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513 Cards in this Set
- Front
- Back
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epinephrine aka? |
hormone adrenaline |
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norepinephrine aka? |
hormone noradrenaline |
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true NT of the sympathetic NS? |
norepinephrine |
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norepinephrine alpha and beta activity |
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epinephrine more beta than alpha activity |
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ortho-dihidroxybenzene moiety aka? |
catechol |
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class of pharmacologically active substances that contain both an amine and an ortho-dihidroxybenzene moiety? |
catecholamines |
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many adrenergic ligands are? |
catecholamines |
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cells bearing adrenergic receptors are called? |
effector cells |
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act on effector cells or act on the neurons that release norepinephrine? |
adrenergic drugs |
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can have a variety of physiological effects and regulate many processes implicated in disease? |
adrenergic drugs |
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what kinds of peripheral effector cells are affected by stimulation of adrenergic receptors? |
cardiac muscle, smooth muscle (lung bronchodilation), liver cells (gluconeogenesis, glycogenolysis), fat cells (lipolysis), secretory epithelia, connective tissue |
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key physiologic effects of stimulation of sympathetic NS? |
increased HR and force of contractions, increased BP, shift in blood flow to skeletal muscles, dilation of bronchioles and pupils, increased blood glucose |
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where does the biosynthesis of norepinephrine take place? |
in adrenergic neurons near the terminus of the axon and junction with the effector cells |
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first step in biosynthesis of norepinephrine? |
active transport of L-tyrosine into the adrenergic neuron |
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rate-limiting step in norepinephrine biosynthesis? |
tyrosine hydroxylase (feedback inhibition may occur) |
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describe the biosynthesis of norepinephrine? |
L-tyrosine (through tyrosine hydroxylase) L-dopa (through aromatic L-amino acid decarboxylase) dopamine (through dopamine beta hydroxylase within storage vesicle) norepinephrine |
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describe the process of norepinephrine release? |
depolarization of presynaptic terminal > activation of voltage dependent Ca channels > fusion of vesicles > release of norepinephrine onto effector cell > activation of adrenergic receptors |
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how are presynaptic alpha-2 receptors involved in norepinephrine termination? |
provide feedback inhibition |
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how is most norepinephrine terminated? |
active reuptake through NET (~95%) |
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what happens to NE once it undergoes reuptake into the terminal? |
either recycled or metabolized by MAO |
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diffusion of NE to extraneuronal sites results in metabolism by? |
COMT or MAO |
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how is NE metabolized in the presynaptic terminal? |
MAO |
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subject to metabolism by COMT? |
catechols (1, 2 diphenolic moiety) |
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often substrates of MAO? |
drugs with aliphatic amino groups |
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how are adrenergic receptor subtypes encoded? |
by distinct genes |
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what type of receptor are adrenergic receptors? |
GPCR |
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have 7 transmembrane helices? |
GPCRs |
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binds G proteins and structural differences in this control the specificity for different G proteins? |
intracellular loops |
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how to adrenergic receptor subtypes mediate distinct cellular responses? |
through coupling to different G proteins |
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alpha-1 receptors are coupled to which G protein? |
Gq |
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The Gq pathway is? |
PLC > DAG + IP3 > DAG activates PKC, IP3 releases intracellular stores of Ca |
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alpha-2 receptors are coupled to which G protein? |
Gi |
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The Gi pathway is? |
inhibit adenylyl cyclase > reduce cAMP concentration |
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beta receptors are coupled to which G protein? |
Gs |
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The Gs pathway works by? |
stimulate adenylyl cyclase, increase cAMP concentration |
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used to treat shock, hypotension? |
alpha-1 agonists |
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used as antihypertensives? |
alpha-2 agonists beta-1 antagonists |
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used as bronchodilators? |
beta-2 agonists |
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GPCR binding with suitable conformational change to stimulate effector signaling cascade; endogenous drug or drug that is similar to NT describes? |
agonist |
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GPCR binding without suitable conformational change and thus no signaling; drug with more complex structure than neurotransmitter or related agonist ligands describes? |
antagonist |
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minimal requirements for adrenergic agonist activity |
primary or secondary aliphatic amine separated by two carbons from a subbed benzene ring basic amino group hydroxyl-subbed carbon in R configuration |
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isoproterenol nonselective beta agonist beta-1 receptor side effects |
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what happens to selectivity as the amine of NE is substituted with larger, lipophilic groups? |
beta receptor agonist activity increased, alpha receptor agonist activity decreased (large enough can become antagonists) |
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colterol beta-2 selective agonist |
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small alkyl group (methyl or ethyl) substitutions at carbon next to amine group in NE structure have what effect? does this have an effect on duration of action for catecholamines? |
slows metabolism by MAO, no as the structure is still a substrate for COMT |
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resistance to MAO activity more important in? |
non-catechol, indirect-acting phenylethylamines |
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alpha-methylnorepinephrine direct acting stereoisomer |
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define indirect-acting? |
displacement of NE from vesicles or reuptake inhibition |
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what is unique about indirect-acting sympathomimetics in terms of metabolism? |
not substrates for COMT and poor substrates for MAO |
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(1R, 2S)-ephedrine direct and indirect activity CNS activity and side effects |
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ephedrine activity? |
direct and indirect |
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(1S, 2S)-pseudoephedrine indirect activity fewer CNS side effects than ephedrine |
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pseudoephedrine activity? |
indirect |
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amphetamine indirect activity dramatic CNS stimulation and abuse potential combined salts used for ADHD (Adderall) |
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amphetamine indirect activity dramatic CNS stimulation and abuse potential combined salts used for ADHD (Adderall) not even once |
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metaproterenol selective beta-2 agonist orally active bronchodilator |
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catechol (3', 4'-dihydroxy) oral activity? |
poor |
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3', 5'-dihydroxy compounds metabolism and selectivity? |
not substrates for COMT, provide beta-2 selectivity |
