DRUG OF ABUSE
Israa omar
Drug of abuse
• Drug of abuse is usually taken to mean the use of
an illicit drugs or the excessive or nonmedical use
of a licit drug.
• It is also denotes the deliberate use of chemicals
that generally are not considered drugs by the lay
public but may be harmful to the user.
• A primary motivation for drug abuse appear to be
the anticipated feeling of pleasure derived from
the CNS effects of the drug.
Drug of abuse
• The older term physical dependence is now
generally denotes as dependence, whereas
psychological dependence is more simply
called addiction.
High-yield terms to learn
• Abstinence syndrome:
– Term used to describe the signs and symptoms
that occur on withdrawal of a drug in a
dependent person.
• Addiction:
– Compulsive drug using behavior in which the
person uses the drug for personal satisfaction,
often in the face of known risks to health;
– Formerly termed psychological dependence.
High-yield terms to learn
• Controlled substance:
– A drug deemed to have abuse liability that is
listed on governmental schedules categorize
illicit drugs, control prescribing practices, and
mandate penalties for illegal possession,
manufacture, and sale of listed drugs.
– Controlled substance schedules are presumed to
reflect current attitudes toward substance
abuse; therefore which drugs are regulated
depends on social judgment.
High-yield terms to learn
• Dependence:
– A state characterized by signs and symptoms,
frequently the opposite of those caused by a
drug, when it is withdrawn from the chronic
use or when the dose is abruptly lowered;
– Formerly termed physical or physiologic
dependence
High-yield terms to learn
• Designer drug:
– A synthetic derivative of a drug, with slightly
modified structure but no major change in
pharmacodynamics action.
– Circumvention of the schedules of controlled
drug is motivation for the illicit drug synthesis
of designer drugs
High-yield terms to learn
• Tolerance:
– Decrease response to drug, necessitating larger doses
to achieve the same effect.
– This can result from increased disposition of the drug
(metabolic tolerance), an ability to compensate for the
effect of a drug (behavioral tolerance), or changes in
receptor or effector systems involved in drug actions
(functional tolerance)
• Withdrawal symptoms:
– May be experienced upon discontinuation.
– Some of these symptoms are generally the
opposite of the drug's direct effect on the
body.
The Dopamine Hypothesis Of
Addiction
• Dopamine is the mesolimbic system appears to
play a primary role in the expression of reward,
but excessive dopaminergic stimulation may lead
to pathologic reinforcement such that behavior
may become compulsive and no longer under
control-common features of addiction.
• Though not necessarily the only neurochemical
characteristic of drug abuse, it appears that most
addictive drugs have actions that include
facilitation of the effects of dopamine in the CNS.
Major groups of drugs that are
subject to abuse
1.
2.
3.
4.
5.
6.
7.
Opioids analgesics: Morphine and Heroin
Sedative/hypnotics.
Stimulants.
Hallucinogens
Marjuana
Inhalants
Steroids
1. Opioid analgesics (Effect)
• The primary targets underlying the action of opioids
analgesics are the δ,µ and ĸ receptors.
• They also have action including disinhibition in
dopaminergic pathways in the CNS.
• The most commonly abused drug in this group are
heroin, morphine, codeine, oxycodone and among
health professionals, meperidine and fentanyl.
• The effect of IV heroin are described by abusers as a
rush or orgasmic feeling followed by euphoria and
then sedation
• IV administration is associated with rapid
development of tolerance , dependence and
addiction.
Opioid Analgesics
(Over dose)
• Overdose of opioids leads to respiratory
depression progressing to coma and death.
• Overdose is managed with intravenous
Naloxone or Nalmefene and ventilatory
support.
Opioid Analgesics
( Withdrawal)
• Deprivation of opioids from physiologically
dependent individuals leads to an abstinence
syndrome that includes lacrimation, rhinorrhea,
yawning, sweating, weakness, gooseflesh,
nausea and vomiting, tremor, muscle jerks and
hyperpnoea.
• Withdrawal from opioids although unpleasant
is rarely fatal
Opioid analgesics
( withdrawal)
• Treatment involves replacement of illicit drug
with a pharmacologically equivalent agent
(e.g. Methadone) followed by dose reduction.
• Buprenorphine a partial agonist at µ and
longer acting (more than 40 h), is also used to
suppress withdrawal symptoms and as
substitution therapy for opioids addicts.
• The administration of naloxone to a person
who is using strong opioids (but not
overdosing) may cause more rapid and more
intense symptoms of withdrawal).
