Neuropharmacology Flashcards
diazepam
CNS spasmolytic
benzodiazepine
GABA-A-R allosteric AGonist
mx:
- postsynaptic inhibitory effect
- facilitates GABA binding/potentiates inhibitory actions
baclofen
CNS spasmolytic
GABA-B-R AGonist
mx:
- pre and post synaptic inhibitory effect
- direct potentiation of inhibitory actions of GABA-R
gabapentin
CNS spasmolytic
antiepileptic
GABA mimic
mx:
- does NOT bind to GABA-R
- mimics GABA actions
- blocks voltage-sensitive Ca++ channels on presynaptic terminal
pk:
- not metabolized
- excreted in urine
- no significant interactions
tizanidine
CNS spasmolytic
alpha-2 adrenergic R AGonist
mx:
- presynaptic inhibitory effect
- centrally acting
uses:
- spasm
- cramping
- muscle tightness d/t MS
- back pain
- spinal injury
BoNT
PNS spasmolytic
mx:
- inhibits ACh release from presynaptic terminal
uses:
- dystonia
- strabismus
- torticollis
- generalized spastic disorders
dantrolene
PNS spasmolytic
mx:
- inhibits Ca++ release from SR
mx drug entry to brain
diffusion
- free drug
- lipid soluble
- small molecule
- YES: cortisol, dexamethosone, some statins
- NO: cholesterol
diffusion w/ ion trapping
- nonionized form of weak acids or bases crosses in
- becomes ionized and can’t get out
facilitated transport
- amino acid tansporters
- Glut-1 transporter
- vitamin transporters at choroid plexus
receptor mediated endocytosis
- transferrin (iron) insulin, leptin, peptides
P-gp efflux pump
P-glycoprotein
ATP-dependent
limits xenobiotics to brain
- analgesics
- antiepileptics
- antidepressants
- anti-HIV
- anti-microbials
ceftriaxone
uses:
- Neisseria meningitidis
- most pneumococcus
mx:
- 3rd gen ceph
- direct TPA binding
dose:
- higher for CNS infections
vancomycin
uses:
- strep pneumonia (incl. meningitis)
mx:
- inhibition of peptidoglycan synthesis by binding peptide chain
dose:
- higher for CNS infections
ampicillin
uses:
- listeria monocytogenes
- part of empiric abx cocktail for meningitis in:
- pregnant
- neonates
- i.c.
dose:
- higher for CNS infections
dexamethasone
uses (among others…)
- part of empiric abx cocktail for meningitis
- (when gram stain back) only continue if strep pneumoniae
rationale:
- massive inflammatory response from abx killing bacteria can worsen CNS damage and possibly sepsis
- only beneficial for strep pneumoniae (based on empiric data) but not harmful in other meningitises
ischemic stroke tx
IV thrombolytics:
- alteplase (1st gen)
- tenecteplase
+endovascular thrombectomy
hemorrhagic stroke tx
- reversal agents for blood thinners
- aggressive bp management
- clotting factors
- blood
levodopa
L-DOPA
DA precursor
effective for PD tx
but large doses required –> sfx and AEs w/ extended use
sfx/AEs: early: - n+v - depression - pychosis - orthostatic hypOtension late: - fluctuating motor responses d/t end-of-dose periods - on/off periods - sudden loss of sx control despite L-DOPA levels * dyskinesias (after several years)
carbadopa
dopa decarboxylase inhibitor
administered w/ levodopa in PD to prevent side effects from peripheral conversion of levodopa to epinephrine
does not cross BBB
levodopa dyskinesias
50-90% of pts w/ long-term use (~60% 10 yr)
involuntary movements
- coreiform (dance-like)
- maybe: dystonia, myoclonus
- any part of body
- potential for respiratory muscle involvement
dopamine receptor agonists
directly activate post-synaptic DA receptors
tx PD
e. g.
- ropinirole
- pramipexole
- rotigotine
sfx/AEs
- n+v
- orthostatic hypOtension
- dose-related psych fx e.g.
