Glossary of Spring POP Midterm UCSD SSPPS SOM

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Three major groups of CNS depressants?
Benxodiazepines, barbiturates, ethanol
6 effects of CNS depressants, in the order of their effect from smallest to largest dose?
Sedation, induction of sleep (hypnosis), unconsciousness, sugical anesthesia, coma, fatal depression of respiration and CV function. (however, BDZs and newer selective sedative-hypnotics cannot produce anesthesia or coma, so no fatal risk)
What about psychomotor effects of CNS depressants?
CNS depressants can cause psychomotor impairment, for which warning labels are required
How do CNS depressants affect memory, sleep, and cognition?
Can cause anterograde amnesia (inability to acquire new memory while under influence of the drug), drowsiness, and confusion
Do users of CNS depressants become more sensitive to their effects, or tolerant?
Tolerant, even cross-tolerant (so a heavy drinker will need a bigger dose of a BDZ to get same effect, unless of course, they use them concomitantly which creates a larger, synergistic effect)
What kind of dependence do users of CNS depressants develop?
Physical dependence, which means they have withdrawal sxs (which are opposite of the effects of the drug) upon discontinuation after chronic use
What are 3 causes of insomnia that are NOT appropriate to treat with sedative-hypnotics?
1) Depression and other psychiatric disturbances, 2) Drug abuse of stimulants, sleeping pills, or ethanol, and 3) Physical disorders like pain and sleep apnea
What are three causes of insomnia that ARE appropriate to treat with sedative-hypotics?
All short-term: 1) Body-clock disturbances, 2) External disturbances like noise, and 3) Stress-associated, like bereavement
What is difference in onset of action between sedative-hypnotics and antipsychotics and antidepressants?
Sedative-hypnotics work immediately, but antipsychotics and antidepressants take time to start working (weeks or more)
What are three criteria for effectiveness and five criteria for safety that the ideal sedative-hypnotic should have?
Effectiveness: 1) reduce sleep latency and increase duration of sleep, 2) produce minimal changes in normal sleep cycle, and 3) not give hangover effect of sedation or rebound anxiety. Safety: 1) Not fatal on overdose, 2) No serious drug interactions, 3) No physical dependence, 4) No rebound insomnia upon d/c, 5) low abuse potential
How do barbiturates work?
Bind to allosteric site (a different one than BDZs) on GABAA receptor, which increases its affinity for GABA, so Cl channels remain open for longer, which leads to increased magnitude of GABA-mediated IPSPs
As opposed to the ideal sedative-hypnotic, what properties to barbiturates have?
Tolerance (partly due to induction of CYPs), Physical dependence (due to life-threatening withdrawal sxs of tremor, insomnia, hypotension, delirium, seizures), Highly Addictive, Low therapeutic index (so can be fatal on overdose), Induce glucuronyltransferase (which messes up kinetics of other drugs), Mess up the sleep cycle (by decreasing REM and slow-wave sleep), have long half-life (so daytime sedation)
What problems (non-ideal characteristics) do BDZs have as sedative hypnotics? And what advantages do they have over barbiturates?
Like barbiturates, they have Tolerance, Physical dependence, abuse potential, and affect sleep cycle (but quality of sleep is better than with barbiturates), However, hay fewer drug interactions and do not induce or inhibit CYPs, safe on overdose (when used alone)
How to BDZs work?
Binds to GABAA receptors allosterically to increase affinity of GABA to its receptor (so without GABA, BDZs don’t work). It causes more frequent ion channel opening. It binds between the α and γ subunits of which there are subtypes that are responsible for the different effect. α1 and γ2 mediate sedative-hypnotic effects, while α2 mediates anxiolytic and muscle realxant effects. Interestingly, no endogenous ligands have been found which bind to the BDZ binding site
What are the four effects of BDZs that they are used therapeutically for?
1) anxiolytic (α2), 2) sedative-hypnotic (α1 and γ2), 3) anticonvulsant, and 4) muscle relaxant (α2 ), which is a CNS effect, not a skeletal muscle effect
4 significant side effects of BDZs?
(1) drowsiness, (2) confusion, (3) anterograde amnesia, and (4) psychomotor impairment
Which route are BDZs administered?
IV and oral (not IM)
“Halcion” Along with flurazepam, is the most rapidly absorbed BDZ. So, it is abused more than alternatives like chlordiazepoxide (20hr half-life) Short duration, so doesn’t accumulate, and effect is gone by morning. Metabolite is hydroxylated.
“Dalmane”. Along with triazolam, is the most rapidly absorbed BDZ. It has a long biological half-life, so can accumulate in body. Metabolite is N-dealkyl.
“Xanax”. Rapidly absorbed BDZ, most often prescribed as anxiolytic (not as hypnotic due to long half-lide of 12hrs). metabolite is hydroxylated. (Intermediate duration)
A BDZ, “Restoril” absorbed slowly. Intermediate Duration, so some effects still left in morning. Only metabolized by glucuronidation.
BDZ “Valium”, absorbed more rapidly than chlordiazepoxide. Metabolite is N-dealkyl. Has long half life
BDZ. “Serax” Intermediate Duration, like alprazolam and temazepam. Slow absorption, and metabolized only by glucuronidation.
BDZ. “Versed” Short duration. Metabolite is hydroxylated. Administered IV for anesthesia
Phase 1 metabolites of BDZs?
Microsomal oxidation by CYPs produce N-dealkyl metabolites and hydroxylated metabolites. The N-desalkyl metabolites (of diazepam, chlordiazepoxide, and flurazepam) are ACTIVE and have LONG half-life. The hydroxylated metabolites (of triazolam, midazolam, and alprazolam) are ACTIVE and have SHORT half-life
Phase 2 metabolites of BDZs?
Glucuronidation is the last step in ALL BDZ metabolism, and is the ONLY step for some BDZs (oxazepam, lorazepam, temazepam). So, the conjugated BDZs are excreted into bile. Liver impairment affects glucuronidation less than CYP function
How do drugs and age affect metabolism of BDZs?
Microsomal oxidation by CYPs can decrease with impaired liver function, such as in the elderly. Also, drugs that use or inhibit CYPs like cimetidine and SSRIs increase the effects of BDZs. However, BDZs that are metabolized only by glucuronidation (oxazepam, lorazepam, temazepam), are less affected by hepatic insufficiency.
What is “biological” half-life?
It means half life of the parent drug and active metabolites
What is advantage and disadvantage to BDZ having short or long half-life?
Short half-life means less hangover effect and psychomotor impairment, but are more likely to cause rebound of original sxs (anxiety, insomnia)
Advantage and disadvantage to BDZs with long half-life?
