Transcript Drugs of Abuse II - London Metropolitan University

Drugs of Abuse II
Dr. Simran Kaur
[email protected]
Commonly abused substances
include:
i. Opiates and narcotics
-
-
powerful painkillers with sedative and euphoric
qualities
Include: Heroin, Opium, Codeine, Pethidine
(meperidine), hydromorphone, oxycontin
ii. Central Nervous system (CNS)
stimulants
Include cocaine, amphetamines, dextroamphetamine,
methamphetamine and methylphenidate (Ritalin)
- Most commonly used stimulants are caffeine and
nicotine.
- These drugs have a stimulating effect and produce
tolerance
-
iii. CNS depressants
- Include barbiturates (amobarbital, secobarbital,
pentobarbital), benzodiazepines (diazepam, lorazepam,
alprazolam), chloral hydrate and paraldehyde.
- Most commonly used is Alcohol
- Produce a soothing sedative effect and anxiety-reducing
effect and can lead to dependence
iv. Hallucinogens
-
-
Include LSD (Lysergic acid diethylamide,
derived from ergot, a grain fungus), mescaline
(from cacti), psilocybin (‘magic mushrooms')
and phencyclidine (PCP or Angel Dust)
Have hallucinogenic properties and produce
psychological dependence
v. Tetrahydrocannabinol (THC)
- Active ingredient in cannabis, marijuana and
hashish.
- Used for their relaxing properties but THCderived drugs can also lead to paranoia and
anxiety.
TREATMENT OF DRUG
DEPENDENCE
Pharmacological
Approaches
1. Substitution/Replacement treatment
- to alleviate withdrawal symptoms/ long-term
maintenance and detoxification or withdrawal
-- Involves administration under medical
supervision of a prescribed medicine with
similar action to the drug of dependence
2. Blocking response
 Use of antagonists
3. Aversive therapy
 Induce unpleasant response to drug of abuse
concerned
4. Modification of craving
 Use of drugs to relieve withdrawal symptoms

Non-pharmacological approach
1. Cognitive- Behavioural Therapy (CBT)
 short-term focused approach to helping drugdependent individuals become abstinent from
drugs
CBT
CBT attempts to help patients recognize, avoid
and cope
 RECOGNIZE the situations in which they are
most likely to use drugs
 AVOID these situations in which they are most
appropriate and
 COPE more effectively with a range of
problems and problematic behaviours associated
with substance abuse
2. Cognitive Therapy
 a system of psychotherapy that attempts to
reduce excessive emotional reactions and selfdefeating behaviour by modifying the faulty or
erroneous thinking and maladaptive beliefs
that underlie these reactions.
3. Community Reinforcement Approach

a broad-spectrum behavioural treatment
approach for substance abuse problems, that
utilizes social, recreational, familial and
vocational reinforcers to aid clients in the
recovery process.
4. Motivational Enhancement Therapy

based on principles of motivational
psychology and employs motivational
strategies to mobilize the client’s own change
resources.
I. NARCOTIC ANALGESICS

Drugs that reduce pain without producing
unconsciousness (cf Anaesthetics)

OPIATES (also opioids) : A class of very
potent painkillers
SOURCE
From Opium – an extract
from the poppy plant
Papaver somniferum
The major active
ingredients include:
 Morphine
 Codeine
 Thebaine
 Narcocotine
TYPES OF NARCOTIC ANALGESICS
1. Natural narcotics
 Morphine
 Codeine
 Thebaine
2. Semi-synthetic
narcotics
 Heroin
 Hydromorphone
 Oxycodone
 Etorphine
3. Synthetic narcotics
 Buprenorphine
 Fentanyl
 Methadone
 Pethidine (Meperidine)
 Pentazocine (Talwin)
 Propoxyphene
(Dextropropoxyphene)
Structures
4. Endogenous opioids
 Peptides which are produced in the brain and
have opiate-like pharmacological effects
 Derived from precursor peptides by protease
cleavage
 b-endorphin (Pro-opiomelanocortin, POMC)
 met-enkephalin and leu-enkephalin
(Proenkephalin)
 dynorphin (Prodynorphin)
ADVERSE EFFECTS OF OPIATES
Dose-related and depend on rate of absorption
a. Low or moderate doses of opiates:
Effects on CNS

have an analgesic effect

depress respiration

cause constriction of pupils

impair ability to concentrate

suppress cough reflex

reduce appetite
Effects on GI tract

reduce gut motility (leads to constipation – has been used to
relieve diarrhoea and dysentery)

b. Higher doses or when drug is administered
via intravenous/inhalation:


lead to state of euphoria
induce nausea and vomiting (due to effect on
chemical trigger zone – the area postrema)
c. At the highest dose/ overdose:




lead to unconsciousness
fall in body temperature and blood pressure
respiratory pressure
ultimately death
Opioid receptor binding studies


