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Toxicology II course PHTX 943

for pharmacy students

9th semester

Lecture 9

Classes of toxic chemicals


(Drugs of abuse)

Dr. Ola Ahmed Heikal


Addiction and Drug dependence

Since the time the man discovered substances to relief pain , produce euphoria
( pleasure) as well as reduce anxiety and facilitate sleep, he has never been so
ambitious to use it and to seeking for more . The first of these substances to
be discovered and used are the Opiates; the first group of drugs that were
subject of abuse and addiction

Drug Abuse : Is the use of a substance in a manner


deviate from the acceptable , social and legal pattern
within a given society ; resulting in long term
physical , mental or social problems

Addiction : It is a term that refer to a pattern of


compulsive drug use that includes physical and
psychic dependence and tolerance
Addiction and Drug dependence
Physical dependence : It is associated with addiction. It exist when the drug users
develop sever withdrawal symptoms

Tolerance : Reference to a situation where after repeated administration of drug


higher doses are required to elicit the same action previously elicited by smaller
doses
These terms are more or less confined to drugs that are primarily used to
induce alteration of mood , perceptions and behavior

Psychoactive drugs
Any drug that affects the mind or behavior.

There are five main classes of

-Opiates and opioids (e.g. heroin and methadone)

-Stimulants (e.g. cocaine, nicotine),

-Depressants (e.g. tranquilizers, antipsychotics, alcohol)

-Hallucinogens (e.g. LSD), and marijuana and hashish

-Miscellaneous inhalants.
CNS acting drugs

Miscellaneous
CNS depressants Hallucinogenic inhalants
CNS stimulants
Cerebral cortex Hypnotics (barbiturates) gasoline, glues),
Amphetamine LSD
Cocaine Sedatives (benzodiazepines) gases (butane, propane,
Caffeine
Antidepressants Tranquillizers (phenothiazines) ( lysergic acid
Medulla & brain stem diethylamide) aerosol propellants,
Analeptics Analgesics (salicylates) nitrous oxide)
Spinal cord Cannabis
Narcotic analgesics Benzene
Strychnine (morphine)
Anticonvulsants
Overview of structure and functions of major components of the brain

Cerebral cortex : High perceptions, visual and


auditory and sensory areas , memory , social sense
behavior , logical , analytical and verbal tasks
Primary motor cortex areas
.
Subcortical :
- Thalamus: (movement regulation )

- Hypothalamus : Responsible for the


integration of neuronal and endocrine
functions

Basal ganglia : (cortical & sub cortical)


movement regulation &cognitive
functions
Limbic system ; ( cortical & sub-
cortical) emotion , mood , basic behavior

Cerebellum : Responsible for voluntary movement ,


maintain posture and balance

Brain stem : midbrain , pons & medulla Primary centers for coordination of vital
functions (respiratory and cardiovascular and reticular activating system ; that
control sleep )
Major areas of the brain that are
involved with drug of abuse activities
Basal ganglia : ( Muscle tone and memory )
are masses of gray matter found deep in the cerebral
hemisphere lateral to the thalamus
- Caudate nucleus
- Putamen
- Nucleus accumbens (center of reward)
- Globus pallidus
Functionally related -Substantia nigra ( part of the brain stem)

Limbic system : ( Emotion , memory and learning )


- Portion of Thalamus& Hypothalamus
- Amygdala
- Hippocampus

Reticular activating system : ( sleep& pain regualion)

It is a dense network of neurons found in the brain


stem and extended up to hypothalamus , thalamus ,
cerebral cortex ( blue lines) and down to the
interneuron of the spinal cord
Reward pathway

ATV : ventral tegmental area

Reward system : is a collection of brain structures which attempts to regulate and control behavior
by inducing pleasurable effects.

Euphoria : Recognized as a mental /emotional state defined as a sense of great (usually exaggerated) wellbeing .
Neurotransmitters &receptor concept

The neurophysiological mechanism , responsible for most of the psychological


behaviors of the brain is mediated through a number of neurotransmitters and
Neuropeptides ( larger molecular weight )

Neurotransmitters are released into the synaptic cleft and cause an


electrophysiological changes in the postsynatic potential in the postsynaptic cells

Producing :
1- Excitatory –postsynaptic
potential (EPSP)
They facilitate the entry of
cations ( Ca 2+, Na+) that
depolarize the postsynaptic cells

2- Inhibitory postsynatic
potential (IPSP)
They facilitating the entry of
anions (Cl-) that hyperpolarizes
the membrane and /or activate
K+ channels
Brain Neurotransmitters

Type Receptor type Cellular effect


Acetylcholine (Ach) Muscarinic) M1, 3,5 IP3/DAG conductance (excitatory)
Nicotinic Ca2+, Na+, K+ conductance (excitatory)

Nor adrenaline α ( 1 A, B, C) IP3/DAG conductance (excitatory)


