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I.
Definition of Terms:
A. Drug Abuse
Substance abuse is any pattern of substance use that results in repeated adverse social
consequences related to drug-taking-for example, failure to meet work, family, or school
obligations, interpersonal conflicts, or legal problems.
The text revision of the fourth edition of Diagnostic and Statistical Manual of Mental
Disorders (DSM-IV-TR) established a set of criteria for each of the conditions concerning the
abuse of drugs including criteria to support drug abuse.
DSM-IV-TR Criteria for Substance Abuse
A. A maladaptive pattern of substance use leading to clinically significant impairment or
distress, as manifested by one 9or more) of the following, occurring within a 12-month
period:
(1) recurrent substance use resulting in a failure to fulfill major role obligations at
work, school, or home (e.g., repeated absences or poor work performance
related to substance use; substance-related absences, suspensions, or
expulsions from school; neglect of children or household)
(2) recurrent substance use in situation in which it is physically hazardous (e.g.,
driving an automobile or operating a machine when impaired by substance use)
(3) recurrent substance-related legal problems (e.g., arrests for substance-related
disorderly conduct)
(4) continued substance use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of the substance
(e.g., arguments with spouse about consequences of intoxication, physical
fights)
B. The symptoms have never met the criteria for Substance Dependence for this class of
substance.
B. Drug Misuse
Drug misuse refers to intake of illegal drugs, or using medicines contrary to the
recommendation of the physician or the manufacturer. Taking medicines in very large
quantities that may be harmful dangerous to one’s health is also an example of drug misuse.
C. Addiction
Addiction consists of compulsive, relapsing drug use despite negative consequences, at
times triggered by cravings that occur in response to contextual cues.
D. Dependence
Every addictive drug causes its own characteristic spectrum of acute effects, but all have in
common that they induce strong feelings of euphoria and reward. With repetitive exposure,
addictive drugs induce adaptive changes such as tolerance (ie, escalation of dose to
maintain effect). Once the abused drug is no longer available, signs of withdrawal become
apparent. A combination of such signs, referred to as the withdrawal syndrome, defines
dependence.
DSM-IV-TR Diagnostic Criteria for Substance Dependence
A maladaptive pattern of substance use, leading to clinically significant impairment
or distress, as manifested by three (or more) of the following, occurring at any time in the
same 12-month period:
(1) tolerance, as defined by either of the following
(a) a need for markedly increased amounts of the substance to achieve intoxication
or desire effect
(b) markedly diminished effect with continued use of the same amount of the
substance
(2) withdrawal, as manifested by either of the following
(3) the substance is often taken in larger amounts or over a longer period than intended
(4) there is a persistent desire or unsuccessful efforts to cut down or control substance use
(5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting
multiple doctors or driving long distances), use the substance (e.g., chain smoking), or
recover from its effects
(6) important social, occupational, or recreational activities are given up or reduced because
of substance use
(7) the substance use is continued despite knowledge of having a persistent or recurrent
physical or psychological problem that is likely to have been caused or exacerbated by
the substance (e.g., current cocaine use despite recognition of cocaine-induced
depression, or continued drinking despite recognition that an ulcer was made worse by
alcohol consumption)
E. Tolerance
Tolerance, the most common response to repetitive use of the same drug, can be defined as
the reduction in response to the drug after repeated administrations.
With tolerance, there is a shift of the curve to the right such that doses higher than initial
doses are required to achieve the same effects.
Tolerance develops to some drug effects much more rapidly than to other effects of the
same drug. For example, tolerance develops rapidly to the euphoria produced by opioids
such as heroin, and addicts tend to increase their dose in order to re-experience that elusive
"high." In contrast, tolerance to the gastrointestinal effects of opiates develops more slowly.
The discrepancy between tolerance to euphorigenic effects (rapid) and tolerance to effects
on vital functions (slow), such as respiration and blood pressure, can lead to potentially fatal
accidents in sedative abusers.
F. Withdrawal
Withdrawal signs and symptoms occur when drug administration in a physically dependent
person is terminated abruptly. Withdrawal symptoms have at least two origins: (1) removal
of the drug of dependence and (2) CNS hyperarousal owing to readaptation to the absence
of the drug of dependence. Pharmacokinetic variables are of considerable importance in the
amplitude and duration of the withdrawal syndrome. Withdrawal symptoms are
characteristic for a given category of drugs and tend to be opposite to the original effects
produced by the drug before tolerance developed. Thus, abrupt termination of a drug (such
as an opioid agonist) that produces miotic (constricted) pupils and slow heart rate will
produce a withdrawal syndrome including dilated pupils and tachycardia.
DSM-IV-TR Criteria for Substance Withdrawal
A. The development of a substance-specific syndrome due to the cessation of (or
reduction in) substance use that has been heavy and prolonged.
B. The substance-specific syndrome causes clinically significant distress or impairment
in social, occupational, or other important areas of functioning.
The symptoms are not due to a general medical condition and are not better accounted for
by another mental disorder.
G. Controlled Drugs
A controlled (scheduled) drug is one whose use and distribution is tightly controlled because
of its abuse potential or risk.
H. Designer Drugs
Designer drugs are a group of illegally produced chemicals that mimics the effect of specific
drugs of abuse. Designer drugs are often made in such a way that their structures are subtly
different from the drugs they imitate.
I. General modes of treatment for drug abuse
People who get addicted to different substances come from all walks of life, across
economic status, and from a wide spectrum of mental and behavioral dispositions.
Treatment for drug addiction varies depending on the drugs used and the characteristics of
the patient. This includes pharmacological, non-pharmacological, and a combination of
these two approaches.
Selecting a treatment
Not all interventions are applicable to all varieties of substance use or dependence, and
some of the more coercive interventions used for illicit drugs are not applicable to
substances that are legally available, one of which is tobacco. Changes in addictive
behaviors go through five stages wherein treatment may be based on the patient’s state
of readiness to change:
(1) Precontemplation
(2) Contemplation
(3) Preparation
(4) Action
(5) Maintenance
Non-pharmacological treatments
These include behavioral therapies, counseling, cognitive or psychotherapies which offer
strategies for coping with drug cravings, teach ways to avoid drugs and prevent relapse in
the treatment, and help patients deal with relapse if it occurs.
Pharmacological treatments
Treatments using medications are especially important to patients with severe mental
illness. The different drugs used for each kind of abuse are discussed below, under specific
treatments.
Principles of Effective Treatment
1. No single treatment is appropriate for all individuals.
2. Treatment needs to be readily available.
3. Effective treatment attends to multiple needs of the individual, not just his or her drug
use.
4. An individual's treatment and services plan must be assessed continually and modified
as necessary to ensure that the plan meets the person's changing needs.
5. Remaining in treatment for an adequate period of time is critical for treatment
effectiveness.
6. Counseling (individual and/or group) and other behavioral therapies are critical
components of effective treatment for addiction.
7. Medications are an important element of treatment for many patients, especially when
combined with counseling and other behavioral therapies.
8. Addicted or drug-abusing individuals with coexisting mental disorders should have both
disorders treated in an integrated way.
9. Medical detoxification is only the first stage of addiction treatment and by itself does
little to change long-term drug use.
10. Treatment does not need to be voluntary to be effective.
11. Possible drug use during treatment must be monitored continuously.
12. Treatment programs should provide assessment for HIV/AIDS, hepatitis B and C,
tuberculosis and other infectious diseases, and counseling to help patients modify or
change behaviors that place themselves or others at risk of infection.
13. Recovery from drug addiction can be a long-term process and frequently requires
multiple episodes of treatment.
II.
Causes of Drug Abuse
Many variables operate simultaneously to influence the likelihood that a given person will
become a drug abuser or an addict. These variables can be organized into three categories:
agent (drug), host (user), and environment.
A. Agent (Drug) Variables
Drugs vary in their capacity to produce immediate good feelings in the user. Drugs that
reliably produce intensely pleasant feelings (euphoria) are more likely to be taken
repeatedly. Reinforcement refers to the capacity of drugs to produce effects that make the
user wish to take them again. The more strongly reinforcing a drug is, the greater is the
likelihood that the drug will be abused. Reinforcing properties of a drug can be measured
reliably in animals. Generally, animals such as rats or monkeys equipped with intravenous
catheters connected to lever-regulated pumps will work to obtain injections of the same
drugs in roughly the same order of potency that human beings will. Thus, medications can
be screened for their potential for abuse in human beings by the use of animal models.
Reinforcing properties of drugs are associated with their capacity to increase neuronal
activity in critical brain areas. Cocaine, amphetamine, ethanol, opioids, cannabinoids, and
