Substance Abuse PHG 414 - PSAU · Amphetamine & Methamphetamine Amphetamine a stimulant drug,...
Transcript of Substance Abuse PHG 414 - PSAU · Amphetamine & Methamphetamine Amphetamine a stimulant drug,...
Prof. Dr. Amani S. Awaad
Professor of Pharmacognosy
Pharmacognosy Department,
College of Pharmacy Salman Bin Abdulaziz University,
Al-Kharj. KSA.
Email: [email protected]
Substance Abuse
PHG 414
You should be able to know:
• What are Amphetamine & Methamphetamine
• Determine pharmacological actions of CNS stimulants..
• Build an addiction treatment plan of CNS stimulants.
Amphetamine & Methamphetamine
Amphetamine a stimulant drug, related in
structure to the neurotransmitters
norepinephrine and dopamine, are synthetic
phenyl ethyl amines.
Methamphetamine known as (Meth, Ice,
Speed), it is derived from amphetamine it is
potent stimulant of central nervous system. Both
are similar in their action:
Amphetamine a group of substances comprised
of synthetic stimulants.
They include several closely related compounds as;
* d-(+)dexamphetamine , l,(-)levamphetamine.
*d- (+) Methamphetamine /l,(-)levomethamphetamine
*Methylenedioxymethamphetamine (MDMA) known
as Ecstasy. Methamphetamine levomethamphetamine
dexamphetamine levamphetamine
Norepinephrine
Methamphetamine Add methy gp to Amphetamine
Amphetamine & Methamphetamine
Methamphetamine
Methamphetamine Add methy gp to Amphetamine
One chiral center, with 2 isomers (R) or (S).
(S) Meth (Stimulant) to treat ADHD, narcolepsy,
fatigue, obesity
(R) Meth is used in nasal congestion
2 optical isomers, (R) and (S)
(R) Meth, legal (over-the-counter drug) used in
inhalers for nasal decongestion
(S) Meth, illegal, stimulant known as speed
(designer drug)
Uses of Methamphetamine
Amphetamine & Methamphetamine
Amphetamine and methamphetamine free bases are
liquids and of low stability.
Therefore they are found in the form of; amphetamine
SO4 or PO4 and methamphetamine HCl salt.
In addition, there are several chemical derivatives of amphetamines with restricted use as
medications such as phemmetrazine, methylphenidate (Ritalin®).
Uses
*Amphetamines have been used for nonmedical
purposes *Obesity caused by overeating. Not endocrine
imbalance (short-term weight loss program )
•Narcolepsy, sleep disorders characterized by rapid and
uncontrolled onset of sleep. Hyperactivity (ADHD)
•Juvenile Attention deficit disorders (ADD) with
hyperactivity in children. Attention Deficit
Hyperactivity Disorders in adults and children (ADHD)
Amphetamine & MethamphetaminePharmacology and Mode of Action
•At low to moderate doses, amphetamine elevate mood and increase
mental alertness and feeling of energy and well being by interfering
with the normal activities of neurotransmitters.
•They also reduce activities of stomach and intestine and reduce feel
of hunger.
•At high doses amphetamines can increase heart rate and BP to
dangerous levels.
MOA:
•Effects result mainly from release of catecholamines, especially noradrenaline
and dopamine.
•Stimulant effect lasts for a few hours and is followed by depression and anxiety
•Tolerance to the stimulant effects develops rapidly, (peripheral
sympathomimetic effects may persist).
* Affect brain neurotransmitters, including dopamine, serotonin, and
norepinephrine.
*Increase heart beat, blood pressure and use to treat asthma, ADHD, obesity,
narcolepsy(paradoxically) to control hyperkinetic children.
*Similar in structure with dopamine, increases dopamine level, feeling of
pleasure and staying alert *High doses causes euphoria and is addictive
Amphetamine & MethamphetaminePharmacology and Mode of Action
The mode of action
The mode of action of amphetamines is directly related to their structures which are very
similar to neurotransmitters ephedrine and pseudoephedrine.
•It is though that amphetamine produces their stimulatory effect by stimulating the receptors
sites for neurotransmitters.
•Also they cause the release of nor-epinepherine from pre-synaptic nerve terminals.
