Pharmacology of

NAPZA
Prof.Aznan
Lelo,dr.PhD,SpFK,
&
Dr.Datten Bangun
MSc,SpFK
Dept.Farmakologi &
Terapeutik

Istilah:
NAPZA: N Arkotik
P sikotropik
Z at
A ddiktif
. Narkoba: Narkotik dan Bahan addiktif

PSYCHOTROPIC DRUGS:
natural or synthetic drugs
which
induce stimulation, depression or
hallucination in the CNS
induce perceptual distortion
disturb the motor functions/cognitive

functions
increase introspection

induce changes in mood

===induce dependence

DEPENDENCE
psychic

- craving - drug seeking behavior, use of drug

repetitively for personal satisfaction/
pleasure

physical

abstinence syndrome - withdrawal of drug,

administration of antagonists induces
characteristic withdrawal symptoms

DIAGNOSTIC
CRITERIA
FROM

DSM-IVTM

AMERICAN PSYCHIATRIC ASSOCIATION

DIAGNOSTIC CRITERIA FOR PSYCHOACTIVE
SUBSTANCE DEPENDENCE (DSM-IV.)

A.

At least three of the followings:

1. Substance often taken in larger amounts or

over a longer period than the person intended.
2. Persistent desire or one or more unsuccessful
efforts to cut down or control substance
abuse.
3. A great deal of time spent in activities
necessary to get the substance (e.g., theft), taking
the substance (e.g., chain smoking), or recovering
from its effects.

DIAGNOSTIC CRITERIA FOR

PSYCHOACTIVE SUBSTANCE
DEPENDENCE DSM-IV. (CONT.)
4. Frequent

intoxication or withdrawal
symptoms when expected to fulfill major role

obligations at work, school, or home (e.g., does

not go to work because hung over, goes to school
or work high, intoxication while taking care of
his or her children), or when substance use is
physically hazardous (e.g., drives when
intoxicated).
5. Important social, occupational, or recreational
activities given up or reduced because of
substance abuse,------- lih.kuliah Psikiatri

Common Definitions of Key

Terms
addiction: to use compulsively or
uncontrollably; to enslave

abuse: to use wrongly or improperly

habit: a constant, often unconscious,
inclination to perform some act,
acquired through its frequent repetition

addiction liability/potential: the

tendency to develop/produce an
addiction

ABUSE POTENTIAL
The strength of a drugs ability to
induce run, rush well being.
It depends on the properties of the
drug and on pattern of use
(route, frequency, dose, etc)

Common Definitions
of Key Terms (cont.)
dependence: state of being
determined, influenced, or controlled
by something else; subordination to
someone or something needed or
greatly desired; required for normal
physiological or psychological
function
physical/physiological
psychological/psychic

Misused and Abused

Substances
Substances are categorized according to their
effects on the body.
Commonly misused and abused substances are

Stimulants.
Depressants.
Hallucinogens.
Narcotics.
Inhalants.
Cannabis products.
Designer drugs.
Steroids.

AMERICAN RED CROSS

FIRST AIDRESPONDING

Specific Signs of Substance

Misuse and Abuse

Signs of stimulant abuse

Respiratory distress, disruption of
normal heart rhythm and even death
can result from using a stimulant.
Very excited.
Restless.
Talkative.
Irritable.
Unconscious.
Signs of depressant abuse
Drowsiness.
Confusion.
Slurred speech.
Slow heart and breathing rates.
Poor coordination.
AMERICAN RED CROSS
FIRST AIDRESPONDING

Specific Signs of
Substance Misuse and
Abuse
Signs of hallucinogen abuse

Sudden mood changes.

Flushed face.
Seeing or hearing something that is
not present.
Anxiousness or being frightened

DRUGS of ABUSE
TYPE
POTENTIAL
1. Opioids

DEPENDENCE
very strong

2. Depressants
barbiturates, ethanol,
benzodiazepines

strong
medium

3. Stimulants
cocaine
amphetamines

very strong
strong

4. Other stimulants
caffeine
nicotine

weak
very strong

DRUGS of ABUSE (cont)

5. Cannanbinoids
cannabis

6. Hallucinogens
(psychedelics, psychotomimetics)
LSD, mescaline,
cyclidines
(phencyclidine, PCP)

7. Inhalants

industrial solvents
anesthetics

weak or

weak or

medium

strong
medium

Psychic
Tolerance
Drug

Physical

Dependence

Morphine & Derivatives

+++
+++

+++

Barbiturate-like

++
++

++

Alcohol

++
++

+++

Amphetamine-like

++
++

(+)

Cocaine

+++
(+)

(+)

Smoking (nicotine)

++
(+)

(+)

LSD-mescalin

WHO SCHEDULE OF CONTROLLED

SUBSTANCES
Schedule

Criterla

Examples*

I
No medical use; high
marihuana, heroin
addiction potential

hallucinogens,

II
opioid

morphine, most other

analgesics, cocaine,
amphetamines, sedatives

Medical use; high

such as

III
paregoric,

pentobarbital sodium
Medical use; moderate

codeine in combination,

potential for dependence. glutethimide, sodium

butabarbital
*List not complete.

