PHA6118: Anti-seizure Drugs, Antipsychotics and Lithium

Seizure

characterized by excessive, hypersynchronous discharge of the cortical neuron activity

Epilepsy

chronic seizure disorder, wherein the seizures occur and recur unpredictably

Symptomatic

if secondary to brain injury, tumor or vascular malformation in the brain

Idiopathic

if secondary to genetic problem, with no structural or metabolic abnormality

Convulsions

violent, involuntary contractions of the voluntary muscles

petit mal

A patient may have an epilepsy without convulsion

Focal Onset Seizures

affects a local cortical site

Focal Aware

(simple partial seizure) – patient retains consciousness or awareness

Focal Impaired

(complex partial seizure) – patient losses consciousness or awareness

Focal-to-Bilateral Tonic-Clonic

(secondary generalized or Grand mal) – seizure starts as a focal type and progress to a generalized tonicclonic type

Tonic

– muscle stiffening of the entire body

Clonic

rhythmic jerking of the limbs and face

Generalized Onset Seizures

affects both hemispheres of the brain

Generalized Tonic-Clonic

(Primary generalized or Grand mal) – involves both hemispheres of the brain and commonly occurs as idiopathic or genetic generalized epilepsies

Generalized Absence

(Petit mal) – common among children, characterized as a brief loss of consciousness with no warning

Generalized Onset Seizures

affects both hemispheres of the brain

Myoclonic

a sudden brief involuntary single muscle or multiple muscle group contractions

Atonic

(drop or astatic seizure) – sudden loss of muscle tone causing a forward fall

Epileptic spasms

(West syndrome) – infantile spasms exhibiting grimacing, head nodding, and subtle eye movement

Single medication

is preferred but for adults, multiple medication is advised due to hard-to-control seizures

Oral anti-seizure medication

depending on the patient’s seizure type of syndromic classification

“Pharmacoresistant”

- if medication is inadequate to control seizures

Epilepsy surgery

(common for focal) to resection of the affected brain region

Electrical stimulation devices

vagus nerve stimulation (VNS), responsive neurostimulator (RNS), and deep brain stimulation (DBS)

ketogenic

Dietary therapies, _ diet for more protein intake helps with children

Mechanism of Action

Interacts with one or more molecular targets in the brain and ultimately inhibit local generation of discharges by decreasing high firing rate of action potential and by reducing neuronal synchronization

Antiseizure action

Modulation of voltage-gated Na, Ca and K

Antiseizure action

Enhancement of fast GABA-mediated synaptic inhibition

Antiseizure action

Modification of synaptic release process

Antiseizure action

Diminution of fast glutamate mediated excitation

Antiseizure drug activity

is generally acting on the balance between excitatory and inhibitory activity in the neurons since seizure occurs if there is imbalance leading to outcomes favorable to excitation

Focal

Generalized

Absence

Myoclonic

Tonic / Atonic

Sodium valproate

contraindicated in women of childbearing age

Diazepam

for acute repetitive seizures

Lorazepam

– for status epilepticus (SE

Midazolam

for acute repetitive seizures; out-of-hospital SE (IM)

Clonazepam

for absence, myoclonic, and atonic seizures

Nitrazepam

– for infantile spasms and myoclonic seizures

Clorazepate

– for focal seizures

Clobazam

– for atonic seizures

Acetazolamide

for decreasing excitation due to bicarbonate influx

Carbamazepine

MOA: Blocks voltage-gated Na channel limiting repetitive neuron firing

Carbamazepine

Well-absorbed orally and metabolized in the liver, induces its own metabolism

Carbamazepine

Enzyme inducer (CYP3A4/2B6) → lower levels of other drugs

Carbamazepine

Used for focal and generalized seizures, used in the management of trigeminal neuralgia and bipolar disorder

Carbamazepine

ADR: hyponatremia (most common reason for discontinuation), neurological effects (ataxia, dizziness, diplopia), hematologic effects (leukopenia, anemia, thrombocytopenia), hepatotoxicity, Steven-Johnson syndrome (rare), teratogenicity (at early pregnancy stages)

Lamotrigine

MOA: Blocks voltage-gated Na channel inhibiting release of glutamate; unknown MOA for Absence seizure

Lamotrigine

Well-absorbed orally and metabolized in the liver primarily via glucuronidation

Lamotrigine

Half-life may be prolonged in patients with hepatic impairment

rashes

Lamotrigine + valproate → efficacious but may lead to serious _

Lamotrigine

Used for focal, generalized tonic-clonic and absence seizures, used in the management of bipolar disorder

Lamotrigine

ADR: neurological effects (ataxia, dizziness, headache), rashes (may be initial signs of Steven-Johnson syndrome), aseptic meningitis (rare) and hyponatremia

Valproate / Valproic acid / Na valproate

MOA: Unknown or unclear; in studies, enhances GABAergic inhibition by increasing the synthesis of GABA and inhibiting GABA degradation

Valproate / Valproic acid / Na valproate

Well-absorbed and extensively metabolized in the liver; highly protein-bound

Valproate / Valproic acid / Na valproate

Inhibit the metabolism of other drugs → increased levels of other drugs

Valproate / Valproic acid / Na valproate

Can increase lamotrigine levels by two-fold by inhibiting its metabolism

Valproate / Valproic acid / Na valproate

Used for focal, generalized tonic-clonic and absence seizures, also used for myoclonic and atonic generalized seizures

