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Academic Half-Day Neuropharmacology

Academic Half-Day Neuropharmacology

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Academic Half-Day Neuropharmacology

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  1. Academic Half-DayNeuropharmacology Ruba Benini Pediatric Neurology (PGY-2) McGill University April 6th, 2011

  2. Preamble • Neuropharmacology: the study of how drugs affect cellular function in the nervous system • Basic neurophysiological properties of the nervous system • Nerve cells are excitable cells • Passive and active mechanisms are used to store potential energy in the form of electrochemical gradients • Movement of charged molecules (ions) along these electrochemical gradients form the basis of electrical signaling in the nervous system

  3. Preamble • Basic neurophysiological properties of the nervous system • Ion channels are transmembrane proteins with hydrophilic pores that allow ions to flow along their electrochemical gradients • Channels differ based on • Gating (voltage-gated vs ligand gated vs stress gated) • Selectivity of ions

  4. Preamble • Basic neurophysiological properties of the nervous system • Generation of action potential allows electrical signal to be transported over long distances • The final output depends on what, when and where in the nervous system • Rapid and precise communication between neurons is made possible by 2 main signaling mechanisms: • Fast axonal conduction • Synaptic transmission

  5. OUTLINE Review the mechanisms of action & pharmacokinetics of: • Anticonvulsants • Movement disorders (PD) • Stroke • Migraine • Dementia

  6. OUTLINE Review the mechanisms of action & pharmacokinetics of: • Anticonvulsants • Movement disorders (PD) • Stroke • Migraine • Dementia • Neurotransmitter • & • Receptor systems • GABA • Glutamate • Acetylcholine • Dopamine

  7. Anticonvulsants • Seizure: clinical manifestation of hyperexcitable neuronal networks where there is a pathologic imbalance between inhibitory and excitatory processes Excitation Inhibition • Paroxysmal depolarizing shift (PDS) Holmes and Ben Ari

  8. Anticonvulsants • Anticonvulsants control seizures either by increasing inhibition or decreasing excitation • Voltage-gated Na channels • Voltage-gated Ca channels • Glutamatergic excitation • GABAergic transmission Excitation Inhibition

  9. Anticonvulsants: Voltage-gated Na channels • Voltage-gated Na channels play important role in generation of action potential

  10. Anticonvulsants: Voltage-gated Na channels • Blockade/modulation of Voltage-gated Na channels is the most common mechanism of action of most of the AEDs • Bind and stabilize inactive forms of channel → prevent repetitive neuronal firing CBZ PHT VPA LTG Oxcarbazepine Eslicarbazepine ? Felbamate Topiramate Zonisamide Rufinamide Lacosamide

  11. Anticonvulsants: Voltage-gated Na channels • Blockade/modulation of Voltage-gated Na channels is the most common mechanism of action of most of the AEDs • Bind and stabilize inactive forms of channel → prevent repetitive neuronal firing

  12. Anticonvulsants: Voltage-gated Ca channels • Voltage-gated Ca channels play an important role in: • Release of neurotransmitter from presynaptic terminal • Activation of Calcium-dependent enzymes • Gene expression • Regulation of neuronal activity • Classified as: • Low-voltage activated • T-type • High-voltage activated • L, N, R, P and Q-type • T-type calcium channels involved in pacemaker/oscillatory activity • Thalamocortical rhythm generation (arousal and sleep) • Spike-wave discharges in absence epilepsy Khosravani and Zamponi (2006)

  13. Anticonvulsants: Voltage-gated Ca channels PHT CBZ Topiramate Phenobarbital Post-synaptic membranes Activation of calcium-dependent enzyme pathways/gene transcription Presynaptic membranes Neurotransmitter release Gabapentin Pregabalin Lamotrigine Phenobarbital ESM Zonisamide Valproic acid

  14. Anticonvulsants: Glutamatergic transmision • Glutamate is the most important excitatory neurotransmitter in the CNS Ionotropic Metabotropic Topiramate Felbamate

  15. Anticonvulsants: GABAergic transmision • GABA is the most important excitatory neurotransmitter in the CNS Brambilla et al (2003)

