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122 Cards in this Set

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what are the common initial complaints of depression?
fatigue
headache
insomnia
GI disturbances
anorexia
weight loss
chronic pain
loss of interest
inactivity
loss of sexual desire
general feeling of despondency
what are the three simple classifications of depression?
reactive/secondary depression
major depressive
bipolar affective
what are the diagnostic features of reactive depression?
aka secondary depression

commonly presents as depression, anxiety, bodily complaints, tension, guilt

caused by loss (adverse life events, physical illness)
common association with drugs and other psychiatric disorders

may respond spontaneously
what type of depression accounts for more than 60% of all depressions?
reactive/secondary depression
what are the diagnostic features of major depressive disorders?
a precipitating life event is not adequate to explain the degree of depression

unresponsive to changes in life

may occur at any age

biologically determined

commonly presents as abnormal sleep rhythms, decreased motor activity, decreased libido, decreased appetite
what treatments are usually effective in major depressive disorders?
antidepressants
electroconvulsive therapy
what are the diagnostic features of bipolar affective disorder?
characterized by cyclic episodes of mania and depression

may be misdiagnosed as major depressive if hypomanic episodes are missed

lithium carbonate stabilizes mood
antipsychotics to treat mania
antidepressants to treat depression
why is it difficult to establish the efficacy of antidepressant drugs?
1) factors inherent in the disease state
- no physiologic msmt of improvement
- high rate of spontaneous remission
- high placebo response
2) need for further studies relating [drug] to efficacy
3) lack of adequate model
why is there a high "noise-to-signal" ratio in experiments dealing with antidepressants?
high rate of spontaneous remission

high placebo response
what is the current animal model for antidepressant drug trials?
put a rat in a tub of water, it gets stiff

if the rat takes longer to get stiff after administration of the antidepressant, then the drug is "good"
what are the therapies for depression?
1) psychotherapy
2) tricyclic antidepressants (TCAD)
3) "second gen" antidepressants
4) MAO inhibitors (old)
5) electroconvulsive therapy (ECT)
what is the best treatment for depression?
electroconvulsive therapy

the "gold standard" for treatment of depression
what are the drawbacks to ECT as a treatment for depression?
it is expensive and not likely to be a permanent solution
how is ECT done?
pt is given a neuromuscular blocker which paralyzes them

the pt is then given an anesthetic and a seizure is electrically induced

seizure lasts > 30 sec
what type of drug is amitriptyline?
tertiary amine tricyclic antidepressants

NE, 5-HT reuptake inhibitor

antidepressant
what are the side effects of amitriptyline?
strong sedation
strong anti-muscarinic effects
strong hypotensive effects
strong cardiac effects
what is amitriptyline used to treat?
depression

treatment for chronic pain of a neural origin (diabetic neuropathy)
what is required for an antidepressant drug to be good for treating neurologic pain?
blockade of reuptake of norepinephrine AND serotonin

**must be both**
what type of drug is nortriptyline?
secondary amine tricyclic antidepressant

selective norepinephrine-reuptake inhibitor

antidepressant
what drug is a metabolite of amitriptyline?
nortriptyline

when a methyl group is removed from the nitrogen in amitriptyline (occurs in the liver), nortriptyline is produced
what does nortriptyline block the uptake of?
norepinephrine
what are the side effects of nortriptyline?
some sedation
some antimuscarinic effects
some hypotensive effects
some cardiac effects

decreased intensity compared to amitriptyline
what type of drug is fluoxetine?
selective serotonin-reuptake inhibitor

antidepressant
what is the advantage of selective serotonin-reuptake inhibitors, compared to tricyclic antidepressants?
fewer side effects

virtually no sedation, anti-muscarinic effects, hypotensive effects, or cardiac effects
what type of drug is citalopram?
selective serotonin-reuptake inhibitor

antidepressant
what type of drug is paroxetine?
selective serotonin-reuptake inhibitors

antidepressant
what type of drug is sertraline?
selective serotonin-reuptake inhibitors

antidepressant
uptake of what is blocked by fluoxetine?
serotonin
uptake of what is blocked by citalopram?
serotonin
uptake of what is blocked by paroxetine?
serotonin
what type of drug is duloxetine?
serotonin/norepinephrine-reuptake inhibitor