Cleared more gradually, so withdrawal is tapered (less rebound sxs). But, can cause progressive psychomotor impairment
BDZs with what half-life are better for anxiety?
Usually short half-life, because less psychomotor impairment, but the need for frequent dosing can cause anxiety
What is the Halcion (triazolam) controversy?
DC’d in UK due to studies showed it was associated with confusion, amnesia, abnormal behaviors, but not that other agents lacked these. In U.S., FDA-recommended dose decreased to 0.125 – 0.25mg (not yet demonstrated to be effective). It does appear to have high anterograde amnesia.
Which BDZ to use for anxiety versus insomnia?
All can be used for both
Selection criteria for BDZs?
Rate of absorption, how metabolized, half-life, etc
Duration to use BDZs?
Short-term. If more than a few days, taper off. If more than a month they are not effective to treat chronic anxiety or insomnia
How can BDZ antagonists be used?
Flumazenil is a BDZ antagonist that competitively binds to the BDZ binding site to decrease affinity of GABA for its receptor. It can be used to treat BDZ overdoses and to reverse BDZ effects after surgery or diagnostic procedures
“Ambien”. Like Zaleplon and Eszopiclone. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 30 min onset and 2 hr half-life. Also comes in CR formulation
Zaleplon? what is it, and what does it bind to?
“Sonata”. Like Zolpidem and eszopiclone. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 10-20 min onset and 1 hr half-life.
“Lunesta”. Like zolpidem and zaleplon. Non-BDZ sedative-hypnotic, binds to GABAA receptor. Produces less sleep cycle problems, psychomotor impairment, amnesia, tolerance, physical dependence, and rebound insomnia than BDZs. They have only weak anxiolytic, muscle relaxant, and anticonvulsant effects (at anti-insomia doses). Zolpidem and Zaleplon, but not eszopiclone, bind selectively to the α1 subunit. 30 minute onset, 6 hr half-life. A side effect is bitter aftertaste. Approved for long-term use (like Ramelteon)
Melatonin agonist (a sub-category within non-BDZ sedative-hypnotic). More selective for MT1 and MT2 receptors than melatonin, so more effective too. Onset 15-25 min, half-life 1-3 hrs. Only hypnotic that is not scheduled.
A non-BDZ anxiolytic. It has NO sedative-hypnotic, anticonvulsant, ot muscle relaxant effects. That is because it doesn’t bind GABA receptors. It is a partial agonist at 5-HT1A receptors. Takes 1-4 weeks to work, and is a good choice if BDZ abuse is a concern
What is preferred agent for tx of long-term severe anxiety?
SSRIs. But some, like fluoxetine, can sometimes produce anxiety. Severe anxiety may include general anxiety, OCD, social phobia, panic disorder, and agoraphobia. Performance anxiety can also be treated with propanolol (a β antagonist)
“Provigil” is used to treat excessive sleepiness, caused by shift work, sleep apnea, and narcolepsy. It is potentially a drug of abuse for persons wishing to extend productive working hours. It causes minimal CV and CNS effects.
What increases the risks for side effects of BDZs?
>65yo, EtOH, using >1 BDZ, highly soluble BDZs
Rules of thumb for when and how to taper off BDZs?
If use >2 weeks, then taper off over 2+ weeks. Give 2-4 doses per day, taper 25% over first 3 days, then slower during second half of tapering period. Also provide support and family help.
What are pt factors that increase risk of BDZ abuse?
Substance abuse hx, psychiatric hx, (however, social and demographic factors are no indicator at all)
Long term use of sedative-hypnotics (>2 weeks) increase what risks?
Side effects, misuse, abuse, dependence (this also includes Lunesta and Ambien)
What does “opiate” mean as opposed to “opioid”?
Opiate is the drugs, opioid is all structures related to opium, including the endogenous opiod peptides. Or more precisely, any substance that acts at the opioid receptor to produce respiratory depression, somnolence, analgesia, and decreased GI motility, and can be reversed with Naloxone
What are the three opiod receptor types?
Mu (μ), agonized by morphine and β-endorphin; delta (δ), agonized by DPDPE and leu-enkephalin and β-endorphin; and kappa (κ), agonized by butorphonol and dynorphin 1-17. All are antagonized by naloxone
What are sigma (σ) and orphan opioid receptor-like receptors?
Once thought to be types of opioid receptors. Sigma can be stimulated by opioids (but probably through PCP), but not blocked by naloxone. ORL is not stimulated by opioids nor blocked by naloxone
How are the mu, kappa, and delta opioid receptors the same?
All from their own single gene (with >75% homology), all are GPCRs, have external N-terminus, and most importantly, they are all negatively coupled to adenylyl cyclase via Gi. Hetero-oligomerization can occur to make pairs of the types, but no clinical relevance exists for these different complexes
How does pertussis toxin (PTX) affect opioid receptors?
It can block the receptor-mediated effects of opioids
How do opioid receptors mediate their action?
Agonist binding leads to inactivation of the neuron. It starts with inactivation of adenylyl cyclase and inactivation of Ca channels (depress NT release, which is either inhibitory or excitatory depending on the particular neuron). Also, activation of G-protein-activated inwardly rectifying K channels (GIRK), leads to hyperpolarization, so reduced excitability of soma.
How does opioid receptor internalization (desensitization) occur?
Agonist binds, internal carboxy terminus gets phosphorylated by g protein coupled receptor kinases (GPRKs), increasing receptor affinity for arrestin, which then recruits c-Src adaptor (AP-2), which links arrestin with clathrin, causing endocytosis. Arrestin binding uncouples the transducing G-protein, so signaling is inhibited. For the mu receptor, etorphine and methadone doe this much greater than morphine and DPDPE. For the delta receptors, DPDPE does this much more than morphine. Side note: receptors are recycled, so new ones don’t have to be transported all the way from the nucleus and ER
What agonist activity do morphine, butorphanol, and buprenorphine have at which opioid receptor subtype?
The only effect buprenorphine has is partial agonist at mu. the only effect butorphanol has is agonist at kappa. morphine is a mu agonist and a kappa partial agonist
Three endogenous opioid peptides and their prohormones?
Enkephalins (from proenkephalin), dynorphins (from prodynorphin), and endorphins (from pro-opiomelanocortin or POMC). Each are cleaved post-translationally by trypsin-like enzymes into the active peptide. The prohormones contain either leu-enkephalin or met-enkephalin, which are pentapeptides offset by arginines and lysines
Prohormone to enkephalins. Contains mutliple met-enkephalins and one leu-enkephalin. Found in brain in multiple populations of interneurons. Made mostly in adrenal chromaffin cells
Pro-opiomelanocortin, the prohormone to endorphins. POMC contains sequences for ACTH, β-lipotropin (β-LPH), α-melanocyte-stimulating hormone (α-MSH). Found in pituitary
Prohormone for dynorphins. Has multiple copies of leu-enkephalin. Found in pituitary and adrenals in small amounts
Differences in affinity of endogenous peptides for opioid receptors?