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albuterol selective beta-2 agonist shorter acting orally active bronchodilator resistant to COMT |
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beta-2 agonist that is resistant to COMT? |
albuterol |
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ritodrine selective beta-2 agonist prevents premature labor, relaxes uterus |
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phenylephrine selective alpha-1 agonist hypotension, dilation of pupil, nasal decongestant, causes vasoconstriction |
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altered substitution pattern and groups on the aromatic ring of the NE parent affords? |
beta-2 selectivity |
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what must be present and where must it be present on the NE parent structure to retain beta activity? |
hydrogen forming group at the 4' position (if it is the only hydrogen forming group on the ring, it must be at this position to retain beta activity) |
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presence of only 3'-OH on NE parent structure means what? |
eliminates activity at beta receptors affording selective alpha-1 agonists |
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epi and NE oral activity? |
none, metabolized by intestinal and liver COMT and MAO |
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both cause vasoconstriction and cardiac stimulation? |
epi and NE |
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between epi and NE, which is more widely used? |
epi |
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used in hypotensive crisis (allergic rxn, anaphylaxis, alpha activity), cardiac arrest (beta activity), asthma (bronchoconstriction) and inhibits uterine contractions (beta-2 activity)? |
epinephrine |
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phenylephrine, metaraminol, and methoxamine are what family of drugs? |
phenyethanolamines |
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metaraminol alpha-1 selective agonist minimal cardiac stimulation not substrate for COMT long duration strong vasoconstrictor used for hypotension treatment in surgery/shock |
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methoxamine alpha-1 selective agonist bioactivated by demethylation to active phenol minimal cardiac stimulation not substrate for COMT long duration strong vasoconstrictor used for hypotension treatment in surgery/shock |
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OTC nasal decongestant with less than 10% oral bioavailability due to hydrophilicity and intestinal 3'-O-glucuronidation? |
phenylephrine |
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xylometazoline alpha-1 selective agonist vasoconstrictor nasal decongestant and eye drop |
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what do bulky, lipophilic meta/para substituents do for selectivity? |
alpha-1>alpha-2 |
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xylometazoline, oxymetazoline, tetrahydrozoline, and naphazoline are what family of drugs? |
2-arylimidazolines |
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oxymetazoline alpha-1 selective agonist vasoconstrictor nasal decongestant and eye drop |
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tetrahydrozoline alpha-1 selective agonist vasoconstrictor nasal decongestant and eye drop |
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naphazoline alpha-1 selective agonist vasoconstrictor nasal decongestant and eye drop |
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clonidine alpha-2A selective agonist antihypertensive other uses: sedation, ADHD, nicotine and opiate withdrawal, glaucoma |
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apraclonidine |
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brimonidine |
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guanabenz open form of clonidine |
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guanfacine open form of clonidine |
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tizanidine alpha-2C selective agonist muscle relaxant reduces spasticity associated with cerebral or spinal cord injury |
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alpha-2 subtype associated with antihypertensives, antiglaucomas, ADHD drugs? |
A |
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alpha-2 subtype associated with antispasmolytics and analgesics? |
C |
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arises from replacing carbon with amine NH to form a guanidino group with the imidazoline ring (NH bridge)? |
alpha-2 selectivity |
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pirbuterol beta-2 selective agonist used as bronchodilator in asthma and other constrictive pulmonary conditions oral dosage or inhalers |
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what can the longer acting nature of some beta-2 agonists be attributed to? |
higher lipophilicity and greater affinity |
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salmeterol beta-2 selective agonist unique binding; "anchoring" by the phenyl group gives high affinity |
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formoterol beta-2 selective agonist inhaled powder, fast onset 12 hour duration |
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indicaterol beta-2 selective agonist newest bronchodilator 24 hour duration (once daily) |
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also governs indirect versus direct activity? |
stereochemistry |
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no aromatic substitution allows for what in adrenergic drugs? |
indirect activity |
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alpha antagonists are expected to be? |
antihypertensive |
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are more structurally removed from NE? |
adrenergic antagonists |
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antagonists typical dosing? |
once daily |
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prazosin alpha-1 selective antagonist |
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terazosin alpha-1 selective antagonist contain quinazoline (far left) and piperazine (second from right) rings |
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doxazosin alpha-1 selective antagonist contain quinazoline (far left) and piperazine (second from right) rings |
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alfuzosin alpha-1A selective antagonist N-group open chain first line in BPH no utility as antihypertensive |
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tamsulosin alpha-1A selective antagonist N-group open chain first line in BPH no utility as antihypertensive |
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silodosin alpha-1A selective antagonist N-group open chain first line in BPH no utility as antihypertensive |
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used to treat HBP, CV problems, glaucoma, migraines, generalized anxiety disorder, hyperthyroidism, certain types of tremors? |
beta antagonists (blockers) |
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are beta blockers first line treatment? |
no, often used in combination |
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dichloroisoproterenol beta antagonist 1950's |
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pronethalol aka arylethanolamine beta antagonist 1962 |
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propranolol aka aryloxypropanolamine beta antagonist 1964 |
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carteolol beta nonselective antagonist multiple uses |
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metipranolol beta nonselective antagonist multiple uses |
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penbutolol beta nonselective antagonist multiple uses |
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pindolol beta nonselective antagonist multiple uses |
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timolol beta nonselective antagonist multiple uses |
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acebutolol beta-1 selective antagonist |
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atenolol beta-1 selective antagonist |
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esmolol beta-1 selective antagonist |
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metoprolol beta-1 selective antagonist |
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what are NRIs? |
NE reuptake inhibitors, a class of antideppressant |
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desipramine NE reuptake inhibitor |
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atomoxetine NE reuptake inhibitor |
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reboxetine NE reuptake inhibitor |
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indications for treatment with serotonergic agents? |
psychosis, irritable bowel, migraine, nausea, depression, emesis |
