► Drugs
and the Nervous
System
► Jennifer
Harrison, BScPhm, MSc
► Pharmacy Clinical Site Leader
► University Health Network
► jennifer.harrison@uhn.ca
► 12 January 2021
► Lecture
•
•
•
•
Overview
Anti-Psychotics
Antidepressants
Anti-Epileptic Drugs (AEDs)
Sedative-hypnotic Drugs
The therapeutic site of action for
these drugs is CNS but side
effects can be due to central
or peripheral actions
► Divisions of the Nervous
System
► Central nervous system (CNS)
► Peripheral nervous system
 Somatic motor system (controls
voluntary muscle movements)
 Autonomic nervous system
(regulates involuntary
processes)
►Parasympathetic
nervous system
►Sympathetic nervous system
► Approach
to Learning About
Drugs and the Nervous System
► To
understand drugs and the
nervous system, you need to
know:
 the type(s) of receptors on
which the drug acts
 the normal response to
activation of those receptors
(receptor function)
 what the drug does to those
receptors (increase or decrease
receptor activation)
► Assigned
readings: Lehne
chapters 12 & 13
► Predicting
Drug Side Effects
► Knowledge
of drug mechanism
of action and what receptors it
acts on can help you predict
some (not all) side effects
► Side effects may be:
 an extension of the therapeutic
effect
►e.g.
hypotension with
antihypertensives
 due to action on different
receptors (poor receptor
selectivity)
 not based on either of the above
and thus not easily predicted
► Predicting
Drug Side Effects
► Side
effects often due to poor
receptor selectivity
► Drugs acting on the nervous
system can have side effects
due to blockade of receptors in
CNS or periphery
► See Lehne Tables 13-2 and
13-3 for summary of functions
of peripheral nervous system
receptors (cholinergic and
adrenergic)
►Receptor
Blockade and
Adverse Effect Profiles
► Anti-Psychotics
► Psychosis
► Schizophrenia
– most common
illness in which psychosis is
observed
► Clinical features:
 Delusions
 Hallucinations
 Grossly disorganized behavior
and speech
► Symptoms
usually emerge in
adolescence or early adulthood
(earlier onset in males)
► Pathophysiology
► Dysregulation
of dopamine (DA) (
or  levels)
► Imbalance of DA and serotonin
also important
► “Positive” symptoms
 Hallucinations, delusions, paranoia,
agitation

“Negative” symptoms
  motivation, blunted affect, poor
self-care, social withdrawal
► Cognitive
symptoms
 Disordered thinking, memory and
learning, lack of focus
► Antipsychotics
► First
generation antipsychotics
(FGA)
 aka typical/conventional agents
 D2 antagonists,  dopamine
transmission
► Second
generation
antipsychotics (SGA)
 aka atypical agents
  serotonin transmission, low
affinity for D2 receptors, may
block other dopamine receptor
subtypes
► Onset
of Antipsychotic Action
► Medicated cooperation stage
(first week)
  agitation, hostility
► Improved
socialization stage
(2 – 6 weeks)
 obeys rules, attends meetings,
etc.
