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High-frequency color Doppler ultrasound images of gastrocnemius hematoma induced by oral anticoagulant use buy 45mg midamor hypertension 150 100. A: One day after symptom occurrence 45mg midamor mastercard prehypertension chest pain, hypoechoic lesions with irregular anechoic regions are visible purchase 45mg midamor visa blood pressure medication range. B: Six days after symptom occurrence order midamor 45mg line blood pressure 5640, soft tissues exhibit a spindle shape with irregular hypoechoic signals. The surrounding muscle was extruded, and an enhanced hyperechoic signal was observed between the muscle and hematoma. Differential diagnosis of isolated calf muscle vein thrombosis and gastrocnemius hematoma by high-frequency ultrasound. A high index of suspicion for the insidious onset of lower extremity compartment syndrome or deep venous thrombosis is important to avoid disaster. The articular surfaces are covered with hyaline cartilage, which are susceptible to arthritis. The joint is completely surrounded by a dense capsule that provides support to the joint. The majority of strength to the ankle joint is provided by the major ligaments which include the deltoid, anterior talofibular, calcaneofibular, and posterior talofibular ligaments (Fig. The joint capsule is lined with a synovial membrane that attaches to the articular cartilage and may give rise to bursae. In addition to arthritis, the joint is susceptible to the development of tendinitis, bursitis, fractures, and disruption of the ligaments, cartilage, and tendons. The ankle joint is completely surrounded by a dense capsule that provides support to the joint. Most of the strength of the ankle joint is provided by the deltoid, anterior talofibular, calcaneofibular, and posterior talofibular ligaments. Osteoarthritis of the joint is the most common form of arthritis that results in ankle joint pain and functional disability, with rheumatoid arthritis and posttraumatic arthritis also causing arthritis of the ankle joint. The ankle joint is the most commonly injured joint in the human body, with sports injuries from basketball, football, tennis, and cross country running being frequent causes of pain and functional disability. Less common causes of arthritis-induced ankle joint pain include the collagen vascular diseases, infection, villonodular synovitis, and Lyme disease (Fig. Acute infectious arthritis of the ankle joint is best treated with early diagnosis, with culture and sensitivity of the synovial fluid, and prompt initiation of antibiotic therapy. The collagen vascular diseases generally manifest as a polyarthropathy rather than a monoarthropathy limited to the ankle joint, although ankle pain secondary to the collagen vascular diseases responds exceedingly well to ultrasound-guided intra-articular injection of the ankle joint. Activity, especially involving dorsiflexion of the ankle joint makes the pain worse, with rest and heat providing some relief. Sleep disturbance is common with awakening when the patient rolls over onto the affected ankle. Some patients complain of a grating, catching, or popping sensation with range of motion of the joint, and crepitus may be appreciated on physical examination. Functional disability often accompanies the pain associated with many pathologic conditions of the ankle joint. Patients will often notice increasing difficulty in performing their activities of daily living and tasks that require walking, climbing stairs, and walking on uneven surfaces are particularly problematic. If the pathologic process responsible for the patient’s pain symptomatology is not adequately treated, the patient’s functional disability may worsen and muscle wasting may occur. Plain radiographs are indicated in all patients who present with ankle pain as not only intrinsic ankle disease as well as other regional pathology may be perceived as ankle pain by the patient (Fig. Based on the patient’s clinical presentation, additional testing may be indicated, including complete blood cell count, sedimentation rate, and antinuclear antibody testing. Sagittal T1-weighted magnetic resonance image showing lumpy synovial thickening of very low signal intensity due to hemosiderin. A high- frequency linear ultrasound transducer is placed in the longitudinal plane over the anterior aspect of the ankle joint (Fig. An ultrasound survey scan is obtained which demonstrates the V-shaped anterior tibiotalar joint (Fig. After the joint space is identified, color Doppler imaging is used to identify major vessels including the dorsalis pedis artery which frequently runs over the superior aspect of the joint (Fig. Correct longitudinal position for ultrasound transducer for ultrasound evaluation of the ankle joint. Longitudinal ultrasound image of the ankle joint demonstrating characteristic