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derived from ergot, a grain fungus, and can cause psychadelic effects involving stimulation of 5-HT receptors in the CNS? |
LSD |
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serotonin (5-HT) indoalkylamine 3,5-disubstituted indole ring |
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(+)-lysergic acid diethylamide |
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what does 5-HT stand for? |
5-hydroxytryptamine |
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name 3 biogenic amines? |
serotonin, norepinephrine, dopamine |
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which NT is an indolalkylamine? |
serotonin |
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results in overproduction of 5-HT? |
tryptophan loading |
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increase synaptic 5-HT and can be antidepressants, but are nonselective and interfere with metabolism of other NT and therapeutics? |
MAO inhibitors |
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amino acid precursor for 5-HT? |
tryptophan |
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rate limiting step in 5-HT synthesis? |
tryptophan hydroxylase |
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where does tryptophan hydroxylase act on tryptophan? |
in the neuron |
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which 5-HT receptor is a ligand-gated ion channel? |
5-HT3 |
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what kinds of ions go through 5-HT3 receptors? |
cations |
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which 5-HT receptors are GPCRs? |
5-HT1,2,4-7 |
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which 5-HT receptors are coupled to Gi and what is the effect of binding? |
5-HT1,5; inhibit adenylyl cyclase, decrease cAMP |
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which 5-HT receptors are coupled to Gs and what is the effect of binding? |
5-HT4,6-7; stimulate adenylyl cyclase, increase cAMP |
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which 5-HT receptors are coupled to Gq and what is the effect of binding? |
5-HT2; PLC > PKC and IP3 > increase of intracellular Ca |
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describe the process of serotonin release? |
depolarization of presynaptic terminal > activation of voltage dependent Ca channels > fusion of vesicles > release of serotonin > activation of serotonin receptors |
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which 5-HT receptor subtype is present on the presynaptic neuron and thus aids in feedback inhibition? |
5-HT1 |
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which 5-HT receptor subtypes are present o n the postsynaptic neuron or effector cell? |
5-HT1-7 (all of them) |
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how is 5-HT signaling mainly terminated? |
active transport reuptake by SERT |
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how is 5-HT metabolized? |
MAO in presynaptic terminal and synaptic cleft |
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most widespread of all of the 5-HT receptors? |
5-HT1A |
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5-HT1A receptors exist in the CNS in high amounts in which areas? |
cerebral cortex, hippocampus, septum, amygdala, raphe nucleus |
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5-HT1A receptors exist in the CNS in low amounts in which areas? |
basal ganglia, thalamus |
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5-HT1A receptors in this area are largely somatodendritic autoreceptors? |
raphe nucleus |
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main focus of drug development for 5-HT1A receptors is for? |
treatment of anxiety and depression |
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first LCAP (long-chain arylpiperazine) to be approved as an anxiolytic agent? |
buspirone |
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important SAR for 5-HT1A binding? |
piperazine |
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many of these are nonselective and have activity at dopamine and adrenergic receptors? |
LCAPs |
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buspirone 5-HT1A LCAP agonist first LCAP to be approved as an anxiolytic agent |
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gepirone 5-HT1A LCAP agonist useful as an antidepressant |
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could involve presynaptic 5HT receptors; increased feedback inhibition and lower serotonergic activity? |
antianxiety actions |
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could involve postsynaptic 5-HT1A receptors? |
antidepressant actions |
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could produce different clinical outcomes? |
full versus partial agonism |
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5-HT1A receptor partial agonists are similar to agonists except for? |
2-methoxyphenyl group |
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new classes of true antagonists bind pre-, post-synaptic 5HT-1A receptors or both? |
both |
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can increase 5-HT concentration by blocking presynaptic feedback inhibition of 5-HT release? |
5HT-1A receptor antagonists |
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are promising therapeutic agents for the treatment of depression? |
5HT-1A receptor antagonists |
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spiperone 5-HT1A receptor antagonist also binds D2 and 5-HT2A receptors |
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can have antagonistic effects on full agonists? |
weak partial agonists |
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dominant serotonin receptor subtype in cerebral blood vessels? |
5-HT1D |
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serotonin receptor in arterial smooth muscles that are the targets of triptans (agonists) used for the treatment of severe migraine (vasoconstriction)? |
5-HT1D |
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a migraine appears to begin when what becomes overactive? |
trigeminal nucleus caudalis (TNC) system (causes blood vessels to dilate) |
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drugs that are tryptamine derivatives? |
triptans |
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which drugs have poor selectivity for 5-HT1D receptors and also often bind 5-HT1B and 1F receptors? |
triptans |
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sumatriptan 5-HT1D agonist original triptan |
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zolmitriptan 5-HT1D agonist newer triptan with improved oral bioavailability and half-life |
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rizatriptan 5-HT1D agonist newer triptan with improved oral bioavailability and half-life |
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almotriptan 5-HT1D agonist newer triptan with improved oral bioavailability and half-life |
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donitriptan 5-HT1D agonist |
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naratriptan 5-HT1D agonist |
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eletriptan 5-HT1D agonist |
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frovatriptan 5-HT1D agonist |
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alniditan 5-HT1D agonist structural outlier, not a tryptamine derivative |
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identified early as 5-HT2 receptor antagonist with no affinity for 5-HT1 receptors; helped identify the 5-HT2 receptors? |
ketanserin |
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ketanserin 5-HT2A/C, alpha-1, H1 receptor antagonist |
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psilocin 5-HT2A receptor agonist psychadelic mushrooms |
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mescalin 5-HT2A receptor agonist acts as full or partial agonist from peyote, used by Nativ Americans in Mexico |
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activation of which receptor is necessary for the effects of "classic" psychadelics like LSD, psilocin, and mescaline? |
5-HT2A |
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effect of 5-HT2A receptor activation in the periphery? |
reduction of intraocular pressure |
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5-HT2A agonists could be useful in the treatment of? |
glaucoma |
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the goal of compounds used to reduce eye pressure? |
reduce pressure without crossing BBB and causing hallucinogenic side effects |
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many of this type of drug's actions involve antagonism of 5-HT2A receptors? |
antipsychotics |
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risperidone 5-HT2A, D2 receptor antagonist schizophrenia alpha-1 activity too |
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ritanserin 5-HT2A receptor antagonist antipsychotic, antianxiety |
