CNS Lecture - Drugs Affecting the Central Nervous System PDF

Pharmacology Lec. 5 College of dentistry Dr Maha Mohsin Khalaf University of Baghdad Drugs affecting the central nervous system An...

Pharmacology Lec. 5 College of dentistry Dr Maha Mohsin Khalaf University of Baghdad Drugs affecting the central nervous system Anxiolytic and hypnotic drugs Disorders involving anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment. However, severe, chronic, debilitating anxiety may be treated with antianxiety drugs (sometimes called anxiolytics) and/or some form of psychotherapy. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep inducing) agents. Some antidepressants are also indicated for certain anxiety disorders. Benzodiazepines Benzodiazepines are widely used anxiolytic drugs. They have largely replaced barbiturates and meprobamate in the treatment of anxiety and insomnia, because benzodiazepines are generally considered to be safer and more effective. Though benzodiazepines are commonly used, they are not necessarily the best choice for anxiety or insomnia. Certain antidepressants with anxiolytic action, such as the selective serotonin reuptake inhibitors, are preferred in many cases, and non-benzodiazepine hypnotics and antihistamines may be preferable for insomnia. Mechanism of action: The targets for benzodiazepine actions are the γ-aminobutyric acid (GABA A) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).] The GABAA receptors are composed of a combination of five α, β, and γ subunits that span the postsynaptic membrane. Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore. The influx of chloride ions causes hyperpolarization of the neuron and decreases neurotransmission by inhibiting the formation of action potentials. Benzodiazepines modulate GABA effects by binding to a specific, high-affinity site (distinct from the GABA-binding site) located at the interface of the α subunit and the γ subunit on the GABAA receptor. [Note: These binding sites are sometimes labeled “benzodiazepine (BZ) receptors.” Common BZ receptor subtypes in the CNS are designated as BZ1 or BZ2 depending on whether the binding site includes an α1 or α2 subunit, respectively.] Benzodiazepines increase the frequency of channel openings produced by GABA. [Note: Binding of a benzodiazepine to its receptor site increases the affinity of GABA for the GABA-binding site (and vice versa).] The clinical effects of the various benzodiazepines correlate well with the binding affinity of each drug for the GABA receptor–chloride ion channel complex. Actions: All benzodiazepines exhibit the following actions to some extent: 1. Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α2 subunit in their GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain. 1 2. Sedative/hypnotic: All benzodiazepines have sedative and calming properties, and some can produce hypnosis (artificially produced sleep) at higher doses. The hypnotic effects are mediated by the α1-GABAA receptors. 3. Anterograde amnesia: Temporary impairment of memory with use of the benzodiazepines is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired. 4. Anticonvulsant: Several benzodiazepines have anticonvulsant activity. This effect is partially, although not completely, mediated by α1-GABAA receptors. 5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. Baclofen is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord. Therapeutic uses: 1. Anxiety disorders: Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxiety, posttraumatic stress disorder, obsessive–compulsive disorder, and extreme anxiety associated with phobias, such as fear of flying. The benzodiazepines are also useful in treating anxiety related to depression and schizophrenia. These drugs should be reserved for severe anxiety only and not used to manage the stress of everyday life. Because of their addiction potential, they should only be used for short periods of time. The longer acting agents, such as clonazepam, lorazepam, and diazepam, are often preferred in those patients with anxiety that may require prolonged treatment. The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. [Note: Tolerance occurs when used for more than 1 to 2 weeks. Tolerance is associated with a decrease in GABA receptor density. Cross-tolerance exists between the benzodiazepines and ethanol.] For panic disorders, alprazolam is effective for short- and long- term treatment, although it may cause withdrawal reactions in about 30% of patients. 2. Sleep disorders: A few of the benzodiazepines are useful as hypnotic agents. These agents decrease the latency to sleep onset and increase stage II of non–rapid eye movement (REM) sleep. Commonly prescribed benzodiazepines for sleep disorders include intermediate-acting temazepam and short-acting triazolam. Long-acting flurazepam is rarely used, due to its extended half-life, which may result in excessive daytime sedation and accumulation of the drug, especially in the elderly. Estazolam and quazepam are considered intermediate- and long-acting agents, respectively. Temazepam: This drug is useful in patients who experience frequent wakening. Triazolam is effective in treating individuals who have difficulty in going to sleep. Tolerance frequently develops within a few days, and withdrawal of the drug often results in rebound insomnia. Therefore, this drug is not a preferred agent. 