REPEATED or CONTINUOUS DRIG

ADMINISTRATION
may induce
TOLERANCE
(days-weeks)

DESENSITISATION
or
TACHYPHYLAXIS
(minutes)

SENSITISATION

change in number of receptor

deficit of mediators

EXPLANATION

pharmacokinetics
adaptative processes

Therapy of drug abuse

Steps
Detoxification
Prevention of relapse
Rehabilitation
Resocialisation

Aim of pharmacotherapy
relief of withdrawal
prevention of relapse

The Major Classes of Controlled

Substances
Depressants induces sleep, relaxation
Narcotics relieves pain, induces stupor
Stimulants relieves fatigue, enhances
alertness
Hallucinogens alters sensory perception
Toxicants / Inhalants CNS depression
Steroids enhances physical performance
Since there are hundreds of examples, and
we have limited time, I will review only a
few of each

Most drugs of abuse

mimic

Most psychoactive drugs of

abuse look similar to
neurotransmitters. These
drugs mimic the action and
appearance of
neurotransitters.
THC Anandamide
Opiates Endorphin Enkephalin
Alcohol, Benzos, Barbs GABA

Drugs of Abuse are

Dopaminergic

Or, in other words, they increase dopamine activity.

EXAMPLE:
THC connects
with receptors
and causes the
release of
dopamine

Natural Rewards Elevate Dopamine Levels

200

% of Basal DA Output

NAc shell
150

100

50

Empty
Box Feeding

SEX

200

150

100

15
10
5
0

0
0

60

120

Time (min)

Source: Di Chiara et al.

180

ScrScr
BasFemale 1 Present
Sample 1 2 3 4 5 6 7 8
Number

Scr

Scr
Female 2 Present

9 10 11 12 13 14 15 16 17
Mounts
Intromissions
Ejaculations

Source: Fiorino and Phillips

Copulation Frequency

DA Concentration (% Baseline)

FOOD

AMPHETAMINE

1
2
3
4
Time After Amphetamine

200

Accumbens
Caudate

150
100

1
2
3 hr
Time After Nicotine

Accumbens

COCAINE
DA
DOPAC
HVA

300
200
100
0

5 hr

NICOTINE

250

% of Basal Release

DA
DOPAC
HVA

400

% of Basal Release

Accumbens

1100
1000
900
800
700
600
500
400
300
200
100
0

% of Basal Release

% of Basal Release

Effects of Drugs on Dopamine Levels

250

2
3
4
Time After Cocaine

Accumbens

5 hr

MORPHINE
Dose (mg/kg)

0.5
1.0
2.5
10

200
150
100

0
Source: Di Chiara and Imperato

2
3
4
Time After Morphine

5hr

The Narcotics
From the Greek
narcos to sleep,
stupor.
Term is often
misused.
Several sub-groups of
narcotics:
Natural origin
Semi-synthetic
Synthetic

Natures Own Narcotics

It all starts with the opium poppy (Papaver
somniferum), which has been around for over
7000 years. Narcotics of natural origin found
in the poppy:

Opium (oldest form used)

Morphine (most prevalent alkaloid)
Codeine (most widely used in the world)
Thebaine (primarily used to produce oxycodone
and similar derivatives)

Semi-synthetics
Heroin

Developed in 1874 as a curative for

morphine addiction
Harrison Narcotics Act
Its action
Usually cut
From 1% to 70%
Legal in some countries

More Semi-synthetics
Dilaudid - marketed in tablets (2, 4, and 8
mg), suppositories, oral solutions, and
injectable formulations

analgesic potency two to eight times that of

morphine, but it is shorter acting and produces
more sedation than morphine

Oxycodone (Oxycotin) derivative of

thebaine
Hydrocodone (Lortab, Vicodin)
equivalent to morphine in potency

Synthetic Narcotics

Meperidine (demerol)
Darvon
Fentanyl
Methadone
Analogues keeping ahead of the
authorities (e.g. -been over 15 for
Fentanyl)

Depressants
Alcohol (C2H5OH) the most widely used of
all
Barbiturates (short to long acting) Seconal,
Nembutal, Tuinal .. And many more.
Benzodiazepines a million of them
(Valium, Librium, Xanax) for anxiety,
insomnia, anticonvulsants.
Rohypnol (roofies) date rape drug
GHB gamma hydroxybutyric acid
Chloral Hydrate

Depressant Data:
Action sought: sedation, anxiety and stress
relief, convulsion control.
Dependence risk: both physical and
psychological
Dangers / side effects: nausea, respiratory /
cardiac arrest, impaired physical performance,
death from overdose.
Prevalence of use: est 150 million users of
alcohol, plus 15 million abusers of legal Rx
drugs. 15 million alcoholics.