V shape of the joint. Longitudinal color Doppler image demonstrating the dorsalis pedis artery overlying the tibiotalar joint. After the joint space and major vessels are identified, the joint is evaluated for the presence of arthritis, synovitis, effusion, crystal deposition, and abnormal masses including ganglion cysts (Figs. If there is history of trauma, the adjacent bone is imaged to identify periosteal defect and bleeding (Figs. There is a moderate ankle joint effusion (asterisk) displacing the anterior fat pad. Longitudinal ultrasound anterolateral aspect of ankle showing quite severe osteoarthrosis with joint space narrowing, marginal osteophytosis (arrows), together with moderate capsular thickening (arrowheads). Longitudinal ultrasound image of the lateral ankle demonstrating significant osteoarthritis of the ankle joint. Longitudinal ultrasound image of the ankle demonstrating findings consistent with osteoarthritis. Note the difference between the healthy ankle (A) and the contralateral ankle showing an acute hemarthrosis (B). The role of ultrasonography in the diagnosis of the musculoskeletal problems of haemophilia. A: Transverse ultrasound image demonstrating crustal arthropathy of the ankle joint. Case number 26: massive cholesterol crystal deposition: unusual location in rheumatoid arthritis. Longitudinal ultrasound image demonstrating avascular necrosis involving the tibiotalar joint. A: Ultrasound image in the sagittal plane over the dorsal ankle shows hypoechoic distention of the anterior ankle joint recess (arrows). Ultrasound-assisted triage of ankle trauma can decrease the need for radiographic imaging. Ultrasound-assisted triage of ankle trauma can decrease the need for radiographic imaging. Ultrasound-assisted triage of ankle trauma can decrease the need for radiographic imaging. Transverse ultrasound image of the anterior talofibular ligament demonstrating an avulsion fracture of the talus. Transverse ultrasound image demonstrating a displaced avulsion fracture of the talus in a patient with a severe sprain of the anterior talofibular ligament. Ultrasound guidance is useful for needle placement for both injection and joint aspiration if careful attention is paid to the regional anatomy (Fig. Intra-articular corticosteroid injections in the foot and ankle: a prospective 1-year follow-up investigation.
For example buy discount midamor 45mg line heart attack 18 year old male, lamotrigine is ofen referred to as inent fuctuations in plasma drug concentrations and increased a selective blocker of voltage-dependent sodium channels purchase 45mg midamor overnight delivery prehypertension need medication, but it has risk of adverse efects at the time of peak discount midamor 45mg fast delivery hypertension 3rd trimester, or seizure breakthrough also been found to inhibit N-type buy cheap midamor 45mg blood pressure 3rd trimester, L-type and P-type calcium chan- at the time of trough. How antiepileptic drugs, a situation that restricts treatment choices in each of these actions could account for therapeutic and adverse ef- the younger age groups. For certain drugs, modifed-release products are available, which While these limitations should be understood, there are situa- allow less frequent dosing, with benefcial efects on convenience tions in which knowledge of modes of action needs to be considered and compliance. In a patient who has shown a paradoxical and tolerability by minimizing fuctuations in plasma drug levels aggravation of seizures on carbamazepine, for example, it would be during the dosing interval [63]. Likewise, as discussed in greater detail in As discussed in Chapter 9, drugs such as phenytoin, levetiracetam Chapter 9, it has been suggested that in patients with refractory sei- and gabapentin can be up-titrated relatively rapidly to the fully ef- zures requiring multiple drug therapy, combinations of drugs pos- cacious dose range, while others, particularly primidone, lamotrigi- sessing diferent modes of action should produce better responses ne, lacosamide, topiramate, zonisamide, perampanel and tiagabine, than combinations of drugs acting through a similar mechanism. In time, research on the relationship between specifc modes of Tere are also advantages in preferring drugs for which dose action and clinical response in well-defned epilepsy syndromes individualization is comparatively easy. Adjusting the dose of could yield important clues for rational treatment; for example, it phenytoin, in particular, can be difcult due to Michaelis–Ment- might be possible in the future to determine which drug produces en pharmacokinetics and large inter-patient variability in dose re- the best response in a patient whose epilepsy is caused by a specifc quirements. Some drugs require special monitoring procedures to ensure optimal When the cost of medication is not a major