Transcript - ISpatula

ALKALOIDS DERIVED FROM
TYROSINE
• Phenylethylamines and Simple
Tetrahydroisoquinoline Alkaloids
• PLP-dependent decarboxylation of Ltyrosine gives the simple
phenylethylamine derivative tyramine,
which on di-N-methylation yields
hordenine, a germination inhibitory
alkaloid from barley (Hordeum vulgare;
Graminae/Poaceae).
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• More commonly, phenylethylamine derivatives
possess 3,4-di- or 3,4,5-tri-hydroxylation
patterns, and are derived via dopamine, the
decarboxylation product from L-DOPA
(dihydroxyphenylalanine)
Pre-eminent amongst these are the
catecholamines∗ noradrenaline
(norepinephrine), a mammalian
neurotransmitter, and adrenaline
(epinephrine), the ‘fight or flight’ hormone
released in animals from the adrenal gland as a
result of stress.
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• These compounds are synthesized by
successive β-hydroxylation and N-methylation
reactions on dopamine (Figure 6.37). Aromatic
hydroxylation and O-methylation reactions in the
cactus
• Lophophora williamsii∗ (Cactaceae) convert
dopamine into mescaline, an alkaloid with
pyschoactive and hallucinogenic properties.
• Note that the sequence of hydroxylations and
methylations exactly parallel those described for
the cinnamic acids.
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Catecholamines
• The catecholamines dopamine, noradrenaline
(norepinephrine), and adrenaline (epinephrine) are
produced in the adrenal glands and nervous tissue and
act as neurotransmitters in mammals.
• Several adrenergic receptors have been identified.
• α-Receptors are usually excitatory and produce a
constricting effect on vascular, uterine, and intestinal
muscles.
• β-Receptors are usually inhibitory on smooth muscle, but
stimulatory on heart muscles.
• Dopamine can act on both vascular α1 and cardiac β1
receptors, but also has its own receptors in several other
structures. In Parkinson’s disease, there is a deficiency
of dopamine due to neural degeneration, affecting the
balance between excitatory and inhibitory transmitters.
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• Treatment with L-DOPA (levodopa) helps to increase
the dopamine levels in the brain.
• Unlike dopamine, DOPA can cross the blood–brain
barrier, but needs to be administered with a DOPAdecarboxylase inhibitor, e.g. carbidopa, to prevent rapid
decarboxylation in the bloodstream.
• Injections of dopamine or dobutamine are valuable as
cardiac stimulants in cases of cardiogenic shock.
• These agents act on β1 receptors; dopexamine
is also used for chronic heart failure but acts on β2
receptors in cardiac muscle.
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• Noradrenaline (norepinephrine)
• is a powerful peripheral vasoconstrictor predominantly
acting on α-adrenergic receptors, and is useful in
restoring blood pressure in
• cases of acute hypotension.
• The structurally related alkaloid ephedrine may be used
in the same way, and synthetic analogues of
noradrenaline, e.g. phenylephrine,
• methoxamine, and metaraminol have also been
developed.
• Methyldopa is used to treat hypertension; it is a
centrally acting agent that becomes decarboxylated and
hydroxylated to form the false transmitter αmethylnoradrenaline, which competes with
• noradrenaline.
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• Adrenaline (epinephrine) (Figure 6.37) is released from
the adrenal glands when an animal is confronted with an
emergency situation, markedly stimulating glycogen
breakdown in muscle, increasing respiration, and
triggering catabolic processes that result in energy
release.
• Adrenaline interacts with both α- and β- receptors,
• an α-response being vasoconstriction of smooth muscle
in the skin.
• β-Responses include mediation of cardiac muscle
contractions
• and the relaxation of smooth muscle in the bronchioles
of the lung. Injection of adrenaline is thus of value in
cases of cardiac arrest, or in allergic emergencies such
as bronchospasm or severe allergy (anaphylactic shock).
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• It is not effective orally. A wide range
of cardioactive β-adrenoceptor
blocking agents (beta-blockers) has
been developed to selectively bind to
β-receptors to control the rate and
force of cardiac contractions in the
management of hypertension and
other heart conditions
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• The prototype of the beta-blocker drugs is
propranolol, in which the catechol ring system
has been modified to a naphthalene ether, and a
bulky N-alkyl substituent has been incorporated.
