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Pharmacology of “NAPZA”
Prof.Aznan Lelo,dr.PhD,SpFK,&
Dr.Datten Bangun MSc,SpFK
Dept.Farmakologi & Terapeutik Zfak.Kedokteran USU
M E D AN
Istilah:
• NAPZA: N Arkotik P sikotropik Z at A ddiktif
. Narkoba: Narkotik dan Bahan addiktif
PSYCHOTROPIC DRUGS:
natural or synthetic drugs
======induce dependenceinduce dependence
induce stimulation, depression or hallucination in the CNS
disturb the motor functions/cognitive functions
induce perceptual distortion
increase introspection
induce changes in mood
which
DEPENDENCE
physical abstinence syndrome - withdrawal of drug, administration of antagonists induces characteristic withdrawal symptoms
psychic - craving - drug seeking behavior, use of drug repetitively for personal satisfaction/
pleasure
DIAGNOSTIC
CRITERIAFROM
DSM-IVTM
AMERICAN PSYCHIATRIC ASSOCIATION DIAGNOSTIC CRITERIA FOR PSYCHOACTIVE
SUBSTANCE DEPENDENCE (DSM-IV.)
A. At least three of the followings:A. At least three of the followings:
1. 1. Substance often taken in Substance often taken in larger amountslarger amounts or or
over a over a longer periodlonger period than the than the person person intended.intended.
2. 2. Persistent desire or one or more Persistent desire or one or more unsuccessful unsuccessful effortsefforts to to cut downcut down or control substance or control substance abuse.abuse.
3. A 3. A great deal of time spentgreat deal of time spent in activities in activities necessary to get the substance (e.g., theft), necessary to get the substance (e.g., theft), taking the substance (e.g., chain smoking), or taking the substance (e.g., chain smoking), or recovering from its effectsrecovering from its effects..
DIAGNOSTIC CRITERIA FOR PSYCHOACTIVE SUBSTANCE DEPENDENCE DSM-IV. (CONT.)
44. . Frequent intoxication or withdrawal Frequent intoxication or withdrawal symptomssymptoms when expected to fulfillwhen expected to fulfill major role major role obligations at work, school, or home (e.g., does obligations at work, school, or home (e.g., does not go to work because hung over, goes to not go to work because hung over, goes to school or work „high,” intoxication while taking school or work „high,” intoxication while taking care of his or her children), or when substance care of his or her children), or when substance use is physically hazardous (e.g., drives when use is physically hazardous (e.g., drives when intoxicated).intoxicated).
5. 5. Important social, occupational, or recreational Important social, occupational, or recreational
activities given upactivities given up or reduced because of or reduced because of substance abusesubstance abuse,-------,------- lih.kuliah Psikiatri lih.kuliah Psikiatri
Common Definitions of Key Terms
• addiction: to use compulsively or uncontrollably; to enslave
• abuse: to use wrongly or improperly
• habit: a constant, often unconscious, inclination to perform some act, acquired through its frequent repetition
• addiction liability/potential: the tendency to develop/produce an addiction
ABUSE POTENTIAL
It depends on the properties of the drug and on pattern of use
(route, frequency, dose, etc)
The strength of a drug’s ability to induce „run”, rush” „ well being”.
Common Definitionsof Key Terms (cont.)
• dependence: state of being determined, influenced, or controlled by something else; subordination to someone or something needed or greatly desired; required for normal physiological or psychological function– physical/physiological– psychological/psychic
AMERICAN RED CROSS FIRST AID–RESPONDING TO EMERGENCIES FOURTH EDITIONCopyright © 2005 by The American National Red CrossAll rights reserved.
Misused and Abused Substances
• Substances are categorized according to their effects on the body.
• Commonly misused and abused substances are— Stimulants. Depressants. Hallucinogens. Narcotics. Inhalants. Cannabis products. Designer drugs. Steroids.
AMERICAN RED CROSS FIRST AID–RESPONDING TO EMERGENCIES FOURTH EDITIONCopyright © 2005 by The American National Red CrossAll rights reserved.
Specific Signs of Substance Misuse and Abuse• Signs of stimulant abuse—
• Respiratory distress, disruption of normal heart rhythm and even death can result from using a stimulant.