- daytime sleepiness
- impulse control disorder
- mood instability/changes
- vivid dreams
- narcolepsy-like sleep attacks
- less dyskinesia vs L-DOPA
ropinirole
dopamine receptor agonist
D2/D3
t1/2 ~6h
PD
pramipexole
dopamine receptor agonist
D2/D3
t1/2 8-12h
rotigotine
dopamine receptor agonist
non-selective
once-daily transdermal patch
apomorphine
short-acting non-ergot dopamine agonist
D1/D2
t1/2 ~40 min
“rescue” med/fast onset
- acute tx of hypOmobility, end-of-dose fx, on-off episodes
sfx:
- n+v
- orthostatic hypOtension
amantadine
DA releaser
- amphetamine like
DA reuptake inhibitor
NMDA receptor ANTagonist
uses
- monotherapy in early PD
- L-DOPA induced dyskinesias
not metabolized
safe in liver disease
MAO-B inhibitors
inhibit DA metabolism
PD
e. g.
- selegiline
- rasagiline
- safinamide
serious drug interactions (d/t also inhibiting NE, 5-HT metabolism)
- SSRIs
- TCAs
- tyramine containing foods
selegiline
irreversible MAO-B inhibitor
PD
rasagiline
irreversible MAO-B inhibitor
PD
safinamide
reversible selective MAO=B inhibitor
inhibits glutamate release
helps with levodopa “off” episodes
muscarinic receptor antagonists in PD
e. g.
- trihexyphenidyl
- benzotropine
mainly tx tremor
weak efficacy
limited clinical utility
in PD:
- dopamine deficit –> excessive ACh activity
istradefylline
use:
- PD add-on (to levodopa/carb)
mx:
- adenosine A2A receptor antagonist
- A2A colocalize w/ D2 receptors, decreases D2 receptor affinity for DA
- inhibitor –> increase D2 receptor activation (inhibitory dopamine receptor)
entacapone
peripheral COMT inhibitor
increases L-DOPA bioavailability for given dose
Sinemet
levodopa/carbidopa combo drug
opicapone
peripheral COMT inhibitor
increases L-DOPA bioavailability
>entacapone
once-daily
PD - add on to levodopa/carb especially if +motor fluctuations
tolcapone
peripheral and CNS COMT inhibitor
hepatotoxicity concerns
mainline PD tx
1+ of (generally tried in this order):
L-DOPA + carbidopa (sinemet)
- most effective, but concern for long-term use
DA D2/3 receptor agonists e.g.:
- ropinirole
- pramipexole
MAO-B inhibitors e.g.:
- rasagiline
- selegiline
- safinamide
individualize to pt needs
lowest dose singly or in combo for pt’s needs
second line / adjuvant PD tx
anticholinergics for tremor e.g.
- benztropine
- trihexyphenidyl
DA releaser/reuptake inhibitor
- amantadine
COMT inhibitors e.g.
- entacapone
- opicapone
- tolcapone
adenosine A2A receptor antagonist
- istradefylline
when to initiate PD therapy
when sx interfere w/ fx or qol
tx is for sx only - no advantage to starting early, and increases sfx burden
drug-induced parkinsonism
d/t:
- antipsychotics - D2 antagonists
- reserpine - depletes NE/5-HT/DA
reversible, but may require weeks to months after stopping med
PET in PD
generally reserved for research or atypical cases
F-DOPA tracer
shows reduced DA uptake in putamen>caudate
typically progresses from unilateral to bilateral
benzodiazapines mx
allosteric GABA-A-R binding
enhances GABA fx (inhibitory)
increase efficiency of GABA-ergic synaptic transmission
membrane hyperpolarization –> decrease firing rate of neurons
benzos pharmacodynamics
well absorbed po
throughout body - very lipid soluble
primary hepatic clearance phase I and II
oxidation –> active metabolites in some cases
- longer effected t1/2
- drug accumulation w/ repeated administration
- diazepam, chlordiazepoxide, clonazepam (valium, librium, klonapin)
oxazepam and lorazepam (serax, Ativan)
- no active metabolites
- minor accumulation
ASM
anti-seizure med
preferred term (now)
more appropriate term than AED/antiepileptic, as drugs target seizures, not underlying causes of epilepsy
when to initiate/dc ASMs
initiate after 2nd seizure
or 1st if EEG/MRI/CT abnormal
withdraw if seizure free >2 years and low risk
drug resistant epilepsy
early in tx failure of 2 drugs
<5% b//c seizure free
