Vernon Rosario, MD, PhD
Associate Clinical Professor
Dept. of Psychiatry and Biobehavioral Sciences
Overview
• Neurotransmission & pharmacodynamics
• Pharmacokinetics
• Some medications affecting the brain and
behavior:
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o
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antipsychotics
mood stabilizers
antidepressants
antianxiety medications
stimulants
Adapted from Steven A. Fink, PhD, Jarred von Snellenberg, PhD, Heidi Combs & MD Shamim Nejad,
MD
Synaptic Transmission:
Action Potentials
http://videosift.com/video/Brain-Synapses-and-Neurotransmission-3D-Animation
Pharamacodynamics:
Where Drugs Act
• Four sites of action
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Receptors (those sites to which a
neurotransmitter can specifically adhere to
produce a change in the cell membranes)
Ion channels
Enzymes
Carrier Proteins
• Biologic action depends on how
its structure interacts with a
receptor
Receptors
• Types of Action
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Agonist: same biologic action
Antagonist: opposite effect
• Interactions with a receptor
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Selectivity: specific for a receptor
Affinity: degree of attraction
Intrinsic activity: ability to produce a biologic
response once it is attached to receptor
Ion Channels
• Drugs can block or
open the ion channels
• Example:
benzodiazepine drugs
facilitate GABA in
opening the chloride
ion channel
Potassium channel. Image Source Page: http://www.beckman.illinois.edu/news/Illinoisgating
Enzymes
• Enzymes catalyze specific biochemical reactions
within cells and are targets for some drugs
• Monoamine oxidase is an enzyme that breaks down
most bioamine neurotransmitters (NE, DA, 5-HT)
• Enzymes may be inhibited to produce greater
neurotransmitter effect.
Carrier Proteins
• Transport neurotransmitters
across cell membranes
• Medications may block or
inhibit this transport
• Example: antidepressants
(SSRI) on serotonin
transporter protein
Image Source Page: http://scientopia.org/blogs/scicurious/2010/08/25/back-to-basics-3-depression-post-6/
Efficacy and Potency
• Efficacy - Ability of a drug to produce a response
as a result of the receptor or receptors being
occupied.
• Potency - Dose required to produce the desired
biologic response.
• Loss of effect
desensitization (rapid decrease in drug effect)
tolerance (gradual decrease in the effect of a drug at
a given dose)
o can lead to patient being treatment refractory
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o
Target Symptoms and
Side Effects
• Target symptoms
Specific symptoms treated for each class of
medication
• Side effects
Responses (+ or -) not related to target symptoms
• Adverse drug reaction
Unwanted effects with serious physiologic
consequences.
Drug Toxicity
• Toxicity
Point at which concentration of the drug in the
blood stream becomes harmful or poisonous to
the body.
•
Image Source Page: http://www.beltina.org/health-dictionary/narrow-therapeutic-index-nti.html
Drug Toxicity
• Therapeutic index
Ratio of the dose that produces toxicity in 50% to
the dose that is therapeutically effective in 50%
• TD50/ED50
 High therapeutic index: wide range between dose at which the
drug begins to take effect and dose that would be considered
toxic
 Low therapeutic index: low range
Image Source Page: http://quizlet.com/5151182/usmle-pharmacology-principles-flash-cards/
Pharmacokinetics:
How the Body Acts on the Drug
• Absorption
• Distribution
• Metabolism
• Elimination
Pharmacokinetics
Blood
Brain
Barrier
P450
Enzymes
J van Snellenberg 2007
Absorption
• From site of administration into the plasma
• Oral - (tablet and liquid)
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Most Convenient
Most variable (food and antacids)
 First pass effect
 Decreased gastric motility (age, disease, medication)
• IM - Short-and long acting
• IV - Rarely used outside hospital
Bioavailability
• Amount of drug that reaches systemic circulation
unchanged
• Often used to compare one drug to another, usually
the higher the bioavailability, the better
Distribution
• Amount of drug found in various tissues,
especially the intended ones
• Psychiatric drugs must pass through blood-brain
barrier (most fat-soluble)
• Factors effecting distribution
Size of organ (larger requires more)
Blood flow (more, greater concentration)
Solubility (greater, more concentration)
Plasma protein (if bound, slower distribution, stays in body longer)
o Anatomic barriers (tissues surrounding)
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Crossing the Blood Brain
Barrier
• Passive diffusion
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Drug must dissolve in the structure of the cell
Lipid solubility is necessary for drugs passing through
blood brain barrier (then, can also pass through
placenta)
• Binding to other molecules
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Plasma protein binding
The more protein binding, the less drug activity.
Can bind to other cells, especially fat cells. Then are
released when blood level decreases.
Image Source Page: http://www.nanowerk.com/spotlight/spotid=19339.php
Metabolism
• Process by which the drug is altered and broken
down into smaller substances (metabolites) that are
usually inactive.
• Lipid-soluble drugs become more water soluble, so
they may be more readily excreted.
