Transcript Stabilizes inactive state of voltage-gated Na

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:
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
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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