MOAs Flashcards
Alcohol MOA
Binds GABAa receptor→ increased Cl- influx→ enhanced inhibitor GABA transmission
Synergistic with drugs that bind GABA at different sites: barbiturates, benzos
Increases dopamine in mesolimbic pathway (addiction)
Inhibits effect of glutamate on NMDA receptor
Naltrexone MOA for alcohol abuse
Blocks ability of alcohol to stimulate the reward pathway
Acamprosate MOA
Structural analogue of GABA→ restores disturbed GABA/glutamate balance (alcoholism) to normal
Disulfiram MOA
Inhibits aldehyde dehydrogenase→ aldehyde build up
Normal alcohol metabolism
Alcohol→ alcohol dehydrogenase (ADH)→ acetaldehyde→ aldehyde dehydrogenase (ALDH) oxidizes using NAD+→ acetate
Asians + Alcohol
lacking ALDH (aldehyde dehydrogenase)
Women + Alcohol
Lower levels of ADH (alcohol dehydrogenase)
Topiramate mechanism for alcoholism
Not understood, decreases craving and increases abstinence
Fomepizole MOA
alcohol dehydrogenase inhibitor
Barbiturates MOA
Bind GABA→ Cl- influx→ inhibitory
Produce inhibition independent of GABA: no ceiling effect
Hypnosis (CNS depressant)
Euphora→ abused
Benzodiazepines MOA
Specific site on GABAa receptor→ prolonged action
GABA dependent effects→ Ceiling effect
Flumazenil MOA
Benzodiazepine Antagonist→ competes for GABA receptor→ reverses effect of benzos and “z-drugs”
Z drugs MOA
Bind to BZ1 subtype of GABA receptor→ increased GABA-mediated inhibition
Suvorexant MOA
Antagonist at orexin receptors
Ramelteon MOA
Melatonin analogue
Chloral hydrate MOA
Converted to trichloroethanol→ similar effect as barbiturates on GABAa receptor→ sedation
Buspirone MOA
Partial agonist at postsynaptic 5-HT1a receptor (serotonin) → inhibition of cell signaling
Full agonist for presynaptic 5-HT1a receptor→ decreased release of 5-HT
Glutamate receptors are called
NMDA
also AMPA but never discussed
Glutamate causes seizures….
By activating NMDA receptors
Goal: decrease glutamate
GABA causes seizures
when GABA receptors are blocked
Goal: increase GABA
Phenytoin / Fosphenytoin MOA
Prolong inactivation of Na+ channels→ decreased glutamate activity
Carbamazepine MOA
Blocks Na+ channels→ decreased glutamate activity
Inhibits NE release + reuptake→ +/- potentiates GABA
Lamotrigine MOA
Inactivation of Na+ channels→ decreased glutamate activity
+/- inhibition of Ca++ channels
Topiramate MOA
Blocks Na+ channels→ decreased glutamate activity Some activity at Ca++ channels Potentiates GABA receptors Inhibits glutamate receptor (NMDA) \+/- Inhibits spread of seizures
Levetiracetam MOA
Binds SV2A→ apparent decrease in glutamate and increase in GABA release
Gabapentin MOA
GABA analog (but doesn’t act on receptor) May augment GABA release
Pregabalin MOA
GABA analog→ binds to alpha-2-delta subunit of voltage-gated Ca++ channels inhibiting excitatory neurotransmitter release
Tiagabine MOA
Inhibits reuptake of GABA (GAT-1) → enhances GABA activity
Vigabatrin MOA
Irreversibly inhibits GABA transaminase (GABA-T) → decreased metabolism→ increased activity
Ethosuximide MOA
Inhibits low threshold (type T) Ca++ channels→ inhibits pacemaker for rhythmic cortical damage
Valproic acid MOA
Blocks Ca++ channels and Na+ channels
+/- Enhances GABA activity
Synaptic vesicular protein (SV2A)
Binding SV2A increases GABA and decreases excitatory glutamate activity
Some glutamate targets that can be blocked
SV2A
Voltage-gated Na+ channels
Thalamic voltage gated-Ca++ channels
Increase GABA by….