ASM CYP P450 inhibitor
valproic acid - 2C
ASM CYP P450 inducers
carbamazepine - 3A4 and 2C
phenobarbital - 3A4 and 2C
phenytoin - 3A4 and 2C
sodium channel blockers
first line ASMs
e. g.:
- lamotrigine - fewest sfx/AEs/fetus risk (t1/2 22h)
- carbamazepine - short-ish t1/2 (8h)
- phenytoin (t1/2 22h)
GABA/chloride channel agonists
benzos - rapid onset; first-line for status epilepticus
valproate
phenobarbital - very high pregnancy risk; 80h t1/2, outdated but common in developing countries
first line for status epilepticus
benzos
usually lorazepam d/t short on-slow off
effective ~1-3 min, 22h t1/2
topiramate
broad spectrum ASM
useful for migraine prevention
t1/2 21 h
multiple mx
- sodium channel
- glutamate R
- GABA-R
high preg risk
low rash risk
mixed hepatic and urinary
gabapentin
action similar to GABA but mx unrelated
binds voltage-gated Ca++ channels
inhibit release of excitatory neurotransmitters
adjuvant for focal seizures
levetiracetam
first-line ASM for all seizure types
SV2A inhibitor - synaptic vesicle protein - inhibition –> no pool of nt-containing vesicles
reduces excitatory nt release
renal clearance
low preg risk
low rash risk
sfx: fatigue irritability HA insomnia
lacosamide
focal onset and primary generalized seizures
enhanced slow inactivation of voltage gated Na channels
t1/2 13h
preg risk
low rsh risk
parampanel
broad spectrum ASM
selective non-competitive AMPA-R (glutamate) blocker
t1/2 105h
preg risk
clobazam
adjuvant for LGS
GABA-A agonist
t1/2 36-42 h
preg risk
low rash risk
absence-only seizure tx
ethosuximide
- t-type Ca++ channel blocker in thalamus; low potency but works well for absence seizures (not other types)
(or)
valproic acid
CBD sz
both CBD and THC show anticonvulsant properties, CBD (–) psychotropic fx
multiple targets
add on to clobazam in LGS
GCSE tx
generalized convulsive status epilepticus
first line tx:
IV lorazepam
if persistent
barbiturate (fosphenytoin, VPA, or phenobarbital)
refractory
midazolam or propofol
super refractory >24 h
high morbidity
tx pentobarbital coma (medically-induced coma)
focal onset epilepsy
first line
levitiracetam
lamotrigine
carbamazepine
primary generalized tonic clonic epilepsy
first line
levetiracetam
lamotrigine
valproic acid
absence only epilepsy
first line
ethosuximide
valproic acid
LGS
first line
valproic acid
levetiracetam
clobazam
more likely to need 2+ to achieve control
lamotrigine
voltage gated Na+ blocker
rash risk
low preg risk
first line for focal onset and primary generalized tonic clonic
nitrous oxide
inhibition at NMDA-R
blockade of glutamate release
non-volatile
inhalational
generalized anesthetic
fx:
- amnesia (explicit emory)
- deep sedation / unconsciousness
- immobility to pain
- autonomic reflex blunting and depression
i. e. near “complete” anesthetic fx
respiratory volume -- rr -- minute vent -- apnea threshold increase bronchodilator airway irritability -- bp down CV fx down SVR up HR down/neutral coronary vasodilation -- no uterine relaxation (can be used for labor pain)
environmental: ozone depletion
114 yr atmospheric lifetime
MAC
minimum alveolar concentration
“dosage” of inhaled anesthetic
sevoflurane
inhalational generalized anesthetic
decrease respiratory volume increased rr decreased minute vent increased apnea threshold bronchodilator airway irritability -- bp down CV fx down SVR down HR -- coronary vasodilation uterine relaxation - caution in c-section
desflurane
inhalational generalized anesthetic
decrease respiratory volume increased rr decreased minute vent increased apnea threshold bronchodilator very increased airway irritability bp down CV fx down SVR down HR up or -- coronary vasodilation uterine relaxation - caution in c-section
environmental: ozone depletion
- 1 h at 1 MAC ~ carbon footprint of 200-400 mi in avg car
isoflurane
inhalational generalized anesthetic