Binding of radioactive 3H naloxone to rat brain
show the classic saturation binding curve.
As the concentration of the opiate ligand
increases, binding to receptors increases linearly
until receptors are fully occupied.
Opiate Bioassay

Han Kosterlitz et al. (1970, 1975)
Opioid
Receptor
subtype
Endogenous
ligand
Functions
m (mu)
Endomorphins
endorphins
Analgesia (+++)
Reinforcement (nucleus accumbens)
Cardiovascular and respiratory depression
Cough suppressant
Emesis
Sensorimotor integration
d (delta)
Enkephalin
endorphins
Analgesia (+)
Reinforcement
Cognitive function
Modulating olfaction
Motor integration
k (kappa)
Dynorphins
Analgesia (++)
Dysphoria
Feeding
Gut motility
Neuroendocrine function
Temperature control
Water balance
OPIOID AGONISTS AND
ANTAGONISTS
1.


Pure agonists
high affinity for m receptors and lower affinity
for d and k receptors
include most morphine-like drugs: Morphine,
codeine, dextropropoxyphene, methadone,
pethidine, etorphine, fentanyl
2. Partial agonists (mixed agonists and
antagonists)


Nalorphine (low dose antagonist at m
receptors and partial agonist on d receptor and
k receptors.
Pentazocine antagonist at m receptors and
partial agonist on d receptor and k receptors.
3. Antagonists


Block m, d and k receptors
Naloxone (short acting 2-4 hours) and
Naltrexone (longer duration of acting t1/2 =
10 hours)
Mechanism of action of Opioids



Reduction of membrane excitability
(hyperpolarization due to increased K+
conductance)
Inhibition of neurotransmitter release
(inhibition of Ca2+ entry)
Suppressing firing rate of inhibitory
interneurons (increasing activity in some
neuronal pathways)
All the opioid receptors are G-protein coupled
receptors
1. They are coupled to the inhibitory G protein
Gi :
 Inhibition of adenylate cyclase

reduce cAMP

decreased function of cAMP-dependent
protein kinases (partially responsible for ion
channel changes)

2. Direct coupling to ion channels reducing
synaptic transmission:
a. Postsynaptic inhibition
 Opioid binding to receptors activate G protein
 Open K+ channel
 Increase K+ conductance
 Hyperpolarization (inhibitory post-synaptic
potential IPSP) decreases rate of firing.
b. Axoaxonic inhibition
 Opioid receptors on presynaptic terminal
activate G protein
 Closes Ca2+ channel
 Decreases conductance of Ca2+
 Decreases release of neurotransmitters (e.g.
noradrenaline, dopamine or glutamate and
substance P released on afferent sensory
neurons that transmit pain signals)
c. Presynaptic autoreceptors
 Via G protein activation of K+ channel
opening and Ca2+ channel closing:
 Somatodendritic autoreceptors hyperpolarize
cells and reduce cell firing
 Presynaptic autoreceptors reduce the release
of neurotransmitters
Rewarding effects of Opiates (Opioid
reinforcement)
Linked to the mesolimbic dopaminergic pathway
 GABAergic cells inhibit this pathway by limiting
dopamine release
 b-endorphin and opiate drugs decrease the
release of GABA by
-opening K+ channels
-reducing influx of Ca2+ on GABA terminals
The inhibition of GABA cells lead to:
 increased firing
 greater dopamine release into the nucleus
accumbens
By means of similar mechanisms, k receptor
agonists (dynorphin) inhibit dopamine neurons
and reduce dopamine release


b-endorphin
stimulates the pathway
In contrast, k receptor
agonists reduce
dopaminergic
neuronal activity and
suppress the pathway
Opioid Tolerance and Dependence