Met- and leu-enkephalin have most affinity for delta. B-endorphin has most for mu, and some for delta. Dynorphin 1-13 has only (a lot) for kappa
Role of endogenous opioids?
Released during stress and exercise from pituitary and adrenals. Give “runner’s high”, decrease pain, and modulate respiration and CV function. Naloxone has no measurable affect on endogenous peptide activity (probably because it is subtle)
Where do opioids exert their analgesic effects? (in general and in what regions of the brain)?
On mu receptors, primarily in the following regions of the brain: amygdala, substantia nigra, periaqueductal gray area (PAG), rostroventral medulla (RVM), and spinal cord. The PAG is best characterized, and maybe the most important
How do opioids produce analgesia in the PAG?
Bind mu receptors on interneurons, block release of GABA from tonically active interneurons (so inhibits the inhibitory action of GABA on the PAG). That permits PAG projections into the medula to activate bulbospinal projections which release 5-HT and/or NE at spinal level. There, 5-HT and NE act through α2 and 5-HT receptors to inhibit spinal pain input.
How do opioids effect analgesia in the spine?
Depresses discharge of spinal dorsal horn neurons activated by small afferents (high threshold). Intrathecally, it attenuates stimulation of sensory afferents. There are several mechanims: hyperpolariazation by activating K channels, block Ca chanels (so small NTs like substance P can’t be released), reduce release of NTs from C-fibers in the substantia gelatinosa
What are the effects of opioids on sleep/wakefulness?
mu and delta receptors. they reduce arousal and promote sedation, via inhibition of ascending excitatory drive from the mesencephalic reticular activating systems.
What are the effects of opioids on respiration? How?
Mu receptors. Reduce respiratory drive by depressing the brainstem response to high CO2. It is useful in patients with “air hunger”
What are the GI effects of opioids?
Mu and kappa receptors. Reduce biliary, pancreatic, and intestinal secretions. Increase tone in intestines, leading to non-propulsive contractions. It leads to increased viscosity, slower passage time, constipation. Mediated by inhibition of Ach in myenteric plexus. Increased biliary tone can also lead to colic
What are the emetic effects of opioids?
Mu, kappa, and delta receptors. Cause nausea and emesis by agonizing receptors in the chemoemetic trigger zone (CTZ)
What are the effects of opioids on euphoria/reward?
Mu receptors. Strong reward, euphoria. Receptors in the nucleoid accumbens inhibit inhibitory GABAergic interneurons, so release more dopamine. Heroine does this fastest because it’s so lipid soluble.
How do opioids affect pupillary caliber?
Mu receptors. Induce constriction (Miosis), due to excitation of p.symp nerves (via inhibition of inhibitory GABAergic interneurons) to contract pupillae constrictor.
How do opiods affect CV function?
Mu receptors. Typically well-tolerated. Increased excitation of vagus, leading to atropine-sensitive decrease in HR. Morphine releases histamine from mast cells, so produces vasodilation and hypotension
How do opioids affect the release of GnRH, CRF, prolactin, ADH?
Inhibit hypothalmic release of GnRH and CRF, but increase release of prolactin by reducing dopamine (an inhibitor of prolactin). Mu agonists increase ADH secretion (so decreases urine flow). But kappa agonists inhibit ADH secretion, so increase urine flow.
μ agonist (and patial κ agonist). For chronic pain (slow release) and for post-operative pain. Half-life 3 hrs. significant 1st pass metabolism oral. Metabolized by glucuronidation (which is still active at 6-position, but not 3-), undergoes hepatic circulation. Side effects are release of histamine from mast cells, so pruritis and hpotension
μ agonist. “Demerol”. Oral or IM. Shorter duration of action than morphine. IM for fast pain relief. Metabolized by demethylation to give normerperidine which has a longer half life, can accumulate if repeated doses, and is a convulsant
μ agonist. Oral, IM. High oral availability. Long duration, so useful in chronic pain and suppressing opioid withdrawals. Metabolized by N-demethylation in liver. Side effects: repeated dosing proteins binding and accumulation in tissues. Has long half-life. Crosses BBB slower than morphine
μ agonist. “Sublimaze”. High potency (more than morphine). Used for anesthesia, or for acute pain in chronic pain patients. Half-life is 3-4 hrs, but effect wears off after 30 minutes. Metabolized by liver → then liver and renal excretion of metabolites. Side effects are extreme rigidity at high doses
μ agonist. “Oxycontin”. For moderate to severe pain, frequently in combo with NSAID. Effect enhanced by cimetidine which inhibits its metabolism
μ agonist. High oral bioavailability. Frequently given with NSAID. Must be activated (3-O-demethylated) by CYP2D6 to become morphine. 10% of caucasian population has deficient 2D6, so no analgesia in these patients. Has ceiling effect because “weak” opioid, but it crosses BBB faster than morphine and is more orally available than morphine
κ agonist. Opioid analgesic. Oral or intranasal. For moderate to severe pain. Has significant first-pass metabolism.
μ PARTIAL agonist, but more potent than morphine. For post-operative pain or maintenance drug for opioid-dependent patients. Long duration of action (more than serum half-life due to slow release from receptor). Excreted in feces. Can be used as antagonist to full agonists
Opioid receptor antagonist. IM or IV. Onset immediate, duration short (half-life 1 hr, which is less than morphine), metabolized by liver conjugation. Can antagonize all effects of agonists
Weak μ agonist, but also weakly inhibits NET and SERT (to block NE and 5-HT reuptake). Half-life 5 hrs, extensice metabolism by N- and O-demethylation and glucuronidation and sulfation. SHOULD NOT BE CO-ADMINISTERED WITH MAOI or TCA
Rules of thumb for DDIs with opioids?
Slowing of hepatic blood flow (e.g. cimetidine,) or inhibit CYPs (cimetidine, ketoconazole, grapefruit), incease action of opioids. Inhibitors of 2D6 (like fluoxetine, quinidine) block activation of codeine. CNS depressants synergize with opioids.
What are the two dimensions of pain?
Sensory-discriminative (quantifiable and relates to a sensory input), and Affective-motivational (emotional context of the pain, e.g. suffering)
What is an acute pain stimulus?
Activation of small, high threshold sensory afferents (Aδ and C fibers) sends transient input into spinal cord, then to neurons contraleterally to the thalamus, and to the somatosensory cortex. (needle stick, hot cup, etc)
What is a tissue injury pain stimulus?
