Drugs And Their Actions Exam 2

Front 1

Caffeine

Back 1

Most used psychoactive drug and used by 80% of adults

Front 2

CYP1A2

Back 2

Member of the cytochrome p450 enzyme. Found in the liver. Breaks Down Caffeine. Inhibited (Increase half life) and Induced (decrease half life) by drugs (ie Smoking and Barbituates, so bad for people who quit smoking). People who are slow metabolizers

Front 3

Pharmacodynamics of Caffeine

Back 3

Caffeine acts as an adenosine antagonist in the CNS.
Adenosine is a neuromodulator- controls many actions.
Adenosine normally has sedative, anticonvulsant, and depressant effects

Front 4

Pharmacokinetics of Caffeine

Back 4

Onset of 30 to 45 minutes (increase seen in blood levels)
Plasma concentration peak is 2 hours
Crosses the Placenta
90% metabolized in liver
Half life of 2.5 to 10 hours

Front 5

Pharmacological Effects

Back 5

Psychostimulant
Positive Effects- more alert, less fatigued, clear thinking, sustained intellectual effort
Negative Effects- Motor skills inhibited, arithmetic skills, timing skills are all impacted
High Doses- Anxiety, insomnia, shakiness, Increase heart rate. LD50 ~ 100 cups of coffee
Can Relieve Headache by constricting cerebral blood vessels

Front 6

Caffeine Tolerance and Dependance

Back 6

Chronic Use can lead to habituation, tolerance and some withdrawal symptoms
Not an addictive drug since it doesn't release DA in central reward pathway

Front 7

Smoking Morbidity and Mortality

Back 7

1 of every 5 deaths is caused by smoking
3000 nonsmoking americans die from lung cancer
Lung cancer, Heart Disease and COPD are the leading causes of death due to smoking

Front 8

Nicotine Pharmacokinetics

Back 8

Readily absorbed
Nicotine reaches brain in seven seconds (smoking)
Brain levels decrease rapidly, causing chain smoking
Metabolized by the enzyme CYP2A6 (liver) with half life of about 2 hours
Cotinine is primary metabolite (18 hour half life)
10-20% is excreted unchanged in urine

Front 9

Nicotine Pharmacodynamics

Back 9

Acts on CNS and periphery
In the periphery nicotine causes:
-increase in epinephrine (aka adrenaline)
-raises blood pressure
-raises heart rate
-relaxation of skeletal muscle
-complex actions on gut
In the CNS facilitates release of dopamine, ACh,
glutamate:
-Activates the reward center
-Higher ACh results in cognitive potentiation, memory
facilitation and possibly arousal effects
-Glutamate might contribute to improved memory
function
-Ach to Nicotinic
-Drug of dependency b/c activates reward center

Front 10

Nicotine Tolerance and Dependence

Back 10

Some tolerance is thought to occur
Induces physiological and psychological
dependence
Multiple withdrawal symptoms- restless, weight gain, insomnia
Many smokers want to quit (about 70%) and
about 40% attempt to quit each year
The success rate for any given attempt is low,
however repeat attempts can increase success

Front 11

Bupropion (WellButrin, Zyban)

Back 11

Antidepressant
Blocks uptake of dopamine (strongly); norepinephrine and serotonin (weakly)
Antagonist of nicotinic receptors
30% of people that used for 8 weeks quit smoking

Front 12

Varenicline (Chantix)

Back 12

- binds more weakly to receptor than does
nicotine
- prevents access of nicotine to receptor
- what is the end pharmacologic effect?
- Increases chances of quitting and
maintaining abstinence for a year 3 fold
(placebo) or 1.5 fold (bupropion)
- Not used in conjunction with nicotine
replacement

Front 13

Anxiety

Back 13

May include heart palpitations, fatigue, nausea,
chest pain, shortness of breath, stomach aches, or
headaches.
Lack of an obvious externalstimulus or trigger.

Front 14

Anxiety and the Brain

Back 14

Neural circuits in the amygdala and hippocampus are
thought to be involved in anxiety.
Anxiety caused by over-active amygdala can be reduced by activation of the GABA pathway.

