Epilepsy (from the Ancient Greek epilēpsía) is a common chronic neurological disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous neuronal activity in the brain. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries.Epilepsy is more likely to occur in young children, or people over the age of 65 years, however it can occur at any time. Epilepsy is usually controlled, but not cured, with medication, although surgery may be considered in difficult cases. However, over 30% of people with epilepsy do not have seizure control even with the best available medications.Not all epilepsy syndromes are lifelong – some forms are confined to particular stages of childhood. Epilepsy should not be understood as a single disorder, but rather as syndromic with vastly divergent symptoms but all involving episodic abnormal electrical activity in the brain.
Epilepsy is one of the most common of the serious neurological disorders. Genetic, congenital, and developmental conditions are mostly associated with it among younger patients; tumors are more likely over age 40; head trauma and central nervous system infections may occur at any age. The prevalence of active epilepsy is roughly in the range 5–10 per 1000 people. Up to 5% of people experience non febrile seizures at some point in life; epilepsy's lifetime prevalence is relatively high because most patients either stop having seizures or (less commonly) die of it. Epilepsy's approximate annual incidence rate is 40–70 per 100,000 in industrialized countries and 100–190 per 100,000 in resource-poor countries; socioeconomically deprived people are at higher risk. In industrialized countries the incidence rate decreased in children but increased among the elderly during the three decades prior to 2003, for reasons not fully understood.
Beyond symptoms of the underlying diseases that can be a part of certain epilepsies, people with epilepsy are at risk for death from four main problems: status epilepticus (most often associated with anticonvulsant noncompliance), suicide associated with depression, trauma from seizures, and sudden unexpected death in epilepsy (SUDEP) Those at highest risk for epilepsy-related deaths usually have underlying neurological impairment or poorly controlled seizures; those with more benign epilepsy syndromes have little risk for epilepsy-related death.
Certain diseases also seem to occur in higher than expected rates in people with epilepsy, and the risk of these "comorbidities" often varies with the epilepsy syndrome. These diseases include depression and anxiety disorders, migraine and other headaches, infertility and low sexual libido. Attention-deficit/hyperactivity disorder (ADHD) affects three to five times more children with epilepsy than children in the general populationEpilepsy is prevalent in autism.
Epilepsy syndromes
There are over 40 different types of epilepsy, including: Absence seizures, atonic seizures, benign Rolandic epilepsy, childhood absence, clonic seizures, complex partial seizures, frontal lobe epilepsy, Febrile seizures, Infantile spasms, Juvenile Myoclonic Epilepsy, Juvenile Absence Epilepsy, lennox-gastaut syndrom, Landau-Kleffner Syndrome , myoclonic seizures, Mitochondrial Disorders, Progressive Myoclonic Epilepsies, Psychogenic Seizures , Reflex Epilepsy, Rasmussen's Syndrome, Simple Partial seizures, Secondarily Generalized Seizures, Temporal Lobe Epilepsy, Toni-clonic seizures, Tonic seizures, Psychomotor Seizures, Limbic Epilepsy, Partial-Onset Seizures, generalised-onset seizures, Status Epilepticus, Abdominal Epilepsy, Akinetic Seizures, Auto-nomic seizures, Massive Bilateral Myoclonus, Catamenial Epilepsy, Drop seizures, Emotional seizures, Focal seizures, Gelastic seizures, Jacksonian March, Lafora Disease, Motor seizures, Multifocal seizures, Neonatal seizures, Nocturnal seizures, Photosensitive seizure, Pseudo seizures, Sensory seizures, Subtle seizures, Sylvan Seizures, Withdrawal seizures, Visual Reflex Seizures amongst others.
Each type of epilepsy presents with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. The most widespread classification of the epilepsies divides epilepsy syndromes by location or distribution of seizures (as revealed by the appearance of the seizures and by EEG) and by cause. Syndromes are divided into localization-related epilepsies, generalized epilepsies, or epilepsies of unknown localization.
Localization-related epilepsies, sometimes termed partial or focal epilepsies, arise from an epileptic focus, a small portion of the brain that serves as the irritant driving the epileptic response. Generalized epilepsies, in contrast, arise from many independent foci (multifocal epilepsies) or from epileptic circuits that involve the whole brain. Epilepsies of unknown localization remain unclear whether they arise from a portion of the brain or from more widespread circuits.
Epilepsy syndromes are further divided by presumptive cause: idiopathic, symptomatic, and cryptogenic. Idiopathic epilepsies are generally thought to arise from genetic abnormalities that lead to alteration of basic neuronal regulation. Symptomatic epilepsies arise from the effects of an epileptic lesion, whether that lesion is focal, such as a tumor, or a defect in metabolism causing widespread injury to the brain. Cryptogenic epilepsies involve a presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.
Some epileptic syndromes are difficult to fit within this classification scheme and fall in the unknown localization/etiology category. People who only have had a single seizure, or those with seizures that occur only after specific precipitants ("provoked seizures"), have "epilepsies" that fall into this category. Febrile convulsions are an example of seizures bound to a particular precipitant. Landau-Kleffner syndrome is another epilepsy which, because of its variety of EEG distributions, falls uneasily in clear categories. More confusingly, certain syndromes like West syndrome featuring seizures such as Infantile spasms can be classified as idiopathic, syndromic, or cryptogenic depending on cause and can arise from both focal or generalized epileptic lesions.
Below are some common seizure syndromes:
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic localization-related epilepsy that is an inherited epileptic disorder that causes seizures during sleep. Onset is usually in childhood. These seizures arise from the frontal lobes and consist of complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. ADNFLE has a genetic basis. These genes encode various nicotinic acetylcholine receptors.
Benign centrotemporal lobe epilepsy of childhood or Benign rolandic epilepsy is an idiopathic localization-related epilepsy that occurs in children between the ages of 3 and 13 years with peak onset in prepubertal late childhood. Apart from their seizure disorder, these patients are otherwise normal. This syndrome features simple partial seizures that involve facial muscles and frequently cause drooling. Although most episodes are brief, seizures sometimes spread and generalize. Seizures are typically nocturnal and confined to sleep. The EEG may demonstrate spike discharges that occur over the centrotemporal scalp over the central sulcus of the brain (the Rolandic sulcus) that are predisposed to occur during drowsiness or light sleep. Seizures cease near puberty.Seizures may require anticonvulsant treatment, but sometimes are infrequent enough to allow physicians to defer treatment.
Benign occipital epilepsy of childhood (BOEC) is an idiopathic localization-related epilepsy and consists of an evolving group of syndromes. Most authorities include two subtypes, an early subtype with onset between 3–5 years and an late onset between 7–10 years. Seizures in BOEC usually feature visual symptoms such as scotoma or fortifications (brightly colored spots or lines) or amaurosis (blindness or impairment of vision). Convulsions involving one half the body, hemiconvulsions, or forced eye deviation or head turning are common. Younger patients typically experience symptoms similar to migraine with nausea and headache, and older patients typically complain of more visual symptoms. The EEG in BOEC shows spikes recorded from the occipital (back of head) regions. The EEG and genetic pattern suggest an autosomal dominant transmission as described by Ruben Kuzniecky et al.Lately, a group of epilepsies termed Panayiotopoulos syndrome that share some clinical features of BOEC but have a wider variety of EEG findings are classified by some as BOEC.
Catamenial epilepsy (CE) is when seizures typically occur around a woman's menstrual cycle.
Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy that affects children between the ages of 4 and 12 years of age, although peak onset is around 5–6 years old. These patients have recurrent absence seizures, brief episodes of unresponsive staring, sometimes with minor motor features such as eye blinking or subtle chewing. The EEG finding in CAE is generalized 3 Hz spike and wave discharges. Some go on to develop generalized tonic-clonic seizures. This condition carries a good prognosis because children do not usually show cognitive decline or neurological deficits, and the seizures in the majority cease spontaneously with onging maturation.
Dravet's syndrome Severe myoclonic epilepsy of infancy (SMEI). This generalized epilepsy syndrome is distinguished from benign myoclonic epilepsy by its severity and must be differentiated from the Lennox-Gastaut syndrome and Doose’s myoclonic-astatic epilepsy. Onset is in the first year of life and symptoms peak at about 5 months of age with febrile hemiclonic or generalized status epilepticus. Boys are twice as often affected as girls. Prognosis is poor. Most cases are sporadic. Family history of epilepsy and febrile convulsions is present in around 25 percent of the cases
Frontal lobe epilepsy, usually a symptomatic or cryptogenic localization-related epilepsy, arises from lesions causing seizures that occur in the frontal lobes of the brain. These epilepsies can be difficult to diagnose because the symptoms of seizures can easily be confused with nonepileptic spells and, because of limitations of the EEG, be difficult to "see" with standard scalp EEG.
Juvenile absence epilepsy is an idiopathic generalized epilepsy with later onset that CAE, typically in prepubertal adolescence, with the most frequent seizure type being absence seizures. Generalized tonic-clonic seizures can occur. 3 Hz spike-wave or multiple spike discharges can be seen on EEG. Prognosis is mixed, with some patients going on to a syndrome that is poorly distinguishable from JME.
Juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy that occurs in patients aged 8 to 20 years. Patients have normal cognition and are otherwise neurologically intact. The most common seizures are myoclonic jerks, although generalized tonic-clonic seizures and absence seizures may occur as well. Myoclonic jerks usually cluster in the early morning after awakening. The EEG reveals generalized 4–6 Hz spike wave discharges or multiple spike discharges. Interestingly, these patients are often first diagnosed when they have their first generalized tonic-clonic seizure later in life when they experience sleep deprivation (e.g., freshman year in college after staying up late to study for exams). Alcohol withdrawal can also be a major contributing factor in breakthrough seizures as well. The risk of the tendency to have seizures is lifelong; however, the majority have well-controlled seizures with anticonvulsant medication and avoidance of seizure precipitants.
Lennox-Gastaut syndrome (LGS) is a generalized epilepsy that consists of a triad of developmental delay or childhood dementia, mixed generalized seizures, and EEG demonstrating a pattern of approximately 2 Hz "slow" spike-wave. Onset occurs between 2–18 years. As in West syndrome, LGS result from idiopathic, symptomatic, or cryptogenic causes, and many patients first have West syndrome. Authorities emphasize different seizure types as important in LGS, but most have astatic seizures (drop attacks), tonic seizures, tonic-clonic seizures, atypical absence seizures, and sometimes, complex partial seizures. Anticonvulsants are usually only partially successful in treatment.
Ohtahara Syndrome is a rare but severe form of epilepsy syndrome combined with cerebral palsy and characterised with frequent seizures which typically start in the first few days of life. Sufferers trend to be severely disabled and their lives short (they are unlikely to reach adulthood).
Primary reading epilepsy is a reflex epilepsy classified as an idiopathic localization-related epilepsy. Reading in susceptible individuals triggers characteristic seizures.
Progressive myoclonic epilepsies define a group of symptomatic generalized epilepsies characterized by progressive dementia and myoclonic seizures. Tonic-clonic seizures may occur as well. Diseases usually classified in this group are Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers (MERRF syndrome), Lafora disease, neuronal ceroid lipofucinosis, and sialdosis.
Rasmussen's encephalitis is a symptomatic localization-related epilepsy that is a progressive, inflammatory lesion affecting children with onset before the age of 10. Seizures start as separate simple partial or complex partial seizures and may progress to epilepsia partialis continuata (simple partial status epilepticus). Neuroimaging shows inflammatory encephalitis on one side of the brain that may spread if not treated. Dementia and hemiparesis are other problems. The cause is hypothesized to involve an immulogical attack against glutamate receptors, a common neurotransmitter in the brain.
Symptomatic localization-related epilepsies Symptomatic localization-related epilepsies are divided by the location in the brain of the epileptic lesion, since the symptoms of the seizures are more closely tied to the brain location rather than the cause of the lesion. Tumors, atriovenous malformations, cavernous malformations, trauma, and cerebral infarcts can all be causes of epileptic foci in different brain regions.
Temporal lobe epilepsy (TLE), a symptomatic localization-related epilepsy, is the most common epilepsy of adults who experience seizures poorly controlled with anticonvulsant medications. In most cases, the epileptogenic region is found in the midline (mesial) temporal structures (e.g., the hippocampus, amygdala, and parahippocampal gyrus). Seizures begin in late childhood and adolescence. Most of these patients have complex partial seizures sometimes preceded by an aura, and some TLE patients also suffer from secondary generalized tonic-clonic seizures. If the patient does not respond sufficiently to medical treatment, epilepsy surgery may be considered.
West syndrome is a triad of developmental delay, seizures termed infantile spasms, and EEG demonstrating a pattern termed hypsarrhythmia. Onset occurs between 3 months and 2 years, with peak onset between 8–9 months. West syndrome may arise from idiopathic, symptomatic, or cryptogenic causes. The most common cause is tuberous sclerosis. The prognosis varies with the underlying cause. In general most surviving patients remain with significant cognitive impairment and continuing seizures and may evolve to another eponymic syndrome, Lennox-Gastaut syndrome.
Responding to a seizure
In most cases, the proper emergency response to a generalized tonic-clonic epileptic seizure is simply to prevent the patient from self-injury by moving him or her away from sharp edges, placing something soft beneath the head, and carefully rolling the person into the recovery position to avoid asphyxiation. In some cases the person may seem to start snoring loudly following a seizure, before coming to. This merely indicates that the person is beginning to breathe properly and does not mean he or she is suffocating. Should the person regurgitate, the material should be allowed to drip out the side of the person's mouth by itself. If a seizure lasts longer than 5 minutes, or if the seizures begin coming in 'waves' one after the other - then Emergency Medical Services should be contacted immediately. Prolonged seizures may develop into status epilepticus, a dangerous condition requiring hospitalization and emergency treatment.
Objects should never be placed in a person's mouth by anybody - including paramedics - during a seizure as this could result in serious injury to either party. Despite common folklore, it is not possible for a person to swallow their own tongue during a seizure. However, it is possible that the person will bite their own tongue, especially if an object is placed in the mouth.
With other types of seizures such as simple partial seizures and complex partial seizures where the person is not convulsing but may be hallucinating, disoriented, distressed, or unconscious, the person should be reassured, gently guided away from danger, and sometimes it may be necessary to protect the person from self-injury, but physical force should be used only as a last resort as this could distress the person even more. In complex partial seizures where the person is unconscious, attempts to rouse the person should not be made as the seizure must take its full course. After a seizure, the person may pass into a deep sleep or otherwise they will be disoriented and often unaware that they have just had a seizure, as amnesia is common with complex partial seizures. The person should remain observed until they have completely recovered, as with a tonic-clonic seizure.
