Pharmacology: Neuro

Review of Neurotransmitter Disorders in Neurology ............................................................................................................. 2

Pathophysiology and Treatment of Parkinson’s Disease ........................................................................................................ 6
Anticonvulsant Drugs ............................................................................................................................................................ 11
General Anesthetics .............................................................................................................................................................. 16

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 Review of Neurotransmitter Disorders in Neurology
Glutamate: major excitatory neurotransmitter
 > 70% synapses in sensory, motor, memory circuits
o most abundant neurotransmitter

 Flavor enhancer in food (MSG), but BBB blocks entry to brain

Glutamatergic synapse:

 Glu produced from Gln in pre-synaptic neuron, packaged into

vesicles  Ca-dep release into synaptic gap
 PUMPS: Reuptake into astrocytes via EAAT (excitatory AA
transporter); transport back to neuron as Gln
o Require energy (Na/K ATPase)
o These pumps responsible for most energy / glucose
consumption when brain is activated
o PET: shows ↑ glc consumption (↑ density of synapses &
activity: used to monitor dementia, etc.)

Post-Synaptic Glutamate receptors:

 NMDA: Ca , Na enter, ↑ nNOS  NO release
+2 +

o + feedback: strengthens synapses  memory

 AMPA: Ca+2 (& Na+) enter, intracellular activation (fire!)
 Metabotropic: linked to 2nd messengers  metabolic changes

Receptors: clustered in post-synaptic density

 Specificity of glutamate at synapse: which receptors are present post-synaptically?

What does glutamate do?

• mediates synaptic activity in the auditory and visual circuits (listen to lecture and see the slides)
• activates the circuits that encode long term memories (remember what was talked about)

GABA: major inhibitory neurotransmitter

 GABA = γ-aminobutyric acid
 synthesized from glutamate (via GAD: glutamate decarboxylase)

GABA-ergic synapse
 Pumps remove GABA (into glia here too like glu) to inactivate signal
 Complicated recycling to form glutamate
 End result: ↑ Cl- flow  hyperpolarization (inhibitory)

GABA receptor: different subunits = different affinities

Benzos: act on GABA / benzodiazepine receptor

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 Glutamate / GABA balance

Glutamate is excitatory; GABA is inhibitory

 Net effect depends on balance between glu / GABA effects

Architecture
 Glutamate synapses: more numerous (3:1)
o but synapses farther away from soma (dendritic spine) – less control!
 GABA synapses: fewer, but more control (on dendrite necks) – closer!

Regulation:
 Can traffic receptors in/out of post-synaptic density to modulate function
o ↑ AMPA: ↑ excitability; ↓ AMPA (sequester): ↓ strength of synapse

Seizures: abnormal sustained repetitive depolarization of neurons in brain

 accompanied by change in motor activity, sensation, attention, thought processes
 From imbalance between glu & GABA (↓ inhibition, ↑ excitation)
 Epilepsy: repeated seizures

Memory formation
 Requires activation of excitatory synapses in HIPPOCAMPUS(Gr. “sea horse”)

LTP: Long-term potentiation

 physiologic correlate at synaptic level of
memory formation in hippocampus

 Activity-dependent plasticity: easier

/ potentiated excitatory firing after
intense stimulation (high-frequency
firing)

 ↑ AMPA  “potentiated” (memory

is enhancement of these connections)

Brain Development & Plasticity

Glu / GABA balance regulates pruning of synapses in adolescent cerebral cortex
 Glu: Reduces excess synapses, stabilizes remaining synapses

 Co-incident pre- and post-synaptic firing preserves synaptic connections

o If both fire together: trophic factors released  synapse preserved!
o “neurons that fire together, wire together”

Activity needed for neurons to remain alive & healthy too!

 also needed in recovery of brain after injury (esp. children)

Plasticity
 Changes in neuronal activity  rearrangement of neuronal circuits
 Common in developing brain
o e.g. learn to play strings in childhood: practice with left fingers  expand area of R. cortex dedicated to that task
o e.g. surgically remove cortex for intractable childhood epilepsy: can often regain speech up to 7-14yo
o Based on surplus of synapses in childhood

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Glutamate-Mediated Excitotoxicity (the “dark side” of plasticity)
 like a “power surge” damages computers ↑ excitatory pathways =
↑ vulnerability to excitotoxicity
Can happen in: stroke, hypoxia-ischemia, hypoglycemia, trauma, seizures ● hippocampus ● cerebral cortex
● thalamus ● cerebellum
Basic mechanism:↓ delivery of glucose / oxygen
 Glu can accumulate in synapses (pumps don’t work without glucose)
 Lack of oxygen  mitochondria don’t work  membrane depolarized
o Mg usually blocks NMDA receptor
o when membrane depolarized, Mg block removed (Ca floods in)

End result: Glu receptors open excessively (↑↑ Ca+ entry postsynaptically: toxic)

Hippocampus especially vulnerable (seizures, ischemia)  amnesia (memory loss!)

