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Academic Half-Day Neuropharmacology Ruba Benini Pediatric Neurology (PGY-2) McGill University April 6th, 2011 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 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 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 OUTLINE Review the mechanisms of action & pharmacokinetics of: Anticonvulsants Movement disorders (PD) Stroke Migraine Dementia OUTLINE Review the mechanisms of action & pharmacokinetics of: Anticonvulsants Neurotransmitter & Movement disorders (PD) Receptor systems •GABA Stroke •Glutamate •Acetylcholine •Dopamine Migraine Dementia 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 Anticonvulsants Anticonvulsants control seizures either by increasing inhibition or decreasing excitation •Voltage-gated Na channels •Voltage-gated Ca channels •GABAergic transmission •Glutamatergic excitation Excitation Inhibition Anticonvulsants: Voltage-gated Na channels •Voltage-gated Na channels play important role in generation of action potential 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 Oxcarbazepine ? Eslicarbazepine Felbamate LTG Topiramate Zonisamide Lacosamide Rufinamide 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 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 High-voltage activated T-type 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) Anticonvulsants: Voltage-gated Ca channels PHT Post-synaptic membranes Presynaptic membranes Neurotransmitter release Activation of calciumdependent enzyme pathways/gene transcription CBZ Topiramate Phenobarbital Gabapentin Pregabalin Lamotrigine Phenobarbital ESM Zonisamide Valproic acid Anticonvulsants: Glutamatergic transmision Glutamate is the most important excitatory neurotransmitter in the CNS Ionotropic Topiramate Metabotropic Felbamate Anticonvulsants: GABAergic transmision GABA is the most important excitatory neurotransmitter in the CNS Brambilla et al (2003) Anticonvulsants: GABAergic transmision Ionotropic Metabotropic GABA(A) receptor GABA(B) receptor Postsynaptic membrane: inward Chloride current that hyperpolarizes the membrane → inhibition •Presynaptic membrane: inward Ca current that depolarizes the membrane → neurotransmitter release •Postsynaptic membrane: outward K current that hyperpolarizes the membrane → inhibition Anticonvulsants: GABAergic transmision Gabapentin VPA LTG Tiagabine (increase GABA levels by unknown mechanism) Felbamate Vigabatrin Barbiturates Benzodiazepines (increase duration of opening of channel) (increase frequency of opening of channel) Brambilla et al (2003) Anticonvulsants: Other mechanisms Levetiracetam: acts on synaptic vessel SV 2A and prevents recycling of synaptic vesicles Anticonvulsants: Summary Drug Mechanism of Action Phenobarbital Agonist of GABA (A) receptors Antagonist of N- and L-type voltage-gated Ca channels Phenytoin Stabilizes inactive state of voltage-gated Na Channels Inhibit presynaptic release of NT via L-type Ca channels Carbamazepine Oxcarbazepine Stabilizes inactive state of voltage-gated Na Channels Inhibit presynaptic release of NT via L-type Ca channels Valproate Stabilizes inactive state of voltage-gated Na Channels Increases GABA levels Blocks NMDA glutamate receptors Blocks T-type voltage gated Ca channels Ethosuximide Antagonist of T-type voltage-gated Calcium channels Benzodiazepines (clobazam) Agonist of GABA (A) receptors Anticonvulsants: Summary Drug Mechanism of Action Lamotrigine Stabilizes inactive state of voltage-gated Na Channels Increases intracellular GABA levels May act at N, P/Q type voltage-gated Calcium channels Vigabatrin Blocks metabolism of GABA through GABA-T Gabapentin Pregabalin Blocks presynaptic release of neurotransmitters via N-type Calcium channels Increases intracellular GABA levels Tiagabine Blocks GAT-1 and prevents uptake of GABA from synapse Anticonvulsants: Summary Drug Mechanism of Action Felbamate Blocks NMDA glutamate receptors Enhances GABA(A) receptor transmission Unclear effect on