Dr. Robert A.

Graf
10/25/06

International Post-Baccalaureate
PharmD. Program (IPBP)

Internal Assessment (IA) Exam

STUDY GUIDE

PHARMACOLOGY- V

© 2006

Notice: The copyright law of the United States (Title 17, United States Code) governs the
making of photocopies or other reproductions of copyrighted material. The courses herein
may contain a variety of copyrighted material, which are made available to you for your
educational use only. You may not disseminate these materials further without the express
written consent of the copyright holder.
 Dr. Robert A. Graf
10/25/06

TABLE OF CONTENTS:
1. INTRODUCTION TO THE CNS: PHARMACOLOGICAL PERSPECTIVE
2. DRUG CLASSES BY ACTION OR DISEASE STATE
A. ALCOHOL AS A DRUG
B. SEDATIVE-HYPNOTICS
C. ANTICONVULSANTS
D. PARKINSONISM
E. ALZHEIMER DISEASE
F. ANTIPSYCHOTICS
G. ANTIDEPRESSANTS

Learning Objectives: The overall goal of this section is to learn the underlying
pertinent anatomy and physiology to understand the condition or disease state.
Additionally, drugs are introduced along with their mechanisms of action, with
selective pharmacokinetic and pharmacodynamics properties, and side effects. It is
the goal of the student to identify with and associate the fundamental key concepts
for drugs with their role in the body and the effects that these drugs have on the
body, including desired and adverse effects.

1. INTRODUCTION TO THE CNS: PHARMACOLOGICAL PERSPECTIVE

Ninety-nine percent of all psychoactive drugs work

at the level of the synapse. Thus, we must look at
how synapses work. For the purposes of
understanding drug action, all the billions of synaptic
connections can be reduced to synapses and a few
neurotransmitters in the brain, as depicted in the
“head diagram” to the right.

Key elements of synaptic transmission:

Impulse conduction
Synthesis
Storage
Release
Inactivation or Uptake
Receptor activation
Signal transduction/responses

Cellular components of the central nervous

system

Elements of the Nervous System

Synapses are connections between neurons and are specialized for electrical and chemical communication.
 Dr. Robert A. Graf
10/25/06

Communication Properties key for electrical information transfer from one neuron to another:
a. impulses convey information in electrical form
b. neurotransmitters convey chemical information across synapses
c. Synaptic transmission encompasses all of these concepts
1. electrical
2. Ca mediated synaptic vesicle release of neurotransmitter
3. Diffusion of
transmitter across
the synaptic cleft
4. Activation of
postsynaptic
receptors
action potential --> Ca influx -->
fusion of vesicles --> release in
synaptic cleft
Individual Channel Proteins and
Receptors
a. Voltage
operated/gated/sensitive channels
1. excitatory category includes:
a. sodium
b. calcium
2. inhibitory category includes:
a. potassium
b. chloride
b. Ligand gated receptors (Rs):
These pass
ionic currents:
1. Excitatory:
i. NMDA-R (agonist: glutamate)
ii. AMPA-R (agonist: glutamate)
iii. ACh-R (agonist:
acetylcholine)
iv. histamine
2. Inhibitory
i. Glycine R (agonist: glycine)
ii. GABA R (agonist: GABA)
(pass choloride)
iii. opioid receptors (pass
potassium)
3. Excitatory and inhibitory
i. dopamine (no ions pass)
ii. norepinephrine (no ions pass)
iii. metabotropic glutamate receptors (no ions pass)

Chemical driving force determines the direction of ion flux. Imagine a dam that holds water as an analogy.
You can see which way the water would flow if you put a hole in the dam left-right. This is the driving
force for the ion: K flows to the right, Na to the left.
 Dr. Robert A. Graf
10/25/06

drivingforce determines the direction of ion

flInside Outside

K
+

+ Na
+ Ca
+ Cl

The selectivity of CNS action is based upon the idea that different transmitters are used
by different neurons.
Presynaptic mechanisms:
transmitter:
synthesis: p-chloropheylalanine blocks
storage: reserpine depletes vesicles of
transmitter
release: capsaicin --> promotes
substance P release
uptake: cocaine blocks the update of
catecholamines at adrenergic
uptake: Anticholinesterases block the
degradation of ACh and prolong its
action.
 Dr. Robert A. Graf
10/25/06

Postsynaptic receptors mediate the cellular response. Their integration determines

whether information is transmitted.

Postsynaptic mechanisms operate at the level of these receptors.

ACh receptor
nicotinic (Na, K)
muscarinic (K)

GABA receptors
A (Cl influx)
B (Cl influx)

Opioid receptors (all open K)

µ (Greek letter mu)
κ (Greet letter kappa)
σ (Greek letter sigma)

Longer Term Effects to Drug Exposure: Down and up

regulation of receptors (days to weeks)

Tolerance involves a decreased response to the effects of

a drug.
The cellular basis of functional tolerance (the most common form) is
that the cell compensates to the prolonged exposure of the agonist by
down regulating
membrne proteins (channels, receptors) and effector
enzymes that mediate the response.
Downregulation Example: Chronic administration of sedatives such
as benzodiapezines can lead to down-regulation of GABA-A receptors
and functional tolerance.
Upregulation: Chronic block of neurotransmitter release can lead to
up-regulation of the postsynaptic receptors.

2. DRUG CLASSES BY ACTION OR DISEASE

STATE

A. ALCOHOL AS A DRUG

I. Ethanol
1. Introduction
Alcohol has been used by humans for over 8,000 years. In western society, beer and wine
were a main staple. Water was often unfit to drink and a source of illness. Liquor provided
calories. In the 1800s, beer and wine became less important for survival. Distilled beverages
appeared and alcohol moved into the realm of recreation and abuse. In the US, 75% of the
society drinks regularly and most of the population enjoys the pleasurable effects of without
allowing the level of consumption to become a health risk. In fact, moderate consumption
may protect against cardiovascular disease.
2. Abuse: the condition where people are unable to limit their ethanol consumption. 10% of the
population (20 million for the US). 70 g of ethanol (EtOH) is about one six pack of beer and
is roughly the amount an alcoholic consumes each day. Fetal alcohol syndrome exposes the
unborn fetus to alcohol. This syndrome is widely understood by the general public yet it is
estimated to occur in 1 of 300 births, which demonstrates the seriousness of alcohol addiction.
 Dr. Robert A. Graf
10/25/06

Consequences of maternal ingestion of alcohol can include miscarriage, stillbirth, low birth
weight, slow postnatal growth, microcephaly, mental retardation, and many other
abnormalities.
3. Alcoholism: a condition where the person continues to drink despite serious societal and
social consequences. There are genetic determinants (adenylyl cyclase). 30% of all hospital
admittees have alcohol problems. Alcohol seriously effects both the CNS and liver (see
below). Onset and progress occurs without evidence of nutritional abnormalities.
4. Pharmacokinetics of Ethanol:
a. Absorption: G-I tract, crosses membranes readily, peak levels in 30 min on empty
stomach
b. Distribution: by volume of water in body, Women have a higher peak concentration for a
given dose because women have a lower total water content than men. Rapidly tissue
levels approximate plasma levels; EtOH readily enters the CNS.
c. Elimination: urine; the rate of oxidation is proportional to the body weight or liver
weight. In fact, the rate of disappearance of EtOH
from the body is markedly reduced by liver damage.
Elimination rate is 150 –220 mM/hr, or one 10 oz.
Beer, 3.5 oz. of wine, or 1 oz distilled 80 proof
spirits.
d d. Mechanism of action:
e Physiological effects:
f i. CNS: Alcohol effects many cellular proteins
including neurotransmitter receptors for amines, amino
acids and opioids. Enzymes are affected including Na-
K-ATPase, acetylcholine esterase, adenylyl cyclase, and
phospholipase C, mitochondrial electron transport
chain, NMDA receptors, and calcium channels are also
affected by EtOH. Alcohol enhances GABAergic
responses.
g
h What specific cellular mechanisms does alcohol act
upon in neurons of the CNS?
i In trigeminal neurons, action potentials, EPSPs and
IPSPs are depressed. In Purkinje cells of the cerebellum
and dopamine neurons of the substantia nigra, low EtOH
enhance action potential rate; whereas high EtOH concentrations inhibit action potential rate.
Only inhibitory responses have been observed in hippocampus, lateral geniculate, and locus
ceruleus.
ii. Liver: Alcohol fatty liver progresses to hepatitis to cirrhosis and finally liver failure.
Patients who drink and have hepatitis B or C tend toward more severe liver disease.
j iii. Heart: Depression of myocardial contractility which puts extra strain on the heart
k iv. Smooth Muscle: EtOH acts as a vasodilator. CNS input causes relaxation due to
depression of the vasomotor center together with direct effects of the accumulating metabolite
acetaldehyde on smooth muscle. In severe cases, hypothermia is caused by EtOH-induced
vasodilation in cold environments. Ethanol relaxes the uterus – was used for the suppression of
premature labor. More effective agents for this are now in use and include: calcium channel
blockers, magnesium ion, NSAIDs, β2-adrenoceptor stimulants.

e. Drug Interactions: EtOH plus CNS depressants often leads to death. The mechanism of action
involves medulla depression which leads to respiratory failure.

f. Toxicity: One must ingest a lot of EtOH to get direct toxicity effects -- enough to qualify it as
a food. Toxicity can lead to liver disease, cancer, accidents, and suicide. NAD/NAD+ builds-up as
a metabolite of EtOH metabolism and leads to a decrease in liver neoglucogenesis, hypoglycemia,
and to ketoacidosis. Triglyceride synthesis is responsible for the fatty deposits in liver
 Dr. Robert A. Graf
10/25/06

parenchyma. Acetaldehyde promotes collagen production and stimulates hepatic inflammation.

