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74 Cards in this Set

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What are the AD's which belong to Classes?
TCA - tertiary amine => IMIPRAMINE (NE/5HT UPTAKE)
TCA - Secondary Amine => DESIPRAMINE (NE UPTAKE)
TCA-Like
SSRI =>FLUOXETINE (5HT UPTAKE)
MAOI => PHENELZINE, TRANYLCYPROMINE (IRREVERSIBLE INHIBITION OF MAO)
Three Mechanisms for increasing NE and/or 5HT in the synapse?
-Blockade of neuronal reuptake
-blockade of intraneuronal metabolism by MAO
-Blockade of negative feedback receptors on neuron (autoreceptors).
Describe blockade of neuronal reuptake?
Presynaptic transporter pumps the transmitters back into the neuron thereby decrease it's concentration in the synapse. Blockade of this will incr the transmitter conc!!!
What is meant by increased release by the NE/5HT neuron?
NE taken back into the cytoplasm is either destroyed by MAO-A in the mitochondria or its stored in storage vesicles for re-use. MOAI's cause increased cytoplasmic conc of NE/5HT then these transmitters flow down their conc gradient using the same transporter/pump which usually removes them from the synapse but in reverse.
Describe the negative feedback mechanism for NE?
High NE conc in the synapse causes stimulations of presynaptic alpha2-adrenoceptors which partially inhibit further NE release. Antagonist of this receptor amplifies the amount of NE relased for any given frequency of neuronal stimulation. THERE ARE NO ANTIDEPRESSANTS WHICH ACT BY BLOCKING INHIBITORY PRESYNAPTIC 5HT RECEPTORS, THOUGH THEY EXIST (THE RECEPTORS).
What are the AD's which do not belong to a Class?
Mirazapine => a2 adrenoceptor autocepter blockade
Bupropion => DA uptake?
Venlafaxine => 5HT uptake (low doses,75mg) plus NE uptake (high doses,>300mg)
Which drugs selectively block the reuptake of NE?
Secondary amine TCAs-(Desipramine)
Which drugs nonselectively block the reuptake of both 5HT and NE?
Tertiary amine TCA's -(Imipramine)
What is IC50? What does a high 5HT:NE ratio mean?
Inhibition concentration of a drug needed to cause 50% inhibition. A high 5HT:NE ratio means the drug is more selective for NE. e.g. 5HT = 100nM, NE = 1nM is the conc required to give IC50.
How do MOAI's work?
Iproniazid was first MOAI discovered by accident, used to treat TB. "psychic energizer". MAOI's bind irreversibly to active sites on MAO.
Whats the Clinical Efficacy of AD's?
No established differences in efficacy among the different types of AD's. 4 weeks or more must pass before the drug exerts it MAXIMAL therapeutic benefits. Overall efficacy of AD's is about 65-75% of patients responding to an extent that is clinically significant.
What are the General Side Effects of TCA's?
Due to blockage of H1 hisamine, Muscarinic, and a1 adrenergic receptors.
*Muscarinic*: dry mouth, urinary retention, blurred vision, constipation, memory impairment, sexual dysfunction.
*H1 Histaminergic* sedation, weight gain.