Very excited. Restless. Talkative. Irritable. Unconscious.
• Signs of depressant abuse— Drowsiness. Confusion. Slurred speech. Slow heart and breathing rates. Poor coordination.
Specific Signs of Substance Misuse and Abuse
• Signs of hallucinogen abuse— Sudden mood changes. Flushed face. Seeing or hearing something that is not present. Anxiousness or being frightened
DRUGS of ABUSE
TYPE DEPENDENCE POTENTIAL
1. Opioids very strong
2. Depressantsbarbiturates, ethanol, strong benzodiazepines medium
3. Stimulantscocaine very strongamphetamines strong
4. Other stimulantscaffeine weaknicotine very strong
DRUGS of ABUSE (cont)
5. Cannanbinoidscannabis weak or
6. Hallucinogens (psychedelics, psychotomimetics)
LSD, mescaline, weak or cyclidines (phencyclidine, PCP) medium
7. Inhalantsindustrial solvents stronganesthetics medium
Psychic PhysicalTolerance
Drug Dependence
Morphine & Derivatives +++ ++++++
Barbiturate-like ++ ++++
Alcohol ++ +++++
Amphetamine-like ++ (+)++
Cocaine +++ (+)(+)
Smoking (nicotine) ++ (+)(+)
LSD-mescalin + (++)
Cannabis (Marijuana) + (+)
WHO SCHEDULE OF CONTROLLED WHO SCHEDULE OF CONTROLLED SUBSTANCESSUBSTANCESSchedule Criterla Examples* I No medical use; high hallucinogens, marihuana, heroin
addiction potential
II Medical use; high morphine, most other opioid analgesics, cocaine,
amphetamines, sedatives such as
pentobarbital sodium
III Medical use; moderate codeine in combination, paregoric,
potential for dependence.glutethimide, sodium butabarbital
IV Medical use; low abuse phenobarbital, chloral hydrate
potential. benzodiazepines, other sedatives
*List not complete.
DESENSITISATION orTACHYPHYLAXIS (minutes)
REPEATED or CONTINUOUS DRIG ADMINISTRATION
may induce
TOLERANCE(days-weeks)
EXPLANATION
change in number of receptor
deficit of mediators
pharmacokinetics
adaptative processes
SENSITISATION
Therapy of drug abuse
DetoxificationDetoxification
RehabilitationRehabilitation
ResocialisationResocialisation
Steps
Aim of pharmacotherapyAim of pharmacotherapy– – reliefrelief of withdrawal of withdrawal– prevention of relapse – prevention of relapse
Prevention of relapsePrevention of relapse
The Major Classes of Controlled Substances
• Depressants – induces sleep, relaxation• Narcotics – relieves pain, induces stupor• Stimulants – relieves fatigue, enhances
alertness• Hallucinogens – alters sensory perception• Toxicants / Inhalants – CNS depression• Steroids – enhances physical performance
Since there are hundreds of examples, and we have limited time, I will review only a few of each
Most drugs of abuse “mimic”
Most psychoactive drugs of abuse look “similar” to neurotransmitters. These drugs mimic the action and appearance of neurotransitters. THC – Anandamide
Opiates – Endorphin Enkephalin
Alcohol, Benzo’s, Barb’s – GABA
Stimulants - catecholamines
Drugs of Abuse are “Dopaminergic”
Or, in other words, they increase dopamine activity.
EXAMPLE:
THC connects with receptors and causes the release of dopamine
00
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Source: Di Chiara et al.Source: Di Chiara et al.
FOODFOOD
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11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717
ScrScrScrScrBasBasFemale 1 PresentFemale 1 Present
ScrScrFemale 2 PresentFemale 2 Present
ScrScr
Source: Fiorino and PhillipsSource: Fiorino and Phillips
SEXSEX
Natural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine Levels
00100100200200300300400400500500600600700700800800900900
1000100011001100
00 11 22 33 44 5 hr5 hr
Time After AmphetamineTime After Amphetamine
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DADADOPACDOPACHVAHVA
AccumbensAccumbens AMPHETAMINEAMPHETAMINE
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AccumbensAccumbensCOCAINECOCAINE
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% o
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AccumbensAccumbens
0.50.51.01.02.52.51010
Dose (mg/kg)Dose (mg/kg)
MORPHINEMORPHINE
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00 11 22 3 hr3 hrTime After NicotineTime After Nicotine
% o
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AccumbensAccumbensCaudateCaudate
NICOTINENICOTINE
Source: Di Chiara and ImperatoSource: Di Chiara and Imperato
Effects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine Levels
The Narcotics
• From the Greek narcos – to sleep, stupor.
