Determining the Therapeutic Index of A Drug Pharmacology Essay

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details
COMPOUND (TRADE
NAME)
here
Some benzodiazepines in clinical use
ROUTES OF
ADMINISTRATION
EXAMPLES OF
THERAPEUTIC USES
COMMENTS
t1/2,
hours
DOSE,
mg/d
Alprazolam (XANAX)
Oral
Anxiety disorders,
agoraphobia
Withdrawal symptoms may be
especially severe
12±2
—
Chlordiazepoxide
(LIBRIUM)
Oral, IM, IV
Anxiety disorders, alcohol
withdrawal
Long-acting and self-tapering
because of active metabolites
10±3.4
50-100,
qd–qid
Clonazepam (KLONOPIN)
Oral
Seizure disorders,
adjunctive treatment in
acute mania
Tolerance develops to anticonvulsant
effects
23±5
—
Clorazepate (TRANXENE)
Oral
Anxiety disorders, seizure
disorders
Prodrug; activity due to formation of
nordazepam during absorption
2.0±0.9
3.7520,
bid–qid
Diazepam (VALIUM)
Oral, IM, IV, rectal
Anxiety disorders, status
epilepticus, muscle
relaxation
Prototypical benzodiazepine
43±13
5-10,
tid–qid
Estazolam (PROSOM)
Oral
Insomnia
Contains triazolo ring; adverse effects
may be similar to those of triazolam
10–24
1-2
Flurazepam (DALMANE)
Oral
Insomnia
Active metabolites accumulate with
chronic use
74±24
15-30
Lorazepam (ATIVAN)
Oral, IM, IV
Anxiety disorders,
preanesthetic medication
Metabolized solely by conjugation
14±5
2-4
8.0±2.4
15-30,
tid–qid
Oxazepam (SERAX)is
emax
Quazepam (DORAL)
Oral same but
Anxiety disorders
the
toff in
,
Metabolized solely by conjugation
potency
Active metabolites accumulate with
Oral
Insomnia
39
7.5-15
chronic
use
As we will discuss
in detail, the
T1/2 of the parent
compound
may be very
different
Temazepam (RESTORIL)
Oral
Insomnia
mainly by conjugation
11±6
7.5-30
than the “effective”
half-life due
the generation Metabolized
of long-lasting
active metabolites
Rapidly inactivated; may cause
0.125-
Comparing Benzodiazepines and Barbiturates
narrow therapeutic
Barbiturates latex
Benzodiazepines
Anti-anxiety: hypnotic
1:4
Hypnotic: Toxic (O.D.)
1 : 30
Toxicity
Therapeutic dose: dose
producing dependence
Time course of tolerance
can
be
afoanbaegeod
Addiction liability
Withdrawal
smaller
•azdaM
can
e-
Confusion, delirium, ataxia,
unconsciousness (not severe)
1 : 6 – 20
Seen after months of high
doses; takes 5-7 days to
appear after discontinue drug:
symptoms similar to barbit.
withdrawal
1 :2
1 :8
Anesthesia to coma to death following
strong respiratory
depression +/- hypotension
dependence at
Lower
> 3 weeks (tolerance develops
to hypnotic effects more than
to anti-anxiety)
Widening of the them Inter
Moderate
ratio
get sleepy
1: 2 – 5
dose
Rapid, $400 billion incurred annually in the U.S. by
addiction:
– Loss of life and productivity – Medical
consequences
(e.g., AIDS, lung cancer, cirrhosis) – Crime and
law enforcement
Diverse Chemical Substances Cause Addiction
①
top attrition
• Opioids (morphine, heroin, oxycontin, vicodin)
② • Cocaine
• Amphetamine and like drugs (methamphetamine,
methylphenidate) • MDMA (ecstasy)
• PCP (phencyclidine or angel dust; also ketamine) •
Marijuana (cannabinoids)
5 • Tobacco (nicotine)
6 • Alcohol (ethanol)
7 • Sedative/hypnotics (barbiturates, benzodiazepines)
:
What is Reward and Reinforcement?
Reward
• Positive emotional effects.
Reinforcement
• A stimulus that causes a response to be maintained and
increased.
• Positive reinforcement: increases behavioral response to get
a positive reward (food, sex, etc.).
• Negative reinforcement: increases behavioral response to
end punishment (pain, starvation).
In this way, rewards and reinforcements in the environment
powerfully shape an individual’s behavior.
Role of Dopamine in Mammals
•Ventral Tegmental Area (VTA) dopamine neurons are “rheostats”
of reward:
– Rewards activate the neurons
– Expectation of rewards activates the neurons
– Absence of expected rewards inhibits the neurons
– Unexpected rewards activate the neurons even more.
•Drugs directly and powerfully activate these neurons with no
connection to purposeful behavior.
•This leads to a profound corruption of the brain’s reward
mechanisms: drugs gradually, progressively, and insidiously
replace natural rewards as the major shaper of behavior.
is a KEY
Dopamine release From UTA to the nucleus accumbens
the nucleus accumbens
step in the reward pathway The topamine suppresses
Gabaergic output The end result = pleasure
.
.
:-||
→
,i¥
Drug
⑦
neurons shrink
and
•
normal
need
to
take
state
impairing
reward
have less reward
–
neurons
accumbens
neurons
In the attract
VTA
nucleus
the
Inhibits
GABAergic
From GTA)
release
dopamine
stimulates
⑥ Directly
Abuse
of
–
–
tag
taking
/
(
pathway
.
more to
chronically
dopamine
get
more
reward
)
of abuse
release
QUESTION:
For two of the three below, discuss the role
that tolerance during chronic
administration plays in determining the
therapeutic index (profile of desired vs.
adverse effects).
• antipsychotics
• benzodiazepines
• opioids
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