Other G-I associated effects of EtOH include gastric and pancreatic secretion which injures the
small intestine and often causes diarrhea. Eventually these injuries can lead to blood and plasma
protein loss from ulcers, weight loss.

5. Behavioral effects of EtOH on the CNS

EtOH depresses all parts of the brain in phases:
1) Excitement:
Depresses all parts of the brain.
Depression of higher inhibitory centers releases the normal control mechanisms responsible
social and behavioral
restraint.
2) Thought processes:
@ 0.05% (50 mg/dl) you lose:
fine discrimination
judgment
motor function sequentially
impaired

@ 0.1% (100 mg/dl) you lose:

legal limit for operating a motor
vehicle in most states
error in judgment are frequent
motor systems are impaired
responses to complex auditory/visual
stimuli are altered.

@ 0.15 - 0.2% (150-200 mg/dl)

legally drunk in most states
ataxia noticeable
walking becomes difficult
staggering becomes common
reaction times increase
behavior often becomes loud lighter hatching indicates EtOH-induced
incoherent speech impairment in figure above.
emotionally instability darker hatching indicates EtOH-induced
violent behavior may ensue

@ 0.2 - 0.3% (200-300 mg/dl)

emesis
amnesia or black-out
failure to recall events
anesthesia ensues
with a low "margin of safety"

@ > 0.3% coma (300 mg/dl)

@ 0.4 - 0.5% (400 - 500 mg/dl) lethal

6. Tolerance and Dependence:

a. Physical dependence exists since people experience withdrawal upon abruptly
discontinuing use. Dependence is the requirement of a user to either provide the usual or
greater dosage of substance to keep withdrawal symptoms from setting-in.
b. Psychological dependence is characterized by a desire to experience the rewarding effects
of alcohol and, for current drinkers, a desire to avoid the negative consequences of
withdrawal.
c. Withdrawal symptoms
 Dr. Robert A. Graf
10/25/06

1. The molecular mechanisms are still not completely understood.

2. It is known that upregulation of NMDA receptors and calcium channels occurs in
neurons.
3. There is GABAergic involvement since benzodiazepines can substitute for alcohol
during withdrawal.
4. Acute EtOH use has been shown to increase serotonin, dopamine, and opioid levels,
whereas chronic EtOH use has been shown to lower these neurotransmitter levels.
5. Chronic EtOH use has been shown to alter the effects of MAO and adenylyl
cyclases, so these enzymes are candidates as useful genetic markers for alcoholism.

7. Clinical Intervention/Pharmacotherapy

Acute intoxication can require emergency treatment. This includes the maintenance of an
adequate airway and support of ventilation and blood pressure. It is important to assess the level of
consciousness relative to the blood alcohol concentration. Acetaminophen concentrations should also be
determined. A short-acting narcotic antagonist is generally administered as a precaution. Glucose may
need to be administered in the event of hypoglycemia, ketoacidosis, of dehydration. The loss of body
fluids may also necessitate IV infusion of fluids containing potassium, magnesium, or phosphate.

The first step toward recovering from chronic alcoholism is detoxification of the patient through
rehabilitation followed by psychosocial therapy. Unfortunately, rehabilitation only works at 50% efficiency
because other problems often initiate the alcoholic syndrome. Alcohol problems are also often associated
with other depressive or anxiety disorders.

a. Drug Intervention/Therapy:
One form of therapy focuses on the idea of negative reinforcement after alcohol ingestion. This has been
most successful with patients who seriously desire to stop ingesting alcohol. A conditioned avoidance
response is induced so that the patient abstains from EtOH to prevent the unpleasant effects of Disulfiram-
induced acetaldehyde accumulation.

i. Disulfiram (tetraethylthiuram; ANTABUSE, 500 mg/day for first week or two, then reduce to
250 mg/day) is an antioxidant used in the rubber industry. It is pharmacologically used as an
alcohol deterrent. It causes extreme discomfort to patients who drink EtOH. When EtOH is
administered alone, it has no effect. Contraindications include being acutely intoxicated,
psychosis, and allergy to rubber.
Absorption: rapid and complete from GI tract. A period of 12 hr of abstinence is needed,
followed by 12 more hr for full action.
Physiological effects with EtOH include flushing, throbbing headache, nausea, vomiting, and
sweating.
Disulfiram is metabolized to acetaldehyde, which in turn accumulates. The drug acts by inhibiting
aldehyde dehydrogenase. (Some Asians have a genetic deficiency of aldehyde dehydrogenase and
become flush upon ingesting alcohol.)
Elimination of the drug is slow.
Behaviorally, hypertension and confusion ensue with a few minutes after drinking EtOH.
This effect lasts for 30 min to several hours depending on the severity of the EtOH. The patient
usually sleeps for several hr after this treatment.
Drug interactions: inhibits metabolism of other therapeutic agents, pheyltoin, oral anticoagulants.

Another form of therapy involves taking advantage of a connection found between opioid receptors and
alcohol that decrease the craving for alcohol and blunting the “high” from it.

ii. Naltrexone (Revia; 50 mg/day for alcoholism) is an inhibitor of opioid receptors. It was
observed that when opioid was administered it caused an increase in alcohol drinking. Conversely,
administration of opioid antagonists inhibited self-administration of EtOH. Naltrexone was found to
decrease the rate of relapse and reduced EtOH craving. Thus patients were better able to control their
 Dr. Robert A. Graf
10/25/06

drinking. Along with the decreased craving came a diminution of the subjective ‘high” associated with
EtOH. Naltrexone undergoes first pass metabolism to active and inactive metabolites. Contraindications:
Do not give to patients with hepatitis or liver failure. Also, naltrexone plus disulfiram (see above) should
be avoided since both drugs are potential hepatotoxins. Patients cannot also be taking opioids with
naltrexone since administration will induce withdrawal.
iii. Benzodiazepines: chlordiazepoxide, clorazepate, diazepam, and oxazepam. These
benzodiazepines are often administered to aid in discomfort associated with alcohol withdrawal symptoms.

2B. SEDATIVE-HYPNOTICS
A. Introduction to Anxiety
Anxiety reducing drugs, anxiolytics, exert a calming effect. All of the antianxiety agents
cause some sedation, which is the suppression of responsiveness to a constant level of
stimulation, with decreased spontaneous activity and ideation. Sedative and anxiolytic are
used interchangeably The same drug can function clinically as both anxiolytic and hypnotic
(sleep inducing agents, depending on dosage). Hypnotics induce and maintain sleep.

Episodes of mild anxiety are commonplace, and even healthy, and do not warrant treatment.
Disorders involving anxiety are the most common mental disturbances. The symptoms of
severe chronic anxiety often warrant drug therapy plus some form of behavioral therapy and
are similar to those of intense fear tachycardia, sweating, trembling, palpitations which
involve sympathetic nervous input.
1. General: enhanced concern/worry elicited as vigilant behavior, motor tension, and autonomic
hyperactivity. Anxiety is often secondary to organic disease states such as acute myocardial
infarction, angina pectoris, G-I ulcers.
2. Situational: provoked by anticipation of frightening procedures (surgery), family illness,
tragedy. Includes panic disorder, where alprazolam is a drug of choice.

The ideal sedative has no effect on mental or motor mechanisms. Ideally, CNS depression
should be minimal.
3. Classes of sedative agents include:
benzodiazepine GABA-A agonists (lorazepam, clonazepam, chlordiazepoxide, oxazepam,
chlorazepate, diazepam, alprazolam)
alcohols (chloral hydrate as a hypnotic, usually prescribed to children, duration of action 6 hr)
barbiturates: thiobarbiturates (thiopental)
novel compounds:
buspirone a 5-HT1A partial agonist with properties much like a benzodiazepine (BDZ).
propanediol carbamates: meprobamate (different compounds, equivalent effects to a
barbiturate)
Other classes of compounds that are effective in certain anxiety states and functional disorders.
antipsychotic tranquilizers (prochlorperazine)
tricyclic antidepressants (peroxetine, sertraline)

B. Introduction to Sleep Problems and Hypnotics

The inability to get to sleep or remain asleep is a widespread problem in our society. First we’ll
discuss sleep in physiological terms, then we’ll discuss potential non-pharmaceutical solutions
for insomnia, followed by pharmacological intervention strategies.
1. General introduction to sleep
A. Essential behavior of mammals
B. Readily reversible state, in contrast to coma, for example
C. Subject is: unconscious
assumes a characteristic posture
reduced activity of most voluntary muscles
decreased responsiveness to sensory stimuli.
2. Physiological definition of sleep :
 Dr. Robert A. Graf
10/25/06

Two forms:
i. Dreams (REM = rapid eye movement, 1 min to hr/sleep)
electromyographic eye movements
ACh and NE are involved in REM sleep
Arousal from REM: vivid, illogical, bizarre dream recall
(nightmares)
ii. Polygraphic (NREM = non rapid eye movement; ~ 95
min/sleep)
can decipher NREM looking at brainwaves
Serotonin (5-HT) and GABA are important in NREM sleep
Arousal from NREM: dream not recalled (night terrors,
sleepwalking)
Stages III and IV (NREM) become less prominent as people
age.
Geriatric patients spend much less time in these stages.
Patients with dementia and schizophrenia / depression have pronounced sleep disturbances.