α2 CAMP conductance, Ca 2+ (Inhibitory )
1,2,3 CAMP conductance (excitatory)
Dopamine D1 like ( D1,5) CAMP conductance (excitatory)
D2 Like ( D2,3,4) CAMP conductance, Ca 2+ (Inhibitory)
5HT ( serotonin) 5HT 1 A, B,D CAMP conductance, K+ (Inhibitory )
5HT 1C, 5HT 2 IP3/DAG conductance (excitatory)
GABA ( Gamma GABA A Cl – conductance (Inhibitory )
aminobutyric acid ) GABA B Ca 2+, K+ conductance (Inhibitory )

Opioids (peptides) µ ( mu) CAMP conductance, K+ ( Inhibitory )


(kappa) CAMP conductance, K+ ( Inhibitory )
(delta)
CAMP conductance, K+ ( Inhibitory )

Glutamate NMDA ( N- methyl –D aspartic CAMP conductance ( excitatory)


acid)
Basal ganglia and related neurotransmitters

Movement regulation &cognitive


functions and emotions

1- Fibers from Caudate nucleus secrete : Ach; In Ach : dementia

2- Fibers from Substantia nirgra secret : Dopamine ; decrease in dopamine as in


the use of tranquilizers such as (phenothiazines that block the dopaminergic
receptors : participate in development of parkinson’s disease

3- Fibers from Globus pallidus and Caudate nucleus secrete : GABA


Basal ganglia acting drugs

Reward pathway

ATV : ventral tegmental area

VTA NA dopaminergic projection has attracted a great deal of attention, because there is much evidence that it plays
a central role in rewarding learning .

A number of highly drugs of abuse, including cocaine amphetamine , and nicotine , are thought to work by increasing
the efficacy of the VTA NA dopamine signal. There is also evidence implicating overactivity of the
VTA dopaminergic projection in schizophrenia
Limbic system and related neurotransmitters
Areas of the limbic system

-Parts of
- thalamus &
hypothalamus
- Amygdala
- Hippocampus

1- Dopamenergic neurons

Involved in the mechanism of motivation ( force that activate behavior to achieve goal)
and reward system ( relaxation , pleasure , satisfaction ) and in motor activity

2- Noradrenergic and adrenergic Pathway : create neuronal innervations in specific


areas of hypothalamic and thalamic areas
Limbic system- acting drugs

1-Dopamergic agonists : Inhibit dopamine reuptake ( increase of


dopamine )
Amphetamine , Cocaine are dopamenrgic stimulants acting as strong
psychoactive drugs

2-Noradrenergic agonist :

Tricyclic antidepressants : block the reuptake of NE and stimulate


the dopamine response
Examples
items Amphetamine Tricyclic Cocaine
antidepressants

Mechanism of action 1- Block the neuronal uptake of the Typically inhibit 1-Block the neuronal
excitatory neurotransmitters both norepinephrine uptake of the excitatory
Dopamine & nor-epinephrine & serotonin neurotransmitters
re-uptake by pre- Dopamine & nor-
synaptic epinephrine
terminals

Pharmacological action -Increase mental alertness -Depression -Local anesthetic on nasal


- Euphoria -Migraine headache and ocular tissues
-Depression with tricyclic a -Anxiety, Insomnia
ntidepressants
Acute Toxicity -Seizures -Anticholinergic -Tachycardia
-Cardiac arrest effect ( anti - -Arrhythmia
-irreversible damage to the muscarinic )
dopaminergic neurons
- Drowsiness
- Hypotension ;
Cardiac rhythm
disturbance
- Tachycardia-Dry
mouth

-5HT
-Hyperthermia
Cont. Examples
Items Amphetamines TCA Cocaine

Chronic Toxicity -Cognitive and


-Psychotic behavior memory -one of the most
Tolerance & Addiction -Delusions difficulties psychological addictive
-Paranoia substance
-Cognitive dysfunction( -Risk of addiction is
massive depletion of low due
endogenous amines) to the lack of
euphoria
caused by the
anticholinergic effect

Abstinence syndromes -Convulsions - No withdrawal


( withdrawal symptom ) -Insomnia symptoms
-Depression

Examples Methylamphetamine Desipramine , -hydrochloride salt sold in


(free base , crock) Imipramine& as street drug for sniffing
Amitriptyline
Powder crack
Floxetine (Prozac)
Ritalin , phentermine
,Meridia
GABA pathway in the brain

GABA is the main inhibitory neurotransmitter in the central nervous system (CNS).
GABA-ergic inhibition is seen at all levels of the CNS, including the hypothalamus,
hippocampus, cerebral cortex. As well as the large well-established GABA
pathways, GABA interneurones are abundant in the brain, with 50% of the
inhibitory synapses in the brain being GABA mediated.

