Cocaine %26 stimulants, Pharmacology - 2010

8/8/2019 Cocaine %26 stimulants, Pharmacology - 2010

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Substance abuse:

Cocaine & stimulant abuse

Pharmacology

Vardan T. Karamyan, Pharm.D, Ph.D.Assistant Professor

Office #: 408

[email protected]


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Learning objectives

Classify the stinulants of abuse

Describe main pharmacodynamic and pharmacokinetic

profiles of cocaine & other stinulants of abuse

Explain main adverse side effects of these drugs


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Classification:

Stimulants of abuse

Class Examples Mechanism of action

Behavioral

stimulants

Cocaine

Amphetamines

Methylphenidate (Ritalin)

Pemoline (Cylert)Phenmetrazine (Preludin)

Increased levels of NE & DA

Antidepressants Imipramine &

Amitriptyline

Tranylcypromine

Blockade of NE/5-HT reuptake

Inhibition of MAOLegal recreational

drugs

Caffeine

Nicotine

Blockade of adenosine

receptors

Stimulation of ACh receptors


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Stimulants:general features

- Psychostimulant effects:

elevated mood/euphoria increased energy

reduced fatigue decreased appetite

improved task performance increased motor activity

- are subject to compulsive abuse

- have limited therapeutic use, significant seide effects & toxicity

high doses: intense irritability, anxiety &psychotic behavior

low doses: alter arousing response to an emergency or to stress


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Cocaine:

introduction

Some quick facts:

- Peru & Bolivia: social use of leaves as religious, mysticaland medicinal stimulant

- 1859: active alkaloid was isolated & named cocaine

- 1884-1903: was widely utilized as a useful drug: Freud advocated its use in depression & chronic fatigue

Koller demonstrated its local anesthetic properties

was used (with caffeine) in Coca-Cola (~60 mgs/8 ounce)

Erythroxylon coca

www.infoplease.com


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Cocaine:

introduction (continued)

- 1891: about 200 reports of cocaine intoxication & 13 deaths

- 1914: Harrison Narcotic Act banned cocaine in medicinesand beverages

- since then many reports, regulations, campaigns

- 20-30 million in U.S. have used cocaine; ~ 4 million peopleuse it regularly

- ~ 300,000 people use it on dailybases, & the number ofusers was ~stable in the last 2-3 decades

- cocaine addicts: typically young (12 to 39 yrs), poly drug-dependent and male (75%)


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Cocaine: introduction (continued)

8th Grade 10th Grade 12th Grade

2007 2008 2007 2008 2007 2008

Past month 0.9% 0.8% 1.3% 1.2% 2.0% 1.9%

Past year 2.0 1.8 3.4 3.0 5.2 4.4

Lifetime 3.1 3.0 5.3 4.5 7.8 7.2

Percent of students reporting cocaine use, 2007-2008

8th

Grade

10th

Grade

12th

Grade

Try crack once/twice 47.1% 56.5% 47.5%

Take crack occasionally 67.9 76.5 65.2

Try powder cocaine once/twice 42.7 49.8 45.1

Take powder cocaine

occasionally 62.7 71.1 61.6

Percent of students reporting risk of using cocaine, 2008

www.whitehousedrugpolicy.gov


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Cocaine: chemistry/physicochemical properties

extracted as coca paste (60-80% cocaine), each leaf

contains 0.5-1.0% cocaine

coca paste is converted to hydrochloride salt before

exportation and sale hydrochloride (crystal or snow): inhaled ~10-25

mg into each nostril

hydrochloride salt is not suitable for smoking

decomposes at high temperature

when extracted in ether free base form (cocaine base

or crack, makes cracking sound when heated)


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Cocaine: routs of administration

Oral(chewing):

- absorption >1hr - ~75% metabolized in liver (1stpass)

- ~25% reaches brain - no feeling of rush

Intranasal(snorting):

- poorly absorbed (HCl salt & vasoconstriction)

- peak levels in 30-60min

Inhalation (smoking or free-basing):

- rapid absorption in lungs (up to 30% if initial dose reaches plasma)- onset of effects in seconds; lasts 5-10min

Intravenous (mainlining):