  16. Anticonvulsants: GABAergic transmision Ionotropic GABA(A) receptor Postsynaptic membrane: inward Chloride current that hyperpolarizes the membrane → inhibition • Metabotropic • GABA(B) receptor • Presynaptic membrane: inward Ca current that depolarizes the membrane → neurotransmitter release • Postsynaptic membrane: outward K current that hyperpolarizes the membrane → inhibition

  17. Anticonvulsants: GABAergic transmision Gabapentin VPA LTG (increase GABA levels by unknown mechanism) Tiagabine Felbamate Vigabatrin Barbiturates (increase duration of opening of channel) Benzodiazepines (increase frequency of opening of channel) Brambilla et al (2003)

  18. Anticonvulsants: Other mechanisms • Levetiracetam: acts on synaptic vessel SV 2A and prevents recycling of synaptic vesicles

  19. Anticonvulsants: Summary

  20. Anticonvulsants: Summary

  21. Anticonvulsants: Summary

  22. Anticonvulsants: Panayiotopoulos (2010)

  23. PART I: What makes nerve cells excitable? Anticonvulsants: Pharmacokinetics • Which of the following AED decrease efficacy of OCP? • Carbamazepine/Oxcarbezepine • Phenobarbital • Valproic acid • Topiramate • Vigabatrin • Phenytoin • Lamictal • Primidone

  24. PART I: What makes nerve cells excitable? Anticonvulsants: Pharmacokinetics • Which of the following AED decrease efficacy of OCP? • Carbamazepine/Oxcarbezepine • Phenobarbital • Valproic acid • Topiramate • Vigabatrin • Phenytoin • Lamictal (decreases with OCP use) • Primidone http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm

  25. PART I: What makes nerve cells excitable? Anticonvulsants: Pharmacokinetics • Enzyme-Inducers: • Increase rate of metabolism of drugs metabolized by CYP enzymes • Results in changes in sex hormone levels and increases clearance of estrogen and progesterone in OCP • Increase metabolism of Vit D (which is metabolized by liver) → rickets and hypocalcemia in children Panayiotopoulos (2010)

  26. PART I: What makes nerve cells excitable? Anticonvulsants: Pharmacokinetics • Which of the following AED will be increased with the concomitant use of erythromycin or clarithromycin? • Carbamazepine • Phenobarbital • Valproic acid • Topiramate • Vigabatrin • Phenytoin • Lamictal • Primidone

  27. PART I: What makes nerve cells excitable? Anticonvulsants: Pharmacokinetics • Which of the following AED will be increased with the concomitant use of erythromycin or clarithromycin? • Carbamazepine • Phenobarbital • Valproic acid • Topiramate • Vigabatrin • Phenytoin • Lamictal • Primidone

  28. Anticonvulsants: Summary Panayiotopoulos (2010)

  29. PART I: What makes nerve cells excitable? Anticonvulsants: Summary Panayiotopoulos (2010)

  30. OUTLINE Review the mechanisms of action & pharmacokinetics of: • Anticonvulsants • Movement disorders (PD) • Stroke • Migraine • Dementia

  31. PART I: What makes nerve cells excitable? Movement Disorders: Parkinson’s Disease • Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a triad of resting tremor, bradykinesia and rigidity. • α-synucleinopathy • Loss of dopaminergic neurons in the SNc • Direct pathway: • Initiation and maintenance of movement • Indirect pathway: • Suppression of movement • Loss of dopaminergic neurons in SNc in PD results in: • ↓ direct pathway • ↑ indirect pathway Bradley Table 75-8

  32. PART I: What makes nerve cells excitable? Movement Disorders: Parkinson’s Disease • There are 6 main classes of drugs used in the symptomatic treatment of PD • Anticholinergics • Amantadine • Levodopa • Monoamine oxidase Inhibitors (MAO-I) • Catechol-O-Methyl Transferase Inhibitors (COMT-I) • Dopamine agonists Bradley Table 75-8

  33. PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission • Dopamine is found in 3 main pathways in the CNS: • Tubero-infundibular system: projection from hypothalamus that plays a role in prolactin release from the pituitary gland • Mesolimbic pathway: dopamine from neurons in the ventral tegmental area tjat project to the prefrontal cortex, basal forebrain and nucleus accumbens (memory and reward behaviour) • Nigrostriatal tracts: dopaminergic neurons from SNc to the neostriatum (motor control)

