Central Nervous System Overview and Pharmacology

Central Nervous System (CNS) Overview

• The CNS includes the cerebrum, diencephalon, brainstem, and cerebellum.
• The cerebrum is the largest part of the brain.
• The diencephalon includes the hypothalamus and thalamus, and the pineal gland (part of the epithalamus).
• The brainstem comprises the midbrain, pons, and medulla oblongata.
• The cerebellum is located beneath the cerebrum.
• The spinal cord connects the brain to the body.
• The central canal runs through the spinal cord.
• The pituitary gland is also part of the CNS.

Neurotransmitters

• Over 100 unique neurotransmitters are identified in the brain.
• Well-known neurotransmitters include dopamine, serotonin, GABA, glutamate, glycine, acetylcholine, norepinephrine, and epinephrine/adrenaline.

Central Nervous System Pharmacology: Antiepileptic Drugs – Benzodiazepines

• Benzodiazepines bind to GABA receptors.
• Clonazepam, diazepam, clorazepate, and lorazepam are benzodiazepines.
• Clonazepam is a potent, long-acting antiepileptic benzodiazepine.
• Diazepam is used for short-term epilepsy therapy; it can cause tolerance and sedation.
• Diazepam is the most potent drug for febrile convulsions in infants and children (given rectally).
• Sedation is a common side effect; the drug should not be stopped abruptly.

Central Nervous System Pharmacology: Antiepileptic Drugs – Carbamazepine

• Carbamazepine blocks Na channels, treating various epilepsies (except absence and myoclonic).
• It also helps with neuropathic pain (trigeminal neuralgia), bipolar disorder, and cancer pain.
• Serum concentrations of carbamazepine vary significantly due to absorption and metabolism differences.
• Carbamazepine can induce microsomal enzyme systems and UGT systems, leading to drug interactions.
• Some of its metabolites are active.
• Older adults may not tolerate carbamazepine well.
• Common side effects include: gastrointestinal issues, neurological issues, hematological problems, allergic reactions, anticholinergic effects, and cardiac problems.

Central Nervous System Pharmacology: Antiepileptic Drugs – Oxcarbazepine and Ethosuximide

• Oxcarbazepine is a 10-MHD, Na-channel anticonvulsant, less potent in inducing CYP3A4 and UGT systems.
• Effective against partial onset seizures and trigeminal neuralgia.
• Higher risk for hyponatremia.
• Ethosuximide inhibits T-type Ca and K channels, primarily for absence seizures.

Central Nervous System Pharmacology: Antiepileptic Drugs – Felbamate

• Felbamate blocks voltage-dependent Na channels, potentiating GABA action, and blocking NMDA-glutamate receptors.
• It has a broad clinical spectrum compared to other antiepileptic drugs, but its use is limited, primarily for Lennox-Gastaut Syndrome.
• Common side effects include nausea, irritability, and insomnia; severe reactions like aplastic anemia and hepatitis are possible.

Central Nervous System Pharmacology: Antiepileptic Drugs – Gabapentin and Pregabalin

• Gabapentin and pregabalin are GABA analogues and mainly affect P/Q type calcium channels, effectively treating partial seizures.
• These drugs are generally safe for older adults.
• Common side effects include sedation and ataxia.

Central Nervous System Pharmacology: Antiepileptic Drugs – Lamotrigine

• Lamotrigine inhibits Na channel functions, blocks Ca channels, and inhibits glutamate release.
• It's effective for absence seizures, bipolar disorders, and interacts with other antiepileptic medications through UGT pathways.
• Possible side effects include hypersensitivity reactions like rashes, which can be life-threatening.

Central Nervous System Pharmacology: Antiepileptic Drugs – Levetiracetam and Phenobarbital

• Levetiracetam's mechanism involves the SV2A protein and treats partial and generalized tonic-clonic seizures.
• It does not interact with CYP or UGT metabolic systems. Excreted primarily unchanged in urine.
• Phenobarbital, a long-acting barbiturate, enhances GABA-mediated neuron inhibitory effects; it treats status epilepticus.

