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Je S4 Lec 4: Drug Abuse and Alcohols by Jason Suquila, MD February 2, 2011
s • most important signs of withdrawal derive from
vi
DRUGS OF ABUSE excessive CNS stimulation: anxiety, tremor, n
a
Drug abuse is usually taken to mean the following: & v, delirium, and hallucinations
M • the use of an illicit drug • seizures are not uncommon and may be life-
vs • the excessive use of a licit drug threatening
Re • the non-medical use of a licit drug • treatment of withdrawal: involves
ai • the deliberate use of chemicals that generally administration of a long-acting sedative-
are not considered drugs by the lay public but hypnotic (e.g. chlordiazepoxide or
diazepam), followed by gradual dose
M
may be harmful to the user
n reduction
SEDATIVE HYPNOTICS
Re

• Sedative-hypnotics include: ethanol,

F.
barbiturates and benzodiazepines
co
Opioid Analgesics
• Short-acting barbiturates (e.g.: secobarbital)
Ri
• most commonly abused drugs in this group:
have high addiction potential.
F.
heroin, morphine, oxycodone
ul • Sedative-hypnotics reduce inhibitions, suppress
Pa anxiety, and produce relaxation
• most commonly abused drugs in this group
among health professionals: meperidine and
vs • Sedative-hypnotics are CNS depressants. fentanyl
Vi • The depressant effects of sedative-hypnotics • the effects of IV heroin are described by
ne are enhanced by concomitant use of opioid abusers as a “rush” or orgasmic feeling,
le analgesics, antipsychotic agents, marijuana, followed by euphoria, and then sedation
Ar and any other drug with sedative properties. • IV administration of opioids is associated with
a • Acute overdoses commonly result in death rapid development of tolerance and
ň through depression of the medullary psychological and physiologic dependence.
respiratory and cardiovascular centers. • oral administration or smoking of opioids
•
Ni
Management of overdose includes causes milder effects, with a slower onset of
maintenance of patent airway plus ventilatory tolerance and dependence
g
an support. • overdose of opioids leads to respiratory
ad
• Flumanezil – can be used to reverse the CNS depression progressing to coma and death
D depressant effects of benzodiazepines • management of overdose: IV naloxone (0.2 -
er
• No antidote for barbiturates or ethanol 0.4 mg; 10 - 20 mg if intoxicated with
h (empty GI through emesis or gastric lavage, propoxyphene, fentanyl derivatives) or IV
ac then administer activated charcoal). nalmefene and ventilatory support
e • deprivation of opioids in physiologically
Flunitrazepam dependent individuals leads to withdrawal
syndrome: lacrimation, rhinorrhea, yawning,
T
• potent rapid-onset benzodiazepine with
ar
marked amnestic properties sweating, weakness, “gooseflesh”/”cold
be
• used in “date rape” turkey”, n & v, tremors, muscle jerks (“kicking
the habit”) and hyperpnea
• added to alcoholic beverages, chloral hydrate
co
• although extremely unpleasant, withdrawal
or γ-hydroxybutyrate (GHB): also render the
Ri
from opioids is rarely fatal (unlike sedative-
ie victim incapable of resisting rape hypnotics)
ck
• Treatment:
GHB
• involves replacement of the illicit drug
Ni
ad • γ-hydroxybutyrate, sodium oxybate
with a pharmacologically-equivalent
Gl • when used as a “club drug”, GHB causes agent (e.g. methadone), followed by
Je euphoria, enhanced sensory perception, and slow dose reduction
euphoria
nz • clonidine and buprenorphine (a
Ay
Withdrawal Symptoms of Sedative Hypnotics longer acting opioid) have also been
used to suppress withdrawal symptoms
• physiologic dependence occurs with continued
h
use of sedative-hypnotics
at
Stimulants (Caffeine, Nicotine,
K
• the s/sx of withdrawal syndrome are most Amphetamine,Cocaine)
o pronounced with drugs that have a t1/2 of • Caffeine and Nicotine
Jh <24h (e.g. ethanol, secobarbital, • caffeine (in beverages) and nicotine
h methaqualone) (in tobacco products) are legal in many
a • however, physiologic dependence may occur cultures even though they have
n with any sedative-hypnotic, including the adverse medical effects
e longer acting benzodiazepines
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el • tobacco use is associated with a high
h incidence of cardiovascular, respiratory
ac and neoplastic disease
R • Withdrawal Symptoms:
” • withdrawal from caffeine is
“G accompanied by lethargy,
irritability and headache
• the anxiety and mental
n
h discomfort experienced from
Jo discontinuing nicotine are
n major impediments to quitting
Ia the habit
a • Toxicity:
n • acute toxicity from overdosage
of caffeine and nicotine:
excessive CNS stimulation with
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tremor, insomnia and
nervousness; cardiac
stimulation and arrythmias;
and respiratory paralysis (in
case of nicotine)
• Amphetamine
• NOTE: drugs in this class include
dextroamphetamine and
methamphetamine (“shabu”)
• amphetamines inhibit transporters of
CNS amines including dopamine,
norepinephrine and serotonin
• amphetamines cause a feeling of
euphoria and self-confidence that
contributes to the development of
psychological dependence
• chronic high-dose abuse leads to a
psychotic state (i.e., with delusions and
paranoia) that is difficult to
differentiate from schizophrenia
• symptoms of overdose: agitation,
restlessness, tachycardia,
hyperthermia, hyperreflexia, and
possible seizures
• chronic abuse may lead to
development of necrotizing arteritis à
cerebral hemorrhage and renal failure
• no specific antidote for
amphetamine overdosage (perform
gastric lavage and administer activated
charcoal)
• supportive measures are directed
toward control of body temperature,
and protection against cardiac
arrythmias (use a short acting β-
blocker [esmolol]) and seizures (treat
agitation or psychosis with a
benzodiazepine [diazepam or
midazolam])
• Withdrawal Symptoms:
• these symptoms may occur
upon withdrawal: increased
appetite, sleepiness,
exhaustion, and mental
depression.