Local release of mediators (bradykinin, prostanoids, potassium causes persistent activation of small sensory afferents, which activates ascending pathways and leads to “spinal sensitization” (so more sensitive to small stimuli (burns, post-incision, abrasion, etc.)
What is nerve injury pain stimulus?
Nerve damage causes anatomical and biochemical changes in nerve and spinal cord to give spontaneous dysesthesias (shooting, burning pain) and allodynia (light touch hurts). Maybe occurs via low threshold afferents (nerve trauma, diabetic neuropathy, neuralgia
What kind of pain are NSAIDS most effective for?
Tissue injury really well, but not acute stimuli or nerve injury
What kind of pain are opioids most effective in treating?
Tissue injury and acute stimuli better or the same as nerve injury
What kind of pain are anticonvulsants and tricyclic antidepressants most effective in treating?
Nerve injury, but not tissue injury or acute stimulus (gabapentin, tipiramate)
what should be used to treat mild or moderate pain?
Mild = NSAIDS, moderate = NSAIDS and/or weak opioids (Buprenorphine and Codeine)
What should be used to treat severe pain?
NSAIDS plus strong opioids, anticonvulsants. Also, adjuvants like laxatives, antiemetics, stimulants, antidepressants
Rules of thumb for combining pain releievers?
Use drugs with non-overlapping MOAs, don’t mix partial agonists with full agonists
What are typical rescue pain meds?
Fentanyl patch or IV PCA
Possible mechanisms or explanations for tolerance?
1) higher clearance or metabolism 2) loss of receptors or receptor coupling 3) increased pain over course of disease, 4) development of non-opioid-sensitive pain (i.e. neurologic pain), 5) don’t block “suffering”, only nociceptive pain
What is dependence?
Withdrawal will produce drug-specific withdrawal symptoms (usually exaggerated symptoms that are supressed by the opioid, like hyperalgesia, diarrhea, agitation)
What is addiction?
Drug-seeking behavior for non-therapeutic purpose, continued use despite harm, craving, and illegal behavior to get drugs.
What drugs are used to treat opioid addiction?
Methadone, buprenorphine (with ot without naloxone)
How common is addiction to opioids after therapeutic use?
Relatively rare, but abuse and diversion are more common
Which endogenous peptide has highest affintity for kappa recerptor?
Which endogenous peptide has highest affinity for mu recerptor?
Which endogenous peptide has highest affintity for delta recerptor?
Met- and leu-enkephalins
Mu agonist at ALL opioid receptors (mu, kappa, delta). Treats diarrhea. Very poorly absorbed (that’s good)
“neurontin”. Anticonvulsant like topiramate (Topamax). Used to treat neuropathic pain, only side effect is some drownsiness
“Topamax”. Anticonvulsant like gabapentin (Neurontin), used in treatment of neuropathic pain
Tricyclic antidepressant. Tertiary amine. Inhibits reuptake of NE and 5-HT. Side effects are dry mouth, CV effects. Used to treat neuropathic pain and also as antidepressant iin chronic pain
“Cymbalta” 5-HT and NE reuptake inhibitor or “SNRI” (like venlafaxine), but not a tricyclic. Inhibits NET at lowe doses than venlafaxine. Can inhibit 2D6. Causes nausea, sedation, but less sex dysfunction. Approved for diabetic neuropathy, to treat neuropathic pain and as an antidepressant in chronic pain
Like Benztropine, a mAChR antagonist used in the treatment of Parkinson’s disease and in combination with antipsychotic drugs to control EPS. Just like all anti-Ach, it can cause constipation, urinary retention, dry mouth, tachycardia, precipitation of attacks of acute narrow-angle glaucoma in susceptible individuals, confusion, and drowsiness
precursor of DA used in the treatment of Parkinson’s disease; generally administered in combination with carbidopa. Alone, it can cause severe nausea and vomiting because L-dopa is converted to dopamine in the periphery by aromatic L-amino acid decarboxylase. The dopamine then stimulates the chemoreceptor trigger zone (CTZ) in the area postrema in the medulla; this region of the brain is not protected by the blood-brain barrier
Carbidopa inhibits what enzyme?
Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase, the enzyme that converts L-dopa to dopamine. It is used with L-dopa because it inhibits the peripheral formation of dopamine (neiher carbidopa nor dopamine crosses the blood-brain barrier, but Dopa does), thereby reducing the nausea and vomiting and increasing the fraction of the administered L-dopa that is available for transport across the blood-brain barrier
Combination levadopa carbidopa
What is a possible side effects of sinemet after chronic use such as in parkinson’s?
Sinemet is Carbidopa/levodopa. It can cause psychosis, caused by the extra dopamine. In Parkinson’s patient, need drug that has no EPS (only one is clozapine). Chronic sinamet use can also lead to dyskinesias, which mechanism is not known. Only recourse is to lower Sinamet dose. The effects of Sinament can also decrease over time probably due to progression of the disease in which there are fewer dopaminergic neurons available to convert L-dopa to dopamine.
Like Trihexyphenidyl, a mAChR antagonist used in the treatment of Parkinson’s disease and in combination with antipsychotic drugs to control EPS. Just like all anti-Ach, it can cause constipation, urinary retention, dry mouth, tachycardia, precipitation of attacks of acute narrow-angle glaucoma in susceptible individuals, confusion, and drowsiness.
Like Pramipexole, a DA agonist used in the treatment of Parkinson’s. DA agonists are first line in parkinson’s to avoid AEs of Dopa.
Like Ropinirole, a DA agonist used in the treatment of Parkinson’s. DA agonists are first line in parkinson’s to avoid AEs of Dopa
Relatively selective MAO-B inhibitor used in the treatment of Parkinson’s, especially for tremor.
COMT inhibitor used in the treatment of Parkinson’s. Gives DA a longer half-life. (one formulation is a combination with L-dopa and carbidopa).
How does degeneration of dopaminergic neurons lead to dyskiniesia in Parkinson’s?
ACh stimulates and DA inhibits (and stimulates) GABAergic neurons, so when DA neurons degenerate, the DA influence decreases, and leads to both bradykinesias, rigitity, and tremors
How does L-dopa therapy lead to psychosis?
Extra DA in the mesolimbic pathway causes psychosis (just like in schizophrenia)
Rank the amount of EPS that will be induced by atypical antipsychotics (in general), risperidone, chlorpromazine, haloperidol, and clozapine?
Haloperidol is the worst (high potency conventional), then chlorpromazine (low potency conventional), then respiridone (the most EPS of the atypicals), then atypical antipsychotics (D2 antagonists). Haloperidol is high potency. Clozapine causes no EPS, but can cause agranulocytosis
What are the sxs of early, middle, and late alzheimer’s?