The Stimulants
Caffeine most widely used in the
world
Nicotine 2nd most widely used
Coffee and a cigarette combination?
Cocaine
Amphetamines
Methcathinone
Methylphenidate

Stimulant Data:
Action sought: excitation, perceived energy boost,
extended wakefulness, some mild hallucination, relief
of fatigue and minor anesthesia
Dependence risk: both physical and psychological
Dangers / side effects: paranoia, loss of sleep,
cardiac arrest, dizziness, tremor, headache, flushed
skin, chest pain with palpitations, excessive sweating,
vomiting, abdominal cramps, agitation, hostility,
panic, aggression, and suicidal or homicidal
tendencies.
Prevalence of use: estimated 2 million cocaine and
amphetamine users in the US

Cocaine

The most potent stimulant of

natural origin
Extracted from the coca plant
Chew, brew, snort, inject
Isolated in 1880s for its local
anesthetic quality
Cocaine hydrochloride
Free-base
Crack
A highly seductive drug
High usually followed by
dysphoric crash
2nd most used after marijuana
in the US. (5/80 ratio)

Cocaine and Neurotransmission

Primary effect on DA
& NE with some 5HT
influence
Block reuptake
Inhibit MAO

Amphetamines
First used in the 1930s as
anti-fatigue, hunger
suppression,
antidepressant
(benzedrine, dexedrine)
Methamphetamine injected or smoked.
Aka - Ice, Crystal Meth
Most clandestine labs
Methcathinone (Cat)
Anorectic a slew of diet
drugs (Didrex, Bontril)
Khat saw this in India

Ecstasy
Methylenedioxymethamphetamine (MDMA)
XTC

Disco Biscuits
Adam

Essenc
e

X
Cristal

Go

Truck Driver
Clarity

Hug
Drug
Ecstasy use is one of the most rapidly growing
phenomena in todays drug scene.

Short-term effects

Feelings of well-being and empathy

Reduced anxiety
Enhanced self-confidence
Greater acceptance of others
Increased energy
Increased desire for physical contact
and visual stimulation
Intensified awareness of senses

Ecstasys downside
Increases in heart rate and blood
pressure
Nausea
Loss of appetite
Jaw tightness
Compulsive chewing and teeth clenching
Anxiety, panic, and depression
Health risks increase if ecstasy is
combined with another drug

The Hallucinogens
Sensory deprivation enhancement
dysfunction
All five senses can be involved
Primary types:
Marijuana
LSD
Psilocybin
Peyote / Mescaline
A raft of others

Hallucinogen Data:
Action sought: sensory distortion, out of body
experience, mood change, relaxation,
Dependence risk: both physical and psychological
Dangers / side effects: paranoia, elevated heart
rate, increased blood pressure, and dilated pupils.
Grandiose feelings can lead to dangerous activity or
decisions. Fearful experiences leading to agitation and
fear of the experience being real.
Prevalence of use: estimated 25 million users of
marijuana in the US and another .5 - 1 million users
of other hallucinogens

Marijuana
Cannabis sativa
1st cultivated for
fibers (Washington)
Cannabinoids
(THC)
Smoked, chewed,
eaten
Marinol medical
use
Potency has
skyrocketed in 30
years (1% to over
20%)

Mechanism of Action
Mostly unknown until the late 1980s
1988 Isolated the receptors
1992 Discovered the first neurotransmitter for
that receptor

THC binds to cannabinoid receptors

Its and Agonist

Anandamide & 2-AG are the NTs for

cannabinoid receptors
Works as a retrograde NT
It modulates the activity of many neurotransmitters
This is way it has such broad effects

Two Receptor Types

CB-1 Receptor

CB-2 Receptor
Mostly in periphery
Found primarily in
immune system

oLocated in CNS and PNS

Found on heart
protects from
inflammation?

Low - Moderate Doses

STM impairment
Disinhibition

Relaxation

Balance
impaired

Drowsiness

Decreased
muscle strength

Exhilaration,
euphoria

Small tremor

Sensory - perceptual
changes

Poor on complex
tasks (e.g.,
driving)

Overestimate time passage

Higher Doses
Psychotomimetic
Pseudo hallucinations
Synesthesias

Impaired
executive function
Increased
impulsivity

Paranoia
Agitation
Disorganized
thoughts
Confusion

Impaired
judgment, slower
RT
Pronounced motor
deficits

Physiological Effects
of Marijuana
Physiological effects
Increase in pulse rate & slight drop in BP
Produces dry mouth & occasional dizziness
Reddening of eyes (dilation of vessels in cornea)
No permanent adverse cardiovascular
People with heart disease should abstain
Increased risk for heart attack four an hour after smoking
Appetite increased
Hypothalamus
Hedonic Hotspot specific area of NAC when stimulated
by cannabinoids there is an increase in the reward value of
natural rewards.