3. Different classes of disorders that involve sleep.

i. insomnias: failure to initiate or maintain sleep
ii. hypersomnias: excessive sleep
iii. parasomnias: dysfunctions associated with sleep; circadian rhythm alterations: jet
lag; shift work changes

4. Behavioral Modification:
Before drug therapy, try behavioral modification:
exercise
reduction of caffeine intake
sleep environment

5. Hypnotics Drug Therapy:

are intended to produce drowsiness and encourage the onset and maintenance of sleep. Individual drugs
differ in the dose versus degree of CNS depression. Hypnotics include benzodiazepines (quazepam,
 Dr. Robert A. Graf
10/25/06

midazolam, estazolam, flurazepam, temazepam, triazolam) , barbiturates (butabarbital, mephobarbital,

pentobarbital) and other compounds (zolpidem). antihistamine agents (hydroxyzine HCl).
These antihistamines are over the counter sleeping pills, they have autonomic properties (called sedative-
autonomic drugs, i.e. hydroxyzine HCl) and a long duration of action. Hypnotics should be prescribed
temporarily (days to weeks).
All drugs work on both normal and ailing subjects.

Barbiturates are not often prescribed as hypnotics anymore (replaced by benzodiazepines) because in
addition to inducing sleep they have some pretty undesirable effects:
REM rebound with intense dream recall and nightmares occurs upon withdrawal.

By studying the various benzodiazepines as a group first, we can sort out which ones are used as
anxiolytics or hypnotics based upon their pharmacokinetic properties. Then we’ll focus on the
barbiturates.

C. Benzodiazepines

1. Introduction
Benzodiazepines are the most important sedative-hypnotics. These are all 1,4 benzodiazepines. Most
contain a carboxamide group in the 7-membered heterocyclic ring structure. This is required for the
sedative-hypnotic effect and is often a halogen or nitro group. Benzodiazepines exert these effects at
dosages that cause only minor CNS depression. At dosages used to treat anxiety, behavioral disinhibitory
effects include euphoria, impaired judgment, and loss of self-control.
Benzodiazepines at higher dosages lead to more pronounced depression of the CNS
(see right). This can be increased by increasing the dosage (dose-dependent
depression).

2. Common benzodiazepine examples: (-am)

Let’s examine the properties of some anxiolytic agents:
Lorazepam (generic, Ativan, Alzapam. Peak blood level takes 1-6 hr., elimination
half-life of 10-20 hr., and has no active metabolites.
Clorazepate (Tranxene; 5 – 7.5 mg twice daily). Peak blood level takes 1-2 hr,
elimination half-life of 50-100 hr. It is a prodrug which is hydrolyzed to the active
form in the stomach.
Diazepam (Valium; 5 mg twice daily) is an anxiolytic agent. Peak blood levels occur
in 1-2 hr. Elimination half-life falls into the range of 20-80 hr. Active metabolites are
formed. There is erratic bioavailability from IM injection (also true of
chlordiazepoxide (Librium)).

Now let’s compare some hypnotics:

Triazolam (halcion) is a short-acting potent hypnotic (0.125 mg – 0.5 mg at bedtime)
with rapid onset (peak blood levels in 1 hr); short duration of action elimination half-
life 2-3 hr. (All half-lives listed include the half-life of the parent compound and any
active metabolites.) It is used to induce sleep in patients with recurring insomnia.
Good for treating problems with getting to sleep. It produces amnesia in jet travelers
under the influence who take this drug during the part of the trip. There is a steep
dose/effect curve--rapid onset rate of oral absorption.
Temazepam is an intermediate acting hypnotic. This drug is useful for patients who
experience repeated awakenings. The onset of action occurs 2-3 hr after an oral dose,
so it must be taken several hours before bedtime. Elimination half life of 10-40 hr
Flurazepam (Dalmane) is a long-acting hypnotic. Peak blood levels occur in 1-2 hr.,
elimination half-life is 40-100 hr, and it produces active metabolites with long half-
lives. e.g. flurazepam --> desalkyflurazepam It reduces both sleep-induction time and
the number of awakenings, and increases the duration of sleep.
 Dr. Robert A. Graf
10/25/06

3. General Pharmacokinetics for Benzodiazepines

a. absorption
reach peak blood and brain concentrations within 1-2 hr rates of oral absorption depend
on lipophility:
triazolam (1 hr), diazepam (1-2 hr) >> oxazepam (2-4 hr), temazepam (2-3 hr),
lorazepam (1-6 hr)
b. distribution
Lipid solubility plays an important role in determining the rate at which a particular
sedative-hypnotic enters the CNS. These drugs bind to plasma proteins at 60 to 95
percent. The drugs can redistribute themselves from the CNS to other metabolically
active tissues, such as skeletal muscle, then later to less metabolically active tissues, such
as adipose tissue. This action contributes toward the termination of action. All sedative-
hypnotics cross the placenta and can contribute to the depression of neonatal vital
functions. They are detectable in breast milk at sufficient concentrations to effect the
developing CNS of infants.
c. biotransformation:
Mechanism of action in part depends on the formation of active metabolites which continues their
effects. Long half life usually indicates CNS depression and daytime sedation will occur the next day.
Drugs with 30-200 hr half lives fall into this category. Also, the half life of the parent drug may have
little consequence in terms of the half life of the CNS effects. Multiple dosing can lead to cumulative
and residual effects such as chronic drowsiness.

d. excretion: The duration of action varies. Benzodiazepines are not excreted unchanged.
Elimination half life is dependent upon metabolism of compound. Hepatic metabolism depends on
phase I microsomal oxidation drug reactions such as N-dealkylation. The metabolites are conjugated
in phase II glucuronosyltransferases, then excreted in the urine. Transformation to more water soluble
metabolites is necessary.

D. Introduction to Barbiturates

They are still agents used to sedate or induce and maintain sleep, but they have been largely
replaced by the benzodiazepines since they suffer from undesirable side effects (tolerance, drug-
 Dr. Robert A. Graf
10/25/06

metabolizing enzymes, physical dependence, and severe withdrawal symptoms).

They are classified according to their duration of action.
Examples (Note -al suffix)
thiopental: rate of onset in seconds (fast), duration of action 30 min Used for
intravenous induction of anesthetic
mephobarbital (mebaral) is used as a sedative
phenobarbital: duration of action greater than a day; used to treat seizures
pentobarbital (nebutal; 100 mg at bedtime), amobarbital , and secobarbital
(100-200 mg at bedtime) are short acting and effective as hypnotics.

E. Pharmacokinetics of Barbiturates
a. absorption: most are well absorbed
b. distribution: widely throughout the body; the drugs are
redistributed in the body from the brain to the splanchnic (visceral)
areas, to skeletal muscle, and finally to adipose tissue.
c. biotransformation: occurs in the liver
d. metabolism: metabolized by the P-450 microsomal enzyme
oxidative system. Alcohols, acids, and ketones are formed and appear
in the urine as glucuronide conjugates. Metabolites of barbiturates lack
pharmacological activity.
e. excretion: they are conjugated with glucuronic acid for
excretion by the kidneys. Most (except phenobarbital) are excreted
chemically altered.
f. factors affecting biodisposition (how drug acts): if hepatic injury,
then lower the dosage. Age: must reduce dosage since metabolism generally slower.

F. Pharmacodynamics of Sedatives and Hypnotics: Barbiturates, benzodiazepines, and imidazopyridines

all bind to the postsynaptic GABAA receptor.

a. molecular biology of the GABAA receptor

16 genes code for 5 subunits
b. neuropharmacology
GABA binds to the α and β subunits where it initiates
gating/opening of the channel which leads to an
influx of chloride current. Benzodiazepine
potentiates GABAergic inhibition of spinal cord,
hypothalamus, hippocampus, substantia nigra,
cerebellar cortex, and cerebral cortex.
 Dr. Robert A. Graf
10/25/06

Benzodiazepines are GABA-A agonists that bind to the gamma subunit and increase the frequency of
channel opening while barbiturates bind to the alpha and/or beta subunit to increase the duration of GABA-
A channel openings (see below). The barbiturates never bind to the gamma subunits. Neither BDZ or

barbiturates bind to the GABA-B receptors, which are presynaptic.

F. Organ level effects for Sedative-Hypnotics:

1. sedation: Barbiturates at low

dosages, benzodiazepines at
low dosages
2. hypnosis: for barbiturates and
benzodiazepines at higher
dosages, followed by
anesthesia
3. anesthesia: certain S-Hs will
take the patient to stage III of
general anesthesia. Each drug
should be consulted for the
rapidity of onset and duration
of effectiveness.
Benzodiazepines are usually
given IV ex. diazepam and
midazolam. Benzodiazepines
 Dr. Robert A. Graf
10/25/06

with short half-lives redistribute quickly in tissues making them effective

sedative candidates. Benzodiazepines with long half-lives can induce post-
operative respiratory depression.
4. anticonvulsants: Most S-Hs are capable of inhibiting the development and
spread of epileptiform activity in CNS.
Benzodiazepines used for seizure states include
clonazepam for chronic treatment of epilepsy
diazepam for grand mal eplileptic seizures and status epilepticus
Barbiturates used for tonic-clonic seizures include phenobarbital
and metharbital.
5. muscle relaxants
S-Hs of the carbamate, benzodiazepine group exert inhibitory
effects on polysynaptic reflexes; at higher doses, may also depress
transmission at the skeletal NMJ.
6. respiration and cardiovascular effects
in healthy patients, S-Hs cause changes in respiration similar to those seen
during natural sleep. At therapeutic doses, significant respiratory
depression can occur in patients with pulmonary disease. These effects are
dose-related and become more apparent when S-H are given intravenously.

G. Tolerance/Dependence for Sedative-Hypnotics

Tolerance is decreased responsiveness to a drug following repeated exposure is
common among S-H use. Cross tolerance occurs with S-Hs and alcohol. An alcoholic will
already have tolerance build-up for benzodiazepine, for example. Tolerance occurs as a
result of down regulation of receptors (over days/weeks) with chronic administration of
benzodiazepines.