Central Nervous System Pharmacology: Antiepileptic Drugs – Phenytoin and Fosphenytoin

• Phenytoin and fosphenytoin block voltage-gated sodium channels. They are effective for partial and generalized tonic-clonic seizures but not absence seizures.
• Phenytoin's metabolism is saturable; blood levels need close monitoring (40–100 μmol/L).
• Side effects may include nystagmus, ataxia, confusion, and gingival hyperplasia.

Central Nervous System Pharmacology: Antiepileptic Drugs – Rufinamide and Stiripentol

• Rufinamide's mechanism involves sodium channel inactivation, preventing GABA re-uptake. It's approved for Lennox-Gastaut syndrome, but food, carbamazepine, and phenytoin can affect blood levels.
• Stiripentol, a related drug, prolongs GABAergic transmission, aiding in child-specific treatments.

Central Nervous System Pharmacology: Antiepileptic Drugs – Zonisamide and Tiagabine

• Zonisamide blocks Na and T-type Ca channels, enhancing GABAergic transmission, and treats partial seizures; side effects include loss of appetite, weight loss, and carbonic anhydrase activity disruption.
• Tiagabine is a GABA transporter inhibitor, mainly treating partial seizures. It should be avoided for other indications.

Central Nervous System Pharmacology: Antiepileptic Drugs – Topiramate

• Topiramate blocks voltage-gated Na channels, reduces L-type calcium currents, stimulates GABA-A receptors, and inhibits glutamate receptors.
• Effective for various epilepsies and migraines. Less severe side effects than phenytoin, but interacts with other medications like antiepileptics and hormonal contraceptives.
• Side effects can include sedation, weight loss (related to decreased appetite), and carbonic anhydrase activity.

Central Nervous System Pharmacology: Antiepileptic Drugs – Valproic Acid and Divaproex

• Valproic acid and divalproex block T-type Ca channels, inhibit GABA transaminase, and treat many epilepsy types, including absence and myoclonic seizures.
• They also help treat bipolar disorders. Divaproex has a notably high binding ratio to albumin (90%).
• Potential side effects include hepatotoxicity (liver damage), teratogenesis (neural tube defects), and hair changes.

Central Nervous System Pharmacology: Antiepileptic Drugs – Vigabatrin

• Vigabatrin is an irreversible, potent GABA transaminase inhibitor.
• Effective for various epilepsy types, especially those resistant to other medications.
• Short half-life, but long-lasting action. Side effects can include visual field defects (benefit-risk needs analysis), sedation, depression, psychosis, and hallucinations.

Novel Mechanisms for New Antiepileptic Agent Development

• Retigabine activates neuronal KCNQ potassium channels.
• Lacosamide slows inactivation of sodium channels.
• Tonabersat is a neuronal gap-junction inhibitor.
• Ganaxolone is a positive allosteric modulator of GABA-A receptors.

Adverse Effects of Antiepileptic Agents

• Common adverse effects include nausea, vomiting, sedation, ataxia, rash, hyponatremia, body weight changes, and osteoporosis.
• Teratogenicity (harmful effects on a developing fetus) is a concern for some drugs.

Other Uses of Antiepileptic Drugs

• Antiepileptic drugs have additional uses, including treating neuropathic pain, migraines, bipolar disorders, and anxiety disorders.

Pregnancy and Antiepileptic Drugs

• Antiepileptic drugs can affect hepatic microsomal enzymes, potentially decreasing the effectiveness of oral contraceptives, and can lead to Vitamin K deficiency in newborns.
• Pregnancy planning is crucial for managing antiepileptic drug use, and dose adjustments might be needed.

Summary of Findings

• The provided text outlines various antiepileptic drugs used in treating different types of seizures.
• It details their proposed mechanisms of action, potential side effects, and other clinical considerations.

Explore the intricate workings of the Central Nervous System (CNS) including its structure, neurotransmitters, and pharmacology related to antiepileptic drugs like benzodiazepines. This quiz covers key components such as the cerebrum, brainstem, and important neurotransmitters like dopamine and serotonin. Test your knowledge on how these elements interact and their significance in medical treatments.