Pharmacotherapy of Generalized seizures

Dr. ANKITA MISHRAJNMCH

AMU, ALIGARH

• A seizure is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain.

• Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.

Classification of Seizures

• Focal seizures

• Generalized seizures– Absence– Tonic clonic– Myoclonic

• May be focal, generalized, or unclear

• Seizures are a result of a shift in the normal balance of excitation and inhibition within the CNS.

• endogenous factors- genetic, high fever• epileptogenic factors- stroke, infection, trauma• precipitating factors- psychological or physical stress,

sleep deprivation, hormonal changes

• dynamic interplay between endogenous factors, epileptogenic factors and precipitating factors.

The Causes of Seizures and Epilepsy

Basic Mechanisms• Epileptogenesis- transformation of a normal neuronal network into

one that is chronically hyperexcitable.

• seizure initiation phase • long-lasting depolarization of the neuronal membrane due to influx of

extracellular Ca2+ opening of volt-dependent Na+ channels influx of Na+ generation of repetitive AP.

• seizure propagation phase• recruitment of surrounding neurons via a no. of mechanisms: 1) an increase in extracellular K+ 2) accumulation of Ca2+ in presynaptic terminals 3) depolarization-induced activation of NMDA receptor 4) ephaptic interactions

Treatment: Generalized Seizures

• Treatment of Underlying Conditions• Avoidance of Precipitating Factors• Antiepileptic Drug Therapy-

Generalized-onset Tonic-Clonic Absence Atypical Absence, Myoclonic, Atonic

First-Line Valproic acidLamotrigineTopiramate

Valproic acidEthosuximide

Valproic acidLamotrigineTopiramate

AlternativesZonisamidePhenytoinCarbamazepineOxcarbazepinePhenobarbitalFelbamateLevetiracetam

LamotrigineClonazepam

ClonazepamFelbamate

Mechanisms of Action of Antiepileptic Drugs(Generalized Seizures)

• inhibition of VG Na+ channel function- phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide,valproate

• Enhancement of GABAergic action-• GABAA receptor allosteric modulators - BZDs, PB, FBM,TPM• Increase amount of GABA- Valproate

• Inhibition of Ca2+ channel- • N type- Lamotrigine• T type- Ethosuximide, Valproate

• NMDA receptor antagonists - Felbamate

• AMPA/kainate receptor antagonists- Topiramate, Phenobarbital

• Enhancers of HCN channel activity- Lamotrigine

• SV2A protein binding- Levetiracetam

• Inhibitors of brain carbonic anhydrase- Topiramate, Zonisamide

Valproic Acid• TherapeuticUses- Tonic-clonic, Absence, Myoclonic, Focal, Atonic

• Pharmacokinetic Properties- t1/2 ~15 hours, Hepatic metabolism -95%, unchanged in urine < 5%. Therapeutic range ~30-100 microg/mL.

• Dosage- initially; 15 mg/kg, increased wkly by 5-10mg/kg/d; max. of 60 mg/kg.

• Toxicity- N, V, sedation, ataxia, tremor, alopecia,wt. gain, hepatotoxicity, ac. pancreatitis, hyperammonemia

• Drug Interactions- inhibits CYP2C9 & UGT- inhibits the metabolism of phenytoin, phenobarbital & lamotrigine, lorazepam;

Lamotrigine

• Therapeutic Uses- Tonic-clonic, Absence, Myoclonic, Partial, Lennox-Gastaut syndrome

• Pharmacokinetics- t1/2 -25 h;14 h metabolized by glucoronidation

• Dosage- 150–500 mg/d;p/o; bid

• Toxicity- N, V, Dizziness, Diplopia, Sedation, Ataxia, Headache, Skin rash, Stevens-Johnson syndrome, DIC

• Drug Interactions- Level decreased by enzyme-inducing drugs;

Level increased by valproic acid.

Topiramate• Therapeutic Uses- Focal, Tonic-clonic, Absence, Lennox-Gastaut syndrome

• Pharmacokinetics- t1/2 is ~1 day; mainly excreted unchanged in the urine.

• Dosage- 200–400 mg/d; p/o; bid

• Toxicity- somnolence, fatigue, weight loss, and nervousness, renal calculi, cognitive impairment, glaucoma, hypospadiasis

Ethosuximide• Therapeutic Use- Absence seizures

• Pharmacokinetics- t1/2 is 40-50 h, adult &30 h, children; 25% excreted unchanged in the urine, remainder metabolized by hepatic enzymes; Therapeutic range- 40-100 microg/ml.