Many structural variants have been produced
and there is now a huge, perhaps bewildering,
variety of beta-blockers in regular use, with
subtle differences in properties and action
affecting the choice of drug for a particular
condition or individual patient.
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• Other β-agonists are valuable as antiasthmatic
drugs. Important examples include salbutamol
(albuterol) and terbutaline, which are very
widely prescribed, principally
• for administration by inhalation at the onset of an
asthma attack, but, as with cardioactive betablockers, a wide range of agents is in current
use. These agents are mainly selective towards
the β2-receptors, an supersede the earlier less
selective bronchodilator drugs such as
isoprenaline (isoproterenol) and
orciprenaline (metaproterenol)
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• Topical application of a beta-blocker to the
eye reduces intraocular pressure by
reducing the rate of production of aqueous
humour. Some drugs in this class, namely
betaxolol, carteolol, levobunolol,
metipranolol, and timolol, are thus useful
in treating glaucoma. Propranolol,
metoprolol, nadolol, and timolol also
have additional application in the
prophylaxis of migraine.
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Inactivation of Catecholamine
• Catecholamine neurotransmitters are subsequently
inactivated by enzymic methylation of the 3-hydroxyl (via
catechol-O-methyltransferase)
• or by oxidative removal of the amine group via
monoamine oxidase.
• Monoamine oxidase inhibitors are sometimes used to
treat depression, and these drugs cause an
accumulation of amine neurotransmitters.
• Under such drug treatment, simple amines such as
tyramine in cheese, beans, fish, and yeast extracts are
also not metabolized and can cause dangerous
potentiation of neurotransmitter activity.
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Entacapone
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Lophophora
• Lophophora or peyote consists of the dried
sliced tops of Lophophora williamsii
(Cactaceae),
• a small cactus from Mexico and the SW United
States.
• The plant has been used by the Aztecs and
since by the Mexican Indians for many years,
especially in religious ceremonies to produce
hallucinations and establish contact with the
gods. The so-called mescal buttons were
ingested and this caused unusual and bizarre
coloured images.
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• The plant is still used by people seeking drug-induced
experiences. The most active of the range of alkaloids
found in lophophora (total 8–9% alkaloids in the dried
mescal buttons) is mescaline, a simple phenylethylamine
derivative.
• Mescaline has been used as a hallucinogen in
experimental psychiatry. The dosage required is quite
large (300–500 mg),
• but the alkaloid can readily be obtained by total
synthesis, which is relatively uncomplicated.
• Mescaline is also found in other species of cactus, e.g.
Trichocereus pachanoi, a substantially larger columnar
plant that can grow up to 20 feet tall, and found mainly in
the Andes.
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Amphetamine
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20 year old male delivered to the ED by an acquaintance
Initial signs and symptoms
Delusions
Paranoia
Tachycardia
Hypertension
Hyperpyrexic
Diaphoretic
Piloerection
Mydriasis
Hyperreflexic
What is this toxidrome?
What compounds may induce this type of
syndrome?
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Further history
The acquaintance relates that the patient
had ingested a “party drug” 2 hours
previously, but he could not remember
what.
What group of drugs does the compound
likely belong to?
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Anticholinergic Syndrome
Cholinergic Syndrome
Sympathomimetic syndrome
Opioid / Ethanol / Sedative Toxidrome
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Amphetamine/amphetamine-like
compounds
Amphetamine-like compounds increase
neurotransmission in central noradrenaline,
dopamine and serotonin systems.
While they produce similar pharmacological
actions, there are differences in effect on
individuals depending on the relative stimulation of
the various neurotransmitter systems (e.g.
increased serotonin causes increased
hallucinogenic effect).