voltage-gated Na channels Levetiracetam Blocks presynaptic vesicle recycling through SV 2A Topiramate Blocks AMPA/Kainate glutamate receptors Blocks L-type voltage gated Ca channels Unclear effect on voltage-gated Na channels May enhance GABA(A) receptor transmission Weak inhibitor of carbonic anhydrase Anticonvulsants: Panayiotopoulos (2010) 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 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 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) 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 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 Anticonvulsants: Summary Panayiotopoulos (2010) PART I: What makes nerve cells excitable? Anticonvulsants: Summary Panayiotopoulos (2010) OUTLINE Review the mechanisms of action & pharmacokinetics of: Anticonvulsants Movement disorders (PD) Stroke Migraine Dementia 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 PART I: What makes nerve cells excitable? Movement Disorders: Parkinson’s Disease DRUG 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 USUAL STARTING DOSE USUAL DAILY DOSE ANTICHOLINERGICS Trihexyphenidyl 1 mg 2-12 mg Benztropine 0.5 mg 0.5-6.0 mg Biperidin 1 mg 2-16 mg Amantadine 100 mg 100-300 mg LEVODOPA (WITH CARBIDOPA) Immediate-release 100 mg 150-800 mg Controlled-release 100 mg 200-1000 mg DOPAMINE AGONISTS Bromocriptine 1.25 mg 15-40 mg Pergolide 0.05 mg 2-4 mg Pramipexole 0.375 mg 1.5-4.5 mg Ropinirole 0.75 mg 8-24 mg Cabergoline 0.25 mg 0.25-4.0 mg CATECHOL-O-METHYL TRANSFERASE INHIBITORS Entacapone 200 mg with each dose 200 mg with each dose Tolcapone 300 mg 600 mg Bradley Table 75-8 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) PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission Dopamine is a catecholamine neurotransmitter PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission There are 5 dopamine receptor subtypes: D1, D2, D3, D4, D5 Excitatory Inhibitory PART I: What makes nerve cells excitable? Movement Disorders: Dopaminergic Transmission D1 and D2 receptors in the striatum mediate different effects PART I: What makes nerve cells excitable? Movement Disorders: Parkinson’s Disease DRUG 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 USUAL STARTING DOSE USUAL DAILY DOSE ANTICHOLINERGICS Trihexyphenidyl 1 mg 2-12 mg Benztropine 0.5 mg 0.5-6.0 mg Biperidin 1 mg 2-16 mg Amantadine 100 mg 100-300 mg LEVODOPA (WITH CARBIDOPA) Immediate-release 100 mg 150-800 mg Controlled-release 100 mg 200-1000 mg DOPAMINE AGONISTS Bromocriptine 1.25 mg 15-40 mg Pergolide 0.05 mg 2-4 mg Pramipexole 0.375 mg 1.5-4.5 mg Ropinirole 0.75 mg 8-24 mg Cabergoline 0.25 mg 0.25-4.0 mg CATECHOL-O-METHYL TRANSFERASE INHIBITORS Entacapone 200 mg with each dose 200 mg with each dose Tolcapone 300 mg 600 mg Bradley Table 75-8 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 Neuroscience 7, 295–309 (April 2006) 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 Neuroscience 7, 295–309 (April 2006) 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 Neuroscience 7, 295–309 (April 2006) 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 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 PART I: What makes nerve cells excitable? Movement Disorders: Summary of anti-PD drugs 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 PART I: What makes nerve cells excitable? Questions? Figure 1. Focal seizures result from a limited group of neurons that fire abnormally because of intrinsic or extrinsic factors. (a) In this simplified diagram, II and III represent epileptic neurons. Because of extensive cell-to-cell connections, termed 'recurrent collaterals', aberrant activity in cells II and III can fire synchronously, resulting in a prolonged depolarization of the neurons. (b) This intense depolarization of epileptic neurons is termed the paroxysmal depolarization shift. The prolonged depolarization results in action potentials and propagation of electrical discharges to other cells. The paroxysmal depolarization shift is largely dependent