CNS Drugs - Page 1
Mennonite College of Nursing
At
Illinois State University
Pharmacotherapeutics for Advanced Practice Nursing 433
Drugs that Act on the Central Nervous System – Part 1
Just a reminder about the Cytochrome P-450 system…
Metabolized by P-450
(biggest problem with drugs
with low therapeutic index)
Warfarin
Cyclosporin
Theophylline
Dilantin
Doxycycline
Benzodiazepines
Calcium channel blockers
Enzyme Inducers (leading
to decreased effect of drug)
Enzyme Inhibitors (leading
to increased drug effect)
Phenobarbital
Rifampin
Anticonvulsants
Prilosec
Smoking
Charbroiled foods
Cimetidine
Erythromycin, Biaxin (but
Zithromax OK)
Diflucan
Ketoconizole, itraconzole
(anti-fungals)
Antidepressants (SSRI’s,
tricyclics)
Protease inhibitors
Antipsychotics
Grapefruit juice
Briefly about Women and Psychopharmacology:
As excerpted from Robinson, GE, Women and Psychopharmacology, Medscape Women’s
Health eJournal 7(1), 2002. Accessed at:
http://www.medscape.com/viewarticle/423938_print
Despite the fact that women are the primary consumers of psychotropic medication, little
attention has been paid to sex differences in psychopharmacology. Sex differences have been
found in the absorption, metabolism, and excretion of many medications. Women tend to
respond more favorably to SSRIs than to tricyclics, have more side effects with psychotropic
medication, and are more likely to develop tardive dyskinesia. They may also be more
concerned about certain side effects such as weight gain from neuroleptic medication. In
treating women patients, the clinician must be aware of the possible effect of the menstrual
cycle on serum levels of medications. It is also essential to understand the effects of such
medication during pregnancy and the postpartum period. Tricyclic and SSRI antidepressants
have not been found to cause organic or behavioral teratogenesis when given in pregnancy.
Lithium has been associated with Ebstein's anomaly and carbamazepine and valproic acid with
the occurrence of neural tube defects. Although small quantities of all psychotropic drugs pass
through breast milk, they do not appear to have an immediate effect on the infant. Women also
take exogenous hormones. Oral contraceptives differentially affect the blood levels of various
benzodiazepines, increasing levels of diazepam, and decreasing levels of temazepam. Drugs
such as carbamazepine can interfere with the action of oral contraceptives. Postmenopausal
women may require lower doses of antipsychotics. Although hormone replacement therapy in
itself does not seem to be a treatment for depression, it may have some benefit in augmenting
the effects of antidepressant medication.
CNS Drugs - Page 2
Antipsychotic Drugs and Mood Stabilizers
Antipsychotic drugs are used to treat:
 serious mental illness such as the bipolar affective disorder, depressive and druginduced psychoses, schizophrenia, and autism
 extreme mania
 certain movement disorders (e.g., Tourette’s syndrome)
 some medical conditions (nausea and intractable hiccups).
The antipsychotics are also referred to as tranquilizers or neuroleptics because they
produce a state of tranquility and work on abnormally functioning nerves.
Antipsychotics
Groups
Examples
Phenothiazine
chlorpromazine (Thorazine)
fluphenazine (Prolixin)
perphenazine (Trilafon)
prochlorperazine (Compazine)
thioridazine (Mellaril)
trifluoperazine (Stelazine)
Thioxanthene
thiothixene (Navane)
Butyrophenone
haloperidol (Haldol)
Dihydroindolone
molindone (Moban)
clozapine (Clozaril)
quetiapine (Seroquel)
“Atypical Antipsychotics”
nd
(2 generation)
risperidone (Risperdal)
olanzapine (Zyprexa)
aripiprazole (Abilify)
ziprasidone (Geodon)
asenapine (Saphris)
iloperidone (Fanapt)
lurasidone (Latuda)
Combination medications (Example)
olanzapine (Zyprexa) + fluoxetine (Prozac)
= Symbyax (for depression with bipolar;
treatment of resistant depression
Note: The phenothiazines are associated with a high incidence of anticholinergic side
effects because they are closely related to the antihistamines.
CNS Drugs - Page 3
Underlying Pathophysiology
In mental illness, there are certain areas of the brain where dopamine activity is
abnormally increased and others where it is abnormally decreased.