• Neonates born to mothers physiologically
dependent on opioids require special
management of withdrawal symptoms
2. Sedative- Hypnotics
• The sedative-hypnotics drugs are responsible for
many cases of drug abuse.
• The group include ethanol, barbiturates, and
benzodiazepines.
• Benzodiazepines are commonly prescribed drugs
for anxiety and as Schedule IV drugs, are judged by
the US government to have low abuse liability.
• Short acting barbiturates have high addiction
potential.
• Ethanol is not listed in schedules of controlled
substances but it has abuse liability.
Sedative- hypnotics (effects)
• Sedative-hypnotics reduce inhibitions, suppress
anxiety, and produce relaxation.
• All of these action are thought to encourage
repetitive use.
• These drugs also enhance brain dopaminergic
pathways, the latter action possibly related to
the development of addiction.
• These drugs are CNS depressants, and their
depressant effects are enhanced by concomitant
use of opioids analgesics, Marijuana,
antipsychotics and any other drugs with sedative
properties.
Sedative- hypnotics(effects)
• Flunitrazepam (Rohypnol), a potent rapid
onset benzodiazepines with marked amnestic
properties, has been used in (date rape).
• Added to alcoholic beverages, chloral hydrate
or ϒ-hydroxybutrate (GABA agonist) also
render the victim incapable of resisting rape.
Sedative- Hypnotics
(Overdose )
• Acute over doses may result in death through
depression of the medullary respiratory and
cardiovascular centers.
• Management of overdose include maintenance
of patent airways plus ventilatory support .
• Flumazenil can be used to reverse the CNS
depressant effect of benzodiazepines, but
there is no antidote for barbiturates or
ethanol.
Sedative- hypnotics
(Withdrawal )
• Physiological
dependence
occur
with
continued use of sedative-hypnotics; the signs
and symptoms of the withdrawal (abstinence)
syndrome are most pronounced with drugs
that have a half life of less than 24 h (e.g.
ethanol, secobarbital).
• However it also occur with any sedativehypnotics, including the longer acting
benzodiazepines.
• The most important signs of withdrawal derive
from excessive CNS stimulation and include
anxiety, tremor, nausea and vomiting, delirium
and hallucination.
• Seizures are not uncommon and may be life
threating.
Sedative- hypnotics
(Treatment of withdrawal )
• Treatment of withdrawal involves administration of
long acting sedative-hypnotics ( chlordiazepoxide
or diazepam) to suppress the acute withdrawal
syndrome, followed by gradual dose reduction.
• Clonidine (inhibits exaggerated neurotransmitter
release) or propranolol may also be of value to
suppress sympathetic over activity.
Sedative- hypnotics
(Treatment of withdrawal)
• The opioid receptor antagonist naltrexone reduces
alcohol-induced reward (unclear mechanism)
• Disulfiram: blockade of ADH lead to accumulation
of acetaldehyde- nausea, flushing, tachycardia,
hyperventilation, panic…
• Aim: to make alcohol consumption unpleasant
and intolerable it is used for treatment of
dependence not for acute withdrawal syndrome.
3. Stimulants
I. Methylxansines
• Natural alkaloids occurring in various beverages,
namely tea, coffee, cocoa and cola-flavored drinks
• Substances: caffeine, theophylline, theobromine
• Pharmacological effects:
1. CNS stimulation
2. Diuresis (vasodilatation of the afferent glomerular
arteriole)
3. Stimulation of cardiac muscle
4. Relaxation of smooth muscle, especially bronchial.
Methylxansines Effects
1. Inhibition of phosphodiesterase, responsible
for intracellular metabolism of cAMP
2. Antagonism on adenosine receptors
• Tolerance and habituation develop to a small
extent and withdrawal effects are very slight
(headache, fatigue)
• Toxicity: from over-dosage of caffeine include
excessive CNS stimulation with tremor, insomnia,
and nervousness; cardiac stimulation and
arrhythmia.
II. Nicotine
• It appears to be the only pharmacologically active
substances in tobacco smoke.
• One cigarette contain about 9-17mg of nicotine, of
which 10% is normally absorbed.