After a seizure, it is typical for a person to be exhausted and confused. (this is known as post-ictal state). Often the person is not immediately aware that they have just had a seizure. During this time one should stay with the person - reassuring and comforting them - until they appear to act as they normally would. Seldom during seizures do people lose bladder or bowel control. In some instances the person may vomit after coming to. People should not be allowed to wander about unsupervised until they have returned to their normal level of awareness. Many patients will sleep deeply for a few hours after a seizure - this is common for those having just experienced a more violent type of seizure such as a tonic-clonic. In about 50% of people with epilepsy, headaches may occur after a seizure. These headaches share many features with migraines, and respond to the same medications.
It is helpful if those present at the time of a seizure make note of how long and how severe the seizure was. It is also helpful to note any mannerisms displayed during the seizure. For example, the individual may twist the body to the right or left, may blink, might mumble nonsense words, or might pull at clothing. Any observed behaviors, when relayed to a neurologist, may be of help in diagnosing the type of seizure which occurred.
Pharmacologic treatment
Anticonvulsant
The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants and their effectiveness differs by epilepsy syndrome. Mechanisms, effectiveness for particular epilepsy syndromes, and side effects, of course, differ among the individual anticonvulsant medications. Some general findings about the use of anticonvulsants are outlined below.
History and Availability- The first anticonvulsant was bromide, suggested in 1857 by Charles Locock who used it to treat women with "hysterical epilepsy" (probably catamenial epilepsy). Potassium bromide was also noted to cause impotence in men. Authorities concluded that potassium bromide would dampen sexual excitement thought to cause the seizures. In fact, bromides were effective against epilepsy, and also caused impotence; it is now known that impotence is a side effect of bromide treatment, which is not related to its anti-epileptic effects. It also suffered from the way it affected behaviour, introducing the idea of the 'epileptic personality' which was actually a result of the medication. Phenobarbital was first used in 1912 for both its sedative and antiepileptic properties. By the 1930s, the development of animal models in epilepsy research lead to the development of phenytoin by Tracy Putnam and H. Houston Merritt, which had the distinct advantage of treating epileptic seizures with less sedation.By the 1970s, an National Institutes of Health initiative, the Anticonvulsant Screening Program, headed by J. Kiffin Penry, served as a mechanism for drawing the interest and abilities of pharmaceutical companies in the development of new anticonvulsant medications.
Currently there are 20 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US: carbamazepine (common US brand name Tegretol), clorazepate (Tranxene), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapentin (Neurontin), lacosamide (Vimpat), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene), and zonisamide (Zonegran). Most of these appeared after 1990.
Medications commonly available outside the US but still labelled as "investigational" within the US are clobazam (Frisium) and vigabatrin (Sabril). Medications currently under clinical trial under the supervision of the FDA include retigabine, brivaracetam, and seletracetam.
Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium, Diastat) and lorazepam (Ativan). Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral), midazolam (Versed), and pentobarbital (Nembutal).
Some anticonvulsant medications do not have primary FDA-approved uses in epilepsy but are used in limited trials, remain in rare use in difficult cases, have limited "grandfather" status, are bound to particular severe epilepsies, or are under current investigation. These include acetazolamide (Diamox), progesterone, adrenocorticotropic hormone (ACTH, Acthar), various corticotropic steroid hormones (prednisone), or bromide.
Effectiveness - The definition of "effective" varies. FDA-approval usually requires that 50% of the patient treatment group had at least a 50% improvement in the rate of epileptic seizures. About 20% of patients with epilepsy continue to have breakthrough epileptic seizures despite best anticonvulsant treatment..
Safety and Side Effects - 88% of patients with epilepsy, in a European survey, reported at least one anticonvulsant related side effect. Most side effects are mild and "dose-related" and can often be avoided or minimized by the use of the smallest effective amount. Some examples include mood changes, sleepiness, or unsteadiness in gait. Some anticonvulsant medications have "idiosyncratic" side-effects that can not be predicted by dose. Some examples include drug rashes, liver toxicity (hepatitis), or aplastic anemia. Safety includes the consideration of teratogenicity (the effects of medications on fetal development) when women with epilepsy become pregnant.
Principles of Anticonvulsant Use and Management - The goal for individual patients is, of course, no seizures and no side effects, and the job of the physician is to aid the patient to find the best balance between the two during the prescribing of anticonvulsants. Most patients can achieve this balance best with monotherapy, the use of a single anticonvulsant medication. Some patients, however, require polypharmacy; the use of two or more anticonvulsants.
Serum levels of AEDs can be checked to determine medication compliance, to assess the effects of new drug-drug interactions upon previous stable medication levels, or to help establish if particular symptoms such as instability or sleepiness can be considered a drug side-effect or are due to different causes. Children or impaired adults who may not be able to communicate side effects may benefit from routine screening of drug levels. Beyond baseline screening, however, trials of recurrent, routine blood or urine monitoring show no proven benefits and may lead to unnecessary medication adjustments in most older children and adults using routine anticonvulsants.
If a person's epilepsy cannot be brought under control after adequate trials of two or three (experts vary here) different drugs, that person's epilepsy is generally said to be medically refractory. A study of patients with previously untreated epilepsy demonstrated that 47% achieved control of seizures with the use of their first single drug. 14% became seizure free during treatment with a second or third drug. An additional 3% became seizure-free with the use of two drugs simultaneously. Other treatments, in addition to or instead of, anticonvulsant medications may be considered by those people with continuing seizures.
Other treatment
Ketogenic diet-
a high fat, low carbohydrate diet developed in the 1920s, largely forgotten with the advent of effective anticonvulsants, and resurrected in the 1990s. The mechanism of action is unknown. It is used mainly in the treatment of children with severe, medically-intractable epilepsies.
Electrical stimulation
- methods of anticonvulsant treatment with both currently approved and investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices include the responsive neurostimulation system and deep brain stimulation.
Vagus nerve stimulation
(VNS)- The VNS (US manufacturer = Cyberonics) consists of a computerized electrical device similar in size, shape and implant location to a heart pacemaker that connects to the vagus nerve in the neck. The device stimulates the vagus nerve at pre-set intervals and intensities of current. Efficacy has been tested in patients with localization-related epilepsies demonstrating that 50% of patients experience a 50% improvement in seizure rate. Case series have demonstrated similar efficacies in certain generalized epilepsies such as Lennox-Gastaut syndrome. Although success rates are not usually equal to that of epilepsy surgery, it is a reasonable alternative when the patient is reluctant to proceed with any required invasive monitoring, when appropriate presurgical evaluation fails to uncover the location of epileptic foci, or when there are multiple epileptic foci.
Responsive Neurostimulator System
(RNS) (US manufacturer Neuropace) consists of an computerized electrical device implanted in the skull with electrodes implanted in presumed epileptic foci within the brain. The brain electrodes send EEG signal to the device which contains seizure-detection software. When certain EEG seizure criteria are met, the device delivers a small electrical charge to other electrodes near the epileptic focus and disrupt the seizure. The efficacy of the RNS is under current investigation with the goal of FDA approval.
Deep brain stimulation (DBS)
consists of computerized electrical device implanted in the chest in a manner similar to the VNS, but electrical stimulation is delivered to deep brain structures through depth electrodes implanted through the skull. In epilepsy, the electrode target is the anterior nucleus of the thalamus. The efficacy of the DBS in localization-related epilepsies is currently under investigation.