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Amphetamine/amphetamine-like compounds
Neurotransmitter release
Low dose – preferential action on noradrenaline release
Moderate dose – noradrenaline and dopamine release
High dose – noradrenaline, dopamine and serotonin
release
Blockade of re-uptake (noradrenaline, dopamine and serotonin)
Inhibition of monoamine oxidase
Note: There is variation between the various
sympathomimetic drugs
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Amphetamine/amphetamine-like compounds
“Amphetamines”
Amphetamine
Amphetamine derivatives / Amphetamine-like drugs
Methamphetamine
(“P” – “pure” crystal methamphetamine)
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3,4-Methylenedioxymethamphetamine
MDMA, Ecstasy, XTC
3,4-Methylenedioxyamphetamine
MDA, Love drug
3,4-Methylenedioxyethamphetamine
MDEA, Eve
Para-methoxyamphetamine
PMA
3,4-methylenedioxy-phenyl-N-methylbutanamine
MBDB
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2,4,5-Trimethoxyamphetamine
TMA-2
4-Methyl-2,5-dimethoxyamphetamine
DOM/STP,Serenity, peace, Tranquility
4-Bromo-2,5-dimethoxyamphetamine
DOB
4-Bromo-2,5 methoxyphenylethylamine
2CB, MFT
Methcathinone
Khat, cat, quat, gat, jeff
Ephedrine
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Plants
Khat, (Catha edulis)
cathine (norpseudoephedrine)
Ma-huang, (Ephedra ma-huang)
Ephedra
Peyote cactus, (Lophophora Williamsii)
Mescaline
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Therapeutic
Dexamphetamine
Benzphetamine
Diethylpropion
Phentermine
Fenfluramine
Pseudoephedrine
Methylphenidate
Phendimetrazine
Pemoline
Propylhexadrine
Dexfenfluramine
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The acquaintance gets off a cell-phone and
tells you the drug is “P”.
What is “P”?
What range of signs and symptoms can be
expected from this drug?
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What is “P”?
“Pure” crystal methamphetamine.
What range of signs and symptoms
can be expected from this drug?
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What range of signs and symptoms
can be expected from this drug?
Mild
Euphoria
Increased alertness
Bruxism
Altered mental status
Tachycardia
Hypertension
Moderate
Agitation
Paranoia
Hallucination
Diaphoresis
Vomiting
Abdominal pain
Palpitations
Chest pain
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What range of signs and symptoms
can be expected from this drug?
Severe
Hyperthermia
Ischaemia/vascular rupture
Metabolic acidosis
Rhabdomyolysis
Hyperkalaemia
Acute renal failure
Coma
Death
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Sympathomimetic syndrome
Sometimes confused with the anticholinergic syndrome,
but the later is associated with dry skin and diminished
bowel sounds.
Mechanism
A drug mimicking the action of the sympathetic system;
Alpha/beta adrenergic stimulation
What compounds may induce this type of syndrome?
Cocaine
Amphetamines and amphetamine-like compounds
OTC decongestants (pseudoephedrine, ephedrine,
phenylpropanolamine)
Theophylline, caffeine
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Captagon
Amphetamine plus Theophylline
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Ephedra sinica
Ephedraceae
Used part:
Aerial stems
which are
woody and
usually
branch only
at the base.
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ephedrine
pseudo ephedrine
Nor – ephedrine
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• Uses: Ephedrine is used for the relief of
asthma and hay fever. Its action is
more prolonged than that of adrenaline,
and it has the further advantage that it
need not be given by injection but may
be administered by mouth.
• In oriental medicine the ephedra are
also used as anti-inflammatory drugs
and this action is ascribed to an
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oxazolidone related to ephedrine.
Catha edulis
Celastraceae
This consists of the fresh leaves
of Catha edulis (Celastraceae).
Used Part: Its traditional use is similar to
that of coca in that the fresh leaves, when
chewed, have a stimulatory effect with
the alleviation of depression and of
the sensations of hunger and
fatigue.
(-)cathine has pharmacological properties analogous to those of (+)-amphetamine,
possessing a similar potency and the same mechanism of action.
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INTAKE AND MODE OF INGESTION
• Fresh Khat leaves are typically chewed like
tobacco.
By filling the mouth to capacity with fresh leaves
the user then chews intermittently to release the
active components. Chewing Khat leaves
produces a strong aroma and generates intense
thirst.
Its intake occurs mostly in moderation esp. in a
special Yemeni style rooms designed especially
for that purpose with the fine famous Yemenifurnishing style provided with water pipes and
these special rooms called " Diwan " which are
so large and wonderful rooms .!