Block GABA reuptake (tiagabine)
Inhibit GABA metabolism (vigabatrin)
Stimulate GABAa receptors (benzos, barbs)
Bind synaptic vesicular protein SV2A (levetiracetam)
Drugs that block Na+ Channels
Phenytoin
Lamotrigine
Carbamazepine
Valproate
Can cause SJS/TENS, screen for HLAB1502
Local Anesthetics MOA
Block Na+ channels and inhibit neuronal firing
Increase threshold for excitation and impulse conduction slows.
Binding increases→ rate of action potential declines→ complete block
A faster local anesthetic is
Smaller, lipophilic
A longer acting local anesthetic….
Binds more extensively to proteins
Elevated Ca++ makes local anesthetics
Less effective
Elevated Ca++ → hyperpolarize membrane → channels in resting state
Elevated K+ make local anesthetics
More effective
Elevated K+ → depolarizes membrane→ more channels inactivated state
Local anesthetics have a high affinity for the Na+ channel in the _______ states
Activated/open state
Inactivated state
Local anesthetics have a low affinity for the Na+ channel in the _______ state
Resting/closed state
Esters cause allergic reactions by
the P-aminobenzoic acid (PABA) metabolite
A myelinated neuron is ______ to local anesthetics than an unmyelinated neuron
Less sensitive
A myelinated neuron is ______ to local anesthetics than an unmyelinated neuron
Less sensitive
Metabolism of ester local anesthetics
rapidly metabolized by plasma butyrylcholinesterase
Mutations affect metabolism
Metabolism of amide local anesthetics
CYP450s
Bupivacaine + Cardio MOA
more lipophilic: increased binding to cardiac Na+ channels, slower dissociative times
More toxic
Cardiac effects of local anesthetics
Inhibition of Na+ and Ca++ channels→ arrhythmias, vasodilation hypotension
Why won’t sulfas work if you’re taking procaine?
PABA metabolite inhibits sulfonamide action
Benzocaine MOA
Pka 3.5→ lipophilic, always non-ionized at physiological pH→ readily transported through membrane, minimal binding to Na+ channel
topical OTC only
Secondary mechanism of cocaine
Inhibits Na+ channels (local anesthetic)
Primary mechanism of cocaine
increasing dopamine in CNS and periphery
What does a lipid sink do?
IV lipids pull lipophilic local anesthetics out of cardiac tissue in toxicity
Ropivacaine is…
S-enantiomer of bupivacaine→ less lipid soluble and cleared more rapidly
Etidocaine effects
Inverse differential block→ causes motor block before or without sensory block
Articaine is….
an Amide with an additional ester→ metabolism by plasma esterases→ decreases half life and systemic toxicity
Baclofen MOA
Agonist at GABAb receptors (Gi/o protein coupled, metabotropic)
- Open K+ channels→ hyper-polarization
- Presynaptic inhibition of Ca++ influx→ decreased transmitter release
- Inhibits adenylyl cyclase→ decrease cAMP→ decreased release of excitatory transmitters in brain and spinal cord
Tizanidine MOA
Alpha2 receptor agonist:
Pre and post-synaptic inhibition of spinal cord synaptic activity→ decreased glutamate→ decreased muscle spasticity
Inhibits pain transmission in dorsal horn
Dantrolene MOA
Blocking ryanodine receptor 1 (RyR1) channel→ inhibits Ca++ release from sarcoplasmic reticulum→ interferes with excitation-contraction coupling of actin and myosin in skeletal muscle fiber
Botulinum Toxin MOA
Inhibits SNAP-25 protein→ inhibition of ACh release from nerve at neuromuscular junction
What is the long term effect of reuptake inhibitors that has an effect on depression
Antidepressants down-regulate auto-receptors; increasing firing rate of 5-HT neurons
Initially when taking a reuptake inhibitor
5-HT levels in synapse will increase but so does feedback inhibition, thus balancing synaptic amine levels
TCA MOA
Inhibit reuptake of NE and 5-HT
Also block alpha-adrenergic, histamine, and muscarinic receptors
Tertiary amine TCAs….
primarily block 5-HT reuptake
Secondary amine TCAs….
primarily block NE reuptake
Side effects of TCAs are due to
Cholinergic blockade
Alpha 1 receptor blockade
Histamine receptor blockage
Analgesic effect of TCAs is due to
activation of descending NE pathways in spinal cord→ increase alpha 2 autoreceptor activation→ decreased glutamate input into pain pathway to brain
SSRIs MOA
Selectively inhibit 5-HT reuptake
SNRIs MOA
Inhibit NE and 5-HT reuptake
MAO-A
Metabolizes NE, DA, 5-HT in both CNS and periphery (GI tract, liver)
MAO-B
selectively metabolizes DA in CNS only
Phenelzine MOA
Inhibits MOA-A and B → increased NE, 5-HT, DA.