constraint, drug se- efcacy and to minimize the risk of adverse efects. For example, in- lection should be based primarily on the expected beneft to risk dividualizing phenytoin dosage can be difcult without measuring its balance in the individual patient. When this is taken into account, plasma concentration [65], which may argue against the preferential the increasing use of newer drugs in the last decade may be justifed use of this drug in settings where a therapeutic drug monitoring service by the improved tolerability profle and the lower interaction po- is unavailable. Likewise, therapy with felbamate requires repeated blood tential which characterize some of these agents. However, evidence chemistry and haematology tests, so this drug should not be prescribed concerning merits and demerits of individual medications should if compliance with safety monitoring tests cannot be guaranteed. In some randomized trials that compared newer with older generation drugs, results may have been biased Cost of treatment by specifcities in the study design which discriminated against the Over 40% of the world’s population live in countries where the per older drugs [68]. For example, when carbamazepine was used as capita annual gross national product barely sufces to buy a year’s comparator, its target dosage was sometimes higher than necessary, supply of carbamazepine or valproic acid for one or two patients. When assessing risks associated with determining whether drug treatment is afordable at all. This prob- specifc medications, it should also be remembered that the latency lem is aggravated by the fact that in many low-income countries the between the introduction of a drug in the market and the discovery price of antiepileptic drugs is considerably higher than in the indus- of potentially important adverse efects can be long. For most patients in developing countries, only since marketing to identify the hepatic toxicity of valproic acid, and phenobarbital is available at prices afordable by the general popu- 8 years to discover vigabatrin-induced visual feld loss [70]. Cost is an important issue also for afuent societies, particu- Approved versus off-label use larly in view of the fact that recently licensed drugs are far more As a general rule, medications should be used according to indi- expensive than older agents. The approval of a spe- medication costs by health services or insurance schemes is only cifc indication is dependent on submission of adequate efcacy applicable to specifc drugs (or formulations), specifc indications and safety data to regulatory agencies. The cost of many an- seizure disorders, however, certain seizure types or syndromes are tiepileptic medications has decreased in recent years because of the rarely investigated in regulatory trials. Advantages and concerns with leptic drugs are not formally approved for some indications or for the use of these products are discussed in Chapter 9. The situation is further complicated by the fact that regulato- Not all antiepileptic drugs are equally easy to use, a consideration ry standards for approval have changed over the years, resulting in that impacts on drug selection. Ease of use encompasses many discrepancies in the quality of supportive evidence between older properties discussed in this chapter: in particular, a broad efcacy and newer generation drugs. Other concerns relate to the appropriateness of dose titra- simple schemes for dose titration and individualization contribute tion schemes and dosing schedules approved by regulatory author- positively to ease of use (Table 27. Tese reproduce dosing procedures in regulatory trials and do not necessarily refect optimal dosing schemes, which are mostly established during post-marketing experience [64]. In view of the above considerations, of-label prescribing is jus- tifable in selected situations, and in many countries there is a legal Broad spectrum of effcacy against all seizure types framework for this. A recent Fast and easy dose escalation rate study from Italy which enrolled 1124 consecutive patients with No tolerance to antiepileptic effects pharmacoresistant epilepsy found that 53% of children and 31% of No withdrawal seizures adults were receiving at least one of-label antiepileptic drug pre- No need for intensive laboratory monitoring scription [73]. Of-label use was especially prevalent in children and in patients with generalized epilepsy syndromes, for which few Availability of convenient formulations (including paediatric drugs are formally approved. Physicians prescribing of-label, how- dosage forms and a parenteral formulation) ever, should be aware of legal liability issues, and must ensure that Low cost their decisions are backed by the best medical evidence available. In Introduction to the Choice of Antiepileptic Drugs 371 some countries, the cost of