Himmelsbach Hypothesis (1943)
the nervous system adapts to the presence of
opiates so tolerance develops
in the event of sudden withdrawal of drug, the
adaptive mechanism continues to function,
causing a rebound in physiological effects
(withdrawal syndrome).
Acute Effects of Opiates and Rebound
Withdrawal Symptoms
Acute action
Withdrawal Sign
Analgesia
Pain and irritability
Constipation
Diarrhoea
Decreased blood pressure
Increased blood pressure
Drying of secretions
Lacrimation (tearing), rhinorrhoea (runny nose)
Euphoria
Dysphoria and depression
Flushed and warm skin
Chilliness and ‘gooseflesh’
Hypothermia
Hyperthermia
Respiratory depression
Panting and yawning
Relaxation and sleep
Restlessness and insomnia
Tranquilization
Fearfulness and hostility
Pharmacological treatment of opiate
addiction/dependence
1. Detoxification
 Elimination of abused opiate from body by
substitution therapy
a. Methadone
 with gradual dose reduction over a 5-7 day
period
b. Symptomatic relief
i. Clonidine, an a2 adrenoceptor agonist

to reduce noradrenaline activity

relieve withdrawal symptoms: chills, lacrimation, rhinorrhoea,
yawning, sweating
ii. Promethazine or hydroxyzine

for nausea and vomiting
iii. Loperamide

for diarrhoea
iv. Methocabamol

for muscle cramps and joint pain
2. Maintenance Therapy
 Methadone, LAAM (L-alpha-acetyl-methadol),
Buprenorphine or narcotic antagonist, Naltrexone
have been used.
 Methadone maintenance programmes are the
most popular (Methadone Clinic)
- Supervised daily administration of the oral form
II. CNS Stimulants (Pysvhomotor
stimulants)




Substances which produce a sense of euphoria
or a feeling of being more awake
Used as therapeutic drugs or recreational drugs
to increase alertness
Used to suppress appetite
Also used and sometimes abused to boost
endurance and productivity
A. COCAINE
Source

Cocaine is an alkaloid
found in the leaves of the
coca shrub (Erythroxylon),
which grows in the Andes
(particularly Bolivia,
Colombia and Peru in
South America). Coca
leaves contain 0.6-1.8 %
cocaine. Coca paste
contains ~80 % cocaine
MECHANISMS OF ACTION
Cocaine binds to the neurotransmitter reuptake
transporters on presynaptic membranes of
dopaminergic neurons and blocks reuptake of
 Dopamine (DA)
 Noradrenaline (Norepinephrine, NE)
 Serotonin (5HT)


A build up of neurotransmitter levels in the
synaptic cleft occurs. Subsequently leading to
increased activation of the dopaminergic reward
pathway and a sense of euphoria and arousal.
As the cocaine level decreases, so does the
dopamine level in the pathway resulting in
depression and a craving for the drug
Pharmacological effects
Increased stimulation of the sympathetic nervous
system:
 By blocking the reuptake of NE
Tachycardia
Hypertension
Mydriasis (pupil dilation)
Tremors
Binding affinity of cocaine:
 5HT transporter > DA transporter > NE
transporter
Blockade of DA reuptake accounts for cocaine’s
ability to:
 STIMULATE
 REINFORCE
 CAUSE ADDICTION
Local anaesthetic action
At relatively high concentrations (~200 mg, 2-3
mg/kg), cocaine prevents action potential
generation by:
 Inhibiting voltage-gated Na+ channels in nerve
cell axons via:
The membrane (hydrophobic pathway)
The open channel gate (hydrophilic pathway)
 The blockade prevents voltage-dependent Na+
conductance, which results in local nerve block
Time course of Plasma Cocaine
Concentration
As a function of different routes of administration
Physiological effects of cocaine
Exhilaration and Euphoria
Heightened energy
Sleep disturbances
Talkativeness (pressure of
speech)
Hyperactive ideation
Anger, verbal aggression
Irritability, hostility
Extreme energy or exhaustion
Insomnia
Rambling, incoherent speech
Mild to moderate anorexia
High self-confidence
Severe anorexia
Delusions of grandiosity
Disjointed flight of ideas
Possible extreme violence
ADVERSE EFFECTS (repeated or
high doses)