nicotine all reliably increase extracellular fluid dopamine levels in the ventral striatum,
specifically the nucleus accumbens region. In experimental animals, usually rats, brain
microdialysis permits sampling of extracellular fluid while the animals are freely moving or
receiving drugs. Smaller increases in dopamine in the nucleus accumbens also are observed
when the rat is presented with sweet foods or a sexual partner. In contrast, drugs that block
dopamine receptors generally produce bad feelings, i.e., dysphoric effects. Neither animals
nor human beings will take such drugs spontaneously. Despite strong correlative findings, a
causal relationship between dopamine and euphoria/dysphoria has not been established,
and other findings emphasize additional roles of serotonin, glutamine, norepinephrine,
opiates, and -aminobutyric acid (GABA) in mediating the reinforcing effects of drugs.
The abuse liability of a drug is enhanced by rapidity of onset because effects that occur soon
after administration are more likely to initiate the chain of events that leads to loss of
control over drug taking.
B. Host (User) Variables
In general, effects of drugs vary among individuals. Even blood levels can show wide
variation when the same dose of a drug on a milligram per kilogram basis is given to
different people. Polymorphism of genes that encode enzymes involved in absorption,
metabolism, and excretion and in receptor-mediated responses may contribute to the
different degrees of reinforcement or euphoria observed among individuals.
Children of alcoholics show an increased likelihood of developing alcoholism, even when
adopted at birth and raised by nonalcoholic parents. The studies of genetic influences in this
disorder show only an increased risk for developing alcoholism, not 100% determinism,
consistent with a polygenic disorder that has multiple determinants. Even identical twins,
who share the same genetic endowment, do not have 100% concordance when one twin is
alcoholic. However, the concordance rate for identical twins is much higher than that for
fraternal twins. The abuse of alcohol and other drugs tends to have some familial
characteristics, suggesting that common mechanisms may be involved.
Innate tolerance to alcohol may represent a biological trait that contributes to the
development of alcoholism. Data from a longitudinal study (Wilhelmsen et al., 2003) show
that sons of alcoholics have reduced sensitivity to alcohol when compared with other young
men of the same age (22 years old) and drinking histories. Sensitivity to alcohol was
measured as the effects of two different doses of ethanol in the laboratory on motor
performance and subjective feelings of intoxication. When the men were re-examined 10
years later, those who had been most tolerant (insensitive) to alcohol at age 22 were the
most likely to be diagnosed as alcohol dependent at age 32. The presence of tolerance
predicted the development of alcoholism even in the group without a family history of
alcoholism, but there were far fewer tolerant men in the negative-family-history group.
While innate tolerance increases vulnerability to alcoholism, impaired metabolism may
protect against it. Ethanol is metabolized by sequential oxidation to acetaldehyde (by
alcohol dehydrogenase) and then to acetic acid by aldehyde dehydrogenase (ALDH2). A
common mutation in the ALDH2 gene results in a less effective enzyme. This allele has a
high frequency in Asian populations and results in excess accumulation of acetaldehyde
after the ingestion of alcohol. Those who are heterozygous for this allele experience a very
unpleasant facial flushing reaction 5 to 10 minutes after ingesting alcohol; the reaction is
more severe in individuals homozygous for the allele, and this genotype has not been found
in alcoholics (Higuchi et al., 1996). Similarly, individuals who inherit a gene associated with
slow nicotine metabolism may experience unpleasant effects when beginning to smoke and
reportedly have a lower probability of becoming nicotine dependent.
Psychiatric disorders constitute another category of host variables. Drugs may produce
immediate, subjective effects that relieve preexisting symptoms. People with anxiety,
depression, insomnia, or even subtle symptoms such as shyness may find, on
experimentation or by accident, that certain drugs give them relief. However, the apparent
beneficial effects are transient, and repeated use of the drug may lead to tolerance and
eventually compulsive, uncontrolled drug use. While psychiatric symptoms are seen
commonly in drug abusers presenting for treatment, most of these symptoms begin after
the person starts abusing drugs. Thus, drugs of abuse appear to produce more psychiatric
symptoms than they relieve.
C. Environmental Variables
Initiating and continuing illegal drug use appear to be influenced significantly by societal
norms and peer pressure. Taking drugs may be seen initially as a form of rebellion against
authority. In some communities, drug users and drug dealers are role models who seem to
be successful and respected; thus, young people emulate them. There also may be a paucity
of other options for pleasure, diversion, or income. These factors are particularly important
in communities where educational levels are low and job opportunities scarce.
III.
Demographic Characteristics
All the data come from the Center-based Admission Data Analysis of the Dangerous Drug
Boards (DDB) as of December 15, 2005.
For the year 2005, the reporting centers totaled to 55 residential and 3 outpatient facilities,
registering an additional 2 residential and another 2 out-patient centers, as compared to
those of 2004.
A total of 5,873 cases were recorded. As compared to the figures of 2004, it was noted that
there was an increase of 3.55% in the new admissions while 9.92% decline in relapse cases.
The National Capital Region (NCR) had the highest percent distribution of cases with 3,330
(56.70%) of the total national admissions. Center admissions were predominantly male. As
to educational attainment, high school level had the highest percent distribution. Most of
the patients were unemployed prior to admission.
A. Profile of Drug Abusers
AGE: Mean age of 29 years old
SEX: Ratio of male to female 10:1
CIVIL STATUS: Single 54.40%
EDUCATIONAL ATTAINMENT: Highschool level
OCCUPATION: Unemployed 38.19%
PLACE OF RESIDENCE: Urban (specifically NCR)
DURATION OF DRUG-TAKING: More than six years
NATURE OF DRUG TAKING: More than six years
DRUGS OF ABUSE: Shabu – 81.36%
Marijuana – 33.65%
Inhalants – 4.82%
B. Classification of Drug Abusers based on:
Classification of Cases for CY 2005
799
14%
850
14%
Out-patient Centers
New
Readmission
4,224
72%
Case Distribution According to Age
1% 2%
13%
14%
14 & below
15-19
20-24
25-29
30-34
35-39
40 & above
not specified
14%
18%
16%
22%
Case Distribution by Civil Status
5%
10%
Single
Married
with Live-in partners
Separated
54%
31%
Case Distribution According to Educational Attainment
0
6
4
No Schooling
27
Elementary Level
20
Elementary Graduate
99
334
54
177
158
158
Education
Highschool Level
1,122
121
110
Highschool Graduate
College Level
746
333
142
College Graduate
32
Vocational/Technical
33
28
1,143
105
407
231
0
0
10
Post Graduate
0
200
400
600
800
1000
Number
Readmission
Out-patient
New
1200
1400
Case Distribution by Classification of Patients
12%
3%
33%
8%
Workers/Employees
Unemployed
Students
Busiessman/Self-Employed
Out-of-School Youth
Not specified
6%
38%
IV.
Basic Pharmacology of Drugs of Abuse
A. Classification of Addictive Drugs of Abuse
1. Drugs that activate Gio-coupled receptors
These drugs include the opioids, cannabinoids and the gamma-hydroxybutyrates
(GHB). Morphine and opioids strongly increase the release of mesolimbic dopamine
by their action on μ-opioid receptors (MORs), which are expressed on inhibitory
GABAergic interneurons of the VTA. MORs have a dual action: they hyperpolarize
GABA neurons and decrease GABA release. Delta-9-tetrahydrocannabinol (THC)
binds to type 1 cannabinoid receptors (CB1Rs) in the brain. In the VTA, these
receptors are expressed on GABA neurons and on terminals of glutamatergic
synapses on dopamine neurons. GHB is an increasingly popular club drug that is
readily self-administered and induces conditioned place preference in animal
models, and leads to addiction in humans. GHB has two binding sites in the brain,
but its pharmacological effects are absent in knockout mice lacking functional
GABAB receptors, suggesting that they are entirely mediated by these receptors.
2. Drugs that mediate their effects via ionotropic receptors
This group includes nicotine, alcohol and the benzodiazepines. Nicotine targets
nicotinic acetylcholine receptors (nAChRs) in the brain. When nicotine binds nAChRs
they become cation-permeable and depolarize the cell. Nicotine increases
dopamine through a complex interplay of actions at these ionotropic receptors on
GABA and dopamine neurons, and glutamatergic inputs to dopamine neurons.
Benzodiazepines (BZD) increase mesocorticolimbic dopamine and can lead to
addiction. BZD are positive modulators of the GABA-A receptor. When injected into
the VTA, the GABA-A receptor agonist muscimol seems to inhibit interneurons more
efficiently compared to dopamine neurons, which may lead to a net disinhibition of
the dopamine neurons. No single receptor mediates all of the effects of alcohol. On
the contrary, alcohol alters the function of a number of receptors and cellular
functions, including GABAA receptors, Kir3/GIRK and other K channels, N-methyl-Daspartate (NMDA) receptors, nAChRs, and 5-HT3 receptors. In addition, ethanol also
interferes with adenosine re-uptake by inhibiting the equilibrative nucleoside
transporter ENT1, although it is not clear if this plays a role in ethanol-induced
dopamine release.
3. Drugs that bind to transporters of biogenic amines
These are the cocaines, amphetamines and methylenedioxymetamphetamines
(MDMA/ecstasy). In the central nervous system, cocaine blocks dopamine,
noradrenaline, and serotonin uptake through inhibition of their respective
transporters. Blocking the dopamine transporter (DAT) leads to an increase of
dopamine
concentrations
in
the
nucleus
accumbens.
Amphetamine,
methamphetamine, and their many derivates exert their effects by reversing the
action of biogenic amine transporters at the plasma membrane. Amphetamines are
substrates of these transporters and are taken up into the cell. Every molecule that
is taken up generates a current causing a depolarization of the dopamine neurons,