Front 15

Anxiety Diagnosis

Back 15

Most frequent psych disorders.
Major Forms:
Ÿ Generalized anxiety disorder
Ÿ Panic disorder
Ÿ Social anxiety disorder
Ÿ Posttraumatic stress disorder
Symptoms affect 30% of population but only 15% to 36% receive treatment

Front 16

Insomnia

Back 16

Onset may be acute or chronic.
Sleep may not be restorative
Considered insomnia > 1 month

Front 17

Insomnia causes and prevalence

Back 17

Pain/illness, drugs, hard exercise, psych issues and environment.
64 million people affected in US/yr

Front 18

Benzodiazepines Pharmacodynamics

Back 18

• Anxiolytic (antianxiety)
• Sedative
• Anticonvulsant
• Amnesic
• Muscle relaxant

Front 19

Diazepam (Valium®)

Back 19

Long-acting agent, Benzodiazepine

Front 20

Chlordiazepoxide (Librium®)

Back 20

Long-acting agent, Benzodiazepine

Front 21

Clonazepam (Klonopin®)

Back 21

Intermediate-acting agent, Benzodiazepine

Front 22

Lorazepam (Ativan®)

Back 22

Intermediate-acting agent, Benzodiazepine

Front 23

Triazolam (Halcion®)

Back 23

Short-acting agent, Benzodiazepine

Front 24

Alprazolam (Xanax®)

Back 24

Short-acting agent, Benzodiazepine

Front 25

Mechanism for Benzodiazepines

Back 25

● Bind to the GABA-benzodiazepine-chloride receptor
● Act as receptor agonists
● Facilitate the binding of GABA but do not directly
stimulate the receptor. GABA is a ligand-gated ion channel.
● Increase the affinity of the receptor for GABA
● Increase the influx of chloride and hyperpolarization

Front 26

GABA a1 sites

Back 26

mediate sedation, amnesia, and ataxic effects of benzodiazepines

Front 27

GABA a2 and a3 sites

Back 27

anxiolytic and muscle-relaxing actions

Front 28

GABA a5 sites

Back 28

some of the memory impairment

Front 29

GABA receptor, drugs for insomnia

Back 29

● Bind more selectively only with GABAA-receptor
isoforms that contain α1 subunits
Other agents affecting GABAA receptors include:
● Alcohol
● Barbiturates
● Intravenous anesthetics etomidate and propofol
● Alphaxalone (anesthetic steroid)
● Volatile anesthetics such as halothane

Front 30

Benzodiazepines
Mechanism of Action (biological)

Back 30

Sites of action are different for different responses
Limbic system (amygdala and orbitofrontal cortex)
● Anxiolytic properties (removing fear)
● Benzodiazepines may reset a high amygdala
threshold
Cerebral cortex and brain stem
● Sedation, increased seizure threshold, cognitive
impairment, muscle relaxation

Front 31

Amygdala and orbitofrontal cortex - Benzodiazepines

Back 31

Low doses: moderate anxiety, agitation and fear

Front 32

Cerebral Cortex and Hippocampus - Benzodiazepines

Back 32

Low doses: mediate mental confusion and amnesia

Front 33

Spinal cord, brain and cerebellum - Benzodiazepines

Back 33

Low Doses: Muscle Relaxation

Front 34

Metabolism and Excretion of Benzodiazepines

Back 34

● Long-acting agents are typically metabolized to
active intermediates that remain longer
● Short-acting agents are typically metabolized
to inactive metabolites

Front 35

Benzodiazepines in the Elderly

Back 35

● Elderly have reduced ability to metabolize long-acting
benzodiazepines and active metabolites
● Half-lives are greatly increased in the elderly
● The cognitive dysfunction can be clinically detrimental
in the elderly so used with caution
● Widely reported increase in the incidence of falls and
fractures for elderly using benzodiazepines

Front 36

Benzodiazepines - Clinical uses and limitations

Back 36

● Act as anxiolytics but not antidepressants
● Adverse effects and dependency potential limit
their usefulness
● Used for short periods (few days up to 3 to 4 weeks)
● Only for conditions where short-term therapy is
beneficial
◦ Short term anxiety
◦ Short term insomnia
◦ Anterograde amnesia for medical procedures
◦ Treatment of alcohol withdrawal
◦ Antiepileptic action