- 30-60 second delay in onset of action, lasts 5-10min


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Cocaine: some pharmacokinetic facts (continued)

easily passes blood-brain barrier; brain concentrations > plasma

easily crosses placental barrier; ~ equal levels in fetus & mother

half-life of 30-90 min

is ~completely metabolized by liver enzymes:

major metabolite: benzoylecgonine (inactive; detected in urine

for ~3 days, and much longer (15-22 days) in chronic users)

small amounts: norcocaine (active intermediate)


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SUBSTANCEDETECTION PERIOD

in trace amounts

DETECTION PERIOD

resulting in positive test

Cocaine

Benzoylecgonine 2-4 days 2-4 days

Chronic Use up to 3 weeks up to 3 weeks

Amphetamines

Amphetamine 2-5 days 1-3 days

Methamphetamine 2-5 days 1-3 days

Cannabis (THC)

Casual Use 2-7 days 1-5 days

Chronic Use up to one month up to six weeks

Phencyclidine (PCP)Casual Use 2-7 days 2-7 days

Chronic Use up to 30 days up to 14 days

Opiates

Codeine 2-5 days 1-3 days

Morphine 2-4 days 1-2 days

Urinary Detection Times http://www.cocaine.org/cokestrut.html


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Cocaine:pharmacodynamics/mechanism of action

Three main effects:

local anesthetic (structuralbasis for design oflocalanesthetics)

blood vessels constrictor

psychostimulant (with strong reinforcing qualities)

Blocks reuptake ofDA,NE & 5-HT (transporters on the presynaptic

terminal)

- increased levels of DA in the reward pathway (ventral tegmental

area &N. accumbens):psychostimulant effects

behavior-reinforcing properties

Serotonin depletion increases efficacy of cocaine as a positive

reinforcer!


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Major psychological changes: mood (giddiness, enhancedself-consciousness) enhanced cognition

enhanced drive states (hunger,sex, thirst) talkative with tangential incoherent speech

suppressed appetite with later rebound

delayed sleep, increased motor activity & restlessness

Other physiological responses:

tachycardia, vasoconstriction & hypertension

broncho & pupillary dilatation

increased body temperature & plasma glucose levels

Delayed effects:

60-90min after administration: mild euphoria with anxiety,followed by long-lasting anxiety (reason for craving more)

high doses: loss of coordination, tremors and seizures

Cocaine effects: short-term, low-dose use:


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Toxic symptoms:anxiety sleep deprivation hyper-vigilance

High dose, long term use:

dysphoria sexual dysfunction

suspiciousness paranoia (paranoidpsychosis)

interpersonal conflicts severe depressive conditions

schizophrenic syndromes affective/personality disorders

Cardiovascular & neurovascular:

strokes brain & heart hypoperfusion (O2 deprivation)

seizures cardiac arrhythmias

Fetal effects (fetal cocaine syndrome, crack babies)

- difficulty with unstructured play & low tolerance for frustration

- cognitive problems, high incidence of ADHD

Cocaine effects: toxic (acute & long term)


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Methamphetamine Fenfluramine Methylphenidate Pemoline

Amphetamine & related drugs

ME: synthesized in 1888, but not used for med. purposes until 1930s

some types of Acacia trees do contain ME (methamphetamine)!

in 1935 to treat narcolepsy, 1935-1946: was indicated for 39

conditions: schizophrenia morphine addiction

tobacco smoking heart block

radiationsickness hypotension

severe hiccups caffeine dependence, etc.

in W.War II: to fight fatigue & enhance performance

starting from 1940s: large scale abuse (oraladministration)

from 1960s injectable forms became available

cocaine-likestimulant effects


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Increase the activity/levels ofmonoamines the synaptic cleft:

inhibit reuptake of NE & DA

facilitate release of monoamines from vesicles

interact with vesicular monoamine transporter decreased

accumulation & increased release of monoamines inhibits MAO (at high doses & mainly the B subtype)

may directly interact with catecholamine receptors

DA levels increase >10 fold

DA is partly degraded into reactive O2 species oxidative

stress neurotoxicity!