which could contribute to enhanced dopamine release. In addition, once in the cell,
amphetamines interfere with the vesicular monoamine transporter, depleting
synaptic vesicles. As a consequence, dopamine increases in the cytoplasm from
where it is released by plasma membrane transporters working in reverse.
B. Non addictive Drugs of Abuse
Substances that alter perception without causing sensations of reward and euphoria are
drugs of abuse that do not lead to addiction. These agents primarily target cortical and
thalamic circuits unlike addictive drugs, which primarily target the mesolimbic dopamine
system. Hallucinogens and NMDA antagonists such as phencyclidine and ketamine are
examples of drugs of abuse that are non addictive.
Lysergic acid diethylamide (LSD), a class of hallucinogen is a naturally occurring
psychedelic drug found in morning glory seeds. LSD was initially derived from the ergot
alkaloids produced by the fungus Claviceps purpurea, a contaminant of wheat and rye
flour. LSD is the most potent psychoactive drug. It activates the serotonin 5-HT2A
receptor in the prefrontal cortex, enhancing glutaminergic transmission onto pyramidal
neurons. These excitatory afferents mainly come from the thalamus and carry sensory
information of different modalities, which may constitute a link to enhanced perception.
Phencyclidine and Ketamine are referred to as dissociative anesthetics because patients
feel detached or disconnected from their pain and environment with their
administration. The use-dependent inhibition of glutamate receptors of the NMDA type
is the mechanism of action of these drugs.
V.
Top Ten Commonly Abused Drugs in the Philippines (DDB’s Statistics on Drug Abuse 2005)
For 2005, Methamphetamine Hydrochloride or Shabu, remained as the top drug of choice and
was abused by 81.36% (4,778) of clients recorded. Marijuana was second with 1,976 cases
(33.65%) while inhalants placed 3rd with 283 cases (4.82%). The other drugs abused were
benzodiazepines (3.37%), cough/cold preparations (2.54%) and Ecstasy (1.63%).
These drugs were commonly taken through inhalation or sniffing and by oral administration.
Most Commonly Abused Drugs 2005
Shabu (Stimulant)
81.36%
Marijuana (Cannabis)
33.65%
Inhalants
4.82%
Benzodiazepines
3.37%
Cough/Cold Preparations
2.54%
Ecstasy (Stimulant)
1.63%
Cocaine (Stimulant)
1.19%
Nubain (Narcotic/Analgesic)
1%
Opium (Morphine/Heroin)
0.48%
Ketamine (Narcotic)
0.31%
Other Drugs
0.14%
0
A.
10
20
30
40
50
60
70
80
90
Shabu (Amphetamine)
Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs
that cause the release of endogenous biogenic amines, such as dopamine and
noradrenaline.
Amphetamine sulfate is a white odorless crystalline powder, with a pH of 5 to 6. It is
freely soluble in water, slightly soluble in alcohol and practically insoluble in ether.
Together with GHB and ecstasy, amphetamines are often referred to as “club drugs”
since they are increasingly popular in the club scene. They differ from ecstasy chiefly
in the context of use: intravenous administration and “hard core” addiction is far
more common with amphetamines, especially methamphetamines.
a. Mechanism of Action
Amphetamines are non-catecholamine, sympathomimetic amines with CNS
stimulant activity. Peripheral actions include elevations of systolic and
diastolic blood pressure, wand weak bronchodilator, and respiratory
stimulant action.
b. Pharmacokinetics
Amphetamines reach peak concentrations at 2.6-3.6 hours with a mean
elimination half-life of 10.1 hours. Methamphetamine is metabolized to
amphetamine (active), p-OH-amphetamine and norephedrine (both
inactive).
c. Pharmacodynamics
Amphetamines and its derivatives exert their effects by reversing the action
of biogenic amine transporters at the plasma membrane. Amphetamines
are substrates of these transporters and are taken up into the cell. Once in
the cell, amphetamines interfere with the vesicular monoamine transporter
(VMAT), depleting synaptic vesicles of their neurotransmitter content. As a
consequence, levels of amine transmitters such as Dopamine in the
cytoplasm increase and quickly become sufficient to cause release into the
synapse by reversal of the plasma membrane DAT.
In general, amphetamines lead to elevated catecholamine levels that
increase arousal and reduce sleep, while the effects on the dopamine
system mediate euphoria but may also cause abnormal movements and
precipitate psychotic episodes. Effects on serotonin transmission may play a
role in the hallucinogenic and anorexigenic functions as well as in the
hyperthermia often caused by amphetamines.
d. Therapeutic uses and effects
Amphetamine sulfate is indicated in: narcolepsy; in attention deficit
disorder with hyperactivity, to stabilize children with a behavioral syndrome
characterized by the following developmentally inappropriate symptoms:
moderate to severe distractibility, short attention span, hyperactivity,
emotional lability, and impulsivity. It is also indicated in exogenous obesity
as a short term adjunct in a regimen of weight reduction based on caloric
restriction. Stuudies suggests that in psychotic children, administration of
amphetamines may exacerbate symptoms of behavior disturbance and
thought disorder. Amphetamines have been reported to exacerbate motor
and phonic tics and Tourette's syndrome. Therefore, clinical evaluation for
tics and Tourette's syndrome in children and their families should precede
use of stimulant medications.
e. Adverse Effects and Addiction
Cardiovascular: Palpitations, tachycardia, elevation of blood pressure.
Central Nervous System: Psychotic episodes at recommended doses (rare),
overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia,
dysphoria, tremor, headaches, exacerbation of motor and phonic tics and
Tourette's syndrome.
Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea,
constipation and other gastrointestinal disturbances. Anorexia and weight
loss may occur as undesirable effects when amphetamines are used for
other than the anorectic effect.
Allergic: Urticaria.
Endocrine: Impotence, changes in libido.
f.
Tolerance and Withdrawal
Tolerance, extreme psychological dependence and severe social disability
have occurred. There are reports of patients who have increased the dosage
to many times that recommended. Abrupt cessation following prolonged
high dosage administration results in extreme fatigue and mental
depression; changes are also noted on the sleep EEG.
Manifestations of chronic intoxication with amphetamines include severe
dermatoses, marked insomnia, irritability, hyperactivity and personality
changes. The most severe manifestation of chronic intoxication is psychosis,
often clinically indistinguishable from schizophrenia.
g. Pharmacologic and Non Pharmacologic Treatment
Non-pharmacologic treatment:
Physicians should establish a therapeutic alliance with patients to deal with
the underlying depression or personality disorder or both.
dependent
patients,
however,
are
difficult
to
be
Heavily
treated
with
psychotherapy.
Pharmacologic treatment:
The
treatment
of
specific
amphetamine-induced
disorders
(e.g.,
amphetamine-induced psychotic disorders and amphetamine-induced
anxiety disorder) with specific drugs such as antipsychotics and anxiolytics
may be necessary on the short-term basis.
Antipsychotics may be
prescribed for the first few days. In the absence of psychosis, diazepam
(Valium) is useful to treat patient’s agitation and hyperactivity. Comorbid
conditions such as depression may respond to antidepressant medication.
Bupropion (Wellbutrin) may be of use after patients have withdrawn from
amphetamine. It has the effect of producing feelings of well-being as these
patients cope with the dysphoria that may accompany abstienence.
B.
Marijuana (Cannabinoids)
Marijuana is a dry, shredded green/brown mix of flowers, stems, seeds, and leaves
of the hemp plant Cannabis sativa, it usually is smoked as a cigarette or in a pipe.
Marijuana smoke has a pungent and distinctive, usually sweet-and-sour odor. There
are countless street terms for marijuana including pot, herb, weed, grass, widow,
ganja, and hash, as well as terms derived from trademarked varieties of cannabis,
such as Bubble Gum, Northern Lights, Fruity Juice, Afghani #1, and a number of
Skunk varieties.
a. Mechanism of Action
The main active chemical in marijuana is THC (delta-9-tetrahydrocannabinol).
Delta-9-THC is believed to exert all of its effects on the brain via the cannabinoid
1 (CB1) receptor. High densities of CB1 receptors are found in the cerebral
cortex (especially frontal), basal ganglia, cerebellum, anterior cingulate cortex,
and hippocampus. They are relatively absent in the brainstem nuclei.
Stimulation of these receptors causes monoamine and amino acid
neurotransmitters to be released. Endogenous ligands for CB1 receptors include
anandamide and 2-arachidonylglycerol—the endocannabinoids.
b. Pharmacokinetics
After intake, THC undergoes metabolism to an inactive metabolite (8-11-DiOHTHC) and also to a highly active metabolite (11-OH-delta-9-THC). Peak plasma
levels are reached ten minutes after smoking and the psychoactive components
are effective for 2-3 hours. The half-life of THC is approximately 4 hours. The
long life of the active metabolite is explained by the incorporation of the
compound in lipid storage depots and similar storage sites in muscle tissue.
Marijuana is metabolized via the cytochrome P450 system and 30% to 60% of
THC, in all forms, is excreted in feces; the remaining amount is excreted in urine
which can be detected months after initial administration.
c. Pharmacodynamics
THC binds to cannabinoid receptors and interferes with important endogenous
cannabinoid neurotransmitter systems. Receptor distribution correlates with
brain areas involved in physiological, psychomotor and cognitive effects.
Correspondingly, THC produces alterations in motor behavior, perception,
cognition, memory, learning, endocrine function, food intake, and regulation of
body temperature.
d. Therapeutic uses and effects
There is some evidence available that medical marijuana has been found to be
an effective medication for some types of ADD by other researchers in the field.
e. Adverse Effects and Addiction
Clinical signs
People who use marijuana may present with either acute effects of intoxication
or symptoms of chronic use. Chronic users may also be noted to have changes in
appetite, diminished drive, and lack of ambition. This "amotivational syndrome"
is also characterized by lack of energy and decreased social and occupational
drive.
The following symptoms may be prominent in acute intoxication:

Euphoria

Relaxation

Subjective feelings of well-being or grandiosity

Perceptual changes (including visual distortions)

Drowsiness and sluggishness

Diminished coordination

Paradoxical hyperalertness

A subjective sense of slowing of the passage of time

Increased appetite (the "munchies")
Although commonly misperceived as universally resulting in a relaxed and
euphoric state, cannabis intoxication can produce a dysphoric reaction.

Feelings of panic

Disorientation and memory impairment (rare; usually occurs only after
ingestion of high-potency cannabinoid preparations)

Paranoia

Mood lability

Altered perceptions (following heavy marijuana use) manifesting as
illusions or frank hallucinations, most often visual in type

Depersonalization

Psychotic episodes

Recurrence of psychosis in patients with schizophrenia
Physical signs
Physical signs and symptoms reflect the effects of marijuana on multiple organ
systems and can be classified according to the system involved.
Effects on central and peripheral nervous systems
Cannabis-induced cerebral atrophy or neuropsychological impairment remains
a controversial diagnosis. Chronic effects of long-term marijuana use may be
related to marijuana's significant fat solubility resulting in high blood levels of
the drug after extended use. Marijuana-induced seizures have been described A
linear relationship exists between level of impairment and serum/saliva THC in
tasks necessary for driving, such as perceptual motor control, motor impulsivity,
and cognitive function. Cannabis use is associated with an increased risk in
youth for developing psychotic symptoms, even with adjustments made for age,
sex, socioeconomic status, urban residence, childhood trauma, predisposition
for psychosis at baseline, use of other drugs, tobacco, and alcohol.
Effects on respiratory system
Cannabis smoke contains carcinogens similar to those found in tobacco smoke,
and chronic heavy marijuana use may predispose people to chronic obstructive
lung disease. Some studies indicate that pulmonary neoplasms are more
common among habitual marijuana users; however, confounding by cigarette
smoking limits the interpretability of some of these reports.
Effects on cardiovascular system
Acute intoxication may induce tachycardia and orthostatic hypotension.
Effects on reproductive system
Marijuana has been linked to infertility. In vitro studies have reported abnormal
cell division and abnormal spermatogenesis resulting in decreased sperm
counts; however, the effects of marijuana on human fertility remain unclear. In
females, marijuana use may increase the number of anovulatory cycles. In
males, marijuana use may cause a decrease in follicle-stimulating hormone,
resulting in a decrease in testosterone production and, possibly, testicular
atrophy.
Effects on gastrointestinal tract
Marijuana has known antinausea properties and the use of marijuana has been
permitted for the treatment of nausea in some US states for this reason. Oddly
enough, a chronic nausea/vomiting syndrome has been reported in numerous
habitual marijuana users. Cessation of use in these cases ends the syndrome.
Dronabinol, a synthetic cannabinoid, and marijuana produce significant,
substantial, and comparable increases in food intake, without adverse effects in
experienced marijuana smokers who have clinically significant muscle mass loss.
f. Tolerance and Withdrawal
Tolerance to most of the effects of marijuana can develop rapidly after only a
few doses, but also disappears rapidly. Tolerance to large doses has been found
to persist in experimental animals for long periods after cessation of drug use.
Withdrawal symptoms and signs typically are not seen in clinical populations. In
fact, relative to the number of marijuana smokers, few patients ever seek
treatment for marijuana addiction. A withdrawal syndrome in human subjects
has been described following close observation of marijuana users given regular
oral doses of the agent on a research ward. This syndrome, however, is only
seen clinically in persons who use marijuana on a daily basis and then suddenly
stop. Compulsive or regular marijuana users do not appear to be motivated by
fear of withdrawal symptoms, although this has not been studied systematically.
A large study of psychotherapy for self-identified marijuana-dependent persons
reported significant reductions in the use of marijuana after treatment, but
there was no control group.
g. Pharmacologic and Non Pharmacologic Treatment
Non-pharmacologic treatment:
The treatment for cannabis rests on abstinence and support. Abstinence can be
achieved through direct interventions, such as hospitalization, or through careful
monitoring on an outpatient basis by the use of urine drug screens, which can
detect cannabis for up to a month after use. Support can be achieved through
the use of individual, family, and group psychotherapies. Education should be a
cornerstone for both abstinence and support programs. A patient who does not
understand the intellectual reasons for addressing a substance-abuse problem
has little motivation to stop.
Pharmacologic treatment:
Antianxiety drug may be useful for short-term relief of withdrawal symptoms.
For other patients, cannabis use may be related to an underlying depressive
disorder that may respond to specific antidepressant treatment.
Marijuana abuse and addiction have no specific treatments. Heavy users may
suffer from accompanying depression and thus may respond to antidepressant
medication, but this should be decided on an individual basis considering the
severity of the affective symptoms after the marijuana effects have dissipated.
The residual drug effects may continue for several weeks. The CB-1 receptor
antagonist rimonabant has been reported to block the acute effects of smoked
marijuana, but there have been no clinical trials of this medication in the
treatment of marijuana dependence.
C.
Corex-DM and Robitussin AC
Corex-DM and Robitussin AC are cough syrups which are widely abused due to its
addictive properties. These drugs are examples of Dextromethorphan, with an
antitussive property for the temporary relief of cough caused by minor sore throat
and bronchial irritation. Dextromethorphan is a safe and effective active ingredient
found in many nonprescription cough syrups, tablets, and gel caps. When used
accordingly to medicine label directions, the ingredient dextromethorphan produces
few side effects and has a long history of safety. When abused in large amounts, it
can produce a "high" feeling as well as a number of dangerous side effects.
a. Mechanism of Action
Corex-DM and Robitussin AC cough syrups are NMDA receptor antagonists.
Robitussin AC is a syrup preparation that combines the expectorant,
guaifenesin, with the cough suppressant, codeine. Guaifenesin enhances the
output of lower respiratory tract fluid. The enhanced flow of less viscid
secretions promotes and facilitates the removal of mucus. Codeine is a
centrally acting agent which elevates the threshold for cough. As a result,
dry, unproductive coughs become more productive and less frequent.
b. Pharmacokinetics
They are rapidly absorbed from the GIT with peak plasma concentrations at
2.5 hours and are widely distributed. They are rapidly and extensively
metabolized by the liver. Dextromethorphan is demethylated to
dextrorphan, an active metabolite, and to 3- methoxymorphinan and 3hydroxymorphinan. It is primarily excreted as unchanged parent drug and
dextrorphan.
c. Pharmacodynamics
Dextromethorphan acts centrally to elevate the threshold for coughing, and
has no significant analgesic or sedative properties at antitussive doses. It is
proposed that dextromethorphan is a glutamate and NMDA antagonist, and
blocks the dopamine reuptake site. It may also increase 5HT 1A activity
possibly via NMDA antagonism.
d. Therapeutic uses and effects
They temporarily controls cough due to minor throat and bronchial
irritation as may occur with the common cold or inhaled irritants. Helps
loosen phlegm (mucus) and thin bronchial secretions to make coughs more
productive.
e. Adverse Effects and Addiction
Adverse effects of Dextromethorphan include body rash or itching,
dissociation, nausea and other GIT disturbances, drowsiness, dizziness,
excitation, vomiting, blurred vision, dilated pupils, sweating, fever,
hypertension, shallow respiration, diarrhea, urinary retention and it
increases heart rate, blood pressure and body temperature.
Like other NMDA receptor antagonists, it is postulated that high doses of
injected dextromethorphan can cause a type of brain damage known as
Olney’s lesions. Studies show that high doses of NMDA receptor antagonist
MK-801 caused vacuoles to form in certain regions of test rats’ brains that
developed into irreversible lesions.
f. Tolerance and Withdrawal
Dextropmethorphan can also produce psychological dependence due to its
potential for recreational use, but it does not produce physical addiction
according to WHO Committee on Drug Dependence.
g. Pharmacologic and Non Pharmacologic Treatment
The initial treatment focuses on the symptoms of the patient, however,
since psychological dependence is the main culprit, therapies and treatment
programs directed to this dilemma is advised.
D.
Rugby
Inhalant abuse is the recreational exposure to chemical vapors such as nitrates,
ketones and aliphatic and aromatic hydrocarbons. These substances are present in
household and industrial products that are inhaled by sniffing, huffing or bagging.
Inhalant abuse starts with sniffing and progress to huffing and eventually bagging as
addiction develops.
In the Philippines, rugby as well as other aromatic solvents is the most common
abusive agent among street children which is one of their means to ease hunger.
Children on the streets, those who work on the street but do not live there; children
of the street, who live and work in the streets; and, completely abandoned and
neglected children, entirely on their own for physical and psychological survival are
the most common rugby abusers. Rugby is the most common inhalant substance
abused in the country due to its low cost and easy procurement and accessibility.
The active component of Rugby is Toluene. It is an aromatic hydrocarbon also
known as Methylbenzene, Toluol, Methylbenzol, or Phenylmethane. Its normal
physical state is liquid. It appears clear, colorless watery liquid with sweet benzene
like odor. It is highly volatile, flammable and has a low viscosity.
a. Mechanism of Action
Most volatile substances’ mechanism of action is unknown but altered
function of ionotropic receptors and ion channels throughout the central
nervous system has been demonstrated.
Although most of the studies
were done on rats it has through a lot of research known to act on two
major systems the GABAergic and dopaminergic systems. It is known to
reversibly enhance GABA (A) receptor-mediated synaptic currents. This
effect has a biphasic effect on neurotransmission such that an initial
excitatory phase is followed an inhibitory phase or depression. The
excitatory phase is characterized by euphoria, delusions, less commonly
visual and auditory hallucinations. Its action of the dopaminergic system