3. Amnesia: The shorter-acting agents are often employed as premedication for anxiety provoking and unpleasant procedures, such as endoscopy, dental procedures, and angioplasty. They cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures. Midazolam is a benzodiazepine used to facilitate amnesia while causing sedation prior to anesthesia. 4. Seizures: Clonazepam is occasionally used as an adjunctive therapy for certain types of seizures, whereas lorazepam and diazepam are the drugs of choice in terminating status epilepticus. Due to cross- tolerance, chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures. 2 5. Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy. Dependence: Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. Benzodiazepines with a short elimination half-life, such as triazolam, induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated such as flurazepam. Adverse effects: Drowsiness and confusion are the most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment. Triazolam often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, as well as amnesia and confusion. Benzodiazepines should be used cautiously in patients with liver disease. These drugs should be avoided in patients with acute angle closure glaucoma. Alcohol and other CNS depressants enhance the sedative–hypnotic effects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently. BENZODIAZEPINE ANTAGONIST Flumazenil is a GABA receptor antagonist that can rapidly reverse the effects of benzodiazepines. The drug is available for intravenous (IV) administration only. Onset is rapid, but the duration is short, with a half-life of about 1 hour. Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. OTHER ANXIOLYTIC AGENTS A. Antidepressants: Many antidepressants are effective in the treatment of chronic anxiety disorders and should be considered as first-line agents, especially in patients with concerns for addiction or dependence. Selective serotonin reuptake inhibitors (SSRIs, such as escitalopram or paroxetine) or serotonin/norepinephrine reuptake inhibitors (SNRIs, such as venlafaxine or duloxetine) may be used alone or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment. After 4 to 6 weeks, when the antidepressant begins to produce an anxiolytic effect, the benzodiazepine dose can be tapered. SSRIs and SNRIs have a lower potential for physical dependence than the benzodiazepines and have become first-line treatment for generalized anxiety disorder (GAD). B. Buspirone: is useful for the chronic treatment of GAD and has an efficacy comparable to that of the benzodiazepines. It has a slow onset of action and is not effective for short-term or “as-needed” treatment of acute anxiety states. The actions of buspirone appear to be mediated by serotonin receptors, although it also displays some affinity for D2 dopamine receptors. The frequency of adverse effects is low, with the most common effects being headaches, dizziness, nervousness, nausea, and light headedness. 3 BARBITURATES The barbiturates were formerly the mainstay of treatment to sedate patients or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance and physical dependence and are associated with very severe withdrawal symptoms. All barbiturates are controlled substances. Certain barbiturates, such as the very short-acting thiopental, have been used to induce anesthesia but are infrequently used today due to the advent of newer agents with fewer adverse effects. Mechanism of action: The sedative–hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission. In addition, barbiturates can block excitatory glutamate receptors. Anesthetic concentrations of pentobarbital also block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity. Actions: Barbiturates are classified according to their duration of action. For example, ultra–short-acting thiopental acts within seconds and has a duration of action of about 30 minutes. In contrast, long-acting phenobarbital has a duration of action greater than a day. Pentobarbital, secobarbital, amobarbital, and butalbital are short-acting barbiturates. 1. Depression of CNS: At low doses, the barbiturates produce sedation (have a calming effect and reduce excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation), and, finally, coma and death. Thus, any degree of depression of the CNS is possible, depending on the dose. Barbiturates do not raise the pain threshold and have no analgesic properties. They may even exacerbate pain. Chronic use leads to tolerance. 2. Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and over- dosage is followed by respiratory depression and death. Therapeutic uses 1. Anesthesia: The ultra–short-acting barbiturates, such as thiopental, have been used intravenously to induce anesthesia but have largely been replaced by other agents. 