► Elimination
of thought disorder
stage (2 weeks – months)
  delusions, hallucinations,
thought disturbances
► Maintenance
stage
 achieves baseline level of
functioning
►Choice
of Agent Based
on Symptomatology
► Positive
symptoms
 Too much dopamine in
mesolimbic area
 FGA (i.e. D2 blockers) or SGA
can be used
► Negative
symptoms
 Not enough dopamine in
mesocortical area
 SGA preferred (helps to restore
balance between serotonin and
dopamine)
► Conventional
► Therapeutic
Agents (FGA)
effect due to blockade
of D2 receptors in mesolimbic area
 relieves positive symptoms
► Many side effects due to blockade
of the following receptors:
 acetylcholine




histamine
norepinephrine
serotonin
dopamine (in other CNS pathways)
► FGA:
Potency
► Recall: potency related to
affinity of drug for receptor
► Classification by potency
 Low vs. high
 Important side effect differences
► Potency can be estimated by
equivalent doses:
Low: Chlorpromazine 100 mg
Med: Loxapine
10 mg
High: Haloperidol 2 mg
►Major
Side Effects of
FGA
► Low
potency agents (low D2
affinity, non-selective)
 Prototype: chlorpromazine (Largactil®)
 Sedation, orthostatic hypotension,
anticholinergic effects, weight gain
► High
potency agents (high D2
affinity/selectivity)
 Prototype: Haloperidol (Haldol®)
 Extrapyramidal symptoms (EPS),
prolactin release (sex hormone
causing lactation, breast growth)
► ECG
changes (prolonged QT
interval) with some agents  risk
of arrhythmias
► Extrapyramidal
Symptoms
(EPS)
► Spectrum
of movement disorders
► Due to blockade of D2 receptors in
nigrostriatal region (extrapyramidal
motor system) creating DA/ACh
imbalance (low DA, high ACh)




Acute dystonia
Parkinsonism
Akathisia
Tardive Dyskinesia – occurs late,
similar risk with all conventional
agents (FGA)
► See
Lehne pp. 334-335 for more
details
► Extrapyramidal
Symptoms
(EPS)
•
•
•
•
Acute dystonia: severe spasm of
muscles in tongue, face, neck,
back
Parkinsonism: tremor, rigidity,
slow shuffling gait
Akathisia: profound restlessness,
pacing, movement
Tardive Dyskinesia: involuntary
twisting, writhing movements of
face, tongue; may be irreversible,
no reliable treatment
Anticholinergic drugs (e.g.
benztropine, diphenhydramine)
restore balance between DA and ACh
and can treat 1, 2 and 3.
►Neuroleptic
Malignant
Syndrome (NMS)
► Idiosyncratic
reaction (rare,
unpredictable), can be fatal
► More likely with high potency
agents
► Symptoms:
 Sudden high fever, muscle
rigidity, sweating,  HR, labile
BP, altered LOC, confusion,
seizures, coma, arrhythmia,
death
► Must
d/c antipsychotic
(problem for depots)
► Supportive measures, drug
therapy
►FGA: Drug Interactions
► Additive side effects with:
 Drugs with anticholinergic
actions (avoid anti- histamines,
OTC sleep aids)
 CNS depressants (avoid alcohol,
antihistamines, benzodiazepines,
barbiturates)
► Levodopa
(and other DA
agonists)
 Used to treat Parkinson’s disease
 Activates dopamine receptors,
exacerbates psychosis
► Atypical
Agents (SGA)
► Less affinity for D2 receptors
so  EPS
► Strong blockade of 5-HT2
receptors
 Helps to restore balance
between DA and 5-HT
 Side effect: weight gain
► Also
block H1, alphaadrenergic, muscarinic
cholinergic receptors (recall
side effects)
► Prototype: Olanzapine
(Zyprexa®)
► Others: Risperidone
(Risperdal®), Clozapine
(Clozaril®), others….
► SGA
► Advantages over FGA:
 Good for positive and negative
symptoms
 As good or better in preventing
relapse
 Less EPS  better adherence (?)