Noninvasive surgery- The use of the Gamma Knife or other devices used in radiosurgery are currently being investigated as alternatives to traditional open surgery in patients who would otherwise qualify for anterior temporal lobectomy
Avoidance therapy-
Avoidance therapy consists of minimizing or eliminating triggers in patients whose seizures are particularly susceptible to seizure precipitants (see above). For example, sunglasses that counter exposure to particular light wavelengths can improve seizure control in certain photosensitive epilepsies
Warning systems-
A seizure response dog is a form of service dog that is trained to summon help or ensure personal safety when a seizure occurs. These are not suitable for everybody and not all dogs can be so trained. Rarely, a dog may develop the ability to sense a seizure before it occurs.Development of electronic forms of seizure detection systems are currently under investigation.
Pathophysiology
Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes.Several ligand-gated ion channels have been linked to some types of frontal and generalized epilepsies. One speculated mechanism for some forms of inherited epilepsy are mutations of the genes which code for sodium channel proteins; these defective sodium channels stay open for too long thus making the neuron hyper-excitable. Glutamate, an excitatory neurotransmitter, may thereby be released from these neurons in large amounts which—by binding with nearby glumtamanergic neurons—triggers excessive CA++ release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell. The hippocampus, which contains a large volume of just such glutamanergic neurons (and NMDA receptors, which are permeable to CA++ entry after binding of both sodium and glutamate), is especially vulnerable to epileptic seizure, subsequent spread of excitation, and possible neuronal death. Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.
Epileptogenesis is the process by which a normal brain develops epilepsy after an insult. One interesting finding in animals is that repeated low-level electrical stimulation to some brain sites can lead to permanent increases in seizure susceptibility: in other words, a permanent decrease in seizure "threshold." This phenomenon, known as kindling (by analogy with the use of burning twigs to start a larger fire) was discovered by Dr. Graham Goddard in 1967. Chemical stimulation can also induce seizures; repeated exposures to some pesticides have been shown to induce seizures in both humans and animals. One mechanism proposed for this is called excitotoxicity. The roles of kindling and excitotoxicity, if any, in human epilepsy are currently hotly debated.
Other causes of epilepsy are brain lesions, where there is scar tissue or another abnormal mass of tissue in an area of the brain.
The complexity of understanding what seizures are have led to considerable efforts to use computational models of epilepsy to both interpret experimental and clinical data, as well as guide strategies for therapy.
Tuesday, November 3, 2009
Monday, October 12, 2009
Cough suppressants
Cough may be a symptom of an underlying disorder, such as asthma gastro-oesophageal reflux disease , or rhinitis which should be addressed before prescribing cough suppressants. Cough may be a side-effect of another drug, such as an ACE inhibitor or it can be associated with smoking or environmental pollutants. Cough can also have a significant habit component. When there is no identifiable cause, cough suppressants may be useful, for example if sleep is disturbed. They may cause sputum retention and this may be harmful in patients with chronic bronchitis and bronchiectasis.Codeine may be effective but it is constipating and can cause dependence; dextromethorphan and pholcodine have fewer side-effects. Sedating antihistamines are used as the cough suppressant component of many compound cough preparations on sale to the public; all tend to cause drowsiness which may reflect their main mode of action.
Children
The use of cough suppressants containing codeine or similar opioid analgesics is not generally recommended in children and should be avoided altogether in those under 1 year of age.
Sub-sections
CODEINE PHOSPHATE 
Indications
dry or painful cough; diarrhoea ,pain
Cautions
asthma; hepatic impairment; renal impairment history of drug abuse
Indications
dry or painful cough; diarrhoea ,pain
Cautions
asthma; hepatic impairment; renal impairment history of drug abuse
Contra-indications
liver disease, ventilatory failure
Side-effects
constipation, respiratory depression in sensitive patients or if given large doses
liver disease, ventilatory failure
Side-effects
constipation, respiratory depression in sensitive patients or if given large doses
Saturday, October 10, 2009
Phaeochromocytoma
Long-term management of phaeochromocytoma involves surgery. Alpha-blockers are used in the short-term management of hypertensive episodes in phaeochromocytoma. Once alpha blockade is established, tachycardia can be controlled by the cautious addition of a beta-blocker a cardioselective beta-blocker is preferred.
Phenoxybenzamine, a powerful alpha-blocker, is effective in the management of phaeochromocytoma but it has many side-effects. Phentolamine is a short-acting alpha-blocker used mainly during surgery of phaeochromocytoma; its use for the diagnosis of phaeochromocytoma has been superseded by measurement of catecholamines in blood and urine.
Metirosine inhibits the enzyme tyrosine hydroxylase, and hence the synthesis of catecholamines. It is rarely used in the pre-operative management of phaeochromocytoma, and long term in patients unsuitable for surgery; an alpha-adrenoceptor blocking drug may also be required. Metirosine should not be used to treat essential hypertension.
Phenoxybenzamine, a powerful alpha-blocker, is effective in the management of phaeochromocytoma but it has many side-effects. Phentolamine is a short-acting alpha-blocker used mainly during surgery of phaeochromocytoma; its use for the diagnosis of phaeochromocytoma has been superseded by measurement of catecholamines in blood and urine.
Metirosine inhibits the enzyme tyrosine hydroxylase, and hence the synthesis of catecholamines. It is rarely used in the pre-operative management of phaeochromocytoma, and long term in patients unsuitable for surgery; an alpha-adrenoceptor blocking drug may also be required. Metirosine should not be used to treat essential hypertension.
Myocardial infarction is part of the spectrum of acute coronary syndromes which includes unstable angina, and myocardial infarction with or without ST-segment elevation.
These notes give an overview of the initial and long-term management of myocardial infarction with ST-segment elevation. For advice on the management of non-ST-segment elevation myocardial infarction and unstable angina, see section 2.6. The aims of management of ST-segment elevation myocardial infarction are to provide supportive care and pain relief, to promote reperfusion and to reduce mortality. Oxygen, diamorphine and nitrates can provide initial support and pain relief; aspirin and percutaneous coronary intervention or thrombolytics promote reperfusion; long-term use of aspirin, beta-blockers, ACE inhibitors, and statins help to reduce mortality further.
Initial managementOxygen should be administered if there is evidence of hypoxia, pulmonary oedema, or continuing myocardial ischaemia; hyperoxia should be avoided and particular care is required in patients with chronic obstructive airways disease.
The pain (and anxiety) of myocardial infarction is managed with slow intravenous injection of diamorphine ; an antiemetic such as metoclopramide (or, if left ventricular function is not compromised, cyclizine) by intravenous injection should also be given
Aspirin (chewed or dispersed in water) is given for its antiplatelet effect ; a dose of 300 mg is suitable. If aspirin is given before arrival at hospital, a note saying that it has been given should be sent with the patient. Clopidogrel, in a dose of 300 mg, should also be given
Patency of the occluded artery can be restored by percutaneous coronary intervention or by giving a thrombolytic drug , unless contra-indicated. Percutaneous coronary intervention is the preferred method and patients should receive a glycoprotein IIb/IIIa inhibitor (section 2.9) to reduce the risk of immediate vascular occlusion. In patients who cannot be offered percutaneous coronary intervention within 90 minutes of diagnosis, a thrombolytic drug should be administered. A low molecular weight heparin or fondaparinux should also be given to all patients; anticoagulant treatment should be continued for up to 8 days, or until percutaneous coronary intervention, or hospital discharge.