Front 37

When to avoid Benzodiazepines

Back 37

● Situations requiring fine motor control, cognitive
skills or mental alertness
● Situations involving alcohol or other CNS
depressants
● Use with the elderly, children or people with a
history of abuse

Front 38

flunitrazepam (Rohypnol®)

Back 38

● Date rape drug with strong amnesic properties
● Street slang = Roofie

Front 39

Side Effects and Toxicity of Benzodiazepines

Back 39

● Extension of the effects noted previously at low doses
● Hypnosis also at high doses
● Rebound increases in anxiety and insomnia
with cessation
● Respiration is not seriously depressed even at
high doses

Front 40

Tolerance and Dependence of Benzodiazepines

Back 40

Dependence and tolerance develop with long term
use but most withdrawal symptoms subside in
1 to 4 weeks

Front 41

Pregnancy and Benzodiazepines

Back 41

● Benzodiazepines and metabolites move across the
placenta
● Small risk of birth defects in the first trimester
● High doses at birth can cause “floppy infant
syndrome” and withdrawal

Front 42

Flumazenil (Romazicon®)

Back 42

Benzodiazepine receptor agonist.
● Binds to benzodiazepine receptor with high affinity but
produces no effect on GABA signaling
(doesn’t do much on its own)
● Reverses the antianxiety and sedative effects of
benzodiazepines
● Short half-life
● Utilized as a benzodiazepine antidote

Front 43

Benzodiazepine Receptor Agonists (BZRAs)

Back 43

n All act at GABA receptors and facilitate
GABA action
Drugs have variable chemical structures
and are generally classified into two groups
● Benzodiazepines

Front 44

Nonbenzodiazepine BZRAs

Back 44

● Prescribed as hypnotics
● Not prescribed as anxiolytics due to short half-lives

Front 45

Zolpidem (Ambien®)

Back 45

● Used for short term treatment of insomnia (primarily
sedative rather than anxiolytic)
● No anxiolytic, anticonvulsant or muscle relaxant
effects but has amnesic effects

Front 46

Zaleplon (Sonata®)

Back 46

● Used for short term treatment of insomnia
● Unique due to its very short half-life (less than one hour)
- Can be taken if there are difficulties falling
asleep (no predicting)
- No detrimental morning effects
- No rebound effects since dependence is unlikely

Front 47

Eszopiclone (Lunestra®)

Back 47

● Used for the short term treatment of insomnia
● Has the longest half-life (5 to 7 hours)
- Probably the most effective for improving sleep
latency and maintenance
- Effectiveness is offset by its sedation the next day

Front 48

Ramelteon (Rozerem®)

Back 48

Melatonin Receptor Agonist.
● Used for insomnia with difficult in sleep onset
● Nonaddicting and devoid of abuse potential
● No rebound insomnia
● Leaves little morning drowsiness
● Efficacy appears to be modest
● No controlled studies against nonbenzodiazepine BZRAs

Front 49

Serotonin Receptor Agonists as Anxiolytics

Back 49

Anxiety may be due in part to defects in serotonin
neurotransmission and drugs that augment serotonin activity
may aid in treatment.
● Six available selective serotonin reuptake inhibitors (SSRIs)
available
● Drugs of first choice to treat anxiety
● Activates 5-HT1A receptors that diminish neuronal
activity and fear
● Slow onset of action (other medications for rapid control)
● Also used as antidepressants (covered future lectures)

Front 50

Buspirone (BuSpar®)

Back 50

● Selective 5-HT1A agonist
● Unique anxiolytic properties
● No sedation or hypnosis even in overdosages so it is
ineffective in promoting sleep
● Minimal amnesia, mental confusion and psychomotor
impairment
● Does not potentiate CNS depressants
● No cross-tolerance or cross-dependence with
benzodiazepines
● Little potential for abuse or addiction
● Has an additional antidepressant effect
● It is characterized by much slower onset of action than
benzodiazepines