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Chemistry and pharmacology
• Cathinone structure
• The stimulant effect of the plant was
originally attributed to "katin", cathine, a
phenethylamine-type substance isolated
from the plant.
• However, the attribution was disputed by
reports showing the plant extracts from
fresh leaves contained another substance
more behaviorally active than cathine. In
1975, the related alkaloid cathinone was
isolated, and its absolute configuration
was established in 1978.
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khat
• Cathinone is not very stable and
breaks down to produce cathine and
norephedrine. These chemicals
belong to the PPA
(phenylpropanolamine) family, a
subset of the phenethylamines
related to amphetamines and the
catecholamines epinephrine and
norepinephrine.
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khat
• Both of khat's major active
ingredients -- cathine and
cathinone -- are , meaning they
are in the same class of chemicals
as amphetamines.
• In fact, cathinone and cathine
have a very similar molecular
structure to amphetamine.
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khat
• When khat leaves dry, the more potent
chemical, cathinone, decomposes within 48
hours leaving behind the milder Schedule IV
chemical, cathine.
• Thus, harvesters transport khat by packaging
the leaves and stems in plastic bags or wrapping
them in banana leaves to preserve their
moisture and keep the cathinone potent. It is
also common for them to sprinkle the plant with
water frequently or use refrigeration during
transportation.
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khat
• When the khat leaves are chewed, cathine and
cathinone are released and absorbed through
the mucous membranes of the mouth and the
lining of the stomach. The action of cathine and
cathinone on the reuptake of epinephrine and
norepinephrine has been demonstrated in lab
animals, showing that one or both of these
chemicals cause the body to recycle these
neurotransmitters more slowly, resulting in
the wakefulness and insomnia
associated with khat use.
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khat
• Receptors for serotonin show a high
affinity for cathinone suggesting that this
chemical is responsible for feelings of
euphoria associated with chewing khat.
• In mice, cathinone produces the same types
of nervous pacing or repetitive scratching
behaviors associated with amphetamines.
The effects of cathinone peak after 15 to 30
minutes with nearly 98% of the substance
metabolized into norephedrine by the liver.
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khat
• Cathine is somewhat less understood, being
believed to act upon the adrenergic receptors
causing the release of epinephrine and
norepinephrine. It has a half-life of about 3 hours
in humans.
• Because the receptor effect are similar to
those of cocaine medication, treatment of the
occasional addiction is similar to that of
cocaine. The medication bromocriptine can
reduce cravings and withdrawal symptoms
within 24 hours
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Effects
• Khat consumption induces mild euphoria
and excitement.
• Individuals become very talkative under
the influence of the drug and may
appear to be unrealistic and
emotionally unstable.
• Khat can induce manic behaviors and
hyperactivity. Khat is an effective anorectic
and its use also results in constipation.
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• Dilated pupils (mydriasis), which are prominent
during khat consumption, reflect the
sympathomimetic effects of the drug, which are
also reflected in increased heart rate and blood
pressure.
• A state of drowsy hallucinations (hypnagogic
hallucinations) may result coming down from
khat use as well. Withdrawal symptoms that may
follow prolonged khat use include lethargy, mild
depression, nightmares, and slight tremor.
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• Long-term use can precipitate the following
effects:
• negative impact on liver function,
• permanent tooth darkening (of a greenish
tinge),
• susceptibility to ulcers,
• and diminished sex drive.
• Those who abuse the drug generally cannot stay
without it for more than 4-5 days, feeling tired
and having difficulty concentrating.
• Occasionally a psychosis can result. It
resembles a hypermanic state in presentation.
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SIDE EFFECTS ( OVERDOSE
SYMPTOMS )
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- Grandiose delusions .
- Insomnia (loss of sleep ( alertness )).
- Anorexia ( loss of appetite ) and loss of weight .
- Breathing difficulties .
- Increase blood pressure .
- Increase heart rate .
- Stomach irritation .
- Constipation which may precipitate hernias .
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• - Khat plant may be treated chemically which
may affect the liver (chemical hepatitis) .
- It interferes with absorption of iron and other
minerals if taken internally .
- Opponents claim that Khat damages health by
suppression of appetite and prevention of sleep .
- when its effects wear off, generates mild lapses
of depression similar to those observed among
cocaine users.
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