507 Exam 1

What is a seizure?

• Brief, discrete(isolated) event

• Occurence - intermittent, irregular, unpredictable

• Results from abnormal, excessive, and synchronous discharge of cortical neurons

• Convulsion - seizure manifested by muscle contractions

What is epilepsy?

• Characterized by recurrent (2 or more) seizures unprovoked by any immediately identifiable cause

• separated by >24 hours

Etiology of epilepsy

• idiopathic - 60-70%

• infants/children 0 congenital malformations, developmental disorders, injury, infection, etc

• adults - head trauma, tumor, infection, AVM

• elderly, CVD, CNS diseases, trauma

• genetics - familial risk 2-3x compared to normal

2 main seizure categories

Partial(focal) - simple and complex partial; only involve part of the brain

Generalized - involve loss of conciousness

Other seizure definitions

AURA - subjective phenomenon that precedes an observable seizure (focal aware)

Automatism - set of unconscious behavior observed during seizures (chewing, swallowing, twitching, etc..)

ICTAL - the seizure period or events due to a seizure

How to assess ASM therapy need?

• Not indicated if

  • if due to reversible cause

  • if first unprovoked seizure

  • certain epilepsies (febrile seizures)

Drugs of choice for seizures - Know the 8 drugs and what seizure type used for

Seizure drugs side effects overview - KNOW

Start of lecture 2

Css equations

ASM protein binding displacement interactions

• salicylates displace phenytoin, VPA

• VPA displaces phenytoin

• Phenytoin and VPA displace warfarin

Hypoalbuminemia adjustment

Absorption ASM interactions

• Food - reduces rate of absorption but no effect on F (longer time to peak)

• Antacid - reduce phenytoin, gabapentin by 20% ; separate 2 hours

• G-tube feeding - reduce phenytoin F (due to g-tube charge cations, reduced motility, etc.)

• 
  

Metabolic pathways involving ASM

• carbamazepine - 85% 3A4

• Phenytoin - Major path 2C9 ; minor 2C19

• VPA - 30-50% glucuronidation, 30-40% B-oxidation, 10-20% 2C9/2C19

ASM hepatic inducers and inhibitors

• inducers

  • Carbamazepine, phenytoin - 1A, 2C, 3A & glucoronidation

• Inhibitors

  • VPA - glucuronidation, 2C9, epoxide hydrolase

Carbamazepine metabolic pathway

• 3A4 —> active epoxide —> epoxide hydrolase —>inactive drug

• VPA inhibits epoxide hydrolase —> increase [CBZ]

Phenytoin

• inducer - glucuronidation, 1A, 2C, 3A

• time dependent interaction with other 2C9 substrates (i.e. warfarin)

  • initial inhibition then induction next 1-3 weeks

• Css total desired = 15-20 mg/kg

• LD(mg) =(weight)(Vd)(Cdesired-Cinitial)/(F*S)

VPA

• inhibits 2C9, glue, epoxide hydroxylase

• therapeutic level - 50-100 mcg/ml

Start of lecture 3

What are common AE with seizure drugs?

• anxiety, irritability, cognitive deficits, etc

• usually related to peak concentration levels

How do we manage AE of seizure drugs?

• start low and go slow

• switch to xr

• shorten dosing interval with lower dose(same total daily split more often) —>lower peak higher trough(mimic XR)

What drugs have what effects?(seizures)

• LTG, OSC, LAC - minimal effects on behavior and cognition

• LEV - minimal effects on cognition, but may alter behavior(aggression, anxiety, irritability)

• TPM, ZNS - impaired thinking, behavioral changes observed

  • severity increased when start too high or increase too raapidly

  • TPM - word finding difficulty

What is the blanket warning for the ASMs?

• suicide rate higher among individuals with epilepsy

• This is due to a flawed meta analysis!!!! - warning not necessarily legitness

How are idiosyncratic AEs defined for seizure drugs?