Front 51

General Effects of CNS depressants

Back 51

Sedative Effects: Reduce anxiety and exert a calming effect.
Hypnotic Effects: They produce drowsiness and sleep onset
Anesthesia and Coma: Can occur at high doses

Front 52

CNS depressants: Sites of Action

Back 52

● Augment GABA activity
- These agents do this in different ways
● Some may reduce glutamate excitatory activity
(NMDA)

Front 53

Abuse of CNS depressants

Back 53

-Tolerance (and cross-tolerance) can develop (Significant to inebriation, but much less tolerance to lethal respiratory depression or cognitive/memory effects)
-Dependence (and cross-dependence) can develop
1) Physical dependence and abstinence syndrome
● Withdrawal signs ranging from sleep disturbances to
life-threatening convulsions
2) Psychological dependence
● Follows from positive reinforcement effect of the drugs

Front 54

Alcohol

Back 54

-Alcohol is the second most widely used psychoactive
substance
-Generated by fermentation
-Consumption of alcohol by man dates back to at least
about 10,000 BC
-Alcohol has been used for nutrition, medicine, ritual and even payment for services rendered

Front 55

Alcohol use in the US

Back 55

7/10 of people don't or consume a low risk amount of alcohol.
3/10 are high risk, heavy drinkers
17.6 million people have a drinking problem

Front 56

Alcohol Pharmacokinetics

Back 56

-Rapidly absorbed in GI tract
● About 10 to 20% is absorbed in the stomach
● About 80 to 90% is absorbed in the upper intestine
-Cells in the stomach contain alcohol dehydrogenase (ADH)
● Men under age 50 have more stomach ADH than women
● Slowed gastric emptying decreases alcohol absorption

Front 57

Alcohol distribution in body

Back 57

- Depends on blood supply to tissue
● Ethanol rapidly crosses blood-brain barrier
● The CNS is highly vascularized
- Fat is more poorly perfused than muscle tissue
● Men usually have more muscle and less fat than women
● The blood alcohol concentration (BAC) of women is higher for a given amount of alcohol
-Ethanol freely crosses placenta
● Issues: FAS or FASD

Front 58

Alcohol Metabolism

Back 58

- Alcohol dehydrogenase metabolizes about 90-95% of the ethanol ingested
● About 85% of this is performed in the liver
● Up to 15% of this is inactivated in the stomach
- cytochrome p450 family of enzyme: small amount
-The lungs excrete a small unchanged amount
● An exhaled air:venous blood alcohol ratio of 1:2300 exists
● Breathalyzer
-A small amount is also secreted unchanged in other fluids (e.g. urine)
Alcohol is metabolized at 0.015% per hour
Zero order kinetics, doesn't depend on alcohol concentration

Front 59

BAC Gender Differences

Back 59

- Differences in gastric ADH levels
● Levels in men are greater than in women
- Differences in body fat
● Fat is less vascularized than muscle
● Women have a higher percentage of body fat

Front 60

Determination of BAC

Back 60

DETERMINATION OF BLOOD ALCOHOL CONCENTRATION
(BAC)
Blood alcohol is expressed as g% (grams of ethanol/ 100 milliliters
of blood) and assumes the specific gravities of alcohol and blood
are equal (one gram = one milliliter)
● What is the safe driving level?
● What is the level for AUTOMATIC Legal intoxication?
● What are fatal levels

Front 61

One Drink

Back 61

The amount of alcohol a person can metabolize in one hour(about 10ml) which is 1 oz 80 proof liquor, 3.5 oz of 12% wine or 12ozs of 3.2% beer

Front 62

Alcohol: Pharmalogical Effects

Back 62

-Behaviorally reinforcing
-Alcohol dilates blood vessels,
-Low doses reduce risk of cardiovascular disease
-Low to moderate doses (2 drinks/day) reduce strokes
-High doses (> 5 drinks/day) increase strokes
-Diuretic effects (inhibits vasopressin release)
-Sexual behavior
● Lower doses disinhibition of behavior
● Higher doses of alcohol cause inhibition of sexual
behavior
● Chronic use of ethanol causes suppression of
reproductive function