Glutamate, GABA and neurologic diseases: Summary

• Glu /GABA used in > 85% of brain synapess
• Glutamate is essential for normal brain function, learning, memory, plasticity
• Hypoxia and hypoglycemia lead to a build up of synaptic glutamate, causing excitotoxic damage
• High glutamate can cause damage in degenerative disorders, e.g. motor neuron disease

Topiramate: blocks AMPA glutamate receptors (prevent migraine; treat epilepsy)

Serotonin
Serotonin fibers: come from raphe nuclei in brainstem
 midbrain  diffuse projection into cerebral cortex

Serotonin (5-HT): synthesized from tryptophan

 AADC synthesizes; VMAT packages into vesicles
 Vesicle release like glutamate
 5-HT transporter for re-uptake (SSRIs block)

Involved in headache (esp. migraine) & depression

 SSRIs: selective serotonin re-uptake inhibitors
o Used to treat depression
 “Triptan” drugs: serotonin agonists
o Act post-synaptically
o used to prevent / abort migraine headaches
Dopamine
Dopamine: Catecholamine neurotransmitter, esp. in basal ganglia (caudate, putamen focused on movement)

Synthesis: Tyrosine hydroxylase is

rate-limiting step

Pathways:
 Nigrostriatal (movement)
 Mesolimbic (reward,
reinforcement)

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Role of dopamine: keeps us moving & keeps us motivated
 Mesolimbic dopamine neurons mediate reward, attention
o Humor, money activate
o COCAINE: blocks re-uptake pumps (↑ synaptic *dopamine+  euphoria); strongly reinforced (addictive)
 Striatonigral pathway faciliates movement

Parkinson’s Disease Schizophrenia

Type of disorder Movement Neuropsychiatric
Dopamine Degeneration of dopamine neurons Overactivity of dopamine neurons
Mesolimbic dopamine pathway
Nigrostriatal dopamine pathway
Pathway Reward, reinforcement: ventral tegmental area  limbic
Movement: Substantia nigra  basal
affected system (nucleus accumbens, amygdala,hippocampus, medial
ganglia  thalamus  cortex
prefrontal ctx)
• Rhythmic tremor
• Muscle rigidity • Hallucinations, delusions
• Stooped posture • Disorganized thought / speech
Symptoms • Difficulty rising and initiating movement • Impaired social cognition
• Micrographia • Avolition / apathy
• Depression (↓ dopamine)
Treatment L-DOPA (↑ dopamine) Antipsychotics (block dopamine receptors)
Psychiatric – gambling, hypersexuality Parkinsonian sx (block dopamine signaling in basal
Rx Side effects
rarely (reward circuitry) ganglia too; go away if stop tx)

Parkinson’s disease: see pic (degeneration of dopamine neurons in substantia nigra)

Things that look like PD:
 Rigidity caused by psychiatric drugs that block dopamine receptors (neuroleptics)
 Degenerative disorders or repeated head trauma (e.g. boxers)
 Inherited disorders of dopamine metabolism

Acetylcholine
ACh neurons: project from basal forebrain to cerebral cortex
 Released into synapse, broken down by acetylcholinesterase
o Choline from AChE taken back up into presynaptic terminal
o Note contrast to others: not pumped back in

Involved in Alzheimer’s disease (Ach neurons degenerate early in Alz Dz)

 ↓ Ach  memory loss, behavioral changes

Drugs for AD:

 AChEi (inhibit acetylcholinesterase  ↑ Ach  ↑ memory, behavior)
 Memantine: block NMDA receptors
(very active in AD: NMDA implicated in overexcitation / excitotoxicity)

Summary (from slides)

Glutamate: the major excitatory neurotransmitter in the brain

 Glutamate excitotoxicity: diverse types of brain damage (stroke and other disorders)
GABA: is the major inhibitory neurotransmitter in the brain
Serotonin is involved in migraine headaches and depression
Degeneration of dopamine neurons causes Parkinson’s disease
Alzheimer’s dementia is associated with loss of acetylcholine neurons

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 Pathophysiology and Treatment of Parkinson’s Disease
Basal Ganglia Review
Basal ganglia: group of subcortical nuclei interconnected
with cerebral cortex, thalamus
 Caudate, putamen, globus paladus, subthalamic nucleus,
substantia nigra

Two main pathways from striatum (caudate, putamen)

Direct pathway ↑ thalamo-cortical activity “gas pedal”
Indirect pathway ↓ thalamo-cortical activity “brake pedal”

Nigro-striatal dopamine pathway

 Modulates basal ganglia output
 Connected heavily to striatum
 Net effect of DA: release brakes & step on gas
o (↑ thalamo-cortical activity)
 If ↓ DA  ↓ thalamo-cortical activity
o (not enough gas, not letting go of brakes)
o Functionally: slowed / reduced movement

Parkinson Disease
Parkinson disease is a dopamine deficiency disorder
 Loss of dopaminergic innervations of caudate / putamen  cortical regions
o Nigrostriatal neurons knocked out
o Pallor in substantia nigra, Lewy bodies Clinical features (4 classic)
 Pharm strategy: replace dopamine Typically asymmetric and responsive to L-DOPA
1. Rest tremor
During life: Dx based on examination 2. Bradykinesia
 Can also visualize loss, not equal on both sides 3. Rigidity
 Loss greater in putamen than caudate 4. Postural Instability

Not just dopamine: various neural systems involved at various levels of neuroaxis (involves other nuclei)

Development of disability: Need to get down to 80-90% loss of brain DA!

Dopamine
 Tyrosine hydroxylase is rate limiting step of synthesis

Problems with using dopamine itself

1. Unstable molecule; degrades on exposure to O 2 in air, body fluids
2. Degraded rapidly by MAO & COMT in liver, other tissues after oral
administration
3. Doesn’t cross BBB
4. Causes extreme nausea

Major strategies of pharm therapy

 L-dopa
 MAO-B inhibitors
 Direct DA receptor agonists
 COMT inhibitors
 Anticholinergics

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L-DOPA
 Remember DA can’t cross BBB; L-DOPA can cross BBB

AADC converts L-DOPA to DA to act in nervous system

 AADC is ubiquitous enzyme, so L-DOPA gets converted all over the place
(not just at target): less than 2% L-DOPA reaches target

 Strategy: inhibit peripheral AADC  ↑ L-DOPA going to brain

Mechanism of Action: Dopamine receptor agonist (via DA, active metabolite)

Effects: L-DOPA converted to DA via AADC (both peripheral and in nervous tissue); augments DA signalling (↓ in PD)

Adminstration:
 Short half life (1-2 hrs); must give several times throughout day
 can result in large swings in serum [L-DOPA]
L-DOPA
Metabolism: Can cross BBB (DA can't).
 Less than 2% reaches CNS (rapidly metabolized by AADC in liver, other tissues).