H. Benzodiazepine Antagonists
Flumazenil is a synthetic benzodiazepine derivative that blocks action of benzodiazepines and
zolpidem. It reverses the sedative actions of benzodiazepines and is approved for
benzodiazepine overdose therapy. It is also used to hasten the recovery following use of
benzodiazepines in anesthetic and diagnostic procedures. Flumazenil is given I-V and acts
rapidly but has a short half life (0.7 to 1.3 hr) due to rapid hepatic clearance. Therefore,
sedation often recurs since benzodiazepines have longer half-lives than flumazenil. Repeated
administration is called for this situation.
Flumazenil is the only available benzodiazepine receptor antagonist. It does not antagonize
barbiturates, meprobamate, ethanol, opioids, general anesthetics. However, benzodiazepines
and tricyclic antidepressants can induce seizures and cardiac arrhythmias following
flumazenil administration.

I. Newer Drugs
Benzodiazepines have many side effects. Drugs that act through non-GABAergic systems
might have a reduced propensity for such actions.
note however:

1. Buspirone (BuSpar; oral 5 mg or 10 mg tablets): relieves anxiety without sedative,

euphoric, hynpotic, anticonvulsant, or muscle relaxing effects.
rapidly absorbed orally (7.5 mg/day initially, increase as necessary by 5 mg/day until
achieving a range of 20-30 mg/day.
Analogs include: iprapirone, gepirone, tandospirone
It is suitable only for generalized anxiety states but not effective for panic
disorder.
Considerations include that it takes a week for onset of action.
is a partial agonist of 5-HT1A receptors.
first pass metabolism: hydroxylation and dealkylination form several active metabolites.
 Dr. Robert A. Graf
10/25/06

elimination half-life is 2 to 4 hr
has minimal abuse liability
withdrawal symptoms occur on abrupt discontinuance
there is a dose-dependent pupil constriction
No rebound anxiety. Does not affect driving. Does not potentiate CNS depressant effects
of S-Hs, EtOH, or tricyclic antidepressants
Buspirone is contraindicated with MAO inhibitors since the combination causes
hypertension.

2. Zolpidem (Ambien):
hypnotic actions with minimal rebound insomnia.
given orally as 5 or 10 mg tablets
minimal muscle relaxing/anticonvulsant effects.
antagonized by flumazenil.
similar to BDZ in mechanism of action and in inducing short-term
insomnia.
can suppress REM sleep at higher doses
less risk of dependence than BDZ; little or no tolerance occurs with prolonged
use rapidly metabolized in the liver: oxidation and hydroxylation
respiratory depression can occur with large amounts of EtOH or other CNS
depressant

J. Clincial Toxicology of Sedative-Hypnotics

1. Direct toxic actions
Epidemiological studies on the incidence of drug-
related death support the assumption that drugs with
steeper dose-response curves are more dangerous in
terms of overdose than those with flatter dose-response
curves.
0.3 deaths per million tablets of diazepam prescribed
versus 11.6 deaths per million capsules of secobarbital
in one study.
Drug A behaves like secobarbital, whereas drug B
reflects a typical benzodiazepine. The benzodiazepines
offer a flatter dose-response curves so they are safer to
use than barbiturates with a steeper curve.

2. Drug Responses
i. Tolerance to pharmacological effects occurs.
Ingestion of many times the usual dosages have been reported
without any toxic effects.

ii. Dependence is the requirement of a user to either

provide the usual or greater dosage of substance to keep
withdrawal symptoms from setting-in. Dependence develops
with chronic use of sedative-hypnotics. Physical dependence
exists since people experience withdrawal upon abruptly
discontinuing use. Psychological dependence is characterized by
a desire to experience the rewarding effects the agent provides
while avoiding the negative consequences of withdrawal. With
benzodiazepines, this dependence may develop beyond that seen
with any other class of drug -- even opioids.

iii. Withdrawal Symptoms include restlessness, anxiety,

weakness, orthostatic hypotension, hyperactive reflexes, and
 Dr. Robert A. Graf
10/25/06

seizures. Withdrawal is treated with longer acting drugs such as chlordiazepoxide, diazepam,
and phenobarbital. Drugs with shorter half lives tend to produce more extreme withdrawal.
Withdrawal depends on the magnitude of the dose just before quitting. Drugs with very short
half lives may lead to symptoms of withdrawal even between doses. Trizolam, a
benzodiazepine with a half life of 4 hr causes daytime anxiety when used to treat sleep
disorders. Drugs with longer half lives are eliminated slowly enough to accomplish
withdrawal with few physical symptoms.

3. Side Effects include drowsiness, impaired judgment, diminished motor skills, increased
reaction times when driving, job performance, and personal relationships. Benzodiazepines
cause dose-related amnesia and can cause nightmares. They impair the ability to learn new
information while leaving the retrieval of previously learned information intact. They are
contraindicated for patients experiencing phobias.

4. Overdose. Higher Doses cause a state of lethargy and exhaustion. Deliberate

overdosing of S-Hs is rarely fatal if detected early and often fatal is detected late. High doses
lead to loss of brainstem motor control and direct myocardial depression.

5. Drug Interactions
i. Enhanced depression can result from combining CNS depressants (EtOH, opioid
analgesics, anticonvulsants, phenothiazines) with S-H This combination has additive effects.
The patient usually starts vomiting and should be treated to ensure adequate respiration while
maintaining plasma volume, renal output, and cardiac function. Flumazenil administration
should be administered to reverse ingested benzodiazepine. Hemodialysis is performed to
remove the drug from the blood.
ii. More subtle but also important, enhanced CNS depression also results from
interactions of S-H and antihistamines, antihypertensive agents, and tricyclic antidepressants.

2C. ANTICONVULSANTS
Overview
1. Introduction: Seizures and epilepsy
2. Seizure classification
3. Treatment
4. Preferred drugs by seizure category
5. Individual antiepileptics
a. Main agents
b. Drug intervention: Other drugs

1. Introduction: Seizures and epilepsy

Half a million Americans are affected with epilepsy, and one percent of the world’s population has epilepsy.
As a disease, it is not a single entity. It is a heterogeneous symptom complex – a chronic disorder
characterized by recurrent seizures. A seizure is a transient disturbance of cerebral function caused by a
temporally finite abnormal neuronal discharge. Epilepsy is a group of disorders characterized by recurrent
seizures and is a common cause of episodic loss of consciousness. Seizures that cause hallucination
involve the
visual
auditory
olfactory lobes
parietal/occipital lobes. Movements are involved if the seizure involves the motor cortex.
Epilepsy is characterized behaviorally by abnormal movements or perceptions. These seizures tend to
recur in certain states In general, the site of discharge determines the symptoms that are produced.
 Dr. Robert A. Graf
10/25/06

2. Seizure classification
Classification of seizure is according to the:
i. site of discharge
ii. extent of electrical activity spread
iii. whether it is tonic-clonic: Initial
maximal tonic contraction of all body
musculature followed by clonic jerking and
prolonged depression of all CNS functions. tonic
Tonic phase lasts about 1 min, may cause
injury, vertebral fracture. This is followed by
synchronous jerking which lasts 2 to 4 min.
The patient stays unconscious for several more
min, gradually recovering feeling ill and
confused.

a. partial focal
i. cortical focal (SIMPLE)
group of hyperactive neurons
abnormal electrical activity
single locus in brain clonic
electrical disorder does not spread
patient maintains consciousness
exhibits abnormal activity of a limb
muscle
can occur at any age

ii. temporal lobe (COMPLEX)

occurs before age 20
sensory hallucinations
mental distortion: confused behavior
impairment of consciousness
motor involvement includes:
chewing
diarrhea
urination

b. generalized

begin locally but spreads abnormal electrical

discharges through both hemispheres of the brain
involves the whole brain including the
reticular formation
convulsive or non-convulsive
causes immediate loss of consciousness

i. tonic-clonic (grand mal)

alternate rapid muscle contraction and
relaxation, loss of consciousness
 Dr. Robert A. Graf
10/25/06

ii. absence (petit mal) The onset occurs at ages 3 to 5 years and lasts until puberty. These seizures involve
a brief, abrupt loss of consciousness. This means the patient abruptly ceases whatever s/he is doing (stops
talking in mid-sentence). Patient stares and exhibits rapid eye-blinking which lasts for 3 to 5 seconds.
The entire seizure usually last less than 30 sec.

iii. myoclonic: These seizures consist of short episodes of muscle contractions that may reoccur
for several minutes. Myoclonic seizures are rare, occur at any age, and are often a result of permanent
neurologic damage acquired as a result of hypoxia, uremia (the retention of excessive by-products of
protein metabolism in the blood, and the toxic condition produced thereby), encephalitis, or drug poisoning.

iv. febrile: Young children (3 mo to 5 yr) frequently develop seizures with illness accompanied by
high fever. The febrile seizures consist of generalized tonic-clonic convulsions of short duration. Although
febrile seizure may be frightening to observers, they are benign and do not cause death, neurologic damage,
injury, or learning disorders, and they rarely require medication.

v. status epilepticus: rapid succession of epileptic spasms without intervening periods of

consciousness.

