Cocaine
Source
• Dried leaves of Erythroxylum coca (Huanuco Coca - commerce) or E. truxillense (Truxillo coca - commerce)
(Fam. Erythroxylaceae)
– Erythroxylum – “Red Wood” (Gr.)
– coca – Spanish name for tree
– truxillense – Truxillo (Coastal Peruvian city)
• Shrub or small tree (6-7 ft.)
• Indigenous to the Andean regions of South America
• Local farmers process Coca leaves into a “paste” for easier transport to processing laboratories
– Cut twigs from the trees in spring
– Separate leaves and air dry
– Repeat pruning in June and in the fall
Constituents
• Tropane-based ecgonine alkaloids
– Cocaine (benzoylmethylecgonine)
– Cinnamoylcocaine
– -Truxilline and -Truxilline
• Biosynthesis
– Conversion of Total Ecgonine Bases to Cocaine
– Extract the total bases from the leaves as previously described
– Hydrolyze with acid to convert all of the ecgonine esters into (-)-ecgonine
– Re-esterify
1. First – methanol
2. Second – benzoic acid
Chemistry
• Benzoylmethylecgonine
• A tertiary amine diester
• Colorless
• Low water solubility
• HCl salt is the most common water soluble derivative
Pharmacodynamics
• Peripheral nervous system – LOCAL ANESTHESIA
– Unionized form (free base)
1. More lipid soluble
2. Reaches effective intracellular concentrations more quickly than the ionized form
– Ionized form (salt)
1. Once at receptor site inside the axon is a most active form because it cannot readily exit from
closed channels
• Central nervous system- STIMULATION
– Cocaine blocks the uptake of the following biogenic amines, via binding to the transporters of these
amines
1. Dopamine
• DAT = Dopamine Transporter
2. Norepinephrine
• NET = Norepinephrine Transporter
3. Serotonin
• SERT = Serotonin Transporter
– CNS Effects
1. Initial feeling of well-being and euphoria, masking fatigue
2. Garrulousness
3. Restlessness
4. Excitement
5. Motor activity
• Small doses – well-co-ordinated
• Large doses – tremors and clonic-tonic convulsions
6. Stimulation of the vasomotor and vomiting (medullary) centers
• Emesis
7. Followed by depression of these centers
• Medullary depression
• Respiratory failure
• Death
8. The block of the dopamine transporter (DAT) resulting in increasing dopamine concentrations
in the nucleus accumbens has been implicated in the “rewarding effects” of cocaine
• Mice with cocaine-insensitive DAT do NOT have the “rewarding effects”
– Cardiovascular Effects
1. The activation of the sympathetic nervous system results principally from blockage of the
norepinephrine transporter (NET)
2. Peripheral sympathetic effects
• Vasoconstriction
• Tachycardia
• Acute increase in arterial pressure
3. Increased risk for
• Intracranial hemorrhage
• Ischemic stroke
• Seizures
• Myocardial infarction
4. Latter stages – blood pressure falls and death may occur
5. Large IV dose may produce IMMEDIATE DEATH due to direct toxicity on the myocardial
musculature
– Body Temperature
1. Marked pyrexia
• Increased muscular activity due to drug amplification of heat production
• Vasoconstriction diminishes heat loss
• Direct action on CNS heat-regulating centers because a chill precedes the onset of
“cocaine fever”
• PROMINENT FEATURE OF OVERDOSAGE
– Autonomic Nervous System (Sympathetic Branch)
1. The activation of the sympathetic nervous system results principally from blockage of the
norepinephrine transporter (NET)
2. Potentiation of both the excitatory and inhibitory responses of sympathetically innervated
organs to norepinephrine (to a greater degree) and epinephrine (to a lesser degree)
3. BLOCKS CATECHOLAMINE UPTAKE AT ADRENERGIC NERVE TERMINI VIA BLOCKAGE OF THE
NOREPINEPHRINE TRANSPORTER (NET)
• This uptake terminates the actions of circulating catecholamines and adrenergic
impulses
4. Cocaine is the only local anestheric known to interfere with the uptake of norepinephrine at
adrenergic nerve termini
• PRODUCES “CATECHOLAMINE SENSITIZATION”
• VASOCONSTRICTION
• MYDRIASIS
Therapeutic Applications
• Topical local anesthetic (via cotton applicators or spray) on accessible mucous membranes
– Oral
– Laryngeal
– Nasa
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NOT USED IN EYE
1. Corneal toxicities
2. Indirect adrenergic effects
•
“Cocaine Mud” – NOT USED TODAY
– Moistening cocaine HCl powder with epinephrine solutions
– Very dangerous, due to known potentiation of cocaine on catecholamines
1. Arrhythmias
2. Ventricular fibrillation
3. Hypertensive episodes
• Facilitate debridement of the corneal surface epithelium in the therapy of dendritic ulcers
• Aid in the differential diagnosis of a miotic pupil
– Horner’s Syndrome
1. Paralysis of cervical sympathetic nerves
– Raeder’s Syndrome
• Brompton’s Cocktail
– An alcoholic solution containing
1. An opioid (morphine/heroin) – analgesic
2. Cocaine (or other) – euphoriant
– An analgesic mixture for terminal pain (heroin is used in England)
– Controversial (heroin)