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clozapine 5-HT2A, D2 receptor antagonist atypical antipsychotic muscarinic acetylcholine activity too |
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olanzapine 5-HT2A, D2 receptor antagonist schizophrenia, bipolar very "dirty" |
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quetiapine 5-HT2A, D2 receptor antagonist atypical antipsychotic |
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ziprasidone? 5-HT2A, D2 receptor antagonist atypical antipsychotic |
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zotepine 5-HT2A, D2 receptor antagonist atypical antipsychotic |
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many hallucinogens bind which receptor and how do they act? |
5-HT2A agonists (LSD for example) |
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5-HT2A drugs can selectively choose the A subtype instead of the C, but which receptor do they also often act on? |
D2 |
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haloperidol binds mostly D2 typical (classical) antipsychotic nonselective (dirty) |
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sertindole binds mostly 5-HT2 atypical antipsychotic |
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which receptor is a member of the cys-loop family of ligand gated ion channels that includes nicotinic acetylcholine, GABA, glycine receptors, and Zn activated ion channels? |
5-HT3 |
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which receptor is a homomeric or heteromeric pentamer? |
5-HT3 |
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which receptor is an ion channel that opens in response to agonist binding to the extracellular domain and is cation permeable? |
5-HT3 |
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mainly used for treatment of chemo and radiation induced emesis and irritable bowel syndrome? |
5-HT3 drugs |
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5-HT3 partial agonists are general used for? |
IBS (investigational) |
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5-HT3 antagonists are generally used for? |
emesis and IBS |
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5-HT3 receptor activation effect in the CNS? |
emesis (brain stem), anxiety, seizures |
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5-HT3 receptor activation effect in the PNS? |
abdominal pain and emesis
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where is the vast majority (~95%) of all 5-HT found in the body? |
gut, involved in regulating normal intestinal function |
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functional bowel disorder largely characterized by abdominal pain? |
IBS |
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impacts quality of life for approximately 10-20% of the world population that is affected? |
IBS |
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two major subtypes of IBS? |
IBS-D (diarrhea predominant), IBS-C (constipation predominant) |
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what type of drug is given to treat IBS-D? |
5-HT3 antagonist or partial agonist |
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what type of drug is given to treat IBS-C? |
5-HT3 agonist or partial agonist |
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what are the SARs for 5-HT3 receptor agonists? |
indole ring or equivalent with amine side chain aromatic with piperazine ring (quipazine analogs) |
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quipazine one of parent structures for SAR of 5-HT3 receptor agonists |
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what is the N4-piperazine nitrogen in quipazine important for? |
binding (N1 nitrogen is not) |
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what is the quinoline nitrogen in quipazine required for? |
high affinity |
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clinically useful for antiemetic properties? |
5-HT3 antagonists (setrons) |
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what head group is typically found in 5-HT3 receptor antagonists? |
tropane |
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which functional group is indicative of a second generation "setron"? |
imidazole ring |
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activity of the second generation "setrons" is defined generally by? |
distances |
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tropisetron 5-HT3 antagonist |
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ondansetron 5-HT3 antagonist |
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5-HT4 receptors are coupled to which pathway and binding produces what effect? |
Gs, stimulates adenylyl cyclase, increase cAMP |
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how do the multiple isoforms of 5-HT4 receptors vary? |
in their intracellular C-terminal region |
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located in the GI tract, urinary bladder, heart (atrium), adrenal gland and CNS? |
5-HT4 receptors |
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5-HT4 receptor antagonists have been developed for the treatment of what? |
IBS |
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which agonists have some structural crossover with 5-HT3 ligands? |
5-HT4 |
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many 5-HT4 agonists are? |
benzamides |
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zacopride 5-HT3, 4 antagonist |
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renzapride 5-HT3, 4 antagonist |
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which NT helps stimulate gut motility? |
5-HT |
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5-HT4 receptor agonists can be used for? |
IBS-C |
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5-HT4 receptor antagonists can be used for? |
IBS-D |
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what is responsible for the termination of serotonergic transmission? |
SERT |
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agents that block this can increase synaptic 5-HT? |
SERT |
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can be useful in the treatment of depression, OCD, panic disorders? |
SERT blocking agents |
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structure is similar to that of NET and DAT? |
SERT |
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SSRI stands for? |
selective serotonin reuptake inhibitor |
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SNRI stands for? |
selective norepinephrine reuptake inhibitor |
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NSRI stands for? |
norepinephrine and serotonin reuptake inhibitor |
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DNRI stands for? |
dopamine and norepinephrine reuptake inhbitor |
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serious depression that interferes with the ability to work, study, eat, sleep, and enjoy? |
major depressive disorder |
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treatment for this can include antidepressants, psychotherapy, and electroconvulsive therapy? |
major depressive disorder |
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mild, chronic depression that lasts for 2 years or longer (1 year in children and adolescents) that is less severe? |
dysthymia, persistant depressive disorder |
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treatment for this can include antidepressants and psychotherapy? |
dysthymia, persistant depressive disorder |
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characterized by cyclical periods of depression and mania with varying duration, frequency, and intensity? |
bipolar disorder, manic-depressive illness |
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treatments for this can include "mood stabilizers" and antipsychotics in combination with antidepressants? |
bipolar disorder, manic-depressive illness |
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what is the monoamine hypothesis? |
depression results from a deficiency in serotonin and/or norepinephrine |
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which type of antidepressant drugs had considerable side effects and are therefore not used anymore? |
MAO inhibitors |
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major pharmacologic treatment for depression but affect many other systems in addition to inhibiting monoamine uptake? |
tricyclic antidepressants (TCAs) |
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have improved safety and tolerability compared to TCAs? |
SSRIs |
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the majority of antidepressants in current use employ which mechanism of action? |
inhibition of reuptake of 5-HT and/or NE |
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desipramine, nortriptyline, and atomoxetine are? |
selective norepinephrine reuptake inhibitors (SNRIs) |
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citalopram, escitalopram, fluoxetine, paroxetine, sertraline are? |