Early is difficulty remembering converstions, date, losing things, social withdrawal, depression, poor judgement and planning. Middle can be anger, violent, paranoia, problems with personal care and communication, as well as motor impairment, 24hr supervision needed. Late is minimal verbal communication, not even basic personal care, can’t recognize people, places, things, can’t walk, smile, and maybe can’t swallow.
Two cellular pathological components to cause of alzheimer’s?
Extracellular neuritic amyloid plaques (can be due to increased synthesis of Aβ plaques or decreased clearance), and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. These lead to degeneration of primarily cholinergic neurons projecting from nucleus basalis to cortex and hippocampus
How does choline supposed to work for alzheimer’s?
A precursor to ACh. Since cholinergic neurons extending from the nucleus basalis to the cortex and hippocampus are degenerated in alzheimer’s, increasing ACh might possibly help. It is limited by the ability of choline to cross both the BBB and get taken up by neurons via (probably) an already saturated uptake receptors.
Tertiary amine Cholinesterase inhibitor used in the treatment of Alzheimer’s. Possible side effects include p.symp stimulation of GI, increase sweating, and other cholinergic responses. To treat these effects, a quaternary amine mAChR antagonist can be given (does not cross BBB)
Besides ACh esterase inhibition, what other strategies can be used to increase ACh transmission in Alzheimer’s?
mAChR agonists that are selective for M1 and M3 (M2 would decrease ACh release due to presynaptic effect. Or, nAChR agonists, at presynaptic effects to increase ACh release.
NMDAR antagonist; used in the treatment of Alzheimer’s disease. Works, possibly by decreasing neuroexcitatory stimulation by NMDA, which otherwise might lead to neuronal degradation. In effect, this means that “noise” that normally has to be overcome to produce memory, is erased, so memories can form with less dramatic excitation
Which part in the sequence of steps in Alzheimer’s progression does Memantine possibly inhibit?
After injury caused by amyloid plaques, memantine might prevent disruption of metabolic and ionic homeostasis, which normally leads to oxidative damage and then neuronal dysfunction
What potential therapies might be explored for treatment of alzheimer’s?
Inhibition of secretase (which protealyzes APP to make Aβ amyloid). Or immunotherapy against the Aβ amyloids
What are the “strong” opioids? “weak” opioids?
Morphine, meperidine, oxycodone, methadone. Weak = codeine and buprenorphine
What is the problem with using multiple short-acting opioids?
They cause tolerance much more than other regimens.
Related to GABA, increases glutamatergic transmission. And diminishes neuronal hyperexcitability during withdrawal from alcoholism; used in the treatment of chronic alcoholism
Newest atypical antipsychotic drug (SDA, with partial agonist effects at D2 receptors and 5-HT1A receptors) “functional selectivity”. Little or no weight gain, metabolic changes, prolactin, lipids, hyperglycemia, or QT changes
GABAB agonist (GPCR), muscle relaxant that works in spinal cord
Competitive GABAA antagonist, binds at GABA-binding site, which is on the beta subunit
atypical antidepressant drug; postulated mechanism: NE/DA reuptake inhibitor (NDRI). No weight gain, sedation, sex dysfunction (can treat sex dysfunction), helps with nicotine withdrawal, more likely to cause seizures, but good effectiveness to safety profile.
conventional (typical) antipsychotic drug like thioridazine. (D2 antagonist); phenothiazine derivative, low potency, causes less EPS than haloperidol, but more than atypicals. Treats pos sxs (hallucinations, delusions, and disorganized thinking), but not neg sxs (withdrawal, loss of motivation)
SSRI, has the most SERT/NET inhibition (but paxil has most SERT block). Has least p450 inhibition and CNS stimulation. Remarketed as escitalopram “lexapro” with no demonstratable advantage except more potent.
Atypical antipsychotic (SDA). Has the highest affinity for 5-HT2A/D2. Selective for mesocortical/limbic. In striatum, presynaptic 5-HT2A is blocked, so increase DA release, so no effect in nigrostriatal. Best for EPS, but can cause agranulocytosis, seizures, wt gain, metabolic changes, hypersalivation, orthostatic hypotension (alpha1). The %-HT2A antagonism can’t explain lack of EPS though, because chlorpromazine has this too, but still EPS. Works in 60% of pts refractory to other meds. Was 1st to inprove neg sxs, doesn’t increase prolactin.
tricyclic antidepressant drug; 2º amine
prodrug, suicide inhibitor of ALDH causing acetaldehyde syndrome; it can also chelate Zn (thus inhibiting ADH), and stimulate transport of nickel and lead (causing neurotoxicity)
Anticonvulsant used as a mood stabilizer
“prozac”, prototype SSRI. Very selective for SERT. Has small mAChR, α1, H1 effects and cardio effects. Long half-life (50hrs), plus an active metabolite (10hr half-life), so less discontinuation syndrome. It can cause agitation, suicide tendencies, irritability, insomnia, akasthesia, inhibits 2D6. Also used for premenstrual dysphoric syndrome.
competitive inhibitor of alcohol dehydrogenase (ADH); used in the treatment of methanol poisoning
Anticonvulsant used as a mood stabilizer
Mood stabilizer. Good for mania, but not mixed state or rapid cycling. Good response for 3 or fewer cycles per lifetime, and for mild illness. May patients are unresponsive to it, has low compliance, narrow therapeutic window, and side effects include tremors rash, GI upset, weight gain, cognitive impairment, teratogenic
atypical antidepressant drug; postulated mechanism: antagonist at presynaptic α2 receptors → ↑NE and 5-HT release (NSSA = noradrenergic and specific serotonergic antidepressant). Has high H1 side effects (sedation), increases appetite and weight gain
toxin that is converted (by MAO-B) to MPP+, which destroys dopaminergic neurons
GABAA agonist. Binds at same site as GABA (the beta subunit)
Long-acting Opioid antagonist, inhibits rewarding effects of EtOH to treat chronic alcoholism
atypical antidepressant drug; postulated mechanism: 5-HT2A antagonist with weak SSRI activity (SARI = serotonin 2A antagonist/reuptake inhibitor). 5-HT antagonism is not enough to cause antidepression, so SERT activity is essential. By blocking 5-HT2A, more activity occurs at 5-HT1A. has H1 side effects, and sometimes liver failure
Atypical antipsychotic (SDA). Along with quetiapine, has weight gain, DM, lipid profile worsening
“paxil”, SSRI. Most potent SERT inhibitor, highly inhibits 2D6, causes more weight gain, sex dysfunction, less CNS stimulation (maybe sedating), and has longer half-life than fluoxetine
Phencyclidine. Blocks NMDA receptor ion channel
Noncompetitive GABAA antagonist. Blocks GABAA receptor ion channel
Atypical antipsychotic (SDA)
Atypical antipsychotic (SDA). First atypical after clozapine. More potent D2 blocker, less H1, alpha1, and mAChR effects. Of the atypicals, it is the worst for EPS and prolactin.