antidepressant
what type of drug is venlafaxine?
serotonin/norepinephrine-reuptake inhibitor

antidepressant
uptake of what is blocked by duloxetine?
serotonin

norepinephrine
what conditions is duloxetine used to treat?
depression

neurologic pain
uptake of what is blocked by venlafaxine?
serotonin

norepinephrine
what is the advantage of serotonin/norepinephrine-reuptake inhibitors, compared to tricyclic antidepressants?
fewer side effects

virtually no sedation, anti-muscarinic effects, hypotensive effects, or cardiac effects
what type of drug is bupropion?
atypical antidepressant

unknown mechanism of action
what is bupropion used to treat?
smoking cessation (3-month treatment period)
what are the side effects of bupropion?
seizures at doses greater than 450mg

**doses must be limited**
what is the generic name for prozac?
fluoxetine
what is the generic name for paxil?
paroxetine
what is the generic name for zoloft?
sertraline
what is the generic name for effexor?
venlafaxine
what is the generic name for wellbutrin?
bupropion
what type of drug is mirtazapine?
atypical antidepressant

blocks postsynaptic 5-HT2 receptors
blocks norepinephrine reuptake
what is blocked by mirtazapine?
postsynaptic 5-HT2 receptors

norepinephrine receptors
what is mirtazapine used to treat?
depressed patients with insomnia
what are the side effects of mirtazapine?
strong sedation
what type of drug is trazodone?
atypical antidepressant

serotonin-reuptake inhibitor
what are the side effects of trazodone?
strong sedation
no anti-muscarinic effects
few hypotensive effects
few cardiac effects
what conditions is trazodone used to treat?
insomnia

**strong sedation and no anti-muscarinic effects**
what are the side effects of trazodone?
strong sedation
no anti-muscarinic effects
weak hypotensive effects
no cardiac effects
how long does it take for any antidepressant to take effect?
4-6 weeks

**side effects occur immediately**
why are patients usually discouraged by antidepressant medications?
time to onset of antidepressant effects is 4-6 weeks, however negative side effects begin immediately
how does efficacy compare between antidepressants?
approximately the same
how should an antidepressant drug be chosen for a patient?
efficacy is approximately the same between differing antidepressants

choice is usually made based on which has the side effects the patient best tolerates
what is the cause of drug interactions with tricyclic antidepressants?
since TCAD's block the amine reuptake pump, any drugs that use the reuptake pump (e.g. guanethidine) will not be able to enter neurons
what are the effects of TCAD overdose?
causes arrhythmias
- ventricular tachycardia (>120 bpm)
- bundle branch block
- cardiac arrest

grand mal seizures
what are the side effects of selective serotonin-reuptake inhibitors?
usually limited to nausea and vomiting
headache
sexual dysfunction
what are the side effects of fluoxetine?
AGITATION
RESTLESSNESS
nausea/vomiting
headache
sexual dysfunction
why must fluoxetine always be taken in the morning?
fluoxetine (in particular among the SSRIs) is associated with agitation and restlessness

if it were taken at night, the patient wouldn't be able to sleep
what are the two drugs that are approved by the FDA to treat obsessive compulsive disorder?
fluoxetine

clomipramine
what is the monamine theory of depression?
predicts that the disruption of NE, 5-HT, and DA neurotransmision plays a key role in the development of depression
1) TCADs block reuptake of NE/5-HT
2) ECT causes seizures
3) MAOIs decrease degradation of NE/5-HT
4) SSRIs block reuptake of NE/5-HT
**1-4 all lead to an increase in amine in the synapse
why does it take 4-6 weeks for the onset of antidepressant effects?
Before Tx: NTs are released at pathologically low levels and exert steady-state levels of autoinhibitory feedback

Acute Tx: increased release/duration of NTs in synaptic cleft, which causes stimulation of inhibitory autoreceptors, w/ inc. NT synthesis and inhibition of exocytosis

chronic Tx: constant stimulation of inhibitory autoreceptors causes their down-regulation and overall desensitization of the inhibitory effect
what is the drug of choice for manic-depressive syndrome?
lithium ("mood-stabilizing" drug)

- combined with antipsychotics when mania breaks through
- combined with antidepressants when depression breaks through
therapeutic window for lithium
VERY narrow (1.0-2.0 mEq/L)