Mechanism of Action:
The antipsychotics attempt to re-establish dopamine pathways and other neurotransmitter
systems and restore normal activity.
Many of the antipsychotics are believed to have a common mechanism of action. They
are believed to block dopamine receptors in the brain and thus to decrease the dopamine
concentration in the CNS. Specifically, the phenothiazines block the receptors that
dopamine normally binds to postsynaptically in certain areas of the CNS, such as the
limbic system and the basal ganglia. These are the areas associated with emotions,
cognitive functioning, and motor functions. This results in a tranquilizing effect in
psychotic patients. Both the therapeutic and toxic effects of these agents are the direct
result of the dopamine blockade in these areas.
Drug Effects
The antipsychotics have many effects throughout the body. Besides blocking the
dopamine receptors in the CNS, they also block alpha receptors, which results in
hypotension and other cardiovascular effects. Many of the adverse effects of these drugs
stem from their ability to block histamine receptors: anticholinergic effects.
Body System
Central nervous
system
Cardiovascular
Gastrointestinal
Genitourinary
Hematologic
Dermatologic
Metabolic and
endocrine
1
Antipsychotics: Adverse Effects
Side/Adverse Effects
Sedation, delirium, neuroleptic malignant syndrome1,
extrapyramidal movement disorders, dystonia, parkinsonism2,
akathisia3, tardive dyskinesia4, seizures
Orthostatic hypotension, syncope, dizziness, ECG changes,
conduction abnormalities
Dry mouth, constipation, paralytic ileus, hepatotoxicity
Urinary hesitancy, urinary retention, impaired erection,
priapism, ejaculatory problems
Leukopenia, agranulocytosis (especially with Clozaril)
Photosensitivity, hyperpigmentation, rash, pruritis
Galactorrhea (due to blockage of ≥ 72% of D2 receptors → ↑
prolactin release), irregular menses, amenorrhea, decreased
libido, increased appetite (weight gain 10# with Zyprexa and
Clozaril, 5# with Risperdal, 1# with Geodon), polydipsia,
impaired temperature regulation (These symptoms are from
increased prolactin levels, resulting from stimulation of
hypothalamic-pituitary dopamine system.)
NMS = combination of catatonic rigidity, stupor, unstable BP, hyperthermia, profuse sweating, dyspnea,
and incontinence. Sometimes occurs as a toxic reaction to potent neuroleptic (antipsychotic) agents in
CNS Drugs - Page 4
therapeutic doses. Condition lasts 5-10 days after discontinuationof drug. Mortality rate up to 20%.
Treatment: bromocriptine, dantrolene if usual treatment for hyperthermia is ineffective.
2
3
Likelihood of worsening Parkinson’s Disease with Risperdal and Zyprexa than with Seroquel or Clozaril
akathisia = inability to sit down because the thought of doing so causes severe anxiety.
4
tardive dyskinesia= a condition of slow, rhythmical, automatic stereotyped movements, either generalized
or in single muscle groups. (e.g. facial grimacing, finger movement, jaw swinging, repetitive chewing,
tongue thrusting). Usually from prolonged use of phenothiazines or butyrophenones (Haldol). Result of a
denervation supersensitivity after prolonged receptor blockade, leading to increased number of postsynaptic
dopamine receptors. Must catch early to reverse! (Can also happen with Reglan)
Black box warning regarding use of atypical antipsychotics in elderly patients with
dementia-related psychosis: NOT approved for behavioral disorders in elderly with
dementia
 increased mortality (heart failure, sudden death, pneumonia
 increased risk of cerebrovascular adverse events including stroke
 previously used “off-label” in nursing homes to control “sundowning” (wandering
the halls and developing agitation during nighttime hours)
Hyperglycemia (severe) and DM → ketoacidosis/coma/death with atypical
antipsychotics
 ? alteration in pancreatic beta cells
 ? alteration in glucose transporters on hepatic and skeletal muscle
 ? ↑ BMI
CNS Drugs - Page 5
Choosing an Antipsychotic
There is very little difference between antipsychotics in the mechanism of actions;
therefore selection of an antipsychotic is based primarily on the least undesirable drug
side effect and the patient’s type of psychosis. Of the currently available antipsychotic
agents, no single drug stands out as being either more or less effective in the treatment of
the symptoms of psychosis. It should also be stressed that antipsychotic drug therapy
does not provide a cure for mental illness, but is only a way of chemically controlling the
symptoms of the illness.