SSRIs |
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amitriptyline, duloxetine, imipramine, venlafaxine are? |
norepinephrine and serotonin reuptake inhibitors (NSRIs) |
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bupropion is what type of drug? |
dopamine and norepinephrine reuptake inhibitor (DNRI) |
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what opportunity is created by variation in selectivity for serotonin and norepinephrine? |
treatment of different symptoms |
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broader antidepressant activity if? |
both NET and SERT inhibited |
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limitations to current antidepressant treatments? |
low remission rates, delayed onset of action, side effects, drug-drug interactions |
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5-HT2A drug side effects? |
insomnia, anxiety/agitation, and sexual dysfunction |
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5-HT2C drug side effects? |
irritability and decreased appetite |
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5-HT3 drug side effects? |
nausea, vomiting, headache |
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why do antidepressants have a delayed onset of action? |
adaptive changes must occur with chronic administration of SSRIs and NSRIs (many theories) |
|
|
which CYPs metabolize antidepressants? |
CYP3A4, CYP2C18, CYP2D6 |
|
|
proven treatments for depression, OCD, and panic disorder with reduced adverse effects compared to TCAs? |
SSRIs |
|
|
first SSRI? |
zimeldine |
|
|
zimeldine first SSRI |
|
|
long term admin of SSRIs causes? |
adaptibe changes in the serotonergic system |
|
|
which SSRI contains a 4 carbon side chain unlike the 3 carbon side chain of 5-HT and the other SSRIs? |
citalopram |
|
|
fluoxetine, paroxetine, and citalopram are what kind of SSRIs? |
phenoxyphenylalkylamine SSRIs |
|
|
many SSRIs contain EWG on which position and what does this do? |
para position, adds SERT selectivity and reduces metabolism |
|
|
fluoxetine SSRI |
|
|
paroxetine SSRI |
|
|
citalopram SSRI 4 carbon chain |
|
|
which drugs have the potential to produce serotonin syndrome? |
SSRIs |
|
|
symptoms of this include agitation, sweating, diarrhea, fever, hyperreflexia, incoordination, confusion, myoclonus, shivering, tremor? |
serotonin syndrome |
|
|
what do the 5-cyano and 4-fluoro gorups do for citalopram? |
yield high selectivity for SERT |
|
|
which enantiomer of citalopram is active? |
S |
|
|
one of the most SERT-selective inhibitors and therefore has few side effects? |
citalopram |
|
|
which SSRI has less potential for drug-drug interactions as a result of weak CYP inhibition and less plasma protein binding? |
citalopram |
|
|
structurally distinct from other SSRIs due to a rigid bicyclic system? |
sertraline |
|
|
have prolonged half lives and require long washout periods before switching to another antidepressant? |
SSRIs |
|
|
extensively metabolized to pharmacologically active N-demethylated metabolites when possible and excreted in urine and feces? |
SSRIs |
|
|
sertraline SSRI rigid bicyclic system |
|
|
which SSRI can undergo glucuronidation as part of its metabolism? |
sertraline |
|
|
often inhibit both NET and SERT but bind to other targets leading to side effects? |
TCAs |
|
|
have been reported to produce a faster and greater antidepressant response compared to an SSRI alone? |
NSRIs |
|
|
active metabolite of venlafaxine? |
ODV |
|
|
venlafaxine NSRI phenylethylamine |
|
|
NSRI that is a phenylethylamine with a 2 carbon chain? |
venlafaxine |
|
|
drug that is associated with withdrawal problems and requires a slow taper? |
venlafaxine |
|
|
30-fold more potent at inhibiting SERT over NET but acts at both? |
venlafaxine |
|
|
5-fold more potent at inhibiting SERT over NET and more potent than venlafaxine? |
duloxetine |
|
|
demonstrates less off-target binding (lower adverse effects) and has a unique crossover into chronic pain treatment? |
duloxetine |
|
|
duloxetine |
|
|
antidepressant that is structurally related to CNS stimulants? |
bupropion |
|
|
this antidepressant is a nicotinic antagonist and it and its metabolites are essentially indirect acting adrenergic and dopaminergic agonists? |
bupropion |
|
|
antidepressant that is indicated for the treatment of MDD and as an aid in smoking cessation? |
bupropion |
|
|
bupropion is activated by which CYP? |
CYP2B6 |
|
|
antidepressant that is a DAT blocker like methamphetamine and also blocks NET? |
bupropion |
|
|
antidepressant that is a potent CYP2D6 inhibitor? |
bupropion |
|
|
glutamate excitatory amino acid NT |
|
|
GABA inhibitor amino acid NT |
|
|
provide most of the excitatory and inhibitory neurotransmission in the NS? |
AA NTs |
|
|
what are the NT criteria? |
presence of the substance within presynaptic cells, must be released from terminals upon stimulation, must have action on postsynaptic cells, must have a mechanism for removal/termination |
|
|
main excitatory NT in CNS? |
glutamate |
|
|
actions of other excitatory NT are mediated through? |
glutamate receptors/transporters |
|
|
main inhibitory NT in the CNS? |
GABA |
|
|
another important inhibitory NT? |
glycine |
|
|
actions of other inhibitory NT are mediated through? |
GABA and glycine receptors/transporters |
|
|
influx of positive ions in neurotransmission leads to? |
depolarization > AP (neuronal firing) |
|
|
influx of negative ions or efflux of positive ions in neurotransmission leads to? |
hyperpolarization > resting state (no neuronal firing) |
|
|
what determines whether the actions in neurotransmission are excitatory or inhibitory? |
ion selectivity |
|
|
essential for CNS processes like perception of pain, neuronal development, memory, learning? |
glutamateric neurotransmission |
|
|
why are there so few FDA-approved glutamatergic drugs? |
because the glutamate system is essential and very sensitive to manipulation |
|
|
glutamate is synthesized in the neuron from glutamine via? |
glutaminase |
|
|
glutamate transported into vesicles by? |
VGLUT1 |
|
|
glutamate activates which kinds of postsynaptic receptors upon release? |
metabotropic (GPCR) and ionotropic (ligand-gated ion channels) |
|
|
very important to the termination of the glutamatergic signal? |
astroglial uptake of glutamate via EAATs |
|
|
which transporter is responsible for the uptake of glutamate? |
excitatory amino acid transporter (EAAT) |
|
|
glial cells aka? |
astrocytes |
|
|
what happens to glutamate inside of astrocytes |
glutamate converted to glutamine via glutamine synthetase |
|
|
what is the purpose of switching glutamate back to glutamine? |
allows silencing of glutamate and shuttling between cells |
|
|
what happens to glutamine once it has been processed by the glial cell? |
secreted by glial cell, taken up by the neuron, and converted back to glutamate and packed back into vesicles |
|
|
what kinds of receptors are NMDA, AMPA, and kainate receptors? |
ionotropic |
|
|
what is the effector for the group 1 metabotropic receptors? |
PLC |
|
|
what is the effect for the group 2 metabotropic receptors? |
decreased cAMP |
|
|
what is the effect for the group 3 metabotropic receptors? |
decreased cAMP |
|
|
have distinct expression patterns in the CNS in terms of both cell types and regions? |
metabotropic glutamate receptors (selective drug effects?) |
|
|
drugs that target which types of glutamate receptors are in general better tolerated? |
metabotropic |
|
|
are there any metabotropic glutamate receptor drugs yet? |
nope |
|
|
potential applications of mGluR allosteric modulators in CNS diseases? (very active area of drug discovery) |
depression! |
|
|
PAM stands for? |
positive allosteric modulator |
|
|
NAM stands for? |
negative allosteric modulator |
|
|
what kinds of ions do NMDA, AMPA, and kainate receptors deal with? |
cations |
|
|
ionotropic glutamate receptors are formed by how many subunits? |
4 (tetrameric) |
|
|
can an NMDA receptor be made up of subunits from the AMPA receptor class? |
no |
|
|
in the continuous presence of agonist, the interface between two agonist binding domains can become unstable leading to the closure of the ion channel with agonist still bound which is a process called? |
desensitization |
|
|
how does glutamate binding trigger opening of an ion channel? |
binding causes closure of the cleft in the agonist binding domain which pulls lower lobes of agonist binding domain apart which triggers opening of ion channel |
|
|
what part of the AMPA receptor is critical for agonist binding? |
conserved arginine in the receptor |
|
|
how do ionotropic glutamate receptor agonists interact with the receptor? |
agonist interacts via its carboxylate group with the arginine in the upper lobe of the receptor |
|
|
NMDA positively charged nitrogen negatively charged acidic oxygens |
|
|
AMPA postively charged nitrogen negatively charged acidic oxygen near nitrogen |
|
|
kainate positively charged nitrogen negatively charged acidic oxygens |
|
|
glutamate agonists must form contacts between?