Benzodiazepines , Alcohols , barbiturates act by opening the Cl- channels and


enhancing GABA effects as anti-anxiety , anticonvulsant , sedative and muscle
relaxant
CNS depressants
items Barbiturates Benzodiazepines Alcohol
Mechanism of action 1-Allosterically modify the 1- Allosterically modify the 1-Alloseric modification of
GABA receptors, thus GABA receptors at different site the GABA receptors
enhancing the inhibitory effect than that of barbiturates 2-It strongly affects the
of GABA neurotransmitter second messenger
(they bend the receptors 3- It acts on the opiate
slightly so that the GABA receptors through its first
molecule attach to it and metabolite , acetaldehyde
activate the open the inhibitory which combine with
Cl- ion channels) dopamine to form
tertahydroisoquinonolone
2-Act directly to open the Cl- (TIQ) that is responsible
ion channels for the euphoric effect in
alcohol intoxication
Pharmacological action -Hypnotic , Antianxiety, sedative (quieting -Euphoria
-Surgical anesthetics, epilepsy without inducing sleep) -General unaesthetic
-Potent vasodilator -Methanol intoxication (to
saturate the alcohol
dehydrogenase ALD )
Acute Toxicity -Respiratory depression -Drowsiness -Flushed face
-Hypotension -Nausea -Extreme nausea -
-Circulatory collapse -Not lethal in overdose like with (building up of
barbiturates Acetaldehyde
Cont. CNS depressants

Items Barbiturates Benzodiazepines Alcohol

Chronic Toxicity
-High abuse potential -Less abuse potential than -Induction of hepatic
Tolerance & Addiction -Poor memory barbiturates microsomal enzymes
-Cerebral disturbance (CYP 450)

Abstinence syndromes -Seizures -Seizures -Excitatory systems ,exert


( withdrawal symptom ) -Insomnia -Insomnia Anxiogenic effect
-Depression -Depression -Dysphoria
-Aggressiveness -Aggressiveness -Severe cases of seizures
even leading to death
Pain areas and related neurotransmitters
To reduce the level of perceived pain, endogenous opioids (enkephalins,
endorphines) are released by interneurons in the dorsal horn in response to
severe/persistent pain. The opioids bind to G proteins associated with µ-type opioid
receptors in areas of the spinal cord and brain

Regions where pain


is perceived are
shown in brown

Regions where opioid


receptors are found are
shown in blue.

with the following results:


-Inhibition of pre-synaptic release of glutamate

-Inhibition of Adenyate –cyclase enzyme ; leading to fall in c-AMP and diminish action
potential

These events prevent the transmission of pain to the higher centers


Opioids mechanism of action

-Decreased Ca++ entry


-Increased outward movement of K+
-Inhibition of adenylate cyclase
Narcotic analgesics
Morphine: is a highly-potent opiate analgesic drug and is the principal active agent in opium .
Morphine acts directly on the CNS to relieve pain, and at synapses like posterior amygdala, hypothalamus,
thalamus, nucleus caudate, putamen, and certain cortical areas.
There are three major subtypes of opioid receptors
These are all G-protein coupled receptors
Recptors Function

delta ( )
Analgesia
Euphoria
Physical dependence

mu ( ) 2:
Respiratory depression MORPHINE
Miosis
Euphoria
Reduced GI motility
Cough center
CTZ (chemo- trigger
zone)
physical dependence
CB1
Cannabinoid
receptor

Opiate
Opiate : Receptor
The euphoric effect also appears to involve
another mechanism in which the GABA-
inhibitory interneurons of the ventral
tegmental area come into play. By attaching
to their mu receptors, exogenous opioids
reduce the amount of GABA released .
Normally, GABA reduces the amount of
dopamine released in the nucleus
accumbens. By inhibiting this inhibitor, the
opiates ultimately increase the amount of
dopamine produced and the amount of
pleasure felt.
Morphine agonists & antagonists
Heroin

Morphine was the most commonly abused narcotic


analgesic in the world until heroin (Diacetylmorphine ) was synthesized (1847) hydromorphone
and came into use

semi -Synthetic opioid : hydromorphone; oxycodone


synthetic – opioids ; meperidine, fentanyl,

heroin and morphine are more liable to abuse and addiction

Morphine antagonists: Opioid antagonists

-Naloxone (CNS, respiratory depression treatment), oxycodone

fentanyl

8 times potent than morphine


Morphine addiction & withdrawal symptoms
Tolerance : develops to sedation and
euphoria and respiratory depression
After 10-14 days

Therapeutic Dose: 5-10


mg Addicts dose : 100-200 mg
Pharmacological Withdrawal symptoms
Insomnia
action
Diarrhea, runny nose
Yawning,
Relief of severe pain

Recreational uses: Sweating


Strong drug craving
Body aches, severe
Euphoria abdominal pain, Nausea
Relaxation and vomiting
Sedation Severe depression
Other uses: Elevated heart rate &
Emetic blood pressure
Heart attack
anti-diarrheal
Blot clot or stroke