*a1 adrenergic* orthostatic hypotension, sexual dysfunction.
What are the Cardiovascular S/E due to TCA's?
-Tachycardia due to anticholinergic actions.
-ECG changes: inversion or flattening of T waves, incr in PR interval
-increased tendency to develop AV block in pt's with preexisting cardiac disease.
-overdosage => arrhythmias
What are the CNS S/E due to TCA's?
-fine rapid tremors of extremities
-initiation of manic episodes in bipolars
-Lower seizure threshold. can increase tonic clonic seizures.
What about overdosages with TCA's?
daily dose is 75-250mg.
2000mg = death
1000mg = severe intoxication.
What are the S/E of MAOI's?
-Hepatic toxicity (only with Phenylzine)
-CNS effects: tremors, insomnia, agitation, precipitation of hypomanic or manic rxn in bipolars.
-CV: orthostatic hypotension due to stimulation of a2 adrenoceptors, or accumulation of the false transmitter "octopamine" in peripheral sympathetic neurons.
-food/drug interactions: "cheese" rxn. eating foods rich in amines => hypertensive crisis.
Uses for Benzodiazepines?
Used to treat generalized anxiety disorder.
Uses for Clomipramine (a TCA)?
Used to treat OCD. SSRI's are also effective.
Beta blockers uses in anxiety?
Used in performance related anxiety.
Uses for SSRI's
Useful in PTSD in non-combat vets as well as social anxiety disorder.
How is GAD treated?
Treated w/ BZ's, Buspirone, Venlafaxine, or SSRI's. BZ are rapidly acting, effective, relatively safe but have withdrawal risks. Buspirone is also effective in GAD tx but w/ slower onset of action.
Uses for Buspirone?
Used to treat GAD. It's a azapirone, not a BZ.
Whats the structure of Benzodiazepine?
Benzene ring fused with a 7 membered diazepine ring with a 5 aryl substituent.
Name the Benzodiazepines?
-alprazolam
-clonazepam
-diazepam
-flurazepam
-oxazepam
-triazolam
Name sites of action of BZ's?
BZ's are CNS depressants with more potent effects at polysynaptic connections. CNS sites of action probably include brain stem (recticular activating system), diencephalon (limbic system), and cerebral cortex.
Actions of BZ's?
Causes CNS depression due to:
-sedative hypnotic properties(decr duration of stage 1, 3/4 and REM and latency to persistent sleep while increasing stage 2 and total sleep time).
-anti-anxiety effects
-anti-convulsant properties
-Muscle relaxant effects (spinal cord level).
MOA of BZ's?
BZ's enhance GABA transmission at post synaptic membrane receptor site by potentiating GABA's effect at GABAa receptors, not via direct GABA agonist. GABAa receptor is a ligand gated ion channel in pentameric assembly. GABA binds at alpha-beta subunit junction and BZ's bind at alpha-gamma junction. GABAa+BZ => regulatory process which facilitates binding of GABA to GABAa!!!!. BZ's increase probability of channel opening so more channels open.
What are the subtypes of GABAa receptors and their effects when bound with BZ?
a1 isoform => important for sedative effect