|
amino acid moiety of agonist and upper lobe of the agonist binding domain |
|
|
NMDA is an analog of? |
aspartate |
|
|
AMPA is an analog of? |
glutamate |
|
|
kainate is an analog of? |
glutamate |
|
|
how must the glutamate agonist interact with the lower lobe? |
in a manner that induces closure of the agonist binding domain |
|
|
how do glutamate agonists interact with the lower lobe? |
through a carboxylate or equivalent bioisostere |
|
|
NMDA receptors can be activated by analogs of which AA? |
aspartate |
|
|
which glutamate receptor agonists share similar SARs? |
AMPA and kainate |
|
|
how can you spot a glutamate analog? |
alpha, beta, gamma |
|
|
can be both aspartate and glutamate analogs? |
NMDA receptor agonists |
|
|
bulky substitutions are generally tolerated on the agonists of which glutamate receptor(s)? |
AMPA and kainate |
|
|
why are bulky substituents poorly tolerated by NMDA receptors? |
tyrosine residue caps the lower portion of the binding socket, there is no room |
|
|
what are the two MOAs of ionotropic glutamate receptor antagonists? |
antagonists bind the conserved arginine and shield it to prevent agonist binding antagonists bind similarly to agonists but are longer and unable to induce agonist binding domain closure |
|
|
NMDA receptor antagonist primary mechanism? |
longer |
|
|
AMPA and kainate receptor antagonist primary mechanism? |
shielding |
|
|
how can a shielding glutamate receptor antagonist be spotted? |
hidden amino acid moiety many are 2,3-quinoxalinediones |
|
|
how are ionotropic glutamate receptor agonists and antagonists tolerated? |
poorly and produce severe side effects |
|
|
over-activation of which NT can cause seizures and neuronal death? |
glutamate |
|
|
over-inhibition of glutamate can cause? |
sedation, psychosis, and also neuronal death |
|
|
agents that lower activity of ionotropic glutamate receptors could be useful for? |
neuroprotection |
|
|
how do NMDA channel blockers work? |
same way Mg blocks receptors in membrane potential dependent manner |
|
|
are NMDA channel blocker selective? |
no |
|
|
NMDA receptor block is not relevant to clinical effect of this drug but abuse potential is mediated by NMDA receptors? |
dextromethorphan |
|
|
NMDA receptor channel blockers must be? |
positively charged |
|
|
amantadine NMDA receptor channel blocker treats AD |
|
|
memantine NMDA receptor channel blocker treats AD fast kinetics |
|
|
phencyclidine (PCP) NMDA receptor channel blocker slow kinetics |
|
|
ketamine NMDA receptor channel blocker fast kinetics |
|
|
dextromethorphan NMDA receptor channel blocker |
|
|
dizocilpine NMDA receptor channel blocker |
|
|
only work when the membrane potential is negative? |
NMDA channel blockers |
|
|
which NMDA channel blockers are well tolerated and useful for neuroprotection? |
fast kinetics |
|
|
which NMDA channel blockers produce severe adverse effects including dissociative and psychomimetic effects? |
slow kinetics |
|
|
which drugs induce all symptoms of schizophrenia? |
NMDA receptor channel blockers |
|
|
enhancement of NMDA receptor transmission via glycine site agonists does what? |
improves symptoms in schizophrenia |
|
|
mice with a partial deletion of GluN1 NMDA receptor subunit showed? |
behavior abnormalities resembling schizophrenia |
|
|
has rapid and potent antidepressant effects in treatment resistant MDD and bipolar depression? |
ketamine NMDA receptor channel blocker |
|
|
a single dose of this NMDA receptor channel blocker rapidly resolves suicidal behavior? |
ketamine |
|
|
have high response rates in treatment of resistant MDD? |
ketamine, other channel blockers |
|
|
rapid and sustained antidepressant effect following a single injection of? |
ketamine |
|
|
currently in clinical trials for the treatment of MDD? |
ketamine, other channel blockers, GluN2B selective antagonists |
|
|
GABA levels in the CNS are? |
very high |
|
|
anxiolytic and anticonvulsant effects, sedation, general anesthesia, coma and death are the effects of enhanced? |
GABAergic transmission |
|
|
anxiety and hyperexcitability, seizures and status epilepticus, and death are the effects of decreased? |
GABAergic transmission |
|
|
important therapeutic target for anxiolytics, sedatives, anticonvulsants, anesthetics? |
GABAergic system |
|
|
rate-limiting enzyme in GABA biosynthesis? |
GAD (glutamic acid decarboxylase) |
|
|
how do the concentrations of GAD compare to that of GABA? |
parallel |
|
|
GABA can be synthesized from? |
glutamate via glutamate decarboxylase |
|
|
enables synthesis of glutamate from alpha-ketoglutarate in the GABAergic presynaptic neuron? |
GABA-T mitochondrial |
|
|
is GABA-T reversible? |
yes |
|
|
GABA metabolism is linked to? |
the Krebs cycle |
|
|
increase levels of GABA by inhibiting metabolism by GABA-T? |
anticonvulsants |
|
|
vigabatrin anticonvulsant pi bond matters |
|
|
acetylenic GABA anticonvulsant pi bonds matter |
|
|
gabaculine anticonvulsant pi bonds matter |
|
|
GABAergic neurotransmission is terminated through? |
active uptake by GABA transporters (GATs) into both the presynaptic neuron and astroglia |
|
|
how many GAT subtypes exist in both neurons and glia cells? |
four |
|
|
tiagabine GAT inhibitor anticonvulsant |
|
|
how is GABA removed? |
by active uptake into both the presynaptic neuron and astroglia |
|
|
how does GABA get back to terminal after uptake into the astroglia? |