drugs prescribed of-label is not reim- steroids in controlling spasms not associated with tuberous sclero- bursed by the national health system or insurance organizations, a sis, however, may be limited to the initial weeks of treatment, even situation that can impact on drug selection. Importance of patient-related factors Considerable eforts in current epilepsy research are being ded- As rational prescribing requires fnding the best match between the icated to the development of new treatments that modify the un- properties of a drug and the characteristics of the patient, careful derlying disease by targeting specifc causes and mechanisms. Pre- assessment of individual features has a crucial role in drug selec- liminary data suggest that therapeutic response to immunotherapy tion. Some of these characteristics relate to demographics, others in patients with epilepsies presumed to be immune-mediated vary to psychosocial aspects, and others to the type and severity of epi- according to the specifc immunological abnormality involved [82]. In considering the Another example of a pharmacological intervention directed at the importance of these factors, the patient’s informed opinion should underlying aetiology is represented by inhibitors of the mammalian be taken into consideration. As discussed earlier in this chapter, antiepileptic drugs difer in their spectrum of efcacy against diferent seizure types. Whenever a diagnosis and for prognosis, and they therefore have an indirect in- diagnosis of epilepsy is established but the precise type of seizures or fuence on the process leading to drug selection. Information on aetiology is also important to establish the epilepsy syndrome, and to formulate a prognosis. In a hospital- Genotypes based observational survey of 2200 individuals, 1-year remission Variation in genes controlling drug-metabolizing enzymes and/or rates on drug therapy were 82% in patients with genetic (idiopathic) the expression of voltage-gated sodium channels has been reported generalized epilepsy, 45% in those with focal epilepsy of unknown to infuence dosing requirements for phenytoin and carbamazepine (cryptogenic) aetiology, 35% in those with structural-metabol- [84,85]. Although a number of gene variants potentially responsible ic (symptomatic) focal epilepsy and only 11% in those with focal for infuencing response to certain antiepileptic drugs have been epilepsy associated with hippocampal sclerosis [74]. Patients with identifed [85], at present no genetic test is available to predict re- hippocampal sclerosis and another lesion had only a 3% probability liably which drug will prove the most efcacious in an individual of achieving seizure freedom. With expanding pharmacogenomic knowledge, however, poral lobe epilepsy responded more poorly to treatment than those this situation may well change in the future. Information on aetiology is also important The mechanisms responsible for many adverse drug reactions are for early identifcation of candidates for epilepsy surgery. For antiepileptic drugs, the most no- little value in predicting which specifc treatment will produce the table example is the determination of the human leucocyte antigen best clinical response. In individuals from these gy defciency and is clearly indicated as the treatment of choice [75]. Certain epilepsies as- with this genotype unless the expected benefts clearly outweigh the sociated with inborn errors of metabolism may also contraindicate risks. Choice mazepine in patients carrying this allele has been found to be efec- of drugs based on identifcation of the underlying aetiology is likely tive in drastically reducing the incidence of carbamazepine-induced to increase in the future, as our understanding of the pathophysiol- serious skin rashes in Taiwan [88]. In the same subjects, it is advisable ogy of the epilepsies and mechanisms of drug action progressively to avoid other antiepileptic drugs potentially associated with serious improves. The range of the risk of developing severe cutaneous reactions from phenytoin was gender-related efects, however, is broader in females. Criteria for drug selection in women of child- ably because of the very low frequency of the allele in people from bearing potential are discussed in Chapter 23. However, in Caucasians, the probability of that gender-related drug efects may extend beyond the endocrine developing carbamazepine-induced skin rashes of any type can be and the reproductive systems. For example, the risk of valproic acid-induced liver tox- this is likely to be an area for fruitful research. A recent report sug- icity is greatly increased in patients with some inborn metabolic gested that genetic variants associated with decreased dopaminer- disorders, such as urea cycle defects, and valproic acid should not gic activity may be a risk factor for developing psychiatric adverse be used in these individuals [99].