**give multiple daily doses of extended release form to avoid a peak in drug concentration**
how is lithium reabsorbed in the kidney?
only in the proximal tubule by the same mechanism governing sodium reabsorption in the proximal tubule
what is the effect of diuretics on patients taking lithium?
increased proximal reabsorption of sodium causes enhanced reabsorption of lithium cuasing toxic levels of lithium to build up
what is the effect of a low-sodium diet on patients taking lithium?
low sodium diet causes extreme reabsorption of sodium from the proximal tubule which causes enhanced reabsorption of lithium which can lead to toxic levels of lithium to build up
what are the uses for lithium?
bipolar disorder
- add antidepressants to tx breakthrough depression
- add antipsychotics to tx breakthrough mania
depression
what is the mechanism of action for lithium?
the mechanism is unknown
what are the side effects of lithium?
SEs at therapeutic doses: nausea, diarrhea, drowsiness, polyuria, polydipsia, weight gain

SEs at high doses: mental confusion, hyperreflexia, gross tremor, seizures leading to death
what is the effect of diuretics on patients taking lithium?
increased proximal reabsorption of sodium causes enhanced reabsorption of lithium cuasing toxic levels of lithium to build up
what is the effect of a low-sodium diet on patients taking lithium?
low sodium diet causes extreme reabsorption of sodium from the proximal tubule which causes enhanced reabsorption of lithium which can lead to toxic levels of lithium to build up
what are the uses for lithium?
bipolar disorder
- add antidepressants to tx breakthrough depression
- add antipsychotics to tx breakthrough mania
depression
what is the mechanism of action for lithium?
the mechanism is unknown
what are the side effects of lithium?
SEs at therapeutic doses: nausea, diarrhea, drowsiness, polyuria, polydipsia, weight gain

SEs at high doses: mental confusion, hyperreflexia, gross tremor, seizures leading to death
why does lithium cause polyuria and polydipsia?
lithium inhibits the action of ADH, so the patient loses excessive water (polyuria) and a subsequent increase in thirst (polydipsia)
opiate vs. opioid
opiate: compound derived from the opium poppy

opiod: synthetic/natural compound with opiate properties, but not derived from the opium poppy
what kind of drug should come to mind when you see a phenanthrene ring?
opiate
what are the strong phenanthrene opioid agonists?
morphine
hydromorphone
oxymorphone
oxycodone
what are the mild/moderate phenanthrene opioid agonists?
codeine
hydrocodone
what are the mixed agonist-antagonist phenanthrene opioids?
nalbuphine
buprenorphine

**stimulate some, but not all receptors**
what are the antagonist phenanthrene opioids?
naloxone
naltrexone
what are the strong phenylheptylamine opioid agonists?
methadone
what are the phenylpiperidines?
opioids

strong agonists: meperidine, fentanyl
mild/moderate agonist: diphenoxylate
what are the morphinens?
opioids

strong agonist: levorphanol
mixed agonist-antagonist: butorphanol
what are benzomorphanes?
opioids

mixed agonist-antagonist: pentazocine
how are opiates metabolized?
mostly converted to polar metabolites by glucuronide conjugation, and then undergo renal excretion
define endorphins
endogenous peptides with opiate-like properties

"endogenous morphine"
what is the precursor protein for beta-endorphins?
pro-opiomelanocortin (POM)
what endorphins are derived from pro-opiomelanocortin (POM)?
beta-endorphins
what is the precursor protein for the enkephalins?
proenkephalin
what endorphins are derived from the precursor protein, proenkephalin?
the enkephalins (met- and leu-enkephalins)
what is the precursor protein for the dynorphins?
prodynorphin
what endorphins are derived from the precursor protein prodynorphin?
the dynorphins (dynorphin A and dynorphin B)
mu receptor
opioid receptor for beta-endorphins from the POM protein

stimulation causes supraspinal and spinal analgesia, euphoria, respiratory depression, and constipation
kappa receptor
opioid receptor for dynorphins (endorphins derived from prodynorphin)

stimulation causes supraspinal and spinal analgesia, dysphoria, and psychotomimetic effects
delta receptor
opioid receptor for enkephalins (endorphins derived from proenkephalin)

stimulation causes supraspinal and spinal analgesia
what is supraspinal analgesia?
analgesia caused by stimulation of receptors in the cortex and limbic area
what causes opioids to have high abuse potential?
stimulation of the mu opioid receptor