Neurotoxic effects are more pronounced at high ambient

temperature (increased levels of NE & DA in hypothalamus)

Amphetamines: mechanism of action


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behavioral & psychomotor stimulation: DA receptors in

mesolimbic system (including N. Accumbens):

increased alertness euphoria excitement

reduced fatigue mood elevation

potent appetite suppressant effect (tolerance develops

rapidly); involves lateral hypothalamus

in adults: aggressive behavior

in children: inhibition of aggressive & ADHD behavior

BP followed by reflector bradycardia (& bronchodilation)

Amphetamines:main CNS effects (low dose)


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Moderate doses: (20-50 mgs)

stimulation of respiration

greater increase in motor activity & agitation

insomnia (recovery takes weeks)

suppressed appetite

High dose: (>50 mgs)

stereotypical behaviors (continuous repetitive acts)

aggression & paranoid delusions severe anorexia

amphetamine psychosis (acute schizophrenic attack)

Amphetamines:main CNS effects


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Upon chronic use (mainly from animalstudies) severe depletion of DA

depletion oftyrosine hvdroxylase

hugely decreased/lost sensitivity to DA (less receptors)

loss of responsiveness to natural reinforcers

Tolerance:

wide interpersonal variation

highly depends on the dose, frequency & duration of use

short term is reasoned by DA depletion; long term plus

downregulation of DA receptors and Try-hydroxylase

usually develops rapidly, is accompanied by dysphoria,

sedation, lassitude

Amphetamines: chronic use & tolerence


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Methamphetamine

rapid absorption into plasma, gradual decline for ~4hr, then

progressive decline

half life: 9-15hr

relatively slow metabolism in liver (some part remainsunchanged)

main metabolites are amphetamine, 4-hydroxyamphetamine,

and 4-hydroxymethamphetamine

Withdrawal:

excessive sleeping depression & anxiety

overeating drug-craving

Amphetamines:pharmacokinetics & withdrawal


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Medical use is restricted & controversial:

1. narcolepsy (chronic sleep disorder; nowadays the use is rare)

2. ADHD (attention deficit hyperactivity disorder)

3. obesity

Amphetamines:Therapeutic uses and status


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most widely used psychoactive substance

80-90% of Americans consume caffeine

caffeine is present in:

chocolate, coffee, tea, sodas

stimulants (No-doz), diet pills (Dexatrim)

analgesics (Anacin, Excedrin, BC powder) cold and sinus preparations (Dristan, Contac)

Caffeine

Substance Serving Caffeine range Caffeine typical

Coffee (drip) 6 oz. 77-150 mg 100 mg

Espresso 1 oz. 30-50 mg 40 mg

Tea 6 oz. 30-90 mg 40 mg

Soda 12 oz. 22-71 mg 40 mg

Analgesics 2 tabs 64-130 mg 80 mg


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perhaps the #1 is energy drinks (50-505 mg per bottle/can)!

in 2006 17% increase in consumption worldwide (~906million

gallons in total)

modern era started with RedBull (1987 in Austria, 1997 in the

US)

in 2006 ~500new brands worldwide & ~200 in the US

Caffeine abuse?

From retailers with >2mln in annual

sales (Reissig C. Et al. 2009)


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According to FDA OTC stimulants must have the following

warnings (e.g.,NoDoz /100mg caffeineper tablet/):

The recommended dose of this product contains about as much

caffeine as a cup of coffee. Limit the use of caffeine containing

medications, foods, or beverages while taking this product because

too much caffeine may cause nervousness, irritability,sleeplessness, and, occasionally, rapid heart beat.

For occasional use only. Not intended for use as a substitute for

sleep. If fatigue or drowsiness persists or continues to recur, consult

a (select one of the following: physician or doctor).

Do not give to children under 12 years of age. Directions: Adults and children 12 years of age and over: oral

dosage is 100200 mg not more often than every 34 h.

500mg energy drink has no warnings or info on caffeine dose!

Caffeine abuse? (cont.)


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Energy drinks + alcohol

Caffeine abuse? (cont.)

