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October 19 Norepinephrine and Dopamine

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Title: October 19 Norepinephrine and Dopamine


1
  • October 19 -Norepinephrine and Dopamine
  • Catecholamines
  • Norepinephrine, epinephrine and dopamine
  • Share certain stages of synthesis pathway
  • Similar chemical structure
  • Share certain breakdown enzymes
  • Drugs often act on all 3
  • Norepinephrine both CNS and Sympathetic Nervous
    System
  • Dopamine mostly CNS
  • Epinephrine (adrenalin) mostly PNS also made
    by adrenal gland

2
II. Synthesis Tyrosine (from food) ----1----?
dopa 1 tyrosine hydroxylase rate limiting
enzyme Dopa ----2----?dopamine 2 dopamine
decarboxylase Dopamine ----3----?
norepinephrine 3 dopamine beta-oxidase Norepine
phrine ----4----? epinephrine 4
phenylethanolamine-N-methyl-transferase (PNMT)
3
  • II. Synthesis
  • Presence of a specific set of enzymes determines
    which neurotransmitter is made in neuron
  • Cells in adrenal gland have all 4 enzymes and
    make epinephrine as hormone
  • All 3 neurotransmitters share tyrosine
    hydroxylase as rate limiting step

4
  • III. Termination of action and degradation of NE
    and DA
  • Activity terminated primarily by reuptake into
    neurons or glia
  • Following reuptake, breakdown inside neurons or
    glia is by monoamine oxidase (MAO)
  • By-products are metabolized and excreted
  • NE is broken down into vanillylmandelic acid
    (VMA) and MHPG index of NE activity
  • DA broken into homovanillic acid (HVA) index of
    DA activity
  • Also some NE and DA broken down in synaptic space
    by catechol-o-methyl-transferease (COMT)

5
  • III. Termination of action and degradation of NE
    and DA
  • IV. Epinephrine
  • Role in brain is poorly understood
  • E appears to modulate NE in certain locations
  • Adrenal gland (adrenal medulla part) secretes
    epinephrine and norepinephrine during stress or
    emotional arousal
  • This source of epinephrine and norepinephrine
    acts as hormones (travels in blood to sites of
    action)
  • E important in blood pressure regulation,
    coordination of eating and visceral activities

6
The Human Nervous System
?
Aim in
Exit
7
  • III. Termination of action and degradation of NE
    and DA
  • IV. Epinephrine
  • V. Norepinephrine
  • Manufactured by cells in adrenal medulla and in
    CNS and PNS
  • NE in the Peripheral Nervous System
  • In sympathetic nervous system, preganglionic
    fibers use acetylcholine, postganglionic release
    NE. Target organs in sympathetic system respond
    to NE.
  • Excitation of heart inc. blood pressure
    vasoconstriction
  • increased breathing rate bronchodilation
  • pupils dilate sweating
  • shunts blood to brain and muscle
  • increases glucose conversion to energy

8
  • V. Norepinephrine
  • NE in the PNS
  • In sympathetic nervous system, preganglionic
    fibers use acetylcholine, postganglionic release
    NE. Target organs in sympathetic system respond
    to NE.
  • Drugs which mimic NE in sympathetic nervous
    system are called sympathomimetics (also
    influence E and DA in peripheral nervous system)
  • Sympathomimetics used to treat blood pressure
    (hypotension shock) asthma heart failure or
    arrhythmias (stimulate heart) decongestants
    incontinence

9
  • V. Norepinephrine
  • NE in PNS
  • In sympathetic nervous system, there are 4 types
    of NE receptors
  • alpha1 excitatory
  • contraction of vascular smooth muscle
    (treatments for hypotension)
  • contraction of urinary smooth muscle
    (treatments for incontinence)
  • contraction of nasal mucosa and muscle
    (treatments for nasal swelling
    decongestants)
  • Drugs in use do not cross the blood-brain
    barrier

