Wednesday, December 28, 2011

IVIg therapy: neurologic indications, contraindications, precautions, and complications

Intravenous immune globulin (IVIg) is a purified preparation of gamma globulin, comprised of 4 subclasses of antibodies (ie, IgG, IgM, IgA, and IgE), approximating the distribution in human serum. IVIg is derived from large pools of human plasma (ie, greater than 1000 donors per lot) and purified to remove infective agents, vasoactive substances, and aggregated proteins.
IVIg is at least 90% intact IgG, the half-life of which is generally from 18 to 32 days in healthy adults, although it varies depending upon patient factors and which specific product is used. IgG is comprised of 4 subclasses of which IgG1 is the major component in normal serum and in IVIg. IgG1 is involved in tissue protection, complement activation, and virus inactivation. Peak serum levels of IgG are attained immediately after IVIg administration, but drop about half during the first week postinfusion, even though the reported half-life of IgG is somewhat longer. IVIg in immune deficient states simply replaces missing antibodies, whereas immunomodulatory doses of IVIg for autoimmune conditions are considerably larger. Various mechanisms have been proposed for immunomodulatatory actions of IVIg, including promoting blockade of Fc receptors in macrophages (thereby preventing phagocytosis of circulating opsonized platelets or cells tagged with autoantibodies), providing anti-idiotypic antibodies to neutralize pathogenic auto-antibodies, absorbing complement, down regulating immunoglobulin production, neutralizing viruses, enhancing suppression cells, inhibiting lymphocyte proliferation, and reducing interleukin (IL-1) production or activity.
IndicationsIVIg therapy is used either for immunomodulation of autoimmune conditions or for antibody replacement. Neurologic indications are genrally associated with an immunomodulatory role, and include Guillain-Barre syndrome and chronic inflammatory demyelinating neuropathy. Other nonneurologic indications associated with an immunomodulatory role include idiopathic thrombocytopenic purpura, Kawasaki syndrome, and acquired hemophilia. Indications suitable for treatment by IgG replacement include general or specific immunodeficiency states, hepatitis A or rubella prophylaxis, chronic lymphocytic leukemia with hypogammaglobulinemia, multiple myeloma with specific antibody deficiency, low birth weight babies at risk for infection, and infants or children with HIV.

Monday, December 26, 2011

Antipsychotic medications

INTRODUCTION — Antipsychotic medications were introduced more than 50 years ago. Although initially targeted to the treatment of schizophrenia, these medications are effective against psychosis irrespective of cause. They are also of benefit for manic episodes, agitation, delirium, impulse control, dissociation, and as augmentation therapy in other psychiatric disorders.
This topic reviews drug selection, treatment protocols, side effects and management of antipsychotic medications. The pharmacological characteristics of these medications in adults is discussed separately, as are identification and treatment of overdose with atypical antipsychotic agents, the target symptoms, the treatment of psychosis in special populations, and the non-pharmacologic treatment of psychosis.

Selective serotonin reuptake inhibitors (SSRIs)

Historical note and nomenclature
  Since its discovery in the mid-20th century, serotonin, which is also called 5-hydroxytryptamine or 5-HT, has played an increasing part in understanding human diseases, particularly those involving the nervous system. Its plays a role in management of depression and other psychiatric disorders with the demonstration of pharmacological manipulation to prevent reuptake. Its role in other neurologic disorders has also expanded. Development of selective serotonin reuptake inhibitors, referred to by the abbreviation SSRI, was a major pharmacological achievement. SSRIs are used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. Historical landmarks in serotonin, serotonin disorders, and drugs based on manipulation of this system are shown in Table 1. The best known SSRI, fluoxetine, was introduced into medical practice in 1988.

