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49 Cards in this Set
- Front
- Back
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Two major kinds of Ion channels in the brain?
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Voltage gated--regulated by changes in membrane potential (axonal Na channels and presynaptic Ca channels--neurotransmitter synaptic vesicle release)
Transmitter gated--directly linked to ion channels or second messanger coupled |
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Voltage regulated ion channels in CNS
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Na+ channels in axonal membranes
Ca2+ channels in presynaptic membranes blocked by some anesthetics and anti-convulsants |
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Neurotransmitter regulated ion channels
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direct coupling
transmitters include GABA, Glutamate, Glycine, ACh targets for some anesthetics, anticonvulsants, cholinergic drugs, sedative-hypnotics G-protein (most amines-ACh, DA, NE, 5HT and endorphins) targets for analgesics, antidepressants, antipsychotics and anxiolytics |
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Glutamic Acid
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Excitatory via influx of cations (direct coupling and G-protein linked)
NDMA receptor (consolidation of long term memory)--potential target for ketamine and PCP |
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GABA A
GABA B |
Inhibitory
GABA A--via Cl- influx GABA B--K+ efflux (direct coupling) GABA activity increased by anticonvulsants, sedatives, hypnotics and some muscle relaxants |
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Dopamine
D1 D2 |
DA--inhibitory
D1--increase cAMP (periphery) activates Beta 1 receptors--increases HR & contractibility--increased systolic pressure/no change in diastolic). Reduces (renal, coronary and splanchic) arteriolal resistance and increases blood flow). High dose--vasoconstriction via alpha 1 D2--decrease cAMP-- open potassium channels, and decrease calcium influx dopamine-containing nuclei: substantia nigra and ventral tegmentum and target: striatum, limbic zones of the cerebral cortex(but in general not to the hippocampus). |
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DA action on pituitary D2 receptors
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dopamine inhibits prolactin secretion from the pituitary
D2 blockers (e.g. Haloperidol)--galactorrea |
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DA hypothesis of schizophrenia
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schizophrenia--due to an excess of DA activity in limbic brain areas, especially the nucleus accumbens
1) The nigrostriatal tract originates:substantia nigra terminates:striatum--- modulation of motoric behavior, cognition and sensory (2) the mesolimbic/mesocortical tracts originate:ventral tegmental area terminate: limbic and cortical structures--affecting cognitive, motivational, and reward systems. (D1) receptor family (D1 and D5) is present in cortex and striatum. (D2) receptor family(D2, D3, and D4) limbic and striatal regions. Presynaptic DA receptors (ie, D2 and D3)--substantia nigra and ventral tegmental area --affect firing of DA cells and synthesis and release of DA, respectively. Decreased DA activity in the prefrontal cortex may mediate the negative symptoms and cognitive dysfunction associated with schizophrenia. |
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Parkinson's
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loss of dopaminergic neurons in substantia nigra (lewy bodies--intracytoplasmic easinophilic inclusions--contain alpha synuclein)
loss of extrapyramidal nigra-striatal pathway |
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Serotonin
synthesis locations breakdown product |
synthesized from L-tryptophan (90% in GI enterochromaffin cells, 10% in platelets, some in brain)
breaks down to 5-HIAA (5-hydroxyindoleacetic acid) |
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5HT-1
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5-HT-1a-f
inhibit cAMP contracts arterial smooth muscle (carotid & cranial) e.g. sumatriptan acts (agonist) on 1-b (vasoconstric) 1-d (inhibits vasodilation) and 1-f |
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5-HT-2
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5-HT-2 increase PL-C--contracts vascular and intestinal smooth muscle, platelet aggregation. CNS--hallusinogenic
Trazodene--used for depression (priapism, sedation) 5-HT-2 & 1B agonist. Also blocks serotonin reuptake |
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5-HT-3
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5-HT-3 coupled to ligand gated ion channel--causes nausea and vomiting via area postrema. Peripheral stimulation--pain
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5-HT-4
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5-HT-4--increase c-AMP--in GI: mediate and increase secretions and peristalsis (e.g. Tegaserod--5-HT-4 agonist--used to tx IBS and constipation)
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Benzodiazepine
mechanism of action |
potentiate GABA by increasing FREQUENCY of Cl- channel opening
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Barbiturates
mechanism uses |
Barbiturates increase the DURATION of Cl- channel opening
used for seizure tx (phenobarbital) and anesthetic (IV--short acting Thipental) |
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Side effects and contraindications of Barbiturates
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CNS depression--nystagmus, ataxia, resp. depression, coma. Additive CNS depression with other drugs.