10
  • V. Norepinephrine
  • In sympathetic nervous system, there are 4 types
    of receptors
  • alpha1 hypotension incontinence decongestants
  • alpha2 inhibitory no relevant PNS only drugs.
  • alpha2 receptors also found in CNS
  • when bound, inhibit the release of NE from
    sympathetic neurons and reduce excitation of
    heart
  • treat high blood pressure (hypertension)
  • Clonidine reduces blood pressure and heart
    rate also used to ease certain withdrawal
    symptoms

11
In sympathetic nervous system, there are 4
types of receptors alpha1 hypotension
incontinence decongestants alpha2 inhibitory
treat hypertension and withdrawal excitation of
heart Beta1 excitatory increase blood
pressure and heart rate Beta blockers
Propanolol Atenolol stage fright and panic
symptoms (acute) - chronic treatment of high
blood pressure
12
alpha1 hypotension incontinence
decongestants alpha2 inhibitory treat
hypertension and withdrawal excitation of
heart beta1 excitatory increase blood
pressure and heart rate (Beta blockers act
here) beta2 excitatory or inhibitory relax
smooth muscle of blood vessels bronchi GI
tract urinary tract increase carbohydrate
and fat metabolism in liver and muscle
stimulate conversion of glycogen to glucose in
liver
13
V. Norepinephrine A. NE in the PNS Non-selective
Beta agonists 1 and 2 older inhalers for
asthma isoproteranol side effects of heart
stimulation Newer Beta2 agonists Alupent
Albuterol (Ventolin) Metaprel more selective
less stimulation of heart B. NE in the CNS
14
  • A. NE in the PNS
  • B. NE in the CNS
  • Most NE releasing neurons are unmyelinated with
    highly branched axon terminals
  • 2 major pathways from brainstem
  • 1. From locus coeruleus to multiple subcortical
    and cortical sites
  • Locus coeruleus large cluster of neurons at
    core of pons 12000 on each side that send axons
    over broad network
  • Project to hippocampus, thalamus, hypothalamus,
    olfactory bulb, cerebellum, cerebral cortex
  • Mostly act at beta adrenergic receptors -
    inhibitory

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16
  • B. NE in the CNS
  • 2 major pathways from brainstem
  • 1. From locus coeruleus to multiple subcortical
    and cortical sites
  • Locus coeruleus large cluster of neurons at
    core of pons 12000 on each side that send axons
    over broad network
  • Project to hippocampus, thalamus, hypothalamus,
    olfactory bulb, cerebellum, cerebral cortex
  • Mostly act at beta adrenergic receptors
    inhibitory
  • Inhibit background discharge rates of multiple
    neurons in above areas, especially cortex
    causes global orientation to stimuli positive
    feelings of emotion involved in basic drive
    states (hunger (suppression) thirst sex)

17
  • B. NE in the CNS
  • 2 major pathways from brainstem
  • 2. Lateral tegmental area (outside of LC but
    same area) to descending and ascending paths
  • - descending to midbrain, brainstem, and spinal
    cord
  • - ascending to amygdala, septum, hypothalamus
    and thalamus
  • Some excitatory some inhibitory actions
  • Intermingled with axons from neurons in LC
    pathway hard to study
  • Receptor types are unclear alpha and beta both.
  • Involved in positive emotion drive states and
    analgesia

18
  • B. NE in the CNS
  • C. Important Diseases/Drugs
  • Depression and mania
  • Certain antidepressants
  • Stimulant drugs (low doses) amphetamine and
    cocaine
  • PNS acting drugs already mentioned
    (decongestants asthma inhalers blood pressure
    meds)
  • Also important for the side effects of many meds
    used to treat Sz

19
  • Serotonin
  • Serotonin is used throughout the body in multiple
    physiological roles.
  • 90 of all serotonin in human body is in the GI
    tract
  • 8 in blood platelets
  • 2 in CNS
  • Neurons in brain make their own none from body
    crosses BBB