Nitrates are used to relieve ischaemic pain. If sublingual glyceryl trinitrate is not effective, intravenous glyceryl trinitrate or isosorbide dinitrate is given.
Early administration of some beta-blockers has been shown to be of benefit and should be given to patients without contra-indications.
ACE inhibitors , and angiotensin-II receptor antagonists if an ACE inhibitor cannot be used, are also of benefit to patients who have no contra-indications; in hypertensive and normotensive patients treatment with an ACE inhibitor, or an angiotensin-II receptor antagonist, can be started within 24 hours of the myocardial infarction and continued for at least 5–6 weeks (see below for long-term treatment).
All patients should be closely monitored for hyperglycaemia; those with diabetes or raised blood-glucose concentration should receive insulin.
Long-term management
These notes give an overview of the initial and long-term management of myocardial infarction with ST-segment elevation. For advice on the management of non-ST-segment elevation myocardial infarction and unstable angina, see section 2.6. The aims of management of ST-segment elevation myocardial infarction are to provide supportive care and pain relief, to promote reperfusion and to reduce mortality. Oxygen, diamorphine and nitrates can provide initial support and pain relief; aspirin and percutaneous coronary intervention or thrombolytics promote reperfusion; long-term use of aspirin, beta-blockers, ACE inhibitors, and statins help to reduce mortality further.
Initial managementOxygen should be administered if there is evidence of hypoxia, pulmonary oedema, or continuing myocardial ischaemia; hyperoxia should be avoided and particular care is required in patients with chronic obstructive airways disease.
The pain (and anxiety) of myocardial infarction is managed with slow intravenous injection of diamorphine ; an antiemetic such as metoclopramide (or, if left ventricular function is not compromised, cyclizine) by intravenous injection should also be given
Aspirin (chewed or dispersed in water) is given for its antiplatelet effect ; a dose of 300 mg is suitable. If aspirin is given before arrival at hospital, a note saying that it has been given should be sent with the patient. Clopidogrel, in a dose of 300 mg, should also be given
Patency of the occluded artery can be restored by percutaneous coronary intervention or by giving a thrombolytic drug , unless contra-indicated. Percutaneous coronary intervention is the preferred method and patients should receive a glycoprotein IIb/IIIa inhibitor (section 2.9) to reduce the risk of immediate vascular occlusion. In patients who cannot be offered percutaneous coronary intervention within 90 minutes of diagnosis, a thrombolytic drug should be administered. A low molecular weight heparin or fondaparinux should also be given to all patients; anticoagulant treatment should be continued for up to 8 days, or until percutaneous coronary intervention, or hospital discharge.
Nitrates are used to relieve ischaemic pain. If sublingual glyceryl trinitrate is not effective, intravenous glyceryl trinitrate or isosorbide dinitrate is given.
Early administration of some beta-blockers has been shown to be of benefit and should be given to patients without contra-indications.
ACE inhibitors , and angiotensin-II receptor antagonists if an ACE inhibitor cannot be used, are also of benefit to patients who have no contra-indications; in hypertensive and normotensive patients treatment with an ACE inhibitor, or an angiotensin-II receptor antagonist, can be started within 24 hours of the myocardial infarction and continued for at least 5–6 weeks (see below for long-term treatment).
All patients should be closely monitored for hyperglycaemia; those with diabetes or raised blood-glucose concentration should receive insulin.
Long-term management
Long-term management involves the use of several drugs which should ideally be started before the patient is discharged from hospital.
Aspirin should be given to all patients, unless contra-indicated, at a dose of 75 mg daily. The addition of clopidogrel has been shown to reduce morbidity and mortality. For those intolerant of clopidogrel, and who are at low risk of bleeding, the combination of and aspirin should be considered. In those intolerant of both aspirin and clopidogrel, warfarin alone can be used. Warfarin should be continued for those who are already being treated for another indication, such as atrial fibrillation, with the addition of aspirin if there is a low risk of bleeding. The combination of aspirin with clopidogrel or warfarin increases the risk of bleeding.
Beta-blockers should be given to all patients in whom they are not contra-indicated. Acebutolol, metoprolol, propranolol, and timolol are suitable; for patients with left ventricular dysfunction, carvedilol, bisoprolol, or long-acting metoprolol may be appropriate
Diltiazem orverapamil can be considered if a beta-blocker cannot be used; however, they are contra-indicated in those with left ventricular dysfunction. Other calcium-channel blockers have no place in routine long-term management after a myocardial infarction.
An ACE inhibitor should be considered for all patients, especially those with evidence of left ventricular dysfunction. If an ACE inhibitor cannot be used, an angiotensin-II receptor antagonist may be used for patients with heart failure. A relatively high dose of either the ACE inhibitor or angiotensin-II receptor antagonist may be required to produce benefit.
Nitrates are used for patients with angina.
Eplerenone is licensed for use following a myocardial infarction in those with left ventricular dysfunction and evidence of heart failure.
Aspirin should be given to all patients, unless contra-indicated, at a dose of 75 mg daily. The addition of clopidogrel has been shown to reduce morbidity and mortality. For those intolerant of clopidogrel, and who are at low risk of bleeding, the combination of and aspirin should be considered. In those intolerant of both aspirin and clopidogrel, warfarin alone can be used. Warfarin should be continued for those who are already being treated for another indication, such as atrial fibrillation, with the addition of aspirin if there is a low risk of bleeding. The combination of aspirin with clopidogrel or warfarin increases the risk of bleeding.
Beta-blockers should be given to all patients in whom they are not contra-indicated. Acebutolol, metoprolol, propranolol, and timolol are suitable; for patients with left ventricular dysfunction, carvedilol, bisoprolol, or long-acting metoprolol may be appropriate
Diltiazem orverapamil can be considered if a beta-blocker cannot be used; however, they are contra-indicated in those with left ventricular dysfunction. Other calcium-channel blockers have no place in routine long-term management after a myocardial infarction.
An ACE inhibitor should be considered for all patients, especially those with evidence of left ventricular dysfunction. If an ACE inhibitor cannot be used, an angiotensin-II receptor antagonist may be used for patients with heart failure. A relatively high dose of either the ACE inhibitor or angiotensin-II receptor antagonist may be required to produce benefit.
Nitrates are used for patients with angina.
Eplerenone is licensed for use following a myocardial infarction in those with left ventricular dysfunction and evidence of heart failure.
Heart failure
Drug treatment of heart failure due to left ventricular systolic dysfunction is covered below; optimal management of heart failure with preserved left ventricular function is not established.
The treatment of chronic heart failure aims to relieve symptoms, improve exercise tolerance, reduce the incidence of acute exacerbations, and reduce mortality. An ACE inhibitor, titrated to a ‘target dose’ (or the maximum tolerated dose if lower), and a beta-blocker is recommended to achieve these aims. A diuretic is also necessary in most patients to reduce symptoms of fluid overload.
An ACE inhibitor is generally advised for patients with asymptomatic left ventricular dysfunction or symptomatic heart failure. An angiotensin-II receptor antagonist may be a useful alternative for patients who, because of side-effects such as cough, cannot tolerate ACE inhibitors; a relatively high dose of the angiotensin-II receptor antagonist may be required to produce benefit.