1st Generation Antipsychotic Agents and Their Comparative Properties
Drug Name
Antipsychotic
Potency
Phenothiazines
Chlorpromazine
Low
Fluphenzine
High
Thioxanthenes
Thiothixene
High
Butyrophenones
Haloperidol
High
Dihydroindolone
Molindone
Intermediate
Dibenzoxdiazepine
Loxapine
Intermediate
Sedation
Anticholinergic
Cardiovascular
Extrapyramidal
symptoms
High
Low
High
Low
High
Low
Low
High
Low
Low
Low
High
Low
Low
Low
High
Intermed.
Intermediate
Intermediate
Intermediate
Intermed.
Intermediate
Intermediate
Intermediate
See: “Comparison of Atypical Antipsychotics” chart for information on 2nd generation
antipsychotic agents.
Drug Interactions
 Antipsychotic + antacids  decreased absorption of phenothiazines
 Antipsychotic + antihypertensives  may potentiate hypotension
 Antipsychotic + CNS depressants  additive effects  increased CNS depression
Patient Teaching
 Take as prescribed…do not double, omit, or skip doses
 May be several weeks before an improvement is experienced.
 Phenothiazines may cause drowsiness, dizziness, or fainting, so change positions
slowly.
 Sunscreen is needed when taking phenothiazines…they cause photosensitivity.
 Avoid taking antacids within 1 hour of a dose of a phenothiazine
 Notify MD or NP immediately for fever, sore throat, yellow discoloration of the skin,
or uncontrollable movements of the tongue when taking a phenothiazine
 Do not take phenothiazines or haloperidol with alcohol or with any other CNS
depressant.
CNS Drugs - Page 6
Antidepressants
Antidepressants are the pharmacologic treatment of choice for:
 Depression
 Dysthymia (chronic depression = >50% of year X 2 years)
 Schizophrenia
 Eating disorders
 Personality disorders
 Obsessive-compulsive disorder
 Migraine headache
 Chronic pain syndrome (often use Elavil @ h.s.)
 Peptic ulcer disease
 Sleep disorders
 Generalized anxiety disorder
 Diabetic neuropathy
 Fibromyalgia
 OTHER USES YOU HAVE HEARD OF?
3 theories regarding cause of depression

biogenic amine hypothesis: postulates that depression results from a
deficiency of neuronal and synaptic catecholamines (primarily
norepinephrine) and mania from an excess of amines at the adrenergic
receptor sites in the brain.

permissive hypothesis: implicates reduced concentrations of serotonin as the
predisposing factor in patients with affective disorders. While depression
results from decreases in both the serotonin and catecholamine levels, mania
results from increased catecholamine but decreased serotonin levels.

dysregulation hypothesis: essentially a reformulation of the biogenic amine
hypothesis. It views depression and affective disorders not simply in terms of
decreased or increased catecholamine activity but as a failure of the
regulation of these systems (new leading theory)
Pharmacotherapeutic Treatment
The drug categories most commonly used in the treatment of affective disorders are the
selective serotonin-reuptake inhibitors (SSRIs), the tricyclic (TCA) and tetracyclic
antidepressants, and the monoamine oxidase inhibitors (MAOIs).
CNS Drugs - Page 7
Selective serotonin-reuptake inhibitors (SSRIs)
 considered first-line drugs for treatment of depression
o proven efficacy
o favorable adverse-effect profile
o long-term tolerance
o once-daily dosing (** Prozac now available in weekly form)
o wide therapeutic index
 very safe, very few drug-drug or drug-food interactions
 take approximately the same amount of time (4-6 weeks) to reach maximum
clinical effectiveness as it does for the TCAs and MAOIs
 highly bound to plasma proteins such as albumin
 have the capacity to inhibit cytochrome P-450
 Examples:
o Celexa (citalopram)
o Luvox (fluvoxamine)
o Paxil (paroxetine)
o Prozac (fluoxetine) – now available in once/week dosing
o Zoloft (sertraline)
Generic
name
Buproprion
Maprotiline
Trazodone
Fluoxetine
Sertraline
Paroxetine
Venlafaxine
Citalopram
HBr
SSRI (and heterocyclic) Side Effects
Brand name Sedation Toxicity in
Anticholinergic
overdose
effects
Wellbutrin
0
+
0
Ludiomil
++
++++
++
Desyrel
++++
+
0
Prozac
0
0
0
Zoloft
0
+
+
Paxil
0
0
0
Effexor
0
0
0
Celexa
0
0
0
CV
Effects
0
++
+
0
+
0
0
0
SSRI Discontinuation Syndrome – a cluster of symptoms caused by sudden cessation of
SSRI use
CNS Drugs - Page 8
Tricyclic antidepressants (TCAs):
 Inhibit the reuptake of norepinephrine and/or serotonin
 Proven efficacy
 Considered second-line now that SSRIs are available
 All are equally effective, but differ in terms of anticholinergic, sedative, and
orthostatics side effects.