•It blocks the active uptake of nor-epinepherine and dopamine back into their pre-synaptic
nerve terminal.
•All these leads to the stimulation of norepinepherine receptors which produce alerting and
awakening of effects in the person taken amphetamine.
•They also stimulate the dopamine receptors and thereby produce increased motor activity and
feeling of euphoria
•The chronic physiological and psychological effects of amphetamine include rapid tolerance and
strong psychological dependence, impotence and episodes of paranoia and psychosis.
Tolerance to amphetamines develops rapidly in regular users, but it develops more rapidly to
some of amphetamines effect than to others. E.g. it develops quickly to its appetite-suppressing
effects, but more slowly to its mood elevating effects.
The route of administration of amphetamines is an important factor in the development of
tolerance, oral and snorting produce slower tolerance while inhalation or IV injection produces
rapid
Amphetamine & Methamphetamine
Most abused form of amphetamines
Methamphetamine is generally a
white or off-white powder that can be
ingested in several ways: Orally
,Snorted , Injected, Smoked
Short term side effects
Excessive Talking
•Increased Activity, Nervousness,
Anxiety / Panic Attacks,
Hallucinations, Excessive Sweating,
Skin Welts, Violent / Suicidal Behavior
Long term side effects
Immune System Damage,
Psychological Problems, Severe
Brain Damage, Fatal Kidney,
Disorders, Fatal Lung Disorders,
Birth Defects, Stroke, Death
Amphetamine & Methamphetamine
Production of illicit amphetamines
illicit amphetamines
The majority of illicit market production of
amphetamines and methamphetamines are
produced by clandestine laboratories,
- lack of quality control and
- variability in potency are characters of illicit
amphetamine and methamphetamine samples.
They often contain by-products and intermediate
results from:
•Impure starting material, Incomplete reactions,
Inadequate purification of intermediate and the
final products
These by-products and intermediate can provide
valuable information concerning the illicit
method of manufacturing.
Amphetamine & Methamphetamine
Production of illicit amphetamines
illicit amphetamines
- Knowledge of impurities is important to know the harmful effects of impurities
can be evaluated as well as potential danger publicized and how to treatment.
- Awareness of impurities is important to forensic analyst.
- Most impurities are weakly basic or neutral in nature and are normally present
in the finished product at level of 2-3’.
I. Synthesis of amphetamine
over the years the Leuckart reaction(a) has
remained the most popular method for synthesizing
illicit amphetamine. Now there are some other
methods such as;
*The Reductive Amination of Benzyl Methyl
Keton(b)
*The Oxime Route ( c)
*The Phenylnitropropene Route(d)
Synthesis of amphetamine
There are different methods for synthesis of amphetamine and methamphetamine
Amphetamine & Methamphetamineillicit amphetaminesI-Synthesis of amphetamines
a.Leuckart reaction
b. The Reductive Amination of Benzyl Methyl Ketone
180-190°C
H2SO4/HCl
(dilute)
90-125 °C
C. The Oxime Route
Raney Nickel, Pt, H2
20-170°C, 1-130 atm,
ethanol, methanol.
H2 &
Raney Nickel
20-170°C, 1-130
atm
D. The Phenylnitropropene Route
LiAlH4, H2
20-100°C, 1-80
atm, CH3OH
Amphetamine & Methamphetamineillicit amphetaminesII-Synthesis of Methamphetamine
a.Leuckart reaction
b. The Reductive Amination of Benzyl Methyl Ketone
170-190°CH2SO4 / HCl
120-170°C
HgCl2/Al
, NaBH4
25-160 °C,
1200 atm,
methanol
c. Reduction of ephedrine and pseudoephedrine
Ephedrine
+
Pseudoephedrine
HI/red phosphorous
H2+Pd/BaSO4
Thiyonyl Chloride
Chloroephedrine
+
Chloropseudoephedrine
methamphetamine
in agood yield
CH3
NH2HO
Nor-ephedrine
Amphetamine & Methamphetamineillicit amphetamines
Licit & Illicit products of amphetaminesLicit Amphetamines Illicit Amphetamines
White coulers products contain the
drug in the form of SO4- or PO4
-
SALTS AS; Tablets, Capsules, Syrups
And Elixir
Products are in form of SO4, and Varies in color from
white to pink, depending on the type and amount of
impurities and adulterants its odor is characteristic
and unpleasant
METH HCl is available as a tablet and
sterile solution for injection
METH HCl is usually in the form of a caked or
gummy powder.