3. Preferred drugs by seizure category:

For simple and complex partial focal seizures, phenytoin and carbamazepine are the first choices.
Alternatives include phenobarbital (simple only) and primidone (simple and complex).
For generalized tonic-clonic seizures, the first choice drugs for adults are phenytoin and carbamazepine.
Alternative drugs include phenobarbital, primidone, and valproic acid.
For children experiencing partial or tonic-clonic, preferred drug choices are carbamazepine and
phenobarbital.
For generalized absence seizures of the petit mal form, treat with ethosuximide and valproic acid.
For myoclonic seizures, preferred choices are valproic acid and clonazepam
For febrile seizures in children, the preferred drug is phenobarbital. The alternative drug is primidone.
For status epilepticus, phenytoin and diazepam are drugs of choice, and phenobarbital is the alternative
choice.

4. Individual Anticonvulsants
a. Main agents

i. Phenytoin (DILANTIN, DIPHENYLAN):

used for tonic-clonic or partial (simple and complex) seizures. This is the drug of initial choice
particularly for adults. Phenytoin slows the rate of recovery of voltage-activated Na channels and
provides selective action on rapidly firing neurons.
Pharmacokinetics:
 Dr. Robert A. Graf
10/25/06

Oral absorption of phenytoin is slow. Peak concentrations may range from 3 hr to 12 hr.
Distribution is rapid and brain concentration are high. Phenytoin is orally administered for
chronic treatment, and by IV for status epilepticus. Phenytoin is metabolized by the hepatic
hydroxylation system. At low doses the drug has a half life of 24 hr, but at higher doses the
hydroxylation system becomes saturated. This makes toxicity an issue to be aware of. Side
effects occur due to CNS depression and include nystagmus and ataxia (lack of muscle
coordination).
G-I problems include nausea and vomiting Gums can grow over the teeth, particularly in children.
The gums retreat back from over the teeth after cessation of drug therapy. The mechanism is
thought to involve the release of a growth factor over the gums. Megaloblastic anemia (marked
by the presence of megaloblasts in the bone marrow) occurs because the drug interferes with
vitamin B12 metabolism. Other side effects occur such as confusion, hallucination, and
drowsiness. Phenytoin IV administration for status epilepticus that is too rapid may cause cardiac
arrhythmias, hypotension, and CNS depression. There is a potential for oral toxicity. Phenytoin
causes teratogenic effects in offspring of mothers given the drug during pregnancy.
Other drugs (chloramphenicol, dicumarol, cimetidine [tagamet], sulfonamides , and isoniazid
[both bacteriocidal) when used chronically will increase the concentration of phenytoin in plasma
by preventing its metabolism.

ii. Carbamazepine (TEGRETOL, CARBATROL)

It is used for simple and complex partial seizures, as well as generalized tonic-clonic seizures. It
is considered the drug of choice for partial seizures. It is highly effective for tonic-clonic seizures.

Mechanism of action includes blocking of Na channels, inhibition of the generation of repetitive

action potentials, and inhibition of action potential formation in the epileptic focus.

The drug is effective in children and adults. Available only in oral form. In adults, dosages of 1-2
g are tolerated. The rate of absorption of carbamazepine varies widely among different patients,
though almost complete absorption apparently occurs in all. Peak levels are usually achieved 6-8
hr after administration. Slowing absorption by giving the drug after meals helps the patient
tolerate larger total daily doses. Distribution is slow. Carbamazepine has a very low systemic
clearance at the start of therapy. The drug has a notable ability to induce microsomal enzymes.
The clearance of carbamazepine increased two-fold over initial treatment. The half-life of 36 hr
observed in subjects following an initial single dose decreases to much less than 20 hours in
subjects receiving continuous therapy. Dosage adjustments are to be expected during the first
weeks of therapy.
Chronic use of this agent can cause stupor, coma, respiratory depression, nausea, vomiting, and
anemia agranulosis. Drug interactions are related predominately to the drug’s enzyme-inducing
properties. The increased metabolic capacity of the hepatic enzymes may cause a reduction in
steady state carbamazepine concentrations and an increased rate of metabolism of primidone,
phenytoin, ethosuximide, valproic acid, and clonazepam. Other drugs such as propoxyphene,
troleandomycine, and valproic acid may inhibit carbamazepine clearance and increase steady state
carbamazepine blood levels. The most common side effects include diplopia (the perception of
two images from one object) and ataxia.

iii. Phenobarbital (LUMINAL)

Phenobarbital is the drug of choice for treatment of young children (infants) with recurrent febrile
seizures. It is useful in the treatment of partial seizures and generalized tonic-clonic seizures. There is little
evidence for its effectiveness in generalized seizures such as absence, atonic attacks, or infantile spasms, it
may worsen certain patients with these seizure types.
It is used at lower doses as an antiepiletic for limiting the spread of seizure discharge. It elevates the
seizure threshold. It used to be used for long-term management of tonic-clonic seizures and status
epilepticus (and still might be on the boards as such), but it’s use has largely been replaced by the other
compounds with lesser sedative effects. Its anticonvulsant activity is distinguishable from its CNS
depression. Despite its long use as one of the safest of the antiepileptic agents, the use of other medication
with lesser sedative effects has been urged.
 Dr. Robert A. Graf
10/25/06

Phenobarbital is well-absorbed orally. The drug freely penetrates the brain. Approximately 75%
of the drug is inactivated by the hepatic microsomal system, the remaining drug is excreted unchanged by
the kidneys. Phenobarbital induces the P-450 system.

iv. Ethosuximide (ZARONTIN)

Drug of first choice for absence seizures. The mechanism of action involves calcium channels, where it
reduces the low threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in
thalamic neurons. The T-type channels are thought to provide a pacemaker current in thalamic neurons
responsible for generating the rhythmic cortical discharge of an absence attack. It also inhibits the Na/K
ATPase, depresses the cerebral metabolic rate, and inhibits GABA aminotransferase.

v. Valproic Acid and Sodium Valproate (DEPACON, DEPAKENE, DEPAKOTE)

These agents reduce the incidence and severity of seizures. These agents reduce the propagation of
abnormal discharge. Active metabolites are produced. Hepatotoxic potential exists. 3% is excreted
unchanged. Gluconylated metabolites are excreted in the urine. Adverse effects include nausea, vomiting,
sedation, ataxia, and tremor.

vi. Primidone (MYSOLINE)

used as an alternate for treating partial seizures and tonic-clonic seizures. Primidone is ineffective
in treating absence seizures. It is often used along with carbamazepine and phenytoin. The mechanism of
actin of primidone itself may be more like phenytoin. Metabolites include phenobarbital (for tonic-clonic
seizures) and phenylethylmalonamide (for partial seizures). The metabolites have a longer half life than the
parent compound. Primidone is often used with carbamazepine and phenytoin, allowing smaller doses of
these agents to be used.

vii. Lamotrigine (LAMICTAL): Lamotrigine was developed when some investigators thought that
the antifolate effects of certain antiepileptic drugs like phenytoin may contribute to their effectiveness.
Lamotrigine’s mechanism of action produces a voltage- and use- dependent inactivation of sodium
channels, thereby prevents repetitive firing and inhibits glutamate and aspartate release. Lamotrigine is
good for treating simple or complex partial seizures and generalized tonic-clonic seizures. Lamotrigine is
metabolized in the liver. Some patients using lamotrigine have developed skin rashes.

viii. Gabapentin (NEURONTIN) This drug is an analog of GABA and is effective against partial
seizures and generalized tonic-clonic seizures. Gabapentin does NOT act on GABA receptors. It may alter
GABA metabolism or its nonsynaptic release. Gabapentin does not bind to plasma proteins and is excreted
by the kidneys, which minimizes the likelihood of drug interactions.

b. Drug Intervention: Other drugs

Benzodiazepines:
Diazepam (VALIUM, DIASTAT): used for grand mal, and acute treatment of status epilepticus.
Clorazepate: for chronic treatment of partial seizures. It is used in conjunction with other drugs. This
drug has a wide margin of safety and few side effects.
Clonazepam (KLONOPIN): used for chronic treatment of absence seizures (petit mal) and is preferred
for generalized myoclonic seizures.
Lorazepam (ATIVAN INJECTION) is used for status epilepticus.
Of all the antiepileptics, the benzodiazepines are the safest and most free from severe side effects. All
benzodiazepines have sedative properties so drowsiness, sleepiness, and fatigue can occur with higher
dosage as well as ataxia, dizziness, and behavior changes.

2D. PARKINSONISM (Paralysis Agitans)

OVERVIEW
I. Etiology
 Dr. Robert A. Graf
10/25/06

II. Symptoms
III. Observations of Parkinsonism
IV. Mechanism of Action
V. Pharmacological Intervention

I. Etiology
Etiology
Parkinsonism is a progressive neurodegenerative movement disorder. It is a dopamine deficiency disorder
that leaves the senses and intellect uninjured. Sixty-six percent of patients with Parkinsonism fall within
being 50 - 69 years of age. An anatomical landmark is loss of the pigment neuromelanin in the substantia
nigra and appearance of Lewy bodies (abnormal cytoplasmic inclusions.)

Eighty percent of the dopamine neurons are lost in the striatum (caudate nucleus and putamen) where the
nerve terminals project. Thus, Parkinsonism is a neuronal disorder caused by the death of a group of brain
cells whose actions are mediated by the neurotransmitter dopamine. What causes this loss of neurons is
still unknown.

II. Symptoms of Parkinsonism include

bradykinesia (slowness of movement & difficulty initiating movement)
muscle rigidity
tremor that occurs during periods of rest and diminishes during voluntary movement
postural instability - inability to maintain normal posture with shuffle gating & frequent falls
Also, there is a condition known as secondary parkinsonism which infrequently follows viral encephalitis
or multiple small vascular lesions. Drugs such as the phenothiazines and haloperiodol, whose major
pharmacological action is blockade of dopamine receptors in the brain, may also produce parkinsonism
symptoms. These drugs should not be used in parkinsonian patients.