20
Serotonin A. Synthesis Made from Tryptophan
amino acid from diet Need 12-13 protein intake
to provide what brain needs. Tryptophan is
actively transported into neurons from
blood. Must compete with other amino acids
(tyrosine phenylalanine) for entry Due to
competition, dietary protein and carbohydrate
content are important.
21
  • A. Synthesis
  • Tryptophan ---1--? 5 hydroxytryptophan
  • 5 hydroxytryptophan -- 2--? 5 hydroxytryptamine
  • 1 tryptophan hydroxylase rate limiting step
  • High serotonin levels within neuron do not
    inhibit enzyme synthesis serotonin just builds
    up (when MAO blocked, etc)
  • Rate of enzyme activity can be modulated by
    second messengers involving cAMP
  • also can be modulated by Oxygen levels in blood
    more oxygen, more synthesis of serotonin

22
  • A. Synthesis
  • Tryptophan ---1--? 5 hydroxytryptophan
  • 5 hydroxytryptophan -- 2--? 5 hydroxytryptamine
  • Serotonin (5HT)
  • 2 5 hydroxytryptophan (5HTP) decarboxylase
  • This enzyme very similar to dopa decarboxylase
  • Production of enzyme and use to make serotonin
    very rapid
  • Cannot manipulate serotonin by manipulating this
    enzyme
  • Release of serotonin is Ca dependent Ca
    must come in to trigger release

23
  • Synthesis of Serotonin
  • Deactivation and breakdown
  • Action terminated by active reuptake process into
    neurons and glia
  • Then broken down by MAO
  • MAO breaks down 5HT into several things
  • 5-hydrozyindoleacetic acid (5HIAA) is a
    metabolite that is often used to index activity
    in system measured in CSF (cerebrospinal fluid)
  • C. Receptors

24
  • Synthesis of Serotonin
  • Deactivation and breakdown
  • C. Receptors
  • 7 major types 3 of relevance to current set of
    medications
  • 5HT1 slow inhibition through G proteins,
    reduce adenylyl cyclase activity exists as
    postsynaptic and presynaptic receptors
  • 5HT2 slow excitation through G proteins,
    increase K and Ca influx. CNS has mostly
    5HT2A (found in prefrontal cortex)
  • 5HT3 fast excitation (ion-coupled receptor
    Na some modulation also of Ca channels) in
    area postrema, trigger vomiting

25
  • Synthesis of Serotonin
  • Deactivation and breakdown
  • C. Receptors
  • D. Pathways in brain
  • Serotonin released as neurotransmitter but also
    released non-synaptically through some axon
    terminals (may act on tone of intracranial blood
    vessels relevance to migraine)
  • 9 neurotransmitter pathways can be consolidated
    into 3 major paths
  • All paths emerge from same set of neurons in the
    Raphe region of the brainstem a group of nuclei
    along midline of midbrain, pons, and medulla

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27
  • D. Pathways in brain
  • Caudal pathway from Raphe nuclei to medulla and
    spinal cord
  • Uses mainly 5HT2 receptors slow excitation
  • Causes contraction of smooth muscle in gut
    gastric motility
  • Causes contraction of uterine muscles - cramps
  • Causes some contraction of blood vessel walls
    blood pressure
  • Causes mild motor neuron excitation
  • Stimulates release of endorphins that then
    inhibit pain messages carried by substance P (nt
    that is a pain messenger) analgesia
  • 5HT3 receptors in Area Postrema trigger vomiting

28
  • D. Pathways in brain
  • Caudal pathway from Raphe nuclei to medulla and
    spinal cord
  • Uses mainly 5HT2 receptors slow excitation
  • 2. Middle pathway from Raphe neurons to
    cerebral cortex and basal ganglia
  • Goes to cortex along with NE axons
  • Goes to basal ganglia along with DA and ACh
    neurons
  • 5HT2 (slow excit) 5HT3 (fast excitation)
    receptors
  • indirectly inhibits mesolimbic and nigrostriatal
    dopamine activity (blockade increases DA action
    in some areas)
  • serotonin induces positive mood and affect
    cortex
  • This is the system where SSRIs work by inhibiting
    the transporter protein necessary for serotonin
    reuptake