Anticholinergics

Historical note and nomenclature
  Anticholinergics are substances that block the neurotransmitter acetylcholine in the central and peripheral nervous systems and are administered to reduce the effects mediated by acetylcholine on acetylcholine receptors in neurons through competitive inhibition. Antimuscarinic agents, a type of anticholinergics, are so called because they block muscarine, a poisonous substance found in the Amanita muscaria, a non-edible mushroom species. Muscarine is a toxic compound that competes with acetylcholine for the same receptors. Antimuscarinic agents are atropine, scopolamine, and ipratropium bromide. Atropine and scopolamine are alkaloids naturally occurring in Atropa belladonna and Datura stramoniumplants whereas ipratropium bromide is a derivative of atropine used to treat asthma.
  Anticholinergic drugs are used in treating a variety of conditions, such as disorders of gastrointestinal (including nausea and vomiting), genitourinary, and respiratory systems. Atropine, an anticholinergic agent, is used as premedication in anesthesia to reduce upper respiratory secretions. This clinical summary focuses on the neurologic applications of anticholinergic drugs, mainly in Parkinson disease, as well as adverse neurologic effects of anticholinergic agents–anticholinergic syndrome.
  Historically anticholinergic agents were known more for their toxicity than for their therapeutic effects. Datura stramonium was described as a poison by Homer in The Odyssey. Anticholinergics agents were introduced as the first effective drugs for Parkinson disease by Charcot at the end of 19th century. With the advent of levodopa and other new drugs for Parkinson disease, and also because of their adverse effects, the use of anticholinergics declined but continues in several other disorders.
  Another use of atropine that is of historical interest now is atropine-induced non-convulsivecoma for treatment of various psychoses and obsessive-compulsive disorder between 1950 and 1975 in the United States and some parts of Europe (Gazdag et al 2005). Although atropine use was eventually abandoned, initial therapeutic results with atropine coma were favorable, and it seemed to be safer and more effective than the widely used insulin coma.

Anticonvulsants

Historical note and nomenclature
  The term “anticonvulsant” is applied to a drug used for the treatment of epileptic seizures, hence, the synonym “antiepileptic,” which is often denoted by the abbreviation AED. This term is applied to other agents such as ketogenic diet and procedures such as vagal nerve stimulation when used for control of seizures. Some drugs from other pharmacological categories have anticonvulsant effect, eg, acetazolamide, which is a carbonic anhydrase inhibitor. Anticonvulsants are also being used in the treatment of neuropathic pain and as mood stabilizers in the treatment of psychiatric disorders such as bipolar disorder.
  The era of anticonvulsant drugs started with the introduction of bromides in 1857 and was followed by the discovery of the anticonvulsant effect of barbiturates in 1912 (Hauptman 1912).Phenytoin (diphenylhydantoin), synthesized in 1908, was not introduced for the treatment ofepilepsy until 1938 (Merritt and Putnam 1938). Although carbamazepine was shown to have antiepileptic properties in 1954, it was first approved in 1968 for the treatment of trigeminal neuralgia and was approved in 1974 for the treatment of epilepsy. Anticonvulsant properties ofvalproic acid, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1963; however, it did not become a major anticonvulsant drug until the 1970s. For the next 2 decades, the older anticonvulsant drugs with new variations remained the mainstay for treatment of epilepsy. During the past 2 decades, several new anticonvulsant drugs have been approved worldwide, and the use of anticonvulsant drugs in indications other than epilepsy has increased. The newer approved anticonvulsants include vigabatrin, zonisamide,oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, levetiracetam,pregabalin, rufinamide, stiripentol, and lacosamide. Several new drugs are in development.
  Several anticonvulsant drugs are reviewed individually in other clinical summaries. This summary compares various anticonvulsants and describes their uses for other indications besides epilepsy.
Pharmacology
  Pharmacodynamics. The main actions of currently used anticonvulsants are:
  (1) Modulation of voltage-gated sodium and calcium channels.
  (2) Synaptic inhibitory neurotransmission by agonist effect on the GABA system.
  (3) Attenuation of brain excitation by decreased glutamate transmission.
  Anticonvulsants can be classified according to their predominant mode of action as shown in Table 1, but some drugs have more than one mechanism of action, and some of the mechanisms are not known. The modifications in channel behavior that are induced by anticonvulsant drugs are often functionally opposite to defects in channel properties that are caused by mutations associated with epilepsy in humans (Rogawski and Loscher 2004).

Table 1. Predominant Mode of Action of Anticonvulsant Drugs

Sodium channel

Calcium channel
GABA
Glutamate
Other mechanisms
Carbamazepine
Rufinamide
Zonisamide
Ethosuximide
Zonisamide
Barbiturates
Benzodiazepines
Valproate
Vigabatrin
Felbamate
Topiramate
Levetiracetam