Disease-related specifics:
Death usually results from complications of immobility
Pulmonary embolism - obstruction of the pulmonary artery
Aspiration pneumonia - inflammation due to aspiration of foreign material into the lungs.

III. Important Observations aiding us in our current view of the disease:

1. Drugs that enhance dopaminergic function reduce the symptoms of Parkinsonism.
2. Interference of nigrostriatal dopaminergic neurons in animals results in motor deficits similar to those in
Parkinsonism.
3. Dopamine cell loss is correlated to the severity of motor symptoms in Parkinsonism.

IV. Mechanism of Action The substantia nigra is the source of dopaminergic neurons that terminate in the
striatum. The dopaminergic projections from the substantia nigra fire tonically, rather than in response to
specific muscular movement or sensory input. Thus, the dopaminergic system appears to serve as a tonic
sustaining influence on motor activity, rather than participating in specific movements. Normally, the
striatum is connected to the substantia nigra by neurons that secrete the inhibitory transmitter GABA at
their termini in the substantia nigra. Cells of the substantia nigra send neurons back to the striatum,
secreting the inhibitory transmitter dopamine at their terminals. This inhibitory-inhibitory system usually
maintains a degree of overall inhibition of the two separate brain areas. Nerve fibers from the cerebral
cortex and thalamus secrete ACh in the neostriatum, causing excitatory effects that initiate and regulate
gross intentional movements of the body. Thus the normal modulating inhibitory influence of dopamine on
the neostriatum is significantly diminished, resulting in the parkinsonian degeneration of the control of
muscle movement.
 Dr. Robert A. Graf
10/25/06

In addition to the abundance of inhibitory dopaminergic neurons,

the neostriatum is also rich in excitatory cholinergic neurons that
oppose the action of dopamine. Many of the symptoms of
Parkinsonism reflect an imbalance between the excitatory
cholinergic neurons and the greatly diminished number of
inhibitory dopaminergic neurons. Therapy is aimed at restoring
dopamine in the basal ganglia and antagonizing the excitatory
effect of cholinergic neurons, thus reestablishing the correct
dopamine/ACh balance.

V. Drug Therapy

L-dopa (Levodopa; Larodopa) Rapidly absorbed, half-life is 1-3

hr, Less than 1% of levodopa penetrates the CNS because of
peripheral decarboxylation.

Precursor: Providing L-dopa leads to an increase in dopamine

production in nerve terminals of the striatum. Two lines of
evidence provide support for this mechanism: 1) homovanillic
acid is a metabolite of dopamine production and is produced in the
CSF of patients taking L-dopa; also, 2) a greater concentration of
dopamine has been found in the striatum of postmortem patients
who have used L-dopa.

L-dopa therapy provides an approach for restoring dopaminergic

function in Parkinsonism. Continuing loss of dopamine nerve
terminals severely limits the long term benefits of L-dopa. The
effectiveness diminishes after 3-5 yr of treatment. This is thought
to be associated with causing neurodegeneration of the dopamine
producing cells, perhaps by producing more free radicals. Patients
sometimes develop an on/off phenomenon where they are on when
the drug works and off (hypokinesia) when it doesn't.
 Dr. Robert A. Graf
10/25/06

Concurrent use of CARBIDOPA is often indicated to alleviate these undesirable effects. Carbidopa is a
dopamine decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa diminishes the
metabolism of levodopa in the GI tract and peripheral tissues; thus, it increases the availability of levodopa
to the CNS. The addition of carbidopa to L-dopa lowers the dose of L-dopa needed by 4- to 5- fold,
thereby decreasing the severity of the side effects of peripherally formed dopamine. Continuous release
formulations of carbidopa-L-dopa are available. Adjunctive therapy with dopamine agonists or selegiline
are used to minimize the on/off phenomenon.

Dopamine agonists do not require the existence of intact dopaminergic neurons for their therapeutic
actions. These agonists are not as effective as L-dopa though, probably since L-dopa activates both D1 and
D2 receptors within the striatum by the dopamine formed by L-dopa.

Agents:
BROMOCRIPTINE – (PARLODEL) Indicated especially if tolerance develops to L-dopa. Given orally.
Bromocriptine is a dopamine agonist that activates both D1 and D2, but the pharmacological effect comes
from its activation of presynaptic D2 receptors. May be used with L-dopa/carbidopa. Adverse effects
include more nausea, hallucinations, confusion, and hypotension than with L-dopa. Less dyskinesia than
with L-dopa.

PERGOLIDE - (PERMAX) Another dopamine agonist that is more potent than bromocriptine. Used as
an adjunct to L-dopa/carbidopa. Given orally. Directly stimulates both D1 and D2, but its clinical effect is
on D2 receptors. Metabolized in the liver, excreted in the kidney. Interactions include reduction of action
due to dopamine antagonists. Side effects include dyskinesia, nausea, rhinitus, constipation, dizziness,
hallucinations, somnolence (sleepiness).

AMANTADINE (SYMMETREL; DuPont Pharma, 100 mg caps) This is a catechol-O-methyltransferase

(COMT) inhibitor. Given orally. Less effective than L-dopa for treating Parkinson’s disease. More
effective than anticholinergics. Also used to treat drug-induced extrapyramidal reactions. Mechanism of
action is still under investigation but it may potentiate dopaminergic function by influencing the synthesis,
release, or reuptake of dopamine. Amantadine was first used as an antiviral compound and was
accidentally found to harbor clinical usefulness for treating Parkinsonism symptoms. It favorably
influences the bradykinesia, rigidity, and tremor of Parkinsonism. Peak plasma concentrations are reached
1-4 hr after an oral dose. The plasma half-life is 2-4 hr. Must adjust dose if renal failure condition exists.
Amantadine alone has few side effects. Anticholinergic interactions enhance CNS side effects including
hallucinations, confusion, and nightmares. The drug is contraindicated in patients with a history of seizures
or congestive heart failure.

ANTICHOLINERGIC AGENTS: These act on muscarinic cholinergic receptors. The rationale is that
there is a balance between the dopaminergic (inhibitory) and cholinergic (excitatory) neurotransmitter
systems. Antimuscarinic drugs may improve the tremor and rigidity of Parkinsonism but have little effect
on bradykinesia. The mechanism of action involves lessening the ACh:dopamine imbalance in the
striatum. If one agent doesn’t work, then another can be used.

TRIHEXYPHENIDYL (ARTANE, TREMIN) Orally administered. Supplement to L-dopa. Can be used alone
when L-dopa is contraindicated. Mechanism of action discussed above. Side effects include cycloplegia (paralysis
of the ciliary muscle, paralysis of accommodation, adjusting the eyes to focus at different distances).

Alternate drugs if Trihexyphenidyl doesn’t work include:

BENZOTROPINE (COGENTIN; 0.5 - 1 mg @ bedtime, 6 mg/day max)

PROCYCLIDINE (KEMADRIN); Oral, 5 mg tablets
BIPERIDEN (AKINETON); Oral, 2 mg tablets, parenteral: 5 mg/mL for injection

MAO-B INHIBITORS (SELEGILINE) function to reduce the breakdown of dopamine. There are two
types of MAO inhibitors, A and B. A metabolizes/inactivates NE and 5-HT. B metabolizes dopamine.
 Dr. Robert A. Graf
10/25/06

SELEGILINE: (ELDEPRYL) When selegiline is used with L-dopa, L-dopa administration can be
reduced since selegiline may decrease the breakdown of dopamine. This drug can also be used in cases
when response to levodopa/carbidopa is no longer adequate. In younger people selegiline may exert a
neuroprotective effect and may slow the progression of Parkinsonism. Selegiline can protect nigrostriatal
dopaminergic neurons from death. A major metabolite of selegiline is amphetamine. Amphetamine may
provide some of selegiline’s action since it is known to trigger the release of dopamine.

Selegiline is rapidly absorbed, crosses the blood-brain barrier, and is metabolized in the liver. Side effects
include nausea and hallucinations. Fatal reactions can occur between meperidine and MAO inhibitors (!)
Patients who take selegiline can eat tyramine-containing foods and still take L-dopa without risk of
hypertensive crises. This is because MAO-A is still present to break down the tyramine so that it doesn't
build-up. (Tyramine is a sympathimimetic amine present in a variety of fermented foods (including aged
and cheddar cheeses, chicken liver, broad beans, smoked or pickled fish, salami, pepperoni, yeast, beer, and
wine.) Tyramines are greatly enhanced in patients treated with a general MAO inhibitor.
tyrosine ----------> tyramine ---------> p-hydroxyphenyl acetic acid
decarboxylase MAO
Other side effects includes hypotension, confusion, dizziness, tremor, agitation, and depression.

Newer drugs are now available and include Tolcapone (TASMAR), which is believed to inhibit the enzyme that
breaks down L-dopa before it can reach the brain. With Tasmar, the brain receives more sustained levels of L-dopa.
Another is Ropinorole (REQUIP). This agent mimics dopamine and is as effective as L-dopa in early stages of the
disease. Pramipexole dihydrocholoride (MIRAPEX) also mimics dopamine.

2E. ALZHEIMER’S DISEASE AND CURRENT TREATMENTS

This disease is an impairment of cognitive abilities that is gradual in onset but is irreversible. Alzheimer’s
disease is a progressive neurodegeneration.
The first clinical feature is impairment of short term memory.
Retrieval of distant memories is relatively unaffected.
The progression of the disease behaviorally is followed by lack of ability to perform activities of daily
living.
Death is most often due to a complication of mobility such as pneumonia or pulmonary embolism.