Also a substrate for MAO.
Selegiline MOA
selectively inhibits MAO-B→ increased DA
Tyramine
Accumulates if MAO-A is inhibited
Tyramine causes release of catecholamines, causing severe hypertensive crisis +/- intracranial bleeding
should be avoided while taking MAOIs
Bupropion MOA
Inhibits reuptake: DA, minimal of NE and 5 H-T
Mirtazapine MOA
Blocks presynaptic alpha 2 receptors→ decreased inhibition of NE and 5-HT release→ increased NE and 5-HT
Atomoxetine MOA
Selective inhibitor of norepinephrine reuptake
Trazodone MOA
5-HT2A receptor antagonist
Classical antipsychotics MOA
Block DA D2 receptor
Target mesolimbic system
Alleviate positive symptoms
Atypical antipsychotics MOA
Block 5-HT2A and DA receptors
Target mesocortical and mesolimbic system
Alleviate both negative and positive symptoms
All the receptors antipsychotics might act on
*D2* (higher affinity for D2=more potent) alpha 1 D4 5-HT2A D1 H1
Chlorpromazine MOA
Blocks DA D2 receptors + alpha adrenergic actions
Haloperidol MOA
Potent blocker of DA D2 receptors
Affinity for DA D1, 5-HT2, and H1 receptors
Clozapine MOA
Blocks 5-HT2A and DA D4 receptors
some DA D2 (least potent of all the antipsychotics)
Olanzapine MOA
Blocks
5-HT2A
DA D4
DA D2
“similar to clozapine”
Ziprasidone MOA
Blocks 5-HT2A, DA D2 receptors
Some antidepressant: 5-HT1a receptor agonist, inhibition of 5-HT reuptake
Risperidone
Blocks 5-HT2A, DA D2 receptors
No effect on DA in nigrostriatal pathway (EPS, TD rare)
Extrapyramidal symptoms from antipsychotics are due to
DA receptor antagonists block DA receptors in the nigrostriatal pathway
Quetiapine MOA
Blocks 5-HT2A, DA D2 receptors
“Similar to clozapine”
Aripiprazole MOA
“Dopamine system stabilizer”
Partial agonist for DA, 5-HT
Antagonist 5-HT2a, alpha 1, histamine receptors
Lurasidone MOA
Blocks D2, 5-HT2a receptors
Partial agonist 5-HT1a
No antihistamine or antimuscarinic
Lithium MOA
Suppress second messengers: IP3
+/- increase ACh, NE, DA
Lithium in the kidney
Reabsorbed by proximal tubule of kidney
Competes with Na+ for reabsorption
Na+ decreases–>Li absorption increases→ Toxicity
Na+ increases→ Li absorption decreases and excretion increases
Li increases→ Na+ absorption decreases→ hyponatremia
Valproic acid MOA for bipolar
Mechanism unknown
Beta-endorphins
decrease pain transmission in spinal cord, facilitate dopamine in reward system→ euphoria
Enkephalins
decrease pain transmission in the spinal cord
Dynorphins
bind to kappa receptors→ analgesia and dysphoria
Mu receptor (MOR)
analgesia, euphoria, sedation, side effects
Kappa receptor
Analgesia or dysphoria
Delta receptor
Dysphoria
Opioids + GABA
GABA→ inhibits descending neuronal pain modulation pathways
Opioids→ decreased GABA release→ allow pathways to be activated→ decreased pain transmission in dorsal horn of spinal cord
Opioids + Glutamate
Decreasing glutamate release in the dorsal
horn reduces activation of the ascending pathway.