Toxicity: big swings are bad: involuntary movements (↑ peak doses); recurrence of symptoms (↓ trough doses).
 chronic spiking blood levels may play role in development of delayed dyskinesias.
 Acute side effects: nausea, orthostatic hypotension, hallucinations
 Chronic side effects (50% of pts after 5 yrs): wearing-off, on-off phenomenon, disabling dyskinesias

Mechanism of Action: L-DOPA with carbidopa (an AADC inhibitor)

Effects: L-DOPA as above; Carbidopa blocks AADC peripherally, increasing delivery to CNS.
 Effectively reduces rest tremor, rigidity and bradykinesia
 Less effective in reversing postural instability

Adminstration: Short half life (1-2 hrs); must give several times throughout day
sinemet  can result in large swings in serum [L-DOPA].
(L-DOPA + carbidopa)  Controlled-release preparations help, but:
o slower onset of action, reduced peak blood levels, and longer duration of action

Metabolism: Can cross BBB (DA can't). Much still metabolized in liver (COMT)

Toxicity: big swings are bad: involuntary movements (excessive peak doses); recurrence of symptoms
(low trough doses). chronic spiking blood levels may play role in development of delayed dyskinesias

Side effects of L-DOPA therapy (overview)

 Acute side effects: nausea (all), orthostatic hypotension, visual hallucinations
o Taper dose up to help avoid
 Chronic side effects:
o Dyskinesia (Abnormal involuntary movements)
o Response fluctuations: “end of dose deterioration” or “freezing” – suddenly can’t move (weird!)
o Psychiatric complications develop with time (confusion, visual hallucinations)

Controversy: are these effects from medication or from disease progression?

 Probably disease progression, although there is concern about “pulsatile” L-DOPA treatment

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MAO-B inhibitors
E.g. Deprenyl (selegiline)

Background story: young heroin users with advanced Parkinsonism in California

 Were trying to synthesize MPPP (synthetic heroin analog), got MPTP instead
 MAO-B converts MPTP  active toxin (MPP+)  rapid, irreversible parkinsonism
o Blocking MAO-B blocks MPTP  MPP+
o Maybe there’s a natural equivalent “toxin” that MAO-B converts? Try blocking MAO-B?

These are supposedly MAO-B selective, but if you ↑↑ dose, you get MAO-A and MAO-B inhibition (side effects!)

Mechanism of Action: MAO-inhibitor, for Parkinson Disease

Effects: Probably related to irreversible MAO inhibition (increases DA by decreasing breakdown) -
symptomatic, not neuroprotective

Indications: Parkinson Disease (complements other anti-PD meds)

Adminstration: twice daily, generic available
selegiline (edepryl)
Metabolism: Complex pharmacokinetics:
 L-amphetamine, L-methamphetamine are metabolites
 parent compound has MAO-B inhibiting activity too
 need to follow MAO-B inhibition as kinetic parameter (not serum levels of drug / dose)
Toxicity: well tolerated; rare weight loss
Other: shown to prolong time until L-DOPA is needed.

MAO-B inhibitor: like selegiline, but once-daily (longer duration of action)

rasagaline (Azilect)
No L-amphetamine / L-methamphetamine metabolites (probably not clinically relevant)

COMT inhibitors
 Inhibit COMT (reversible, selective); ↓ conversion of dopamine  3MT
o Don’t cross BBB; increases peripheral L-DOPA concentration
o Helps stabilize L-dopa concentrations over time
 Like L-DOPA, need to give 3-4x/day (combination med with sinemet)
o Short half life (0.8-1hr)

Mechanism of Action: COMT inhibitor.

Effects: helps block hepatic metabolism of L-DOPA (increases half-life in brain, L-DOPA to brain)
Entacapone
Administration: with sinemet (L-DOPA + carbidopa, an AADC inhibitor). Need to give 3-4x daily (like L-DOPA
(Comtan)
Metabolism: don't cross BBB: increase peripheral L-DOPA, helps stabilize concentrations over time
Toxicity: generally well tolerated with occasional GI complaints, can cause urine to turn reddish brown

Tolcapone: linked to fatal liver failure, best avoided

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Dopamine Receptor Agonists
 Direct stimulation of DA receptors
 Side effects: nausea, somnolence, hallucinations, orthostatic hypertension
o Generally well tolerated, either alone or in combination

Bromocriptine Parlodel
Older, Ergot-like; more side effects
Pergolide Permax
Pramipexole Mirapex
Newer, Non-ergot-derived; less side effects
Ropinirole Requip

Mechanism of Action:Non-ergot DA receptor agonists (directly stimulate DA receptors).

Adminstration: multiple daily doses (like L-DOPA)

pramipexole (Mirapex) Toxicity: Generally well tolerated (alone / in combo).

 Nausea, somnolence, hallucinations, orthostatic hypertension.
ropinirole (Requip)  Can see mental status changes in elderly, daytime sleepiness
 compulsive gambling (unusual side effect)

Other: Above info for pramipexole; riponerole is very similar

Other DA receptor agonist options?

Dopamine Agonist Availability? Mode of Delivery L-DOPA Dopamine Agonists
Cabergoline Europe Once daily pill Efficacy excellent good
Apomorphine Apokyn Intramuscular injection nausea
Rotigotine Neupro Skin patch Short-term somnolence
side effects hypotension
hallucinations
dyskinesias
DA agonists may slow DAT loss? Long-term
on-off phenomena
dyskinesias
 Not great results (not halting disease progress) side effects
accelerated disease?
on-off phenomena

Anti-cholinergics
 Theory: some kind of ACh / dopamine balance that you can restore? ↓ DA so ↓ Ach? Nebulous idea.