(stimulation of kappa receptors causes dysphoria, so it decreases abuse potential)
what opioid receptor is stimulated by morphine?
mu receptor
what opioid receptor is stimulated by methadone?
mu receptor
what opioid receptor is stimulated by fentanyl?
mu receptor
what opioid receptor is stimulated by sufentanil?
mu receptor
what opioid receptor is stimulated by buprenorphine?
partial agonist of mu receptors

antagonist of kappa receptors
what opioid receptors are antagonized by naloxone?
mu, delta, and kappa receptors
what opioid receptors are antagonized by naltrexone?
mu, delta, and kappa receptors
what is the advantage of buprenorphine?
it is a partial agonist with very high affinity for the mu receptor (causes excellent analgesia with low addiction/abuse potential)
if endorphins stimulate multiple opioid receptors, why are they so specific for one receptor type?
they are only released at a certain type of opioid receptor

1) enkephalins stimulate mu and delta receptors, but are only released at delta receptors
2) endorphins stimulate mu and delta receptors, but are only released at mu receptors
3) dynorphins stimulate mu, delta, and kappa receptors, but are only released at kappa receptors
where is the density of opioid receptors highest?
dorsal horn of the spinal cord
nucleus raphe magnus
locus ceruleus
hypothalamic nuclei
thalamic nuclei
what is the effect of opioids binding to receptors?
bind to neurons transmitting pain impulses and alter the progression of the impulse

bind sites in the limbic system, which changes the emotional response to pain (does NOT cause analgesia)
what is the effect of mu-opioid receptor stimulation on presynaptic primary sensory neuron central terminals?
the presynaptic opioid receptor is a G-protein coupled receptor inhibits voltage gated calcium channels in the synaptic nerve terminal, which blocks exocytosis of pain sensory neurotransmitters (CGRP, substance P, glutamate)
what is the effect of mu-opioid receptor stimulation on postsynaptic secondary sensory relay neurons?
the postsynaptic opioid receptor is a G-protein coupled receptor stimulates voltage gated potassium channels in the cell membrane of a post-synaptic axon terminal

stimulates efflux of potassium (increases potassium conductance out of the cell), which causes hyperpolarization of the post-synaptic neuron and blocks action potential transmission
what is the mechanism of developing tolerance and dependence to opiates?
mu opioid receptors inhibit adenylate cyclase and stimulate a potassium channel

with acute administration of opiates, conversion of ATP to cAMP is inhibited thereby inhibiting PKA, and then blocking activation of CREB (a transcription factor responsible for transcription of adenylate cyclase) and activation of a sodium channel

with chronic administration of opiates, CREB and subsequently adenylate cyclase transcription is up-regulated, so the same dose of morphine cannot inhibit all of the adenylate cyclase molecules; cAMP levels return to nearly normal, activating PKA and subsequently the sodium channels allowing for easier depolarization
what is the theory behind patient-controlled analgesia (PCA) pumps?
gives patients control over when they receive more pain medication, so they have less fear about the pain returning; this decreases the total amount of pain-killers the patient needs and increases the efficacy because the drug is given before the pain returns
what are the CNS effects of opiates?
analgesia
euphoria
sedation
respiratory depression
cough suppression
miosis
what are the peripheral effects of opiates?
1) increases tone of GI tract, but decreases peristalsis (causes constipation)
2) increases tone of bronchial tube smooth muscle (induces asthma attack in an asthmatic)
3) increases smooth muscle of ureters, bile duct, etc (causes more pain if pt has gall/kidney stones)
why do opiates causes paradoxical increase in pain in patients with kidney/gall stones?
cause contraction of smooth muscle in the ureters and/or bile duct, which causes squeezing of the stone and more pain

Solutions: increase the narcotic dose or use ketorolac (an NSAID; doesn't inc. smooth muscle tone)
what is the major drawback of opiates?
respiratory depression
what receptors mediate the cough suppression caused by opiates?
opiate and non-opiate receptors
what is indicated by a patient in a coma with miosis (pupillary constriction)?
opiate overdose