Cumbow V, The Huntsville Times

Energy drinks linked to alcohol problems

By Amanda Gardner, Health.comNovember 16, 2010 4:36 p.m. EST

http://www.cnn.com/2010/HEALTH/11/17/alcohol.caffeine.drinks/index.html

FDA calls 7 caffeine-alcohol drinks unsafeBy the CNNWire Staff

November 17, 2010 9:14 p.m. EST


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Caffeine:pharmacokinetic facts

is well absorbed after ingestion; reaches ~99% within ~45min

up to 4-fold interindividual variations in plasma concentrations

low-moderate binding to plasma proteins

well penetrates into brain (also reaches the fetus) and is

distributed in tissues with high blood perfusion half-life is: 2.5-4.5hr in young and elderly humans

~15hr in 3-5 months old infants

~80hr in newborn infants (fullterm)

>100hr in premature infantsin smokers: 30-50% reduction (inducedCYP-450 1A2!)

in women taking oral contraceptives: ~2-fold increase

in women at the last trimester of pregnancy: up to 15hr!


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Caffeine:pharmacokinetic facts (continued)

it is possible that in the brain more theophylline is generated

theophylline is 3-5 times more potent antagonist of Adenosine

receptors

CYP-450 1A2


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Caffeine:physiological & psychological effects

Among peripheral effects are:bronchodilation increased gastric acid secretion

diuresis increased BP & decreased heart rate

AmongCNS effects are (regular doses):

increased: alertness cognitive performance

reaction time auditory vigilance

Symptoms of intoxication (>250 mg of caffeine):

restlessness nervousness rambling speechexcitement anxiety muscle twitching

flushed face diuresis tachycardia/arrhythmia

GI disturbances insomnia psychomotor agitation

inexhaustibility low seizure threshold


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Caffeine: targets & mechanism(s) of action

- at regular concentrations (25mg/kg in rodents) also:

inhibits phosphodiesterases (PDE3) more cAMP

increases iCa2+ levels (affects uptake & storage)


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Adenosine and its specific receptors


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Caffeine: mechanism of action

Mobbs, 2005

Early pharmacologicalstudies

Recent genetic studies

A1 receptors

abundant in the brain

release of neurotransmitters

(K+,Ca2+ & cAMP) decreased neuronal firing

A2a receptors

DA rich regions in the brain

GABA release affinity of DA for receptors

Caffeine blocks both A1 andA2a receptors !


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Caffeine: mechanism of action (continued)

At (very) high doses caffeine inhibits phosphodiesterase (PDE):

At (very) high doses caffeine interferes with the uptake & storage

of intracellular Ca2+ in striated muscles increased strength &

duration of contractions in skeletal & cardiac muscles.

Inhibited PDE cAMP Gs effects

PDE inactivates cAMP Gs effects


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Caffeine: withdrawal

have been described in medical literature for >100 years is recognized as an official diagnosis in ICD-10

(InternationalClassification of Diseases, revision 10

/WHO, 1992/) and a research diagnosis inDSM-IV-TR

(Diagnostic and StatisticalManualof MentalDisorders,FourthEdition, Text Revision, 2000)

symptoms:

headache (12-24h after the last dose), in ~50% of patients

tiredness/fatigue sleepiness/drowsiness

dysphoric mood inability to concentrate

depression irritability

nausea/vomiting muscle aches/stiffness


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Caffeine: tolerance & self-administration?!

Tolerance is developed to some (notall) effects of caffeine:

- BP elevations in blood pressure and decreases in heart rate (is

lostaftera briefperiod of caffeine abstinence)

- non-users report tension-anxiety, jitteriness,

nervousness, increased energy after acute caffeine exposure

regular consumers do not report these effects

Self-administration: is it for the positive, mood elevating effectsor to remove the negative effects (headache, fatigue), or to

avoid withdrawal symptoms?!


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Caffeine: addictive?!

DSM-IV does not classify substances as addictive, but sets forth

criteria for substance dependence:

1) tolerance

2) substance-specific withdrawal syndrome

3) substance often taken in larger amounts or over a longer period

than expected

4)persistent desire or unsuccessful efforts to cut down or control use

5) a great deal of time spent in activities necessary to obtain, use, or

recover from the effects of the substance

6) important social, occupational, or recreational activities given upor reduced because of the substance

7) use continued despite knowledge of a persistent or recurrent

physical or psychological problem likely to have been caused or

exacerbated by the substance

Documents

Cocaine %26 stimulants, Pharmacology - 2010