Mechanism of Action: Anti-cholinergic agents (anti-PD)

Effects: Restores "Ach/DA balance" in theory (less DA in PD, so cut down on Ach)
benztropine (Cogentin)
Indications: Parkinson Disease, especially in younger patients with tremor as predominant complaint.
 Generally contraindicated in elderly (cognitive problems)
trihexyphenidyl (Artane)
Toxicity: impaired cognition, constipation, urinary retention, dry mouth
Other: Use in PD largely supplanted by MAO-i and direct DA agonists

Amantadine
Mechanism of Action: anti-Parkinson Disease agent, multiple effects (poorly understood)
amantadine Effects: weak anti-cholinergic, weak DA-releaser, weak glutamate antagonist
(Symmetrel) Toxicity: hallucinations, insomnia
 effects common to other anticholinergics too: impaired cognition, dry mouth, constipation, urinary retention

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 Treatment of Parkinson Disease: General Points
No set “best treatment” – begin with L-DOPA, MAO-B inhibitor, whatever & start combining
 Use combinations of drugs!
 Want to raise dopamine (replace, inhibit metabolism, etc)

Neurosurgery (DBS)
 Reduce abnormally increased activity of GPi and STN
 Surgical ablation (pallidotomy) or inactivation by high frequency electrical stimulation (deep brain stimulation)
 Not initial therapy (1% intraoperative risk of stroke): use for advanced PD

Good surgery candidate Poor surgery candidate

Good response to L-DOPA Poor response to L-DOPA
Prominent tremor Prominent gait and balance trouble
Prominent dyskinesias Prominent dysphagia
Significant on-off swings Co-morbid dementia
Few other co-morbidities Co-morbid dysphagia
Refractory psychiatric problems

Take home message:

 We don’t have any good medications to slow the disease progression yet!
 These are symptomatic therapies!

Future: better DA therapies, address non-DA deficits (NE, 5-HT, etc), refine DBS, stem cells, halt dz process!, genetics?

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 Anticonvulsant Drugs
Anticonvulsant drugs: reduce intermittent, uncontrolled electrical discharges in the brain associated with seizures
 Reduce high frequency sustained repetitive activity, but not normal activity needed for cognition
 In contrast, anesthetics suppress both normal physiologic activity and seizure activity

Seizures: sustained repetitive firing of neurons

 “Organizes” activity: entire electrical activity taken over by signal (often from temporal area)
 Neuronal level: sustained repetitive neuronal depolarization
o During seizures: Na, Ca enter (glutamate)
o During recovery: Cl enters (GABA)
 Seizures: TOO MUCH GLUTAMATE and/or NOT ENOUGH GABA

Activity of voltage-gated sodium channels allows for this repetitive firing

Activity-dependent actions of anticonvulsants

 Proteins for Na, Ca channels assume different conformations as they open & close
 Anticonvulsants: bind open channels preferentially (selective for areas of ↑ activity like seizure)
o Targeting epileptic neurons (activity-dependent): goes where it’s needed!

Mechanisms of Action
• Directly block rapidly opening/closing voltage
dependent sodium channels to inhibit
sustained repetitive firing
• Directly block voltage dependent calcium channels
• Increase activity of GABA synapses
• Reduce activity of glutamate synapses
• Bind to synaptic vesicles

Na-channel blockers
directly block rapidly firing Na channels to inhibit sustained, repetitive firing
• Phenytoin (diphenylhydantoin)
• Carbamazepine
• Lamotrigine
• Valproic Acid (dipropylacetic acid)

Mechanism of Action: Anticonvulsant, blocks rapidly opening Na channels

Effects: bind open channels selectively, limiting sustained repetitive transmission

Indications: use for common seizure types

(generalized / focal motor seizures, partial seizures with behavioral manifestations)

Metabolism: Saturable hepatic metabolism

(low levels = 1st order, high levels = zero order like alcohol: saturate enzymes - can have sudden unexpected toxicity)
phenytoin
Toxicity:
 High levels: ataxia, nystagmus, also gum hypertrophy, increased hair
 Bradycardia & cardiac arrhythmias if administration too rapid
 Purple glove syndrome with IV phenytoin (skin / venous damage; can use pro-drug "Fosphenytoin" - water
soluble with extra PO4 group - to avoid)
 Induces metabolism of carmazepine
 Teratogen
Other: less sedating than barbituates

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 Mechanism of Action: Anticonvulsant, blocks rapidly opening Na channels
Effects: bind open channels selectively, limiting sustained repetitive transmission

Indications: use for common seizure types (generalized / focal motor seizures, partial seizures with behavioral
manifestations). One of most prescribed anticonvulsants

carbamazepine Metabolism:
 Hepatic metabolism to epoxide metabolite
 Induces own metabolism

Toxicity: Few cognitive side effects.

 Don't use in absence seizures (can make them WORSE!).
 Teratogen

Mechanism of Action: Anticonvulsant, blocks Na channels associated with pre-synaptic glutamate release
Effects: limits sustained repetitive transmission

Indications:
 common seizure types (generalized / focal motor seizures, partial seizures with behavioral manifestations).
 Also used for less common seizure types e.g. generalized absence seizures
lamotrigine
Metabolism:
 Hepatic metabolism via glucuronidation
 half life prolonged by other drugs (e.g. valproic acid).

Toxicity: Severe skin rashes in 1% children, 0.3% adults. Teratogen

Mechanism of Action: Anticonvulsant

 blocks rapidly opening Na channels
 enhances GABA / BZ receptors
 may have other mechanisms?