decreased respiratory volume rr -- very decreased minute ventilation increased apneic threshold bronchodilation airway irritability bp down CV fx down SVR down HR up coronary vasodilation uterine relaxation - caution in c-section
propofol
IV anesthetic
induction and maintenance
most frequent
use:
- short cases
- outpt
- neurosurg
- optho
- other cases, as long as normal myocardial fx
fx:
- no analgesia
- hypnosis (GABA-A mediated)
- sedation
- anti-emetic
- dopaminergic - nucleus accumbens (abuse potential, euphoria)
- decreases CBF in elevated ICP
- respiratory depression
- inhibits hypercapneic respiratory drive
- low incidence of anaphylaxis
- decreased bp, co, svr, rr; ?hr
sfx:
- injection site pain
- sepsis/infections
- liver metabolism
ketamine
IV or IM anesthetic
phencyclidine/PCP
glutamic acid inhibitor at NMDA-R
uses:
- trauma + hypOvolemia/shock
- peds, esp CV repair
- asthmatics
- adjuvant for chronic pain, others at sub anesthetic doses
fx:
- analgesia
- no injection site pain
- sedation
- dissociation
- increased CBF and ICP
- increased bp, hr, co, sir
- rr –, bronchoconstriction
sfx:
- psych rxn on awakening:
- vivid dreams
- extracorporeal experiences
- illusions
- excitement, confusion, euphoria and/or fear
- possible benzo attenuation
etomidate
IV anesthetic
GABA-A mediated
uses:
- CV surg
- any case involving compromised CV fx
- neurosurg (second choice to propofol)
fx:
- hypnosis / sedation
- no analgesia
- burst suppression on EEG / barbiturate-like effect
- decreased CBF and ICP
- neutral bp, hr, co, svr, rr
sfx:
- increases EEG activity in epileptogenic foci
- transient decrease in cortisol
- injection site pain
- n+v
- myoclonus
- hiccups
dexmedtomidine
selective alpha-2 receptor agonist
IV anesthetic
uses:
- intubated pts in ICU
- pts w/ ventilation issues requiring sedation
fx:
- sleep like hypnosis
- no reliable amnesia
- minimal respiratory fx
- decreased hr, co, bp
succinylcholine
depolarizing NMB
structurally similar to ACh
binds alpha subunit of Nic-R
continuous Na+ opening –> persistent depolarization / fasciculations –» flaccid paralysis
use:
- rapid / brief paralysis
- intubation
- very short procedures e.g. laryngoscopy, biopsy
fx returns after 5-10 min
metabolism by plasma pseudocholinesterase
sfx:
- myalgias
- increased ICP, IOP, intragastric pressure
- prolonged paralysis if atypical pseudocholinesterase
- hypER-K esp if recent burns, certain neurologic/muscular disorders, renal failure
- malignant hyperthermia in susceptible pts
short acting NDMB
non-depolarizing muscle blocker
mivacurium 12-20 min
- pseudocholinesterase metabolism
- not available in US
intermediate acting NDMB
rocuronium 35-75 min
- appropriate for rapid intubation
- most commonly used NDMB
atracurium/cisatracurium 40-75 min
- common in liver/kidney disease
vecuronium 45-90 min
long acting NDMB
pancuronium 60-90 min
- renal excretion
- may increase hr by vagal antagonism
NDMB c/i
anaphylaxis risk
- c/i in asthma, sepsis, other susceptible pts
NDMB reversal
ACh-ase-I + antimuscarininc
- usually neostigmine + glycopyrrolate (sometimes atropine)
- antimuscarinic counteracts parasympathetic cholinergic sx
- possible cholinergic crisis / SLUDGE
sugammedex
- bind NDMB
- works best w/ rocuronium
- does not work w/ benzylisoquinolines i.e. cisatracurium
atropine
anticholinergic
reversal of anesthesia
tx organophosphate poisoning (acute; definitive is pralidoxime)
anti-SLUDGE
fast onset, short duration
crosses bbb
also used to tx bradycardia (ACLS algorithm)
glycopyrrolate
anticholinergic reversal of anesthesia intermediate onset, longer duration does not cross BBB may also be used to t x bradycardia
organophosphates
irreversible ACh-ase-I
in ophthalmology:
- miosis (pupillary constriction)
- reduce IOP
pralidoxime
definitive tx for organophosphate poisoning
give ASAP b/f irreversible conjugate forms
