Academic Half-Day
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
Movement disorders (PD)
Stroke
Neurotransmitter
&
Receptor systems
•GABA
•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
•Glutamatergic excitation
Excitation
Inhibition
•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
Presynaptic membranes
Neurotransmitter release
Post-synaptic membranes
Activation of calciumdependent enzyme pathways/gene transcription
PHT
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 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
Tiagabine
Gabapentin
VPA
LTG
(increase GABA levels by unknown mechanism)
Felbamate
Barbiturates
(increase duration of opening of channel)
Benzodiazepines
(increase frequency of opening of channel)
Vigabatrin
Brambilla et al (2003)

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

Anticonvulsants: Summary
Drug
Phenobarbital
Phenytoin
Carbamazepine
Oxcarbazepine
Valproate
Mechanism of Action
Agonist of GABA (A) receptors
Antagonist of N- and L-type voltage-gated Ca channels
Stabilizes inactive state of voltage-gated Na Channels
Inhibit presynaptic release of NT via L-type Ca channels
Stabilizes inactive state of voltage-gated Na Channels
Inhibit presynaptic release of NT via L-type Ca channels
Stabilizes inactive state of voltage-gated Na Channels
Increases GABA levels
Blocks NMDA glutamate receptors
Blocks T-type voltage gated Ca channels
Antagonist of T-type voltage-gated Calcium channels Ethosuximide
Benzodiazepines (clobazam) Agonist of GABA (A) receptors

Anticonvulsants: Summary
Drug
Lamotrigine
Vigabatrin
Gabapentin
Pregabalin
Tiagabine
Mechanism of Action
Stabilizes inactive state of voltage-gated Na Channels
Increases intracellular GABA levels
May act at N, P/Q type voltage-gated Calcium channels
Blocks metabolism of GABA through GABA-T
Blocks presynaptic release of neurotransmitters via N-type Calcium channels
Increases intracellular GABA levels
Blocks GAT-1 and prevents uptake of GABA from synapse

Anticonvulsants: Summary
Drug
Felbamate
Levetiracetam
Topiramate
Mechanism of Action
Blocks NMDA glutamate receptors
Enhances GABA(A) receptor transmission
Unclear effect on voltage-gated Na channels
Blocks presynaptic vesicle recycling through SV 2A
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

 Carbamazepine/Oxcarbezepine
 Phenobarbital
 Valproic acid
 Topiramate
 Vigabatrin
 Phenytoin
 Lamictal
 Primidone

PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics



 Valproic acid

 Vigabatrin

 Lamictal
(decreases with OCP use)

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

 Carbamazepine
 Phenobarbital
 Valproic acid
 Topiramate
 Vigabatrin
 Phenytoin
 Lamictal
 Primidone

PART I: What makes nerve cells excitable?
Anticonvulsants: Pharmacokinetics


 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
 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
DRUG
ANTICHOLINERGICS
USUAL STARTING
DOSE
Trihexyphenidyl
Benztropine
Biperidin
1 mg
0.5 mg
1 mg
Amantadine 100 mg
LEVODOPA (WITH CARBIDOPA)
Immediate-release 100 mg
Controlled-release 100 mg
USUAL DAILY DOSE
2-12 mg
0.5-6.0 mg
2-16 mg
100-300 mg
150-800 mg
200-1000 mg
DOPAMINE AGONISTS
Bromocriptine
Pergolide
Pramipexole
Ropinirole
1.25 mg
0.05 mg
0.375 mg
0.75 mg
15-40 mg
2-4 mg
1.5-4.5 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
 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
DRUG
ANTICHOLINERGICS
USUAL STARTING
DOSE
Trihexyphenidyl
Benztropine
Biperidin
1 mg
0.5 mg
1 mg
Amantadine 100 mg
LEVODOPA (WITH CARBIDOPA)
Immediate-release 100 mg
Controlled-release 100 mg
USUAL DAILY DOSE
2-12 mg
0.5-6.0 mg
2-16 mg
100-300 mg
150-800 mg
200-1000 mg
DOPAMINE AGONISTS
Bromocriptine
Pergolide
Pramipexole
Ropinirole
1.25 mg
0.05 mg
0.375 mg
0.75 mg
15-40 mg
2-4 mg
1.5-4.5 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 on glutamate excitation and activation of voltage-gated calcium and