Effects :
1. In the brain it causes neuronal excitation that can be
blocked by Mecamyline
2. In the spine it inhibits spinal reflex and thus causing
muscle relaxation
3. In the peripheral tissues, nicotine stimulates the
receptors at the ganglion and causes tachycardia,
hypertension and reduced GI motility
Nicotine
• Tolerance: to peripheral (not central) ganglionic
stimulation, perhaps due to desensitization of
receptors
• Physical dependence craving: increased irritability,
anxiety, impaired performance of psychomotor
tasks, aggressiveness and sleep disturbances,
headache increased appetite lasts for 2-3 weeks.
• Psychological dependence and addiction.
• Severe toxicity has been described in children
who ingest nicotine gum or patches.
Nicotine
(Treatment of dependence)
1. Counselling
2. Nicotine replacement therapy
– Nicotine in patches (controlled release), chewing
gums, nasal sprays several times daily (short effect)
3. Adjunct therapy
– Bupropion, TCAs and MAOI
– Mecamylamine
– Varenicline: which occlude the rewarding effect of
nicotine
– Rimonabant: is also used in smoking cessation
III. Amphetamines
• Substances: Amphetamine, dextrometamphetamine
and methamphetamine
• Routes of administration: oral, nasal, inhalation and
parenteral
• Mechanism of action:
– Indirect CNS ‘sympathomimetic’ effect – release
of monoamines (noradrenaline, dopamine, or 5HT) from nerve terminals in the brain.
Main effects on CNS:
1. Locomotor stimulation
2. Euphoria and excitement, increased selfconfidence, stereotyped behavior, resistance
to fatigue, decreased appetite, anorexia
Amphetamines
(Withdrawal syndrome)
• Tolerance develops rapidly to the peripheral
sympathomimetic and anorexic effects, but
more slowly to the central effects
• No clear-cut physical withdrawal syndrome
→ dependence seems to be a consequence
of the unpleasant after-effects (i.e. fatigue,
lethargy, anxiety, depression, hunger) and
the effort to avoid them.
Amphetamines
(Dependence)
• Full-blown dependence occurs in 5% of users –
characterized by strong craving, increased doses,
and common uncontrolled ‘runs’)
• Amphetamine psychosis – closely resembles the
Schizophrenic attack – incoherent thought,
hallucinations, paranoia, aggression.
• Chronic abuse can cause necrotizing arteritis
leading to cerebral hemorrhage and renal failure.
• Therapeutic use: minimal e.g. narcolepsy,
hyperkinetic syndrome and treatment of obesity
IV. Congeners Of Amphetamines
• Several chemical congeners of amphetamines
have hallucinogenic properties.
• These include:
– 2,5-dimethylamphetamine (DOM)
– Methylene dioxyamphetamine (MDA)
– Methylene dioxymetamphetamine (MDMA)
Congeners Of Amphetamines
• MDMA has more selective action on
serotonin transporter in the CNS and is used
to cause euphoria and as sexual enhancer.
• Overdose toxicity include hyperthermia,
serotonin syndrome and seizures.
• Withdrawal syndrome with protracted
depression has been described in chronic
users of MDMA.
V. Cocaine
• The most expensive drug illegally sold
• Routes of administration: Salt - nasal or I.V., free
base: smoking-inhalation
Mechanism of action:
• Inhibition of catecholamine Re-uptake → increase
noradrenaline and dopamine transmission
• Indirect ‘sympathomimetic’ agent
Pharmacological effects:
• Very similar to those of amphetamines yet less
prone to cause stereotyped behavior, paranoia,
delusions.
Cocaine
• Duration of effect is much more shorter (30 min,
I.V) than in amphetamines,
• Rapid metabolism – liver and plasma esterase (hair
deposit of metabolites).
• No clear-cut physical dependence syndrome but
depression, tiredness and dysphoria coupled with
very intensive craving for the drug (strong
psychological dependence).
4. Hallucinogens
I. Phencyclidine PCP
• Antagonist at NMDA receptors, has no action on
dopaminergic neurons in the CNS.
• The most dangerous of the hallucinogenic agents.
• Chemically related to ketamine (anesthetic drug)
and originally also developed as a drug with this
indication.
• Not so frequent among abusers, unpleasant
vegetative effects.
• Can cause severe delusions and/or hallucination
which may turned into the violent behavior
• Overdose can cause nystagmus, marked
hypertension, and seizures, which can be fatal.
II. LSD (Lysergic Acid Diethylamide)
• Originally produced as a drug candidate in Sandoz
Labs in 1938 by Albert Hoffman
• It is among the most potent drugs known so far
• Mechanism of action:
– Acting on different 5-HT receptors in CNS no
effect on dopamine receptor.