Pharmacokinetics
• Absorption/Distribution
– From mucous membranes
– May be amplified in the presence of inflammation, producing systemic effects
– Local anesthesia
1. Onset – 1 min.
2. Peak – 5 min.
3. Persists – 30 min.
– Oral doses are absorbed, but frequently not noticeable
• Metabolism/Elimination
– t1/2 – 50 min. but “crack” users desire more in 10-30 min.
– Hydrolysis via serum esterases
1. Major metabolite – benzoylecgonine
2. Found in urine 2-5 days after a binge
3. Heavy users have detectable limits for up to 10 days
– Partial hepatic demethylation and renal excretion (< 10% unchanged)
Adverse Effects
• Usually result from rapid and excessive absorption of cocaine HCl after topical use
– CNS and CV effects
• LARGE IV DOSES MAY CAUSE IMMEDIATE DEATH FROM CARDIAC FAILURE DUE TO DIRECT EFFECTS ON
MYOCARIDAL MUSCLE
• Topical application to the eye
– Sloughing of the corneal epithelium
1. See therapeutic applications
– Corneal pitting
– Corneal ulceration
• Fatal Dosage
• Approximated at 1.2 grams
• Severe toxic effects have been noted from doses as low as 20 mg
• Specific therapy for acute overdosage
– IV short-acting barbiturate
– IV diazepam
– Artificial respiration may be necessary
Cocaine Abuse
• Three major variables that promote abuse (“addiction”)
– Euphoria
1. Intensely pleasant feelings
– Strong reinforcement properties
1. Promotes strong desire to use repeatedly
– Rapid onset
• Street Names
– Blow
– C
– Candy
– Charlie
– Coke
– Corinne
– Flake
– Girl
– Gold Dust
– Lady
– Sleighride
– Snow
– Toot
– White Lady
• Common in major urban areas
• >23 million Americans have used once, with >700,000 frequent users (at least weekly)
• Minimum of 75 tons of illicit cocaine enter the USA yearly, mainly from Colombia
• South American Coca Paste is converted to its HCl salt that is
– Diluted with inert substances
– Imported for abuse usage
• Coca Paste
– Mostly HCl salt in the USA
– May be the sulfate salt in South America
1. Euphoria
2. Irritability
3. Hypertalkativeness
4. Insomnia
5. Stereotypical behaviors
6. Weight loss
7. Toxic psychosis
8. Absence/neglect of work
• “Freebasing”
– Diluted drug from the marketplace is “freebased” in order to increase the effects/potency
1. Alkalinize solution with NaHCO3
• Converts cocaine salts (ionized tertiary amine) to cocaine free base (unionized tertiary
amine), the latter precipitating from water
2. Extract free base with diethyl ether
3. Evaporate the ether
4. Remaining residue is smoked
– Volatilization occurs at the mp
1. Cocaine HCl - 195oC
2. Cocaine - 98oC
– If drug is smoked
1. Salt
• Some has decomposed at the higher temperature and is not available
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Free base
1. Much less decomposition at lower temperature, thus much more available
– Cocaine is smoked
1. Absorbed via pulmonary capillaries
2. Travels from lungs to left side of heart
3. TRAVELS DIRECTLY TO BRAIN
4. EFFECTS PERCEPTIBLE IN 7-10 SECONDS
5. RAPIDITY AND INTENSITY OF EUPHORIA ARE POWERFUL
“Crack” Cocaine
– A solution of cocaine HCl is treated with alkaline water (sodium bicarbonate, household ammonia
[ammonium hydroxide]) to precipitate the free amine, cocaine ->-> SMOKED
1. “Crack” or “Rock” Cocaine
2. Pieces may be heated and will “crackle”
3. “Base”, “Bazooko”, “Hubba”, “Pasta”, “Petillos”
Cocaine “Snorting”
– Intranasal ingestion
1. Powder arranged in lines that are 3-5 cm. In length on a flat surface, frequently glass
2. Line is inhaled through the nose via a straw or rolled paper
3. “Runs” or “Sprees” , may occur (just as with the amphetamines)
Cocaine Euphoria
– Euphoric effects dissipate more rapidly after repeated intranasal or IV use
1. Possible tolerance is suspected
– A cocaine abuser trying to maintain euphoria will take the drug repeatedly q30-40 min.