TCA Side Effects
Generic
Brand name Sedation Toxicity in
Anticholinergic CV
name
overdose
effects
Effects
amitriptyline Elavil
++++
++++
++++
++++
clomipramine Anafranil
++++
++++
++++
++++
desipramine
Norpramin
+
++++
+
++++
doxepin
Sinequan
++++
++++
+++
+++
imipramine
Tofranil
+++
++++
+++
++++
nortriptyline Pamelor
+++
++++
+++
++++
trimipramine Surmontil
++++
++++
++++
++++
 Disadvantages: Narrow therapeutic index and potential for overdose may be lifethreatening
 Examples:
o Anafranil (clomipramine)
o Elavil (amitriptyline)
o Norpramin (desipramine)
o Pamelor (nortriptyline)
o Sinequan (doxepin)
o Surmontil (trimipramine)
o Tofranil (imipramine)
Monoamine oxidase inhibitors (MAOIs):
 Considered “last” line agents for the treatment of depression that is not responsive
to other pharmacologic therapies
 Useful clinically for the treatment of any type of depression but especially useful
for the atypical types such as those characterized by reverse vegetative symptoms
(increased sleep and appetite) or by marked panic, phobic, or other anxiety
symptoms
 Inhibit monoamine oxidase, the enzyme that normally metabolizes the
neurotransmitters NE and serotonin  increased amount of NE and serotonin
available to the receptors  decreased sx. of depression
CNS Drugs - Page 9


Problem: A hypertensive crisis occurs in approximately 8% of the patients on
MAOIs.
o Occurs if taken with wine and cheese or with Sudafed
o It is believed to occur when MAO inactivates GI and liver tyramine, which
then enters the bloodstream. (Tyramine is normally degraded by MAO in
the intestines). This tyramine displaces presynaptic NE, and this NE in
conjunction with the increase in the NE stored and released from nerve
terminals through the actions of the MAOIs becomes too much, and
hypertension ensues.
o Chief complaints in such patients are severe occipital headache, stiff neck,
flushing, palpitations, diaphoresis, nausea and vomiting and elevated BP.
o Once ingestion occurs, it is considered a medical emergency and
immediate treatment should be sought.