Effects: bind open channels selectively, limiting sustained repetitive transmission; other mechanisms too?
valproic acid
Indications: useful for all seizure types
Metabolism: Hepatic metabolism (as fatty acid)

Toxicity:
 Fatal hepatic necrosis in children < 2 yo, especially if on second anticonvulsant (incidence 2/1000).
 Slows metabolism of phenobarbital, lamotrigine.
 Teratogen (strongly associated with spina bifida, can reduce risk with folic acid)

Ca-channel blockers
directly block voltage-dependent Ca channels

Mechanism of Action: anticonvulsant

 blocks voltage-dependent Ca channels

Effects: Decreases excitatory signaling (blocks Ca reuptake into

ethosuxamide presynaptic neuron and Ca influx into post-synaptic neuron)

Indications: Generalized absence seizures

Toxicity: Teratogen
Glutamate & GABA agents
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 • Normally glutamate and GABA work together: glutamate depolarizes neurons and GABA comes along a little
later to repolarize them
• In a seizure, too much glutamate depolarization with too little GABA repolarization
• GABA is synthesized from glutamate (cycling!)

GABA Agents (want to ↑ activity)

Most common way: activate the GABA receptor

 GABA drives Cl into neurons, hyperpolarizing & inhibiting
Can also: block GABA transaminase, block re-uptake of GABA

Enhance GABA Receptor

 Barbiturates: Phenobarbital, Pentobarbital, Valproic Acid
 Benzodiazepines: Lorazepam, Diazepam
Block Re-uptake of GABA
 Tiagabine
Block Metabolism of GABA
 Vigabatrine

Mechanism of Action: barbituate anticonvulsants

Effects: Enhance GABA / benzodiazepine receptor function, increasing chloride influx and
causing hyperpolarization / inhibition of synaptic transmission

Indications: powerful, use for common seizure types (generalized / focal motor seizures, partial seizures with
phenobarbital behavioral manifestations)
primidone
Metabolism: in liver, long half lives, 1st order kinetics over broad range.
 Primidone converted to phenobarbital & PEMA (both anticonvulsants) via in vivo metabolism.
Toxicity:
 Cognitive and behavioral side effects, depression.
 Teratogen

Mechanism of Action: benzodiazepine anticonvulsants

Effects: Enhance GABA activity (bind benzo receptor), increasing inhibitory signaling
lorazepam
 (hyperpolarizes by increasing Cl influx postsynaptically)
diazepam
Indications: used for rare seizure types, 1st line IV in status epilepticus
Toxicity: powerful but sedative, cognitive side effects

Glutamate Synapses (want to ↓ activity)

 Drugs not as well developed as they are for GABA synapses
Topiramate: blocks AMPA receptors
Mechanism of Action: Anticonvulsant, blocks AMPA glutamate receptors
topiramate Effects: decreases excitatory glutamate signaling
Toxicity: Memory & speech problems (AMPA receptors involved in memory formation)

Dextromethorphan (cough syrup) & felbamate block NMDA receptors

Levetiracetam binds to synaptic vesicle receptor

Mechanism of Action: Anticonvulsant, binds SV2A vesicle protein on synaptic vesicles
levetiracetam Effects: inhibits Ca-mediated glutamate exocytosis from pre-synaptic neuron
Toxicity: teratogen

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 Clinical use
Sodium channel drugs Relatively selective, fewer cognitive side effects
GABA-R/benzoR drugs Most powerful, but have sedative, cognitive side effects (used in status epilepticus)
Glutamate drugs Potentially protective but also cognitive side effects
Often need to combine drugs with different mechanisms (don’t put two of the same together – make ‘em complimentary)

Indications
Most common seizure types: generalized or partial (focal) motor seizures, or partial complex seizures
 Carbamazepine, phenytoin, valproic acid, phenobarbital, lamotrigine or combinations effective for many pts

Generalized absence seizures (3/second spike wave activity)

 ETHOSUXAMIDE (blocks Ca channels), valproic acid, lamotrigine
 Carbamazapine can make these seizures WORSE

Rare seizure types (epileptic encephalopathies of childhood: very chaotic, hypsarrhythmia pattern: very high gain on EEG)
 Benzodiazapines, valproic acid, ketogenic diet, ACTH (hormone)

Pharmacogenetics: starting to find specific mutations in some syndromes & ID treatment based on known mutations

Side effects of Anticonvulsants

Severe skin reactions: Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis
Drug-drug interactions (interfere with each other’s metabolism)
 Phenytoin: induces metabolism of carmazepine
 Valproic acid: slows metabolism of phenobarbital, lamotrigine
 Pharmacogenetic markers have been discovered (affect anticonvulsant action, metabolism)

Teratogenicity
 Anticonvulsants cause BIRTH DEFECTS! “anticonvulsant embryopathy” (20-28% exposed infants vs 8.5% controls)

Anticonvulsant embryopathy
• Microcephaly, growth retardation, cleft palate, finger, neural tube, urogenital, heart malformations, NTD with valproic acid
• Most occur in first month of gestation (often before mother knows she’s pregnant
• Mechanism: Anticonvulsants antagonize folic acid ↑ oxygen free radicals
• Can ↓ activity of epoxide hydrolase (detoxifies oxidative metabolites of certain anticonvulsants)
• Other drugs, genetics  ↓ epoxide hydrolase  ↑ risk

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  Valproic acid strongly associated with spina bifida
o ↓ spina bifida with folic acid: all women on anticonvulsants should take folic acid

 Anticonvulsants can alter metabolism of birth control pills too!