– MONKEYS CONSISTENTLY TREATED WITH COCAINE WILL ALWAYS CHOOSE COCAINE OVER FOOD, FOR
UP TO 8 DAYS
– This euphria is due to COCAINE POTENTIATION OF CNS CATECHOLAMINE (DOPAMINE) actions
Cocaine Toxic Syndrome
– Hallucinations
1. Visual
• Vivid
• Cocaine “bugs”
2. Auditory
3. Tactile
• Cocaine “bugs”
– Skin
1. Intense pruritus
2. Picking and excoriation
• Cocaine “bugs”
– Nasal stuffiness, with tender and bleeding mucosa
1. Bronchodilation combined with Vasoconstriction of nasal blood vessels makes breathing
easier
2. As drug effect diminishes, nasal vessels dilate promoting nasal stuffiness and mucosal
bleeding
3. More drug is then “sniffed” which delays, but intensifies symptoms
– Corona
– Paranoia
1. Paranoid ideation in an individual with a clear sensorium
“Freebasing”/ “Crack”
– Produces very intense effects in comparison to the HCl salt
– Greatly magnifies and increases the production of
1. ACUTE PANIC STATES
2. TOXIC PSYCHOSIS
3. PARANOID SCHIZOPHRENIA
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COCAINE PRODUCES THE HIGHEST DEGREE OF PSYCHIC DEPENDENCE AMONG ALL RECREATIONALLY ABUSED
DRUGS
– Very likely characterized by possessing an addictive syndrome
– Termination of a long period of high dose abuse produces a profound physical and emotional
depression (withdrawal)
Addiction Factors
• Widespread availability
• Males > females (2x)
• Smoked cocaine in young women of childbearing age
• There is no one single drug that is yet available that can be reliably employed in the treatment of cocaine
addiction
Hallucinogens
Mechanism of Action
• The compounds of both of these groups have a high affinity for the serotonin 5-HT2A receptor
• Permit an individual to escape from reality while commonly being in a state of full consciousness
• The following do not occur
– Addiction (tolerance + dependence)
– Withdrawal (symptoms)
Terms
• Psychotomimetic
– A substance capable of inducing an alleged psychotic state or psychoses
– There is disagreement about this because their effects are usually not like those behavior patterns
observed during psychotic episodes
• Psychedelic
– A substance capable of inducing visual, auditory, or other hallucinations, which then produce(s)
separation of the individual from reality
– Cognitive and perceptive disturbances may be induced
• Hallucinogen = Psychedelic –=Psychotomimetic
LSD
•
Street name
– Acid
– Travel Agent
– Christmas Tree
– Instant Zen
– Swiss Purples
– California Sunshine
– Sandozes
Source/Chemistry
• Does not occur naturally
• Prepared in one of two manners
– Chemically, via semi-synthesis from (+)-lysergic acid chloride + diethylamine
– Microbially, via the growth of Claviceps paspali with the hydroxyethylamide
• White solid
• Tartrate salt commonly prepared (crystallizes well)
• Marked behavioral effects occur in EXTREMELY SMALL DOSES – 25-50 nanograms
• Street forms
– Solution
1. Sugar cubes
2. Pieces of blotter paper
3. Postage stamp-sized papers
– Solid
1. “Micro-dot” tablets that are very small and colorful
• TACHYPHYLAXIS
– Rapid production of tolerance
– Occurs on repeated use
– There is rapid recovery from tolerance and the use of a constant dose is possible if the drug is used
only once weekly
– Cross-tolerance exists with mescaline and psilocybin
• PHYSICAL DEPENDENCE
– Does NOT occur
Pharmacokinetics – p.o.
• Rapid absorption
• Wide distribution
• Crosses placenta
• Onset – 30-60 min.
• Duration – 10-12 hours
• Hepatic metabolism is predominant
– Extremely small amounts of metabolites produced
– Conventional screening tests do not detect
– Collect urine up to 30 hours post-ingestion and use RIA (radioimmunoassay)
• Major actions are on the CNS
– Affects both pyramidal (conical portion of medulla oblongata) and extrapyramidal systems
– Induces mood/behavior changes for 6-12 hrs.
