Module7_Dr. Frazer_Neuro

Front 1

What are the AD's which belong to Classes?

Back 1

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)

Front 2

Three Mechanisms for increasing NE and/or 5HT in the synapse?

Back 2

-Blockade of neuronal reuptake
-blockade of intraneuronal metabolism by MAO
-Blockade of negative feedback receptors on neuron (autoreceptors).

Front 3

Describe blockade of neuronal reuptake?

Back 3

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!!!

Front 4

What is meant by increased release by the NE/5HT neuron?

Back 4

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.

Front 5

Describe the negative feedback mechanism for NE?

Back 5

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).

Front 6

What are the AD's which do not belong to a Class?

Back 6

Mirazapine => a2 adrenoceptor autocepter blockade
Bupropion => DA uptake?
Venlafaxine => 5HT uptake (low doses,75mg) plus NE uptake (high doses,>300mg)

Front 7

Which drugs selectively block the reuptake of NE?

Back 7

Secondary amine TCAs-(Desipramine)

Front 8

Which drugs nonselectively block the reuptake of both 5HT and NE?

Back 8

Tertiary amine TCA's -(Imipramine)

Front 9

What is IC50? What does a high 5HT:NE ratio mean?

Back 9

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.

Front 10

How do MOAI's work?

Back 10

Iproniazid was first MOAI discovered by accident, used to treat TB. "psychic energizer". MAOI's bind irreversibly to active sites on MAO.

Front 11

Whats the Clinical Efficacy of AD's?

Back 11

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.

Front 12

What are the General Side Effects of TCA's?

Back 12

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.

Front 13

What are the Cardiovascular S/E due to TCA's?

Back 13

-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

Front 14

What are the CNS S/E due to TCA's?

Back 14

-fine rapid tremors of extremities
-initiation of manic episodes in bipolars
-Lower seizure threshold. can increase tonic clonic seizures.

Front 15

What about overdosages with TCA's?

Back 15

daily dose is 75-250mg.
2000mg = death
1000mg = severe intoxication.

Front 16

What are the S/E of MAOI's?

Back 16

-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.

Front 17

Uses for Benzodiazepines?

Back 17

Used to treat generalized anxiety disorder.

Front 18

Uses for Clomipramine (a TCA)?

Back 18

Used to treat OCD. SSRI's are also effective.

Front 19

Beta blockers uses in anxiety?

Back 19

Used in performance related anxiety.

Front 20

Uses for SSRI's

Back 20

Useful in PTSD in non-combat vets as well as social anxiety disorder.

Front 21

How is GAD treated?

Back 21

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.

Front 22

Uses for Buspirone?

Back 22

Used to treat GAD. It's a azapirone, not a BZ.

Front 23

Whats the structure of Benzodiazepine?

Back 23

Benzene ring fused with a 7 membered diazepine ring with a 5 aryl substituent.

Front 24

Name the Benzodiazepines?

Back 24

-alprazolam
-clonazepam
-diazepam
-flurazepam
-oxazepam
-triazolam

Front 25

Name sites of action of BZ's?

Back 25

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.

Front 26

Actions of BZ's?

Back 26

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).

Front 27

MOA of BZ's?

Back 27

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.

Front 28

What are the subtypes of GABAa receptors and their effects when bound with BZ?

Back 28

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.

Front 29

What are non-BZ "Z" drugs?

Back 29

-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

Front 30

Describe BZ Pharmacokinetics: rate of absorption?

Back 30

determines onset of action and is mainly determined by lipid solubility. Diazepam has the highest!!

Front 31

Describe BZ Pharmackoinetics: duration of action?

Back 31

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

Front 32

Describe the Metabolism of BZ's?

Back 32

Primarily metabolized in the liver by oxidative or conjugation rxns. Aging doesn't effect conjugation but it decr. oxidation. Oxazepam is metabolized via conjugation.

Front 33

What are the S/E's of BZ's?

Back 33

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.

Front 34

Withdrawal rxn of BZ's?

Back 34

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!!!

Front 35

What is Flumazenil?

Back 35

Benzodiazepine Antagonist

Front 36

What does Flumazenil do?

Back 36

-blocks BZ receptor.
-Uses limited: BZ overdosage.
Has very short half life, problem!!