29
  • D. Pathways in brain
  • 2. Middle pathway from Raphe neurons to
    cerebral cortex and basal ganglia
  • 5HT2 (slow excit) and 5HT3 (fast excitation)
    receptors
  • modulates movement
  • induces positive mood and affect cortex
  • SSRIs Ecstasy
  • 5HT2A blocked by new antipsychotics inhibits
    excess DA function
  • Rostral pathway Raphe nuclei to 5 areas
  • Uses 5HT1 (slow inhibition) and 5HT2 (slow
    excitation)

30
  • D. Pathways in brain
  • 3. Rostral pathway Raphe nuclei to 5 areas
  • Uses 5HT1 (slow inhibition) and 5HT2 (slow
    excitation)
  • a. Raphe nuclei (within)
  • Within Raphe, there are autoreceptors (5HT1
    self inhibit)
  • b. Raphe to sensory cortex
  • Sensory cortex - particularly visual perception
    5HT2 -relevant to hallucinogens (LSD psilocybin
    mushrooms)
  • c. Raphe to limbic system
  • Limbic system pleasure anxiety slow
    inhibition at 5HT1 receptors
  • BuSpar (buspirone) binds with 5HT1 receptors here
    and helps reduce anxiety

31
  • D. Pathways in brain
  • Rostral pathway
  • a. Raphe nuclei (within)
  • Within Raphe, there are autoreceptors (5HT1
    self inhibit)
  • b. Raphe to sensory cortex
  • c. Raphe to limbic system
  • Limbic system pleasure anxiety slow
    inhibition at 5HT1 receptors
  • d. Raphe to hypothalamus and thalamus
  • Uses 5HT1 receptors in thermoregulation
  • Ecstasy causes elevated body temp thru here

32
  • D. Pathways in brain
  • Rostral pathway
  • c. Raphe to limbic system
  • Limbic system pleasure anxiety slow
    inhibition at 5HT1 receptors
  • d. Raphe to hypothalamus and thalamus
  • Uses 5HT1 receptors in thermoregulation
  • Ecstasy causes elevated body temp thru here
  • e. Raphe to suprachiasmatic nucleus
  • Uses 5HT1- slow inhibition
  • Important in sleep/wakefulness

33
  • D. Pathways in brain
  • Rostral pathway
  • e. Raphe to suprachiasmatic nucleus
  • Uses 5HT1- slow inhibition
  • Important in sleep/wakefulness
  • Serotonin induces sleep inject into brain,
    sleep occurs
  • Inhibit serotonin (by PCPA, inhibits tryptophan
    hydroxylase and production of serotonin) no
    sleep increased activity
  • But other neurotransmitters also important in
    sleep

34
  • E. CNS Relevant Diseases/Drugs
  • depression
  • anxiety
  • possibly some interactive role in schizophrenia
  • migraine headaches 5HT1 agonists cause
    constriction of intracranial blood vessels may
    block endogenous inflammatory agents
  • LSD and psilocybin mushroom hallucinogens
  • Ecstasy empathogen
  • high levels of amphetamine

35
Antidepressants
36
  • Biological Causes of Depression
  • (history NE hypothesis SE hypothesis)
  • 1. Genetic influences
  • Monozygotic twins - 40-65 concordance (chance
    that if one twin has it, the other does too)
  • Dizygotic twins - 10-20 concordance
  • 2. Neurochemical characteristics
  • a. reduced levels of metabolites of
    norepinephrine in cerebrospinal fluid and urine

37
  • 2. Neurochemical characteristics
  • b. abnormal endocrine functions controlled by
    norepinephrine
  • High cortisol levels - dysfunction in
    hypothalamic-pituitary-adrenal axis control
    system
  • Neurons in hypothalamus use NE as the
    neurotransmitter that tells other hypothalamic
    neurons to stop releasing CRF