Front 63

Chronic Effects of Alcohol

Back 63

1) Metabolic (Pharmacokinetic)
● Liver increases alcohol metabolizing enzymes
2) Tissue or functional tolerance (Pharmacodynamic)
● Neurons adapt to drug
-Appear less intoxicated but still have cognitive and memory defects
3) Behavioral tolerance
● become conditioned to adjust to drug effects

Front 64

Alcohol withdrawal symptoms

Back 64

-Jumpiness or nervousness
-Shakiness
-Anxiety
-Irritability or easy excitability
-Rapid emotional changes
-Depression
-Fatigue
-Difficulty thinking clearly
-Bad dreams
Mild-to-moderate physical symptoms:
-Headache: general, pulsating
-Sweating: especially the palms of the hands or the face
-Nausea and vomiting
-Loss of appetite
-Insomnia
-Pallor
-Rapid heart rate
-Dilated pupils
-Clammy skin
-Tremor of the hands
-Involuntary, abnormal movements of the eyelids
Severe symptoms:
-Delirium tremens: severe form of alcohol withdrawal
-Agitation
-Fever
-Convulsions
-Delirium: severe, acute loss of mental functions

Front 65

Disulfram (Antabuse)

Back 65

An alcohol sensitizing drug
Mechanism of action(s):
1) Inhibit aldehyde
dehydrogenase
2) Also may work by
Modulating neurotransmitters
involved in addiction
End result: alcohol ingestion causes build up of acetaldehyde
Efficacy of disulfiram for treatment of alcoholism has been called into question may have utility in treating cocaine dependence

Front 66

NALTREXONE (REVIA, VIVITROL)

Back 66

Goal: Reduce craving for alcohol
Mechanism of action: opioid antagonist, thought that
reinforcing properties of alcohol involve opioid systems
Effects are small, but issue with non-compliance
Evidence that genetics may influence efficacy
Vivitrol- extended release, injectable naltrexone

Front 67

ACAMPROSATE (CAMPRAL)

Back 67

Thought to restore balance of GABA/glutamate
neurotransmission
Mechanism of action: thought to have GABA-agonistic
action and an inhibitory action at NMDA receptors
Approved mainly on data from studies in Europe
META-ANALYSIS showed some benefit

Front 68

Issues with Barbiturate Use:

Back 68

1. Lethal in overdose
2. Narrow therapeutic-to-toxic range
3. High potential for tolerance, dependence and abuse
4. Can have dangerous drug interactions

Front 69

Some Clinical Uses of Barbiturates:

Back 69

1. Anticonvulsants
2. Anesthetics
3. Provide

Front 70

BARBITURATE PHARMACOKINETICS: SOLUBILITY

Back 70

Different solubilities
a. Ultrashort duration agents
● Exceedingly lipid soluble
● Rapidly absorbed into the CNS
● Then rapidly distributed throughout the body
b. Intermediate duration agents
● Lipid and water solubilities between ultrashort and
long duration agents
● Most likely class of barbiturates to be abused
c. Long duration agents
● More water soluble than the other two classes of
barbiturates
● Less rapidly absorbed into the CNS than other
barbiturate classes
● Longest half-lives of the classes of barbiturates
Long half life barbituates are used for Epilepsy.
Intermediate half life barbituates are used for Insomnia.
Short half life barbituates are used for Anesthesia

Front 71

Barbituates: Pharmacodynamics

Back 71

1) Act to facilitate GABA activity
- GABA receptor is a chloride channel,
- Thought to increase the duration of the chloride channel
openings caused by GABA
2) At high doses may open the channel in the absence of
GABA
- Differs from benzodiazepines
3) Can depress the actions of the excitatory
neurotransmitter glutamate
4) Can also have effects on cell membranes in parallel to
their effects on neurotransmitter receptors
> differences in effects between barbiturates and
benzodiazepines

Front 72

Barbiutates: Pharmalogical Effects

Back 72

>Generally considered unselective CNS depressants
-Low degree of selectivity and low therapeutic index and can

Front 73

Barbituates: Withdrawal

Back 73

-From clinical doses: usually causes sleep difficulties
-Withdrawal from higher doses: May result in hallucinations, restlessness, disorientation, and even convulsions