Stroke or seizure
Cardiovascular problems (cardiac arrythmias,
cardiac myopathy, myocardial infarction)
Organ damage (pulmonary oedema,
hepatotoxicity, kidneys)
Perforation of nasal septum
Abnormality in development of offspring
(attention deficits, behavioural, cognitive)
Panic attacks/temporary paranoid psychosis
B. AMPHETAMINES
Amphetamine derivatives
are synthetic stimulants



Dextroamphetamine
Methamphetamine
Methylphenidate
Mechanisms of Action
Binds to presynaptic
dopaminergic neurons and
induces release of dopamine from
nerve terminals
 Interacts with dopaminecontaining synaptic vesicles and
provokes release into cytoplasm
of the terminal
 Binds to DAT (dopamine
reuptake transporters) causing
them to act IN REVERSE.
(i.e. Dopamine reuptake reduced and
free Dopamine also transported
out of the nerve terminal)

At higher concentrations:


Inhibits MAO-A
Induces release of NE into synaptic cleft and
inhibits NE reuptake transporters.
Pharmacological Effects
High dose or Chronic Use
Central effects:
Heightened alertness
Increased confidence
Feeling of exhilaration
Reduced fatigue
Euphoria and excitement
Insomnia
Psychotic reactions:
Visual and/or auditory hallucinations
Behavioural disorganization
Stereotyped behaviour
Exarcebating schizophrenia
Risk of dependence
Enhanced peipheral sympathomimetic
action:
Hypertension
Inhibition of GI motility
Neurotoxicity:
Reduced numbers of DAT
Damage to DA axons and terminals
(animal studies)
Muscle Damage
Renal Failure
Clinical Use
Treatment of ADHD in children (a behavioural
disorder characterized by inattention,
hyperactivity and impulsivity) [methylphenidate]
 Narcolepsy (a sleep disorder with episodes of
uncontrollable sleepiness during waking hours)
 Appetite suppressant, for obesity
(Amphetamine derivatives, e.g.
fenfluramine/dexfenfluramine abandoned due
tendency to cause pulmonary hypertension)

CNS Stimulant Withdrawal
Syndromes



Depression, Hypersomnia, Fatigue, Headache,
Irritability, Poor Concentration and Restlessness
are characteristic.
Drug craving is prolonged and intense
In severe cases, suicide attempts, paranoia and
acute psychosis may occur.
Pharmacological Treatment
Determined by specific withdrawal symptoms:
i.
Paranoid psychosis: Haloperidol and
thioridazine
ii.
Depression: Tricyclic antidepressants,
desipramine or SSRIs.
iii. Panic Attacks: Antidepressant or
Benzodiazepine
iv. Generalized withdrawal symptoms: adrenergic
agonists and calcium channel blockers
C. METHYLXANTHINES
Source:
Various beverages:
Coffee
Tea
Cocoa
Main components:
Caffeine
Theophylline
Mechanism of Action
1. By antagonizing Adenosine activity at A1 and
A2A adenosine receptors
2. Inhibition of cAMP-phosphodiesterase
(intracellular metabolism of cAMP)
- increasing intracellular cAMP
In CNS, Adenosine:
 Exerts a pre- or postsynaptic depressant
action
 Reduces motor activity
 Depresses respiration
 Induces sleep
 Reduces anxiety
Pharmacological Effects




CNS stimulation
Diuresis
Stimulation of cardiac muscle
Relaxation of bronchial smooth muscle
Unwanted Effects: Very few but An overdose
of caffeine (a very rare event) can result in:





Restlessness
Nervousness
Excitement
Insomnia
Flushed face





Diuresis
Muscle twitching
Tachycardia
Psychomotor
agitation
Gastrointestinal
complaints
III. CANNABIS (Marijuana)
Source:
 From flowering hemp of
the weed-like plant
Cannabis sativa
 Contains over 60 unique
chemicals known as
cannabinoids
Is available in different forms:


Marijuana (intoxicating plant) – crude mixture
of dried and crumbled leaves, small stems and
flowering tops of plants
Hashish/ hash oil – a resin preparation obtained
by solvent extraction, containing a very high
content of cannabinoids