► Disadvantages:
 Weight gain, diabetes, 
cholesterol
 Some agents prolong the QT
interval
 Expensive
► Depot
forms available
(Risperidone Consta®)
►Depot
Formulations
► Long-acting
injectables (IM or SC)
► Convert to depot once stabilized on
oral regimen
► Advantages:
 Slow, steady absorption gives
constant plasma levels
 Dosing interval = 2 – 4 weeks 
enhanced adherence
 Lower rate of relapse than oral
therapy
► May
get more EPS with SGA depot
formulations
► Clozapine
(Clozaril®)
► Most effective agent, works
when other drugs have failed
► Risk of agranulocytosis limits
use
 1-2% of patients, cause
unknown, can be fatal (due to
sepsis)
 Health Canada mandates a Risk
Management Program with
regular (weekly – biweekly)
monitoring of WBC and
neutrophil counts
 Patient, MD, pharmacist, lab
tracked in registry
 Must hold or d/c therapy if
counts drop
 Importance of patient education
► Anti-Depressants
►Neuropathophysiology
of Depression
► Monoamine
hypothesis
 Deficit of norepinephrine (NE),
serotonin (5-HT) or dopamine
(DA) neurotransmission
► Antidepressants
work to
increase neurotransmitter
levels in synaptic cleft
 Prevent reuptake into
presynaptic membrane
 Inhibit metabolism of
neurotransmitter
► Pharmacotherapy
Depression
of
► Chronic
condition – most
patients have > 1 episode
► Two phases of therapy:
 Acute (first 8-12 weeks) – goal is
remission of symptoms
 Maintenance – goal is prevention
of relapse
► Maintenance
therapy –
minimum 6 months; may
require 2+ years for patients
at high risk of recurrence
► Depression
Symptomatology
► Principal symptoms
 Depressed mood, loss of
interest/pleasure
► Somatic
symptoms
 changes in sleep pattern ( or
(
► Other
depressive symptoms
 lethargy, feelings of
guilt/worthlessness, poor
concentration, suicidal thoughts
► Time
to Response
somatic symptoms in 1 – 3
weeks
►
►
in depressive
symptoms by 4 weeks, max
response in 1 – 2 months
 discrepancy between
biochemical effects and onset
of clinical response
►Side
effects occur early
► Anti-Depressant
Drug Classes
 Selective Serotonin Reuptake
Inhibitors (SSRIs)
• Serotonin/Norepinephrine
Reuptake Inhibitors (SNRIs)
• Tricyclic antidepressants
(TCAs)
 Atypical Antidepressants
 Monoamine Oxidase
Inhibitors (MAOIs) (seldom
used today, will not cover)
► Drug Class: SSRIs
► Prototype: fluoxetine
(Prozac®)
► Mechanism of action:
 block 5-HT reuptake pump on
pre-synaptic nerve terminal ( 5HT in synapse)
 little effect on other monoamine
neurotransmitters
► Long
daily
half-lives  dose once
► Safest
and best tolerated drug
class
► Most common first-line agents
► SSRIs: Side Effects
► Do not block H1, NE, 5-HT or
ACh receptors
 no sedation, orthostatic
hypotension, anticholinergic
effects or cardiotoxicity
► Sexual
dysfunction ++
► Nausea, HA, weight gain
► CNS stimulation (nervousness,
insomnia, anxiety)
► SSRIs: Serotonin Syndrome
► Due
to excessive serotonin
transmission when combining > 1
-HT
 avoid combo of SSRI with SNRI, TCA,
MAOI, certain opioid analgesics,
migraine drugs (‘-triptans’) – see
Table 32-4
► Onset
within hours - days of
starting second drug
► Symptoms:
 altered mental status (confusion,
agitation, hallucination),  muscle
tone, tremor, rigidity, sweating, fever
► Resolves
with drug discontinuation
but can be fatal if not managed
►SSRIs:
Dosing and
Administration
► Once
daily dosing (usually AM)
► Start with low dose, 
gradually
► Taking with food can  GI side
effects
► Washout period if switching
agents (to prevent serotonin
syndrome)
► Slow withdrawal (taper) if
stopping to prevent withdrawal
syndrome
► Drug Class: TCAs
► Prototype: amitriptyline
(Elavil®)
► Very
effective esp. in severe
cases
► Mechanism of action:
 Block neuronal reuptake of NE
+/- 5-HT
► Long
half-lives  dose once
daily
► Second-line therapy (safety
and tolerability issues)
► TCAs:
Side Effects
► Sedation (H1 receptor
blockade)
► Orthostatic hypotension
(blockade of alpha1-
adrenergic receptors on