• unpredictable, not dose related

• within 1-3 months of therapy initiation

• uncommon, EXCEPTION is skin rash

Pathology of idiosyncratic rxns(seizure)

• Delayed hypersensitivity - Aromatic ring ASMs

• Direct toxic effect of metabolite - Valproic Acid (VPA)

  • unsaturated metabolites (2-n-propyl-4-pentenoic acid) toxic to target organ

  • not indicated for <2 y/o

• Aromatic ring ASM - CBZ, LTG, OXC, PHT

  • rash, fever, increase eosinophil

  • cross sensitivity 40-60% among aromatic ring ASMs

  • immune mediated rxn

Skin rash characteristics for ASMs

• usually first 3 weeks

• usually mild, macular-papular rash

• reversible with D/C of ASM

• may rarely progress into SJS(<10% of skin) or TEN(>30% of skin)

When managing skin rash ASM AE why do we wait 3-7 days?

• The patient may still be clearing previous drug and if run does not subside quickly the new drug may also get blamed

High risk groups for status epilepticus?

AA, children, Elderly

Status epilepticus (SE) definition?

• neurological emergency

• 2 or more seizure episodes between which patient does not regain consciousness

  • also continuous seizure activity for 5 minutes

• 2 types

  • Generalized convulsive SE (GCSE) - positive physical signs (eg. rhythmic jerking of extremities)

  • nonconvulsive SE (NCSE) - negative physical signs (only activity on EEG)

Drugs thatt induce seizures

Pathophysiology of status epilepticus

• Glutamate - excitatory neurotransmitter

  • stimulates post-synaptic NMDA receptors causing calcium influx and depolarization

• GABA - inhibitory neurotransmitter

  • stimulates GABAa receptors and promotes hyper polarization through chloride mediated inhibition

  • GABA inhibitions decreases as SE progresses

SE sign/symptoms

• convulsion

• impaired consciousness

• post-ictal

  • disorientation

  • pain from convulsion(secondary)

Systemic evidence of SE (Phases)

Phase 2 is harder to treat —> TIME IS KEY

Initial assessment and management of SE

Goals of therapy for SE (KNOW)

• identify source

• stop BOTH clinical and subclinical seizure activity

• prevent further seizures

• minimize side effects of meds used to treat SE

• Treat complications of SE

TIME IS BRAIN(KEY)

Timeline status of SE treatment (KNOW)

• Emergent(10 min) - stabilize vitals + parenteral benzodiazepines

• Urgent(20 min) - send lab, get hx, parenteral ASM(anti seizure med)

• 30 min(identify and treat any underlying causes(re-bolus ASM if needed)

Emergent therapy - benzodiazepines dosing (KNOW)

• IV

  • Lorazepam 0.1mg/kg IVP @2mg/min (MAX 4 mg)

  • Diazepam 0.15mg/kg IVP @5mg/min (MAX 10 mg)

  • Midazolam 0.2mg/kg IVP @2mg/min

• IM

  • 13-40kg - midazolam 5mg IM

  • >40kg - midazolam 10mg IM

• Rectal

  • diazepam .2mg/kg PR

Monitoring of benzodiazepines

Urgent therapy dosing - ASM

• Phenytoin (dilantin)

  • load 15-20 mg/kg IV (50 mg/min)

  • MD - 4-6 mg/kg/day IV or PO 12 hours post load

• Fosphenytoin (Cerebyx)

  • Load 15-20 mg/kg IV (150mg/min) or IM

  • MD - 4-6 mg/kg/day IV or IM 12 hours post load

Urgent therapy ASM other meds

ASM monitoring

ASM monitoring therapeutic levels

Urgent therapy - levetiracetam (keppra)

• new gen

• few drug interaction

• linear kinetics

• not hepatic metabolism

• renal elimination

• LD regimen - 1-4.5 g IV (500 mg/min)

• MD: 500-1500 mg IV/PO q12h

urgent therapy - Lacosamide (vimpat)

• new gen

• few drug interactions

• linear kinetics

• hepatic metabolism

• renal elimination

• LD 200-400 mg IVP (80 mg/min)

• MD - 100-200 mg IV/PO q12h

Advantages and disadvantages of anti epileptics

Carbamazepine

• 1st gen AED

• broad spectrum

• iminostilbene with a carbamyl group

• Na+ channel blocker

• reduction of glutamate release

• CYP 3A, 2C and UGT INDUCER

• metabolic auto induction(stimulates its own metabolism)