• Term is often misused.
• Several sub-groups of narcotics:
– Natural origin– Semi-synthetic– Synthetic
Nature’s Own Narcotics
• It all starts with the opium poppy (Papaver somniferum), which has been around for over 7000 years. Narcotics of natural origin found in the poppy:
– Opium (oldest form used)– Morphine (most prevalent alkaloid)– Codeine (most widely used in the world)– Thebaine (primarily used to produce
oxycodone and similar derivatives)
Semi-synthetics
• Heroin – Developed in 1874 … as a curative
for morphine addiction– Harrison Narcotics Act – Its action– Usually cut– From 1% to 70%– Legal in some countries
More Semi-synthetics
• Dilaudid - marketed in tablets (2, 4, and 8 mg), suppositories, oral solutions, and injectable formulations– analgesic potency two to eight times that
of morphine, but it is shorter acting and produces more sedation than morphine
• Oxycodone (Oxycotin) derivative of thebaine
• Hydrocodone – (Lortab, Vicodin) – equivalent to morphine in potency
Synthetic Narcotics
• Meperidine (demerol)• Darvon• Fentanyl• Methadone• Analogues – keeping ahead of the
authorities (e.g. -been over 15 for Fentanyl)
Depressants
• Alcohol (C2H5OH) – the most widely used of all
• Barbiturates (short to long acting) – Seconal, Nembutal, Tuinal .. And many more.
• Benzodiazepines – a million of them (Valium, Librium, Xanax) for anxiety, insomnia, anticonvulsants.
• Rohypnol (roofies) – date rape drug• GHB – gamma hydroxybutyric acid• Chloral Hydrate
Depressant Data:
• Action sought: sedation, anxiety and stress relief, convulsion control.
• Dependence risk: both physical and psychological
• Dangers / side effects: nausea, respiratory / cardiac arrest, impaired physical performance, death from overdose.
• Prevalence of use: est 150 million users of alcohol, plus 15 million abusers of legal Rx drugs. 15 million alcoholics.
The Stimulants
• Caffeine – most widely used in the world
• Nicotine – 2nd most widely used• Coffee and a cigarette
combination?• Cocaine• Amphetamines• Methcathinone• Methylphenidate
Stimulant Data:
• Action sought: excitation, perceived energy boost, extended wakefulness, some mild hallucination, relief of fatigue and minor anesthesia
• Dependence risk: both physical and psychological
• Dangers / side effects: paranoia, loss of sleep, cardiac arrest, dizziness, tremor, headache, flushed skin, chest pain with palpitations, excessive sweating, vomiting, abdominal cramps, agitation, hostility, panic, aggression, and suicidal or homicidal tendencies.
• Prevalence of use: estimated 2 million cocaine and amphetamine users in the US
Cocaine
• The most potent stimulant of natural origin
• Extracted from the coca plant • Chew, brew, snort, inject• Isolated in 1880’s for its local
anesthetic quality• Cocaine hydrochloride• Free-base• Crack• A highly seductive drug• High usually followed by
dysphoric crash• 2nd most used after marijuana
in the US. (5/80 ratio)
Cocaine and Neurotransmission
• Primary effect on DA & NE with some 5HT influence– Block reuptake– Inhibit MAO
Amphetamines• First used in the 1930’s
as anti-fatigue, hunger suppression, antidepressant – (benzedrine, dexedrine)
• Methamphetamine - injected or smoked.