via the glutamate-glutamine cycle |
|
|
which GABA receptor is a ligand-gated ion channel? |
GABAa |
|
|
which ion does GABAa select for? |
Cl |
|
|
which GABA receptor is a GPCR? |
GABAb |
|
|
which pathway is GABAb coupled to and what is the effect? |
Gi, decreased cAMP GIRK channels |
|
|
are obligatory dimers of B1 and B2 subunits? |
GABAb receptors |
|
|
which part of GABAb does GABA bind? |
B1 subunit |
|
|
cellular responses to GABAb activation depend on? |
their location |
|
|
presynaptic activation of GABAb receptors leads to? |
inhibition of Ca channels, reduced cAMP (reduced NT release overall) |
|
|
postsynaptic activation of GABAb receptors leads to? |
activation of K channels (GIRKs) (hyperpolarization) reduction of cAMP (regulation of gene expression) |
|
|
how many types of GABAb receptors are there? |
one |
|
|
baclofen selective GABAb agonist muscle relaxant for spasticity adverse side effects such as exacerbation of seizures, reduction of cognitive function, insomnia |
|
|
phaclofen selective GABAb antagonist |
|
|
do GABAb receptors bind GABAa agonists or antagonists? |
no |
|
|
are GABAb receptors modulated by benzodiazepines? |
no |
|
|
what might GABAb antagonists be good for treating? |
mild cognitive impairment by indirectly increasing glutamatergic transmission |
|
|
what are the two combinations in which GABAa subunits come together to form pentamers? |
2 alpha + 2 beta + gamma 2 alpha + 2 beta + delta |
|
|
where does GABA bind the GABAa receptor and how many GABA are required for binding? |
alpha-beta interface, two GABA |
|
|
where do benzodiazepines bind GABAa receptors? |
alpha-gamma interface (or alpha-delta) |
|
|
what are the two types of GABAa receptors? |
extrasynaptic and synaptic |
|
|
what is special about alpha-4 and alpha-6 containing GABAa receptors? |
not sensitive to benzodiazepines because they contain delta subunits |
|
|
which drugs are alpha-1 preferring "agonists" that bind to the benzodiazepine site? |
Z drugs |
|
|
alpha-5 is high in the hippocampus GABAa receptors and alpha-5 antagonists could do what? |
improve cognition |
|
|
alpha-1 in GABAa receptors does what? |
mediates sedative effects |
|
|
alpha-2 in GABAa receptors does what? |
mediates anxiolytic effects |
|
|
bicuculline selective GABAa antagonist |
|
|
isoguvacine GABAa agonist |
|
|
muscimol GABAa agonist |
|
|
garboxadol GABAa agonist |
|
|
picrotoxinin GABAa antagonist (convulsant) blocks GABAa receptors |
|
|
clinically useful general anesthetic that enhances GABAa receptor activity? |
propofol |
|
|
vapour concentration that prevents patient movement in response to a supramaximal stimulus in 50% of subjects? |
MAC |
|
|
MAC relationship to potency? |
inverse |
|
|
how is the MAC of a volatile substance related to its lipid solubility? |
inversely proportional |
|
|
propofol GABAa agonist general anesthetic has a specific binding site in the GABAa receptor |
|
|
enhance GABAa receptor activity but directly open the GABAa receptor channel at high concentrations? |
barbiturates |
|
|
barbiturates are largely replaced by what drug in routine medical practice but are still used in general anesthesia and epilepsy? |
bezodiazepines |
|
|
where is the barbiturate binding site? |
interface between the alpha and beta transmembrane domains of the GABAa receptor |
|
|
pentobarbital GABAa agonist sedative/hypnotic controls convulsions and is used in assisted suicide and euthanasia |
|
|
ligands at the benzodiazepine binding site are what? |
allosteric modulators |
|
|
what are the 4 groups of the ligands at the benzodiazepine binding site? |
benzo agonists (PAMs) non-benzo agonists (PAMs) benzo inverse agonists (NAMs) benzo antagonists (neutral ligand) |
|
|
new non-benzo agonists aka? |
Z drugs |
|
|
what are the Z drugs? |
zolpidem, zaleplon, eszopicolone |
|
|
zolpidem non-benzo agonist (PAM) Z drug sedative/hypnotic |
|
|
zaleplon non-benzo agonist (PAM) Z drug sedative/hypnotic |
|
|
eszopiclone non-benzo agonist (PAM) Z drug sedative/hypnotic |
|
|
indications for anxiolytics? |
generalized anxiety disorder, phobic disorders, psychological factors affecting anxiety, panic disorder, OCD, PTSD |
|
|
what kinds of drugs can be used for sleep disorders? |
sedative/hypnotics |
|
|
reduces anxiety and exerts a calming effect? |
a sedative drug |
|
|
produces drowsiness and reduces the latency to onset of sleep? |
a hypnotic drug |
|
|
what determines a drugs utility as either anxiolytics and/or sedative hypnotics? |
PK and PD properties |
|
|
sedative hypnotics drug classes? |
benzodiazepines Z drugs barbiturates |
|
|
major factors determining the clinical use of benzodiazepines? |
rate and extent of absorption, presence and absence of active metabolites, degree of lipophilicity |
|
|
a long acting benzodiazepine that has slow absorption, low lipophilicity, and active metabolites could be used for what purpose? |
anxiolytic |
|
|
a short acting benzodiazepine that has rapid absorption, high lipophilicity, without active metabolites could be used for what purpose? |
sedative |
|
|
how do class A benzos differ from class B benzos? |
class B benzos have a 1,2-annelation (extra ring) |
|
|
benzo inverse agonists and antagonists are lacking in which SAR? |
phenyl ring |
|
|
do benzos and their metabolites bind plasma proteins? |
yes |
|
|
how are benzos metabolized? |