• if the above withdrawal
symptoms occur,
antidepressant drugs may be
indicated
• Cogeners of Amphetamines
• the chemical cogeners of
amphetamine include: 2,5-
dimethoxy-4-
methylamphetamine (DOM,
STP), methylene
dioxyamphetamine (MDA) and
methylenedioxymethampheta
mine (MDMA)
• MDMA
• “ecstasy”
• has a more selective
action than
amphetamine on the
serotonin transporter in
the CNS
• is purported to
facilitate interpersonal
communication and act
as a sexual enhancer
• overdose toxicity:
hyperthermia and
seizures
• Cocaine
• cocaine is also an inhibitor of CNS
transporters of dopamine,
norepinephrine and serotonin, and has
a marked amphetamine-like effects
• cocaine abuse continues to be
widespread partly because of a free-
base form (“crack”) that can be
smoked
• the euphoria, self-confidence and
mental alertness produced by cocaine
are short-lasting and positively
reinforce its continued use
• overdoses of cocaine commonly result
in fatalities from arrythmias, seizures,
or respiratory depression
• in addition, the powerful
vasoconstrictive action of cocaine may
lead to severe hypertensive episodes,
resulting in MI and strokes
• no specific antidote is available for
cocaine overdosage (treat
symptomatically; use gastric lavage or
activated charcoal for ingestion)
• Withdrawal Symptoms:
• the abstinence syndrome after
withdrawal from cocaine is
similar to that after
amphetamine discontinuance
• severe depression of mood is
common and strongly
reinforces the compulsion to
use the drug (thus,
antidepressants may be
indicated in this case)
Hallucinogens
• the arylcyclohexylamine drugs include
phencyclidine (PCP) and ketamine (“special K”)
PCP
• “angel dust”
• is probably the most dangerous of the
currently popular hallucinogenic agents
• psychotic reactions are common with this drug
• impaired judgment often leads to reckless
behavior
• effects of overdosage: nystagmus, marked
hypertension, seizures (which may be fatal)
• parenteral benzodiazepines (e.g.:
diazepam, lorazepam) are used to curb
excitation and protect against seizures
Miscellaneous Hallucinogens
• lysergic acid diethylamide (LSD), mescaline
and psilocybin
• the CNS effects of these drugs are described as
“psychedelic” and “mind revealing”
• there is little evidence that use of these agents
leads to the development of physiologic
dependence
Marijuana
• marijuana (“grass”) is a collective term for the
psychoactive constituents present in crude
extracts of the plant Cannabis sativa (hemp)
• the active compounds found in marijuana
include tetrahydrocannabinol (THC),
cannabidiol (CBD), and cannabinol (CBN)
• “hashish” is a partially purified material that is
more potent
• CNS effects of marijuana: feeling of being
“high”, with euphoria, disinhibition,
uncontrollable laughter, changes in perception,
and achievement of a dream-like state
• mental concentration may be difficult
• vasodilation occurs, and the pulse rate is
characteristically increased
• habitual users show a reddened conjunctiva
• the dangers of marijuana use concern its
impairment of judgment and reflexes, effects
that are potentiated by concomitant use of
sedative-hypnotics, including ethanol
• potential therapeutic effects of marijuana
include: its ability to decrease IOP and its anti-
emetic actions
Abused Inhalants
• Certain gases or volatile liquids are abused
because they provide a feeling of euphoria and
disinhibition.