The beta-blockers bisoprolol and carvedilol are of value in any grade of stable heart failure and left-ventricular systolic dysfunction; nebivolol is licensed for stable mild to moderate heart failure in patients over 70 years. Beta-blocker treatment should be started by those experienced in the management of heart failure, at a very low dose and titrated very slowly over a period of weeks or months. Symptoms may deteriorate initially, calling for adjustment of concomitant therapy.
Patients with fluid overload should also receive either a loop or a thiazide diuretic (with salt or fluid restriction where appropriate). A thiazide diuretic may be of benefit in patients with mild heart failure and good renal function; however, thiazide diuretics are ineffective in patients with poor renal function (estimated creatinine clearance less than 30 mL/minute, see Appendix 3) and a loop diuretic is preferred. If diuresis with a single diuretic is insufficient, a combination of a loop diuretic and a thiazide diuretic may be tried; addition of metolazone may also be considered but the resulting diuresis may be profound and care is needed to avoid potentially dangerous electrolyte disturbances.
The aldosterone antagonist spironolactone can be considered for patients with moderate to severe heart failure who are already taking an ACE inhibitor and a beta-blocker; low doses of spironolactone (usually 25 mg daily) reduce symptoms and mortality in these patients. If spironolactone cannot be used, eplerenone may be considered for the management of heart failure after an acute myocardial infarction with evidence of left ventricular dysfunction. Close monitoring of serum creatinine and potassium is necessary with any change in treatment or in the patient’s condition.
Digoxin improves symptoms of heart failure and exercise tolerance and reduces hospitalisation due to acute exacerbations but it does not reduce mortality. Digoxin is reserved for patients with atrial fibrillation and also for selected patients in sinus rhythm who remain symptomatic despite treatment with an ACE inhibitor, a beta-blocker, and a diuretic.
Patients who cannot tolerate an ACE inhibitor or an angiotensin-II receptor antagonist, or in whom they are contra-indicated, may be given isosorbide dinitrate with hydralazine but this combination may be poorly tolerated. In African-American patients, the combination of isosorbide dinitrate and hydralazine may be considered in addition to standard therapy if necessary.
The treatment of chronic heart failure aims to relieve symptoms, improve exercise tolerance, reduce the incidence of acute exacerbations, and reduce mortality. An ACE inhibitor, titrated to a ‘target dose’ (or the maximum tolerated dose if lower), and a beta-blocker is recommended to achieve these aims. A diuretic is also necessary in most patients to reduce symptoms of fluid overload.
An ACE inhibitor is generally advised for patients with asymptomatic left ventricular dysfunction or symptomatic heart failure. An angiotensin-II receptor antagonist may be a useful alternative for patients who, because of side-effects such as cough, cannot tolerate ACE inhibitors; a relatively high dose of the angiotensin-II receptor antagonist may be required to produce benefit.
The beta-blockers bisoprolol and carvedilol are of value in any grade of stable heart failure and left-ventricular systolic dysfunction; nebivolol is licensed for stable mild to moderate heart failure in patients over 70 years. Beta-blocker treatment should be started by those experienced in the management of heart failure, at a very low dose and titrated very slowly over a period of weeks or months. Symptoms may deteriorate initially, calling for adjustment of concomitant therapy.
Patients with fluid overload should also receive either a loop or a thiazide diuretic (with salt or fluid restriction where appropriate). A thiazide diuretic may be of benefit in patients with mild heart failure and good renal function; however, thiazide diuretics are ineffective in patients with poor renal function (estimated creatinine clearance less than 30 mL/minute, see Appendix 3) and a loop diuretic is preferred. If diuresis with a single diuretic is insufficient, a combination of a loop diuretic and a thiazide diuretic may be tried; addition of metolazone may also be considered but the resulting diuresis may be profound and care is needed to avoid potentially dangerous electrolyte disturbances.
The aldosterone antagonist spironolactone can be considered for patients with moderate to severe heart failure who are already taking an ACE inhibitor and a beta-blocker; low doses of spironolactone (usually 25 mg daily) reduce symptoms and mortality in these patients. If spironolactone cannot be used, eplerenone may be considered for the management of heart failure after an acute myocardial infarction with evidence of left ventricular dysfunction. Close monitoring of serum creatinine and potassium is necessary with any change in treatment or in the patient’s condition.
Digoxin improves symptoms of heart failure and exercise tolerance and reduces hospitalisation due to acute exacerbations but it does not reduce mortality. Digoxin is reserved for patients with atrial fibrillation and also for selected patients in sinus rhythm who remain symptomatic despite treatment with an ACE inhibitor, a beta-blocker, and a diuretic.
Patients who cannot tolerate an ACE inhibitor or an angiotensin-II receptor antagonist, or in whom they are contra-indicated, may be given isosorbide dinitrate with hydralazine but this combination may be poorly tolerated. In African-American patients, the combination of isosorbide dinitrate and hydralazine may be considered in addition to standard therapy if necessary.
Management of arrhythmias
Management of an arrhythmia requires precise diagnosis of the type of arrhythmia, and electrocardiography is essential; underlying causes such as heart failure require appropriate treatment. 
Ectopic beats
If ectopic beats are spontaneous and the patient has a normal heart, treatment is rarely required and reassurance to the patient will often suffice. If they are particularly troublesome, beta-blockers are sometimes effective and may be safer than other suppressant drugs.
Atrial fibrillation
Atrial fibrillation can be managed by either controlling the ventricular rate or by attempting to restore and maintain sinus rhythm.Ventricular rate can be controlled with a beta-blocker or diltiazem [unlicensed indication], or verapamil. If rate control is inadequate during normal activities, digoxin can be added; in those who require additional rate control during exercise, a combination of diltiazem or verapamil with digoxin should be used, but care is required if ventricular function is diminished. Digoxin is usually only effective for controlling ventricular rate at rest, therefore digoxin monotherapy should only be used in predominantly sedentary patients; digoxin is also used if atrial fibrillation is accompanied by congestive heart failure.
Sinus rhythm can be restored by electrical cardioversion, or pharmacological cardioversion with an intravenous anti-arrhythmic drug e.g. propafenone, flecainide, or amiodarone. If necessary, sotalol or amiodarone can be started 4 weeks before electrical cardioversion to increase success of the procedure. If drug treatment is required to maintain sinus rhythm, a beta-blocker is used. If a standard beta-blocker is not appropriate or is ineffective, an oral anti-arrhythmic drug such as sotalol flecainide, propafenone, or amiodarone, is required.
In symptomatic paroxysmal atrial fibrillation, ventricular rhythm is controlled with a beta-blocker. Alternatively, if symptoms persist or a beta-blocker is not appropriate, an oral anti-arrhythmic drug such as sotalol, flecainide, propafenone, or amiodarone can be given.
All haemodynamically unstable patients with acute-onset atrial fibrillation should undergo electrical cardioversion. Intravenous amiodarone, or alternatively flecainide, can be used in non-life-threatening cases where electrical cardioversion is delayed. If urgent ventricular rate control is required, a beta-blocker, verapamil, or amiodarone can be given intravenously.
All patients with atrial fibrillation should be assessed for their risk of stroke and the need for thromboprophylaxis. Anticoagulants are indicated for those with a history of ischaemic stroke, transient ischaemic attacks, or thromboembolic events, and those with valve disease, heart failure, or impaired left ventricular function; anticoagulants should be considered for those with cardiovascular disease, diabetes, hypertension, or thyrotoxicosis, and in the elderly. Anticoagulants are also indicated during cardioversion procedures. Aspirin is less effective than warfarin at preventing emboli, but may be appropriate if there are no other risk factors for stroke.
