academic half-day neuropharmacology

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


Anticonvulsants


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


•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


•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)


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


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



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



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


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


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



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: SummaryPART I: What makes nerve cells excitable?


OUTLINE


Anticonvulsants


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


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)


Dopamine is a catecholamine neurotransmitter


There are 5 dopamine receptor subtypes: D1, D2, D3, D4, D5

Excitatory Inhibitory


D1 and D2 receptors in the striatum mediate different effects


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



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



Catechol-O-Methyl Transferase Inhibitors (COMT-I)

Entacapone (peripheral) Tolcapone (central, but

hepatotoxicity limits use) Prevents conversion of

levodopa (peripheral and central)

X

X


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


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.

academic half-day neuropharmacology

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