• ANESTHETICS:
• NO, chloroform, diethylether
• these agents are hazardous because
they affect judgment and induce LOC
• inhalation of NO as the pure gas (i.e.,
with no O2 has caused asphyxia and
death
• INDUSTRIAL SOLVENTS:
• gasoline, paint thinners aerosol
propellants, glues, rubber cements,
and shoe polish
• because of the availability, these
substances are most frequently abused
by children in early adolescence
• ORGANIC NITRITES:
• amyl nitrite, isobutyl nitrite, and other
organic nitrites are referred to as
“poppers” and are mainly used as
sexual intercourse “enhancers”
• inhalation of nitrites may cause
dizziness, tachycardia, hypotension,
and flushing
• with the exception of
methemoglobinemia, few serious
adverse effects have been reported
Steroids Abuse
• anabolic steroids are controlled substances
based on their potential for abuse
• effects sought by abusers are increases in
muscle mass and strength rather than
euphoria
• excessive use of steroids can have adverse
behavioral, cardiovascular and musculoskeletal
effects
ALCOHOLS
Ethanol
• Pharmacokinetics
o After ingestion, ethanol is rapidly and
completely absorbed; the drug is then
distributed to most body tissues, and
its Vd = Total Body Water (0.5-0.7
L/kg)
o Two enzyme systems metabolize
ethanol to acetaldehyde
o ALCOHOL DEHYDROGENASE (ADH)
 the reaction has zero-order
kinetics, resulting in a fixed-
capacity for ethanol
metabolism of 7-10 g/h
 GI metabolism of ethanol is
lower in women than in men
o MICROSOMAL ETHANOL OXIDIZING
SYSTEM (MEOS)
 At blood ethanol levels >100
mg/dL, the liver microsomal
mixed function oxidase system
that catalyzes most phase I
drug metabolizing reactions
contributes significantly to
ethanol metabolism
 Aldehyde dehydrogenase is
inhibited by disulfiram,
metronidazole, oral
hypoglycemics, and some
cephalosporins
 o Promotes protein plugs formation and
calcium carbonate-containing stones
o Gastritis
o Increased susceptibility to blood and
plasma loss
 Can contribute to anemia and
protein malnutrition
o Small intestine injury
 Diarrhea
 Weight loss
 Multiple vitamin deficiency
• Nervous System
o Tolerance and Physical/Psychologic
Dependence
o Withdrawal Symptoms:
 Hyperexcitability (mild)
 Seizures, toxic psychosis and
delirium tremens (severe)
o GABA neurotransmission are believed
to play a central role in tolerance and
withdrawal
• Pharmacodynamics o Affects neurotransmitter in brain
Blood Clinical Effects reward circuits
alcohol  Serotonin
concentr  Opioids
ation  Dopamine
(mg/dL) o Naltrexone
 Non selective opioid antagonist
50-100 Sedation, subjective “high”,
slower reaction times  Helps patients who are
recovering from alcoholism
100-200 Impaired motor function, abstain from drinking
slurred speech, ataxia • Neurotoxicity
o leads to neurologic deficits
200-300 Emesis, stupor o generalized symmetric peripheral
nerve injury
300-400 Coma
 most frequent neurologic
>500 Respiratory depression, death abnormality
 begins with distal paresthesias
of the hands and feet
Effects of Chronic Ethanol Consumption
o exhibit gait disturbances and ataxia
• Tissue damage
o Increased oxidative stress coupled with  due to degenerative changes in
depletion of glutathione the CNS
o Mitochondrial damage o dementia
o Growth factor dysregulation o demyelinating disease (rare)
o Cytokine-induced injury potentiation o Wernicke-Korsakoff syndrome
• Associated with increased risk of death (uncommon)
o Caused by liver disease, cancer,  characterized by paralysis of
accidents, suicide the external eye muscles,
• Liver ataxia, and a confused state
o Common medical complication of  can progress to coma and
alcohol abuse death
o Alcoholic fatty liver (reversible)  associated with thiamin
o Alcoholic hepatitis deficiency
o Cirrhosis and Liver failure  Wernicke's encephalopathy
• GIT (acute phase)
o Chronic pancreatitis • longer duration of
o Toxic effect on pancreatic acinar cells confusion
o Alters pancreatic epithelial • absence of the
permeability agitation
  most patients are left with
Korsakoff's psychosis (chronic
disabling memory disorder)
o impair visual acuity (withpainless
blurring)
 usually bilateral and symmetric
 followed by optic nerve
degeneration
• Cardiovascular System
o dilated cardiomyopathy with
ventricular hypertrophy and fibrosis
o changes in heart cells that may
contribute to cardiomyopathy
 membrane disruption
 depressed function of
mitochondria and SR
 intracellular accumulation of
phospholipids and fatty acids
 up-regulation of voltage-
dependent calcium channels
o can interfere with the effects of β-
blockers and ACE inhibitors
o atrial and ventricular arrhythmias
(binge drinking)
 abnormalities of potassium or
magnesium metabolism
 enhanced release of
catecholamines
 Seizures, syncope, and sudden