Palpate for tendon ruptures (start your palpation on the ulnar side of the hands) 45mg midamor sale blood pressure chart heart rate. Ask the patient to perform the following movements: Grip and squeeze two of your fingers and perform a fine pinch buy midamor 45mg cheap can blood pressure medication cause jaw pain. Place their hands in a ‘pray position’ to demonstrate wrist dorsiflexion (Figure 7 purchase 45mg midamor mastercard blood pressure medication and gout. Place their hands in a ‘reverse pray position’ to demonstrate wrist flexion (Figure 7 buy discount midamor 45 mg online blood pressure medication that starts with m. Special tests Functional assessment: Power grip Pincer grip (pick up a coin or key) Button and unbutton shirt Hold a pen and write Neurological assessment (Sensation): Radial nerve (dorsum of first interosseous webspace) Median nerve (palmar/volar aspect of index finger) Ulnar nerves (palmar/volar aspect of little finger) Table top test: Ask the patient to place their hands flat on a table. Extra-articular manifestations of rheumatoid disease: Systemic – Weight loss, fever, malaise, vasculitis and amyloidosis Skin – Subcutaneous (rheumatoid) nodules Eyes – Keratoconjunctivitis sicca, scleritis, episcleritis Cardiovascular – Pericardial effusion, pericarditis, myocarditis Respiratory – Pleurisy, pleural effusion, nodules and fibrosing alveolitis Neurological – Entrapment neuropathy (carpal tunnel syndrome), atlantoaxial instability and multifocal neuropathies Abdominal – Splenomegaly, Felty’s syndrome Haematological – Anaemia, leucopenia and lymphadenopathy Muscular-Skeletal – Knees (valgus/varus deformity, popliteal ‘Baker’s’ cysts), scars for shoulder, knee or hip replacements Complete the hand examination Perform a full neurological assessment of the upper limbs. Assess for extra-articular manifestations of rheumatoid disease (eyes, respiratory, cardiovascular, neurological systems). The examination of the spine follows the same logical pattern as examination of any other joint. This includes Look Feel Move Special tests Look General Look around bed for walking aids and supports (Miami J collar, thoracolumbar brace). Specific Whilst the patient is standing, inspect Skin – Scars, sinuses, hairy tufts, café au lait spots Soft tissues – Muscle wasting Bone – Scoliosis, kyphosis, lumbar lordosis, gibbus Feel Ask the patient whether they are in pain before you begin. Palpate and percuss over the entire spine for any bony or muscle tenderness and assess for step deformities. Ask the patient to tilt their head to the right and left towards their ear (lateral flexion 45° each direction). Lateral flexion – Ask the patient to slide their hand down one side of the body (30°). Rotation – Ask the patient to sit down, cross their hands across their body and rotate their body (40°). Special tests Cervical spine Lhermitte’s sign (the barber-chair phenomenon) is demonstrated when you ask the patient to bend their cervical neck forward. The presence of a shooting pain down the arm may indicate cervical root compression. Lumbar spine Straight leg raise and sciatic nerve test (Lasègue’s straight leg test; Figure 7. With the patient’s knees extended, raise the patient’s leg whilst supporting the patient’s heel. At this limit, gently dorsiflex the ankle, which will apply further tension on the nerve root (Bragard’s sign). Complete the spine examination Perform a full neurological assessment of the upper and lower limbs. Perform an abdominal examination (to exclude an abdominal aortic aneurysm) and assess anal tone by performing a digital rectal examination. Set the agenda Begin with open-ended questions to ascertain the patient’s perspective. Pathological diagnosis Personal information Name, age, gender, handedness, occupation and ethnic origin. Presenting complaint (in the patient’s own words) History of presenting complaint Chronological order of the symptoms – Time course, onset, duration, frequency, progression, location, quality, quantity, severity, aggravating and relieving factors and associated symptoms. Social history Marital status Occupation and exposures Smoking history (number of pack-years) Alcohol intake (units/week) Recreational drug use Living accommodation Level of support (family and carers) Recent travel history System review During your targeted history taking, ask only the relevant questions based on the patient’s history. General/constitutional Skin/breast Eyes/ears/nose/mouth/throat Cardiovascular Respiratory Gastrointestinal Genitourinary Musculoskeletal Psychiatrical Immunologic/lymphatic/endocrine Thank the patient. Specific Inspection for involuntary movements (tremor, fasciculation, choreiform). Assess direct and consensual reflex in each eye in turn with the use of a pen torch. Test accommodation by asking the patient