Front 74

Methaqualone (Quaalude)

Back 74

Non-Barbituate Sedative
● Highly abused in the 1980s
● Served as an early date rape drug since it had
amnesic properties
● It is now banned from sale

Front 75

Chloral hydrate (Noctec)

Back 75

● It is rapidly metabolized to trichloroethanol
● Added to alcohol it forms a

Front 76

GAMMA HYDROXYBUTYRATE (GHB)

Back 76

In some countries used as anesthetic
Used to treat narcolepsy (Xyrem)
Sedative/hypnotic
Abused
Used as a

Front 77

Depression

Back 77

Is the fourth most disabling disease worldwide.
Depression worsens the health of people with other
chronic diseases and is associated with increasing
disability over time

Front 78

Depression Incidence

Back 78

10% of men and 25% of women experience depression
in their lives.
Depression is responsible for 70% of psychiatric
hospitalizations.
Depression is responsible for 40% of suicides.
Only about 21% of cases yearly are adequately treated.

Front 79

Depression is an Affective Disorder

Back 79

Diagnosis based on presence of at least 5 symptoms
daily (or almost every day) for at least two weeks.
Symptoms involve energy, sleep, mood, self-concept, weight, thoughts of suicide.
Anxiety is also seen in many patients with depression
(Antidepressant drugs are indicated for anxiety)

Front 80

Depression Symptoms

Back 80

w Persistent sad, anxious or "empty" feelings
w Feelings of hopelessness and/or pessimism
w Feelings of guilt, worthlessness and/or helplessness
w Irritability, restlessness
w Loss of interest in activities or hobbies once
pleasurable, including sex
w Fatigue and decreased energy
w Difficulty concentrating, remembering details and
making decisions
w Insomnia, early–morning wakefulness, or excessive
sleeping
w Overeating, or appetite loss
w Recurrent thoughts of death or suicide, suicide
attempts
w Persistent aches or pains, headaches, cramps or
digestive problems that do not ease even with
treatment

Front 81

Major Depressive Disorder

Back 81

w MDD is characterized by a combination of symptoms that
interfere with a person's ability to work, sleep, study,
eat, and enjoy once–pleasurable activities.
w MDD is disabling and prevents a person from functioning
normally
w An MDD episode may occur only once in a person's
lifetime
w Often MDD recurs throughout a person's life

Front 82

Dysthymic Disorder

Back 82

w also called dysthymia
w dysthymia is characterized by long–term (two years or
longer) but less severe symptoms compared to MDD
w Symptoms may not disable a person but can prevent one
from functioning normally or feeling well
w People with dysthymia may also experience one or more
episodes of major depression during their lifetimes

Front 83

Postpartum Depression

Back 83

w Is diagnosed if a new mother develops a major
depressive episode within one month after delivery
w It is estimated that 10 to 15 percent of women experience
postpartum depression after giving birth

Front 84

Seasonal Affective Disorder

Back 84

w Is characterized by the onset of a depressive illness
during the winter months
w Is related to the relative lack of natural sunlight
w The depression generally lifts during spring and summer
w SAD may be effectively treated with light therapy, but nearly half of those with SAD do not respond to light
therapy alone
w Antidepressant medication and psychotherapy can reduce SAD symptoms, either alone or in combination with light therapy

Front 85

Neurogenic Theory

Back 85

● Existing neurons can repair and remodel
● The brain can make new neurons
● Depression is associated with the damage and loss
of neurons
● Depression is associated with the failure to make
new neurons

Front 86

Pathophysiology of Depression

Back 86

w For understanding depression, neurogenesis in the
hippocampus and the frontal cortex are thought to be
critical
w Hippocampus influences attention, concentration and memory
w Hippocampus is sensitive to trauma including stress, some hormones, low oxygen, low sugar, toxins,
infections
w Long-term depression is associated with a shrinking
hippocampus (net loss of neurons)
w Dendrites and neurons overall become smaller in size
w The timing of neurogenesis and net neuron gains in
response to antidepressant drugs fits with the time
frame of therapeutic response in patients