2. Anticonvulsant: Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression. It is used in long-term management of tonic–clonic seizures. However, phenobarbital can depress cognitive development in children and decrease cognitive performance in adults, and it should be used only if other therapies have failed. Similarly, phenobarbital may be used for the treatment of refractory status epilepticus. 3. Sedative/hypnotic: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. When used as hypnotics, they suppress REM sleep more than other stages. However, the use of barbiturates for insomnia is no longer generally accepted, given their adverse effects and potential for tolerance. Butalbital is commonly used in 6 combination products (with acetaminophen and caffeine or aspirin and caffeine) as a sedative to assist in the management of tension-type or migraine headaches. Adverse effects: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness. Hypnotic doses of barbiturates produce a drug “hangover” that may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur. Barbiturates 4 are contraindicated in patients with acute intermittent porphyria. Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death. Death may also result from overdose. Severe depression of respiration is coupled with central cardiovascular depression and results in a shock-like condition with shallow, infrequent breathing. Treatment includes supportive care and gastric decontamination for recent ingestions. Other hypnotic drugs: A. Zolpidem: The hypnotic zolpidem is not structurally related to benzodiazepines, but it selectively binds to the benzodiazepine receptor subtype BZ1. Zolpidem has no anticonvulsant or muscle-relaxing properties. It shows few withdrawal effects, exhibits minimal rebound insomnia, and little tolerance occurs with prolonged use. Adverse effects of zolpidem include nightmares, agitation, anterograde amnesia, headache, GI upset, dizziness, and daytime drowsiness. Unlike the benzodiazepines, at usual hypnotic doses, the non- benzodiazepine drugs, zolpidem, zaleplon, and eszopiclone, do not significantly alter the various sleep stages and, hence, are often the preferred hypnotics. This may be due to their relative selectivity for the BZ1 receptor. All three agents are controlled substances. B. Ramelteon is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors. Melatonin is a hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep–wake cycle. Stimulation of MT1 and MT2 receptors by ramelteon is thought to induce and promote sleep. Ramelteon is indicated for the treatment of insomnia characterized by difficulty falling asleep (increased sleep latency). It has minimal potential for abuse, and no evidence of dependence or withdrawal effects has been observed. Therefore, ramelteon can be administered long term. Common adverse effects of ramelteon include dizziness, fatigue, and somnolence. Ramelteon may also increase prolactin levels. C. Antihistamines: Some antihistamines with sedating properties, such as diphenhydramine, hydroxyzine, and doxylamine, are effective in treating mild types of situational insomnia. However, they have undesirable side effects (such as anticholinergic effects) that make them less useful than the benzodiazepines and the non-benzodiazepines. Some sedative antihistamines are marketed in numerous over-the-counter products. D. Antidepressants The use of sedating antidepressants with strong antihistamine profiles has been ongoing for decades. Doxepin, an older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action, was recently approved at low doses for the management of insomnia. Other antidepressants, such as trazodone , mirtazapine, and other older tricyclic antidepressants with strong antihistamine properties are used off-label for the treatment of insomnia. 5 Figure 1 summarizes the therapeutic disadvantages and advantages of some of the anxiolytic and hypnotic drugs Figure 1 Drugs for epilepsy Symptoms of epilepsy include loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated. Medications are the most widely used mode of treatment for patients with epilepsy. ETIOLOGY OF SEIZURES Changes in physiologic factors, such as an alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deprivation, alcohol intake, and stress can trigger epilepsy. The neuronal discharge in epilepsy results from the firing of a small population of neurons in a 6 specific area of the brain referred to as the “primary focus.” Epilepsy can be due to an underlying genetic, structural, or metabolic cause or an unknown cause. Types: A. Genetic epilepsy These seizures result from an inherited abnormality in the central nervous system (CNS). B. Structural/metabolic epilepsy: a number of causes, such as illicit drug use, tumor, head injury, hypoglycemia, meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures. C. Unknown cause When no specific anatomic cause for the seizure, such as trauma or neoplasm, is evident, a patient may be diagnosed with seizures where the underlying cause is unknown. Most cases of epilepsy are due to an unknown cause. CLASSIFICATION OF SEIZURES A. Focal: Focal seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. Focal seizures may progress to become generalized tonic–clonic seizures. 