Major important active ingredient is
D9-tetrahydrocannabinol (THC) formed from its
precursor of Cannabidiol.
The inactive metabolite Cannabinol is formed
spontaneously from THC
Cannabinoid Receptors

1.
2.
3.
4.
Are G-protein coupled receptors that:
Inhibit adenylate cyclase activity (Gi)
Inhibit calcium channels
Activate Potassium channels
Inhibit release of neurotransmitters [ACh, DA,
NE, 5-HT, Glutamate and d-aminobutyric acid
(GABA)]
RECEPTOR TYPES
a. Brain cannabinoid Receptors (CB1 subtype)
Located mainly in
 Hippocampus (memory impairments)
 Cerebellum
 Substantia nigra (motor disturbances)
 Cortex
 Mesolimbic dopamine pathway (Reward)
 Also found on terminals (presynaptic) (Inhibit
neurotransmitter release)
b. Peripheral cannabinoid receptors (CB2 subtype)
 Located mainly in the Immune (lymphoid)
system (Inhibitory)
 ~ 45 % homology with the CB1 subtype
 But show different pharmacological specificity
from CB1 receptors
 Function NOT well established
ENDOCANNABINOIDS
Endogenous cannabinoid
Agonist synthesized by the
brain
 ANANDAMIDE (amide
derivative of arachidonic acid
producing short-lasting
cannabinoid-like effects)
Antagonist
 Rimonabant (Acomplia) used
for obesity
Pharmacological Effects of THC
a. CENTRAL EFFECTS
A mixture of psychomimetic and depressant
effects
 Feeling of relaxation and well-being
 Exhilaration and disinhibition
 Enhanced visual and auditory perception
 Visual Illusions
 Slowing of passage of time


OTHERS:
Impairment of
Motor-coordination
 Short term memory





Catalepsy (retention of fixed unnatural postures)
Analgesia
Antiemetic action
Stimulation of appetite
b. PERIPHERAL EFFECTS
 Bronchodilation
 Vasodilation (characteristic of cannabis smokers:
bloodshot eyes)
 Tachycardia
 Reduction of intraocular pressure
TOLERANCE AND DEPENDENCE



Only occur to minor degree in heavy users
No evidence of psychological dependence
Withdrawal Symptoms:
Relatively mild
 No compulsive urge to take drug


Similar to that of ethanol/opiate withdrawal
PHARMACOLOGICAL TREATMENT
OF DEPENDENCE
Protocols in trials included:
 Antidepressants: Bupropion (Wellbutrin/Zyban)
and Nefazodone (Serzone, withdrawn due to
hepatotoxicity)
 Mood stabilizers: Divalproex (Depakote,
originally indicated for epilepsy and bipolar
disorder)
 Oral THC: during initial withdrawal period
Pharmacological Usage
Use of cannabis is still illegal in most countries
Anecdotal usage
 Symptomatic treatment for patients suffering from:
A. AIDS
 Chronic Neuropathic Pain
 Anorexia-cachexia (wasting syndrome)
B. Multiple Sclerosis
 Pain
 Muscle Spasms
C. Chemotherapy-induced nausea and emesis
 Nabilone (Cesamet), a derivative of cannabinoids
D. Glaucoma
REFERENCES
CANNABIS:
 Piomelli, D. et al. (2000) The endocannabinoid system as a target for therapeutic drugs.
Trends in Pharmacological Sciences. 21: 218-224
DA:
 Spanagal and Weis (1999) The dopamine hypothesis of reward: past and current
research. Trends in Neurosci. 22: 521-527
OPIATES:
 Musto (1991) Opium, cocaine and marijuana in American history. Scientific Am. 265:
40-47
 Kieffer (1999) Opioids: first lessons from knockout mice. Trends in Pharmacol Sci.
20:19-26
 Snyder and Pasternak (2003) Historical review: opioid receptors. Trans Pharmacol Sci.
2: 198-204
ANALGESICS AND PAIN
 Yaksh (1999) Trends in Pharmacol Sci 20: 329-337
COCAINE
 Johanson and Fischman (1998) Pharmacol Rev. 41: 3-47
CAFFEINE
 Fredholm (1999) Pharmacol Rev. 51: 83-133