Induces cytochrome P450's--drug interaction e.g Warfarin. Increases Heme synthesis--contraindicated in Porphyrias |
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Benzodiazepines
uses & characteristics |
tx of anxiety, sleep disorders. Dose dep CNS depression, anterograde amnesia possible (Midazolam) (safer than barbiturates)--flatter dose-response curve), additive w/ other depressants
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Benzodiazapine antidote
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Flumezanil (IV) shorter T 1/2 than BZ
BZ receptor antagonist also used to facilitate recovery from anethesia |
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Benzodiazepine
extrahepatic BZ's? |
"Out The Liver"
Oxazepam Temezepam (sleep) Lorazepam (IV--status epilepticus, preop sedation) extrahepatic metabolism--do not form active metabolites |
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Alprazolam
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BZD
Anxiety, panic, phobias |
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Diazepam
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BZD (IV--not useful as PO for seizures)
fast onset but redistributed rapidly to other tissues (in 1 hr)--central effects wane. Plasma T 1/2 1-2 days effective agent for treatment of status epilepticus, its shorter duration of action is a disadvantage, leading to the more frequent use of lorazopam (T 1/2 14 hrs) |
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Zolpidem
Zaleplon |
non BZD used in sleep disorders (Ambien)
act on BZ1 receptor--reversed by Flumazenil |
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Midazolam
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shortest acting BZD
preop sedation, anesthesia anterograde amnesia (good for colonoscopy) |
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Buspirone
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for generalized anxiety--takes 1-2 weeks to work
No effects on GABA--possibly partial agonist of 5HT1a Non-sedating, no additive CNS depression |
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Tx of Barbiturate OD
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alkalinization of urine as barbiturates are weak acids
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Methanol metabolites
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Methanol via alcohol dehydrogenase--formaldehyde--via aldehyde dehydrogenase--formic acid (blindness, respiratory failure, severe anion gap metabolic acidosis)
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Fomepizole
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long acting inhibitor of alcohol dehydrogenase (affinity for the enzyme that is 8000 times that of ethanol)
should be considered the drug of choice when inhibition of alcohol dehydrogenase is desired if allergy or not avail--use ethanol--traditional initial treatment of methanol intoxication, competitively inhibits the metabolism of methanol by alcohol dehydrogenase. Ethanol's affinity for the enzyme is 10 to 20 times that of methanol, and its presence largely inhibits the formation of the toxic metabolites. |
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ethylene glycol metabolites
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(antifreeze) ethylene glygol via alcohol dehydrogenase--glycoaldehyde-via aldehyde dehydrogenase--glycolic acid--oxalic acid
CNS depression metabolic acidosis nephrotoxicity |
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Anticonvulsants
Mechanism of action |
increase GABA-BZ and Barb
block fast Na+ (carbamazepine, phenytoin, (at high doses) valproic acid and barbs block T-Ca2+ channels (ethosuximide and valproic acid) decrease exitation of glutamic acid (lamotrigine, topiramate(AMPA block), felbamate (NMDA block) |
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Phenytoin
mechanism use side effects |
Anticonvulsant
First choice (also Carbamazepine)for tx of general tonic-clonic seizures blocks axonal Na+ in their inactivated state (state/rate-dependent blockage) also used as class 1B antiarrythmic and backup drug for bipolar SE: Nystagmus, diplopia, ataxia, SLE, hirsutism, gingival hyperplasia, acne, osteomalacia, hematotoxicity (anti-folate effect) teratogenic--cleft palate steep dose response--low therapeutic index--monitor plasma levels fosphenytoin--parenteral- allows more rapid loading |
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Carbamazepine
mechanism use side effects |
blocks axonal Na+ in their inactivated state, slowing of the rate of recovery of voltage-activated Na+ channels from inactivation (state/rate-dependent blockage)
Used to tx trigeminal neuralgia backup drug for bipolar (structurally related to tricyclics) First choice (also Phenytoin)for tx of general tonic-clonic seizures & electroshock seizures NOT SEDATING at therap. dose Induces P450--including its own metabolism SE: hematoxicity (aplastic anemia and agranulocytosis--monitor blood!) teratogenic-craniofacial abnormalities & spina bifida, sedation, ataxia, diplopia, osteomalacia, H2O retention (+ ADH), exfoliative dermatitis |
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Ethosuximide
mechanism use side effects |
Used in absence seizures only
Blocks T-type Ca2+ channels in thalamus (thalamus plays an important role in generation of 3-Hz spike-and-wave rhythms typical of absence seizures--Ethosuximate reduces this current) SE: GI distress, fatigue, lethargy, Rare: hematotoxicity, SLE, exfoliative dermatitis, Stephen Johnsons, extrapyramidal dysfunction, Photophobia No renal or hepatic tox reported |
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Valproic Acid
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Used in many seizures (e.g. myoclonic), bipolar and as migrane prophylaxis