– Interestingly it dose not cause dependence.
– Mainly as agonist on 5-HT2A autoreceptors in
CNS →↑firing of 5-HT neurons in Raphe N
• Somatic effects:
– Sympathomimetic (↑BP and HR)
– Tolerance: develops quickly (on CNS effects)
• Adverse effects:
– Persistent mental disorder
– Schizophrenia
– Injury due to violent behavior
5. Marijuana
• Extracts of the hemp plant; originally from
Himalaya and Kashmir
• Marijuana - dried leaves and flower heads
• Hashish - extracted resin
• Active substances: cannabinoids (lipophilic nonalkaloid natural compounds)
• Routes of administration: mainly inhaled in
cigarette smoke
Marijuana
(mechanism of action)
• Through cannabinoid receptors (GPCR type)
1. CB1- brain
– Highly abundant in: hippocampus (memory), cerebellum
(loss of coordination), and substantia nigra (motor
disturbances), hypothalamus (appetite) and mesolimbic
dopaminergic pathway (reward) and cortex.
– Mostly localized presynaptically– their activation inhibits
neurotransmitter release
– Their paucity in the brain stem → lack of serious
respiratory and cardiovascular toxicity.
– Endogenous agonist: anandamide
2. CB2- periphery
– immune system (immunosuppressive effects?!)
Marijuana
(Pharmacological effect)
On CNS a combination of psychotomimetic,
depressant effect:
• A feeling of relaxation, well-being and euphoria without accompanying aggression
• Uncontrolled laughing without reason
• A feeling sharpened sensory awareness
• Impairment of motor coordination (driving),
short-term memory and judgment.
• Feeling of time passing slowly, depersonalization;
increased appetite.
• Analgesia, antiemetic action
• In high doses: hallucination, paranoia, anxiety
Marijuana
(Pharmacological effect)
Peripheral effects:
• Vasodilatation (obvious on conjunctive vessels)
• Tachycardia
• Bronchodilation (but opposite may appear during
smoking)
• Reduction of intraocular pressure
• Tolerance and physical dependence occur only to a
minor degree in heavy users
Withdrawal syndrome:
• Weak and usually mild irritability, restlessness,
confusion, sweating tremor and sleep disturbances
Marijuana
(Harmful effect)
• Relatively safe from the viewpoint of acute drug
overdose
• Problems are rather with chronic use:
– Somatic effects: decreased testosterone and
sperm count
– Long-term psychological changes: apathy,
impaired memory and decision ability, may
promote schizophrenia in pre-disposed
patients.
6. Inhalants
• Certain gases or volatile liquids are abused
because they provide a feeling of euphoria or
disinhibition.
• This group include:
1. Anesthetics
2. Industrial solvents
I. Anesthetics
• This group includes nitrous oxide, chloroform and
diethylether.
• Such agents are hazardous because they affect
judgment and include loss of consciousness.
• Inhalation of nitrous oxide as the pure gas (with
no oxygen) has caused asphyxia and death.
II. Industrial solvents
• Solvents and wide range of volatile compounds
are present in commercial products such as
gasoline, paint thinners, glues and shoe polish.
• Because their ready availability, these substances
are most frequently abused by children in early
adolescence.
• Active ingredients that have been identified
include benzene, hexane, methylethylketone,
toluene and trichloroethylene
• Many of these are toxic to liver, kidneys, lungs,
bone marrow, and peripheral nerves and cause
brain damage in animals.
III. Organic Nitrites
• Amyl nitrite, isobutyl nitrate, and other organic
nitrates are referred to as poppers and are mainly
used as sexual intercourse enhancer .
• Inhalation of the nitrites causes dizziness,
tachycardia , hypotension and flushing.
• With the exception methaemoglobinaemia the
adverse effect are usually mild .
7. Steroids
• In many countries, including the US, anabolic
steroids are controlled substances based o their
potential for abuse.
• Effect sought by the abusers are increases in
muscle mass and strength rather than euphoria .
• However, excessive use can have adverse
behavioral, cardiovascular, and musculoskeletal
effects.
• Behavioral manifestation include increase libido
and aggression (roid rage)
Steroids
• Severe acne and female masculinization are
anticipated androgenic adverse effects.
• Hepatic dysfunction has been reported, and
increase risk of myocardial infarction.
• A withdrawal syndrome has been described with
fatigue and depression of mood.
Good luck
Reference:
• pharmacology by Lange
• Rang and dale pharmacology