Valproate / Valproic acid / Na valproate

ADR: most common dose-related toxicity: nausea, vomiting, GI pain and heartburn; reversible ADRs: weight gain, hair loss (alopecia) and tremors (at high doses); rare ADRs: idiosyncratic hepatotoxicity, pancreatitis, thrombocytopenia; teratogenicity at early pregnancy stages

Ethosuximide

MOA: Blocks T-type Ca-channels to reduce Ca-currents leading to stable neuronal membranes; reduces neuronal firing in the thalamocortical networks

Ethosuximide

Well-absorbed orally, primarily metabolized in the liver, excreted in the urine

Ethosuximide

Half-life of the drug increases with age of the patient

Ethosuximide

Very few drug interactions • Drug of choice for absence seizures

Ethosuximide

ADR: most common dose-related toxicity: gastric distress like pain, nausea and vomiting; temporary ADRs: transient lethargy, fatigue, headaches, dizziness, hiccups, euphoria

Levetiracetam

MOA: Binds to synaptic vesicle protein 2A (SV2A), which is responsible for modulating neurotransmitter release (glutamate)

Levetiracetam

Rapidly and completely absorbed orally with minimal hepatic metabolism

Levetiracetam

Excreted mostly unchanged in the urine • Very minimal drug interactions

Levetiracetam

Adjunct therapy for focal, myoclonic, generalized tonic-clonic seizures

Levetiracetam

ADR: generally well-tolerated with minimal side effects (drowsiness, nervousness and headache)

Topiramate

MOA: Enhances GABAergic inhibition by increasing GABA activity and inhibiting excitatory glutamate receptors

Topiramate

Well-absorbed orally, metabolized moderately in the liver, primarily excreted unchanged in the urine, hepatic and renal impairment may affect elimination

Topiramate

Used for focal and generalized onset epilepsy, also used for migraine, neuropathic pain, essential tremor and bipolar disorder

Topiramate

ADR: common CNS effects (dizziness, somnolence, cognitive dysfunction), metabolic effects (weight loss, metabolic acidosis, risk of kidney stones), also associated with glaucoma development, oligohydrosis and hyperthermia (when exposed to hot weather), teratogenicity (at early pregnancy stages)

Gabapentin

MOA: Blocks 𝛼2𝛿 subunit of voltage-gated Ca-channel leading to Ca-influx inhibition resulting to reduced neurotransmitter release (glutamate)

Gabapentin

Not metabolized and is excreted unchanged in the urine (low potential for interaction); has a dose-dependent bioavailability with peak concentration two to three hours after administration

Gabapentin

Primarily used for neuropathic pain, adjunct therapy for focal seizures, restless leg syndrome, postherpetic neuralgia, and for migraine prophylaxis

Gabapentin

MOA: Blocks voltage-gated Na-channel to reduce neuronal excitability

Phenytoin

Follows zero-order kinetics at therapeutic doses

Phenytoin

Can induce levels of hepatic enzymes leading to reduced levels of other drugs metabolized by CYP450

Phenytoin

Used for epilepsy (focal and generalized onset seizures), also for status epilepticus and trigeminal neuralgia

Phenytoin

MOA: Enhances GABAergic inhibition by increasing the duration of GABAmediated Cl-channel opening

Phenobarbital

Metabolized in the liver (CYP450), undergoes enterohepatic recycling, mainly excreted in the urine

Phenobarbital

Can induce levels of hepatic enzymes leading to reduced levels of many anticonvulsant drugs, contraceptives, steroids and warfarin

Phenobarbital

Used for epilepsy (focal unaware, generalized tonic-clonic, and febrile seizures), mainly used as a sedative-hypnotic, and induction of anesthesia

Phenobarbital

ADR: common ADRs: CNS depression (sedation, ataxia), respiratory distress (major sign of toxicity), can develop dependence and tolerance, hypersensitivity reactions (rare but associated with its use)

Psychosis

variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not

Antipsychotic drugs

able to reduce the psychotic symptoms in varying conditions like schizophrenia, bipolar disorder, psychotic depression, psychoses related to dementia and drug-induced forms

Neuroleptic

subtype of antipsychotic agents that produce a high incidence of extrapyramidal side effects (EPS) at clinically effective doses which is common with first generation

second generation

Neuroleptic

Currently, _ antipsychotic or the atypical agents are used for the management of these psychotic conditions

Schizophrenia

most common psychiatric disorder characterized by having a clear sensorium but marked thinking and perceptual disturbances

Serotonin hypothesis

abnormal transmission in 5-HT2A and 5HT-2C leading to hallucinatory effects in schizophrenia

Dopamine hypothesis

hyperactivity in mesolimbic dopamine receptor transmission contributes to the positive symptoms of hallucinations

Glutamate hypothesis

hypoactivity of NMDA receptor leading to reduced inhibitory influences contribute to cognitive impairment and psychosis

Positive Symptoms

Delusions, hallucinations, combativeness, insomnia

Negative Symptoms

Affective flattening (flat effect) – poor eye contact, lack of expression

Alogia – poor vocabulary, poor content of speech

Avolition / Apathy – indifference, detachment

Anhedonia / Asociality – lack of interest

Attention problems - inattentiveness

Typical Antipsychotics

Aliphatic Phenothiazines

Piperidine Phenothiazines

Piperazine Phenothiazines

Thioxanthenes

Butyrophenones

Aliphatic Phenothiazines

Chlorpromazine, Promethazine, Triflupromazine