Central Nervous System Pharmacology (Week 10) PDF

# Overview of the CNS - **Cerebrum** - **Diencephalon:** - Hypothalamus - Thalamus - Pineal gland (part of epithalamus) - **Brainstem:** - Midbrain - Pons - Medulla oblongata - **Cerebellum** - **Pituitary gland** - **Spinal cord** - **Central canal** # Neurotransmitters:...

# Overview of the CNS - **Cerebrum** - **Diencephalon:** - Hypothalamus - Thalamus - Pineal gland (part of epithalamus) - **Brainstem:** - Midbrain - Pons - Medulla oblongata - **Cerebellum** - **Pituitary gland** - **Spinal cord** - **Central canal** # Neurotransmitters: - Chemical messengers of the brain. - More than 100 unique neurotransmitters have been identified. - **Well-known neurotransmitters:** - Dopamine - Serotonin - GABA - Glutamate - Glycine - Acetylcholine - Norepinephrine / Noradrenaline - Epinephrine / Adrenaline # Central Nervous System Pharmacology ## Chapter 1: Antiepileptic Drugs - **Benzodiazepines** - They bind to GABA receptors. - Clonazepam, Diazepam, Clorazepate and Lorazepam - **Clonazepam:** - Potent and long-acting antiepileptic benzodiazepine. - **Diazepam:** - Used in short-term therapy of epilepsy (tolerance and sedation) - Status epilepticus - Most potent drug for febrile convulsions in infants and children (rectal administration). - **Sedation** is a common adverse effect. - Should not be stopped immediately. - **Carbamazepine** - Block the Na channels. - **Therapeutic areas:** - All epilepsy types (except absence and myoclonic) - Neuropathic pain (trigeminal neuralgia) - Bipolar disorders, DI, Cancer pain - **Pharmacokinetic properties:** - Serum concentrations show large variations (absorption and metabolism) - Powerful inducer of microsomal enzyme system and UGT system (drug interactions, adjuvant antiepileptic use), *autoinduction* - Some of the metabolites are active. - May not be tolerated well in elderly. - **Adverse effects:** - GIS disorders, Neurological disorders, Hematological problems, Allergic reactions, Anticholinergic effects, Cardiac problems and edema - **Na channels and Epilepsy** - Diagram of a voltage-gated sodium channel: - Open - Inactivated - Activation gate - Inactivation gate - Carbamazepine - Phenytoin - Lamotrigine - Valproate - **Oxcarbazepine and Ethosuximide** - **Oxcarbazepine:** - Less potent inducer of CYP3A4 and UGT systems. - Effective on partial onset seizures and TN - Higher risk for hyponatremia - Eslicarbazepine - **Ethosuximide:** - Inhibition of T-type Ca channels and K channels - Effective on absence seizures (little or no effect on other types)-narrow antiepileptic spectrum - *Nausea/Vomiting and Anorexia* are common adverse effects. - Lethargy, dizziness and headache - Blood counts are required (eosinophilia) - **Felbamate** - **Multiple Proposed Mechanisms of Action:** - Block voltage-dependent sodium channels - Potentiate the GABA action - Blocking NMDA-glutamate receptor. - Has a broader clinical spectrum than earlier antiepileptic drugs, but the use is limited to refracter epilepsies (Lennox-Gastaut Syndrome) - **Adverse effects are:** - nausea, irritability and insomnia - severe reactions like aplastic anaemia and hepatitis. - **Carisbamate:** - New drug in clinical trial with a lower risk of aplastic anaemia - **Lennox-Gastaut Syndrome** - **What is LGS?** - Lennox-Gastaut Syndrome (LGS) is a rare and severe form of childhood-onset epilepsy that is characterized by *frequent* seizures, *multiple* seizure types, a *resistance* to medication and/or therapies, behavior disturbances and moderate to severe cognitive dysfunction. - Although there is no cure for Lennox-Gastaut Syndrome, it is our hope that new treatment options will become available and will help improve the overall outcome and quality of life for all patients living with this disorder. - **Gabapentin and Pregabalin** - **Gabapentin:** analogue of GABA - **Pregabalin:** analogue of gabapentin - Multiple mechanisms of actions are proposed, but mainly act on P/Q type Ca channels. - They are effective against partial seizures. - **Relatively safe antiepileptic agents:** - Absorption: L-amino acid carrier. - Less adverse effects (sedation and ataxia) - Less drug interactions (adjuvant with other antiepileptics) - Short plasma half-life (about 6-9 h) – multiple dosing - Effective in neuropathic pain treatment. - Excreted unchanged in urine - **Safer in elderly** - **Lamotrigine** - Inhibit Na channel function, additionally Ca channel blockage and inhibition of glutamate release. - Wide spectrum antiepileptic agent (significant effect on absence seizures). - Approved for *bipolar disorders*. - Metabolized by UGT pathway- interaction with antiepileptic agents. - Carbamazepine **↓** - Phenytoin **↓** - Valproate **↑** - Hypersensitivity reactions like rashes may be life-threatining. - Minor side effects, so well-tolerated in elderly. - **Levetiracetam and Phenobarbital** - **Levetiracetam:** - Mechanism of action: SV2A protein. - Partial and generalized tonic-clonic seizures. - **Pharmacokinetic properties:** - Does not interact with CYP nor UGT metabolism systems. - Excreted mostly in unchanged form via urine. - Brivaracetam: ten-fold higher affinity to SV2A protein. - **Phenobarbital:** - It is a long-acting barbiturate (1-2 days) - Enhance the inhibitory effects of GABA-mediated neurons. - Status epilepticus - **Phenytoin and Fosphenytoin** - **Main mechanism of action:** Blocks voltage-gated Na channels. - Effective in partial and generalized