  34. PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission • Dopamine is a catecholamine neurotransmitter

  35. PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission • There are 5 dopamine receptor subtypes: D1, D2, D3, D4, D5 Excitatory Inhibitory

  36. PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission • D1 and D2 receptors in the striatum mediate different effects

  37. PART I: What makes nerve cells excitable? Movement Disorders: Parkinson’s Disease • There are 6 main classes of drugs used in the symptomatic treatment of PD • Anticholinergics • Amantadine • Levodopa • Monoamine oxidase Inhibitors (MAO-I) • Catechol-O-Methyl Transferase Inhibitors (COMT-I) • Dopamine agonists Bradley Table 75-8

  38. Movement Disorders: Parkinson’s Disease • Carbidopa/Levodopa (Sinemet) • Dopamine does not cross the BBB • Levodopa can cross the BBB • L-DOPA is combined with carbidopa/benserazide • This inhibits the peripheral DDC • Prevents peripheral conversion to dopamine • Increases CNS availability of L-DOPA • Reduces peripheral side effects of dopamine (nausea which can be treated with domperidone – a peripheral dopamine antagonist) X Youdim et al.Nature Reviews Neuroscience7, 295–309 (April 2006)

  39. Movement Disorders: Parkinson’s Disease • Monoamine Oxidase Inhibitors • MAO exists in 2 forms: • MAOA and MAOB • Selegeline & Rasagilline prevent dopamine metabolism by inhibiting MAOB • Improve motor symptoms (reduce fluctuations) but do not delay progression of disease • May delay need for Levodopa X X Youdim et al.Nature Reviews Neuroscience7, 295–309 (April 2006)

  40. Movement Disorders: Parkinson’s Disease • Catechol-O-Methyl Transferase Inhibitors (COMT-I) • Entacapone (peripheral) • Tolcapone (central, but hepatotoxicity limits use) • Prevents conversion of levodopa (peripheral and central) X X Youdim et al.Nature Reviews Neuroscience7, 295–309 (April 2006)

  41. Movement Disorders: Parkinson’s Disease • Dopamine agonists • Non-ergot dopamine D2 agonists • Pramipexole (mirapex) • Ropinerole (requip) • Rotigotine patch • Both have some D3 agonism • Insomnia, compulsive behaviour, dyskinesia • Monotherapy in symptomatic management of early PD to delay use of levodopa • ?neuroprotective role • Ergot derived dopamine D2 agonist • Bromocriptine • Pergolide – discontinued because of cardiac valve fibrosis

  42. Movement Disorders: Parkinson’s Disease • Anticholinergics • Due to selective degeneration of striatonigral neurons, there is a cholinergic output overactivity • Artane and other anticholinergics antagonize central muscarinic AchR • Helpful for tremor • Amantadine • Antiviral for influenza A • Unknown mechanism in PD & controversial effectiveness (ineffective as per Cochrane review 2003) • Believed to increase dopamine release from the presynaptic terminal

  43. PART I: What makes nerve cells excitable? Movement Disorders: Summary of anti-PD drugs

  44. PART I: What makes nerve cells excitable? References: • Deckers et al. Conference Report. Current limitations of antiepileptic drug therapy:a conference review. Epilepsy Research 53 (2003) 1–17. • Joana Guimara˜es, and Jose´ Augusto Mendes Ribeiro. Pharmacology of Antiepileptic Drugs in Clinical Practice. The Neurologist 2010;16:353–357. • Johannessen SI, Landmark CJ. Antiepileptic drug interactions - principles and clinical implications. Curr Neuropharmacol. 2010 Sep;8(3):254-67. • Panayiotopoulos CP. A Clinical Guide to Epileptic Syndromes and Their treatment. Second Edition. 2010. • Rezak M. Current Pharmacotherapeutic Treatment Options in Parkinson’s Disease. Dis Mon 2007;53:214-222 • http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm

  45. PART I: What makes nerve cells excitable? Questions?