• Dosage- 750–1250 mg/d (20-40 mg/kg); qd-bid

• Toxicity- N, V, drowsiness, lethargy, euphoria, dizziness, headache, Parkinson-like symptoms and photophobia, restlessness, agitation, anxiety, aggressiveness, inability to concentrate, BM depression, urticaria, SLE

Phenytoin• Therapeutic Uses- Partial, Tonic-clonic seizures

• Pharmacokinetics- t1/2 -6-24 hours at plasma concentrations ~ 20 microg/mL, increases with higher concentrations;

metabolized in the hepatic endoplasmic reticulum by CYP2C9/10 and to a lesser extent CYP2C19;

Therapeutic range- 10–20 microg/mL

• Fosphenytoin, a water-soluble prodrug, given IM/IV; t1/2 of 8-15 mins.

• Toxicity- Overdose toxicity- nystagmus, diplopia, CNS depression, cardiac arrythmia

• Chronic toxicity- gingival hyperplasia, coarsening of facial features, megaloblastic anaemia, vit K &D deficiency, hyperglycemia, hypersensitivity rxn, lymphadenopathy

• Drug Interactions- increases metabolism of corticosteroids,OCPs, doxycycline, rifampicin, theophylline, levodopa.

• Enzyme inhibitors decrease its metabolism.• Carbamazepine & phenytoin or phenobarbitol & phenytoin

increase eachothers metabolism.• Valproate displaces protein bound phenytoin & inhibits its

metabolism.

Carbamazepine• Therapeutic Uses- Generalized Tonic-clonic, Partial seizures

• Pharmacokinetics- t1/2 -10–17 h; Excreted in urine • Therapeutic Range- 6–12 microg/mL

• Dosage- 600–1800 mg/d (15–35 mg/kg); bid-qid

• Toxicity- ataxia, dizziness, diplopia, vertigo, aplastic anemia, GIT irritation, hepatotoxicity, water retention, hypersensitivity reaction

Phenobarbital• Therapeutic Uses- Tonic-clonic, Focal-onset

• Pharmacokinetics- t1/2 – 90 hrs; 25% renal excretion of the unchanged drug; remainder by hepatic microsomal enzymes

Therapeutic Range -10–40 microg/mL

• Dosage- 60–180 mg/d; qd

• Toxicity- sedation, ataxia, confusion, dizziness, depression, irritability, rash, megaloblastic anemia, osteomalacia, hypoprothrombinemia with hemorrhage in newborns

Levetiracetam• Therapeutic Use- Refractory myoclonic, Partial-onset,

Generalized tonic-clonic seizures

• Pharmacokinetics- t1/2 – 90 hrs; primarily excreted in the urine

• Dosage- 1000–3000 mg/d; qd-bid

• Toxicity- sedation, fatigue, incoordination, mood changes, anaemia, leucopenia

Clonazepam• Therapeutic Use- Absence seizures, Myoclonic seizures

• Pharmacokinetics- t1/2 – 23 hrs; metabolized principally by reduction of the nitro group to inactive 7-amino derivatives. Therapeutic Range- 10–70 ng/mL;

• Dosage- 0.2mg/kg/d; qd-tid.

• Toxicity- ataxia, sedation, lethargy, anorexia, aggression, hyperactivity, irritability, cardiovascular and respiratory depression on I/V admn.

Felbamate• Therapeutic Use- Poorly controlled Focal-onset, Tonic-clonic.

• Pharmacokinetics- t1/2 – 16- 22hrs

• Dosage- 2400–3600 mg/d, tid-qid

• Toxicity- aplastic anemia, hepatic failure, weight loss, gi irritation

• Withdrawn in some countries.

Zonisamide• Therapeutic Use- Adjunctive therapy- Focal-onset, Tonic-

clonic.

• Pharmacokinetics- t1/2 ~63 hrs excreted in the urine

• Dosage- 200–400 mg/d; qd-bid

• Toxicity- somnolence, ataxia, anorexia, nervousness, metabolic acidosis, renal calculi

GENERAL CONSIDERATIONS

When to Initiate Antiepileptic Drug Therapy

• Seizure recurrence in a patient with an apparently unprovoked or idiopathic seizure is uncertain (31 to 71% in the first 12 months).