Front 87

Pathophysiology of Depression: Mechanistic Description

Back 87

w Activation of adenylate cyclase and Ca2+ dependent
kinase pathways enhance that activity of the Cyclic
AMP response-element binding protein (CREB)
w CREB is a transcription factor that binds to DNA to
regulate the expression of other genes
w Brain-derived neurotrophic factor (BDNF) is thought to be a key transcriptional target for CREB.
Inadequate neurotransmitter activity for serotonin and/
or NE thought to lead to less CREB and BDNF activity
in individual suffering depression

Front 88

Brain-derived neurotrophic factor (BDNF)

Back 88

BDNF is thought to be key
● BDNF affects the normal development and
health of the nervous system
● Chronic stress decreases the production of
BDNF
● BDNF is decreased in blood levels in depressed
patients (reversed with antidepressants)

Front 89

TCAs

Back 89

w Block presynaptic norepinephrine and serotonin
reuptake transporters
w Block postsynaptic histamine, acetylcholine and
norepinephrine receptors

Front 90

TCAs side effects

Back 90

w Anticholinergic activity can lead to confusion, memory
and cognitive impairment, dry mouth, blurred vision,
increased heart rate, and urinary retention
w Antihistaminic activity can cause drowsiness and
sedation
w Antiadrenergic effects can cause postural hypotension
w Life-threatening effects are a concern, especially for
overdose in a patient population that may consider
suicide
● Cardiac effects like arrythmias
● Excitement and convulsions
● Respiratory depression and coma

Front 91

1st generation MAOIs

Back 91

Drugs are inhibitors of monoamine oxidases
● MAO-A metabolizes dopamine, norepinephrine
and serotonin
● These antidepressants inhibit this form causing
neurotransmitter build-up
● MAO-B metabolizes dopamine
w Three MAOIs have been used to treat major
depressive illnesses
w A representative agent is phenelzine (Nardil®)

Front 92

MAOIs and Tyramine metabolism

Back 92

w In addition to therapeutic action on neurotransmitters,
MAOIs inhibit tyramine metabolism
w Tyramine is at significant levels in several foods
including cheese, wine, beer, liver, some beans,
fermented and/or pickled sauces and vegetables,
cured and/or aged meats, others
w Tyramine increases blood pressure
w Eating a high tyramine food like cheese while taking a
MAOI drug can easily raise systolic blood pressure
30mm-HG or more
w In extreme cases, ingesting tyramine containing foods
while taking MAOIs can cause an “adrenergic storm”
causing extreme tachycardia, extreme hypertension,
and possibly death
w MAOIs also have drug interactions with some nasal
sprays, antiasthma and cold medicines

Front 93

Trazodone (Desyrel®) Mechanism of Action

Back 93

- Does not block the reuptake of norepinephrine or
serotonin
- Trazodone blocks 5-HT2 receptors
- Its metabolite m-chlorophenylpiperazine is a
serotonin agonist

Front 94

Trazodone (Desyrel®) side effects

Back 94

- Drowsiness is most common
- Priapism is a rare but more serious side effect
- Priapism requires surgery in about 33% of cases
and can cause permanent impotence
- Trazodone has only modest effects on cognitive
functioning even with overdoses

Front 95

SSRIs Mechanism of Action

Back 95

Ÿ All act as serotonin reuptake inhibitors
Ÿ Some also act as norepinephrine reuptake blockers
Ÿ These agents vary greatly (12-fold) in their ability to
block norepinephrine reuptake
Ÿ Citalopram is the most selective for 5-HT
Ÿ Fluoxetine is the least selective for 5-HT

Front 96

citalopram (Celexa®)

Back 96

SSRI - most selective for 5-HT

Front 97

fluoxetine (Prozac®)

Back 97

SSRI - least selective for 5-HT, helps treat bulimia

Front 98

paroxetine (Paxil®)

Back 98

SSRI

Front 99

sertraline (Zoloft®)

Back 99

SSRI

Front 100

fluvoxamine (Luvox®)

Back 100

SSRI

Front 101

escitalopram (Lexapro®)