  Use of anticonvulsants in epilepsy. The primary criterion for the selection of anticonvulsant drugs is the patient’s seizure type; determination is largely based on drug studies that assess the drugs’ effectiveness for specific seizure types rather than the defined causes of seizures. Despite restriction to partial seizures, the response to an investigational anticonvulsant is quite variable. The reasons for this include: (1) patient-to-patient variation in the metabolism of the drug, (2) variations in the ability of drug to bind to the target, (3) variations in the amount of drug target produced by different individuals, and (4) different pathophysiological events accounting for the same seizure phenotype.
  No single anticonvulsant is clearly superior to others. Causes of variability of effects of anticonvulsants include genetic differences, pathogenesis and severity of epilepsy, age, nutritional status, renal and liver function, concomitant illnesses, and drug interactions.
  Effect of anticonvulsants as analgesics. Similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the use of anticonvulsants in the symptomatic management of neuropathic pain. Pain-relieving effects require doses that are in each drug’s antiepileptic dose range. Given their diverse chemistries and different patterns of activity in seizure models, it seems exceedingly unlikely that these anticonvulsants are all working on neuropathic pain via the same mechanism. Table 2 shows the mechanism of action as well as indications for use of various anticonvulsant drugs for management of pain.

Table 2. Use of Anticonvulsant Drugs for Management of Pain

Drug
Mechanism of action

Uses in pain
Carbamazepine
Slows recovery rate of voltage-gated sodium channels. Stabilization of cell membrane.
First line therapy of trigeminal neuralgia, glossopharyngeal neuralgia

Gabapentin
Inhibits repetitive firing of neurons by action at calcium channels
Neuropathic pain, migraine

Ganaxalone
An epalon that modulates GABA receptors

Migraine
Lamotrigine
Inhibits repetitive firing of neurons by action at sodium channels

Neuropathic pain, migraine
Phenytoin
Enhances active sodium extrusion and inhibits passive sodium entry, leading to normalization of the sodium gradient and stabilization of the membrane.

Second line therapy of trigeminal neuralgia
Pregabalin
Enhancement of GABA-mediated inhibition
Shown to be effective in controlled studies in diabetic neuropathy andpostherpetic neuralgia

Rufinamide
Inhibits repetitive firing of neurons by action at sodium channels

Neuropathic pain
Topiramate
Suppresses repetitive depolarization from injured sensory neurons.

Neuropathic pain, migraine, diabetic neuropathy
Valproic acid
Inhibits repetitive firing of neurons by action at sodium channels
Migraine