especially on the mesolimbic pathway is responsible for the substance
dependence of this drug. It increases the intracellular dopamine levels in
the, nucleus accumbens, striatum and changes in neuronal firing of
dopamine neurons of the VTA.
b. Pharmacokinetics
40-60% is absorbed via the respiratory tract. Dermal absorption is rapid
while GI absorption is slow. Toluene may also be absorbed through the
eyes. It is widely distributed once absorbed with the highest concentration
in adipose tissue, followed by the bone marrow, adrenals, kidneys, liver,
brain and blood. The mixed function oxidase system metabolizes 60-75% of
the absorbed toluene to benzoic acid. Toluene is hydroxylated to form
benzylalcohol. Benzylalcohol is conjugated with glycine to form hippuric
acid. Hippuric acid can easily be measure from the urine.
20-40% of
absorbed toluene is eliminated unchanged in the expired air. Following
single acute exposure elimination is complete within 24 hours.
c. Pharmacodynamics
Most inhalants produce euphoria; increased excitability of the VTA that may
underlie its addiction risk.
d. Therapeutic uses and effects
Toluene is frequently abused for its intoxicating effects. Recreational use is
most common among younger adolescents primarily because it is readily
available and inexpensive. The initial excitatory phase characterized by
euphoria, delusions, less commonly visual and auditory hallucinations is
followed by depression.
Acute effects may cause irritation of the
respiratory tract. Inhalation may also cause difficulty in seeing in bright light.
High vapor/aerosol concentrations (greater than approximately 1000 ppm)
are irritating to the eyes and the respiratory tract may cause headaches,
dizziness anesthesia, drowsiness, unconsciousness, central nervous system
effects, brain damage and possibly death. It may cause irritation of the skin.
Peculiar skin sensations may be produced such as a "pins and needles
feeling" or numbness. Occasional brief contact with the liquid will not result
in significant irritation unless evaporation is impeded. Skin contact may
aggravate an existing dermatitis condition. May cause irritation, but does
not injure eye tissue.
e. Adverse Effects and Addiction
Toluene vapor causes narcosis. Early to moderate central nervous system
depression may be evidenced by giddiness, headache, dizziness and nausea;
in extreme cases, unconsciousness and death may occur. Aspiration
pneumonitis may be evidenced by coughing, labored breathing and cyanosis
(bluish skin); in severe cases death may result. Repeated or prolonged
exposure to liquid toluene may cause drying and cracking of the skin.
Prolonged intentional Toluene abuse may lead to brain damage
characterized by disturbances in gait, personality changes and loss of
memory. Comparable central nervous system effects have not been shown
to result from occupational exposure to Toluene. Toluene may be harmful
to the human fetus based on positive test results with laboratory animals.
Case studies reveal that prolonged intentional abuse of Toluene during
pregnancy may cause birth defects in humans.
f. Tolerance and Withdrawal
A literature regarding tolerance to toluene has not been established, but
may occur but is considered difficult to estimate in humans. It seems to be
established after 1–2 months of repetitive exposure to volatile solvents.
The acute neurobehavioural effects of volatile solvents, including anxiolysis
and sedation, are those typically associated with central nervous system
depressants, and these effects may lead to continued use, tolerance and
withdrawal.
g. Pharmacologic and Non Pharmacologic Treatment
Non-pharmacological treatment:
Street outreach and extensive social service support have been offered to
severely deteriorated, inhalant-dependent, homeless adults. Patients may
require extensive support within their families or in foster or domiciliary
care.
Pharmacologic treatment:
Confusion, panic, and psychosis mandate special attention to patient safety.
Severe agitation may require cautious control with haloperidol (5 mg
intramuscularly per 70 kg body weight). Sedative drugs should be avoided
as they may aggravate the psychosis. Inhalant-induced anxiety and mood
disorders may precipitate suicidal ideation, and patients should b carefully
evaluated for that possibility. Antianxiety and antidepressants are not
useful in the acute phase of the disorder; they may be of use if there is a
coexisting anxiety or depressive illness.
E.
Nubain and Opium
Nubain (Nalbuphine Hydrochloride) is a synthetic opioid agonist-antagonist
analgesic of the phenanthrene series. It is chemically related both to the widely
used opioid antagonist, naloxone, and the potent opioid analgesic,
oxymorphone. It is a sterile solution suitable for subcutaneous, intramuscular,
or intravenous injection.
Opium is a narcotic formed from the latex released from the immature seed
pods of opium poppies (Papaver somniferum). It contains up to 16% morphine,
an opiate alkaloid, which is more frequently processed chemically to produce
heroin for the illegal drug trade.
An opioid is a chemical substance that has a morphine-like action in the body.
Opioids are ligands on opioid-receptors and they possess an intrinsic activity.
The main use is for pain relief. These agents work by binding to opioid
receptors, which are found principally in the central nervous system and the
gastrointestinal tract. The receptors in these two organ systems mediate both
the beneficial effects, and the undesirable side effects.
a. Mechanism of Action
Opioid receptors in the mammalian CNS include mu, kappa, sigma, delta,
and epsilon subtypes. These receptors are located in the brain (mostly in the
periaqueductal grey), spinal cord, peripheral nerves, adrenal medulla,
ganglia, and gut. Stimulation of mu and sigma receptors produces intense
feelings of well being and euphoria. Kappa-receptor stimulation produces
dysphoria. Antagonism at these receptors may produce dysphoria, but not
consistently. Antagonists block euphoria produced by opioids. Endogenous
opioids, though not highly selective, have a preference for specific receptor
types. Beta-endorphin is an endogenous ligand for the mu-receptor;
enkephalins and dynorphins have an affinity for sigma- and kappareceptors, respectively. The dopaminergic mesolimbic system, which
originates in the ventral tegmental area (VTA) of the midbrain and projects
to the nucleus accumbens, is crucial in (1) the reward effects of intracranial
self-stimulation, (2) the natural rewards of water and food intake, and (3)
the action of drugs of abuse, including opioids.
Basal activity of this system, expressed in dopamine release in the nucleus
accumbens, is under the tonic control of 2 opposing opioid systems,
activation of mu- and sigma-receptors increases, while kappa-receptor
activation decreases the basal activity of the mesolimbic system.
Experimental evidence with laboratory animals supports the idea that
manipulation of these receptors with opioids and other substances of abuse
(as well as electrical stimulation) affects self-administering behavior. These
reward pathways are thought to have evolved for the natural rewards such
as food and water intake.
Opioid receptors, like other G protein–coupled receptors, are characterized
by 7 transmembrane domains. High densities of opioid receptors are
located in all areas of the CNS known to be involved in integrating
information about pain—the brainstem, the medial thalamus, the spinal
cord, the hypothalamus, and the limbic system. Opioid receptors also have
been identified in the periphery. Drugs that bind to opioid receptors are
classified as agonists, partial agonists, mixed agonist-antagonists, and
antagonists. Receptor activation by an agonist initiates pharmacologic
actions, whereas an antagonist occupies the receptor without these effects.
b. Pharmacokinetics
Opioids have 81% bioavailability at 10 mg and 83% at 20 mg
intramuscularly; subcutaneously, it has 79% at 10mg and 76% at 20 mg
bioavailability. It reaches peak effect in less than 15 minutes when
administered subcutaneously or intramuscularly and within 2 to 3 minutes
when administered intravenously. It undergoes hepatic metabolism with
half-life of 5 hours. Excretion is via urine or feces and 7% are metabolites.
c. Pharmacodynamics
The principal effects of opioid analgesics with affinity for mu receptors are
on the CNS; the more important ones include analgesia, euphoria, sedation,
and respiratory depression. Other CNS effects include cough suppression, a
well recognized action of opioids; miosis, which is the constriction of pupils
seen in all agonists; truncal rigidity, which involves action at the supraspinal
levels that reduces thoracic compliance, thus, interfering with ventilation;
nausea and vomiting by the activation of the brainstem chemoreceptor
trigger zone; and temperature regulation wherein stimulation of mu
receptors induce hyperthermia, while kappa agonists induce hypothermia.
Opioids also affect the different peripheral systems. Most opioids have no
significant direct effects on the heart, and other than bradycardia, no major
effects on the cardiac rhythm, with an exception for meperidine, which can
result to tachycardia due to antimuscarinic action. Constipation is a longrecognized effect of opioids on the gastrointestinal tract, and which does
not diminish with continued use. Other effects are as follows: biliary colic
(biliary tract), depression of renal function, prolongation of labor (uterus),
stimulate secretion of ADH, prolactin, and somatotropin while inhibiting the
release of luteinizing hormone, pruritus, and many others.
d. Therapeutic uses and effects
Analgesia is one of the clinical uses of opioids. Severe, constant pain is
usually relieved with opioid analagesics with high intrinsic activity, while
sharp, intermittent pain is not as effectively controlled. They are also useful
in relief of dyspnea due to pulmonary edema associated with left ventricular
failure. Proposed mechanisms include reduction of anxiety (perception of
shortness of breath), and reduction of preload (reduced venous tone) and
afterload (decreased peripheral resistance). Morphine can be particularly
useful in treating painful myocardial ischemia with pulmonary edema.
Crude opium preparations (e.g., paregoric) were used to control diarrhea
until recently when synthetic surrogates with more selective gastrointestinal
effects and few or no CNS effects are more widely used.
Opioid agonists also have the propensity to reduce shivering, the most
pronounced of which is meperidine. Its action on subtypes of alpha-2
adrenoceptors, apparently block shivering.
e. Adverse Effects and Addiction
Most opioids associated with abuse and dependence are mu-agonists, such
as heroin, morphine, hydrocodone, oxycodone, and meperidine. Some
partial mu-agonists, such as buprenorphine, or some that have no muagonism, such as pentazocine, also can possess reinforcing properties. Rapid
development of physical dependence and a protracted abstinence
syndrome are unique to opioid use and can make abstinence difficult.
Common adverse reactions in patients taking opioids for pain relief:

nausea and vomiting

drowsiness

dry mouth

miosis,

Constipation
f. Tolerance and Withdrawal
Opioid
dependence
is
considered
a
biopsychosocial
disorder.
Pharmacological, social, genetic, and psychodynamic factors interact to
influence abuse behaviors associated with drugs. However, pharmacological
factors can be especially prominent, more so than in other types of drug use
disorders.
Injection of a heroin solution produces a variety of sensations described as
warmth, taste, or high and intense pleasure ("rush") often compared with
sexual orgasm. There are some differences among the opioids in their acute
effects, with morphine producing more of a histamine-releasing effect and
meperidine producing more excitation or confusion. Even experienced
opioid addicts, however, cannot distinguish between heroin and
hydromorphone in double-blind tests. Thus, the popularity of heroin may be
due to its availability on the illicit market and its rapid onset. After
intravenous injection, the effects begin in less than a minute. Heroin has
high lipid solubility, crosses the blood-brain barrier quickly, and is
deacetylated to the active metabolites 6-monoacetyl morphine and
morphine. After the intense euphoria, which lasts from 45 seconds to
several minutes, there is a period of sedation and tranquility ("on the nod")
lasting up to an hour. The effects of heroin wear off in 3 to 5 hours,
depending on the dose. Experienced users may inject two to four times per
day. Thus, the heroin addict is constantly oscillating between being "high"
and feeling the sickness of early withdrawal .This produces many problems
in the homeostatic systems regulated at least in part by endogenous
opioids. For example, the hypothalamic-pituitary-gonadal axis and the
hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts. Women
on heroin have irregular menses, and men have a variety of sexual
performance problems. Mood also is affected. Heroin addicts are relatively
docile and compliant after taking heroin, but during withdrawal, they
become irritable and aggressive.
g. Pharmacologic and Non Pharmacologic Treatment
Non-pharmacological treatment:
Various kinds of therapies may be useful such as individual psychotherapy,
behavioral therapy, cognitive-behavioral therapy, family therapy, support
groups, and social skills training. Family therapy is usually indicated when
the patient lives with family members.
Pharmacologic treatment:
(1) In Overdose treatment – The first task is to ensure an adequate airway.
Tracheopharyngeal secretions should be aspirated; an airway may be
inserted. The patient should be ventilated mechanically until naloxone, a
specific opioid antagonist, can be given. This is administered IV at a slow
rate (initially about 0.8 mg per 70 kg of body weight). Too much naloxone
may produce signs of withdrawal as well as reversal of overdosage. If there
is no response to the initial dosage, naloxone administration may be
repeated after intervals of a few minutes. The duration of action is short
compared with that of many opioids. Repeated administration may be
required to prevent recurrence of opioid toxicity.
(2) Withdrawal and Detoxification
Methadone – a synthetic narcotic (an opioid) that substitutes for heroin and
can be taken orally. It suppresses withdrawal symptoms. A daily dosage of
20 – 80 mg suffices to stabilize a patient. It has a duration of action
exceeding 24 hours; thus, once daily is adequate. Maintenance is continued
until the patient can be withdrawn from methadone, which itself causes
dependence. An abstinence syndrome occurs with methadone withdrawal,
but patients are detoxified from methadone more easily than from heroin.
Clonidine (0.1 to 0.3 mg three to four times a day) is usually given during the
detoxification period.
Advantages include: (1) It frees persons with opioid dependence from using
injectable heroin and thus reduces the chance of spreading HIV through
contaminated needles; (2) It produces minimal euphoria and rarely causes
drowsiness or depression when taken for a long time; (3) it allows patients
to engage in gainful employment instead of criminal activity. The major
disadvantage of methadone is that patients remain dependent on a
narcotic.
Other opioid substitutes – This includes (1) Levomethadyl, a longer-acting
opioid than methadone, which is also used to treat opioid dependence. This
can be administered in dosages of 30 – 80 mg three times a week. (2)
Buprenorphine, an opioid partial agonist and an analgesic with opioid
antagonist activity approved only for treatment of moderate to severe pain.
A daily dose of 8 to 10 mg appears to reduce heroin use. It is also effective
in thrice-weekly dosing because of its slow dissociation from opioid
receptors.
Opioid antagonists – Do not exert narcotic effects and do not cause
dependence. This includes naloxone, which is used in the treatment of
opioid overdose because it reverses the effects of narcotics, and naltrexone,
the longest-acting (72 hours) antagonist. The theory for using an antagonist
for opioid-related disorders is that blocking opioid agonist effects,
particularly euphoria, discourages persons with opioid dependence from
substance seeking behavior and thus deconditions this behavior. The major
weakness of the antagonist treatment model is the lack of any mechanism
that compels a person to continue to take the antagonist.
F.
Cocaine
Cocaine is 2Beta-carbomethoxy-3Beta-benzoxytropane, an alkaloid found in the
leaves of Erythroxylon coca. It has been extracted and used in clinical medicine,
mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud
proposed its use to treat depression and alcohol depression, but addiction quickly
brought an end to it.
Cocaine Hydrochloride is a water-soluble, crystalline, granular, or powder salt. It
can be injected or absorbed by any mucosal membrane. When heated in an
alkaline solution it is transformed into the free base, “crack cocaine”, which could
then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and
penetrates swiftly into the brain, producing an almost instantaneous “rush”.
a. Mechanism of Action
Cocaine inhibits voltage-gated sodium channels in the peripheral nervous system,
thus blocking the initiation and conduction of action potentials and effecting local
anesthetic action. In the central nervous system, cocaine blocks the uptake of
dopamine, noradrenaline, and serotonin through their respective transporters.
The block of the dopamine transporter (DAT), by increasing dopamine
concentrations in the nucleus accumbens, has been implicated in the rewarding
effects of cocaine. The activation of the sympathetic nervous system results
mainly from the block of the norepinephrine transporter (NET) and leads to an
acute increase in arterial pressure, tachycardia, and often, ventricular arrythmias.
b. Pharmacokinetics
Cocaine is rapidly absorbed following smoking, snorting and intravenous
administration. Bioavailability is 57% following snorting and ~70% following
smoking. Cocaine is 91% bound in plasma. Cocaine is extensively metabolized to a
variety of compounds: benzoylecgonine, ecgonine, and ecgonine methyl ester are
the major metabolites and are centrally inactive. Benzoylecgonine is produced
upon loss of the methyl group and is the major urinary metabolite. Norcocaine is a
very minor metabolite, but is active and neurotoxic. Cocaethylene, formed
following concurrent ingestion of cocaine and alcohol, is also active and is
equipotent to cocaine in blocking dopamine reuptake. The apparent half-life for
cocaine is short, approximately 0.8 ± 0.2 hours, while the half-life of
benzoylecgonine is 6 hours.
c. Pharmacodynamics
Cocaine is a strong CNS stimulant that interferes with the reabsorption process of
catecholamines, particularly dopamine, a chemical messenger associated with
pleasure and movement. Cocaine prevents the reuptake of dopamine by blocking
the dopamine transporter which leads to increased extracellular dopamine,
resulting in chronic stimulation of postsynaptic dopamine receptors. This results in
the euphoric ‘rush’. When dopamine levels subsequently fall, users experience a
dysphoric ‘crash’. Similarly, cocaine interferes with the uptake of norepinephrine
and serotonin (5-HT), leading to accumulation of these neurotransmitters at
postsynaptic receptors. As a local anesthetic, cocaine reversibly blocks the
initiation and conduction of the nerve impulse. Cocaine additionally produces
vasoconstriction and dilated pupils.
d. Therapeutic uses and effects
Cocaine Hydrochloride topical solution is indicated for the introduction of local
(topical) anesthesia of accessible mucous membranes of the oral, laryngeal and
nasal cavities.
e. Adverse Effects and Addiction
Adverse reactions are systemic in nature and involve the central nervous system
and/or the cardiovascular system. CNS reactions are excitatory and/or depressant,
and may be characterized by nervousness, restlessness and excitement. Tremors
and eventually clonicotonic convulsions may result. Emesis may occur. Central
stimulation is followed by depression, with death resulting from respiratory
failure. Small doses of cocaine slow the heart rate, but after moderate doses, the
rate is increased due to central sympathetic stimulation. Cocaine is pyrogenic,
augmenting heat production in stimulating muscular activity and causing
vasoconstriction which decreases heat loss. Cocaine is known to interfere with the
uptake of norepinephrine by adrenergic nerve terminals, producing sensitization
to catecholamines, causing vasoconstriction and mydriasis. Cocaine causes
sloughing of the corneal epithelium, causing clouding, pitting, and occasionally
ulceration of the cornea.
The fatal dose of cocaine has been approximated 1.2 g, although severe toxic
effects have been reported from doses as low as 20 mg. The symptoms of cocaine
poisoning are referable to the CNS, namely the patient becomes excited, restless,
garrulous, anxious and confused. Enhanced reflexes, headache, rapid pulse,
irregular respiration, chills, rise in temperature, mydriasis, exophthalmos, nausea,
vomiting, and abdominal pain are noticed in severe overdoses, delirium, CheyneStokes respiration, convulsions, unconsciousness and death from respiratory
arrest result. Acute poisoning by cocaine is rapid in developing.
f. Tolerance and Withdrawal
Sensitization is a consistent finding in animal studies of cocaine and other
stimulants. This is produced by intermittent use and typically is measured by
behavioral hyperactivity. In human cocaine users, sensitization for the euphoric
effect is not commonly seen. On the contrary, most experienced users report
requiring more cocaine over time to obtain euphoria, which is tolerance. In the
laboratory, tachyphylaxis (rapid tolerance) has been observed with reduced
effects when the same dose is given repeatedly in one session. Sensitization may
involve conditioning. Cocaine users often report a strong response on seeing
cocaine before it is administered, which consists of physiological arousal and
increased drug craving with concomitant activation of brain limbic structures. In
humans, this has been linked to paranoid, psychotic manifestations of cocaine use
based on the observation that cocaine-induced hallucinations and paranoia
typically are seen after long-term exposure (mean 35 months) in vulnerable users.
Since cocaine typically is used intermittently, even heavy users go through
frequent periods of withdrawal or "crash."
Careful studies of cocaine users during withdrawal show gradual diminution of
these symptoms over 1 to 3 weeks. Residual depression may be seen after
cocaine withdrawal and should be treated with antidepressant agents if it
persists. With mild to moderate cocaine use, withdrawal symptoms end within 18
hours. However, with heavy use, as in dependence, withdrawal symptoms can
last up to a week but usually peak in 2-4 days.
g. Pharmacologic and Non Pharmacologic Treatment
Non-pharmacological treatment:
Negative reinforcements are experimentally linked to cocaine intake.
The
clinician must take a broad treatment approach and include social, psychological,
and biological strategies. Negative reinforcers may take the form of work and
family-related problems brought on by cocaine.
Pharmacologic treatment:
No pharmacologic treatments, presently, decrease cocaine use. A variety of
pharmacological agents, however, most of which are approved for other uses,
have been, and are being, tested clinically for the treatment of cocaine
dependence and relapse.
Treatment with methylphenidate (Ritalin) and lithium (Eskalith) can be attributed
to
the
presumption
that
cocaine
users
have
pre-existing
attention-
deficit/hyperactivity disorder (ADHD) or mood disorders, respectively. These
drugs are of little or no benefit in patients without the disorders, and clinicians
should adhere strictly to maximal diagnostic criteria before using either of them in
the treatment of cocaine dependence. In patients with ADHD, slow-release forms
of methylphenidate may be less likely to trigger cocaine craving, but the impact of
such pharmacotherapy on cocaine use remains to be demonstrated.
Drugs on trial include agents that induce GABAergic inhibition, which could
reduce reinstatement of cocaine self-administration. This finding prompted a
controlled clinical trial of topiramate (TOPAMAX) that showed a significant
improvement for this medication approved for use in epilepsy. Topiramate also
was found to reduce the relapse rate in alcoholics, prompting current studies in
patients dually dependent on cocaine and alcohol. Baclofen (LIORESAL, others), a
GABAB agonist, was found in a single-site trial to reduce relapse in cocaine addicts
and currently is being studied in a multiclinic trial. A different approach was taken