• Risk factors for recurrent seizures- 1) abnormal neurologic examination, 2) presenting as status epilepticus, 3) postictal Todd's paralysis, 4) strong family history of seizures, 5) an abnormal EEG.

• If 1 or more risk factors- initiate treatment.

Drug Selection for Generalized Seizures• Valproic acid & lamotrigine -best initial choice for primary

generalized, tonic-clonic seizures.

• Topiramate, zonisamide, phenytoin & carbamazepine -suitable alternatives.

• Valproic acid –DOC for generalized epilepsy syndromes having mixed seizure types.

• Ethosuximide - uncomplicated absence seizures.

• Lamotrigine - effective in mixed, generalized seizure types such as JME & Lennox-Gastaut syndrome.

Initiation and Monitoring of Therapy• Prevent seizures and minimize the side effects of therapy.

• Monotherapy should be the goal.

• Starting doses are usually the lowest value.

• Increased after achieving a steady state with the previous dose.

• Key determinants are clinical measures of seizure frequency & presence of side effects, not the laboratory values.

When to Discontinue Therapy• Attempt withdrawal of therapy after 2 yrs in patient –

• 1) complete medical control of seizures for 1–5 years 2) single seizure type, either focal or generalized 3) normal neurologic examination, including intelligence 4) normal EEG.

• Reduce the dose of drug gradually over 2–3 mths.

Treatment of Refractory Epilepsy• 1/3rd patients do not respond to a single antiepileptic drug.

• Myoclonic seizures resistant to valproic acid may benefit from the addition of Levetiracetam.

• Absence seizures may respond to a combination of valproic acid and ethosuximide.

• Monitoring of therapeutic response, toxicity, and serum levels for monotherapy apply to polypharmacy & potential drug interactions need to be recognized.

• No improvement- third drug can be added.

Status Epilepticus• Continuous seizures or repetitive, discrete seizures with

impaired consciousness in the interictal period.

• Typically when seizures last beyond 5 minutes.

• Neurological emergency, mortality ~ 20%

• First steps- attend to acute cardiorespiratory problems or hyperthermia, a brief medical and neurologic examination, establish venous access, send samples for lab studies.

Oxcarbazepine• keto analog of carbamazepine

• Pharmacokinetics- main active metabolite-10-monohydroxy derivative;

t1/2 -10–17 h (for active metabolite); inactivated by glucuronide conjugation and eliminated by

renal excretion.

• Dosage- 900–2400 mg/d (30–45 mg/kg); bid

• Oxcarbazepine is a less potent enzyme inducer than carbamazepine

• Opioid addiction became a serious problem initially during and after the American Civil War, when opioids were widely prescribed to alleviate acute and chronic pain, other types of discomfort, and stress. However, nonmedical opioid use continued on a smaller scale, mainly opium smoking among Chinese immigrants and members of the “underground” Caucasian groups (e.g., prostitutes, gamblers, petty criminals), addiction due to iatrogenic reasons were much more common (White 1998). During the late 19th century, approximately two-thirds of opioid addicts (including opium, morphine, and laudanum) were middle and upper class white women, a fact Brecher and the Editors of Consumer Reports (1972, p. 17) attributed to the widespread prescribing of opiates for menstrual and menopausal discomfort. By 1900, around 300,000 persons were addicted to opioids in the United States (Brecher and Editors 1972; Courtwright 2001; Courtwright et al. 1989).

• Soon the chronic nature of opioid addiction became evident and many people who were admitted to sanatoriums for a cure relapsed to addictive opioid use after discharge. (Courtwright 2001).

• By the end of the 19th century, doctors became more cautious in prescribing morphine and other opioids, and the prevalence of opioid addiction decreased. Small groups still practiced opium smoking, but most Americans regarded it as socially irresponsible and immoral. It is noteworthy, however, that heroin, introduced in 1898 as a cough suppressant, also began to be misused for its euphoric qualities, gradually attracting new types of users. This development, along with diffusion of the hypodermic technique of drug administration, which gained popularity between 1910 and 1920, had a profound effect on opioid use and addiction in the 20th century and beyond (Courtwright 2001).