  Effect of anticonvulsants in psychiatric disorders. Anticonvulsant drugs are widely used in psychiatric indications. These include mainly alcohol and benzodiazepine withdrawal syndromes, panic and anxiety disorders, dementia, schizophrenia, mood disorders (bipolaraffective disorders in particular), and, to some extent, personality disorders (Grunze 2008).Electroconvulsive therapy can be safely and effectively administered to patients treated with various anticonvulsants, but there is no evidence that combination of the 2 treatment modalities augments therapeutic efficacy (Sienaert and Peuskens 2007). An analysis of randomized controlled trials shows that although anticonvulsant mood stabilizers are clearly beneficial in some patients, they cannot be recommended at present for routine use in the treatment of behavioral and psychological symptoms of dementia (Konovalov et al 2008).
  The relative neurocognitive effects of the various psychotropic anticonvulsant drugs in patients with bipolar disorder are consistent with relative effects in patients with epilepsy. Lamotrigine and oxcarbazepine have the least neurotoxicity, whereas topiramate, valproic acid, and carbamazepine have the most (Gualtieri and Johnson 2006).
  The effectiveness of anticonvulsants in mood disorders raises the question whether the analgesic effects of antiepileptic drugs in patients with neuropathic pain may result, at least in part, from their beneficial effects on mood. For example, gabapentin treatment significantly ameliorates depression, anxiety, fatigue, and other mood symptoms and also improves sleep in patients with postherpetic neuralgia and painful diabetic neuropathy.
  Pharmacokinetics. Pharmacokinetics is described in the articles dealing with individual anticonvulsant drugs.
  Pharmacogenetics. Pharmacogenetic alterations can affect efficacy, tolerability, and safety of anticonvulsants, including variation in genes encoding drug target, drug transport, drug metabolization, and human leucocyte antigen proteins. The current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions. However, several observations (eg, that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine) are helpful in improving our knowledge of how genetic variation affects the treatment of epilepsy (Loscher et al 2009). A better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individual patients with epilepsy.
Clinical trials
  Numerous clinical trials in epilepsy have been conducted with newer anticonvulsant drugs, often as add-on to established older drugs. These are described in the clinical summaries for individual anticonvulsants. There are fewer clinical trials comparing monotherapies using various anticonvulsants. Remarks on specific trials are given according to indication categories such as epilepsy, pain, and psychiatric disorders.
  Epilepsy. Carbamazepine has been a drug of choice for the treatment of simple or complex partial seizures and secondary generalized seizures in adults and children. After introduction ofvigabatrin, an open prospective trial showed that vigabatrin is safe and effective as primary monotherapy for epilepsy in children, with a similar proportion of side effects as carbamazepine(Sobaniec et al 2005). Following clinical trials, levetiracetam and controlled-release carbamazepine were shown to produce similar seizure-free rates in newly diagnosed epilepsy at optimal dosing in a setting resembling clinical practice (Brodie et al 2007).
  Pain. Clinical trials with individual anticonvulsant medications for pain are mentioned in the clinical summaries discussing the individual drugs. Most of the trials are in patients with pain refractory to treatment with conventional analgesics. One anticonvulsant agent is usually not compared against another in clinical trials.
  Cochrane Database review of clinical trials shows that anticonvulsants reduce migraine frequency by about 1.3 attacks per 28 days compared with placebo–more than double the number of patients for whom migraine frequency is reduced by 50% relative to placebo(Mulleners and Chronicle 2008). Sodium valproate/divalproex sodium and topiramate were better than placebo, whereas acetazolamide, clonazepam, lamotrigine, and vigabatrin were not.
  Psychiatric disorders. Clinical trials of anticonvulsant disorders are described in the clinical summaries discussing the individual anticonvulsant agents. There few studies that compare one anticonvulsant agent against another in psychiatric disorders. In a randomized, single-blind treatment of hypomanic symptoms in patients with bipolar disorder, oxcarbazepine was found to be as effective as valproic acid in the treatment of hypomania (Suppes et al 2007).
  Clinical trial databases. Information about current clinical trials can be obtained from various databases accessible on the Internet. As of June 2009, the largest number of clinical trials on anticonvulsants were listed on the clinical trial database of the National Institutes of Health (www.ClinicalTrials.gov). Of the 858 clinical trials, the largest numbers involved etiracetam, gabapentin, lamotrigine, pregabalin, and topiramate.
Indications
  Anticonvulsant medications have been approved for the treatment of epilepsy, pain, and psychiatric disorders. Details of indications are given in the clinical summaries dealing with individual anticonvulsants.
  Off-label and investigational uses. Several studies of newer anticonvulsants in epilepsy, pain and psychiatric disorders are still on-going.
Contraindications
  Contraindications are specified for each drug individually (see individual clinical summaries for each drug). There are no contraindications for anticonvulsants as a class.
Goals and duration of treatment
  Goals vary according to the disease and anticonvulsant used. Duration varies for acute to chronic, with most of the indications being chronic conditions.
  Personalized approach to use of anticonvulsants. Physicians try to match a drug to a patient by trial and error. The final choice may take several months and depends on the efficacy and tolerability of adverse effects. However, the problems still remain of adverse side effects and failure to control seizures in more than 30% of patients.