Blocks T-type Ca2+ channels, blocks axonal Na+, inhibits GABA transaminase--increases GABA inhibits P450--drug interactions (e.g. carbamazepine, phenytoin) SE: Hepatotoxicity (transaminases rise in 40%), GI distress, pancreatitis, alopecia, CNS--ataxia, sedation, tremor, photosensitivity, wt gain teratogenic--spina bifida |
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Divalproex Sodium
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"Depakote"
1:1 Valproic Acid: Valproate Sodium--absorbed more slowly |
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Felbamate
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adjuncive anticonvulsant
Lennox-Gastaut syndrome NOT USED MUCH due to adverse effects blocks Na and Ca2+ channels and glutamate receptors (NMDA) SE: Aplastic anemia (1:3000) Acute liver failure (1:10,000) |
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Gabapentin
mechanism use Side Effects |
adjuncive anticonvulsant
used in partial seizures, bipolar, migrane & neuropathic pain (post herpetic neuralgia) Increases GABA effects presynaptically to promote GABA release SE: Sedation, Ataxia, cognitive change, tremor |
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Lamotrigine
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Monotherapy and as adjuncive anticonvulsant
for partial and secondarily generalized tonic-clonics (adults) absence and partial seizures and Lennox-Gastaut syndrome (disorder of childhood characterized by multiple seizure types, mental retardation, and refractoriness to antiseizure medication) blocks Na and glutamate receptors (like phenytoin and carbamazepine) SE: sedation, ataxia, diplopia, headache, steven-johnson's syndrome, DIC |
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Tiagabine
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adjuncive anticonvulsant
partial and tonic-clonic seizures & electroshock seizures blocks GABA transporter (GAT-1)(uptake) SE: sedation, dizziness, flu-like, confusion, ataxia |
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Topiramate
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Monotherapy and adjuncive anticonvulsant
used for partial seizures/epilepsy drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome blocks glutamate (AMPA receptors)--increased GABA effects SE: sedation, ataxia, wt loss, word finding difficulty, acute myopia & glaucoma, renal stones, nervousness |
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Vigabatrin
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adjuncive anticonvulsant
used for partial seizures (rarely) inhibits GABA transaminase SE: irreversible visual dysfunction, psychosis, depression |
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Tx of partial seizures
Drugs of Choice |
simple-localized, consciousness not altered
complex-loss of consciousness DOC: Phenytoin & Carbamazepine Backup: Valproic acid, if pregnant--phenobarbitol Clorazepate dipotassium--adjunct w/ complex partial |
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General-tonic clonic seizures
Drugs of Choice |
General-tonic clonic seizures (Grand Mal)
DOC: Phenytoin, Carbamazepine Backup: Valproic acid, if pregnant--phenobarbitol |
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General Absence Seizures
Drugs of Choice |
DOC:
Ethosuximide Backup: Valproic Acid, Clonazepam (potent, long acting--sedation) reduce the flow of Ca2+ through T-type Ca2+ channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures Lamotrigine |
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General Myoclonic Seizure
Drugs of Choice |
DOC:
Valproic Acid Backup: Clonazepam, Felbamate (liver damage, blood damage) |
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Status Epilepticus
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Status Epilepticus--prolonged seizure of over 20 min of any type
DOC: IV Lorazepam or Diazepam--followed by Phenytoin or Fosphenytoin (IV) or phenobarbitol (IV) |
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Clozapine
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5-HT2A/2C receptor antagonist
atypical antipsychotic drugs with reduced incidence of extrapyramidal side effects SE: Agranulocytosis fatal myocarditis (contraindicated in patients with severe heart disease) lowers the seizure threshold sedation, hypotension, increased liver enzyme levels, hypersalivation, respiratory arrest, weight gain, and changes in both the ECG and the EEG |
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Neuroleptic Malignant Syndrome
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catatonia-like state manifested by extrapyramidal signs, blood pressure changes, altered consciousness, and hyperpyrexia; it is an uncommon but serious complication of neuroleptic treatment. Muscle rigidity, involuntary movements, confusion, dysarthria, and dysphagia are accompanied by pallor, cardiovascular instability, fever, pulmonary congestion, and diaphoresis and may result in stupor, coma, and death
Treatment includes controlling fever and providing fluid support. Dopamine agonists such as Bromocriptine & Amantadine can be used. Dantrolene to control rigidity |
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Aripiprazole
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Dopamine stabilizer.
partial agonist at the dopamine D2 and serotonin 5-HT1 receptors and an antagonist at 5-HT2 receptors, it is effective against positive and negative symptoms of schizophrenia. It functions as an antagonist or agonist, depending on the dopaminergic activity at the dopamine receptors. This may help decrease side effects. More activating than sedating. Lower risk of prolonged QT, extrapyramidal symptoms, weight gain and hyperprolactinemia |