Opioids MOA
Coupled to Gi/o → decrease cAMP
Close voltage gated Calcium channels on presynaptic nerve terminals→ decreased neurotransmitter release, decreased neuronal activity
Mu receptors open K+ channels→ hyperpolarization→ inhibition of nerve transmission→ difficult to respond to pain signals
3 opioids that paradoxically cause CNS excitement in overdose
Codeine
Meperidine
Proxyphene
Opioids and respiratory depression mechanism
Decreased response of brainstem to elevated CO2 +/- bronchoconstriction
Opioids and ICP mechanism
Increased CO2→ vasodilation→ increased cerebral blood flow→ increased intracranial pressure
Opioids and body temperature mechanism
Hypothermia, dysregulation in hypothalamus
Atropine
blocks parasympathomimetic effects
Reverses opioid miosis
Opioid CV effects mechanism
CNS vasomotor depression and/or vasodilation via histamine release
Opioid GI effects mechanism
Decreased gastric activity: CNS and local effect inhibition of transmitter release
Opioids cause itching because
they cause histamine release
not an allergy
Opioid tolerance mechanism
Due to receptor desensitization, down regulation and uncoupling from G- proteins in thalamus and spinal cord
Opioid physical dependence mechanism
Results from desensitization of mu receptors, or receptor uncoupling
Opioid hyperalgesia mechanism
Mediated by increases in spinal cord dynorphin→ more effective pain transmission
NMDA receptor antagonists + opioids
Decrease tolerance and hyperalgesia
Changes in the brain from addiction
Addictive drugs→ more dopamine release than normal rewards→ down regulation of dopamine receptors→ substance provides less pleasure but more craving
Morphine MOA
stimulates all opioid receptors, potent, produces all effects
Methadone MOA
Stimulates mu receptors
+/- block NMDA receptors
+/- inhibit NE/5-HT reuptake
Meperidine MOA
Mu agonist
Pentazocine MOA
Kappa receptor agonist
Mu receptor partial agonist
Buprenorphine MOA
Partial agonist on mu +/- kappa
Tramadol MOA
Weak mu agonist
Inhibits NE/5-HT→ contributes to analgesia
Dextrometorphan MOA
Blocks NMDA receptors→ abuse potential
L-dopa MOA
Dopamine does not cross blood brain barrier, but L-Dopa does→ converted into dopamine in neuron
Carbidopa MOA
inhibits dopa-decarboxylase in the periphery (doesn’t cross blood brain barrier) → Decreases the dose of l-dopa needed
Inhibition of MAO-B in the CNS
reduces striatal metabolism of DA
MAO inhibitors used for parkinsons
COMT…
Catechol-O-methyltransferase (COMT) metabolizes DA and l-dopa
COMT-I → Inhibit DA and l-dopa metabolism
Tocalpone MOA
COMT inhibitor in CNS and periphery
Entacopone MOA
COMT inhibitor in periphery only, inceases pool of l-dopa for transport into brain
Dopamine receptor antagonists primarily target
DA D2
Amantidine MOA
Increased dopamine neurotransmission
+/- increased release of dopamine
+/- inhibition of dopamine reuptake
Anticholinergics MOA
Muscarinic receptor antagonists→ restores DA/ACh balance in striatum
Galantamine MOA
inhibit metabolism of ACh by acetylcholinesterase
Increases the amount of ACh in the nerve terminal
AND
blocks presynaptic acetylcholine autoreceptor
Donepezil and rivastigmine MOA
Inhibit metabolism of AC by acetylcholinesterase Increase the amount of ACh in the nerve terminal
Memantine MOA
NMDA receptor antagonist (channel blocker)
Blocks pathological activation of NMDA receptors
Reduces excitotoxic effect of glutamate and slows degeneration
(meth)amphetamine MOA
Reverses dopamine transport through DAT (reuptake) → increased release of dopamine
Cocaine MOA
inhibits DA reuptake
Crack cocaine aka freebase cocaine
No HCl group on cocaine, can be inhaled for more rapid onset
Nicotine MOA
Activates nicotinic receptors in the CNS and periphery→ increases 5-HT and DA release
MDMA MOA
Increases 5-HT activity by blocking
reuptake and stimulating 5-HT receptors
Marijuana (THC) MOA
Stimulates presynaptic CB1
receptors to inhibit transmitter (ACh) release
LSD, Mescaline, Psilocybin MOA
Act on 5-HT receptors in the brain
PCP and Ketamine MOA
NMDA receptor antagonists
GHB MOA
GABA receptor weak agonist
MOA of inhalants
Mechanism unknown→ +/- alter
ionotropic receptors and increase DA
Amyl and Butyl nitrite (poppers or snappers) MOA
Smooth muscle relaxants