 Alterations in endogenous hormones  ovarian dysfunction

Status Epilepticus
30 minutes of continuous seizure activity or 2 or more seizures without full recovery of consciousness
 Can damage brain, impair other organ function

Therapy
 ABC support (airway, breathing, circulation)
 IV access with glucose-containing fluid
 IV anticonvulsants (lorazepam or diazepam  + phenytoin
 + phenobarbital  anesthesia with benzos / general
anesthesia)

Adverse effects of treatment:

 Coma (benzos), apnea / need for ventilator, cardiac
arrhythmias, skin damage (phenytoin)

Anticonvulsant therapy in children

Often TEMPORARY
 Up to 70% children started on anticonvulsants for seizures can discontinue after several years seizure-free

↑ risk of need to continue with:

 Older age at onset  FHx of seizures
 large # seizures before remission  past Hx of status epilepticus
 presence of chronic neuro disability (e.g. CP)

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 General Anesthetics
Classification of General Anesthetics based on Usage Profile
Inhaled Intravenous
Potent, volatile agents Induction agents Continuous agents
 Halothane
 Sevoflurane  Thiopental
 Propofol
 Isoflurane  Propofol
 Remifentanil
Nitrous Oxide (N2O)  Desflurane  Etomidate
 Dexmedetomidine
 Ketamine
 Ketamine
Potent (need small %)
Volatile (stored as liquid,
need to pass through vaporizer)

Definition of Anesthesia: a reversible state of unconsciousness characterized by:

• hypnosis (loss of awareness),
• amnesia (loss of antegrade memory),
• analgesia (insensitivity to pain),
• immobility (gold standard for anesthetic potency)
No other unconsciousness state fulfills all 4 criteria

Minimum Alveolar Concentration (MAC)

(actually a median)
 Basically an ED50: concentration that abolishes movement to noxious stimulus in 50% of pts (e.g. incision)
 Potency = 1/MAC (lower MAC = more potent)

MAC ↓ with: old age, other sedatives, hypothermia (need less anesthesia)
 Genetic variation may affect MAC in animals

Anesthesiologist knows MAC for population

(but needs to determine MAC for individual by careful observation)
 95% CI = MAC ± 25%

4 Stages of Anesthesia
Classic: 4 stages of depth of anesthesia

Stage I Analgesia, amnesia

Delirium: more historical; don’t see with modern
Stage II
anesthetics (very short)
Stage III Surgical anesthesia (where you do surgery)
Medullary depression (anesthetic overdose):
Stage IV hypotension, ↓ respiration  apnea (need life
support or will arrest)

Stage IV reached during operations sometimes:

but anesthesiologist picks up sign, reduces concentrations

Anesthetics have a relatively narrow therapeutic index

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 MAC: clinical implications
MAC-awake (0.3 x MAC) the point where you lose ability to respond to commands
1 x MAC 50% of pts immobile, surgical stage
1.3 x MAC 95% of pts immobile
2-4 x MAC bad; pts will die without life support

Sample question: at what sevoflurane concentration would you expect a 95 year old female pt to lose ability to respond to
commands (if MAC is 2% for sevoflurane)?
A) 2% B) 2.4% C) 0.6% D) 0.4%
Why D? MAC-awake is 0.3 x MAC, but she’s old (↓ MAC) so you need an answer that’s less than 0.3xMAC

Inhaled Anesthetic Pharmacokinetics

Anesthesiologist: sets machine to get to anesthetic partial pressure in brain, SC to levels for stage III anesthesia
 Machine trachea  bronchi  alveoliDiffuse along partial pressure gradient into arterial blood (pulmonary circ) 
 Some goes into solution, some undissolved; undissolved proportion of gas generates a partial pressure in blood
 Circulates  diffuses into brain along partial pressure gradient  hits receptors 
 back into venous circulation  lungs
 Eventually, the partial pressures equalize in the lungs and net diffusion stops

4 Key Points of Anesthetic Pharmacokinetics

1) Onset of anesthesia determined by partial pressure, not the concentration, of anesthesia in CNS (PCNS)
2) At equilibrium: PCNS = Palv (partial pressure in CNS = partial pressure in alveoli)
a. So changing PAlv governs the onset of anesthesia
b. Equilibrium set by anesthesiologist (Pmachine)
3) Blood flow into brain does not affect the magnitude of PCNS at equilibrium
a. But it does affect the time to reach equilibrium
4) Other factors that determine time constant for PCNS
a. Solubility (partition) coefficient (λ) of the anesthetic gas: physical property of gas, defines relative
affinity of anesthetic between two compartments
b. Gradient between arterial (or alveolar) and mixed venous
partial pressures of anesthetic

Gas laws:
• The partial pressure of a gas dissolved in a liquid = partial pressure of
the free gas in equilibrium with that liquid.
• Partial pressure of an anesthetic gas (Panes) rises at roughly equal rates in
all compartments but with a phase delay (brain<muscle<fat)
• The phase delay is governed by the time constant for the compartment
(tissue group).
• At equilibrium, the partial pressure is equal in all compartments.

Solubility

Henry’s Law: Concentration= Partial pressure(P) × Solubility Coefficient(𝛌)

HIGHLY SOLUBLE GAS has LOWER PARTIAL PRESSURES on both sides of the membrane
• See example slide: ↓ solubility constant means that you have a higher partial pressure for a given concentration
• Drug design: want more & more insoluble gases (can reach target partial pressures more easily)

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Time constants (τ)
 Flow rate & volume capacity determine the time to reach the set partial pressure
𝒕
 𝑷𝒄𝒐𝒎𝒑𝒂𝒓𝒕𝒎𝒆𝒏𝒕 = 𝑷𝒇𝒍𝒐𝒘 (𝟏 − 𝒆𝝉 )
(𝝀𝒄𝒐𝒎𝒑𝒂𝒓𝒕𝒎𝒆𝒏𝒕×𝒗𝒐𝒍𝒖𝒎𝒆𝒄𝒐𝒎𝒑𝒂𝒓𝒕𝒎𝒆𝒏𝒕)
 𝝉= = capacity (l) / flow (l/min)
𝒇𝒍𝒐𝒘𝒄𝒐𝒎𝒑𝒂𝒓𝒕𝒎𝒆𝒏𝒕
o For alveoli: τalv = FRC/VA (= capacity / flow)

