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49 Cards in this Set

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Two major kinds of Ion channels in the brain?
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
Voltage regulated ion channels in CNS
Na+ channels in axonal membranes

Ca2+ channels in presynaptic membranes

blocked by some anesthetics and anti-convulsants
Neurotransmitter regulated ion channels
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
Glutamic Acid
Excitatory via influx of cations (direct coupling and G-protein linked)
NDMA receptor (consolidation of long term memory)--potential target for ketamine and PCP
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
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).
DA action on pituitary D2 receptors
dopamine inhibits prolactin secretion from the pituitary

D2 blockers (e.g. Haloperidol)--galactorrea
DA hypothesis of schizophrenia
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.
Parkinson's
loss of dopaminergic neurons in substantia nigra (lewy bodies--intracytoplasmic easinophilic inclusions--contain alpha synuclein)

loss of extrapyramidal nigra-striatal pathway
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)
5HT-1
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
5-HT-2
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
5-HT-3
5-HT-3 coupled to ligand gated ion channel--causes nausea and vomiting via area postrema. Peripheral stimulation--pain
5-HT-4
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)
Benzodiazepine

mechanism of action
potentiate GABA by increasing FREQUENCY of Cl- channel opening
Barbiturates

mechanism

uses
Barbiturates increase the DURATION of Cl- channel opening

used for seizure tx (phenobarbital) and anesthetic (IV--short acting Thipental)
Side effects and contraindications of Barbiturates
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
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
Benzodiazapine antidote
Flumezanil (IV) shorter T 1/2 than BZ
BZ receptor antagonist

also used to facilitate recovery from anethesia
Benzodiazepine

extrahepatic BZ's?
"Out The Liver"
Oxazepam
Temezepam (sleep)
Lorazepam (IV--status epilepticus, preop sedation)

extrahepatic metabolism--do not form active metabolites
Alprazolam
BZD
Anxiety, panic, phobias
Diazepam
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)
Zolpidem
Zaleplon
non BZD used in sleep disorders (Ambien)
act on BZ1 receptor--reversed by Flumazenil
Midazolam
shortest acting BZD
preop sedation, anesthesia
anterograde amnesia (good for colonoscopy)
Buspirone
for generalized anxiety--takes 1-2 weeks to work

No effects on GABA--possibly partial agonist of 5HT1a
Non-sedating, no additive CNS depression
Tx of Barbiturate OD
alkalinization of urine as barbiturates are weak acids
Methanol metabolites
Methanol via alcohol dehydrogenase--formaldehyde--via aldehyde dehydrogenase--formic acid (blindness, respiratory failure, severe anion gap metabolic acidosis)
Fomepizole
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.
ethylene glycol metabolites
(antifreeze) ethylene glygol via alcohol dehydrogenase--glycoaldehyde-via aldehyde dehydrogenase--glycolic acid--oxalic acid

CNS depression
metabolic acidosis
nephrotoxicity
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)
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
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
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
Valproic Acid
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
Divalproex Sodium
"Depakote"
1:1 Valproic Acid: Valproate Sodium--absorbed more slowly
Felbamate
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)
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
Lamotrigine
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
Tiagabine
adjuncive anticonvulsant

partial and tonic-clonic seizures & electroshock seizures

blocks GABA transporter (GAT-1)(uptake)

SE: sedation, dizziness, flu-like, confusion, ataxia
Topiramate
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
Vigabatrin
adjuncive anticonvulsant
used for partial seizures (rarely)

inhibits GABA transaminase

SE: irreversible visual dysfunction, psychosis, depression
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
General-tonic clonic seizures
Drugs of Choice
General-tonic clonic seizures (Grand Mal)
DOC: Phenytoin, Carbamazepine
Backup: Valproic acid, if pregnant--phenobarbitol
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
General Myoclonic Seizure
Drugs of Choice
DOC:
Valproic Acid
Backup: Clonazepam, Felbamate (liver damage, blood damage)
Status Epilepticus
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)
Clozapine
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
Neuroleptic Malignant Syndrome
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
Aripiprazole
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