o Foods and beverages to avoid (high tyramine content)
 Cheese, especially aged or matured
 Pickled or smoked fish (herring)
 Yeast or protein extract
 Beef or chicken liver
 Fermented or aged protein foods
 Beer, red wine, sherry
 Fava or broad bean pods
 Spoiled or overripe fruit
o Food and beverages to be consumed with some caution (variable tyramine
content; some people may be sensitive to these foods)
 Yogurt and sour cream
 Chocolate and caffeine-containing beverages
 Soy sauce, Miso soup
 Sauerkraut
o Medications to avoid
 Cold medications (containing ephedrine, phenylephrine or
phenylpropanolamine)
 Meperidine (Demerol)
 Local anesthetics with epinephrine
 Weight-reducing pills, pep pills, stimulates (amphetamines,
methamphetamine, methylphenidate)
 Methyldopa, quanetidine, reserpine, clonidine
 Nasal and sinus decongestants
 Inhalants for asthma
 Dopamine, metaraminol
 L-dopa, L-tryptophan
 Tricylic antidepressants or other MAOIs
 Cocaine
Examples
o Marplan (isocarboxazid)
o Nardil (phenelzine sulfate)
CNS Drugs - Page 10
o Parnate (tranylcypromine)
Other antidepressants (heterocyclics)
 Wellbutrin [alias Zyban] (bupropion) = aminoketone
o Dopamine reuptake blocker
o Good for use in depressed patients who do not respond to or cannot
tolerate SSRI’s
o Similar to SSRIs in its energizing effects
o Little or no effect on MOA or the neurotransmitters serotonin and NE
o No effect on sexual function; good for depressed patients treated with
SSRIs who develop sexual dysfunction (impotence and delayed ejaculation
in males and anorgasmia in females)
 Desyrel (trazodone) = triazolopyridine and Serzone (nefazodone) =
phenylpiperazine
o Tend to be sedative and orthostatics in their chemical effects
 Effexor (venlafaxine) [also available in XR formulation]
o Is a serotonergic noradrenergic reuptake inhibitor (SNRI)
o Because it blocks NE as well as serotonin, its adverse effects and drug
interactions more closely resemble those of the TCAs
o Unlike some newer agents, have been shown to be effective even in severe
depression when compared to placebo and the SSRI fluoxetine (Prozac)
o Also being used to treat hot flashes (lower dose = Effexor XR 37.5 mg)
 Remeron (mirtazapine) = tetracyclic
o Increases both NE and serotonin
o Onset of action and efficacy similar to the TCAs
 Ludiomil (maprotiline) = tetracyclic
o Used in depressive illness associated with dysthymic disorder, manicdepression, and major depressive disorder
Choosing a Medication for Depression
 Some questions to ask:
o Has the patient ever had a response to this medication?
o Has someone within the family had a response to this type of drug?
 TCAs are highly lethal when taken as an overdose…many providers are reluctant
to prescribe them to severely depressed patients
 Probably best to stay away from MAOIs:
o Using an SSRI concurrently with an MAOI is contraindicated.
o These drugs must be separated by a period of 14 days when given in
sequence.
 Failure to observe this “washout period” can result in a serious
interaction called serotonin syndrome.
 Signs/symptoms can include: mental status changes,
altered muscle tone, autonomic nervous system instability,
and even coma and death
CNS Drugs - Page 11


SSRI’s are frequently prescribed in combination with TCAs
o A small dose of a sedating TCA at bedtime may help a patient who
experiences trouble sleeping because of the SSRI’s stimulating effect.
o But exercise caution: SSRI’s may slow the rate at which the TCA is
metabolized and increase the risk of TCA toxicity.
 Observe carefully for signs of possible toxicity such as increased
heart rate, hypotension, and arrhythmias and confirm that the dose
of TCA is minimal
When used appropriately, SSRIs offer safe, effective relief to patients with various
emotional disorders
o Generally considered more tolerable because they have no effect on
cholinergic or adrenergic systems and don’t affect histamine
o Less dangerous when taken as an overdose, although they still must be
used cautiously in severely depressed patients
o However, be aware that SSRIs can cause several sets of opposite, or
contradictory effects: one or the other in different patients or even both
extremes in the same patient at different times. Such a response may
masquerade as the underlying condition being treated:
 Anxiety and sedation
 The SSRIs increase serotonin, which can cause sedation,
but they can also cause a decrease in dopamine, which
frequently causes akathisia (anxiety, tremors, and motor
restlessness).
 You may have trouble identifying the SSRI as the culprit,
especially in patients who are also taking antipsychotic
medications such as haloperidol [Haldol], which are well
known for causing the same problems.
 Stimulation followed by a “crash” or letdown
 Warn your patient not to abruptly stop taking an SSRI on
her own. Tell her to decrease the dosage gradually under
your supervision.
 Anorexia and weight gain
 Although some patients report anorexia, and two serotoninrelated drugs indicated specifically for weight loss
(fenfluamine [Pondimin] and dexfenfluramine [Redux])
were removed from the market for causing mitral valve
disease and pulmonary hypertension, other patients report
weight gain (which can lead to the patient refusing to take
the med)
 Warn your patient about the possibility of both adverse
reactions.
 Mood swings
 Designed to elevated mood, the SSRIs also can cause
irritability and occasional mania.
 Assess for changes in the patient’s mental status.