a2,a3 isoforms => important for anxiolytic effects.

BZ receptors according to subtypes: BZI (a1 subtype) and BZII (a2,a3, or a5).

*BZ's currently used clinically do not differentiate b/w subtypes of BZ receptors nor does Eszopiclone.
What are non-BZ "Z" drugs?
-Zolpidem
-Zaleplon
-Eszopiclone

They act at GABAa receptor also.
BZ receptor agonists, less abuse potential, mild S/E, little effect on sleep stages, no alcohol potentiation. these are sedatives, not anxiolytics
Describe BZ Pharmacokinetics: rate of absorption?
determines onset of action and is mainly determined by lipid solubility. Diazepam has the highest!!
Describe BZ Pharmackoinetics: duration of action?
For single dose, determined by the rate and extent of drug distribution. Diazepam is lipophilic and rapidly and extensively distributed throughout the tissues, so it has a short duration of action.
For repeated doses, duration is determined by Half Life.

Triazolam 2.7-4.5 hrs
Oxazepam 3-21 hrs
Alprazolam 7-15 hrs
Clonazepam 20-40 hrs
Diazepam 20-90 hrs
Flurazepam 50-100 hrs
Describe the Metabolism of BZ's?
Primarily metabolized in the liver by oxidative or conjugation rxns. Aging doesn't effect conjugation but it decr. oxidation. Oxazepam is metabolized via conjugation.
What are the S/E's of BZ's?
Sedation, dizziness, uncoordination, paradoxical agitation, impairment of cognitive function. They have minimal suicide potential. They have minimal capacity to induce hepatic enzymes and little organ toxicity.
Withdrawal rxn of BZ's?
occurs at clinically accepted doses, frequently encountered in pt's taking high doses or using longer than 8 mths. Symptoms = flu like: cramps, abdominal pain, diarrhea. Seizures with short half life compounds: Triazolam 2.7-4.5 hrs; Oxazepam 3-21 hrs, Alprazolam 7-15 hrs. PREVENT BY TAPERING OFF THE DOSE!!!
What is Flumazenil?
Benzodiazepine Antagonist
What does Flumazenil do?
-blocks BZ receptor.
-Uses limited: BZ overdosage.
Has very short half life, problem!!
What is Buspirone?
A Non Benzodiazepine Anti Anxiety Agent.
What does Buspirone do?
MOA: direct activation of serotonin receptors (5HT1a)
-slower onset than BZ's
-minimal withdrawal probs
-S/E's: dizziness and nausea.
What drugs are used to treat Panic disorders?
TCA's, MAOI's,and SSRI's represent the standard tx for PD. BZ's help minimize anticipatory anxiety but its ineffective against the condition itself.
What do BZ's do for Panic Disorders?
BZ's help minimize anticipatory anxiety but its ineffective against the condition itself. high potency BZ's (Alprazolam, Clonazepam) are used; there's too much sedation w/ lower potency drugs. Doses are higher for PD than used for GAD. WARNING: increased risk of seizures/severe withdrawal rxn when quitting high doses of Alprazolam.
What do TCA's, MOAI's, and SSRI's do for PD's?
Demonstrated efficacy in PD tx. Necessary to use the same doses for the usual periods of time in order to obtain effective control of symptoms of PD. Same S/E profiles and dietary limitations (MAOI's) apply.
How is OCD treated?
Clomipramine, chloride derivative of imipramine is effective in OCD tx. SSRI's are also effective in OCD tx. Current approved SSRI's for OCD are Fluoxetine, FLUVOXAMINE, Paroxetine, & Sertraline
Clomipramine MOA?
Has NE reuptake blocking effects but it is most distinctive among TCA's for being a very potent inhibitor of serotonin reuptake. Serotonin reuptake inhibition seems necessary for efficacy in OCD!! Desipramine is ineffective.
How is PTSD treated?
-no evidence for any drug having efficacy in PTSD in combat veterans.
-SSRI's have efficacy in PTSD, especially women w/ sexual abuse.
Treatment of Social Anxiety Disorder?
SSRI's are effective. TCA's are NOT!!!
Define Neuroleptic? and Largactyl?
Neuroleptic=affecting the nervous system.
Largactyl=large # of actions.
What are the "typical Antipsychotics?"
-Chlorpromazine = Low potency
-Haloperidol = High potency
*Both are D2 antagonist.

These may improve positive symptoms better than negative symptoms.
What are the Atypical antipsychotics?
-Clozapine=D2/5HT antagonist
-Risperidone=D2/5HT antagonist
-Olanzapine=D2/5HT antagonist
-Aripiprazole=D2 partial agonist/5HT antagonist.

Have good efficacy(better on negative symptoms) w less incidence of EPS or Tardive Dyskinesia.
What's the deal with Atypical antipsychotics?
May be superior in efficacy to that of typical drugs. They work in neuroleptic resistant patients when typical drugs don't plus they have greater effect on negative symptoms, cognitive function and disorganized behavior seen with typical antipsychotics.
Criteria for Atypical Neuroleptics?
CLINICAL
-antipsychotic efficacy
-low likelihood of extrapyramidal side effects (Involuntary movements (tardive dyskinesia),Tremors and rigidity (Parkinsonism),Body restlessness (akathisia),Muscle contractions (acute dystonia))
-no long term tardive dyskinesias
-no to sm incr in plasma prolactin.
-efficacy on negative symptoms.
PRECLINICAL
-greater potency in blocking 5HT than D2 receptors. So it has a low 5HT/D2 ratio.
Efficacy of neuroleptics? Usefulness in prophylaxis?
-In tx of schizophrenia, antipsychotics were superior 89% of the time. 15-30% of pts were neuroleptic resistant pt's.
-They are useful in prophylaxis = 58% relapse on placebo vs. 16% on drug.
What are the positive and negative symptoms in Schizophrenia?
Positive: Hallucinations, Delusions, Conceptual disorganization in Speech and Behavior, agitation.