vessels)
► Anticholinergic effects – dry
mouth, blurred vision,
constipation, urinary retention,
tachycardia, etc. (muscarinic
cholinergic receptor blockade)
► Weight gain (5-HT2 receptor
blockade)
► TCAs: Side Effects and
Interactions
► Cardiac
toxicity (arrhythmias) 
periodic ECGs
► Diaphoresis
► Seizures (lower seizure threshold)
► Hypomania
► Sexual
dysfunction
► Drug interactions
 Anticholinergic agents, antihistamines
(additive side effects)
 CNS depressants (avoid alcohol,
opioids, barbiturates)
 MAOIs - severe HTN, avoid combo
► TCAs:
Dosing and
Administration
► Start at low dose, titrate to
clinical effect
► Once daily QHS dosing rationale:
 Simple – facilitates compliance
 Promotes sleep (maximal
sedation at nighttime)
  daytime side effects
► Caution
in elderly, patients
with seizure disorders or
cardiac conditions
►Drug
Class: Serotonin
Norepinephrine Reuptake
Inhibitors (SNRIs)
► Prototype:
XR®)
venlafaxine (Effexor
► Mechanism
of action: block
reuptake of NE and 5-HT into
nerve terminals
► Efficacy similar SSRIs and
TCAs
► Do not block H1, NE, 5-HT or
ACh receptors
► Side effects: nausea, weight
loss/anorexia, HA, insomnia,
sexual dysfunction,  BP
► SNRIs: Dosing and
Administration
► Once daily AM dosing for XR
product
with low dose, 
gradually
► Taking with food can  GI side
effects
► Atypical Antidepressants:
Bupropion (Wellbutrin®)
► Unique agent, blocks DA and
NE reuptake
► Efficacy similar to SSRIs and
TCAs
► Do not block H1, NE, 5-HT or
ACh receptors
► Side effects: agitation, HA,
nausea, dry mouth, insomnia,
► Start
constipation, weight loss,
psychosis (rare)
► Seizures with high doses/rapid
 dose
► No sexual dysfunction
► Bupropion (Wellbutrin®)
► Avoid in patients with seizure
disorder, psychosis, anorexia
or bulimia
► Some SSRIs may  bupropion
levels  avoid combo due to
seizure risk
► Shorter half life than other
anti-depressants
 dosing is 2-3 times daily
 space 8-12 hrs apart to reduce
seizure risk or use long acting
once daily formulation
► Other
use: smoking cessation
(Zyban®)
►Important
Considerations in
Pharmacotherapy of
Depression
► Cannot
use antidepressants
PRN
► Therapeutic trials are at least 1
month
► Patient education points:
 time required to see benefit
 side effect profile
 need for continued therapy even
after symptoms improve
 avoid abrupt discontinuation
 dose spacing (bupropion)
 cannot be used PRN
► Anti-Epileptic
► Goals
Drugs (AEDs)
of Anti-Epileptic Therapy
► Control
seizure disorder,
prevent recurrence
► Minimize side effects of
medications
► Achieve good long-term
compliance
► Return patient to normal
lifestyle (e.g. work, driving,
social interaction)
► To eventually withdraw
medication with continuing
control
*Drug selection depends on
seizure type*
► AEDs: The Old and the New
► Conventional





Phenytoin
Carbamazepine (CBZ)
Valproic Acid
Phenobarbital
Benzodiazepines (BZD) – status
epilepticus only
► Newer






agents:
agents:
Gabapentin
Lamotrigine
Topiramate
Levetiracetam
Pregabalin
Others...
► AEDs:
Mechanisms of Action
Suppress discharge of neurons
within a seizure focus ( neuronal
firing) and/or propagation of
seizure activity
► Drug impact cell to cell
communication in CNS via
interruption of electrochemical
(i.e. action potentials) or
biochemical (i.e.
neurotransmitter) processes
 Suppression of sodium or
calcium influx
 Potentiation of GABA
(inhibitory transmitter)
 Blockade of receptors for
glutamate (excitatory
transmitter)
►
► Phenytoin
(Dilantin®)
► Inhibits Na+ influx
► Useful for most major forms of
epilepsy except absence
seizures
► Unusual pharmacokinetics
 Small dose changes  large
changes in blood levels (see
Lehne Fig 24-1)
 High risk of toxicity or subtherapeutic levels
 Narrow therapeutic index MUST MONITOR BLOOD LEVELS
(TDM)
►Therapeutic
Drug
Monitoring (TDM)
► High
PK variability for most
AEDs  poor correlation
between dose and drug levels
► Why measure level of drug in
blood?