38
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39
The hypothalamic-pituitary-adrenal axis Stress
stimulates neurons in the hypothalamus to release
corticotropin-releasing factor (CRF) CRF
stimulates limbic system- emotional
response CRF stimulates anterior pituitary to
release adrenocorticotrophic hormone
(ACTH). ACTH stimulates release of
glucocorticoids from the adrenal cortex.
40
  • 2. Neurochemical characteristics
  • b. abnormal endocrine functions controlled by
    norepinephrine - high cortisol levels
  • c. abnormal response on dexamethasone suppression
    test
  • Dexamethasone - synthetic cortisol.
  • Measure cortisol levels at 1100 PM
  • Then give dexamethasone.
  • Next day, should have lower cortisol.
  • Not so in many depressed people.

41
  • 2. Neurochemical characteristics
  • d. reduced levels of metabolites of serotonin
    (respond to drugs that increase serotonin)
  • e. Increased density of NE and 5HT2
    receptors
  • f. Serotonin plays an important role in blood
    platelets which helps protect them from excess
    clumping. Among depressed, more platelet
    aggregation is seen, along with increased risk
    for heart attack and stroke.
  • g. drugs that block or deplete NE or SE can cause
    depression (Reserpine and certain drugs used to
    treat high blood pressure)

42
  • 2. Neurochemical characteristics
  • g. drugs that block or deplete NE or SE can cause
    depression
  • h. animals showing learned helplessness have
    reduced levels of NE and SE (and elevated
    cortisol)

43
  • 3. Illnesses that may produce depression
  • Cushings Syndrome
  • Pituitary tumors produce too much ACTH --gt then
    adrenals release too much cortisol
  • or
  • Adrenal tumors may produce too much cortisol.
  • Excessive treatment with corticosteroids may
    mimic syndrome.
  • All causes lead to obesity and unusual body hair
    growth

44
  • 3. Illnesses that may produce depression
  • Cushings Syndrome (85 )
  • Thyroid disorders (underactive - depression
    overactive - excessive energy reduced sleep
    needs possible mania) certain toxicants are
    thyroid disruptors
  • Parkinsons Disease (50)
  • Substance abuse disorders
  • Long term use of certain drugs at high levels
    alters relevant neurochemical systems (NE, DA,
    SE) - Cocaine, Methamphetamine Ecstasy.

45
  • Suicide
  • 80 of those who commit suicide suffer from
    depression or bipolar disorder
  • among the depressed, 15 commit suicide each year
  • suicide victims have lower concentrations of
    serotonin in their brain
  • suicide victims show high levels of cortisol

46
  • General Health
  • Depression increases the risk of dying after
    heart attack or stroke.
  • Chronic overactivation of the stress circuit
    increases risk for heart disease and stroke.

47
  • Drugs Used to Treat Depressive Disorders
  • MAO inhibitors
  • 2. Tricyclic antidepressants
  • 3. Selective Serotonin Reuptake Inhibitors

48
  • II. Antidepressants
  • A. Monoamine Oxidase Inhibitors
  • in early 1950s, iproniazid, used to treat
    tuberculosis, was noted to elevate mood
  • use as antidepressant began in late 1950s, but
    caused liver toxicity
  • other drugs then developed, but use has always
    been limited by severe side effects
  • second line med - play a role in treating
    treatmentresistant

49
  • Pharmacodynamics
  • inhibition of monoamine oxidase(s) the enzyme
    family that breaks down monoamine transmitters,
    NE, E, DA, SE following reuptake
  • there are 2 MAO types A and B
  • MAO A breaks down E, NE, DA, and SE within
    neurons and some glial cells
  • MAO B breaks down DA in nigrostriatal regions
    also breaks down tyramine and other substances in
    neurons and some glial cells (protects the
    neuron)
  • does not break down the neurotransmitters inside
    vesicles only the ones found or reuptaken into
    cytoplasm
  • in gut, MAOs, especially MAO B break down
    several food stuffs importantly tyramine

