2. An arrested man was told, in a police station by a doctor, that he was drunk.
The man asked, âDoctor, could a drunk man stand up in the middle of this room,
jump into the air, turn a complete somersault, and land down on his feet?â
The doctor was injudicious enough to say, âCertainly notâ â and was then and there
proved wrong (Worthing C L. 1957 British Medical Journal i:643)
The introduction of the breath-analyzer, which has a statutory role only in road
traffic situations, has largely eliminated such professional humiliations.
3. Introduction
⢠Drug use for non-medical purposes (abused, misused, used for
recreational purposes) presents a range of social problems, all of
which have important pharmacological dimensions
4. Definition
Drug abuse:
⢠Intentional use of excessive drugs for purposes other than the
indication for which the drug was prescribed.
⢠It can be persistent or sporadic
5. Definition
Drug addiction:
⢠Compulsive drug use characterized by overwhelming involvement
with the use of drug.
⢠Procuring the drug and using it take precedence over other activities
7. Drug dependence
⢠It is a state in which use of drugs for personal satisfaction is given a
higher priority than other basic needs, often in face of known risks to
health.
Types :
⢠Psychological dependence
⢠Physical (Physiological) dependence
8. Dependence
⢠Psychological dependence :
⢠It is said to have developed when the individual believes that optimal
state of well being is achieved only through the actions of drug
9. Dependence
⢠Physical dependence :
⢠Physical dependence implies that repeated exposure to a drug
induces adaptive changes in the body so that tolerance occurs and
discontinuation results in a withdrawal reaction
10. Basic neurobiology of drug abuse
⢠Every addictive drug causes its own spectrum of acute effects, but all
induce strong feelings of euphoria and reward
⢠With repetitive use, addictive drugs induce adaptive changes such as
tolerance (ie, escalation of dose to maintain effect)
⢠Once the abuse drug is no longer available, signs of withdrawal become
apparent
⢠Relapse is very common in addicts after a successful withdrawal
11. Basic Neurobiology: Dopamine Hypothesis of
Addiction
⢠The mesolimbic dopamine system is the prime target of addictive
drugs:
⢠As a general rule, all addictive drugs activate the mesolimbic
dopamine system
Mesolimbic system:
ďź This system originates in the ventral segmental area (VTA) and projects to the nucleus
accumbens, the amygdala, the hippocampus, and the pre-frontal cortex.
ďź Most projection neurons of VTA are dopamine-producing neurons
ďź When the dopamine neurons of the VTA begin to fire in bursts, large quantities of
dopamine is released in the nucleus accumbens and the prefrontal cortex
12. Common pathway of
drugs of addiction on the
dopaminergic neurones
Increasing evidence suggests that
drugs of addiction all act by
modulating dopaminergic
transmission in the medial forebrain
bundle. (MFB)
(Mesolimbic system is a component
of MFB)
13. Basic Neurobiology: Tolerance & Withdrawal
⢠With chronic exposure to addictive drugs, the brain shows signs of
adaptation: this phenomenon is called tolerance
⢠For example, if morphine is used at short intervals, the dose has to be
progressively increased over the course of several days to maintain
rewarding or analgesic effects.
⢠Adaptive changes become fully apparent once drug exposure is
terminated. This state is called withdrawal and is observed to varying
degrees after chronic exposure to most drugs of abuse
14. Basic Neurobiology:
Addiction: A disease of maladaptive learning
⢠Addiction is characterized by a high
motivation to obtain and use drug despite
negative consequences.
