CNS Drug Mechanisms Flashcards
Binds GABA-A receptor → Prolonged Receptor Opening → Cl- influx → hyperpolarization → decreased neuron activity
Barbiturates
BZs or Barbs?
Effects can occur independent of GABA
Barbs
Binds GABA-A receptor → More Frequent Receptor Opening + Increased GABA Affinity → Cl- influx → hyperpolarization → decreased neuron activity
Benzodiazepines
Competitive antagonist at GABA receptor → reversal of BZ effects
Also binds site of “Z drugs”
Flumazenil/BZ Antagonists
Partial agonist at postsynaptic 5-HT1A Serotonin Receptor → Inhibition of cell signaling
Full agonist at presynaptic 5-HT1A Serotonin autoeceptor → decreased 5-HT release
Buspirone
What about Buspirone’s mechanism prevents its use for EtOH withdrawal?
GABA independent
How long does it take for buspirone’s mechanism to take full therapeutic effect? This means it is a bad choice for what type of anxiety?
2 weeks, not good for acute anxiety
Buspirone exerts effects outside of the GABA system, that means that it lacks what 3 properties?
sedation
muscle relaxant
anticonvulsant
Binds BZ1 GABA Receptor → Increased GABA-Mediated Inhibition → strong, rapid sedation
No anxiolytic, anticonvulsant, muscle relaxant properties
Zolpidem, Zaleplon, Eszopiclone
Z Drugs
Orexin Receptor Antagonist: orexin regulates sleep-wake cycle, promotes wakefulness
GABA Independent
Suvorexant
Melatonin Analogue → reset sleep-wake cycle → promotes sleepiness
GABA Independent
Ramelteon
H1 Receptor Antagonist → antihistamine properties
Also causes sedation, major ingredient in OTC insomnia meds
Deiphenhydramine
The Mechanism of EtOH is similar to which 2 drug classes?
BZs and Barbs
Receptor Downregulation → Tolerance
Inhibits Glutamate on NMDA Receptor → up-regulation of NMDA Receptor
Increases DA in mesolimbic pathway
EtOH
Opioid Receptor Antagonist → blocks reward pathway stimulation
(not acute)
Naltrexone
Structural analogue of GABA
Restores normal balance of GABA & Glutamate
Acamprosate
Inhibits aldehyde dehydrogenase → acetaldehyde build up → flushing, HA, Nausea, Confusion
Disulfiram
Spasmolytic
Response depends of alpha receptor subtype
Alpha 1: Sedative + Anticonvulsant
Alpha 2: Anxiolytic
Alpha 2/3/5: Muscle Relaxant
Diazepam
GABA-B Agonist → opening of K+ channels → Hyperpolarization → inhibition of presynaptic Ca2+ Channels → Decreased NT Release
Inhibitions AC and cAMP formation to reduce excitatory NTs
Spasolytic
Baclofen
Spasmolytic
Alpha 2 Receptor Agonist → Presynaptic and Postsynaptic inhibition of spinal cord synaptic activity → decreased spasticity
Inhibits pain transmission in dorsal horn
Tizanidine
Spasmolytic
Competitive Antagonist to SR RyR1 Channel → Inhibited Ca2+ release → impaired E-C Coupling → decreased spasm of skeletal muscle
Dantrolene
Brain stem sedative → decreased neuronal activity in spinal cord
Antimuscarinic Activity → sedation, confusion, hallucination
Acute spasm drug
Cyclobenzaprine
Brain stem sedative → decreased neuronal activity in spinal cord
Similar to barbiturates, caution recovering addicts
Acute Spasm Drug
Carisoprodol
Block GABA reuptake
Tiagabine
Irreversible inhibition of GABA Transaminase → decreased GABA metabolism
Vigabatrin
Binds Synaptic Vesicular Protein SV2A
Levetiracetam
Blockage of T-type Ca2+ channels (2)
Ethosuxamide, Valproate
Block sodium and calcium channels
Valproate
Carbamazepine MoA
Inhibition of Na+ Channels
Phenytoin MoA
Inhibition of Na+ Channels
Topiramate MoA
Inhibition of Na+ Channels
Lamotrigine MoA
Inhibition of Na+ Channels
Zonisamide MoA
Inhibition of Na+ Channels
GABA analogue…
Gabapentin
GABA analogue┃Binds voltage-gated Ca2+ channels → inhibited excitatory NT release
pregabalin
Selective 5HT reuptake inhibition → increased 5HT in cleft → downregulation of 5HT postsynaptic receptors
2-3 weeks for effects to begin
SSRIs
Fluoxetine Paroxetine Sertraline Citalopram Escitalopram
Inhibits reuptake of NE & 5HT
More S/Es than SSRIs
SNRIs
Venlafaxine, Duloxetine
Inhibit reuptake of NE & 5HT
(No euphoria, low abuse potential)
(2-4 weeks for effect)
Block alpha adrenergic, histamine, muscarinic receptors
TCAs
Amitriptyline (Elavil)┃Imipramine (Tofranil)┃Nortriptyline (Pamelor)┃Desipramine (Norpramin)
General: Irreversible MAO inhibition → increased NE, DA, 5HT in cleft
MAOIs
Phenelzine (Nardil)┃Selegiline (Deprenyl)
Inhibits DA < NE and 5HT
Combined w. SSRI
Bupropion
Blocks presynaptic Alpha 2 Receptors → blocked inhibitory pathway → increased NE & 5HT
Eliminates SSRI S/Es (anxiety, insomnia, nausea, sexual dysfunction)
Mirtazapine (Remeron)
Selective NE reuptake inhibitor
Atomoxetine
5HT2A Antagonist
Trazodone
Gi signal transduction → decreased cAMP → closing presynaptic voltage-gated Ca2+ channels → decreased NT release & neuron activity
Opioids
Which opioid receptor?