  Control of epilepsy with phenytoin can be a difficult and lengthy process because of the wide range of doses required by different patients and the drug’s narrow therapeutic index. Similarly, appropriate doses of carbamazepine take time to determine because of the drug’s variable affects on patient metabolism and its potential neurologic side effects. People with epilepsy are genetically different from one another, and some of those differences affect their responses to drugs in a predictable manner. Variants of 2 genes have been identified that are more likely to be found in patients who required higher dosages of the antiepileptic drugs carbamazepine and phenytoin (Tate et al 2005). One variant of the gene that encodes CYP2C9 shows a significant association with the maximum dose of phenytoin taken by patients with epilepsy. Moreover, a variant of a second gene, called SCN1A, with activity in the brain, is found significantly more often in patients on the highest doses of both carbamazepine and phenytoin. SCN1A has been implicated in many inherited forms of epilepsy and is the drug target for phenytoin. Detection of these gene variants might determine, in advance, which patients will need the higher dose and enable a more optimal dose schedule at the start. Otherwise, it could take months to get the seizures under control. These new findings provide a direction for a dosing scheme that could be tested in a clinical trial to assess whether pharmacogenetic testing can improve dosing decisions. Such a trial might also enable physicians to identify patients who might safely take a smaller dose, thereby minimizing their risk for adverse side effects.
Dosing
  The doses are specified in the individual clinical summaries for each anticonvulsant.
Precautions and use in special groups
  Pediatric. Many of the anticonvulsants used in adults also have been used in children without any extra risk. However, safety of anticonvulsants for the treatment of psychiatric disorders in the pediatric age group is not supported by adequate clinical trials.
  Geriatric. The use of anticonvulsants in the elderly for the management of epilepsy is safe.
  Pregnancy. There is concern about teratogenicity as the incidence of congenital malformations in offspring of women treated with anticonvulsants during pregnancy is somewhat higher than in offspring of women not exposed to these drugs. Most anticonvulsant drugs fall into category C of the United States Food and Drug Administration. Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  For women on anticonvulsant therapy who are breast-feeding, there are still limited data regarding the degree to which anticonvulsants cross the placenta and penetrate into breast milk. In general, women with epilepsy can breast-feed their babies safely with some cautions(Hovinga and Pennell 2008). Phenobarbital and primidone should be avoided, and with ethosuximide, levetiracetam, lamotrigine, topiramate, and zonisamide there is a potential for significant breast milk concentrations.
  Anesthesia. There are no anesthetic implications for use of anticonvulsants.
Interactions
  Anticonvulsant drugs may interact with each other as well as with other drugs. These are specified in the individual clinical summaries for each agent.
Adverse effects
  The adverse effects of anticonvulsants involve practically every system of the body. These are described in the separate clinical summaries of individual anticonvulsants. However, some adverse effects are common to most anticonvulsant agents, for example, adverse skin reactions, dose-related neurotoxicity, and psychiatric complications. Long-term use of anticonvulsants may lead to some metabolic and endocrine disturbances.
  Drug resistance. Problems with the use of anticonvulsants include loss of efficacy and development of drug resistance. One third of patients with epilepsy develop resistance to drugs, which is associated with an increased risk of death and debilitating psychosocial consequences. Because this form of epilepsy is resistant to multiple anticonvulsant drugs, the mode of resistance is considered to be nonspecific, involving drug-efflux transporters. Another mechanism underlying drug resistance in epilepsy may be the same as in cancer: a cellular pump called P-glycoprotein, which protects cells from toxic substances by actively exporting the offending compounds. In epilepsy resistant to phenytoin, low levels of phenytoin have been demonstrated in association with high levels of P-glycoprotein expression, the product of theMDR1 gene. Genotyping differences have been shown between responders and non-responders. Further studies in this direction might eventually enable the drugs to be tailored to the patient’s profile.
  Cellular mechanisms underlying drug resistance have been studied by comparing resected hippocampal tissue from 2 groups of patients with temporal lobe epilepsy; the first group displaying a clinical response to the anticonvulsant carbamazepine and the second with therapy-resistant seizures (Remy et al 2003). It was shown that the mechanism of action of carbamazepine, use-dependent block of voltage-dependent sodium channels, is completely lost in carbamazepine-resistant patients. Likewise, seizure activity elicited in human hippocampal slices is insensitive to carbamazepine. In marked contrast, carbamazepine-induced use-dependent block of sodium channels blocked seizure activity in vitro in patients clinically responsive to this drug. These data suggest that study of changes in ion channel pharmacology and their contribution to the loss of anticonvulsant drug efficacy in human epilepsy may provide an important impetus for the development of novel anticonvulsants specifically targeted to modified ion channels in the epileptic brain. It is possible to use human tissue for the demonstration of drug resistance in an in vitro preparation, providing a unique tool in the search for novel, more efficient anticonvulsants.
  A study of the properties of transmitter receptors of tissues removed during surgical treatment of drug-resistant temporal lobe epilepsy showed use-dependent rundown of neocortical GABAA-receptor (Ragozzino et al 2005). This represents a temporal lobe epilepsy-specific dysfunction in contrast to stable GABAA-receptor function in the cell membranes isolated from the temporal lobe of temporal lobe epilepsy patients afflicted with neoplastic, traumatic, or ischemic temporal lesions and can be antagonized by brain-derived neurotrophic factor. These findings may help to develop new treatments for drug-resistant temporal lobe epilepsy.
  Management. Treatment of adverse effects of anticonvulsants usually requires discontinuation of the offending agent and replacement with one that is better tolerated.
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Grunze HC. The effectiveness of anticonvulsants in psychiatric disorders. Dialogues Clin Neurosci 2008;10(1):77-89.

Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed 2006;8(3):46.

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