50
A. Monoamine Oxidase Inhibitors (MAO B also in
gut) Phenylzine (Nardil) - non-selective and
irreversible Isocarboxazid (Marplan) -
non-selective and irreversible Tranylcypromine
(Parnate) - non-selective and irreversible Selegil
ine (Eldepryl) selective B, irreversible Moclobe
mide (Manorix Aurorix)- selective A and
reversible Brofaromine (Consonar) - selective A
and reversible Taken orally Delayed
action Efficacy of 70-80 for reduction of
depressive symptoms.
51
  • Unpleasant, possibly Life-Threatening Drug-Food
    Interaction
  • in gut, MAOs, especially MAO B break down
    several food stuffs importantly tyramine
  • inhibition of breakdown by MAO due to these
    drugs leads to buildup of tyramine which causes
    toxic sympathomimetic effects
  • these coupled with elevated actions of NE lead
    to dangerous hypertensive crisis elevated blood
    pressure heart rate increase, severe occipital
    headache motor agitation, sweating -gt if
    untreated, stroke, loss of consciousness, death
  • effects occur in 20 min- 1 hour after ingestion
    of the food containing tyramine
  • must avoid aged foods cheese, sausages,
    alcohols, sauerkraut, pickled or fermented foods,
    and others

52
Other Side Effects Dizziness Fatigue Headache
Jaundice Dry mouth Anorgasmia Insomnia
Erectile dysfunction Postural hypotension
Blurred vision Urinary retention/hesitancy
Nausea Peripheral edema Constipation Muscle
weakness/jerking Multiple reasons beyond just
brain-based actions.
53
  • B. Tricyclic Antidepressants (and tetracyclic)
  • main treatment for depression from 1960-1980
  • still among best treatments for the moderately
    to severely depressed (non-delusional) person
    80 response
  • many side effects and poor safety margin
  • oldest is Imipramine (Tofranil)
  • 10 are on US market

54
B. Tricyclic Antidepressants (and
tetracyclic) Imipramine (Tofranil) Desipramine
(Norpramin) Amitriptyline (Elavil) Nortriptyline
(Aventyl Pamelor) Clomipramine
(Anafranil) Trimipramine (Surmontil) Doxepin
(Sinequan Adapin) Protriptyline
(Vivactil) Amoxapine (Asendin) Maprotiline
(Ludiomil)
55
  • Pharmacokinetics
  • Well absorbed orally
  • Peak in 2-6 hours
  • Individual differences in metabolism slow
    metabolizers and fast metabolizers
  • Liver metabolism by CYP2D6
  • Renal clearance
  • Most TCAs have half-life around 24 hours
  • Allows once/day dosing for all
  • Elderly may need lower doses
  • Very narrow therapeutic index 6-10 with fatal
    cardiac arrhythmias as cause of death (can
    overdose on a 1 week supply)
  • Plasma concentrations are monitored

56
  • Pharmacodynamics
  • vary in ratio of blocking NE and SE reuptake
    all block NE
  • also block muscarinic cholinergic receptors,
    alpha receptors for NE in PNS, and histamine
    receptors
  • Actions on NE (and SE) occur within hours, but
    depression reduction takes 1-2 weeks Why?
  • 1. Receptor Sensitivity Hypothesis correlates
    of depressive symptom reduction
  • With repeated increase in the NE supply due to
    tricyclic action, beta adrenergic receptors for
    NE in brain down regulate by reducing in number
  • Also enhanced serotonergic transmission at 5HT1A
    receptors alongside down regulation of 5HT2
    receptors