1. Simple partial 2. Complex partial B. Generalized: Generalized seizures may begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness. 1. Tonic–clonic: 2. Absence: 3. Myoclonic 4. Clonic 5. Tonic 6. Atonic Mechanism of action of antiepilepsy medications: Drugs reduce seizures through such mechanisms as blocking voltage-gated channels (Na+ or Ca2+), enhancing inhibitory γ-aminobutyric acid (GABA)-ergic impulses and interfering with excitatory glutamate transmission. Some antiepilepsy medications appear to have multiple targets within the CNS, whereas the mechanism of action for some agents is poorly defined. Antiepilepsy medications suppress seizures but do not “cure” or “prevent” epilepsy. ANTIEPILEPSY MEDICATIONS A. Benzodiazepines: Benzodiazepines bind to GABA inhibitory receptors to reduce firing rate. Most benzodiazepines are reserved for emergency or acute seizure treatment due to tolerance. However, clonazepam and clobazam may be prescribed as adjunctive therapy for particular types of seizures. Diazepam is also available for rectal administration to avoid or interrupt prolonged generalized tonic– clonic seizures or clusters when oral administration is not possible. B. Carbamazepine: Carbamazepine blocks sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus and preventing their spread. Carbamazepine is effective for treatment of focal seizures and, additionally generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar 7 disorder. Carbamazepine should not be prescribed for patients with absence seizures because it may cause an increase in seizures. C. Eslicarbazepine: It is a voltage-gated sodium channel blocker and is approved for partial-onset seizures in adults. D. Ethosuximide: Ethosuximide reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels. It is only effective in treating absence seizures. E. Ezogabine: Ezogabine is thought to open voltage-gated M-type potassium channels leading to stabilization of the resting membrane potential. Possible unique side effects are urinary retention, QT interval prolongation, blue skin discoloration, and retinal abnormalities. F. Felbamate Felbamate has a broad spectrum of anticonvulsant action with multiple proposed mechanisms including the blocking of voltage-dependent sodium channels, competing with the glycine coagonist binding site on the N-methyl-d-aspartate (NMDA) glutamate receptor, blocking of calcium channels, and potentiating GABA action. It is reserved for use in refractory epilepsies because of the risk of aplastic anemia and hepatic failure. G. Gabapentin Gabapentin is an analog of GABA. However, it does not act at GABA receptors, enhance GABA actions or convert to GABA. Its precise mechanism of action is not known. It is approved as adjunct therapy for focal seizures and treatment of postherpetic neuralgia. Gabapentin is well tolerated by the elderly population with partial seizures due to its relatively mild adverse effects. It may also be a good choice for the older patient because there are few drug interactions. H. Lacosamide: Lacosamide in vitro affects voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide is approved for adjunctive treatment of focal seizures. It is available in an injectable formulation. The most common adverse events that limit treatment include dizziness, headache, and fatigue. I. Lamotrigine: Lamotrigine blocks sodium channels, as well as high voltage-dependent calcium channels. Lamotrigine is effective in a wide variety of seizure types, including focal, generalized and absence seizures. It is also used to treat bipolar disorder. J. Levetiracetam Levetiracetam is approved for adjunct therapy of focal onset, myoclonic, and primary generalized tonic–clonic seizures in adults and children. The exact mechanism of anticonvulsant action is unknown. It demonstrates high affinity for a synaptic vesicle protein (SV2A). K. Oxcarbazepine is a prodrug that is rapidly reduced to the 10-monohydroxy (MHD) metabolite responsible for its anticonvulsant activity. MHD blocks sodium channels, preventing the spread of the abnormal discharge. It is also thought to modulate calcium channels. It is approved for use in adults and children with partial-onset seizures. L. Perampanel: is a selective AMPA post synaptic Na+ channel antagonist resulting in reduced excitatory activity. Perampanel has a long half-life enabling once-daily dosing. It is approved for adjunctive treatment of partial-onset seizures in patients 12 years or older. M. Phenobarbital and primidone: The primary mechanism of action of phenobarbital is enhancement of the inhibitory effects of GABA-mediated neurons. Primidone is metabolized to phenobarbital (major) and phenylethylmalonamide, both with anticonvulsant activity. Phenobarbital is used primarily in the treatment of status epilepticus when other agents fail. 8 N. Phenytoin and fosphenytoin Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery. It is effective for treatment of focal and generalized tonic– clonic seizures and in the treatment of status epilepticus. Phenytoin exhibits saturable enzyme metabolism resulting in nonlinear pharmacokinetic properties (small increases in the daily dose can produce large increases in