hepatic, microsomal oxidation including N-dealkylation and aliphatic hydroxylation, conjugation and excretion in the urine, rates vary |
|
|
what is the problem with long lived benzo metabolites? |
adverse effects, residual hypnotic effects, daytime drowsiness, oversedation, cognitive decline, confusion |
|
|
triazolam GABAa agonist benzodiazepine rapid absorption, short half-life, one active metabolite |
|
|
difference between benzos and Z drugs in terms of selectivity? |
benzos non-selective of alpha units but Z drugs are more selective of alpha-1 (sedative effects) |
|
|
absorbed faster than benzos, less side effects, better for sleep? |
Z drugs |
|
|
timeline of GABAa receptor sedatives? |
barbiturates, benzos, Z drugs |
|
|
how many approved barbiturates are there? |
5 |
|
|
how can barbiturates form water soluble salts? |
keto-enol tautomerization |
|
|
produce dose dependent sedation? |
barbiturates |
|
|
replaced in routine treatment of sleep disorders but still used in general anesthesia, pre-op sedation, and acute treatment of seizures? |
barbiturates |
|
|
barbiturate adverse effects? |
tolerance, dependence, potential for abuse, low toxicity threshold |
|
|
an abnormal mental state involving a loss of contact with reality? |
psychosis |
|
|
characterized by delusions, hallucinations, absent or inappropriate emotions, reduced motor activity? |
psychosis |
|
|
symptom of psychiatric disorder and sometimes other causes? |
psychosis |
|
|
are psychosis and schizophrenia the same thing? |
no, symptoms of schizophrenia include psychosis |
|
|
positive symptoms of schizophrenia? |
hallucinations, thought disorders, delusions, disorganized behavior, catatonia |
|
|
negative symptoms of schizophrenia? |
social withdrawal, anhedonia, poverty of speech, emotional flattening |
|
|
cognitive symptoms of schizophrenia? |
memory, executive function, attention |
|
|
core symptom of schizophrenia? |
cognitive decline |
|
|
risk factors contributing to schizophrenia? |
genetic components, developmental errors caused by infections or trauma, autoimmune diseases, NT abnormalities, stress |
|
|
is the risk of schizophrenia if one twin has it 100% for the other twin? |
no |
|
|
antipsychotics that block dopamine receptors are known as? |
neuroleptics |
|
|
the hypothesis that enhanced dopaminergic neurotransmission leads to schizophrenia and decreasing it would reduce psychotic symptoms? |
dopamine hypothesis does not explain cognitive symptoms |
|
|
history of antipsychotic treatment? |
chlorpromazine (phenothiazine and thioxanthene neuroleptics)
haloperidol (butyrophenone neuroleptics) clozapine (atypical antipsychotic) |
|
|
primary action of neuroleptics? |
reduce dopaminergic signaling in the mesolimbic-mesocortical pathways |
|
|
how are neuroleptics supposed to work primarily? |
as antagonists of D2 like dopamine receptors |
|
|
what type of receptors are dopamine receptors? |
GPCR |
|
|
which are the D1 like receptors and what is their effect? |
D1 and D5, increase cAMP |
|
|
which are the D2 like receptors and what is their effect? |
D2, 3, and 4, decrease cAMP |
|
|
which dopamine pathway is involved in motor control (Parkinson's)? |
nigrostriatal system |
|
|
which dopamine pathway is involved in reward (drug abuse)? |
mesolimbic system |
|
|
which dopamine pathway is involved in the symptoms of schizophrenia? |
mesolimbocortical system |
|
|
which dopamine pathway is involved in hormone release? |
projections to the pituitary gland |
|
|
which antipsychotic class is associated with extrapyramidal effects and only improve positive symptoms? |
classical or typical antipsychotics |
|
|
which receptors are altered in schizophrenic brains? |
5-HT1A and 2Ai |
|
|
is the serotonin hypothesis of schizophrenia correct? |
no |
|
|
induce synesthesia, pleasant perceptual perturbations? |
psychadelics like LSD |
|
|
act indirectly through the serotonergic system to enhance dopaminergic signaling in the striatum? |
atypical antipsychotics |
|
|
NMDA receptor channel blockers induce all symptoms of schizophrenia is a part of which hypothesis? |
glutamate hypothesis of schizophrenia |
|
|
have any drugs been developed based on the glutamate hypothesis for treatment of schizophrenia? |
no |
|
|
development began with antihistamines (sedatives) and ended with antipsychotics? |
phenothiazine neuroleptics |
|
|
achieved symptomatic relief of agitation and anxiety and had a reducing effect on psychosis? |
chlorpromazine |
|
|
initiated a new era in the drug therapy of the mentally ill? |
chlorpromazine |
|
|
chlorpromazine typical antipsychotic phenothiazine neuroleptic chloride confers asymmetry there must be 3 carbons separating nitrogen atoms |
|
|
thioxanthene typical antipsychotic |
|
|
which configuration of thioxanthene is the most active neuroleptic? |
cis |
|
|
what is the benefit to long acting neuroleptics? |
less side effects and better patient compliance |
|
|
were discovered in an attempt to obtain more potent analgesics? |
butyrophenone neuroleptics |
|
|
how is haloperidol dosed? |
daily |
|
|
neuroleptic associated with very high extrapyramidal side effects, less weight gain, little sedation, used in schizo and psych emergencies, used for Tourette syndrome and manic phase of bipolar? |
haloperidol |
|
|
neuroleptic that is short-acting, heavily sedating, anti-emetic, used in pre-op and psych emergencies? |
inapsine |