-Aqueous solution of methamphetamine HCl commonly called gold fish. in
Egypt is commonly called Maxton ice,
-Amphetamine SO4 or PO4 salts are most frequently taken orally (tablets or
capsules) or intranasal through snorting.
-Methamphetamine HCl is most frequently prepared for injection or for
smoking (ice) but also is available as tablet.
•Ice is commonly abused by inhalation through smoking and special glass pipe
is used. Smoke able ice (crank) is characterized by a rapid onset and long
duration of action, 7 seconds for 4-14 hours.
•Ice is also abused by IV injection either alone or with heroin in speed ball.
Chronic uses exhibit weight loss, reduced resistance to diseases and damage of
the lungs, liver and kidney.
Administration:
Amphetamine & Methamphetamineillicit amphetamines
Dependence
as tolerance develops it is often
accompanied by a strong
psychological dependence.
Amphetamine abusers feel they
cannot face the day without the drugs.
Withdrawal Abusers can easily become
addicted. Amphetamine effects are
similar to cocaine. Tolerance Effect.
Withdrawal symptoms: Confusion,
apathy, irritability, depression,
increased appetite and need for sleep
Should talk to a doctor before going off
of amphetamines if taken for a long
time
Amphetamine & Methamphetamine
Metabolic pathways of Amphetamines
Elimination of amphetamines involve
1-Biotransformation by liver enzyme to more polar
compounds and excretion in the urine.
2-In activation by conjunction to form the glucouronides and
sulphate conjugates.
-Amphetamines begin to cupper in the urine within 20
minutes of administration.
Blood concentration in fatalities is normally above 500 mg/l
-Amphetamine is excreted the unchanged drug, typically 20-
30% of the dose and as deaminated (hippuric acid and benzoic
acids)
-The rate of excretion and the fraction of the dose excreted as
uncharged drug. Vary according to PH of the urine.
-In alkaline urine about 45% of the dose is excreted in 24
hours,2% as unchanged drugs.
-In acid urine, up to 78% of the dose may be excreted in 24
hours, 68% as the unchanged drugs.
Amphetamine & Methamphetamine
Metabolic pathways of Amphetamines
Metabolic Pathway of Amphetamine
NH2
OH
NH2
NH
OH
Glucouronides and
Sulphate
Conjugates
N-Oxidation
-hydroxylation
Norehedrine
Amphetamine
NH2
HO
4-Hydroxy amphetamine
Glucouronides and
Sulphate
Conjugates
OCH3
O
Major
Metabolic route
(Deamination)
Phenyl acetone
COOH
Benzoic Acid
NHCH2COOH
O
Hippuric Acid
Amphetamine & Methamphetamine
Metabolic pathways of Amphetamines
*The recommended target analyses are therefore, the unchanged drug.
*Methamphetamine is excreted as the unchanged drug 44% and its major metabolites are
amphetamine (6-20%) and 4-hydroxy methamphetamine (10%).
*As with amphetamine the rate of excretion increase by rendering the urine acidic also the
percentage of unchanged drug excreted (increase).
*After chronic administration, abusers have shown amphetamine concentration in urine of 1-
90 mg/ml and methamphetamine concentration of 25-300 mg/ml
NHCH3
NH2
As Amphetamine
N-demethylation
Methamphetamine
NHCH3
HO
4-Hydroxy Mthamphetamine
Glucouronides and
Sulphate
Conjugates
Amphetamine
Aromatic
Hydroxylation
Metabolic Pathway
of Methamphetamine
i-Colur Test
Simple immersion in alcohol is sufficient for extraction
of alkaloids.
Marquis Test: (HCHO/H2SO4)Small amount of the sample+ 1-2 drops of Marquis Reagent
(Orange)---------Brown Color (for amphetamines &
methamphetamines)..
Simon’s Test:
Small amount of the sample+ one drop of sodium nitroprusside/
acetalanhydryde+ one drop Na2CO3. [Amphetamine (Blue),
methamphetamines (pink to cherry red color)]..