Back 101

SSRI

Front 102

SSRI side effects

Back 102

Ÿ Very few anticholinergic and antihistaminic
effects except for fluoxetine which is very
sedating
Ÿ These drugs are not fatal in overdose
(No cardiac toxicity like TCAs)
w Sexual dysfunction occurs in up to 80% of patients
w Sexual dysfunction may reduce compliance
w Other side effect can include insomnia, anxiety,
agitation, or nausea
w Treatment options may involve antidepressant class
switching or use of erectile dysfunction drugs

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Current Theory on SSRI Actions

Back 103

w Therapeutic and side effects are due to are due to
postsynaptic actions of serotonin
w Serotonin action at 5-HT1 receptors produces
antidepressant and anxiolytic effects
w Serotonin actions at 5-HT2 receptors produces
adverse effects including insomnia, anxiety, agitation,
sexual dysfunction
w Serotonin actions at 5-HT2 receptors may cause
“serotonin syndrome” at high doses
w Serotonin actions at 5-HT3 produces adverse effects
including nausea

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"Serotonin Syndrome"

Back 104

Caused difficulties due to conjoint medication of SSRIs and natural remedies.
w Cluster of responses due to high doses or increased
serotonin due to drug combination
- Cognitive disturbances (disorientation, confusion)
- Behavioral agitation and restlessness
- Autonomic nervous system dysfunction (fever,
hypertension, tachycardia, others)
- Neuromuscular impairment (ataxia, increased
reflexes, myoclonus)
w Correlated to specificity for serotonin reuptake
transporter
w Paroxetine is most implicated in causing serotonin
syndrome
w May occur when SSRIs are used in combination with
St. John’s wort or valerian root
w Generally resolves in 24 to 48 hours of drug
discontinuation

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Serotonin Discontinuation Syndrome

Back 105

w Occurs in 60% of patients upon abrupt cessation of
SSRI drug intake
w Onset is within a few days and it usually lasts 3 to 4
weeks
w Includes five core somatic symptom sets:
disequilibria, gastrointestinal symptoms, flulike
symptoms, sensory disturbances, and sleep
disturbances
w Thought to be due to relative deficiency of serotonin

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Dual-Action Anti-Depressant, Venlafaxine (Effexor®)

Back 106

inhibits both serotonin and
norepinephrine reuptake
w Inhibits serotonin reuptake at lower doses
w No anticholinergic and antihistaminic effects
w Comparable efficacy to imipramine in treating OCD

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Venlafaxine (Effexor)

Back 107

Ÿ Sexual dysfunction
Ÿ Increases blood pressure in a low percentage of
patients
Ÿ Possibly more toxic in overdose than other
SSRIs

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Duloxetine (Cymbalta®)

Back 108

seems to have more complete
blockade of reuptake systems than venlafaxine
w Also appears to reduce headache, backache, muscle
and joint pain
w Approved for the management of neuropathic pain of
diabetic peripheral neuropathy
w Most prevalent side effects are nausea, dizziness,
and dry mouth

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Bupropion (Welbutrin®)

Back 109

w Bupropion (Welbutrin®) is the only dopamine-
norepinephrine reuptake inhibitor (DNRI)
w Does not affect serotonin reuptake so it does not have
the side effects of SSRIs
w Dopamine potentiation is used to treat children with
ADHD
w Produces effects of minimal sexual dysfunction or
enhanced sexual functioning

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Bupropion (Welbutrin) side effects

Back 110

w Bupropion (Welbutrin®) may result in weight loss
w Bupropion general side effects include anxiety,
restlessness, tremor and insomnia
w Bupropion serious side effects include psychosis and seizures
w Bupropion has a mechanism like cocaine but it is not generally abused

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Burpropion and smoking

Back 111

● Approved in 1997 as a treatment for smoking cessation
● Twice as many people treated with bupropion as with
placebo have a reduced urge to smoke
● Patients appear to experience fewer mood symptoms
and less weight gain
● Bupropion appears to be about as effective as
nicotine patches in smoking cessation
● Mechanism is unknown
- Drug may mimic nicotine's effects on dopamine
and norepinephrine
- Drug may antagonize nicotinic receptors
- Nicotine has antidepressant effects in some
and bupropion may substitute