to look into the distance and then focus on an object close to their face. Demonstrate the ‘red reflex’ by shining the light in each pupil and then examine each fundi, optic discs and macula. Ask the patient to follow your finger up and down, right (up and down) and then left (up and down). If present, ask the patient to close each eye in turn to identify the side of the false image. Assess convergence by asking the patient to focus on your finer as it is brought in from a distance towards the tip of their nose. Sensory function: Assess sensation (fine touch, temperature) in the three divisions (ophthalmic, maxillary, mandibular) and compare both sides of the face. Jaw jerk: Place your finger in the midline over the tip of the patient’s mandible, with the patient’s mouth slightly open. Ask the patient to raise their eyebrows, wrinkle forehead (frown), close their eyes, smile, show their teeth, blow out their cheeks and pucker their lips. Sensory function (taste): Test the anterior two-thirds of each side of the patient’s tongue (using sweet/salt, bitter/or sour). Perform Weber’s test (lateralizing sign) in each ear by placing a vibrating turning fork over the middle of the patient’s forehead. A normal response to cold water irrigation is for the patient to develop nystagmus towards the contralateral side. A normal response to warm water irrigation is for the patient to develop nystagmus towards the ipsilateral side. Assess tactile sensation of the tonsil, palate and upper pharynx with a tongue depressor. Assess strength on lateral deviation by asking the patient to move their tongue from side to side and then assess bulk and contraction strength. Visual fields – Stand 2 feet in front of the patient and ensure you are at eye level. Move your hands to side half way between yourself and the patient, wiggle fingers, ask the patient when they see movement. Pupil reaction – To light reaction (direct, consensual and swinging light test) and accommodation. In addition, ask the patient to frown, show their teeth and puff out their cheeks. Rub your fingers to create noise on one side and keep the other hand still, then switch hands. If hearing loss is identified, inspect the external auditory canals and the tympanic membranes. Then move the tuning fork neck to the patient’s ear canal so they can hear the sound. A normal response is that air conduction (ear) is better heard than bone conduction (mastoid). Weber’s test (lateralization) Apply tuning fork (256 Hz) to the top of patient’s head on middle of forehead. Turn the patient’s head against resistance, inspect and palpate the sternocleidomastoid muscle.
New avenues for anti-epileptic confrmatory add-on phase 3 studies at a later stage generic 45 mg midamor otc blood pressure monitor walmart, which would involve drug discovery and development 45 mg midamor with amex arrhythmia in fetus. Efects of marketed antiepileptic drugs and placebo in the human photosensitivity screening protocol cheap midamor 45 mg overnight delivery arteria subscapularis. How predictive are photosensitive epilepsy models as proof of This chapter focuses on the development of an investigational principle trials for epilepsy? In addition midamor 45 mg lowest price arrhythmia caffeine, the development of new treatment areas for size and duration-a case study. Placebo-controlled study of levetiracetam in idiopathic Acknowledgements generalized epilepsy. Natural history of treated childhood-onset epilepsy: pro- sy in patients given adjunctive antiepileptic treatment for refractory seizures: a spective, long-term population-based study. Modern antiepileptic drug development has failed to deliv- tic drugs in the 21st century: obstacles and solutions. Efcacy and leptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia safety of pregabalin versus lamotrigine in patients with newly diagnosed partial 2010; 51: 7–26. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: ini- 37. Codevelopment of Two or More New Investigational Drugs tial monotherapy outcomes at 12 months. Child Neurology Society; American Acade- Gabapentin versus vigabatrin as frst add-on for patients with partial seizures that my of Neurology. Evidence-based guideline update: medical treatment of infantile failed to respond to monotherapy: a randomized, double-blind, dose titration spasms. Epilepsia 2000; 41: Academy of Neurology and the Practice Committee of the Child Neurology 1289–1295. Stiripentol: in severe myoclonic epilepsy of infancy (Dravet syn- antiepileptic drugs in randomized controlled trials: a systematic review and me- drome). Placebo responses in rand- of death among children with Lennox–Gastaut syndrome and infantile spasms. Prevention of generalized tonic–clonic seizures in alin versus levetiracetam as adjunctive therapy in patients with partial seizures: a refractory focal epilepsy: a meta-analysis. What