Oxcarbazepine

• keto analog of CBZ and acts through similar mechanism

• not metabolized into epoxide or o-quinone

• No CYP interactions

• Safer than CBZ

Phenytoin

• Indicated for tonic-clonic partial seizures, but NOT absence seizures

• Na channel blocker

• 2C9 and 3A4 inducer

Fosphenytoin

• water soluble PRODRUG of phenytoin—>in vivo release

• avoids administration complications associated with parenteral phenytoin admin

Lamotrigine

• Na channel blocker

• metabolized mainly by clucuronidation

• Major metabolites are 2-N-glucuronide(75%) and 5-N-glucuronide(10%)

Lacosamide elimination med chem

• 40% excreted unchanged

Vigabatrin(Sabril)

• AA that is structural analog of y-aminobutyric acid (GABA), but does not bind to GABA receptors

• Irreversible inhibitor of GABA-transaminase, the enzyme that degrades GABA—>therefore increases GABA levels

• Racemic compound, S enantiomer is active

• Little to no metabolism —> Excreted unchanged

Levetiracetam (Keppra)

• ethyl analog of cognitive enhancer piracetam

• S isomer is aniconvulsant

• Appears to have no GABA or glutamate receptor affinity - mechanism unclear

• NO know enzyme interaction - little drug-drug interactions

• Major metabolic path is enzymatic hydrolysis of acetamide group. Metabolites are inactive

Topiramate

• sulphamate substituted monosaccharide —> derived from D-fructose

• multiple MOA

• not extensively metabolized —> mostly excreted unchanged in urine (70)

• 20% is hepatic metabolism (2C19), hydroxylation, hydrolysis, and glucoronidation

VPA (depakote)

• multiple MOA ; Na channel inhibitor, GABA agonist)

• well tolerated

• 2 rare side fx —> hepatotoxicity, teratogenicity

  • Inhibits 2C9 —> increase phenytoin [ C ]

  • inhibits glucuronidation —> increase lamotrigine [ c ]

  • inhibit carbamazepine epoxide hydrolase —> increase CBZ 10,11 [ c ]

VPA metabolism picture

Zonisamide (zonegram)

• sulfonamide derivative

• multiple MOA

• 35% excreted unchanged

• metabolic pathway to form 2-(sulphamoylacetyl)-phenol involves hydrolytic ring cleavage either by 3A4 or intestinal bacteria

• caution in sulfa hypersensitivity

Neurochem and catecholamine drugs on NMDA receptor OBJ

Catecholamines

• distinct structure of benzene ring with 2 -OH groups (catechol) and an ethyl chain with terminal amine group

• produced mainly by adrenal medulla and postganglionic fibers of SNS

• in CNS, dopamine, norepinephrine, and epinephrine are neurotransmitters

• dopamine (DA) is present in mammalian brain, with highest lvls in the striatum

Parkinsons disease (PD)

• low DA levels

• due to loss of neurons that produce dopamine

• symptoms manifest when 50-60% of dopaminergic neurons in susbtantia are lost

• Treatment : increase dopamine

Biosynthesis of dopamine

PD treatment strats

• Direct admin of dopamine does NOT work due to BBB

• L-DOPA —> transported into brain then converted

• Inhibition of dopamine metabolizing enzymes

  • MAO or COMT inhibition

• Dopamine agonists - do not increase dopamine in brain but stimulate pathways to provide symptom release

L-DOPA and DOPA decarboxylase inhibitor MOA

What does carbidopa do?

• carbidopa does not cross BBB—> blocks peripheral conversion of L-DOPA to dopamine until it crosses BBB

MAO and COMT inhibition MOA

MAO-B inhibitors

• block breakdown of dopamine—>prolog dopaminergic activity

• can be adjunctive to L-DOPA

• Ex.

