Asystole is a form of pulseless arrest associated with absent cardiac electrical activity. Ventricular fibrillation is chaotic and disorganized series of depolarizations that causes only a quivering myocardium without any cardiac output. The ventricular fibrillation may be a coarse with high amplitude waveform or fine with low amplitude waveforms. Less frequently there is a sudden impairment of cardiac output with an initially normal rhythm but without pulses and with poor perfusion. High- dose epinephrine may be considered in exceptional circumstances such as beta-blocker overdose. The drugs that are commonly used in acute care settings are briefed below17 (Table 13. A higher dose may be required for peripheral administration than central venous administration. Administer adenosine and follow with a rapid saline flush to promote flow toward the central circulation. The severity of the hypotension is related to the infusion rate and is less common with the aqueous form of amiodarone. Calcium Routine administration of calcium does not improve outcome of cardiac arrest. In critically ill children, calcium chloride may provide greater bioavailability than calcium gluconate. Preferably administer calcium chloride via a central venous catheter because of the risk of sclerosis or infiltration with a peripheral venous line. Intravenous calcium is the drug of choice when arrhythmias are suspected due to hyperkalemia or hypocalcemia. Epinephrine the alpha-adrenergic-mediated vasoconstriction of epinephrine increases aortic diastolic pressure and thus coronary perfusion pressure, a critical determinant of successful resuscitation. It is a good practice to administer all catecholamines through a secure line, preferably into the central circulation; local ischemia, tissue injury, and ulceration may result from tissue infiltration.