SSRI, used mostly for OCD, not depression. Less P450 inhibition and CNS stimulation than prozac or paxil
Glycine receptor antagonist
Conventional antipsychotic like chlorpromazine. (D2 antagonist), phenothiazine derivitive, low potency. Can cause retinitis pigmentosa and QT elongation
MAO inhibitor used as antidepressant
Atypical antidepressant, the first SNRI. Is SNRI at low doses and NET inhibitor at high doses. Minimal effects on 5-HT. causes nausea, sedation, sex dysfunction, but more effective than SSRIs
Atypical antipsychotic (SDA). Little or no weight gain, but can cause QT elongation like thioridazine (black box)
5 steps to tx of methanol poisoning?
Manage respiration, infuse ethanol (to compete for ADH), infuse bicarb for acidosis, give folate to get rid of formate, give FOMEPIZOLE to inhibt ADH (probably better than EtOH)
What are the four major effects of methanol poisoning?
ABCD (acidosis, blindness, CNS and respiratory depression). Blindness is due to formic acid → retinal hyperemia, edema, and demylenation of optic nerve. It is also renally toxic
How is methanol metabolized?
NAD+-dependent enzymes (ADH and ALDH) to form formaldehyde (rate-limiting step) and then formic acid. this increases the NADH/NAD+ ratio, which increases lactate. The formic acid is turned to formate in a pH-dependent process. Formate gives off CO2 and H20, but requires folate (that’s why give folate)
What makes an antipsychotic clinically atypical?
Reduced EPS, but also possibly effective in pts refractory to standard agents, efficacy against negative sxs, and efficacy against cognitive sxs
How/when are 1st generation antipsychotics used?
Acute ot adjunctive therapy, but used less and less
All atypical antipsychotics are what class?
SDAs. They cause less EPS than 1st gen, and work better on negative sxs
Side effects of 1st gen vs atypical antipsychotics?
1st gen have EPS (acute dystonia, parkinsonian tremor bradykinesia rididity, akasthesia, tardive dyskinesia). They also have little or no hematological effects, weight gain, sedation, cardiac conduction probs, retinal probs, orthostasis. Atypicals can cause weight gain, drooling, sedation, seizures, and clozapine causes no EPS except akasthesia, but may cause agranulocytosis
Parkinsonian sxs and dyskinisias are most similar to pos or neg sxs?
Parkinsonian is like neg sxs. Dyskinesias are like pos sxs
What does 4-7 tremor cycles indicate?
Compare dystonia, parkinsonism, and akasthesia?
Dystonia is sustained muscle contraction, occurs within 1-2 days of therapy, in 2-10% of pts. Acute is more likely in young pts. Treatable with anticholinergics. Parkinsonism is bradykinesia, tremors, rigidity. Occurs within weeks of therapy, 50-60% of pts. More common in elderly. Flexed posture, shuffling steps, no swinging arms, mult steps to turn around. Akasthesia is voluntary movement to try to relieve inner discomfort. 50% of pts, more common in elderly. Difficult to treat.
How to treat seizures from EtOH withdrawal?
Chronic GI effects of EtOH?
Intestinal malabsorption, vitamin deficiency, liver disease, stimulation of CYP2E1 leads to tolerance to EtOH and drugs that are metabolized with 2E1. The increased O2 use by 2E1 also decreased ATP production and depletes NAD+ stores. Increased acetylaldehyde, producing protein adducts and giving an immune response.
Chronic CV effects of EtOH?
Cardiomyopathy, degenerative changes, CHF
Chronic effects of EtOH on CNS?
increase NMDA, increase Ca channels, decrease GABA, all leading to increased output, which leads to dependence
Acute GI effects of EtOH?
Increase acid secretion and gamma-amino-levulinic acid synthase (makes porphyria worse)
Acute effects of EtOH on CV?
Dilates cutaneous vessels (flushing) via central vasomotor depression. Acetylaldehyde directly dilates sm musc. Increases catecholamine release from adrenal medulla
Acute CNS effects of EtOH?
Depressant. Increase 5-HT action, and GABA leading to inhibition activity. Also decreases NMDA, Kainate, Ca channels, and adenosine uptake. It perturbs membrane fluidity and electrical activation, blocks nerve conduction. Inhibits secretion of ADH from post pit. Hangovers caused by fusels, which are contaminants of formulation process.
What’s reductive storage?
NADH:NAD+ ratio increases from 1:4 to >1 as a result of EtOH consumption, due to build up of NADH, acetate, pyruvate, NADPH, lactate, acetyl CoA. Causes increased blood lactate (acidosis from competition with ureate production), increases ketones from fat, hyperlipidemia due to high FA synthesis intermediates, fatty liver from hepatocyte FA synthesis and decreased VLDL export. But increases HDL/LDL ratio with moderate alcohol
Primary and secondary pathway for EtOH metabolism?
Primary (75%): EtOH goes to acetylaldehyde by ADH, followed by conversion to acetate by acetylaldehyde dehydrogenase (ALDH). ADH is zn-containing, and is inhibited by pyrazole. ALDH is inhibited by disulfram, and is deficient in 30-50% of asians. Secondary (25%): induced in chronic alcoholism. First step is CYP2E1, which is part of the microsomal ethanol oxizing system (MEDS) in smooth ER. Second step is acetylaldehyde to acetate by ALDH or a non-specific aldehyde oxidase
How fast is EtOH metabolized?
About 10g (10mL) per hour in 70kg person
How does Vd of EtOH differ in women and elderly?
EtOH distributes to all body water in proportion to blood flow (so brain is high). Vd is lower in elderly and women due to less water per kg body mass
How to calculate amt EtOH consumed based on blood level?
Weight (kg) x Vd (L/kg) x 1000ml/L x % (g/100mL) = amt (g).
How is absorption and bioavailability of EtOH?
0.8 to 1.0. 1st order absorption (so faster at first), takes 1-4 hrs to complete. Food slows absorption by slowing gastric emptying.
St John’s Wort for depression?
Not more effective than placebo, can interact with drugs in many ways
How often need to use combo therapy or augmenting agents for antidepressants?
About 50% respond to monotherapy. Augmenters not to be used alone, only in combo with antidepressant
Side effects of MAOIs?
Change BP, insomnia, increased appetite. Potentiate effects of sympathomimetics and tyramine and TCA and SSRIs. Can cause Serotonin syndrome which is too much 5-HT, causing GI sxs, CNS toxicity, hyperthermia, CV collapse. It can also occur when switching between MAOI and SSRI
How do MAOIs work?