⢠With time, drug use becomes compulsive
(âwanting without likingâ)
⢠Even after successful withdrawal: Individuals
have a high risk of relapse
ďRelapse is triggered by one of the following:
ďźRe-exposure to addictive drug
ďźStress
ďźSetting that recalls prior drug use (eg. People,
places, or drug paraphernalia)
⢠A neutral stimulus can motivate
addiction-related behaviour and
act as a âtriggerâ when it is
paired with drug use :
ďźThis phenomenon may involve
synaptic plasticity in the target
nuclei of the mesolimbic
projection
(Synaptic plasticity is involved in learning &
memory)
16. Ethanol
⢠Alcohol is the most commonly abused substance in modern society
MOA:
⢠Enhanced effect of the inhibitory neurotransmitter GABA
⢠Increased release of endogenous opioids
⢠Altered levels of serotonin and dopamine
17. Ethanol
⢠At low doses, ethanol is a selective CNS depressant (decreased
inhibition), resulting in drunken behaviour
⢠At high doses, it is a general CNS depressant, resulting in coma and
respiratory depression
Ethanol is a major cause of fatal automobile
accidents, drownings, and fatal falls and is a
related factor in many hospital admissions
21. Ethanol
⢠Ethanol is highly lipid soluble
âŚâŚ.rapidly absorbed from stomach and duodenum
⢠Food decreases absorption
⢠Peak levels are attained in 20 minutes to 1 hr after ingestion
⢠95% Ethanol is metabolized by alcohol dehydrogenase and then by
aldehyde dehydrogenase in liver
⢠Remainder is excreted in breath, sweat and urine
22. Ethanol
Ethanol
Acetaldehyde
Acetate
Alcohol dehydrogenase
Aldehyde dehydrogenase
Al low doses, ethanol is metabolized by
first order kinetics
When blood level exceeds 15 â 40
mg/dL/hr, it follows zero-order kinetics
Reason: enzymatic processes are
saturated
Responsible for
toxicity
Genetic
deficiency of
aldehyde
dehydrogenase
causes flushing,
headache and
nausea after
small amounts of
alcohol due to
accumulation of
acetaldehyde (as
seen in Japanese)
Breath sample can be used to
determine blood alcohol levels:
There is a constant blood-to-breath
ratio of 2100:1
23. Ethanol
Chronic ethanol abuse can
cause profound hepatic,
cardiovascular, pulmonary,
hematologic, endocrine,
metabolic and CNS damage
25. Effect of chronic alcohol use (contd)
Chronic alcohol use has profoundly negative psychosocial impact
26. Ethanol
⢠Sudden cessation of ethanol ingestion in patients with physical
dependence can precipitate withdrawal symptoms:
ďźTachycardia
ďźSweating
ďźTremor
ďźAnxiety
ďźAgitation
ďźAcute psychotic attack (delirium tremens)
ďźHallucination
ďźConvulsions
In 6 hours
In 72 hours
Withdrawal symptoms are
managed with symptomatic care,
benzodiazepines and long-term
addiction treatment
27. Treatment of alcohol dependence
⢠Disulfiram:
⢠Disulfiram blocks the oxidation of acetaldehyde
to acetic acid by inhibiting aldehyde
dehydrogenase
⢠This results in the accumulation of acetaldehyde
in the blood, causing flushing, tachycardia,
hyperventilation, and nausea.
⢠Patient abstains from alcohol to prevent the
unpleasant effects of disulfiram induced
acetaldehyde accumulation
⢠Naltrexone:
ďźCompetitive and
long-acting opioid
antagonist
⢠Acamprosate:
ďźActs on NMDA
receptors
ďźDecreases
cravings
30. Opioids
⢠Most commonly abused opioids:
ďźMorphine
ďźHeroin (diacetylmorphine)
ďźCodeine
ďźOxycodone
ďźMeperidine abuse is common among health professionals
All these drugs induce strong
tolerance and dependence
The withdrawal syndrome may be very severe (except for codeine) :
intense dysphoria, nausea or vomiting, muscle aches, lacrimation,
rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever
31. Opioids: treatment
Treatment of overdose:
⢠Opioid antagonist: Naloxone
⢠Naloxone administration also provokes an acute withdrawal symptoms in a
dependent person
Treatment of opioid addiction:
⢠Long acting opioid: Methadone, Levomethadone OR
⢠Partial agonist: Buprenorphine
⢠Oral methadone is administered as a substitute for the opioid of abuse, and the patient is then
slowly weaned from methadone. The withdrawal syndrome with Methadone is milder but more
protracted (days to weeks) than that with other opioids
32. Cocaine
Obtained from Erythroxylum coca
MOA:
⢠Cocaine inhibits the reuptake of NE into the
adrenergic neuron ď increased availability of NE
at the synapse
⢠Stimulates pleasure center in the brain (due to
inhibition of reuptake of dopamine and serotonin)
33. Cocaine
⢠It is a CNS stimulant
⢠Patient presents to emergency
with:
ďźAgitation/Paranoia
ďźConvulsions
ďźHyperthermia
ďźChest pain
Management:
⢠Benzodiazepine (lorazepam)
âŚhelps to calm the agitated patient,
treat and prevent convulsions
⢠Cooling the patient
âŚhyperthermia is major cause of
cocaine mortality
⢠Symptomatic supportive care
34. Amphetamine
⢠Amphetamines act by enhancing the release of biogenic amines from
nerve terminals
⢠Clinical effects are similar to cocaine
⢠Effects may last longer with less euphoria
⢠Treatment is similar to cocaine
36. Methylenedioxymethamphetamine
⢠MDMA is also known as âecstacyâ or âMollyâ
⢠It is a hallucinogenic amphetamine with profound serotonin releasing
property
⢠Common in rave parties and with social offenders
⢠MDMA abuse can cause profound hyperthermia, altered mental
status, and movement disorders known as the âserotonin syndromeâ
⢠Like amphetamines, MDAM can cause âbruxismâ and âtrismusâ
37. Mechanism of action of MDMA
⢠Because of its unique serotonin properties,
the term âempathogen,â meaning
âgenerating a state of empathyâ was first
coined for MDMA
⢠Many users describe a sense of well-being
and social interactivity, and sexual offenders
take advantage of this
38. Methylenedioxymethamphetamine
Treatment:
⢠Benzodiazepines: help to calm and cool the patient.