• Aka - Ice, Crystal Meth• Most clandestine labs • Methcathinone (Cat)• Anorectic – a slew of diet
drugs (Didrex, Bontril)• Khat – saw this in India
EcstasyMethylenedioxymethamphetamine (MDMA)Methylenedioxymethamphetamine (MDMA)
XTCXTCXTCXTC Disco Disco BiscuitsDisco Disco Biscuits
Hug DrugHug DrugHug DrugHug Drug
AdamAdam XX
ClarityClarityClarityClarity
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Ecstasy use is one of the most rapidly growing phenomena in today’s drug scene.
EssenceEssenceCristalCristalCristalCristal
Truck DriverTruck DriverTruck DriverTruck Driver
Short-term effects
• Feelings of well-being and empathy• Reduced anxiety• Enhanced self-confidence• Greater acceptance of others• Increased energy• Increased desire for physical contact and
visual stimulation• Intensified awareness of senses
Ecstasy’s downside
• Increases in heart rate and blood pressure• Nausea• Loss of appetite• Jaw tightness• Compulsive chewing and teeth clenching• Anxiety, panic, and depression• Health risks increase if ecstasy is combined
with another drug
The Hallucinogens
• Sensory deprivation – enhancement – dysfunction
• All five senses can be involved• Primary types:
– Marijuana– LSD– Psilocybin– Peyote / Mescaline– A raft of others
Hallucinogen Data:
• Action sought: sensory distortion, out of body experience, mood change, relaxation,
• Dependence risk: both physical and psychological
• Dangers / side effects: paranoia, elevated heart rate, increased blood pressure, and dilated pupils. Grandiose feelings can lead to dangerous activity or decisions. Fearful experiences leading to agitation and fear of the experience being real.
• Prevalence of use: estimated 25 million users of marijuana in the US and another .5 - 1 million users of other hallucinogens
Marijuana• Cannabis sativa• 1st cultivated for
fibers (Washington)
• Cannabinoids (THC)
• Smoked, chewed, eaten
• Marinol – medical use
• Potency has skyrocketed in 30 years (1% to over 20%)
• Mostly unknown until the late 1980s – 1988 – Isolated the receptors– 1992 – Discovered the first neurotransmitter for that receptor
• THC binds to cannabinoid receptors– It’s and Agonist
• Anandamide & 2-AG are the NTs for cannabinoid receptors– Works as a retrograde NT
• It modulates the activity of many neurotransmitters– This is way it has such broad effects
Mechanism of ActionMechanism of Action
Two Receptor TypesTwo Receptor TypesCB-1 ReceptorCB-1 Receptor CB-2 ReceptorCB-2 Receptor
• Mostly in periphery
• Found primarily in immune system
• Found on heart – protects from inflammation?
oLocated in CNS and PNS
– Disinhibition – Relaxation
– Drowsiness
– Exhilaration, euphoria
– Sensory - perceptual changes
• Overestimate time passage
– STM impairment
– Balance impaired
– Decreased muscle strength
– Small tremor
– Poor on complex tasks (e.g., driving)
Low - Moderate DosesLow - Moderate Doses
• Psychotomimetic – Pseudo hallucinations
– Synesthesias
– Paranoia
– Agitation
– Disorganized thoughts
– Confusion
• Impaired executive function– Increased impulsivity
– Impaired judgment, slower RT
– Pronounced motor deficits
Higher DosesHigher Doses
Physiological effects• Increase in pulse rate & slight drop in BP• Produces dry mouth & occasional dizziness• Reddening of eyes (dilation of vessels in cornea)• No permanent adverse cardiovascular
– People with heart disease should abstain• Increased risk for heart attack four an hour after smoking
• Appetite increased– Hypothalamus– “Hedonic Hotspot” – specific area of NAC when stimulated
by cannabinoids there is an increase in the reward value of natural rewards.
Physiological EffectsPhysiological Effectsof Marijuanaof Marijuana
THC suppresses immune system, but not enough to increase risk of infection it appears.