Pathophysiology
• atrophy of the cerebral cortex
• loss of cortical and subcortical neurons
• hallmarks of AD are senile plaques: accumulations of beta-amyloid, degenerating neuronal processes,
and neurofibrillary tangles (paired helical filaments).
• abundance of tangles is roughly proportional to the severity of cognitive impairment.
• tangles are prominent in hippocampus, associative regions of cortex
• visual and motor cortex is spared.
• impairment of memory and abstract reasoning
• decrease in neurotransmitter levels parallel neuronal loss
• cholinergic deficit was characterized
• subcortical cholinergic neurons of the basal forebrain (nucleus basalis of Meynert) provide cholinergic
innervation to the whole cerebral cortex.
• atropine can induce a confused state
• choinergic hypothesis
• treatment currently targets acetylcholine hypothesis
• inhibitors of AchEsterase like physostigmine
• reversible AchE inhibitor
• improves animal learning
 Dr. Robert A. Graf
10/25/06

• mild improvement in memory

• 4 inhibitors are approved by the FDA
• tacrine (COGNEX)
• donepezil (ARICEPT)
• rivastigmine (EXCELON)
• galantamine (REMINYL)
• new drugs:
• memantine, NMDA-receptor antagonist
• antioxidants (no established efficacy)
• antiinflammatory agents (no established efficacy)
• estrogens (no established efficacy)

2F. ANTIPSYCHOTICS/NEUROLEPTICS

A. Psychoses
1. Schizophrenia
2. Bipolar Disorder
B. Drug Therapy

Psychosis generally refers to a mental disorder caused by some inherent dysfunction of the brain.
This disorder can be of organic or emotional origin. Characterized by derangement of
personality, loss of contact with reality (often with delusions, hallucinations, and illusions), and
thinking or speech disturbances.

Schizophrenia is a type of psychosis characterized by delusions, hallucinations (often in the form

of voices), thinking or speech disturbances. Schizophrenia is a chronic and disabling disorder
with a strong genetic component. It occurs in about 1% of the population.
It often afflicts people during adolescence and probably reflects some fundamental biochemical
abnormality, possibly an overactivity of the mesolimbic dopaminergic neurons.
One or two drugs from each class of drugs can be used to treat the symptoms.
Neuroleptics are the only efficacious treatment and not all patients respond.
Traditional agents treat the positive symptoms (delusions, hallucinations, and thought disorder)
Newer 5-HT blockers treat negative symptoms (withdrawal, blunted emotions, reduced ability to
relate to people, vomiting, nausea, and motion sickness)
Nausea resulting from emotions should be treated with sedatives and antihistamines, not
neuroleptics.
Motion sickness is often treated with scopolamine.

Neuroleptic Drug Therapy

Introduction
Antipsychotics are used to help patients cope with schizophrenia, manic states, and delirium. These drugs
are not curative and do not eliminate the fundamental thinking disorder. Neuroleptics do permit the
psychotic patient to function in a supportive environment.
The different drugs have different receptor profiles. The traditional neuroleptics are competitive inhibitors.
Antipsychotic effects reflect competitive blocking of dopamine receptors (thiothixene, haloperidol,
fluphenazine).

Newer “atypical” antipsychotic drugs appear to owe their unique activity to blockade of serotonin receptors
(risperidone, clozapine). The newer drugs vary in their potency but not in their efficacy. The dosage
range is quite broad.
 Dr. Robert A. Graf
10/25/06

In general, there is variability between patients for the same drug. One drug might work, whereas another
drug might not. This speaks to a difference in the amount and distribution of certain receptors between
individuals.
The mechanism of action of all neuroleptics is binding to dopamine receptors so that they are
inhibited/blocked. The clinical efficacy results from the blockade of D2 dopamine receptors. D1 and D5
activation results in activation of adenylyl cyclase. D2, D3, and D4 receptor activation results inhibition of
adenylyl cyclase.
Newer “atypical” agents inhibit serotonin receptors. For
example, clozapine has a high affinity for the S2 serotonin
receptor, D1 and D4, as well as muscarinic ACh-R, α-adrenergic
R, and D2. Risperidone blocks the S2 receptor much more than
it blocks the D2 receptor. Note that Haloperidol has a very high
affinity for the D2 receptor.

It is important to note that any other compound that increases

dopamine release such as L-dopa or amphetamines, will
antagonize the effects of neuroleptic drugs.

Drug Actions
1. Antipsychotic:
Neuroleptics reduce the hallucinations and agitation by blocking
dopamine receptors in the mesolimbic system. The agents calm
and reduce spontaneous physical movements. Neuroleptics do
not depress intellectual function of the patient. These effects
usually take several weeks suggesting therapeutic effects are
related to secondary changes in cortico-striatal pathways.

2. Extrapyramidal effects:
Parkinson’s effects occur since these drugs decrease the
efficacy of dopamine in the brain generally. Related
effects include akathisia (motor restlessness) and tardive
dyskinesia due to block of dopamine receptors in the
nigrostriatal pathway. Tardive kinesia is involuntary repetitive
movements of the facial, buccal, oral, and cervical musculature,
affecting chiefly the elderly, induced by long-term use of
antipsychotic agents, which may persist after withdrawal of the agent. These effects occur with much less
frequency with clozapine and risperidone.

3. Antiemetic (vomiting) effects:

Mediated by block of dopamine D2 receptors at the trigger zone of the medulla. Thioridazine is an
exception to this statement – it does not work through D2 receptors.

4. Antimuscarinics
Agents that also block the muscarinic ACh receptors cause blurred vision, dry mouth, sedation, confusion,
inhibition of G-I and urinary smooth muscle (constipation and urinary retention).

5. Other effects:
Block of α-adrenergic receptors results in orthostatic hypotension, lightheadedness, temperature regulation,
and increased prolactin secretion from the pituitary due to block of D2 receptors.

Individual Agents
 Dr. Robert A. Graf
10/25/06

Neuroleptic agents include different classes: Phenothiazines, Benzisoxazoles, Dibenzodiazepines,

Butyrophenones, and Thioxanthenes.

NEUROLEPTIC DRUGS NEUROLEPTIC DRUGS

PHENOTHIAZINES DIBENZODIAZEPINES
Chlorpromazine (Alphatic) THORAZINE Clozapine CLOZARIL
Fluphenazine (Piperazine) PERMITIL,PROLIXIN
Prochlorperazine (Piperazine) GENERIC,COMPAZINE BUTRYPOHENONES
Promethazine (Alphatic) GENERIC,SPARINE Haloperidol HALDOL
Thioridazine (Piperidine) GENERIC,MELLARIL
THIOXANTHENES
BENZISOXAZOLES Thiothixene NAVANE
Risperidone RISPERDAL

Clozapine and risperidone primarily block serotonin receptors.

Clozapine is indicated for refractory schizophrenia. Orally administered. Not recommended for children
under 16 years of age. Clozapine can be immediately discontinued if the medical condition warrants. Has
little extrapyramidal toxicity. Monitor WBC count since agranulosis occurs in 2% of patients.
Contraindicated if coma or CNS depression exists. Do not administer to pregnant mothers or epileptic
patients.

Risperidone has a broad efficacy, little or no extrapyramidal system dysfunction at low doses (4 mg). With
higher doses (> 16 mg), extrapyramidal dysfunction and hypotension.

The following antipsychotics act primarily at dopamine receptors. Their adverse effects are largely
manifestations of dopamine receptor block and include Parkinson's syndrome, akathisia, and dystonias.

Fluphenazine is indicated for psychosis. Not recommended for children. Contraindicated in coma, CNS
or bone marrow depression or liver disease. Drug interactions: CNS depressants with alcohol and other
CNS depressants. Antagonized by anticholinergics. May cause false pregnancy test.

Thiothixene may produce decreased tardive dyskinesia (TD) compared to other agents. TD is the most
unwanted side effect of antipsychotics. It is probably caused by a relative cholinergic deficiency secondary
to supersensitivity of dopamine receptors in the caudate-putamen. It is treated by decreasing dopamine
receptor by discontinuing the antipsychotics drug or by reducing the dose. If these steps do not help,
diazepam at 30-40 mg/d may be added.

Haloperidol can be orally administered to adults and children. Injection is for adults only. Indicated for
psychosis, severe childhood disorders, and acute hyperactivity. Haloperidol is antagonized by
anticholinergics.

Chlorpromazine acts primarily by blocking α1 adrenergic receptors as well as H1-histamine receptors.

Indicated for psychosis or intractable hiccups, acute intermittent porphysia, and short-term treatment of
hyperactivity. Advantages include that it is available generically (inexpensive). Disadvantages include
autonomic side effects such as loss of accommodation, dry mouth, difficulty urinating, and constipation.
Sedative drugs can also be used with antipsychotics.
Antiparkinsonism agents are most frequently added for relief of anxiety and insomnia.
Amantadine: an antiviral compound used for type A influenza augments the release of dopamine.

Thioridazine acts primarily by blocking muscarinic cholinergic receptors. Indicated for psychosis.
Muscarinic ACh side effects are common and include dry mouth, constipation, urinary retention. Drug
 Dr. Robert A. Graf
10/25/06

interactions include increased CNS depression with EtOH. Contraindicated with patients experiencing
coma or CNS depression, or severe hypertensive or hypotensive cardiac disease.

