Drug List 7 & 9: Moa [Pharmacology I]

Front 1

Mechanisms of Action for Phenytoin (fen’ i toyn)

Back 1

Phenytoin binds to and prolongs the fast inactivated state of presynaptic, voltage-gated Na+ channels, limiting the repetitive firing of action potentials, and thereby inhibiting the release of excitatory neurotransmitters. Phenytoin is also said to “enhance synaptic release of GABA.”

Front 2

Mechanism of Action for Fosphenytoin (fos fen’ i toyn)

Back 2

Fosphenytoin is a prodrug of phenytoin bearing a disodium phosphate ester moiety that enhances water solubility. It is rapidly converted to phenytoin in the plasma.

Front 3

Mechanisms of Action for Carbamazepine (kar ba maz’ e peen)

Back 3

Carbamazepine binds to and prolongs the fast inactivated state of presynaptic, voltage-gated Na+ channels, limiting the repetitive firing of action potentials, and thereby inhibiting the release of excitatory neurotransmitters. Carbamazepine also exerts a mood-stabilizing effect through an inositol depletion mechanism.

Front 4

Mechanism of Action for Oxcarbazepine (ox car baz’ e peen)

Back 4

Oxcarbazepine binds to and prolongs the fast inactivated state of presynaptic, voltage-gated Na+ channels, limiting the repetitive firing of action potentials, and thereby inhibiting the release of excitatory neurotransmitters.

Front 5

Mechanisms of Action for Phenobarbital (fee noe bar’ bi tal)

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A subject of debate, phenobarbital’s anticonvulsant action appears to result from a combination of effects, including the enhancement of GABA-A receptor-mediated inhibitory processes, the diminution of glutamate-mediated excitatory transmission, and the suppression of firing from abnormal neurons.

Front 6

Mechanism of Action for Primidone (pri’ mi done)

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Primidone is metabolized to either phenobarbital or phenylethylmalonamide (PEMA). All three are active anticonvulsants. Primidone itself is thought to have a MOA like that of phenytoin.

Front 7

Mechanisms of Action for Lamotrigine (la moe’ tri jeen)

Back 7

Lamotrigine binds to and prolongs the fast inactivated state of presynaptic, voltage-gated Na+ channels, limiting the repetitive firing of action potentials, and thereby inhibiting the release of excitatory neurotransmitters. Lamotrigine also inhibits presynaptic, voltage-gated, N- and P/Q-type calcium channels that control the entry of Ca2+ responsible for triggering the exocytosis of excitatory neurotransmitters.

Front 8

Mechanisms of Action for Felbamate (fel bam’ ate)

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Felbamate potentiates GABA-A receptor responses and produces a use-dependent inhibition of the NR1-2B subtype of glutamate-activated NMDA receptors.

Front 9

Mechanisms of Action for Gabapentin (ga’ ba pen tin)

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Gabapentin binds to the alpha2-delta subunit of presynaptic, voltage-gated, N-type calcium channels, inhibiting the entry of Ca2+ responsible for triggering the exocytosis of excitatory neurotransmitters, such as glutamate. Gabapentin is also thought to enhance the release of GABA, given the increased GABA concentrations that are observed.

Front 10

Mechanism of Action for Pregabalin (pre gab’ a lin)

Back 10

Pregabalin has a mechanism of action that mimics that of Gabapentin.

Front 11

Mechanisms of Action for Lacosamide (la koe’ sa mide)

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Lacosamide prolongs the slow inactivated state of presynaptic, voltage-gated Na+ channels, which are more populated with repetitive action potential firing. Thus it exerts a use-dependent dampening effect on the release of excitatory neurotransmitters. Lacosamide also binds the collapsing-response mediator protein CRMP-2, blocking the effect of neurotrophins, such as BDNF and NT3, theoretically modulating the disease-modifying axonal outgrowth of primary hippocampal cells associated with epilepsy.

Front 12

Mechanism of Action for Levetiracetam (lee ve tye ra’ se tam)

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Levetiracetam selectively binds the (presynaptic) synaptic vesicular protein SV2A, which is thought to modify the release of GABA and glutamate.

Front 13

Mechanism of Action for Tiagabine (ty ag’ a been)

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Tiagabine preferentially inhibits GABA Uptake Transporter Isoform 1 (GAT-1) in both neurons and glia, thus increasing extracellular GABA levels in the forebrain and hippocampus.

Front 14

Mechanisms of Action for Topiramate (toe pyre’ a mate)

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Topiramate blocks neuronal sodium channels in a voltage- and frequency-dependent manner. It blocks kainate and AMPA subtypes of the glutamate receptor and it enhances GABA-A receptor actions through a site that is distinct from the one acted upon by benzodiazepines or barbituates. According to Dr. Oaks, it has multiple actions on synaptic function, “probably via actions on phosphorylation.”

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Mechanisms of Action for Zonisamide (zoe nis’ a mide)

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Zonisamide’s “primary site of action appears to be the sodium channels,” where it “blocks high-frequency firing,” though it “may act on voltage-gated calcium channels.”

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Mechanism of Action for Ethosuximide (eth oh sux’ i mide)

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Ethosuximide inhibits the lower threshold, T-type Ca2+ channels that provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack.

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Mechanism of Action for Vigabatrin (vye ga’ ba trin)

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Vigabatrin is an irreversible inhibitor of GABA aminotransferase, a.k.a. GABA transaminase (GABA-T), which is the enzyme responsible for the degradation of GABA.

Front 18

Mechanisms of Action for Valproic Acid (val proe’ ik)

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VPA has a number of pharmacological effects. It blocks neuronal sodium channels in a voltage- and frequency-dependent manner. It also blocks NMDA receptor-mediated excitation from glutamate. It increases GABA in the brain by facilitating glutamic acid decarboxylase (GAD), which converts glutamate to GABA, and possibly by inhibiting the GABA transporter GAT-1 as well. VPA is also a potent inhibitor of histone deacetylase, thus it can up-regulate gene expression. VPA may indirectly reduce GSK-3 activity. VPA may also inhibit inositol signaling through an inositol depletion mechanism.

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Mechanism of Action for Clobazam (kloe' ba zam)

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Clobazam “potentiates GABA-A receptor responses.” It is used as “add-on therapy for Lennox-Gastaut syndrome” as well as for absence seizures, myoclonic seizures, and infantile spasms.

Front 20

Mechanism of Action for Rufinamide (roo fin' a mide)

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Rufinamide “prolongs sodium channel inactivation” and “may inhibit mGluR5 glutamate receptors.”

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Mechanism of Action for Lithium (lith’ ee um)

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Lithium inhibits inositol monophosphatase (IMPase), which converts IP1 to Inositol and is said to be the rate-limiting enzyme in the inositol recycling process. It also inhibits inositol polyphosphate 1-phosphatase, which converts IP2 to IP1. These inhibitions deplete the free inositol needed to regenerate PIP2, the source of IP3 and DAG utilized in secondary messenger pathways exhibiting markedly increased activity during manic episodes. Lithium also inhibits glycogen synthase kinase-3 (GSK-3), which is involved in neuronal and nuclear regulatory processes.