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Ruba BeniniPediatric Neurology (PGY-2)
McGill UniversityApril 6th, 2011
Academic Half-Day
Neuropharmacology
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
Movement disorders (PD)
Stroke
Migraine
Dementia
Neurotransmitter
&
Receptor systems•GABA
•Glutamate
•Acetylcholine
•Dopamine
Anticonvulsants
Seizure: clinical manifestation of hyperexcitable neuronal networks where there is a pathologic imbalance between inhibitory and excitatory processes
Inhibition
Excitation
Paroxysmal depolarizing shift (PDS)
Holmes and Ben Ari
Anticonvulsants
Anticonvulsants control seizures either by increasing inhibition or decreasing excitation
Inhibition
Excitation
•Voltage-gated Na channels
•Voltage-gated Ca channels
•Glutamatergic excitation
•GABAergic transmission
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
LTG
Oxcarbazepine
Eslicarbazepine
Lacosamide
?Felbamate
Topiramate
Zonisamide
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
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)
Anticonvulsants: Voltage-gated Ca channels
ESM
Zonisamide
Valproic acid
PHT
CBZ
Topiramate
Phenobarbital
Post-synaptic membranes
Activation of calcium-dependent enzyme pathways/gene transcriptionPresynaptic membranes
Neurotransmitter release
Gabapentin
Pregabalin
Lamotrigine
Phenobarbital
Anticonvulsants: Glutamatergic transmision
Glutamate is the most important excitatory neurotransmitter in the CNS
Ionotropic Metabotropic
Topiramate Felbamate
Anticonvulsants: GABAergic transmision
GABA is the most important excitatory neurotransmitter in the CNS
Brambilla et al (2003)
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
Anticonvulsants: GABAergic transmision
Brambilla et al (2003)
Barbiturates(increase duration of opening of channel)
Benzodiazepines(increase frequency of opening of channel)
Tiagabine
Vigabatrin
Gabapentin
VPA
LTG(increase GABA levels by unknown mechanism)
Felbamate
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) receptorsAntagonist of N- and L-type voltage-gated Ca channels
Phenytoin Stabilizes inactive state of voltage-gated Na ChannelsInhibit presynaptic release of NT via L-type Ca channels
CarbamazepineOxcarbazepine
Stabilizes inactive state of voltage-gated Na ChannelsInhibit presynaptic release of NT via L-type Ca channels
Valproate Stabilizes inactive state of voltage-gated Na ChannelsIncreases GABA levelsBlocks NMDA glutamate receptorsBlocks 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 ChannelsIncreases intracellular GABA levelsMay act at N, P/Q type voltage-gated Calcium channels
Vigabatrin Blocks metabolism of GABA through GABA-T
GabapentinPregabalin
Blocks presynaptic release of neurotransmitters via N-type Calcium channelsIncreases intracellular GABA levels
Tiagabine Blocks GAT-1 and prevents uptake of GABA from synapse
Anticonvulsants: Summary
Drug Mechanism of Action
Felbamate Blocks NMDA glutamate receptorsEnhances GABA(A) receptor transmissionUnclear effect on voltage-gated Na channels
Levetiracetam Blocks presynaptic vesicle recycling through SV 2A
Topiramate Blocks AMPA/Kainate glutamate receptorsBlocks L-type voltage gated Ca channelsUnclear effect on voltage-gated Na channelsMay enhance GABA(A) receptor transmissionWeak inhibitor of carbonic anhydrase
Anticonvulsants:
Panayiotopoulos (2010)
Anticonvulsants: PharmacokineticsPART I: What makes nerve cells excitable?
Which of the following AED decrease efficacy of OCP? Carbamazepine/Oxcarbezepine Phenobarbital Valproic acid Topiramate Vigabatrin Phenytoin Lamictal Primidone
Anticonvulsants: PharmacokineticsPART I: What makes nerve cells excitable?
http://basic-clinical-pharmacology.net/chapter%2024_%20antiseizure%20drugs.htm
Which of the following AED decrease efficacy of OCP? Carbamazepine/Oxcarbezepine Phenobarbital Valproic acid Topiramate Vigabatrin Phenytoin Lamictal (decreases with OCP use)
Primidone
Anticonvulsants: PharmacokineticsPART I: What makes nerve cells excitable?
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)
Anticonvulsants: PharmacokineticsPART I: What makes nerve cells excitable?
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: PharmacokineticsPART I: What makes nerve cells excitable?
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)
Anticonvulsants: SummaryPART I: What makes nerve cells excitable?
Panayiotopoulos (2010)
OUTLINE
Review the mechanisms of action & pharmacokinetics of:
Anticonvulsants
Movement disorders (PD)
Stroke
Migraine
Dementia
Movement Disorders: Parkinson’s DiseasePART I: What makes nerve cells excitable?
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
Movement Disorders: Parkinson’s DiseasePART I: What makes nerve cells excitable?
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
DRUGUSUAL 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: Dopaminergic TransmissionPART I: What makes nerve cells excitable?
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)
Movement Disorders: Dopaminergic TransmissionPART I: What makes nerve cells excitable?
Dopamine is a catecholamine neurotransmitter
Movement Disorders: Dopaminergic TransmissionPART I: What makes nerve cells excitable?
There are 5 dopamine receptor subtypes: D1, D2, D3, D4, D5
Excitatory Inhibitory
Movement Disorders: Dopaminergic TransmissionPART I: What makes nerve cells excitable?
D1 and D2 receptors in the striatum mediate different effects
Movement Disorders: Parkinson’s DiseasePART I: What makes nerve cells excitable?
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
DRUGUSUAL 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
Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006)
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
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
Movement Disorders: Summary of anti-PD drugsPART I: What makes nerve cells excitable?
References:PART I: What makes nerve cells excitable?
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
Questions?
PART I: What makes nerve cells excitable?
Seizing hold of seizuresGregory L Holmes & Yezekiel Ben-Ari
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 on glutamate excitation and activation of voltage-gated calcium and sodium channels. After the depolarization, the cell is hyperpolarized by activation of GABA receptors as well as voltage-gated potassium channels. Axons from the abnormal neurons also activate GABAergic inhibitory neurons (green) which reduce the activity in cells II and III in addition to blocking the firing of cells outside the seizure focus (cells I and IV). An electroencephalogram (EEG) recorded during this time would show a spike and a subsequent slow wave. When the balance of excitation and inhibition is further disturbed, there will be a breakdown in containment of the epileptic focus and a seizure will occur. (c) A sustained depolarization without repolarization occurs in many cells during the seizure. An EEG would show repetitive spikes during the seizure. By inducing cells to release galanin, an endogenous anticonvulsant that reduces glutamate release, Haberman et al. successfully increased inhibition and thereby reduced seizure susceptibility.