Negative: Social/emotional withdrawal, blunted affect, Poverty of speech, Anhedonia (lack of pleasure), Avolition(lack of initiation goal directed behavior).
How is Dopamine involved in Schizophrenia?
Excessive dopaminergic activity in the limbic system produces psychotic symptoms(+ symptoms) whereas negative symptoms and cognitive defects are related to reduced dopaminergic activity in prefrontal cortex. Thus, Prefrontal may be site of action of atypical drugs to improve cognitive dysfunction and negative symptoms.
Where are Dopamine systems in the Brain?
DA containing neurons arise in midbrain and project to:
-Basal ganglia [ESP's] (nigrostriatal pathway; motor function)
-limbic system [+symp] (mesolimbic projections; arousal; motivation; reward)
-frontal cortex [-symp] (mesocortical projections; cognition; motivation).

DA system within hypthalamus links hypothalamus => pituitary gland(tubero-infundibular pathway; inhibition of prolactin secretion)
Aripiprazole?
*note: Ratio of affinities for 5HT:D2 receptors separates typical from atypical drugs with exception of Aripiprazole!!

Aripiprazole is a partial D2 agonist. it acts as a D2 agonist in absence of DA. at sufficient concentration, blocks the agonist effect of DA. (partial agonist only exhibit partial physiological response compared to a full agonist)
How are DA and 5HT receptors related?
-D2 receptor-positive correlation b/w potencies at D2 receptor and clinical doses of antipsychotics.

-5HT nerves inhibit firing rate of DA-nergic cell bodies and release of DA in Striatum and cortex. These effects are mediated by 5HT2 receptors so antagonist here would increase release of DA in these areas.

-Agonism of 5HT1a receptors can increase DA release in Accumbens and cortex by inhibiting 5HT releasing neuron.
What is depolarization inactivation?
a decrease in firing rate of dopaminergic neurons due to their over-excitation.
What does chronic treatment w/ typical antipsychotics do?
Decreases dopaminergic cell firing in both nigrostriatal(motor function) and mesocortical(cognition; motivation) pathways.
What does chronic treatment w/ atypical antipsychotics do?
Selectively decreases dopaminergic cell firing in mesolimbic pathway(arousal; motivation;reward); no decrease in nigrostriatal or mesocortical pathway.

Atypicals cause greater increase of DA release in prefrontal cortex than in striatum. Not seen with typicals.
So how do Atypicals work?
-Decrease in limbic dopaminergic activity may underlie therapeutic effects.
-Decrease in striatal dopaminergic activity may underlie the production of extrapyramidal symptoms(typicals).
-Lack of decrease of mesocortical DA neurons could underlie the beneficial effects on cognition and negative symptoms(atypicals).
Autonomic side effects of Typicals?
-antiadrenergic(a1,a2): sedation, orthostatic hypotension.
-anticholinergic: dry mouth,blurred vision, urinary retention, sinus tachycardia, constipation.
-antihistamine(H1): sedation, weight gain.
-General Toxicity: skin rxns,jaundice,ventricular arrhythmias,agranulocytosis.
Neuroendocrine side effects of Typicals?
Due to antagonism in hypothalamic/pituitary tract(tubero-infundibular pathway): increased prolactin leading to gynecomastia, galactorrhea, or amenorrhea; weight gain.
Neurologic/EPS side effects of Typicals?
Due to DA antagonism in basal ganglia. Symptoms:
-acute dystonia: muscle spasma
-Parkinsonism: rigidity,tremor,shuffling gait.
-Akathisia: motor restlessness.
-Tardive dyskinesias:oral-facial dyskinesias.
How do you select Typical antipsychotics based on S/E's?
Low potency(Chlorpromazine) vs high potency(haloperidol): Low potency drugs are more anticholinergic, more sedative, and more likely to produce orthostatic hypotension. High potency drugs are more likely to produce EPS but less likely to cause autonomic S/E's.
What are the Atypicals autonomic S/E's?
Similar autonomic profile as typicals but:
-Risperidone and Quetiapine aren't anticholinergic.
-Olanzapine is very very antihistaminic!!(weight gain)
What are the Atypicals Neurologic/EPS S/E's?
Much less incidence. No dystonia, some akathesia.
-Risperidone: incidence of EPS is dose related.
-no incidence of tardive dyskinesia. Clozapine can actually decrease tardive dyskinesias in pts who develop it after taking typicals.
What are the Atypicals neuroendocrine S/E's?
Increased prolactin not seen with clozapine, olanzapine, or quetiapine.