 Without removal (uptake) from a compartment, it takes

o 3τ for Palv to reach 95% of equilibrium partial pressure (Pequil)
o 1τ for Palv to reach 63% of equilibrium partial pressure (Pequil)
 Example (see slide): If FRC is 3L and VA = 6 L/min, then τalv = 0.5 min, so you’ll reach 95% Pequil in 3τ = 1.5 min

Breathing deeper lets you reach equilibrium more quickly (↑ VA so ↓τalv)

So in a patient:
1. Palv equilibrates with Pmachine in 3τ (1.5 min in example above), where τ = FRC / VA
2. Part equilibrates immediately with Palv (big surface area of lung in contact with whole cardiac output)
3. PCNS equilibrates shortly thereafter based on time constant for specific anesthetic in CNS

Tissue groups:
 Brain: 2% of body mass but consumes lots of cardiac output
 Muscle: 50% of body mass, consumes about the same as brain,
isoflurane is more soluble
 Fat: 20% of body mass; note that solubility is much higher for isoflurane
o Anesthesizing morbidly obese person: deposit anesthetic in fat compartment
o Dissolves in fat compartment  takes a long time to mobilize anesthetic & pt wake up
o Obese pts remain groggy for much longer

Example: How long will it take brain partial pressure to equilibrate, if isofluorane has a blood/brain solubility coefficient (λ) of 1.6,
volume of adult brain is 1.4 L, and blood flow to the brain is 20% of CO (1L/min)?
 τbrain = λ*vol/flow = 1.6*1.4/1 = 2.2 min, so 95% of Pequil is reached in 3x2.2 = 6.6 min

Uptake
 In real life, uptake slows rate of rise of Palv (anesthetic being removed from alveoli into pulmonary blood flow)
o Analogous to creating a larger arterial blood compartment
 ↑ uptake from lung (= slower rise of Palv, higher capacity of blood compartment) with:
o ↑ solubility of anesthetic (↑ λblood/gas)
o ↑ CO
o ↑ partial pressure gradient (between arterial blood & mixed venous blood: Part – Pven)
 Pven reflects partial pressure of venous blood
coming back from all compartments, weighted
by % cardiac output received (so brain & heart 𝐿 𝜆 × 𝑄 × (𝑃𝑎𝑟𝑡 − 𝑃𝑣𝑒𝑛 )
are big players) 𝑼𝒑𝒕𝒂𝒌𝒆 =
𝑚𝑖𝑛 𝑃𝐵
Anesthetic uptake stops when Pven = Part
 after some time, well-perfused tissues are saturated  no gradient for net diffusion

Time course of anesthesia

1st minute Part = Pven = 0 so no uptake from lung (Palv ↑ very rapidly)
Next few minutes Palv, Part ≫ Pven so Part – Pven ↑↑  ↑ uptake from lungs  slows rise of Palv
Equilibrium Pven≈Part so no net uptake; Palv ≈ PCNS, equilibrium

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Sample question: how do you know when anesthetic has reached equilibrium?
 Exhaled anesthetic concentration = inhaled anesthetic concentration

Factors that speed induction

Inspired gas concentration
Alveolar ventilation
Lung capacity (FRC)
Gas solubility
Cardiac output
(or pulm blood flow)
Airway effects
Gas Property Patient Physiology Anesthesiologist Decision
- -  Gas concentrations ( “overpressure”)
- spontaneous ventilation mechanical ventilation
-  (e.g., child) -
Less soluble -
- ↓(e.g., shock) -
Non-irritant

Shock: pt will go to sleep very quickly & hit stage IV with normal concentration of anesthesia! (↓ CO, so faster induction – ↓uptake)
Anesthesiologists: sometimes give temporary “OD” (called “overpressure”) to speed induction, then turn it down
Irritation: pts will refuse; would take longer

Anesthesiologists cannot measure Panes.

• They can only measure inspired and expired anesthetic concentrations.
• Concentration  partial pressure
• Even though concentration is measured as vol%, it is abbreviated as F (fraction of 1).
• Equilibrium is: FA = FI
• where FA = alveolar anes conc ( Palv) and FI = inspired anes conc (PI).
• Speed of induction of anesthesia: FA / FI

Inhaled Anesthetics in Current Use

Chemical Blood:Gas
Anesthetic MAC, % Metabolism Comments
Structure Solubility Coefficient
Slow onset/recovery
Halothane Alkane 0.75 2.3 <40%
Myocardial depressant.
Medium onset/recovery
Isoflurane Ether 1.2 1.4 Minimal
Slightly pungent odor.
Rapid onset/recovery
Sevoflurane Ether 2.0 0.69 <5%
Emergence delirium.
Rapid onset/recovery
Desflurane Ether 6.5 0.42 Minimal
Airway irritant
Other Must be given with O2
Nitrous oxide >100 0.47 None
N=N-O and other anesthetics

Note: Nitrous oxide has high MAC; would be lethal in doses needed for total anesthesia (need to give others)
Desflurane: irritant; need to induce with something else first

Development: want as insoluble as possible with halothane (=2.3) as the baseline (possible, but with a price):
• Isoflurane =1.4, but airway irritant (coughing)
• Sevoflurane =0.69, but emergence delirium
• Desflurane =0.42, but severe airway irritant (laryngospasm)

