Substance Abuse PHG 414 - PSAU · Amphetamine & Methamphetamine Amphetamine a stimulant drug, related in structure to the neurotransmitters norepinephrine and dopamine, are synthetic

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

Welcome Back

Dears

Central Nervous System Stimulants

Amphetamine & Methamphetamine

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 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


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 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


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


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.


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


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.



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



*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



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).


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


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.

Substance Abuse PHG 414 - PSAU · Amphetamine & Methamphetamine Amphetamine a stimulant drug, related in structure to the neurotransmitters norepinephrine and dopamine, are synthetic

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