57
1. Receptor Sensitivity Hypothesis correlates
of depressive symptom reduction With repeated
increase in the NE supply due to tricyclic
action, beta adrenergic receptors for NE in brain
down regulate by reducing in number Also enhanced
serotonergic transmission at 5HT1A receptors 2.
May stimulate neuronal proliferation and increase
number of neurons in limbic areas (fits with idea
that stress ultimately destroys hippocampal
neurons as part of how chronic stress may cause
depression)
58
Tricyclic Action Side effects
  • Reuptake blockade of NE heart arrhythmias
  • Blockade of Muscarinic Receptors Dry mouth and
    eyes
  • (anticholinergic effects) Urinary retention
  • Constipation
  • Blurred vision
  • Confusion-gt Delirium
  • Blockade of alpha-NE Postural hypotension
  • receptors in the PNS Dizziness
  • (anti-adrenergic effects) Drowsiness
  • Blockade of histamine receptors Sedation
  • Weight gain
  • (15 lbs in 6mo)

59
  • Tricyclic Antidepressants Drug Interactions
  • based on liver enzyme competition or induction
  • Prozac and TCAs TCA levels build up to
    dangerous level
  • MAOIs also dangerous stroke seizures
  • Haloperidol and Phenothiazines (antipsychotics)
    can block metabolism of TCAs they build up
  • Barbiturates induce metabolism - need higher
    dose of TCAs
  • Phenytoin (Dilantin) Phenytoin may be elevated
    into toxic range

60
  • C. Selective Serotonin Reuptake Inhibitors
    SSRIs
  • first one, Prozac, entered US market in 1987
  • in 1988, sales of Prozac matched that for all
    antidepressants combined in 1986
  • strong promotion as equal efficacy (70) but
    with fewer side effects, easier standardized
    dosing, no need for blood monitoring, and greater
    safety
  • equal efficacy plus can treat people who could
    not take alternative meds due to side effects and
    personal health characteristics (70 respond) or
    who did not respond to other meds (50-60
    respond)
  • also used for certain anxiety disorders, eating
    disorders, and post-addiction therapies

61
SSRIs Fluoxetine (Prozac) Depression, Bulemia,
OCD Fluvoxamine (Luvox) - OCD Citalopram (Celexa)
- Depression Sertraline (Zoloft) Depression,
OCD, Panic Disorder, Paroxetine (Paxil)
Depression, OCD, Panic, Social Anxiety
Disorder All SSRIs share similar pharmacodynamic
action, efficacy, ease of dosing, and somewhat
similar side effect profiles in large group
studies (but individual differences lead some to
prefer one over another)
62
  • Pharmacokinetics
  • oral dosing with little variability in needs
    across people
  • Prozac standardized dose is 20-40 mg/day orally
    (may be elevated to 60-80 if no response)
  • one Prozac death recorded at overdose of 7000 mg
    wide safety margin TI much above 100 (one
    attempted overdose of 12000, but threw up)
  • does bind with blood proteins (94 of dose),
    must saturate first then efficacy in about 1 week
    (not 2 as for tricyclics)
  • metabolized by liver CYP2D6 so some drug
    interactions and variability across slow vs fast
    metabolizers

63
  • Pharmacodynamic Action
  • inhibit the serotonin reuptake transportor more
    potently than NE or DA
  • far less potent binding to muscarinic receptors
    for Ach than tricyclics, hence fewer
    anticholinergic side effects
  • far less potent binding to histamine receptors
    than tricyclics, hence fewer side effects of
    sedation
  • need to taper dose to reduce withdrawal signs

64
Side Effects ( are for Prozac) Anxiety,
nervousness, insomnia 10-15 Appetite
suppression 9 of people (not weight gain, but
loss of 5 of bodyweight) Nausea, dizziness,
headache 5 Allergic skin rash 4 Mania 1
rate (about same as for Tricyclics) Seizures -
lt1 - but not used in seizure-disordered patients
due to interactions with Phenytoin and
Tegretol Hypoglycemia during use and
hyperglycemia on withdrawal careful monitoring
or exclusion of use in diabetic patients Sexual
dysfunction impotence, ejaculatory disturbance
(perhaps less for Prozac and Luvox)
65
Drug Interactions Tricyclics - enzyme
competition Carbamazepine(Tegretol)and Phenytoin
(Dilantin) Dextromethorphan MAOI can experience
fatal effects serotonin syndrome
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