opening of K+ channels → hyperpolarization → inhibited nerve transmission → decreased pain signaling
Mu receptor
Stimulates all opioid receptors
Strong Agonist
Production of all opioid effects
Morphine
Stronger than morphine, similar duration, same routes
Moderate to severe pain
No metabolite accumulation → use if renal dysfunction
No histamine release → less itching
hydromorphone (Dilaudid)
Mu receptor agonist
Maintenance Tx for addicts
Long-term Pain Control
Methadone
Mu agonist
Metabolite → Seizures
Anticholinergic Effects → Tachycardia, Pupil Dilation
Meperidine (Demerol)
metabolite = Normeperidine via CYP2D6
Cough Suppressant
PO in combo with acetaminophen
Must be metabolized by CYP2D6 to be active
Codeine
Kappa Agonist, Mu Partial Agonist
Used for Moderate Pain
Pentazocine/Naloxone
Partial Mu agonist
Ceiling effect = not much euphoria → low abuse potential
Used for opioid addiction/withdrawal, combined with Naloxone
Buprenorphine (Suboxone)
Mild-Moderate Pain
Weak Mu Agonist, Inhibits NE/5HT reuptake
Tramadol
No analgesia, Cough Suppressant
Blocks NMDA Receptors, decreased 5HT reuptake
dextromethorphan
Which DA pathway?
VTA → Limbic System
Emotion
Mesolimbic
Which DA pathway?
VTA → Frontal Cortex
Cognition, emotion
Mesocortical
Which DA pathway?
Substantia Nigra → Striatum
Motor Control
Nigrostriatal
Which DA pathway?
Hypothalamus → Pituitary
Prolactin
Tuberoinfundibular
block D2 Receptors and alpha adrenergic actions → alleviate positive sxs
requires 60% receptor occupancy
Chlorpromazine
classical antipsychotic
Selective for D2, less anticholinergic activity → more EPS
alleviate positive sxs
requires 60% receptor occupancy
Fluphenazine
classical antipsychotic
Potent D2, D1, 5HT and H1 receptor blocker→ alleviate positive sxs
Haloperidol
classic antipsychotic
Blocks 5HT2A & D2 Receptors
No effect on DA transmission in nigrostriatal pathway
Risperidone
atypical antipsychotic
Blocks 5HT2A & DA D2 Receptors
5HT1A agonist → Some antidepressant activity
Ziprasidone
atypical antipsychotic
Which class has the below mechanism?
blockage of 5HT2A and DA D4 Receptors
Atypical Antipsychotics
Blocks 5HT2A, D4, D2
Some anticholinergic activity
Olanzapine
atypical antipsychotic
Partial agonist for D2 and 5HT1A; Antagonist for 5HT2A
Low DA tone: DA receptors Activated
High DA tone: DA receptors Blocked
Also blocks alpha1 and histamine receptors
Aripiprazole
atypical antipsychotic
DA system stabilizer
Aripiprazole
atypical antipsychotic
suppression of secondary messengers (IP3)
May increase ACh, NE, DA
Effective in 60% of patients
Lithium
mood stabilizer
crosses BBB and is converted to DA by neurons, low bioavailability (1-3% makes it to CNS)
l-dopa
inhibit Dopa-Decarboxylase + no BBB passage → Increased CNS bioavailability of l-dopa
Decreased peripheral conversion → decreased S/Es
Decreased peripheral conversion → decreased l-dopa dose
carbidopa
Reduce Striatal Metabolism of DA
Doesn’t affect peripheral metabolism by MAO-A
MAO-B (CNS) Inhibitor
Selegiline, Rasagiline, safinaminde
inhibits COMT in CNS and Periphery leading to increased DA
COMT Inhibitors
Tolcapone
Entacapone
What is the mechanism of the below?
Bromocriptine
Ropinirole
Pramipexole
Apomophine
DA D2 Receptor Agonists
Antiviral, may increase DA release/inhibit reuptake
Early/Mild PD
Amantadine
inverse agonist/antagonist for 5-HT Receptors
doesn’t affect DA, Adrenergic, Cholinergic, Histamine Receptors
pimavanserin
M receptor antagonists → restored DA/ACh balance in striatum
Anticholinergics: Benztropine, Trihexyphenidyl, benadryl
increases ACh in nerve terminal
Cholinesterase Inhibitors: Donepezil, Rivastigmine, Galantamine
Galantamine blocks AChE and what other channel?
Presynaptic ACh Autoreceptor
NMDA Receptor Antagonist → reduced excitotoxic effects of glutamate and slows degeneration
memantine
what drug class has the following mechanism, making them useful for…
Direct action at tissue inflammation
inhibition of dorsal horn excitatory NTs
thalamic action
opioids, pain
stimulation of opioid _____ receptors causes increased postsynaptic IPSPs
Mu
Stimulation of presynaptic ______ receptors by opioids causes decreased NT release
mu, delta, kappa
opioids have _____ effect on GABA release which allows activation of the descending pain inhibition pathway
inhibitory GABA effect