tonic-clonic seizures (*but not for absence epilepsy*). - **Pharmacokinetic aspects:** - Well absorbed and highly bound to albumin (valproate interaction). - Metabolism of phenytoin shows a *saturable* characteristics. - Therapeutic range is quite narrow (40-100 μmol/l)-plasma monitoring - **Unwanted effects:** - Nystagmus, ataxia, vertigo, headache (Sedation is not a subject) - Confusion, intellectual deterioration and increased seizure frequency. - Gingival hyperplasia, Hirsutism - Megaloblastic anaemia, peripheral neuropathies, osteoporosis, hypersensitivity reactions-skin rashes, fetal malformations - **Fosphenytoin:** - Can be administered intramuscularly (phenytoin cannot) - Cerebyx-Celebrex-Celexa - **Rufinamide and Stiripentol** - **Rufinamide:** - **Mechanism of action:** - Na channel inactivation (main mechanism) - Inhibition of GABA re-uptake - Approved for adjunctive treatment for Lennox-Gastaut syndrome. - Serum concentrations are affected by; - Food ↑ - Carbamazepine and phenytoin ↑ - Valproate ↓ - Birth control tablet interactions - Shortened QT-interval in ECG. - **Stiripentol:** - Prolongs GABAergic transmission - Has some efficacy as an adjunctive therapy in children. - **Zonisamide and Tiagabine** - **Zonisamide:** - **Mechanism of action:** - Block Na and T-type Ca channels - Enhance GABAergic transmission - Approved for use in patients with partial epilepsy. - **CNS side effects:** ataxia, confusion, sedation and concentration disturbances - Loss of apetite and weight loss - Carbonic anhydrase acitivity - Oligohidrosis - Increased body temperature - Decreased sweating - Kidney stones - **Tiagabine:** - Inhibitor of GABA transporter-1 - Mainly used as an add-on therapy for partial seizures - Should not be used for any other indication. - **Topiramate** - **Does a little of everything:** - Blocks voltage-dependent Na channels - L-type Ca currents are reduced. - GABA-A receptor stimulation - Inhibition of glutamate receptor activity - Very wide spectrum of anti-epileptic activity - Also approved for treatment of migraine - Topiramate has similar spectrum of action with phenytoin but; - Less severe side effects, - Devoid of pharmacokinetic properties of phenytoin - **Unwanted effects:** - Drug interactions (antiepileptics and hormonal contraceptives) - Sedation, weight loss due to apetite supression - Carbonic anhydrase activity - Teratogenic - **Valproic Acid and Divalproex** - **Valproic acid:** simple monocarboxylic acid - **Divalproex:** Sodium valproate + Valproic acid - **Mechanisms of action:** - T-type Ca channel inhibition (absence epilepsy) - Na-channel blockage - Inhibition of GABA transaminase (*like vigabatrin*) - Effective in many kinds of epilepsy including absence and myoclonic seizures. - Used in the treatment of bipolar disorders. - High albumin binding ratio (90%). - **Unwanted effects:** - Hepatitis - Teratogenicity-neural tube defects like spina bifida and impaired cognitive function. - Hair thinning and curling (10%). - **Vigabatrin** - Irreversible and potent inhibitor of GABA transaminase. - Half-life is short, but long duration of antiepileptic action (*once a day*). - Effective on almost all types of epilepsies; particularly resistant patients to the established drugs. - Peripheral visual field defect (*benefit-risk ratio*) - Sedation, depression, psychotic disturbances and hallucinations. - **Mechanisms for antiepileptic action** - Diagram showing the mechanism of action of AEDs: - Inhibitory presynaptic nerve terminal - GABA transaminase - Valproic Acid - GABA transporter - Tiagabine - Excitatory presynaptic nerve terminal - Action potential - Zonisamide - Ethosuximide - Na+ channel - Ca++ channel - Topiramate - Felbamate - Glutamate receptors - Ca++, Na+ - Glutamate - GABA - GABA receptor - Postsynaptic neuron - Potentiates - Phenytoin - Carbamazepine - Valproic acid - Felbamate - Topiramate - Lamotrigine - Oxcarbazepine - Zonisamide - **Novel Mechanisms for New Antiepileptic Agent Development** - **Retigabine:** - Activate neuronal KCNQ (Kv7) potassium channels - **Lacosamide:** - Slow inactivation of Na channels - CRMP-2 binding-collapsin response mediator protein - Approved for adjunctive therapy of partial seizures - Due to euphoria side effect, it is a controlled substance. - **Tonabersat:** - Neuronal gap-junction inhibitor - **Ganaxolone:** - Positive allosteric modulator of GABA-A receptors - **Adverse Effects of Antiepileptic Agents** - Nausea and vomiting - Sedation - Ataxia - Rash - Hyponatremia - Body weight changes - Osteoporosis - Teratogenicity - **Other Uses of Antiepileptic Drugs** - **Treatment for painful conditions:** - Neuropathic pain (gabapentin, pregabalin, carbamazepine, lamotrigine) - Migraine prophylaxis (valproate, gabapentin, topiramate) - **Bipolar disorders:** - Valproate - Carbamazepine - Oxcarbazepine - Lamotrigine - Topiramate - **Anxiety disorders:** - Gabapentin - **Pregnancy and Antiepileptic Drugs** - **Inducing hepatic microsomal enzymes:** - Decrease the effect of oral contraceptives - Result with Vitamin K deficiency in newborns - **Teratogenicity:** - Taken during pregnancy, drugs such as: - Phenytoin - Valproate - Topiramate - Carbamazepine - Lamotrigine - **Pregnancy planning is very important.** - **Before pregnancy,** - Antiepileptic drugs with teratogenicity risk must be switched - Lowest dose that control the seizure should be adjusted prior to pregnancy. # The End - the end of one chapter is just the beginning of another.