⢠Neuromuscular blockers: to control excessive movement and heat
generation.
⢠Cyproheptadine (serotonin antagonist): to treat serotonin syndrome
⢠Endotracheal intubation
39. Lysergic Acid diethylamide (LSD)
⢠LSD produces its psychedelic effects through serving as a potent partial agonist at
5-HT2A receptors.
⢠Aside from the very colorful hallucinations, the drug is also responsible for mood
alterations, sleep disturbances, and anxiety.
⢠Repeated use rapidly produces tolerance through down-regulation of the
serotonin receptors.
⢠LSD may cause tachycardia, increased blood pressure and body temperature,
dizziness, decreased appetite, and sweating.
⢠Loss of judgment and impaired reasoning are associated with use of LSD.
⢠This can sometimes be an exaggerated effect with extreme panic, which is known
by individuals as a âbad trip,â and may lead to suicide.
40. Marijuana
⢠Cannabis sativa is the plant most often used for its hallucinogenic properties
⢠Marijuana is the most frequently used illicit drug â (dried flowers, leaves,
stems and seeds of the cannabis plant).
⢠The main psychoactive alkaloid contained in marijuana is Î9-
tetrahydrocannabinol (THC)
⢠Cannabinoid or CB1 receptors: targets for THC
⢠When CB1 receptors are activated by marijuana, the effects produced include
physical relaxation, hyperphagia (increased appetite), increased heart rate,
decreased muscle coordination, conjunctivitis, and minor pain control
41. Marijuana
⢠The half-life of THC is about 4 hours.
⢠The onset of effects of THC after smoking marijuana occurs within
minutes and reaches a maximum after 1â2 hours
The most prominent effects are euphoria and
relaxation
43. Marijuana
⢠The justification of medicinal use of marijuana was examined by the Institute of
Medicine (IOM) of the National Academy of Sciences in its 1999 report,
Marijuana & Medicine âŚ. This continues to be a controversial issue
⢠Marijuana has been used to help in the treatment of:
ďźchemotherapy-induced nausea and vomiting
ďźcachexia secondary to cancer and AIDS
ďźepilepsy
ďźchronic pain,
ďźmultiple sclerosis
ďźanxiety.
Dranabinol: Synthetic THC
prescribed to treat emesis and to
stimulate the appetite.
Nabilone: Î 9 -THC analog, used for
adjunctive therapy in chronic pain
management.
44. Drugs and sport
⢠Drugs are frequently used to enhance performance in sport
⢠Detection can be difficult when the drugs or metabolites are closely related to
endogenous substances, or when the drug can be stopped well before the event.
⢠Detection of levels of the naturally occurring compound above a âbenchmarkâ
indicates potential doping.
Mass spectrometry: to detect the isotope content of compounds might enable differentiation of
natural and synthetic steroids
Other indirect methods: Testosterone and its related compound, epitestosterone, are both
eliminated in urine.
ďźThe ratio of testosterone to epitestosterone increases with use of anabolic steroids and can be
used to detect anabolic steroid use
49. References
Goodman, L. S., Brunton, L. L., Chabner, B., & Knollmann, B. C.
(2011). Goodman & Gilman's pharmacological basis of therapeutics.
New York: McGraw-Hill.
Katzung, B. G., Masters, S. B., & Trevor, A. J. (2017). Basic & clinical
pharmacology. New York: McGraw-Hill Medical.
Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Pharmacology (Sixth
edition.). Philadelphia: Wolters Kluwer.
Bennet PN, Brown MJ, Sharma P. (2012). Clinical Pharmacology.
Churchill Livingstone, Elseivier
Editor's Notes
The blood concentration of alcohol has great medicolegal importance. Alcohol in alveolar air is in equilibrium with that in pulmonary capillary blood, and reliable, easily handled measurement devices (breathalysers) are used by police at the roadside on both drivers and pedestrians
Non-substance-dependent disorders, such as pathological gambling and compulsive shopping, share many clinical features of addiction.