  • Rasagiline, selgiline, safinamide

• Patient should be counseled to limit tyramine intake (aged cheese, red wine, chocolate). MAO inhibitors facilitate absorption of tyramine—>increase norepinephrine—>hypertensive urgency

COMT inhibitors

• adjunct to L-dopa

• Tolcapone (Tasmar)

  • acts in both CNS and in periphery

  • hepatotoxic

  • NOT recommended

  • 3 hr half life and better BBB penetration than entacapone

• Entacapone

  • No liver toxicity

  • co-admin with carbi/levo dopa increases L-DOPA effect

  • inhibit metabolism of L-DOPA

Dopamine receptor agonists

• do not increase dopamine levels; bind to dopamine receptor and stimulate signaling pathway for symptom relief

ionotropic glutamate receptor

• ionotropic glutamate receptor

  • ligand gated cation channels that are activated by the neurotransmitter glutamate

  • allow passage of Na, K, and Ca2+ and produce excitatory postsynaptic responses

  • key fro synaptic plasticity, thus important for learning and memory

  • 3 main subtypes

    • AMPA

    • Kainate

    • NMDA receptors

NMDA receptor

At rest, pore is blocked by Mg2+—> depolarization of postsynaptic cell, either by excitatory inputs or repetitive firing of presynaptic cell unblocks pore—>Opening the channel requires simultaneous binding of glutamate and co-agonist glycine—>NMDA receptor allows entry of Ca2+ and monovalent cations like Na+ and K+—> As a result, increase concentration of Ca2+ within postsynaptic neuron acts as second messenger to activate signaling cascade

NMDA receptor clinical effects

• Agonism leads to excitotoxicity and neuroplasticity

• Blocking it treats things like PD, epilepsy, Alzheimers, huntingtons

• 7 different NMDA subunits—>different targets available

NMDA antagonists

• 4 binding sites (picture)

Competitive (glutamate) NMDA antagonists

• DL-AP5 - selective to glutamate binding site

  • conformational restriction ; a-amino acid group and side chain in a piperidine ring—>increase affinity, but more neurotoxic

• D-AP7 - anticonvulsant activity in wide range of generalized focal epilepsy but poor absorption and undesirable muscle relaxation

• R-CPPene - highly potent, but psychogenic s/fx

• LY 233053 - tetrazole group

Glycine NMDA antagonists

• generally less s/fx compared to competitive but low BBB penetration

• 
  

Polyamine binding site NMDA antagonist

honestly a lot of info, not sure if we need to memorize yet(will update if important)

Ion channel NMDA antagonists (non-competitive)

• Amantadine - originally anti-flu drug

• Memantine - originally anti diabetes

• Ketamine - nasal spray used for depression treatment

• Phencyclidine (PCP) - recreational drug

• MK-801 - severe psychotic effects (BAD)

• Remacemide - low affinity NMDA Na channel blocker

  • weak affinity but active metabolite has high affinity

Headache 2

Gepants

• patients with CI to ergots or triptans or have failed to respond/tolerate 2 oral triptans

• MOA - CGPR receptor antagonists

• inhibit dilation of meningeal blood vessels

• decrease in pain signaling

• Benefits

  • can be used in patients with high CV risk or hx of CV event

  • no concern for med overuse headaches

  • 
    

Repant agents

migraine abortive therapy guideline

other migraine abortive therapy

• antiemetics - metoclopramide, chlorpromazine, prochlorperazine

  • helps if associated with N/V

  • 15-13 mins before abortive tx

  • metoclopramide or prochlorperazine 10mg IV at onset may also be used for acute relief symtpoms

• opioids

  • generally not recommended due to risk of overuse

When to use prophylaxis medications in migraine

• recurring migraines that acute therapy cannot fix

• occur more than 2x/week

• risk off developing medication overuse HA

• CI, failure, or overuse of acute tx

  • 10+days/month of ergot, triptan, opioid, combo analgesia, and combo of drugs that are from non overused drugs

  • >15 day per month for nonopijoid analgesics, APAP, NSAID

• patient preference to limit attacks

Initiating migraine prophylaxis

Prophylaxis agents to know

Recommendations for migraine prophylaxis (exceptions Venn diagram)

BB in migraine

Anti epileptic in migraine

Side effects decide which one

Gepants (prophylaxis)

CGRP monoclonal antibodies

• MOA - block binding of CGRP to receptors by either binding to receptor itself or to the CGRP

• dosed infrequently, minimal side effects, no need to titrate therapy—> BUT expensive

CGRP monoclonal antibodies prophylaxis