Block metabolism of NE, 5-HT, so leak out into synapses. Mechanism unknown because amine levels increase immediately, but effects take weeks. Can be reversible or irreversible and selective or nonselective
Which SSRIs can be used for kids?
Sertraline and fluoxetine.
Side effects of SSRIs?
GI: N/V/D, cramps, bleeding. CNS: HA, anxiety, motor restlessness, insomnia, sexual dysfunction. Inhibit P450s, if stopped, cause discontinuation syndrome. Can cause serotonin syndrome with MAOIs, which is altered mental state, agitation, tremor, ataxia, fever, GI upset
How do SSRIs work, and compare to TCAs?
Block SERT, as well as NET a little. Less anti-ACh, alpha1, and H1 effects than TCAs, and safer on oerdose than TCAs.
What are the 2nd gen TCAs and what are the advantages, problems?
Amoxapine, maprotiline. Less sedation, less anti-ACh, less cardiac tox. But, can cause seizures and amoxapine can cause EPS (they are not drugs of choice)
Triad for TCA toxicity?
Coma, seizures, and ECG abnormalities. They are highly lipid-soluble, so accumulate in tissues. Tx is supportive care
What are the side effects of TCAs?
In additionto blocking NET (how they work), they block mAChR, alpha1, and H1 (like conventional antipsychotics). Alpha1 efects are postural hypotension. Sinus tachycardia, conduction delays, arrhythmias (hallmark of TCA tox), esp amitriptyline
Major DDIs of TCAs?
Block NET, so potentiate catecholamines, block sympathomimetics
What is endogenous versus reactive depression?
Endogenous can manifest as guilt, sad, appetite, weight, sleep, ambition, sex desire, devaluation, hopelessness (not “real events”). Reactive is related to life events, so antidepressants not usually used because those probs go away
Worst antipsychotic for EPS and increasing prolactin?
Worst antipsychotics for weight gain and metabolic changes (2)?
Clozapine and olanzapine. Black box warning. Should take familiy hx of DM, obesity, lipids, BP, etc…
Which antipsychotic changes QT interval?
Which antipsychotic is the worst for sedation?
Atypicals in elderly?
Can cause strokes and increase mortality. (black box)
Compare side effects of low vs. high potency conventional antipsychotics?
Low = more alpha1, mAChR, and H1 effects, but mAChR effects are beneficial to balance out anti D2 in striatum, so less EPS. High = low mAChR blocking, but that means more EPS
What is neuroleptic malignant syndrome?
Rare, dangerous form of EPS that resembles PD, and is especially likely with high doses of high potency agents. 10% fatal. Can be treated by D/C drugs, give muscle relaxants, and hydrate
What is the late EPS caused by antipsychotics?
Tardive dyskinesias. Very common, can happen months so years after starting therapy, usually upon withdrawal. It consists of face convulsions, and is more common with high doses, long duration, and elderly. Can be reversible. Caused by increased DA receptor sensitivity. mAChR blockers make it worse.
What is the acute EPS caused by antipsychotics?
Due to D2 blockage in nigrostriatal pathway. Has three forms (dystonia, akasthesia, parkinsonian). Dystonia is sudden uncoordination, muscle spasms. Akasthesia is inner restlessness. Parkinsonian is rigidity, bradykiniesia. Acute (but not late) dyskinesias can be treated by mAChR blockers (balance), or just give lower dose of antipsychotic.
Three classes conventional antipsychotics?
Phenothiazines (chlorpromazine, thioridazine, fluphenazine), thioxanthines (thiothixene), butyrophenones (haloperidol). Flu and halo are high potency. Chlor and Thoir are low potency
Contraindications for antipsychotics?
BPH, glaucoma, urinary retention (due to anticholinergic), other effects are orthostatic hypotension (alpha1), and sedation (H1). Other side effects are lower seizure theshold, weight gain, sun sensitivity, Thioridazine and Chlorpromazine can cause retinitis pigmentosa. Thioridazine and Ziprasidone can cause QT elongation
How do conventional antipsychotics work? What is effect on CTZ? How affect pos or neg sxs? High or low potency antipsychotics have more side effects?
Block D2 receptors. Antiemetic due to effect on CTZ. Don’t help neg sxs. Low potency have more autonomic side effects because need higher dose (lose specificity). They can also increase prolactin and cause EPS (but EPS is more common with higher potency agents)
What is the EP system for? The meso-cortical and limbic? The tuberofundibular?
EP for motor, meso-cortical and limbic for cognition and emotion, the tuberofundibular inhibits prolactin by ant. Pit. All these systems are mediated by DA, so when D2 antagonists are used to treat the extra DA in schizophrenia, they also block the D2 in the other pathways, leading to increased prolactin and EPS
Antipsychotics like neuroleptics and respiradone have antipsychotic effects, but what else?
Like all antipsychotics (except clozapine), these produce EPS, but in risperidone and neuroleptics, maybe when 50% have antipsychosis, 15% already have EPS
How does NMDAR stimulation proposed to cause neuronal damage?
Decreased blood flow, O2, glucose (anything that leads to decreased ATP production) leads to more glutamate in synapse. Also, dying cells release glutamate and K+, which depolarizes cells, leading to NMDAR activation, increased Ca concentration, and neuron death. (a lot of Ca is bad, a little is good)
How is NMDAR involved in memory?
Repetitive or prolonged depolarization due to activated GluRs→ activates NMDARs. This causes Ca to enter the cell causing a permanent change via p’lation of ion channel (puts more receptors on membrane). The strength of the signaling increases with repetitive use, and may last for hours, and is associated with memory
Compare the relative roles of NMDAR, AMPA, and kainate?
NMDAR are usually only activated secondary to prolonged loss of inhibitory signaling, such as occurs from GABAergic degeneration or blocked Cl channels. The continued depolarization leads to open NMDAR channels, which sustains spiking and spreads activity. Seizures can result, so treated by increasing GABAergic transmission.
How are NMDARs permeable to Na and Ca, but GluRs (AMPA) only to Na?
A point substitution of R instead of Q in the GluR subunit makes AMPA impermeable to Ca. As long as the Q isn’t there, it is permeable, such as asparigine in NMDAR
What are the two types of GluRs? How are they different in their activation from NMDAR?
AMPA and kainate. They conduct Na to produce EPSPs, and they don’t require glutamate binding to do this. However, NMDARs require glutamate binding to conduct both Na and Ca. NMDAR can be clogged up by Mg when polarized. Must be depolarized to open up.
What substances other than glutamate and NMDA affect NMDARs?