• Lesser actions on the ANS
– Sympathetic - predominant
– Parasympathetic – less dominant
Signs/Symptoms of Acute Intoxication
• Mydriasis
• Hypertension
• Tachycardia
• Hyperglycemia
• Hyperthermia
• Piloerection
• Hyperactive tendon reflexes
• Euphoria
– Laughter
• Anxiety
– Sadness/crying
• Panic w/wo depersonalization
• Paranoia
• Clear sensorum
• Time distortions
• Visual distortions
• Visual hallucinations
– Colors of objects increase in intensity
– Objects undulate and flow
– Flat surfaces assume a depth
– Visual distortions “go on forever” because of time distortion
– Colored geometric patterns occur in various shapes (cones, spirals, cobwebs, honeycombs) & are
iridescent with kaleidoscopic motion
• Disruption of ego-function
• Fear of self-destruction
• Body parts feel “unnatural” or “foreign”
“The Trip” or “Tripping”
• Commonest form of abuse
• Abuser uses the drug to
– “Intensify” the environment
– Have a “novel” experience
• “Bad Trips” or “Bum Trips”
– Post large-dose ingestion
– First-time user’s lack of experience – perceive bad effects
– Three well-established groups of adverse effects occur
1. Acute panic reactions
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Rarely produce major complications
“My body and the chair are one”
Continued reassurance by another is necessary
• Repetition of the users name and surroundings
• “Patient hypersuggestability”
2. Hallucinogen Persisting Perception Disorder (HPPD)
• Not predictable
• 1 in 20 users
• Previous “bad trippers” are at slightly increased risk but first-time users may be
affected
• Suicide is possible
• Symptoms
• Color flashes
• Geometric pseudohallucinations
• False fleeting perceptions in visual fields
• Positive afterimages
• visual disturbances remain as a permanent alteration of visual acuity in about 50% of
all patients
• Treatment
• Diazepam (Valium®) – p.r.n. but usually 20 mg once
• Phenothiazines – Not used; exacerbate symptoms
• Triggers to these recurrences or “flashbacks”
• Marihuana
• Antihistamines
• Fatigue
• Neuroleptics
• Anxiety states
• Entrance into a dark area
3. Prolonged psychoses
• States of paranoia and schizophrenia may occur long after the general state of
intoxication has passed
Other Plant Sources of Hallucinogenic Ergot Alkaloids
• (+)-Lysergic Acid Amide
• Ololiuqui seeds
– Turbina corymbosa (Fam. Convovulaceae)
– Ancient Aztec hallucinogen
– Used by Mexican Indians as a “Sacred” Morning Glory
• Tlitliltzin seeds
– Ipomoea violacea (Fam. Convolvulaceae) and other Ipomoea sp.
Psilocybin
Indoleamine Hallucinogens
• At least 5 genera of mushrooms (fruiting bodies [carpophores]) of fungi
– Psilocybe mexicana (Fam. Agaricaceae)
• “Sacred” mushrooms of Mexico
• 4-Hydroxydimethyltryptamine phosphate ester
• Ingestion results in hydrolysis of the phosphate ester -> psilocin
Actions of Psilocybin
• Very similar to LSD
– Mydriasis
– Blurred vision
– Limpness
– Dizziness
– Difficulty in concentration
– Hilarity
– Auditory hallucinations
– Visual hallucinations
1. Lifelike
2. Pleasant
3. Brightly colored patterns
4. Sharply defined objects
5. Constant motion
– Visual hallucinations are followed by
1. Lassitude
2. Mental depression
3. Physical depression
4. Alteration of time and space perception
– The “dream-like state” becomes “reality”, resulting in great indifference to the surroundings
– Pleasant “reawakening” to reality with a lack of tiredness or “hangover”
• Duration of action
– About 3 hours
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N,N-Dimethyltryptamine
Indoleamine Hallucinogens
• Occurs in the leaves of a plant of the Amazon
– Prestonia amazonica (Benth.) Macbride (Fam. Apocynaceae)
• Actions are very similar to psilocybin
Mescaline
Phenethylamine Hallucinogens
Source/Chemistry
• Lophophora williamsii (Lemaire) Coulter (Fam. Cactaceae)
• Small cactus
– Fleshy and spineless
– Rounded gray-green tips
– Tufts of white hair
– Long carrot-like root
• Habitat – Northern Mexico and Southwestern United States
• Hallucinogenic effects due to mescaline
– 3,4,5-Trimethoxy--phenethylamine
Actions of Mescaline
• One or more buttons (up to 30) may be ingested
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At an oral dose of 5 mg/kg, the hallucinogenic and sensory effects are very similar to those of psilocybin
Mydriasis
Tachycardia
Hypertension
Depressed deep tendon reflexes
Hallucinations of “feeling”
Visual hallucinations
– Bright, colored lights
– Geometric designs
– Animals
– People
• Auditory hallucinations
– Actions of Mescaline
• The period of intoxication may be divided into two periods
– One of extrasensitivity and contentment
– One of artificial calm and muscular sluggishness during which time the individual pays less attention
to the immediate environment and increases introspective mediation
Pharmacokinetics (p.o.)