Prochlorperizine is indicated for psychosis. Administered orally. Prescribed to children. Injectable form
for rapid control of psychosis. Change dose gradually. Monitor anticoagu

Some specifics:
1. Once the patient is refractory to two or more antipsychotics, next drug choice is clozapine.
2. If the patients are refractory to the sedative haloperidol, 30 - 50 % of the patients can be salvaged on
clozapine.
3. Combining antipsychotics and tricyclic antidepressants can be done.
4. Lithium is sometimes added to the antipsychotic regime if the lithium doesn't work on its own. Such
cases could represent a misdiagnosis of mania.
 Dr. Robert A. Graf
10/25/06

2G. MOOD DISORDERS AND ANTIDEPRESSANTS

I. Depression

1. Introduction
Depression is one of the mood altering disorders (or illnesses). Depression is one of the most common
psychiatric disorders. It is easy for a depressed person to go overlooked in our society, since they are
perfectly capable of functioning on a day to day basis. Depressed people can show subtle-seeming
symptoms such as vague complaining. These people may seem a bit neurotic. Depression effects energy,
sleep, appetite, libido, and the overall ability to function. Depression does not produce disturbances of
thought, and should be distinguished from schizophrenia as such. Symptoms include intense feelings of
sadness, hopelessness, despair, and the inability to experience pleasure.

2. Classifications
A. according to behavior
Major and minor (dysthymia) depression are pure depression, whereas bipolar disorder and cyclothymic
disorder represent mania in combination with depression. (Mania is much the opposite of depression in
that there is enthusiasm, rapid thoughts and speech patterns, extreme self-confidence, and impaired
judgments.)
B. according to origin
i. reactive secondary response to real stimuli (death, crisis)
ii. endogenous genetically determined biochemical disorder that involves the inability to cope with stress.
iii. manic-depressive disorder.

II. Antidepressant Agents

1. General Introduction and Concepts
All the antidepressant drugs potentiate amine neurotransmitters (norepinephrine, serotonin (5-HT), and
dopamine. Their effects and side effects can be largely attributed to whether they are selective blockers
(serotonin only, for example) or mixed blockers (serotonin and norepinephrine, for example).

Biogenic Amine Theory

In the 1950s, it was found that reserpine induced depression. It was known, as we discussed in the first
lecture, that reserpine blocked the uptake of serotonin into synaptic vesicles in the presynaptic terminal). It
 Dr. Robert A. Graf
10/25/06

was concluded that depression is due to a deficiency of monoamines (NE, 5-HT, D). This became a strong
driving force in the way of a theory known as the biogenic amine theory. Conversely, mania was
hypothesized to result from overproduction of these neurotransmitters. This theory has widely been viewed
more recently as too simplistic. For example, the block of reuptake occurs immediately but the
antidepressant effects take weeks to appear after drug administration. This observation has modified the
thinking to include that uptake is an initial event and other events, such as up-regulation or down-regulation
of receptors occurs as well. The theory has been with us and guided our thinking sufficiently to
predominate how we classify antidepressants.

2. Tricyclic antidepressants (TCAs)

First generation tricyclic antidepressants have a characteristic 3 ring structure. Imipramine and
amitriptyline are prototype tricyclic antidepressants that have been prescribed for forty years. These are
mixed serotonin and norepinephrine uptake inhibitors. Other first generation TCAs include desipramine,
nortriptyline, protripyline, and doxepin. Second generation TCAs have actions similar to imipramine but
have slightly different pharmacokinetic properties. Second generation agents include amoxapine and
maprotiline.
A. Mechanism of action
i. in addition to inhibiting neurotransmitter uptake, TCAs commonly have numerous autonomic actions as
well. This accounts for some of the side effects listed below.
ii. blocking of receptors
TCAs block a number of receptors including the norepinephrine, serotonin, α1-adrenergic, H1-histamine R,
and muscarinic AChR.

B. Actions
elevate mood, improve mental alertness, increase physical activity. These drugs do not produce CNS
stimulation or mood elevation in normal individuals so they can be used for prolonged treatment. It is
important to note that tolerance develops as well as physical and psychological dependence.

C. Therapeutic uses
Effective in treating severe major depression. Imipramine has recently been shown to also be just as
effective as MAOI or BDZ in treating panic disorder, but the latter drugs are still preferred since they are
better tolerated and their clinical effects occur rapidly after drug administration. Imipramine is also
effective in treating bed wetting. (It causes constriction of the bladder sphincter and this effect is
antimuscarinic). Be aware of side-effects (see below)

D. Pharmacokinetics
i. Absorption and distribution
Dosages are listed in the accompanying table. The TCAs are well-absorbed upon oral administration.
They are lipophilic and readily penetrate the CNS. They have long half-lives (4-17 hr for imipramine.)
They undergo first pass metabolism in the liver. TCAs have low and inconsistent bioavailability so the
patients response behaviorally is used to adjust the dose.
ii. Fate
They use the hepatic microsomal system. The compounds are conjugated with glucuronic acid. TCAs are
finally excreted as inactive metabolites by the kidney.

E. Adverse Effects
Side effects are subdivided by category and/or mechanism of action.
i. Antimuscarinic effects
blurred vision, dry mouth, urinary retention, constipation, aggravation of glaucoma and epilepsy

ii. Anti α-adrenergics: leads to orthostatic hypotension and reflex tachycardia.

iii. catecholamines: Increased production of catecholamines results in cardiac overstimulation. An
overdose is life threatening. Slowing of atrial ventricular conduction puts the elderly especially at risk.
 Dr. Robert A. Graf
10/25/06

iv. Sedation occurs during the first several weeks of treatment.

v. Precautions to be aware of:

These drugs have a narrow therapeutic index so 5-6X the maximum daily dosage can be lethal.
Use of TCAs for manic-depressive disorder will treat the depression leaving the mania unmasked. This
could be dangerous to the patient and to others (you).

3. Selective serotonin reuptake inhibitors (SSRIs).

These are more specific than TCAs, and therefore generally have fewer side effects. Since there are less
anticholinergic effects, there is lower cardiotoxicity. They are relatively newer compounds so there is less
of a track record of their use compared to the TCAs.

A. Fluoxetine (PROZAC) - This is the prototype SSRI. It is currently (August, 1998) the second most
prescribed drug nationally.

i. Therapeutic uses
It is as effective at treating depression as the TCAs.
It is also used to treat panic disorder, anorexia nervosa, and premenstrual syndrome.

ii. Pharmacokinetics
These drugs are taken orally for several weeks until the antidepressant effects appear. The drug is usually
given as a combination of R and S enantiomers. The compound is demethylated to the active metabolite
(norfluoxetine). 1-10 days is the half-life of the parent compound, but the active metabolite has a half-life
of 3-30 hr. Fluoxetine interferes with elimination of the TCAs, neuroleptics (antipsychotics), and beta-
adrenergic antagonist drugs.

iii. Adverse Effects

Sexual side effects include loss of libido and delayed ejaculation. An overdose can produce seizure in some
instances, but one study a 20 mg/day normal dose was increased to 1200 mg/day (OD) without any
noticeable problems in the patients.

B. Other SSRIs
The other SSRIs can be distinguished by their differences in which of the amines they take up. Their side
effect profiles are different as well. If one of the compounds administered produces tolerance in the
patient, other choices are appropriate and other compounds can be prescribed within this class. (One
compound may work well and another may not depending on the individual.)

4. MAO (Monoamine oxidase) Inhibitors

This enzyme occurs in the mitochondria of neurons where it oxidatively deaminates amines. Agents
include isocarboxazid, phenelzine, and tranylcypromine.

A. Mechanism of action
Most MAOIs form stable (irreversible) complexes with the mitochondrial enzyme monoamine oxidase,
which inactivates "stray" neurotransmitter that has not been packaged into synaptic vesicles for release.
Isocarboxazid interacts with MAO this way. By inhibiting this action, there is more NT in the cytosol that
"leaks" into the synaptic cleft where it is thought to potentiate postsynaptic responses.

B. Actions
The antidepressant effects appear 2 - 4 weeks after drug administration. There is a mild amphetamine-like
stimulant effect.

C. Therapeutics
MAOIs are indicated for patients who are unresponsive, allergic, or who experience strong anxiety to
TCAs.
 Dr. Robert A. Graf
10/25/06

D. Pharmacokinetics
MAOI are well absorbed orally. Since the treatment is irreversible, it takes several weeks for the enzyme to
be regenerated in neurons (upregulation). When switching drugs, allow 2 wk delay before starting another
antidepressant.

E. Adverse Effects/Interactions
MAO inhibitors effect the processing of tyramine. Tyramine is a compound found in some foods such as
red wine, beer, chicken liver, and aged cheeses. It is normally inactivated in the gut, which contains MAO
as well. Since MAO inhibitors block its metabolic breakdown, tyramine causes large amounts of
catecholamines to be released from nerve terminals. This action leads to headaches, tachycardia, nausea,
hypertension, cardiac arrhythmia, and even stroke. Other side effects from the MAOs include drowsiness,
orthostatic hypotension, blurred vision, dryness of mouth, dyuria, and constipation.
MAOI in combination with SSRI can lead to 5-HT syndrome. A wash-out period of six weeks is necessary
before changing from MAOIss to SSRIs, or from SSRIs to MAOIs.

5. Lithium
Lithium salts are very toxic. Li is usually given as lithium carbonate. Lithium is used to treat manic-
depressive disorder. Lithium has no effect when administered into individuals who do not experience
manic-depressive disorder. Side effects include ataxia, tremors, confusion, and convulsions. Lithium is not
a sedative, euphoric, or depressant.

Bipolar Affective Disorder

This used to be called manic-depressive disorder. Bipolar more clearly adds the connotation that the mood
swings back and forth. Lithium is used for the manic phase together with benzodiazepines.
In severe cases, clonazepam and lorazepam are administered. After mania is controlled, the antipsychotic
can be stopped. Benzodiazepines and lithium can then be continued. For the depressive phase, concurrent
use of an antidepressant is often used.
An MAO inhibitor (such as isocarboxyazid) may be the antidepressant of choice.