Possible with risperidone!!!
What is Clozapine's (atypical) special consideration?
can cause induced granulocytopenia and/or agranulocytosis but it's not dose related.

-incidence is higher w/ atypicals than with typicals.
-80% of cases occur within first 18 weeks.
-if WBC<2000, discontinue!!!
What are other S/E's of Atypicals?
-Greater weight gain than with typicals. (5HT2 and H1 blockade).
-Development of type II diabetes and hyperlipidermia.
What is Neuroleptic Malignant Syndrome(NMS)?
Idiosyncratic drug reaction: Pertaining to an abnormal susceptibility to some drug or other agent, peculiar to the individual.
-hyperthermia
-severe EPS
-Autonomic dysfunction
-clouded consciousness,leukocytosis,elevated CPK >300.
-Mortality: as high as 30%
-treatment: dantrolene(sk muscle relaxant); hydration.
-Also use Bromocriptine
What is used to treat Bipolar Disorder?
Lithium, typically given as lithium carbonate.
-effective as a antimanic agent, also for prophylaxis of bipolar disorder. i.e. it reduces the severity of mood swings.
-Need plasma concentration of 1mM to work.
What are S/E's of Li?
Li is excreted by kidneys.
-It has a low therapeutic index meaning it's toxic at close to therapeutic levels.
-CNS effects: tremor,fatigue/drowsiness,ataxia, and cognitive deficits. rare but more serious S/E's are hallucinations,encephalopathy,delirium, and coma.
-Renal effects: polyuria and polydipsia (due to ADH interference). very common.
-Endocrine: direct antithyroid effects => hypothyroidism
-Pregnancy/nursing: increased incidence of CV abnormalities in fetus, secreted in milk.
-CV: nonspecific T-wave change,dysrhythmias,SA block,tachycardia.
-Hematologic: Leukocytosis(benign).
-*weight gain* leads to pt noncompliance!!!
What are lithium precautions?
Patient should have adequate renal function as evidenced by elevated creatinine levels or BUN levels, and they should drink plenty of fluids to prevent dehydration; excessive sodium loss can produce lithium toxicity (avoid excessive sweating). Anything causing hyponatremia increases levels and could cause toxicity; toxicity is closely related to serum levels and can occur at therapeutic doses.
Whats the MOA of Lithium?
Common effect is to inhibit or dampen processes that are overactive but can cause different behavioral effects.
-overactive excitatory pathways
-overactive inhibitory pathways

-MOA: inhibits coupling of G-protein coupled receptors to G-proteins by competing with Mg for low affinity binding sites on G-protein. Binding of these sites is essential for Guanine nucleotide exchange!!!

-**Inhibits enzymes through competition for Mg binding site. Inositol phosphatases inhibition depends on concentration of enzyme substrate, i.e. greater the concentration of substrate, the greater the inhibition of IP. This accounts for selective effects of Li in overactive pathways. Also inhibits glycogen synthase kinase-3 by the same mechanism.

-Also inhibits agonist mediated activation of adenylyl cyclase to cause less stimulation of cyclic AMP.