PCP and ketamine plug up the channel like Mg to decrease excitation. Glycine is REQUIRED as a coagonist with glutamate ot NMDA. Polyamines bind several sites to potentiate agonism, but can inhibit at high conc.
What are the four types of glutamate receptors?
Ionotropic: AMPA, kainate, NMDA. Metabolic: mGluRs. The mGluR is named for glutamate as substrate even though they all use glutamate as a substrate. The ionotropic ones are named for their synthetic ligands.
Characterize glutamate as an NT, its synthesis and metabolism?
It is the major excitatory NT in CNS (75-80%), and it’s nonessential because it is synthesized from glucose in the CNS and doesn’t cross the BBB. It is terminated by reuptake via Na-dependent glutamate transporters (EAAT)= excitatory AA transporter
Characterize the glycine receptors?
Similar to GABAA. Ionotropic, ligand-gated. They increase Cl conductance to create IPSPs. Strychnine is a glycine receptor agonist, so blocks inhibition, giving more motor output (skeletal and facial muscle convulsions)
Characterize glycine NT?
Glycine is the GABA of the spinal cord (major inhibitor). Glycine is synthesized from serine via hydroxymethyltransferase (SHMT). It is highly concentrated in synapse, low in vesicles. It is reuptaken by astrocytes and neurons
What is difference between GABAA and GABAB receptors?
GABAA is ligand-gated and ionotropic, increases Cl conductance. It has thousands of combos of subunits. GABAB is GPCR and metabotropic. They both activate K channels to hyperpolarize (which inhibits NT release)
Where does GABA bind to GABA receptor?
Beta subunit.
Where effect do steroids have on GABA receptors?
Increase GABAergic transmission
How does GABA inhibit motor activity?
Increase Cl conductance→ IPSP, which prevents excitatory signals from reaching threshold
How is GABA involved in Huntington’s disease?
Decreased EP GABAergic function in nigrostriatal pathway leads to huntington’s (less GABA→ more motility)
How prevalent is GABA in CNS? How is it synthesized? How is it terminated?
The major inhibitory NT (15-20% of synapses). Made from glutamate via glutamic acid decarboxylase. Interestingly, glutamate is the major excitatory NT, and is made from glucose in brain. Terminated by GABA-T, which is GABA transaminase, found in GABAergic neurons to make succinate and glutamate. In astrocytes, transported by GAT, and products recycled
ACh in memory?
Nucleus basalis (basal forebrain) to cortex and hippocampus.
ACh in vestibular control (balance)?
Involved, but not explained how. It explains the amnesia from scopalamine.
How is ACh involved in motor control?
In nigrostriatal pathway, ACh is balanced against DA, so if DA is degenerated (like in Alzheimer’s), antiACh can help restore chemical balance and motor control
How is DA implicated in Parkinson’s?
Dopaminergic neuron degeneration in nigrostriatal pathway leads to movement problems.
How is HVA related to Parkinson’s?
HVA (the breakdown product of DA) in CSF is associated with Parkinson’s.
MPTP and Parkinson’s?
A contaminant of heroin. It is converted by MAO-B to MPP+, which kills dopaminergic neurons in nigrostriatal pathway and gives parkinson’s sxs
How is DA involved in schizophrenia?
Increased DA in meso-limbic and meso-cortical pathways affects cognition and emotion.
How can amphetamines cause psychosis?
Increase DA release, leading to psychosis similar to schizophrenia
What is the biogenic theory of mood disorders?
That the availability of amines at synapses underlies depression. For example, reserpine, which blocks VMAT-2, depletes NE and 5-HT, causing depression
What is the problems with the biogenic amine theory of mood disorders?
Not all uptake blockers are antidepressants (e.g. cocaine), and time course is slower than increase in synapse amine conc.
Where and how much is 5-HT found outside the CNS?
90% of 5-HT is made in gut by enterochromaffin cells. It is released by stretch, vagal stimulation, toxins, drugs. It helps with peristalsis, secretion, release of other NTs. Platelets also have SERT and VMAT-2, and release 5-HT when aggregate to help hemostasis and thrombosis
Nature of serotinergic pathways in the brain?
Diffuse like NE, except originate in raphe nuclei. All 5-HT receptors are GPCRs except 5-HT3, which is ligand-gated (the only monoamine receptor that is ligand-gated). 5-HT mediates mood, sleep, anxiety, sexual function, appetite, and also vascular effects for migraine
How is serotonin synthesis like DA synthesis?
Tryptophan goes to L-5-hydroxytryptophan, then to serotonin with the exact same enzymes that tyrosine goes to dopa then to dopamine. Those enzymes are hydroxylase and then aomatic-L-AA-decarboxylase. Serotonin can also be made into melatonin in the pineal gland. It is broken down by MAO or reptaken by SERT (the target of SSRIs)
What is the effect of amphetamine and antipsychotics on mesolimbic, mesocortical pathways?
These pathways are involved in emotion and cognition. Amphetamines increase DA output, while antipsychotics decrease D2 activity.
What does the nigrostriatal pathway do, and how do antipsychotics and DA agonists affect it?
Voluntary movement. Antipsychotics cause EPS, while DA agonists and L-dopa inprove EP function
How is prolactin controlled?
DA on D2 receptors in ant. Pit. Antipsychotics that block D2 increase prolactin secretion
How is emesis mediated by D2 receptors?
In CTZ, which is unprotected by BBB, D2 agonists cause emesis
How is pleasure mediated by D2 receptors?
In the nucleus encumbens, D2 agonists increase activity
What are the three main pathways of dopaminergic transmission in the brain?
Nigrostriatal (substantia nigra to striata) responsible for voluntary movement, mesocortical and mesolimbic (midbrain to cortical and limbic areas) responsible for cognition and emotion, tuberoinfundibular (hypothalamus to median eminence (DA goes to ant pit to prevent prolactin secretion).
Distribution and effects of NE transmission in brain?
Nuclei in locus coeruleus, and is diffuse. It mediates mood, reward, arousal, and BP
What is most abundant catecholamine in brain? Ho is NE and DA broken down in brain compared to periphery?
DA is most abundant, more than NE and EPI (but all play small role overall). DA is transported into vesicles by VMAT-2, then beta-hydroxylated to NE. in brain and periphery, DA is metabolized into HVA. NE is broken down to MOPEG in brain, but VMA in periphery. DA and NE are both reuptaken by DAT and NET respectively
What are two kinds of pharacologic placticity?
P’kinetic: a drug inhibits or induces its own metabolism (less than 5x changes). Or P’dynamic, in which cells adapt (can be >1000x changes)
What ion channels mediate IPSP, EPSP, and AP?
IPSP = Cl in or K out, EPSP= Na in, AP=large depolarization secondary to EPSP (rapid Na in)

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