• Most metabolism is carried out in the liver
Cytochrome P450 (CYP)
Largest class of enzymes catalyzing oxidation of
organic substances in all living things
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11,550+ identified ; 57 in humans
High affinity for fat-soluble drugs
Involved in metabolism of most psychiatric medications
Inactivate drugs (or in some cases activate them)
Chemicals may increase or decrease CYP activity
Example:
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SSRIs inhibitors of the subfamily CYP2D6
Compounds in grapefruit juice inhibit CYP3A4
Tobacco induces CYP1A2
Elimination
• Clearance: Total amount of blood, serum, or
plasma from which a drug is completely removed
per unit time
• Half-life: Time required for plasma concentrations
of the drug to be reduced by 50%
• Only a few drugs eliminated by kidneys (lithium)
• Most excreted via the liver
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excreted in the bile and delivered to the intestine
may be reabsorbed in intestine and “re-circulate” (up
to 20%)
Dosing and Steady State
• Dosing: Administration of
medication over time, so that
therapeutic levels can be
achieved.
• Steady-state:
drug accumulates and plateaus
at a particular level
o rate of accumulation determined
by half life
o reach steady state in about five
times the elimination half-life
o
Pharmacokinetics: Ethnicity
• 9% of whites - genetically defective CYP2D6
• Asian descent
o Metabolize ethanol to produce higher
concentrations of acetaldehyde (flushing,
palpitations)
o Require 1/2 to 1/3 dose antipsychotics and have
more severe side effects
• Cardiovascular effects of propranolol
o Asian descent - more sensitive
o African descent - less sensitive
Phases of Drug Treatment
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Initiation
Stabilization
Maintenance
Discontinuation
Psychiatric Medications
• Antipsychotic Medications
• Movement Disorders Medication
• Mood Stabilizers
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Antimanic
Antidepressant
• Antianxiety and Sedative-Hypnotic
• Stimulants
Antipsychotic Medications
• Target symptoms: psychosis
• Types
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Conventional
Atypical
• Absorption: variable
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clinical effects seen 30-60 min
IM less variable (avoid 1st pass)
when immobile, less absorption of IM
• Metabolism: liver
• Excretion: slow
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accumulates in fatty tissues
1/2 life of 24 hours or more
Antipsychotic Medications
• Preparations
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Oral
IM
Depot - haloperidol and fluphenazine
• Side Effects
Cardiovascular: orthostatic hypotension
Weight-gain: blocking histamine receptor
Endocrine and sexual: block dopamine, interfere with
prolactin
o Blood dyscrasias: agranulocytosis
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Antipsychotic Medications
• Conventional
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Phenothiazines (Thorazine, Prolixin)
Thioxanthenes (Navane)
Dibenzoxazepines (Loxitane)
Haloperidol (Haldol)
• Atypical or Novel
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Clozapine (Clozaril)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Asenapine (Saphris)
Iloperidone (Fanapt)
Lurasidone (Latuda)
Paliperidone (Invega)
Antipsychotic Side Effects
• Cardiovascular: arrhythmia, incr. heart rate
• Anticholinergic: dry mouth, dry eyes, imbalance, pupil dilatation, double
vision, constipation, confusion, delirium
• Weight Gain
• Endocrine: hyperprolactinemia > milk production, irregular periods,
hyperthermia, diabetes
• Blood Disorders: decr. white blood count
• Miscellaneous: jaundice, rash, photosensitivity
Medication-Related Movement
Disorders: Acute Syndromes
• Can occur in 90% of all patients
• Dystonia: involuntary muscle spasms, abnormal
postures, oculogyric crisis, torticollis
• Parkinsonism: rigidity, akinesia (slow movement),
and tremor, masklike face, loss of spontaneous
movements
• Akathisia: Inability to sit still, restlessness
• Extrapyramidal Symptoms (EPS) (11 min)
Movement Disorders: Acute
(cont.)
• Etiology (acute):
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Related to dopamine in nigrostrial pathway that
increases cholinergic activity
• Treatment
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Anticholinergic medication for dystonia, parkinsonism
(Artane and Cogentin)
Akathisia does not usually respond to anticholinergic
medication. Beta blockers have best success.
Movement Disorders:
Chronic
• Tardive Dyskinesia
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Irregular, repetitive involuntary movements of mouth,
face, and tongue, including chewing, tongue
protrusion, lip smacking, puckering of the lips, and
rapid eye blinking. Abnormal finger movements are
common. More common in women and elderly.
• Symptoms
Begin after 6 months, but also as antipsychotics are
withdrawn
o Irreversible - controversy
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Movement Disorders:
Chronic
• Etiology
believed that chronic dopamine suppression in the
EPS causes an overactivation of the system
o increases in antipsychotic meds, suppresses
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• Treatment
prevention by using lowest possible dosage, minimize
use of PRN, closely monitor individuals in high-risk
groups
o monitoring tools
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Mood Stabilizers: Antimania
Lithium Carbonate
• Action: uncertain, crosses cell membranes,
altering sodium transport, not protein bound
• Side Effects: thirst, metallic taste, increased
frequency or urination, fine head and hand
tremor, drowsiness, and mild diarrhea
• Blood levels monitored (lithium toxicity - severe
diarrhea, vomiting, drowsiness, muscular
weakness, and lack of coordination, withhold)
Lithium Carbonate
• Monitor creatinine concentrations, thyroid
hormones, and CBC every 6 months.