Atrial flutter
The ventricular rate at rest can sometimes be controlled with digoxin. Reversion to sinus rhythm (if indicated) may be achieved by cardiac pacing or appropriately synchronised d.c. shock. Alternatively, amiodarone may be used to restore sinus rhythm, and amiodarone or sotalol to maintain it. If the arrhythmia is long-standing a period of treatment with anticoagulants should be considered before cardioversion to avoid the complication of emboli.
Paroxysmal supraventricular tachycardia
In most patients this remits spontaneously or can be returned to sinus rhythm by reflex vagal stimulation with respiratory manoeuvres, prompt squatting, or pressure over one carotid sinus (important: pressure over carotid sinus should be restricted to monitored patients—it can be dangerous in recent ischaemia, digitalis toxicity, or the elderly).
If vagal stimulation fails, intravenous administration of adenosine is usually the treatment of choice. Intravenous administration of verapamil is useful for patients without myocardial or valvular disease For arrhythmias that are poorly tolerated, synchronised d.c. shock usually provides rapid relief.
In cases of paroxysmal supraventricular tachycardia with block, digitalis toxicity should be suspected. In addition to stopping administration of the cardiac glycoside and giving potassium supplements, intravenous administration of a beta-blocker may be useful. Specific digoxin antibody is available if the toxicity is considered life-threatening .
Arrhythmias after myocardial infarction
In patients with a paroxysmal tachycardia or rapid irregularity of the pulse it is best not to administer an antiarrhythmic until an ECG record has been obtained. Bradycardia, particularly if complicated by hypotension, should be treated with 500 micrograms of atropine sulphate given intravenously; the dose may be repeated every 3–5 minutes if necessary up to a maximum total dose of 3 mg. If there is a risk of asystole, or if the patient is unstable and has failed to respond to atropine, adrenaline should be given by intravenous infusion in a dose of 2–10 micrograms/minute, adjusted according to response. For further advice, refer to the most recent recommendations of the Resuscitation Council (UK) available at www.resus.org.uk.
Ventricular tachycardia
Drug treatment is used both for the treatment of ventricular tachycardia and for prophylaxis of recurrent attacks that merit suppression. Ventricular tachycardia requires treatment most commonly in the acute stage of myocardial infarction, but the likelihood of this and other life-threatening arrhythmias diminishes sharply over the first 24 hours after the attack, especially in patients without heart failure or shock. Lidocaine (lignocaine) is the preferred drug for emergency use. Other drugs are best administered under specialist supervision. Very rapid ventricular tachycardia causes profound circulatory collapse and should be treated urgently with d.c. shock.
Torsade de pointes is a form of ventricular tachycardia associated with a long QT syndrome (usually drug-induced, but other factors including hypokalaemia, severe bradycardia, and genetic predisposition are also implicated). Episodes are usually self-limiting, but are frequently recurrent and can cause impairment or loss of consciousness. If not controlled, the arrhythmia can progress to ventricular fibrillation and sometimes death. Intravenous infusion of magnesium sulphate is usually effective. A beta-blocker (but not sotalol) and atrial (or ventricular) pacing can be considered. Anti-arrhythmics can further prolong the QT interval, thus worsening the condition.
Ectopic beats
If ectopic beats are spontaneous and the patient has a normal heart, treatment is rarely required and reassurance to the patient will often suffice. If they are particularly troublesome, beta-blockers are sometimes effective and may be safer than other suppressant drugs.
Atrial fibrillation
Atrial fibrillation can be managed by either controlling the ventricular rate or by attempting to restore and maintain sinus rhythm.Ventricular rate can be controlled with a beta-blocker or diltiazem [unlicensed indication], or verapamil. If rate control is inadequate during normal activities, digoxin can be added; in those who require additional rate control during exercise, a combination of diltiazem or verapamil with digoxin should be used, but care is required if ventricular function is diminished. Digoxin is usually only effective for controlling ventricular rate at rest, therefore digoxin monotherapy should only be used in predominantly sedentary patients; digoxin is also used if atrial fibrillation is accompanied by congestive heart failure.
Sinus rhythm can be restored by electrical cardioversion, or pharmacological cardioversion with an intravenous anti-arrhythmic drug e.g. propafenone, flecainide, or amiodarone. If necessary, sotalol or amiodarone can be started 4 weeks before electrical cardioversion to increase success of the procedure. If drug treatment is required to maintain sinus rhythm, a beta-blocker is used. If a standard beta-blocker is not appropriate or is ineffective, an oral anti-arrhythmic drug such as sotalol flecainide, propafenone, or amiodarone, is required.
In symptomatic paroxysmal atrial fibrillation, ventricular rhythm is controlled with a beta-blocker. Alternatively, if symptoms persist or a beta-blocker is not appropriate, an oral anti-arrhythmic drug such as sotalol, flecainide, propafenone, or amiodarone can be given.
All haemodynamically unstable patients with acute-onset atrial fibrillation should undergo electrical cardioversion. Intravenous amiodarone, or alternatively flecainide, can be used in non-life-threatening cases where electrical cardioversion is delayed. If urgent ventricular rate control is required, a beta-blocker, verapamil, or amiodarone can be given intravenously.
All patients with atrial fibrillation should be assessed for their risk of stroke and the need for thromboprophylaxis. Anticoagulants are indicated for those with a history of ischaemic stroke, transient ischaemic attacks, or thromboembolic events, and those with valve disease, heart failure, or impaired left ventricular function; anticoagulants should be considered for those with cardiovascular disease, diabetes, hypertension, or thyrotoxicosis, and in the elderly. Anticoagulants are also indicated during cardioversion procedures. Aspirin is less effective than warfarin at preventing emboli, but may be appropriate if there are no other risk factors for stroke.
Atrial flutter
The ventricular rate at rest can sometimes be controlled with digoxin. Reversion to sinus rhythm (if indicated) may be achieved by cardiac pacing or appropriately synchronised d.c. shock. Alternatively, amiodarone may be used to restore sinus rhythm, and amiodarone or sotalol to maintain it. If the arrhythmia is long-standing a period of treatment with anticoagulants should be considered before cardioversion to avoid the complication of emboli.
Paroxysmal supraventricular tachycardia
In most patients this remits spontaneously or can be returned to sinus rhythm by reflex vagal stimulation with respiratory manoeuvres, prompt squatting, or pressure over one carotid sinus (important: pressure over carotid sinus should be restricted to monitored patients—it can be dangerous in recent ischaemia, digitalis toxicity, or the elderly).
If vagal stimulation fails, intravenous administration of adenosine is usually the treatment of choice. Intravenous administration of verapamil is useful for patients without myocardial or valvular disease For arrhythmias that are poorly tolerated, synchronised d.c. shock usually provides rapid relief.
In cases of paroxysmal supraventricular tachycardia with block, digitalis toxicity should be suspected. In addition to stopping administration of the cardiac glycoside and giving potassium supplements, intravenous administration of a beta-blocker may be useful. Specific digoxin antibody is available if the toxicity is considered life-threatening .