using modafinil (PROVIGIL), a medication that increases alertness and is approved
for the treatment of narcolepsy. This medication was found to reduce the
euphoria produced by cocaine and to relieve cocaine withdrawal symptoms. After
a single-site, double-blind study found it effective in reducing relapse, modafinil is
being studied in a multisite trial among cocaine-dependent patients.
Two completely different approaches are also under study: a compound that
competes with cocaine at the dopamine transporter and a vaccine that produces
cocaine-binding antibodies. However, these should be regarded as innovative
ideas that have yet to be shown to be useful clinically. The recent spate of positive
findings from placebo-controlled trials suggests that an effective medication for
cocaine addiction may be on the horizon. For now, the treatment of choice
remains behavioral, with medication indicated for specific coexisting disorders
such as depression.
G.
Ecstasy (MDMA)
MDMA (3,4 methylenedioxymethamphetamine) is a synthetic, psychoactive drug
chemically similar to the stimulant methamphetamine and the hallucinogen
mescaline. It is one of the most popular recreational psychoactives, most commonly
sold in the form of “ecstasy” tablets. It appears as white, crystalline powder in
capsule or tablet form taken orally. MDMA is known for its empathogenic, euphoric,
and stimulant effects, and has also been used in psychotherapy. Street names
include: XTC, X, Adam, hug, beans, and love drug. MDMA is an illegal drug that acts
as both a stimulant and psychedelic, producing an energizing effect, as well as
distortions in time and perception and enhanced enjoyment from tactile
experiences.
a. Mechanism of Action
MDMA causes release of biogenic amines by reversing the action of their
transporters, preferentially for serotonin transporter (SERT) and therefore
most strongly increases the extracellular concentration of serotonin.
b. Pharmacokinetics
MDMA is rapidly absorbed and t he half-life of MDMA is ~ 7 hours, although
non-linear pharmacokinetics have been observed due to stereoselective
pharmacokinetics of the enantiomers. MDMA is metabolized to MDA which
is the only metabolite reported in blood and plasma. S-(+)- MDA
accumulates in blood due to stereoselective metabolism of S-(+)-MDMA.
MDA is further metabolized to its 3-hydroxy-4-methoxy and 3,4-dihydroxy
derivatives (HMA and HHA). Additional MDMA metabolites include 3hydroxy-4-methoxymethamphetamine
dihydroxymethamphetamine
(HHMA).
(HMMA)
These
polar
and
3,4-
hydroxylated
metabolites are conjugated prior to their excretion in urine.
c. Pharmacodynamics
MDMA is a phenylethylamine that has stimulant as well as psychedelic
effects. MDMA is related in structure and effects to methamphetamine,
however, it has significantly less CNS stimulant properties than
methamphetamine. MDMA has a high affinity for 5-HT 2 receptors. Both Sand R- enantiomers of MDMA cause acute depletion of presynaptic
serotonin (5-HT), depression of 5-HT synthesis by tryptophan hydroxylase,
and retrograde destruction of 5-HT neurons following high doses. MDMA
also increases levels of norepinephrine and dopamine. The MDMA
metabolite, S-(+)- MDA, elicits more stereotypic behavior and is an even
more potent neurotoxin than the parent drug. MDA destroys serotonin-
producing neurons which play a direct role in regulating aggression, mood,
sexual activity, sleep, and sensitivity to pain.
d. Therapeutic uses and effects
Short-term effects include feelings of mental stimulation, emotional
warmth, enhanced sensory perception, and increased physical energy.
MDMA causes entactogenesis, which is a generalized feeling that all is right
and good with the world. People on MDMA often describe feeling "at
peace" or experiencing a generalized "happy" feeling. Chronic users of
MDMA perform more poorly than nonusers on certain types of cognitive or
memory tasks. Some of these effects may be due to the use of other drugs
in combination with MDMA, among other factors.
Before it was made illegal, MDMA was gaining a reputation among the
psychiatric community as a valuable therapeutic tool. In 2001, the FDA
granted permission for experimental administration of MDMA to patients
suffering from post-traumatic stress disorder. This research is being
sponsored by the Multidisciplinary Association for Psychedelic Studies
(MAPS). A parallel similar study is currently underway in Switzerland which
should finish in 2008.
e. Adverse Effects and Addiction
In high doses, MDMA can interfere with the body’s ability to regulate
temperature. On rare but unpredictable occasions, this can lead to a sharp
increase in body temperature (hyperthermia), resulting in liver, kidney, and
cardiovascular system failure, and death. Potentially harmful levels can be
reached by repeated drug use within short intervals because MDMA can
interfere with its own metabolism (breakdown within the body).
The acute effects of MDMA have an initial onset of 30 minutes after oral
intake and are characterized by anxiety, tachycardia, and elevated blood
pressures. Associated symptoms include diaphoresis, bruxism, jaw
clenching, paresthesias, dry mouth, increased psychomotor activity, and
blurred vision. Within 1 hour, these sympathomimetic effects are replaced
by feelings of relaxation, euphoria, and increased empathy and
communication. While overt auditory and/or visual hallucinations are
uncommon, patients report increased sensory tactile enhancement and
mild visual distortions, such as halos. These effects plateau for up to 90
minutes and then diminish over 3-4 hours.
MDMA causes massive serotonin release, and numerous case reports link
MDMA toxicity to the serotonin syndrome. Serotonin syndrome is a
condition in which central 5-HT receptor hyperstimulation results in classic
findings of hyperthermia, mental status changes, autonomic instability, and
altered muscle tone and/or rigidity.
f. Tolerance and Withdrawal
Ecstasy users found that 43 percent of those who reported ecstasy use met
the accepted diagnostic criteria for dependence, as evidenced by continued
use despite knowledge of physical or psychological harm, withdrawal
effects, and tolerance (or diminished response), and 34 percent met the
criteria for drug abuse. Almost 60 percent of people who use Ecstasy report
withdrawal symptoms, including fatigue, loss of appetite, depressed
feelings, and trouble concentrating.
g. Pharmacologic and Non Pharmacologic Treatment
No established protocols exist for treating MDMA intoxication. However, the
most important treatment should be directed towards its important adverse
effects such as lowering the body temperature and maintaining adequate
hydration to avoid acute renal failure due to rhabdomyolysis and
myoglobinuria. The cases of hyponatremia associated with MDMA that have
resulted in seizures, coma, and cerebral edema indicate that it is extremely
important to avoid overhydration of the patient during treatment.
Supportive care is currently the standard of treatment.
H.
Trazepam (Benzodiazepine)
Benzodiazepines are a class of drugs with sedative, hypnotic, anxiolytic,
anticonvulsant, amnestic and muscle relaxant properties. They are often used for
short-term relief of severe, disabling anxiety or insomnia. They began to be widely
prescribed for stress-related ailments. Their chemical structure is based upon
diazepine and phenyl groups.
Classes :
1. 2-ketobenzodiazepine – chlordiazepoxide, diazepam, chlorazepate, flurazepam
2. 3-hydroxy benzodiazepines – lorazepam, femazepam
3. triazolobenzodiazepines – alprazolam, triazolam, estazolam
4. imidazo-benzodiazepines – imidazolam
a. Mechanism of Action
Rohypnol, a trade name for flunitrazepam, belongs to a class of drugs
known as benzodiazepines. Rohypnol can incapacitate victims and prevent
them from resisting sexual assault. It can produce “anterograde amnesia,”
which means individuals may not remember events they experienced while
under the effects of the drug. Also, Rohypnol may be lethal when mixed
with alcohol and/or other depressants.
Benzodiazepines are positive modulators of the GABAA receptor, the most
prolific inhibitory receptor within the brain, increasing both single channel
conductance and open-channel probability. In order for GABAA receptors to
be sensitive to the action of benzodiazepines they need to contain an α and
γ
subunit,
where
the
benzodiazepine
binds.
Once
bound,
the
benzodiazepine locks the GABAA receptor into a conformation where the
neurotransmitter GABA has much higher affinity for the GABAA receptor,
increasing the frequency of opening of the associated Chloride ion channel
and hyperpolarizing the membrane. This potentiates the inhibitory effect of
the available GABA leading to sedatory and anxiolytic effects.
b. Pharmacokinetics
It is absorbed more effectively in the duodenum, highly protein bound and
highly lipophilic. Peak plasma levels at 1-3 hours with secondary peak
plasma levels: 6-12 hours after enterohepatic circulation. It is redistributed
from CNS to other tissues such as muscles and adipose tissues. Metabolism
is via the liver.
c. Pharmacodynamics
Benzodiazepines appear to act at the limbic, thalamic and hypothalamic
levels of the CNS.
d. Therapeutic uses and effects
Anxiolytic - Relief of anxiety, Hypnotic - promotion of sleep, Myorelaxant muscle relaxation, stop fits & convulsions, Amnesia - impair short-term
memory
e. Adverse Effects and Addiction
Benzodiazepines are usually a secondary drug of abuse, used mainly to
augment the high received from another drug or to offset the adverse
effects of other drugs.
Symptoms
may
include
confusion
(continuing), convulsions
(seizures), drowsiness (severe) or coma; shakiness, slow heartbeat, slow
reflexes, slurred
speech
(continuing), staggering, troubled
breathing
and weakness (severe).
f. Tolerance and Withdrawal
Tolerance develops in many of the therapeutic effects of benzodiazepines
rapidly with daily or frequent use. Generally, tolerance to the hypnotic and
sedative effects occurs within days; however, tolerance to the anxiolytic
effects of benzodiazepines takes longer to develop. Long-term use of
benzodiazepine may actually worsen anxiety in some people with or
without prior psychiatric history. A possible explanation for increased
anxiety from chronic use of benzodiazepines is that it is a side effect of
tolerance with increasing doses required to suppress withdrawal effects.
However, patients should be aware that this could lead to a cycle of
increasing doses and worsening side effects. In addition, as dosage is
increased, the potential for addiction becomes greater.
Withdrawal from benzodiazepines occurs within days of stopping the
medication and varies as a function of the half-life of elimination. Symptoms
include: irritability, insomnia, phono- and photophobia, depression, muscle
cramps and seizures. These symptoms typically taper off within 1-2 weeks.
g. Pharmacologic and Non Pharmacologic Treatment
A nonbenzodiazepine such as buspirone may be prescribed to replace
patients with anxiety taking benzodiazepines but this agent usually is less
effective. Some authorities recommend transferring the patient to a longhalf-life
benzodiazepine during detoxification; other recommended
medications include the anticonvulsants carbamazepine and Phenobarbital.
The specific benzodiazepine receptor antagonist flumazenil has been found
useful in the treatment of overdose and in reversing the effects of long
acting benzodiazepines used in anesthesia.
It has been tried in the
treatment of persistent withdrawal symptoms after cessation of long-term
benzodiazepine treatment.
A long acting benzodiazepine such as diazepam or clorazepate (TRANXENE)
or a long-acting barbiturate such as phenobarbital can be used to block the
sedative withdrawal symptoms. The phenobarbital dose should be
determined by a series of test doses and subsequent observations to
determine the level of tolerance. Most complex detoxifications can be
accomplished using this phenobarbital loading-dose strategy.
After detoxification, the prevention of relapse requires a long-term
outpatient rehabilitation program similar to the treatment of alcoholism.
I.
Alcohol
Alcohol is a group of chemical compounds containing a hydroxyl group. The most
popular subtype is the ethyl alcohol or ethanol. Ethanol is manufactured from the
fermentation of sugar. It is the alcohol found in liquors like beer, wine and brandy.
Abuse to alcohol has been a serious health problem because of the many diseases
associated with alcoholism.
a. Mechanism of Action
Alcohol alters the function of a number of receptors and cellular functions,
including GABAA receptors, Kir3/GIRK channels, glycine receptor, N-methylD-aspartate (NMDA) receptors, and 5-HT3 receptors. In addition, ethanol
also interferes with adenosine re-uptake by inhibiting the equilibrate
nucleoside transporter ENT1, although it is not clear if this plays a role in
ethanol-induced dopamine release but seems to be involved in alcohol
dependence through an accumulation of adenosine, stimulation of
adenosine A2 receptors and ensuing enhanced CREB signaling.
b. Pharmacokinetics
Ethanol is a water soluble substance that is rapidly absorbed in the
gastrointestinal tract. In a fasting state, its peak concentration is achieved
thirty minutes after ingestion. In the contrary, the presence of food slows
absorption by delaying gastric emptying. The volume of distribution of
alcohol approximates the total body water (0.5-0.7 L/kg). Women have
higher peak of concentration than men because women have lower total
body water content. Ethanol easily reaches the central nervous system
because it can cross the biologic membranes.
The liver is the major site for the oxidation of alcohol. It follows a zero-order
kinetics. Two mechanisms for the metabolism have been identified: Alcohol