This is supported by the clinical observation that, as an adverse effect of dopamine agonist medications, patients with Parkinsonâs disease may become pathological gamblers.
Other patients may develop a habit for recreational activities, such as shopping, eating compulsively or hypersexuality.
Although large scale studies are not available, an estimated one in seven parkinsonian patients develop an addiction-like behaviour when receiving dopamine agonists.
Addiction is characterized by a high motivation to obtain and use drug despite negative consequences.
With time, drug use becomes compulsive (âwanting without likingâ)
Even after successful withdrawal: Individuals have a high risk of relapse
A neutral stimulus can motivate addiction-related behaviour and act as a âtriggerâ when it is paired with drug use :
This phenomenon may involve synaptic plasticity in the target nuclei of the mesolimbic projection
(Synaptic plasticity is involved in learning & memory)
Relapse is triggered by one of the following:
Re-exposure to addictive drug
Stress
Setting that recalls prior drug use (eg. People, places, or drug paraphernalia)
Tolerance to opioids may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (Pharmacokinetic tolerance)
Alternatively, it may involve changes of Îź-opioid receptor function .eg. Internalization of receptor (pharmacodynamic tolerance).
Alcohol enhances dopamine release, inhibits the reuptake of brain amines and enhances (inhibitory) GABAA-stimulated flux of chloride through receptor-gated membrane ion channels, a receptor subtype effect that may be involved in the motor impairment caused by alcohol.
Other possible modes of action include inhibition of the (excitatory) N-methyl-D-aspartate (NMDA) receptor and inhibition of calcium entry via voltage-gated (L type) calcium channels
Stimulant action is due to removal of inhibitory action
Pharmacokinetics:
Absorption: The gastrointestinal absorption of alcohol taken orally is rapid as it is highly lipid soluble and diffusible.
Absorption is delayed by food, especially milk, the effect of which is probably due to the fat it contains. Carbohydrate also delays absorption of alcohol
Distribution: It is distributed rapidly and throughout the body water (dist. vol. 0.7 L/kg men; 0.6 L/kg women) with no selective tissue storage. Maximum blood concentrations after oral alcohol therefore depend on numerous factors including: the total dose; sex; the strength of the solution; the time over which it is taken; the presence or absence of food in the stomach; the time relations of taking food and alcohol, and the kind of food eaten; the speed of metabolism and excretion.
Alcoholic drinks taken on an empty stomach will probably produce maximal blood concentration at 30â90 min.
Tolerance develops in habitual users due to induction of alcohol metabolizing enzymes
Codeine-containing cough syrup abuse is also common in most parts of the world
Fentanyl adulterated heroin use has also increased
When taken for recreational purposes, opioids are highly addictive. The relative risk of addiction is 4 out of 5 on a scale of 1 (non-addicitive) to 5 (highly addictive)
A heroin addict may be given methadone as part of a gradual withdrawal programme, for this drug has a long duration of action and blocks access of injected opioid to the opioid receptor so that if, in a moment of weakness, the subject takes heroin, the âkickâ is reduced
Hyperthermia is caused by cocaine-induced CNS stimulation that increases heat production and vasoconstrictive effects of cocaine that minimizes heat loss
Chest pain can be chest muscle pain or cardiac pain (cocaine can constrict coronary arteries)
Cocaine consumed along with alcohol, creates a metabolite: COCAETHYLENEâŚ..it is cardiotoxic
Bruxism = teeth grinding
Trismus = jaw clenching
LSD, lysergic acid diethylamide, is perhaps the most commonly considered drug in the hallucinogen class.
LSD was first created from ergot in 1938 by Dr. Albert Hoffman.
It was later popularized by Dr. Timothy Leary, a Harvard psychologist who encouraged its use among young people.
THC causes disinhibition of dopamine neurons
Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, eg, in hashish , result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, eg, increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics.
Synthetic cannabinoids are sold over the Internet or in head shops (retail outlets specializing in tobacco paraphernalia often used for consumption of marijuana or related substances) and are often known under the names of âSpiceâ or âK2.â The synthetic THC-containing compounds were originally created in Germany in 2008 in the hopes that they could be used for medicinal purposes. Since the molecular structure of synthetic cannabinoids is much different from the cannabinoids found in marijuana plants, users do not test positive for THC with traditional drug tests. The effects of these designer agents may be up to 800 times greater than the effects observed with cannabis.