Arrhythmias after myocardial infarction
In patients with a paroxysmal tachycardia or rapid irregularity of the pulse it is best not to administer an antiarrhythmic until an ECG record has been obtained. Bradycardia, particularly if complicated by hypotension, should be treated with 500 micrograms of atropine sulphate given intravenously; the dose may be repeated every 3–5 minutes if necessary up to a maximum total dose of 3 mg. If there is a risk of asystole, or if the patient is unstable and has failed to respond to atropine, adrenaline should be given by intravenous infusion in a dose of 2–10 micrograms/minute, adjusted according to response. For further advice, refer to the most recent recommendations of the Resuscitation Council (UK) available at www.resus.org.uk.
Ventricular tachycardia
Drug treatment is used both for the treatment of ventricular tachycardia and for prophylaxis of recurrent attacks that merit suppression. Ventricular tachycardia requires treatment most commonly in the acute stage of myocardial infarction, but the likelihood of this and other life-threatening arrhythmias diminishes sharply over the first 24 hours after the attack, especially in patients without heart failure or shock. Lidocaine (lignocaine) is the preferred drug for emergency use. Other drugs are best administered under specialist supervision. Very rapid ventricular tachycardia causes profound circulatory collapse and should be treated urgently with d.c. shock.
Torsade de pointes is a form of ventricular tachycardia associated with a long QT syndrome (usually drug-induced, but other factors including hypokalaemia, severe bradycardia, and genetic predisposition are also implicated). Episodes are usually self-limiting, but are frequently recurrent and can cause impairment or loss of consciousness. If not controlled, the arrhythmia can progress to ventricular fibrillation and sometimes death. Intravenous infusion of magnesium sulphate is usually effective. A beta-blocker (but not sotalol) and atrial (or ventricular) pacing can be considered. Anti-arrhythmics can further prolong the QT interval, thus worsening the condition.
Management of acute severe asthma
Acute severe asthma can be fatal and must be treated promptly and energetically. All patients with acute severe asthma should be given high-flow oxygen (if available) and an inhaled short-acting beta2 agonist via a large-volume spacer or nebuliser; give 4–10 puffs of salbutamol 100 micrograms/metered inhalation, each puff inhaled separately via a large-volume spacer, and repeat at 10–20 minute intervals if necessary. If there are life-threatening features, give salbutamol or terbutaline via an oxygen-driven nebuliser every 15–30 minutes. In all cases, a systemic should be given. For adults, give prednisolone 40–50 mg by mouth for at least 5 days, or intravenous hydrocortisone 100 mg (preferably as sodium succinate) every 6 hours until conversion to oral prednisolone is possible. For children, give prednisolone 1–2 mg/kg by mouth (max. 40 mg) for 3–5 days or intravenous hydrocortisone (under 1 year 25 mg, 1–5 years 50 mg, 6–12 years 100 mg) (preferably as sodium succinate) every 6 hours until conversion to oral prednisolone is possible. If the child has been taking an oral corticosteroid for more than a few days, then give prednisolone 2 mg/kg (CHILD under 2 years max. 40 mg, over 2 years max. 50 mg). In life-threatening asthma, also consider initial treatment with ipratropium by nebuliser
Most patients do not require and do not benefit from the addition of intravenous aminophylline or of intravenous beta2 agonist; both cause more adverse effects than nebulised beta2 agonists. Nevertheless, an occasional patient who has not been taking theophylline may benefit from aminophylline infusion. Patients with severe asthma may be helped by magnesium sulphate [unlicensed indication] 1.2–2 g given by intravenous infusion over 20 minutes, but evidence of benefit is limited.
Treatment of acute severe asthma is safer in hospital where resuscitation facilities are immediately available. Treatment should never be delayed for investigations, patients should never be sedated, and the possibility of a pneumothorax should be considered.
If the patient’s condition deteriorates despite pharmacological treatment, intermittent positive pressure ventilation may be needed.
Most patients do not require and do not benefit from the addition of intravenous aminophylline or of intravenous beta2 agonist; both cause more adverse effects than nebulised beta2 agonists. Nevertheless, an occasional patient who has not been taking theophylline may benefit from aminophylline infusion. Patients with severe asthma may be helped by magnesium sulphate [unlicensed indication] 1.2–2 g given by intravenous infusion over 20 minutes, but evidence of benefit is limited.Treatment of acute severe asthma is safer in hospital where resuscitation facilities are immediately available. Treatment should never be delayed for investigations, patients should never be sedated, and the possibility of a pneumothorax should be considered.
If the patient’s condition deteriorates despite pharmacological treatment, intermittent positive pressure ventilation may be needed.
Dyspepsia
Dyspepsia covers pain, fullness, early satiety, bloating, and nausea. It can occur with gastric and duodenal ulceration and gastric cancer but most commonly it is of uncertain origin.
Urgent endoscopic investigation is required if dyspepsia is accompanied by ‘alarm features’ (e.g. bleeding, dysphagia, recurrent vomiting, or weight loss). Urgent investigation should also be considered for patients over 55 years with unexplained dyspepsia that has not responded to treatment.
Patients with dyspepsia should be advised about lifestyle changes (see Gastro-oesophageal reflux disease, below). Some medications may cause dyspepsia—these should be stopped, if possible. Antacids may provide some symptomatic relief.
If H. pylori is present in patients with functional (investigated, non-ulcer) dyspepsia, eradication therapy should be provided. However, most patients with functional dyspepsia do not benefit symptomatically from H. pylori eradication. If symptoms persist, treatment with either a proton pump inhibitor or a histamine H2-receptor antagonist can be given for 4 weeks. These antisecretory drugs can be used intermittently to control symptoms long-term.
Thursday, October 8, 2009
Pharmaceutics
Pharmaceutics is the discipline of pharmacy that deals with all facets of the process of turning a new chemical entity (NCE) into a medication able to be safely and effectively used by patients in the community. Pharmaceutics is the science of dosage form design. There are many chemicals with known pharmacological properties but a raw chemical is of no use to a patient. Pharmaceutics deals with the formulation of a pure drug substance into a dosage form. Branches of pharmaceutics include:
Pharmacokinetics
Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds ingested or otherwise delivered externally to an organism, such as nutrients, metabolites, hormones, toxins, etc.
Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites of the drug
Pharmacodynamics
Pharmacodynamics is the study of the physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect.One dominant example is drug-receptor interactions as modeled by L=ligand (drug), R=receptor (attachment site), reaction dynamics that can be studied mathematically through tools such as free energy maps. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug. Pharmacodynamics is sometimes abbreviated as "PD", and when referred to in conjunction with pharmacokinetics can be referred to as "PKPD".
Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.
Pharmacokinetics
Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds ingested or otherwise delivered externally to an organism, such as nutrients, metabolites, hormones, toxins, etc.
Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the body does to the drug. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites of the drug
Pharmacodynamics
Pharmacodynamics is the study of the physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect.One dominant example is drug-receptor interactions as modeled by L=ligand (drug), R=receptor (attachment site), reaction dynamics that can be studied mathematically through tools such as free energy maps. Pharmacodynamics is often summarized as the study of what a drug does to the body, whereas pharmacokinetics is the study of what the body does to a drug. Pharmacodynamics is sometimes abbreviated as "PD", and when referred to in conjunction with pharmacokinetics can be referred to as "PKPD".
Pharmacogenomics
Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimise drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects. Such approaches promise the advent of "personalized medicine"; in which drugs and drug combinations are optimized for each individual's unique genetic makeup.Pharmacogenomics is the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs.
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