dehydrogenase pathway and Microsomal ethanol oxidizing system (MEOS).
The primary pathway utilizes alcohol dehydrogenase enzyme (ADH) which
catatalyzes the conversion of ethanol to acetaldehyde and NADH+. ADH is
primarily found in the liver. Minute amounts can also be found in the
stomach and brain. The second pathway uses NADPH+ as a cofactor. At
blood alcohol level below 100mg/dl, oxidation of alcohol is primarily
through the ADH system. However, as the concentration rises above 100
mg/dl, the ADH is saturated because of the depletion of its cofactor NAD+.
There is now a shift to MEOS which also yields acetaldehyde. The
acetaldehyde from both pathways is converted to acetic acid.
c. Pharmacodynamics
At high doses, ethanol acts as an agonist on synapses, particularly on the
GABA A-2L receptor.
d. Therapeutic uses and effects
Chronic intake of modest doses of alcohol can have some beneficial effects.
A maximum of one to two drinks per day may decrease the risk for
cardiovascular death, perhaps through an increase in high-density
lipoprotein (HDL) cholesterol or changes in clotting mechanisms. In one
large national study, cardiovascular mortality was reduced by 30 to 40%
among individuals reporting one or more drinks daily compared to
nondrinkers, with overall mortality lowest among those consuming
approximately one drink per day. Recent data have also corroborated the
decreased risk for ischemic, but not hemorrhagic, stroke associated with
regular light drinking.
e. Adverse Effects and Addiction
The abuse potential of alcohol rises from the fact that ethanol consumption
produces marked sedation, relief of anxiety and neurochemical conditioning
leading to the perception that alcohol benefits the drinker psychologically or
socially.
f. Tolerance and Withdrawal
Dependence becomes apparent 6-12 hours after cessation of heavy drinking
as a withdrawal syndrome that may include tremor, nausea and vomiting,
excessive sweating, agitation and anxiety. In some individuals visual, tactile
and auditory hallucinations follow 12-24 hours after cessation. Generalized
seizures may manifest after 24-48 hours. An alcohol withdrawal delirium
may become apparent after 48-72 hours after cessation in which the person
hallucinates, disoriented and shows evidence of autonomic instability.
g. Pharmacologic and Non Pharmacologic Treatment
Naltrexone
Naltrexone is chemically related to the highly selective opioid-receptor
antagonist naloxone (NARCAN) but has higher oral bioavailability and a
longer duration of action. Animal research and clinical experience suggested
that naltrexone might reduce alcohol consumption and craving; this was
confirmed in clinical trials (see O'Malley et al., 2000; Johnson and Ait-Daoud,
2000). There is evidence that naltrexone blocks activation by alcohol of
dopaminergic pathways in the brain that are thought to be critical to
reward.
Naltrexone helps to maintain abstinence by reducing the urge to drink and
increasing control when a "slip" occurs. It is not a "cure" for alcoholism and
does not prevent relapse in all patients. Naltrexone works best when used in
conjunction with some form of psychosocial therapy, such as cognitive
behavioral therapy. It typically is administered after detoxification and given
at a dose of 50 mg/day for several months. Adherence to the regimen is
important to ensure the therapeutic value of naltrexone and has proven to
be a problem for some patients. The most common side effect of naltrexone
is nausea, which is more common in women than in men and subsides if the
patients abstain from alcohol. When given in excessive doses, naltrexone
can cause liver damage. It is contraindicated in patients with liver failure or
acute hepatitis and should be used only after careful consideration in
patients with active liver disease.
Disulfiram
Disulfiram, given alone, is a relatively nontoxic substance, but it inhibits
ALDH activity and causes the blood acetaldehyde concentration to rise to 5
to 10 times above the level achieved when ethanol is given to an individual
not pretreated with disulfiram. Following the administration of disulfiram,
both cytosolic and mitochondrial forms of ALDH are irreversibly inactivated
to varying degrees, and the concentration of acetaldehyde rises. Several
active metabolites of the drug, especially diethylthiomethylcarbamate,
behave as suicide-substrate inhibitors of ALDH in vitro. These metabolites
reach significant concentrations in plasma following the administration of
disulfiram.
The drug never should be administered until the patient has abstained from
alcohol for at least 12 hours. In the initial phase of treatment, a maximal
daily dose of 500 mg is given for 1 to 2 weeks. Maintenance dosage then
ranges from 125 to 500 mg daily depending on tolerance to side effects.
Unless sedation is prominent, the daily dose should be taken in the morning,
the time when the resolve not to drink may be strongest. Sensitization to
alcohol may last as long as 14 days after the last ingestion of disulfiram
because of the slow rate of restoration of ALDH.
Acamprosate
The mechanism of action of acamprosate is obscure, although there is some
evidence that it modulates the function of NMDA receptors in brain. A
number of double-blind, placebo-controlled studies have demonstrated that
acamprosate decreases drinking frequency and reduces relapse drinking in
abstinent alcoholics. It acts in a dose-dependent manner (1.3 to 2 g/day)
and appears to have efficacy similar to that of naltrexone. Studies in
laboratory animals have shown that acamprosate decreases alcohol intake
without affecting food or water consumption. Acamprosate generally is well
tolerated by patients, with diarrhea being the main side effect. No abuse
liability has been noted.
Other Agents
Ondansetron, a 5-HT3-receptor antagonist and antiemetic drug (see
Chapters 11 and 37), reduces alcohol consumption in laboratory animals and
currently is being tested in humans. Preliminary findings suggest that
ondansetron is effective in the treatment of early-onset alcoholics, who
respond poorly to psychosocial treatment alone, although the drug does not
appear to work well in other types of alcoholics. Ondansetron
administration lowers the amount of alcohol consumed, particularly by
drinkers who consume fewer than 10 drinks per day. It also decreases the
subjective effects of ethanol on 6 of 10 scales measured, including the
desire to drink, while at the same time not having any effect on the
pharmacokinetics of ethanol.
Topiramate, a drug used for treating seizure disorders, appears useful for
treating alcohol dependence. Compared with the placebo group, patients
taking topiramate achieved more abstinent days and a lower craving for
alcohol.
Rehabilitation of Alcoholics
Maneuvers in rehabilitation fall into several general categories, which are
applied to all patients regardless of age or ethnic group. However, the
manner in which the treatments are used should be sensitive to the
practices and needs of specific populations. First are attempts to help the
alcoholic achieve and maintain a high level of motivation toward abstinence.
These include education about alcoholism and instructing family and/or
friends to stop protecting the person from the problems caused by alcohol.
The second step is to help the patient to readjust to life without alcohol and
to reestablish a functional life-style through counseling, vocational
rehabilitation, and self-help groups such as Alcoholics Anonymous. The third
component, called relapse prevention, helps the person to identify
situations in which a return to drinking is likely, formulate ways of managing
these risks, and develop coping strategies that increase the chances of a
return to abstinence if a slip occurs.
J.
Ketamine
Ketamine is classified as “club drugs” and is also known as “angel dust”, “Hog” and
"Special K”. It is a white crystalline powder in its pure form but on the street it is
sold in liquid or in capsule or pill from which can be snorted, ingested, injected or
smoked.
a. Mechanism of Action
Ketamine is a noncompetitive antagonist of the NMDA receptor.
b. Pharmacokinetics
Ketamine is an intravenous anesthetic drug. It has a faster onset of action
than inhaled gaseous agents such as sevuflurane. It is a highly lipophilic drug
that is rapidly distributed to the highly perfused organs. It is eliminated
through biliary and urinary excretion.
c. Pharmacodynamics
Upon IV administration, ketamine induces marked sensory loss and the
effects of ketamine became apparent when the patient undergoing surgery
reported unpleasant vivid dreams and hallucinations after anesthesia. It
produces analgesia, amnesia, paralysis of the movement without actual loss
of consciousness. It increases the heart rate, arterial blood pressure and
cardiac output. This is done by the excitation of the central sympathetic
nervous system and probably by the inhibition of the reuptake of
norepinephrine at the sympathetic nerve terminals.
Ketamine activates specific opioid receptors which is the sigma opioid
receptors in the central nervous system. The sigma opioid receptor has
been implicated in many of the symptoms of schizophrenia. Specifically,
Ketamine acts to decrease functioning of the thalamus, which is a sort of
routing station for perceptual signals in the brain. The result is that sensory
perception is blunted wherein the users feel emotionally detached from
reality.
d. Therapeutic uses and effects
Ketamine is used as an anesthetic drug especially for patients with unknown
medical history. At low doses ((0.1–0.5 mg/kg/h) has an analgesic,
particularly for the treatment of pain associated with movement and
neuropathic pain. At these doses, the psychotropic side effects are less
apparent and well managed with benzodiazepines. Ketamine is a coanalgesic, requiring a concomitant low-dose opioid to be effective.
e. Adverse Effects and Addiction
The effects of ketamine are dose dependent. At low doses of 1.0-2.0 mg/kg
BW produces an intense feeling of hallucination, floating sensation including
increased blood pressure, impaired memory function and visual alterations
lasting for an hour.
At high doses, the user experiences “K-hole”. It has a dissociative effect that
is equated to an out of body or near death experience. It is described as
dreamlike hallucinations, floating sensations, perceptions of increased
efficiency and creativity, feelings of arousal and euphoria, and mystical
experiences of self-transcendence.
Associated symptoms are severe
respiratory depression and muscle twitches.
f. Tolerance, Dependence, and Withdrawal
Tolerance to ketamine can develop very quickly, with people needing more
and more to achieve the same euphoric and psychedelic effects.
There is evidence that people who regularly use ketamine can develop a
psychological dependence. People who are psychologically dependent on
ketamine may experience cravings. They may feel compelled to use
ketamine to function effectively or feel good in certain situations—such as
at a dance party.
There is currently little evidence to support the view that people who are
dependent on ketamine experience physical withdrawal symptoms if they
suddenly stop taking it.
g. Pharmacologic and Non Pharmacologic Treatment
Haloperidol
Because dissociative drugs affect so many neurotransmitters, some
discrimination is necessary in choosing a treatment protocol for intoxication.
Most of the clinically significant symptoms of dissociatives are produced by
presynaptic dopamine stimulation and cholinergic antagonism.5 These
symptoms can be reversed with haloperidol (Haldol), which is a presynaptic
dopamine antagonist. The dopamine-blocking action of haloperidol also shifts
the dopamine-acetylcholine activity ratio in the limbic system. This
"functionally" counteracts the anticholinergic actions of dissociatives.
Haloperidol is prescribed in an initial dosage of 5 mg given intramuscularly
every 20 to 30 minutes until the patient is stabilized. Intramuscular
administration of 1 g of ascorbic acid can potentiate the action of haloperidol
and increase the rate of dissociative elimination by acidifying the urine.
Risperidone
A second treatment option is risperidone (Risperdal). This agent counteracts
the dopaminergic and serotoninergic effects of dissociatives but not their
anticholinergic effects.
Haloperidol has several advantages over risperidone. It can be administered
intramuscularly, it works within 20 minutes and it is readily available in most
emergency departments. In contrast, risperidone must be administered orally
and takes one to two hours to work. Risperidone, however, is more useful in
reducing paranoid behavior. It can also be useful when haloperidol produces
no effect.
Antidepressants
Long-term use of dissociatives suppresses the production of norepinephrine
and dopamine. Consequently, the abuser is likely to experience
postwithdrawal
depression.
The
depression
can
be
treated
with
antidepressants that counteract this suppression. Desipramine (Norpramin),
a relatively specific noradrenergic tricyclic antidepressant, is prescribed
initially in a dosage of 50 mg taken at bedtime. The dosage is increased in 50mg increments every other day to a final dosage of 200 mg taken at bedtime.
This dosage is maintained for three to nine months.
There are no antidotes to ketamine and the majority of therapy is based on
psychotherapy and behavior modification.
References:
Basic and Clinical Pharmacology, 10th edition, Katzung, B.G.
Goodman & Gilman’s The Pharmacological Basis of Therapeutics – 11th edition (2006)
Kaplan & Saddock’s Synopsis of Psychiatry – 9th edition (2003)
Principles of Drug Addiction Treatment (A Research-based guide) – National Institute on Drug
Abuse.
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