Lowers testosterone levels & sperm count as well as estrogen
Crosses placental barrier◦ Lower birth weight◦ Some evidence suggests a relation between
mother smoking while pregnant and childhood cancer
Most severe side effects ◦ Respiratory - can lead to asthma & bronchitis◦ Anxiety/panic in some users
Side Effects of MarijuanaSide Effects of Marijuana
• Almost impossible to OD– 1-1.8 kg w/5% taken orally in a female– THC not toxic in this sense
• Pot smoke contains more tar than cigarette smoke– Does one smoke the same?– Cancer and respiratory possibilities
• Data on cancer is very mixed – recent studies show no relationship
• THC found to kill cultured hippocampal cells, but so far not in other cells high in CB receptor density– Effect reversed with NSAIDS– Possible mechanism for memory loss
THC ToxicityTHC Toxicity
• Tolerance develops with heavy long-term use• Reverse tolerance in consistent users
• Cross tolerance with sedatives - alcohol• Dependence – mild (like SSRIs)
– Mild withdrawal symptoms in humans, with irritability, depression, sleep disturbances, nausea, diarrhea, sweating, tremors, reduced food intake, and salivation
• 50% of heavy users may experience it• 30 mg THC / 4 hrs / 10-20 days (unusual levels of
intake)• Begin within 48 hours after cessation and lasts
2 – 10 days
THC – Tolerance & DependenceTHC – Tolerance & Dependence
• Amotivational Syndrome– Most research has not found this to be true– Is it a HOST effect?
• It may be psychopathology independent of use• Gateway Drug
– Most well-designed studies suggest this is false.• “Common liability model” is a better explanation
– Alcohol and cigarettes are stronger gateway drugs if one accepts the data
Highly Debated EffectsHighly Debated Effects
LSD• Lysergic acid
diethylamide (LSD) is the most potent hallucinogen known to science
• 1938 Dr. Albert Hoffman
• Very potent in pure form
• Alters sensory perception
• Not much use until late 50’s and into 60’s for study of mental illness
• The late Dr. Timothy Leary
Psilocybin• Found in the wild
throughout the Americas as well as cultivated (basements, caves)
• One of the tryptamines – naturally occuring but can be synthesized
• Potency varies by variety and cultivation
Peyote and Mescaline• Small cactus that
contains the chemical mescaline
• Used by some Native American tribes in religious ceremonies (movie: Altered States)
• The buttons are dried and eaten or made into a type of tea or tonic. Has been synthesized, too.
Hallucinogens – Analogue Heaven
• Of all the classes, this one seems to bring about the most chemically altered analogues
• Never ending battle to keep up with those in the illicit drug enterprise business. Examples are:– MDMA (Ecstasy)– PCP (Angel Dust)– Ketamine (Special K)
The Toxicants / Inhalants
• Includes a wide variety of volatile substances:
– Glue / gasoline / hairspray
– Toluene– Butyl nitrate– White Out– Nitrous oxide– Freon– Magic Markers?
Toxicant / Inhalant Data:
• Action sought: euphoria, disorientation, dizziness
• Dependence risk: psychological• Dangers / side effects: suffocation, kidney
abnormalities, liver damage, headaches, nausea, slurred speech, and loss of motor coordination, bronchial damage, and risk of explosion and burns. Mental effects may include fear, anxiety, depression and memory loss.
• Prevalence of use: estimated 1 million users, mostly adolescents. In 2005 national survey 25 million said they had used inhalants sometime in their life.
The Steroids
• Used for performance enhancement and weight gain
• Natural:– testosterone
• Synthetics / anabolics:– Boldenone– Methenolone– Nandrolone
Steroid Data:
• Action sought: muscle enhancement, increased size and strength of muscles, improve endurance, and decrease recovery time between workouts
• Dependence risk: psychological• Dangers / side effects: Elevated blood pressure and
cholesterol levels, severe acne, premature balding, reduced sexual function, and testicular atrophy. In males, abnormal breast development. In females, a masculinizing effect, resulting in more body hair, a deeper voice, smaller breasts, and fewer menstrual cycles. Several of these effects are irreversible. In adolescents, abuse of these agents may prematurely stop the lengthening of bones, resulting in stunted growth. Also reported: psychotic reactions, manic episodes, feelings of anger or hostility, aggression, and violent behavior (roid rage).
• Prevalence of use: estimated 1-3 million users in US.
Betel Nut
• The fruit of the Areca catechu tree
• Contains Arecoline• Mild stimulant that is a
cholinergic agonist• Not a high abuse
potential