 Helps with dose titration to keep
blood levels in appropriate
therapeutic range
 Monitor patient adherence
 Determine cause of poor seizure
control
 Identify causes of drug toxicity
 Manage drug interactions
► Phenytoin:
Side Effects
► CNS effects
 Sedation, ataxia, ocular effects
(diplopia, nystagmus) cognitive
impairment
► Gingival
hyperplasia –
overgrowth of gum tissue
► Rash
► GI upset
► Hirsutism, coarsening of facial
features
► IV - arrhythmias (bradycardia)
and hypotension if infused too
rapidly
► Phenytoin:
Drug Interactions
► Phenytoin induces CYP450
enzymes to reduce
levels/efficacy of many other
drugs:
 warfarin, oral contraceptives,
corticosteroids, TCAs,
cyclosporine
►
levels (e.g. valproic acid)
► Additive effects with other CNS
depressants (e.g. alcohol)
► Carbamazepine
(Tegretol®, CBZ)
► Inhibit Na+ influx
► Absorption
delayed and
variable
► Metabolized in liver – half-life
decreases with prolonged
therapy (induces its own
metabolism)
► Another narrow therapeutic
index drug, TDM required
► CBZ: Side Effects
► Neurologic effects:
 Visual disturbances, ataxia,
vertigo, HA
 Tolerance may develop
► Hematologic
effects:
 Leukopenia, anemia,
thrombocytopenia
► GI
upset (n/v), dry mouth
► Hepatotoxicity
► Water retention
► Rash
► CBZ:
Drug Interactions
► Induces CYP 450 enzymes to
reduce levels/efficacy of many
other drugs:
 warfarin, oral contraceptives,
digoxin, TCAs, valproic acid,
cyclosporine, CBZ itself!
► Valproic
Acid
► Mechanism of action:
 Inhibits Na+ influx, Ca2+ influx,
and augments GABA activity
(inhibitory neurotransmitter)
► Different
forms:
 Valproic acid, valproate
(Depakene®)
 Divalproex sodium (Epival®)
► Valproic
► GI
Acid: Side Effects
upset
► Hepatotoxicity (do not use in
liver disease)
► Tremor,
hair loss, weight gain,
rash
► Highly teratogenic
 usually avoided in pregnancy
 women of child-bearing age
must use effective contraception
and take folic acid to prevent
neural tube defects in case
pregnancy occurs
►General
Principles for
Dosing and Administration
of Conventional Agents
(Phenytoin, CBZ, Valproic
Acid)
► Start
with low dose and
gradually titrate up to effective
dosage
► Dosing is individualized – TDM
used as a guide
► Administer with food to
minimize GI upset
► Never stop abruptly!
► Drugs
that Potentiate GABA
► GABA = gamma aminobutyric
acid, an inhibitory
neurotransmitter in brain
►  GABA activity  suppress
seizure activity
► Benzodiazepines and
barbiturates: directly bind to
GABA receptors and enhance
activity
► Gabapentin: may promote
release of GABA
► Barbiturates: direct GABA
agonist at high doses
►GABA-Receptor
Chloride Channel
Complex
► Barbiturates:
► Mechanism
Phenobarbital
of action: enhance
GABA action, bind to and activate
GABA-R (i.e. agonist at high doses)
► Uses: status epilepticus and
maintenance therapy
► Effective, cheap, convenient (once
daily) but narrow therapeutic
index/safety issues limit use
► Strong respiratory depressant –
fatal in overdose
► Other
side effects: drowsiness,
lethargy, depression, impaired
cognition and dependence
► Many drug interactions – induces
CYP450
► Gabapentin
(Neurontin®)
► Most commonly used newer
agent
 Adjunctive therapy of partial
seizures
► Mechanism
of action:
promotes release of GABA
► Not
metabolized, excreted
unchanged in urine   dose
in renal dysfunction
► No role for TDM
► Gabapentin: Side Effects,
Interactions and
Administration
► Side effects
 Drowsiness, dizziness, ataxia,
fatigue, nystagmus
 Effects mild-moderate and 
over time
 Rapid dose titration (3 days) can
► Few
drug interactions so good
choice for adjunctive therapy

bioavailability – do not take
within 2 hrs of antacid
 Additive sedation with CNS
depressants
► Status
► Seizure
Epilepticus (SE)
for > 20 min  medical
emergency