CNS Drugs - Page 12

Also think of other reasons for symptoms:
o Attention-deficit disorder  high anxiety; if can’t take Ritalin, try
imipramine (Tofranil) or Prozac
o Check labs and EKG – mitral valve prolapse  high level of anxiety
o With situational depression (divorce, death, etc.), get good history, check
other meds that may cause depression (such as Inderal, Indocin)
 Keep in mind: 33% of geriatric patients are depressed, especially males.
o Look at sedation of proposed med; if patient can’t remember taking meds,
DON’T use TCAs.
o Note: Prozac is a parent drug that breaks down into norfluoxetine – long
1/2 –life (72 hours), even longer in geriatrics (don’t use in geriatrics)
o Zoloft with 15-20 hour ½-life and once daily dosing is good
o Best to start at lower dose
 Remember: the meds are used to return the person to a normal mood; do not
usually cause euphoria
 Don’t give large number of TCAs…will take them all! Use SSRIs instead.
o Prozac doesn’t cause suicide…but does give patient enough energy to see
how hopeless things are. Counsel, follow-up, keep connected.
 Sexual side effects: Management strategies
o Watchful waiting
o Dosage reduction
o Drug holiday
o Switching antidepressants
o Add-on therapy
Side Effect Profiles of TCAs, SSRIs, and other agents1
Drug
Type
Anticholinergic
effects
amitriptyline
doxepin
imipramine
desipramine
nortriptyline
venlafaxine
nefazodone
fluoxetine
paroxetine
sertraline
TCA
TCA
TCA
other
other
other
other
SSRI
SSRI
SSRI
+++
++
++
+
+
+
+
+
++
++
1
Orthostatic
hypotension
+++
+++
+++
++
++
+
++
+
+
+
Sedation
Agitation/
RestlessNess
Headache
Migraine
Sexual
Dysfunction
Weight
Gain
+++
+++
++
+
++
+
++
+
++
+
0
0
+
+
+
++
0
++
+
+
+
+
+
+
+
+++
+++
+++
+++
+++
++
++
++
+
+
++
+
+++
+++
+++
++
++
++
+
+
0
0
+
+
+
+++ = frequently (>20% incidence); ++ = occasionally (10-19% incidence), + = rarely (1-9% incidence);
0 = not reported (0% incidence)
Dosing
 Initiation of therapy
CNS Drugs - Page 13

o Start with small dose of TCA and increase every 2-3 days to reach desired
dose
o SSRIs can be started at full therapeutic dose
o See again in 1 week.
o Treat for at least 3 weeks…if no change, reconsider dose, diagnosis,
medication, need for blood level (for TCAs such as imipramine, nortriptyline)
Maintenance therapy
o Maintain medication 6-12 months following remission
o Taper medication slowly
 Abrupt discontinuation of anticholinergic antidepressants (TCAs) may
result in a withdrawal syndrome (cholinergic rebound) of malaise,
muscle aches, chills, cold sweats, nausea, vomiting, abdominal
cramps, diarrhea, anxiety, headaches, sleep disturbance, dizziness,
motor restlessness, and/or irritability
 Check what’s going on in the patient’s life before tapering
 If taking something in AM with coffee, may get lethargic; if
take at noc, may not sleep well at first after decreasing dose.
 Inform patient that they may at times, need to increase dose
temporarily during taper
Questions/concerns
 Question of risk of suicidal behavior with SSRIs and TCAs; especially in children
and adolescents < 24 years old. (Black Box Warning)
 Reports suggest a possible interaction between Aricept (donepezil) used for
Alzheimer’s patients, and Paxil (paroxeine), an SSRI. Paxil is a potent
cytochrome P450 2D6 inhibitor that may slow the metabolism of Aricept, leading
to insomnia, confusion, severe diarrhea, etc. Zoloft and Celexa are weaker
inhibitors and may be less likely to interact with Aricept.
 Possible connection between SSRIs and cerebral vasoconstriction and stroke
 OSA may affect response to antidepressants (2015)
Other “Off-Label” Applications of SSRIs include:
 Premature ejaculation
 Migraine headache prophylaxis
 Neurocardiogenic syncope
Question: What about interactions between herbal products and SSRIs?
Review handouts:
 Choosing and Switching Antidepressants
 Combining and Augmenting Antidepressants
 Treatment-Resistant Depression
Discuss: SSRI-induced hyponatremia