death
o Hypertension
o moderate alcohol consumption
 prevents CHD
 ethanol's ability to raise serum
levels of high-density
lipoprotein (HDL) cholesterol
 inhibit some of the
inflammatory processes that
underlie atherosclerosis
 antioxidants (especially red
wine) can also protect against
atherosclerosis
• Blood
o indirectly affects hematopoiesis
(metabolic and nutritional effects)
o directly inhibit the proliferation of all
bone marrow cellular elements
o mild anemia
 resulting from alcohol-related
folic acid deficiency
o Iron deficiency anemia
 from gastrointestinal bleeding
o cause of several hemolytic syndromes
 associated with hyperlipidemia
and severe liver disease
• Endocrine System and Electrolyte Balance
o gynecomastia and testicular atrophy
 derangement in steroid
hormone balance
o ascites, edema, and effusions (with
chronic liver disease)
o Alterations of whole body potassium
 induced by vomiting and
diarrhea
o severe secondary aldosteronism
 contribute to muscle weakness
 worsened by diuretic therapy
o hypoglycemia
 result of impaired hepatic
gluconeogenesis
o ketosis
 caused by excessive lipolytic
factors (especially cortisol and
growth hormone)
• Fetal Alcohol Syndrome
o teratogenic effects
o leading cause of mental retardation
and congenital malformation
o intrauterine growth retardation
o microcephaly
o poor coordination
o underdevelopment of midfacial region
(flattened face)
o minor joint anomalies
o triggers apoptotic neurodegeneration
o causes aberrant neuronal and glial
migration in the developing nervous
system
o striking reduction in neurite outgrowth
o interference with synthesis and
function:
 critical for cell recognition and
migration
• L1
o immunoglobuli
n cell adhesion
molecule
• gangliosides
o major
structural
components of
neuronal
plasma
membranes
• Immune System
o Inhibits lung immune function
 increases the mortality risk of
patients with pneumonia
o Enhances liver and pancreas immune
function
 enhanced function of Kupffer
cells
o suppression of the function of alveolar
macrophages
o inhibition of chemotaxis of
granulocytes
o reduced number and function of T cells
• Increased risk of Cancer
o cancer of the mouth, pharynx, larynx,
esophagus, and liver
 o breast cancer in women • polyhydric alcohol that is used as heat
exchangers, in anti-freeze formulations, and as
Treatment for Acute and Chronic Alcoholism industrial solvents
• Excessive CNS depression • Industrial exposure to ethylene glycol (by
• intoxication resulting in acute ingestion inhalation or by skin absorption) or self-
of ethanol is managed by maintenance administration (e.g., by drinking anti-freeze
of VS and prevention of aspiration after products) leads to severe acidosis and renal
vomiting damage (from the metabolism of ethylene
• IV dextrose is standard glycol to oxalic acid)
• thiamine administration is used to • Prompt treatment with IV ethanol (which
protect against Wernicke-Korsakoff competes for oxidation by alcohol
syndrome dehydrogenase) or fomepizole may slow
down or prevent formation of this toxic
• correction of electrolytes may be
metabolite
required
• to achieve useful inhibition, serum ethanol
• Alcohol withdrawal syndrome
concentration should be 100 mg/dL
• in individuals physically dependent on ethanol,
discontinuance can lead to withdrawal
syndrome: insomnia, tremor, anxiety; and in
severe cases: life-threatening seizures and
delirium tremens (DTs)
• peripheral effects include: nausea, vomiting,
diarrhea and arrythmias
• abstinence syndrome is managed by
correction of electrolyte imbalance and
administration of thiamine and a sedative-
hypnotic
• a long-acting benzodiazepine (e.g.,
diazepam, chlordiazepoxide) is preferred; if
with compromised liver function, a short-
acting benzodiazepine with less complex
metabolism (e.g., lorazepam) is preferred
• Treatment of Alcoholism
• alcoholism is a complex sociomedical problem,
characterized by a high relapse rate
• Naltrexone: an opioid receptor antagonist;
useful in some patients
• Acamprosate: an NMDA glutamate receptor
antagonist, is FDA approved for treatment of
alcoholism
• agents under investigation: ondansetron,
topiramate

Methanol
• “wood alcohol”
• A constituent of windshield cleaners and
“canned heat”
• Methanol is sometimes ingested intentionally
• Intoxication causes visual dysfunction, GI
distress, SOB, LOC, and coma
• Methanol is metabolized to formaldehyde and
formic acid, which can cause severe acidosis,
retinal damage and blindness
• The formation of formaldehyde is retarded by:
• prompt IV administration of
ethanol (which acts as a preferred
substrate for alcohol dehydrogenase
and competitively inhibits the oxidation
of methanol)
• fomepizole (inhibitor of alcohol
dehydrogenase)

Ethylene Glycol