plasma concentration, resulting in drug-induced toxicity). Gingival hyperplasia may cause the gums to grow over the teeth (figure 2). Long-term use may lead to development of peripheral neuropathies and osteoporosis. Although phenytoin is advantageous due to its low cost, the actual cost of therapy may be much higher, considering the potential for serious toxicity and adverse effects. Fosphenytoin is a prodrug that is rapidly converted to phenytoin in the blood within minutes. Whereas fosphenytoin may be administered intramuscularly (IM), phenytoin sodium should never be given IM, as it causes tissue damage and necrosis. Fosphenytoin is the drug of choice and standard of care for IV and IM administration of phenytoin. Figure 2: Gingival hyperplasia O. Pregabalin binds to the α2-δ site, an auxiliary subunit of voltage-gated calcium channels in the CNS, inhibiting excitatory neurotransmitter release. The exact role this plays in treatment is not known, but the drug has proven effects on focal-onset seizures, diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Weight gain and peripheral edema have been reported. P. Rufinamide acts at sodium channels. It is approved for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome (Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy. It is characterized by multiple and concurrent seizure types, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG)) in children over age 4 years and in adults. As with other antiepilepsy medications, serum concentration of rufinamide is induced by carbamazepine and phenytoin and inhibited when given with valproate. Adverse effects include the potential for shortened QT intervals. Patients with familial short QT syndrome (Short QT syndrome is a condition that can cause a disruption of the heart's normal rhythm (arrhythmia). In people with this condition, the heart (cardiac) muscle takes less time than usual to recharge between beats) should not be treated with rufinamide. Q. Tiagabine blocks GABA uptake into presynaptic neurons permitting more GABA to be available for receptor binding, and therefore, it enhances inhibitory activity. Tiagabine is effective as adjunctive treatment in partial-onset seizures. 9 R. Topiramate has multiple mechanisms of action. It blocks voltage-dependent sodium channels, reduces high-voltage calcium currents (L type, and may act at glutamate (NMDA) sites. Topiramate is effective for use in partial and primary generalized epilepsy. It is also approved for prevention of migraine. Adverse effects include somnolence, weight loss, and paresthesias. Renal stones, glaucoma, oligohidrosis (decreased sweating), and hyperthermia have also been reported. S. Valproic acid and divalproex Possible mechanisms of action include sodium channel blockade, blockade of GABA transaminase, and action at the T-type calcium channels. These varied mechanisms provide a broad spectrum of activity against seizures. It is effective for the treatment of focal and primary generalized epilepsies. T. Vigabatrin acts as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T). GABA-T is the enzyme responsible for metabolism of GABA. Vigabatrin is associated with visual field loss ranging from mild to severe in 30% or more of patients. U. Zonisamide: is a sulfonamide derivative that has a broad spectrum of action. The compound has multiple effects, including blockade of both voltage-gated sodium channels and T-type calcium currents. Zonisamide is approved for use in patients with focal epilepsy. In addition to typical CNS adverse effects, zonisamide may cause kidney stones. Oligohidrosis has been reported, and patients should be monitored for increased body temperature and decreased sweating. Zonisamide is contraindicated in patients with sulfonamide or carbonic anhydrase inhibitor hypersensitivity. STATUS EPILEPTICUS: In status epilepticus, two or more seizures occur without recovery of full consciousness in between episodes. These may be focal or primary generalized, convulsive or non- convulsive. Status epilepticus is life threatening and requires emergency treatment usually consisting of administration of a fast-acting medication such as a benzodiazepine, followed by a slower-acting medication such as phenytoin. Dentistry and epilepsy: Epileptic seizures are the third most common medical incident in dental surgeries. Dentists should ask patients about a history of epilepsy and should know how to manage an epileptic seizure. Falls caused by seizures increase the risk of dental injuries, and fixed dental replacements (e.g., tooth implants) are recommended to reduce the risk of aspiration. Phenytoin induces gingival hyperplasia in 50% to 60% of patients (figure 2), treatment options include a switch to alternative anticonvulsant drugs and improved dental hygiene. In addition to conventional dental care, the use of electric toothbrushes and the application of chlorhexidine and regular professional dental cleaning may prevent the development of gingival hyperplasia.. There are case reports of reflex epileptic seizures caused by (prolonged) brushing of teeth. 10 Table 1: Summary of antiepileptic drugs and their mechanisms of action 11