clinical trial designs have been used to test antiepileptic drugs (Subcommission on Mortality). Do preclinical seizure models preselect certain adverse efects of an- monotherapy designs. Anti-epileptogenic clinical trial designs in double-blind, randomised, multicentre, historical control study. Conversion to monotherapy with eslicarbazepine peutic intervention to suppress epileptogenesis. Antiepileptic drugs have been devel- Main action Only at high concentrations oped either through serendipity, such as the fortuitous discov- Carbamazepine Phenobarbital ery of the antiepileptic effects of bromides and phenobarbital, or Eslicarbazepine Benzodiazepines through screening in animal epilepsy models. Indeed, the recent Lacosamide growth in antiepileptic drug development has been due to ex- Lamotrigine tensive screening of over 25 000 compounds in animal epilepsy Oxcarbazepine models. Designing antiepileptic drugs with specific mechanisms Phenytoin of action is a recent approach that has not to date been particu- larly fruitful, first, because some drugs have been found not to Importance unknown have the mechanism which was predicted (e. Many antiepileptic drugs have multi- Zonisamide ple potential targets, and it is often not possible to discern which are the most relevant. Moreover, the network/cellular effects can be complex, even when an antiepileptic drug has one target (e. Rather than describe the possible mechanisms underlying each critical for action potential generation and propagation [1]. The antiepileptic drug in turn (this is covered in individual chap- sodium channel exists in three principal states: (i) at hyperpo- ters), we here describe the more important targets of antiepileptic larized potentials the channel is in the resting closed state; (ii) drugs, and which drugs afect those targets. This inactivation is removed More recently, drugs have been designed to target α-amino-3-hy- by hyperpolarization (Figure 6. Lastly, there over a matter of seconds, and so this state determines sodium is growing evidence that some antiepileptic drugs may target in- channel availability. Depolarization predominantly results in a tracellular metabolic pathways, which could have multiple efects transient inward sodium current that rapidly inactivates. The sodium channel consists of a 260-kDa α-subunit that forms Main targets the sodium-selective pore (Figure 6. Passage of ions through voltage-gated for the voltage-dependent activation, as these are highly charged. Na channel Na channel the channels become inactive at less negative membrane potentials) Open Closed and, second, to delay the return of the channel to the resting, closed Depolarized conformation following hyperpolarization. Phenytoin, lamotrigine, oxcarbazepine and carbamazepine have a similar mode of action Active Inactive Active [2]. All bind in the inner pore of the sodium channel, and their Na channel Na channel Na channel binding is mutually exclusive, suggesting binding to identical or Closed Closed Closed common amino acids [2]. However, there may be diferences in the Hyperpolarized fashion in which drugs interact with adjacent amino acids which Figure 6. The channel then inactivates, and hyperpolarization is necessary for reactivation of the channel. Tere is also of antiepileptic drug interactions with the sodium channel difer, so a slow inactivated state, which results from conformational change (see that, for example, carbamazepine binds less potently, but faster, than text). The conventional view has been that such binding prevents sustained repetitive fring [5]. In contrast, slow inacti- is critically determined by the rate at which the sodium channels vation results from a conformational change. If this time is delayed, two auxiliary β-subunits (β1 and β2) that infuence the kinetics and then the ‘refractory period’ is prolonged. Tere are at least 10 diferent so- carbamazepine, oxcarbazepine and lamotrigine, for example, could dium channel isoforms (Nav1. Tese isoforms have some functional channels that have entered this state, the greater the drug binding. In addition, the so- This results in a ‘use-dependent’ phenomenon in which repetitive dium channel can be modulated by protein phosphorylation, which fring results in greater amounts of the drug bound and so greater afects the peak sodium current, and the speed and voltage depend- inhibition. As these drugs have a slow rate of binding to the sodium ence of channel inactivation [1]. Mechanisms of Antiepileptic Drug Action 77 Control Phenytoin Peak Late channel sodium openings 5 pA 5 pA current 200 ms 200 ms –30 –30 –100 –100 Figure 6. Sodium channels open with depolarization (peak current), followed by late channel openings. Phenytoin reduces the initial peak current, but more impressively reduces the late channel openings.
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