Front 37

What is Buspirone?

Back 37

A Non Benzodiazepine Anti Anxiety Agent.

Front 38

What does Buspirone do?

Back 38

MOA: direct activation of serotonin receptors (5HT1a)
-slower onset than BZ's
-minimal withdrawal probs
-S/E's: dizziness and nausea.

Front 39

What drugs are used to treat Panic disorders?

Back 39

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.

Front 40

What do BZ's do for Panic Disorders?

Back 40

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.

Front 41

What do TCA's, MOAI's, and SSRI's do for PD's?

Back 41

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.

Front 42

How is OCD treated?

Back 42

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

Front 43

Clomipramine MOA?

Back 43

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.

Front 44

How is PTSD treated?

Back 44

-no evidence for any drug having efficacy in PTSD in combat veterans.
-SSRI's have efficacy in PTSD, especially women w/ sexual abuse.

Front 45

Treatment of Social Anxiety Disorder?

Back 45

SSRI's are effective. TCA's are NOT!!!

Front 46

Define Neuroleptic? and Largactyl?

Back 46

Neuroleptic=affecting the nervous system.
Largactyl=large # of actions.

Front 47

What are the "typical Antipsychotics?"

Back 47

-Chlorpromazine = Low potency
-Haloperidol = High potency
*Both are D2 antagonist.

These may improve positive symptoms better than negative symptoms.

Front 48

What are the Atypical antipsychotics?

Back 48

-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.

Front 49

What's the deal with Atypical antipsychotics?

Back 49

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.

Front 50

Criteria for Atypical Neuroleptics?

Back 50

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.

Front 51

Efficacy of neuroleptics? Usefulness in prophylaxis?

Back 51

-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.

Front 52

What are the positive and negative symptoms in Schizophrenia?

Back 52

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).

Front 53

How is Dopamine involved in Schizophrenia?

Back 53

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.

Front 54

Where are Dopamine systems in the Brain?

Back 54

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)

Front 55

Aripiprazole?

Back 55

*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)

Front 56

How are DA and 5HT receptors related?

Back 56

-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.

Front 57

What is depolarization inactivation?

Back 57

a decrease in firing rate of dopaminergic neurons due to their over-excitation.

Front 58

What does chronic treatment w/ typical antipsychotics do?

Back 58

Decreases dopaminergic cell firing in both nigrostriatal(motor function) and mesocortical(cognition; motivation) pathways.

Front 59

What does chronic treatment w/ atypical antipsychotics do?

Back 59

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.

Front 60

So how do Atypicals work?

Back 60

-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).

Front 61

Autonomic side effects of Typicals?

Back 61

-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.

Front 62

Neuroendocrine side effects of Typicals?

Back 62

Due to antagonism in hypothalamic/pituitary tract(tubero-infundibular pathway): increased prolactin leading to gynecomastia, galactorrhea, or amenorrhea; weight gain.

Front 63

Neurologic/EPS side effects of Typicals?

Back 63

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.

Front 64

How do you select Typical antipsychotics based on S/E's?

Back 64

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.

Front 65

What are the Atypicals autonomic S/E's?

Back 65

Similar autonomic profile as typicals but:
-Risperidone and Quetiapine aren't anticholinergic.
-Olanzapine is very very antihistaminic!!(weight gain)

Front 66

What are the Atypicals Neurologic/EPS S/E's?

Back 66

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.

Front 67

What are the Atypicals neuroendocrine S/E's?

Back 67

Increased prolactin not seen with clozapine, olanzapine, or quetiapine.

Possible with risperidone!!!

Front 68

What is Clozapine's (atypical) special consideration?

Back 68

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!!!

Front 69

What are other S/E's of Atypicals?

Back 69

-Greater weight gain than with typicals. (5HT2 and H1 blockade).
-Development of type II diabetes and hyperlipidermia.

Front 70

What is Neuroleptic Malignant Syndrome(NMS)?

Back 70

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

Front 71

What is used to treat Bipolar Disorder?

Back 71

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.

Front 72

What are S/E's of Li?

Back 72

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!!!

Front 73

What are lithium precautions?

Back 73

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.

Front 74

Whats the MOA of Lithium?

Back 74

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.