► Goals of treatment: maintain
ventilation, correct hypoglycemia,
terminate seizure
► Establish
IV line for administration
of glucose, AEDs and to draw
electrolyte and glucose levels
► Initially: lorazepam or diazepam IV
► Then: phenytoin IV
► If SE persists: phenobarbital IV
► Respiratory support may be
required
► Many
► Bipolar
Other Uses of AEDs
disorder
► Neuropathic pain
► Migraine prophylaxis
► Sedation, sleep induction
► Arrhythmias
► Leg cramps
►Medications
That
Increase Risk of Seizure
(lower the seizure threshold)
► Bupropion
► TCAs
► Clozapine
► Some antibiotics (e.g. penicillins,
cephalosporins)
► Cyclosporine – immunosuppressant
drugs
► Alcohol
► Street drugs: cocaine, heroin,
ecstasy, amphetamine
► Herbals: ginseng, green tea, St
John’s Wort
► Sedative-Hypnotic
Drugs
► Sedative-Hypnotics
► Depress
CNS function
► Some drugs (e.g. BZD) used
for both anxiety and insomnia
 Low dose  relieves anxiety
(anxiolytic)
 Higher dose  promotes sleep
(hypnotic)
► Main
classes: benzodiazepines
(BZD), barbiturates, nonbenzodiazepine agonists, other
► Barbiturates: Secobarbital
► Barbiturates
have multiple uses
due to general CNS depressive
effects
 daytime anxiety, insomnia, epilepsy,
general anesthesia
► Secobarbital:
short-intermediate
acting  for anxiety
► Phenobarbital: long-acting  for
seizures
► Seldom used due to narrow
therapeutic index and poor safety
profile
 respiratory depression, tolerance,
physical dependence, abuse, drug
interactions, etc.
► Benzodiazepines
► Prototype:
(BZD)
lorazepam (Ativan)
► Drugs
of choice for anxiety and
insomnia – safer than barbiturates
►
less abuse, physical dependence and
tolerance, safer, fewer drug
interactions
► Therapeutic
and most side effects
due to CNS actions (enhance GABA
actions)
► Therapeutic effects:  anxiety, 
time to fall asleep,  awakenings,
relax muscles
►BZD:
Relative Onset and
Duration (not for
memorization)
►BZD:
Side Effects and
Interactions
► Daytime
sedation, confusion,
anterograde amnesia
► Weak respiratory depression
(problematic in patients with
respiratory disorders)
► Risk of severe respiratory
depression, hypotension,
cardiac arrest when given IV
► Interactions:
 significant respiratory depression
if combined with other CNS
depressants (alcohol,
barbiturates, opioids)
►BZD:
Dosing and
Administration
► Little
tolerance to
anxiolytic/hypnotic effects (contrast
to anti-seizure effects)
► Some physical dependence – need
gradual withdrawal if stopping
therapy
► For insomnia, use lowest effective
dose for shortest time required
► Insomnia – single oral dose at
bedtime
► Anxiety – orally 3 to 4 times daily
► Lorazepam (Ativan) SL – faster
onset vs. oral
► Other
Drugs for Insomnia
► Zopiclone (Imovane®)
 Non-benzodiazepine agonist,
similar properties to
intermediate-acting BZDs
 Rapid onset, half life about 5 hrs
 Side effects: bitter/metallic
taste, daytime impairment
 Some tolerance/dependence
with long term use
► Other
Drugs for Insomnia:
Over the Counter
(e.g.
diphenhydramine)
► Antihistamines
 less effective than BZD, tolerance
develops quickly
 safe for occasional use, but
anticholinergic side effects
► Valerian
– herbal med
 may help with falling asleep but not
staying asleep
 effects take at least 1 week to
develop
► Melatonin
 may be effective for falling asleep and
maintaining sleep
 higher doses can cause hangover,
headache, nightmares and other side
effects, long term effects unknown
► Approach
to Studying
► Drug
class and prototype (where
applicable)
► Mechanism of action
► Therapeutic effects
► Major side effects
► Notable drug interactions (where
applicable)
► Dosing and administration
► Application of the above to patient
assessment, monitoring and
education
► Lehne – Summary of Major Nursing
Implications for each chapter may
be helpful