• Rapid and almost complete absorption
• Effects from a single dose last about 12 hours
• t1/2 = 6 hours
• Peak plasma levels = 2 hours post-ingestion
• Renal excretion
– 60-90% unchanged
• The oral dose is very high
– Frequently 500 mg of sulfate salt
– Extremely facile metabolism via MAO
• There have been no known fatalities, even from massive overdosage
Amphetamines
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Synthetic phenethylamines
– All the drugs of this group generally exhibit
1. LSD-like actions at lower dosage
2. Adrenergic agonism at higher dosage
– “raves” or “rave drugs” or “club drugs”
– Both drugs promote increased
1. Socialization
2. Empathy
3. Self-esteem and elation
4. Feelings of closeness to others
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Indirect-acting sympathomimetic drugs that promote the release of endogenous bioamines, including
dopamine (DA) & norepinephrine (NE)
Produce their effects by reversing the action of biogenic amine transporters at the plasma membrane –
preventing uptake
– Amphetamines - Background
Referred to as “club drugs”
Differ from Ecstasy (MDMA) in their mode of use, with the following being more common with amphetamines
– IV injection
– Hard core addiction, particularly with methamphetamine
use correlates with elevated levels of
– Catecholamines (norepinephrine, dopamine)
– Serotonin
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• Initial use is usually oral, then proceeds to injection or inhalation (smoking)
Symptoms (within hours)
• Euphoria
• Agitation
• Confusion
• Bruxism (teeth grinding)
• Higher dosage
– Tachycardia and dysrhythmias
– Vasoconstriction
– Hypertensive crises – stroke/death
MDA
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3,4-Methylenedioxyamphetamine
The synthetic prototype of the group
Street Names
– Adam
– Hug Drug
– Love Drug
– MDA
– Mellow Drug of America
• Popular hallucinogen producing auditory and visual effects after oral ingestion or inhalation
• Produces an overwhelming desire to be/talk with others – “Love Drug”/”Hug Drug” – strong empathy
• Mild visual hallucinations with actions perceived within 30 min; peaking at 90 min; lasting 8-12h
Adrenergic/CNS effects
• Tachycardia
• Tachypnea
• Hypertension
• Xerostomia
• Mydriasis
• Hyperthermia
• Seizures
MDMA, XTC
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3,4-Methylenedioxymethamphetamine
Originally patented as an anorexiant in 1914 (Merck) but not marketed
>50 different street names, with “Ecstasy” being widely recognized
Popular on college campuses during the decade of the 80’s
– “Enhance insight and self-knowledge”
Like methamphetamine, MDMA causes the release of biogenic amines via reversing the action of their
respective transporters
– Serotonin transporter (SERT) - STRONG REVERSAL
– Dopamine transporters (DAT) - REVERSAL
– Norepinephrine transporters (NET) - REVERSAL
Effect on dopaminergic neurons is to
– Block dopamine uptake
– Produce synaptic depletion
1. Single dose produces marked serotonin depletion for 24h
2. Repeated dosage may lead to permanent serotonin depletion
Net effect - Strong increase the extracellular concentrations of these biogenic amines, particularly serotonin
Administration is usually oral but the drug may also be smoked, snorted or injected (IV)
Effects persist for 2-8h
– Decrease inhibition
– Promote elation and euphoria
– Mild hallucinogen
– Lacks production of anxiety, dissociation or perceptual distortion
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Acute toxicity
– Hyperthermia with dehydration (may be fatal)
1. Attempts to drink excessive amounts of water have led to hyponatremia, seizures, death
– Serotonin syndrome
1. Altered mental status (visual hallucinations, panic, anxiety, depression, paranoia)
2. Hyperactivity of ANS (adrenergic stimulation)
3. Neuromuscular abnormalities
4. Seizures/death
MDMA has been unequivocally demonstrated to destroy serotonin-producing neurons in animals
Strong evidence in humans of permanent brain serotonin neuron neurotoxicity with resultant
– Performance deficits
– Memory problems
– Semantic recognition/verbal reasoning