Analysis of Amphetamine & Methamphetamine
There are different methods for analysis of amphetamines which
can be as following:
a. Colure Test
b. Chromatographic examination
c. Chromatographic analysis
TLC:
•TLC F254 with MeOH:NH4OH, (100:1.5) detection UV at 254 nm or, spray with,
ninhydrin reagent (violet or pink spot).
GLC:
Accurate weight of the sample salt is dissolved in H2O.Add
internal standard. Liberate free base which is volatile base
liberated from salt by 0.1 N NaOH. Extract free base by
EtOAc. No derivatization, carrier gases He with FID
•HPLC:
Amphetamine and methamphetamine can be directly
analyzed by isocratic technique, on both normal and
reversed phase column.
•Spectroscopic Analysis:
By using IR spectroscopic techniques
Analysis of Amphetamine & Methamphetamine
Analysis of Amphetamine & Methamphetamine
Detection and Assay of Amphetamine in
Biological Samples:
Inhalation and IV injection produce CNS effect
immediately snorting and ingestion produce much
slower onset of action
Initial Screening Methods
•Immuno-assay technique may be used for
screening purposes and positive finding must
be confirmed by a different, more specific
method. Immune assay kits available from
commercial sources for amphetamine and
methamphetamine involve Enzyme Immuno
assay (ESA), Fluorescence polarization
immuno assay (FPIA), latex agglutination
inhibition (LAI) and radio immune assay
(RIA).
Analysis of Amphetamine & Methamphetamine
Detection and Assay of Amphetamine in Biological Samples:
Initial Screening Methods•TLC: Amphetamine and methamphetamines are first extracted from urine at
alkaline pH, when the amino group is in the unchanged state.
Extraction is done by: Liquid-liquid extraction or Solid phase extraction using
cartilage of normal silica, Rp-18 cation-exchanger. NB concentration of the
urine extract should be done under careful conditions to avoid the
evaporation of the free base by using mixture of MeOH: HCl to the extract
to form corresponding salt. The solvent systems are (MeOH:NH4OH
(100:1.5), EtOAC:MeOH:NH4OH (85:10:5)
1-Fast black K salt: Violet with amphetamine Orange with methamphetamine.
The limits of detection for amphetamines and methamphetamines are 0.1 µg, respectively.
observe
under 366 nmDry TLC by hot dryer bright yellow fluorescent spot with amphetamine
methamphetamine is not detected.
120
15 minNinhydrine R Violot or pink spot
3-Fluorescamine
Reaction (Fluorescamine
in acetone)
For spraying reagents
2-Ninhydrine R
The detection limit for amphetamines and other primary amines
is about 10 ng.
Analysis of Amphetamine & MethamphetamineDetection and Assay of Amphetamine in Biological Samples:
Initial Screening Methods
Color Tests
•it is specific and sensitive test for
methamphetamines in urine.
Modifies Simon’s test
(acetaldehyde+HoAC, MeOH) + Sodium
nitroprusside--------Blue Color.
Confirmatory Chromatographic Method
GLC: the urine sample extract can be analyzed for
amphetamine content as underivatized or derivatized
samples qualitative by Rt and quantitative by peak area
and internal standard methods.
GC-MS: Characteristic fragments appear for amphetamine
and methamphetamine as well as their derivatives.
HPLC: using ODS column, qualitative by Rt and
quantitation by peak area and internal standard method
Analysis of Amphetamine & Methamphetamine
Conclusion
*unchanged amphetamine has been detected into the urine up to 29 hours after
single oral dose of 5 mg amphetamine and after 23 hours following single dose of
methamphetamine.
*Appositive amphetamine analysis indicates the use of amphetamines within the
previous 24 hours. However, three additional points should be considered:
•Some drugs like ephedrine and phenyl propanol amine present in some
pharmaceutical preparations which used as decongestant and anorexia, can be
detected by EMIT and RIA tests.
•Several prescription drugs such as fenfluramine, phentermine, mephentramine,…….
Etc can also produce positive Immuno assay results.
•Some drugs give amphetamine and methamphetamine in the urine as their
metabolite. The urine should be re-examined for the presence of the parent drug.