• The size and composition of the U.S. opioid-addicted population began to change in the early 20th century with the arrival of waves of European immigrants. Courtwright (2001) portrays most users of opioids of this period as young men in their 20s: “down-and-outs” of recent-immigrant European stock who were crowded into tenements and ghettos and acquired their addiction during adolescence or early adulthood. They often resorted to illegal means to obtain their opioids, usually from nonmedical sources and specifically for the euphoric effects. “Gone was the stereotype of the addicted matron; in its place stood that of the street criminal” (Courtwright 2001, p. 1).

• The initial treatment response in the early 20th century continued to involve the prescriptive administration of short-acting opioids. By the 1920s, morphine was prescribed or dispensed in numerous municipal treatment programs (Courtwright et al. 1989).

• Addictive use of opium, cocaine, and heroin, along with drug-related crime, especially in poor urban communities, increasingly concerned social, religious, and political leaders. The tolerance and empathy shown toward Civil War veterans and middle-aged women evaporated; negative attitudes toward and discrimination against new immigrants probably colored views of addiction. Immigrants and others who trafficked in and abused drugs were viewed as a threat. As detailed below, society's response was to turn from rudimentary forms of treatment to law enforcement (Brecher and Editors 1972; Courtwright 2001; Courtwright et al. 1989). For more on trends in the 1920s and 1930s, see “Early treatment efforts” below.

• McCoy (n.d.) refers to a forced decline in opioid addiction during World War II, brought about by restrictions on shipping and strict port security, which produced a marked hiatus in global opium trafficking and caused the U.S. opioid-addicted population to drop to a historic low of about 20,000. Once smuggling resumed after the war, the population that had used opioids resumed the habit.

• Another major change in the U.S. opioid-addicted population occurred after World War II. As many European immigrants moved from crowded cities, Hispanics and African-Americans moved into areas with preexisting opioid abuse problems, and the more susceptible people in these groups acquired the disorder (Courtwright 2001; Courtwright et al. 1989).

• The post-World War II shift in the composition of opioid-addicted groups coincided with hardening attitudes toward these groups, leading some researchers to conclude that stigmatization of people with addiction disorders and their substances of abuse reflected, at least in part, class and ethnic biases. A portion of U.S. society appeared to view with disdain and fear the poor White, Asian, African-American, and Hispanic people with addiction disorders who lived in the inner-city ghettos (Courtwright et al. 1989).

• Brecher and the Editors of Consumer Reports (1972) point out that, by the mid-1960s, the number of middle-class young White Americans using heroin was on the rise, as was addiction-related crime. By the 1970s, U.S. military involvement in Vietnam also was having an effect. From one-fourth (Brecher and Editors 1972) to one-half (Courtwright 2001) of American enlisted men in Vietnam were believed to have used or become addicted to heroin; however, White (1998) points out that the feared epidemic of heroin addiction among returning veterans did not materialize fully. He concludes, “Vietnam jidemonstrated that a pattern of drug use could emerge in response to a particular environment and that spontaneous remission could occur when the environment was changed” (p. 303).

• By the 1980s, an estimated 500,000 Americans used illicit opioids (mainly heroin), mostly poor young minority men and women in the inner cities. Although this number represented a 66-percent increase over the estimated number of late 19th-century Americans with opioid addiction, the per capita rate was much less than in the late 19th century because the population had more than doubled (Courtwright et al. 1989). Nevertheless, addiction became not only a major medical problem but also an explosive social issue (Courtwright 2001; Courtwright et al. 1989).

• By the end of the 1990s, an estimated 898,000 people in the United States chronically or occasionally used heroin (Office of National Drug Control Policy 2003), and the number seeking treatment was approximately 200,000 (almost double the number during the 1980s). The abuse of opioids that normally were obtained by prescription was a growing concern because of both their damaging effects and their potential as gateway drugs to other substance use. Treatment admission rates for addiction to opioid analgesics more than doubled between 1992 and 2001 (Substance Abuse and Mental Health Services Administration 2004), and visits to emergency rooms related to opioid analgesic abuse increased 117 percent between 1994 and 2001 (Substance Abuse and Mental Health Services Administration 2003b ).( Center for Substance Abuse Treatment. Medication-Assisted Treatment for Opioid Addiction in Opioid Treatment Programs. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2005. (Treatment Improvement Protocol (TIP) Series, No. 43.) Chapter 2. History of Medication-Assisted Treatment for Opioid Addiction. Available from: http://www.ncbi.nlm.nih.gov/books/NBK64157/?report=classic)