Side Effects of Marijuana

THC suppresses immune system, but not enough
to increase risk of infection it appears.
Lowers testosterone levels & sperm count as
well as estrogen
Crosses placental barrier
Lower birth weight
Some evidence suggests a relation between
mother smoking while pregnant and childhood
cancer
Most severe side effects
Respiratory - can lead to asthma & bronchitis
Anxiety/panic in some users

THC Toxicity
Almost impossible to OD
1-1.8 kg w/5% taken orally in a female
THC not toxic in this sense
Pot smoke contains more tar than cigarette
smoke
Does one smoke the same?
Cancer and respiratory possibilities
Data on cancer is very mixed recent
studies show no relationship
THC found to kill cultured hippocampal cells,
but so far not in other cells high in CB receptor
density
Effect reversed with NSAIDS
Possible mechanism for memory loss

THC Tolerance & Dependence

Tolerance develops with heavy long-term use
Reverse tolerance in consistent users

Cross tolerance with sedatives - alcohol

Dependence mild (like SSRIs)
Mild withdrawal symptoms in humans, with irritability,
depression, sleep disturbances, nausea, diarrhea,
sweating, tremors, reduced food intake, and salivation
50% of heavy users may experience it
30 mg THC / 4 hrs / 10-20 days (unusual levels of
intake)
Begin within 48 hours after cessation and lasts 2
10 days

Highly Debated Effects

Amotivational Syndrome
Most research has not found this to be true
Is it a HOST effect?
It may be psychopathology independent of
use
Gateway Drug
Most well-designed studies suggest this is
false.
Common liability model is a better
explanation
Alcohol and cigarettes are stronger gateway
drugs if one accepts the data

LSD

Lysergic acid
diethylamide (LSD) is
the most potent
hallucinogen known to
science
1938 Dr. Albert Hoffman
Very potent in pure form
Alters sensory
perception
Not much use until late
50s and into 60s for
study of mental illness
The late Dr. Timothy
Leary

Psilocybin
Found in the wild
throughout the Americas
as well as cultivated
(basements, caves)
One of the tryptamines
naturally occuring but
can be synthesized
Potency varies by variety
and cultivation

Peyote and Mescaline

Small cactus that
contains the chemical
mescaline
Used by some Native
American tribes in
religious ceremonies
(movie: Altered States)
The buttons are dried
and eaten or made into a
type of tea or tonic. Has
been synthesized, too.

Hallucinogens Analogue
Heaven

Of all the classes, this one

seems to bring about the
most chemically altered
analogues

Never ending battle to keep

up with those in the illicit
drug enterprise business.
Examples are:
MDMA (Ecstasy)
PCP (Angel Dust)
Ketamine (Special K)

The Toxicants / Inhalants

Includes a wide
variety of volatile
substances:
Glue / gasoline /
hairspray
Toluene
Butyl nitrate
White Out
Nitrous oxide
Freon
Magic Markers?

Toxicant / Inhalant Data:

Action sought: euphoria, disorientation, dizziness
Dependence risk: psychological
Dangers / side effects: suffocation, kidney
abnormalities, liver damage, headaches, nausea,
slurred speech, and loss of motor coordination,
bronchial damage, and risk of explosion and
burns. Mental effects may include fear, anxiety,
depression and memory loss.
Prevalence of use: estimated 1 million users,
mostly adolescents. In 2005 national survey 25
million said they had used inhalants sometime in
their life.

The Steroids
Used for performance
enhancement and
weight gain
Natural:
testosterone
Synthetics /
anabolics:
Boldenone
Methenolone
Nandrolone

Steroid Data:

Action sought: muscle enhancement, increased size and

strength of muscles, improve endurance, and decrease
recovery time between workouts
Dependence risk: psychological
Dangers / side effects: Elevated blood pressure and
cholesterol levels, severe acne, premature balding,
reduced sexual function, and testicular atrophy. In males,
abnormal breast development. In females, a masculinizing
effect, resulting in more body hair, a deeper voice, smaller
breasts, and fewer menstrual cycles. Several of these
effects are irreversible. In adolescents, abuse of these
agents may prematurely stop the lengthening of bones,
resulting in stunted growth. Also reported: psychotic
reactions, manic episodes, feelings of anger or hostility,
aggression, and violent behavior (roid rage).
Prevalence of use: estimated 1-3 million users in US.

Betel Nut
The fruit of the
Areca catechu tree
Contains Arecoline
Mild stimulant that
is a cholinergic
agonist
Not a high abuse
potential