Elimination of inhaled anesthetics

↓ FI by anesthesiologist  ↓ FA  ↓ FBrain
 Just the reverse of uptake & distribution Faster elimination by:
 ↑ ventilation
Metabolism inconsequential except for halothane  ↑ pulmonary blood flow
 ↓ solubility 19
Malignant Hyperthermia: the only anesthetic disease
Molecular defect: Autosomal dominant inheritance
 point mutation in RYR1 (Ca++ release channel) gene (50% of patients)
 sustained Ca++ release from sarcoplasmic reticulum
Incidence: 1:4000 (mild) – 1:250,000 (fulminant)
Triggers: volatile anesthetics, succinylcholine
Manifestations: muscle rigidity, temp, heart rate, pCO2, pH, rhabdomyolysis
Therapy: Dantrolene (a muscle relaxant)
Diagnostic Test: contracture test (caffeine or halothane) – muscle contracts, doesn’t relax: diagnotic

IV General anesthetics
General Overview
• Very rapid induction of sleep (20-60 sec)
• Work in one circulation time
• Useful for emergency surgery (“rapid sequence induction - RSI”)
• Get endotracheal tube in before pt can vomit
• Oxygenate, apply cricoid pressure (keep GI contents down), get tube in, release pressure
• Do not provide all 4 components of anesthesia
• usually combined with other sedatives, opioids, or volatile agents (“balanced anesthesia”)

3 compartment model
 inject into central compartment (V1)
 rapid distribution to V2 (highly perfused tissues, e.g. brain) - so rapid effect
 slow distribution to V3 (muscle, then fat)
o note that ↑ time to wake up with ↑ fat
o Gradual return (hours) of anesthetic from V3 to the central compartment 
metabolized (liver) eliminated.

Offset time after continuous infusion depends on infusion duration

 “context sensitive half-time”: Longer infusion = groggy for longer
 If rate of elimination is faster than V3V1 rate, then [drug]brain ↓ fast  wake
up quickly. Example: propofol (pts. wake up promptly)
 If V3 is big and rate of elimination is slower than V3V1 rate, then drug is
slowly released from V3, maintaining [drug] in V1 & V2, prolonging effects.
Example: thiopental (takes 6x longer to wake up than propofol)

IV Anesthetics in Clinical use

See next page for table

Ketamine: NMDA glutamate channel blocker

 Different from other IV anesthetics:
o wide-eyed but unresponsive to command (dissociative anesthesia)
o Profound cutaneous analgesia
o Stimulates SNS (unlike others): ↑ HR, ↑ BP, bronchodilation, ↑ CBF
 Phencyclidine (PCP = angel dust) is a derivative

Another question: a burn patient requires debridement (really painful):

anesthetic binding to which molecular target is most likely to produce analgesia & sedation w/o depressing respiration
A) NMDA receptor B) Opiod receptor C) GABA receptor D) α2 adrenergic receptor
Answer: use KETAMINE (cutaneous analgesia, doesn’t depress respiration)

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 Molecular Cardio-respiratory Adverse Effects
Clinical Use
Target Effects
 Rapid sequence induction
 BP,  BP
Thiopental (for emergency surgery)
hypovolemia  Extravasationtissue
 Continuous infusion
 Apnea necrosis
(for seizures or brain edema)
 Induction agent
 Continuous infusion  Anaphylaxis (egg, soy)
Propofol GABA  Mild BP
(for diagnostic procedures)  Burning sensation
agonists  Respirations
 Continuous infusion + opiod during injection
(for surgical procedures)
 Rapid sequence induction  Inhibits 11-
Etomidate for emergency surgery  Apnea hydroxylase
(esp. unstable pts) cortisol. (continuous
infusion contraindicated)
 “Dissociative” anesthesia (open  ↓ seizure threshold
eyes, but unresponsive)  HR (relatively contra-
 Profound cutaneous analgesia  Stable BP and indicated in epilepsy)
Ketamine NMDA (anesthesia for burn dressing respirations  ↑ intracranial
blockade changes)  Bronchodilator pressure (contra-
 Rapid sequence induction (used for severe indicated in head
for emergency surgery asthma in ICU) trauma)
(esp. unstable pts)  Oral secretions
 Excellent sedative
(e.g., long-term ICU sedation)
 Stable
Dexmedetomidine central 2  Little or no withdrawal syndrome
respiration  Very expensive
agonist after prolonged infusion
 BP
 Combined with opioids for
anesthesia in OR
 Combined with sedative  Chest wall rigidity
(e.g.,propofol) or inhaled (need neuromuscular
opioid anesthetic in OR  Apnea blockade and
Remifentanil
receptor  Useful when very rapid offset is  BP endotracheal intubation
desired (metabolized by plasma before patient can be
cholinesterase) ventilated)

Molecular Mechanisms of Action

Old model: the Meyer-Overton Rule
• Anesthetic potency  solubility in olive oil
• Inference: nonspecific action on hydrophobic lipid moieties in cell membranes
• Now generally replaced by specific molecular models

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Drug Class based on Target & Effects:
Hypnosis & Slowing of
Analgesia
Examples Action Amnesia cortical EEG
(NMDA effect)
(GABAA effect ) (GABAA effect )
Etomidate,
Act primarily via specific GABAA receptors
Group 1 propofol, and
(with different subunit types).
barbiturates
Less selective; target:
N2O and  glutamate receptors
Group 2
ketamine (NMDA, AMPA, kainate)
 two-pore K+ channels.
Volatile Least selective group
Group 3
anesthetics Target many molecular sites.

Volatile Agents
 Target both inhibitory & excitatory receptors (less specific)
 Either:
o ↑ inhibitory ion channel and/or
o ↓ excitatory ion channel

GABA
 GABA released from inhibitory presynaptic neuron  binds
postsynaptically  opens chloride channel
 Hyperpolarizes post-synaptic membrane (inhibitory)
 General anesthetics bind to a separate site on the subunit and appear to increase the sensitivity of these
subunits to GABA. This prolongs the postsynaptic inhibitory current in response to GABA discharge.

22