• Kidney damage may be a risk
• Thyroid function may be altered usually after 618 months. Observe for dry skin, constipation,
bradycardia, hair loss, cold intolerance
• Avoid during pregnancy (associated with cardiac
defects and arrhythmia)
Mood Stabilizers: Antimania
Anticonvulsants
• Valporate and derivatives (divalproex sodium Depakote)
• Carbamazapine (Tegretol)
• Gabapentin (Neurontin) (least side effects)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)
• Highly protein bound
• Metabolized by the cytochrome P450 system
• Side effects: dizziness, drowsiness, tremor, visual disturbance,
nausea, & vomiting
Anticonvulsant Mood Stabilizers
• Only carbamazepine is approved for mania.
• Used when patients have not responded to lithium
• Pharmacokinetics
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Highly protein bound, metabolized by P450 system
(potential drug-drug interaction)
Carbamazepine
Side Effects
• Dizziness, drowsiness, tremor, visual disturbances,
nausea, and vomiting
• Minimized by treating in low doses
• Give with food
• Weight gain
• Alopecia (hair loss)
Antidepressants
Tricyclic: Tertiary Amines
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Amitriptyline (Elavil)
Clomipramine (Anafranil)
Doxepine (Sinequan)
Imipramine (Tofranil)
Trimipramine (Surmontil)
Antidepressants:
Secondary Amines
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Amoxapine (Asendin)
Desipramine (Norpramin)
Nortriptyline (Aventyl, Pamelor)
Protrypyline (Vivactil)
TCAs: Side Effects
• Most common uncomfortable side effects
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sedation
orthostatic hypotension
anticholinergic
• Others
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tremors,
restlessness, insomnia, confusion
pedal edema, headache, and seizures
blood dyscrasias
sexual dysfunction
• Adverse
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cardiotoxicity
Antidepressants
• Most antidepressants block the re-uptake of a
neurotransmitter of one or more of the
bioamines: serotonin, norepinephrine, dopamine
• SSRIs = Selective Serotonin Reuptake Inhibitors
Selective Serotonin Reuptake
Inhibitors (SSRI)
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Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Escitalopram (Lexapro)
SSRI: Side Effects
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Headache
Anxiety
Transient nausea
Vomiting
Diarrhea
Weight gain
Sexual dysfunction
SSRIs
• Usually given in morning, unless sedation occurs
• Higher doses, especially paroxetine, can produce
sedation
• Paroxetine associated with weight gain
Antidepressants:
Monoamine Oxidase Inhibitors (MAOIs)
• Action: Inhibit enzyme responsible for the
metabolism of serotonin, dopamine, norepinephrine,
and tyramine.
• Increases levels of norepinephrine and serontonin in
the CNS
• Interacts with food -- low tyramine diet (no cheese,
liver, fermented or cured foods)
Antidepressants
Others
• Serotonin-Norepinephrine Reuptake Inhibitors
(SNRIs)
o Venlafaxine (Effexor)
o Desvenlafaxine (Pristiq)
o Duloxetine (Cymbalta)
• Mirtazapine (Remeron)
• Trazodone (Desyrel)
• Nefazodone (Serzone withdrawn due to rare liver failure)
• Bupropion (Wellbutrin)
Antianxiety and SedativeHypnotic Medication
• Used for anxiety, not long-term
• Benzodiazepines
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diazepam (Valium)
lorazepam (Ativan)
alprazolam (Xanax)
• Nonbenzodiazepines
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busipirone (BuSpar)
zolpidem (Ambien)
• Side effects
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Sedation and CNS depression
Tolerance and dependence (benzos)
Avoid benzos in children & elderly
Psychostimulants
• This class of drugs, in low to moderate doses, generally
have the following effects
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Heightened mood (euphoria)
Increase vigilance and alertness
Reduce fatigue
Alertness
• In order of prevalence of use
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Caffeine
Nicotine
Amphetamines/Cocaine
Psychostimulants
• Amphetamine, etc (cont.)
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Low to moderate doses
 Facilitate performance on sustained attention tasks, and those
requiring physical quickness or strength
 Especially if fatigued (Benzedrine used extensively in WW II)
 Increased energy, concentration, alertness, self-confidence, and
mood
 Social interactions may be enhanced
 Suppresses appetite
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High doses generally interfere with performance
 Also can lead to dysphoria, social withdrawal, and depression
Psychostimulants
• Amphetamine, etc (cont.)
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Extremely high doses or chronic use can lead to amphetamineinduced psychosis
 Almost indistinguishable from paranoid schizophrenia
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Simple movements are often repeated for long periods
 E.g. continuous chewing, teeth grinding, tongue movement
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Chronic use leads to marked tolerance and, in chronic users, the
administration of very high doses