drug abuse ppt by nirav
DESCRIPTION
addiction and abuseTRANSCRIPT
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Drug abuse and addiction
14-times Olympic gold medal winner Michael Phelps caught with cannabis pipe
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Confusion in definition !!! Various terms like
- Drug addiction - Drug abuse
- Drug dependence
- Drug habituation
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American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM)
New term – substance dependence
a cluster of symptoms indicating that individual persists with use of the substance despite significant substance related problems
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Substance Dependence A. A maladaptive pattern of substance use leading to clinically
significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period:
Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home
Recurrent substance use in situations in which it is physically hazardous
Recurrent substance-related legal problems
Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance
B. The symptoms have never met the criteria for Substance Dependence for this class of substance.
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Pharmacology behind addiction - reinforcement The capacity of drugs to produce effects that make the
user wish to take them again
all addictive drugs activate the mesolimbic dopamine system and increase dopamine level
Starting point is ventral tegmental area (VTA)
This tiny structure projects into nucleus accumbens amygdala prefrontal cortex
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THE MESOLIMBIC DOPAMINERGIC REWARD PATHWAY
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Animal models
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Animal models Addiction is a disease that does not respect animal boundaries
Addicted rats with cocaine
- Prolong self administration of cocaine
- Behavior closely resemble human addiction
- Rats administered the drug despite negative consequences
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The Dopamine Hypothesis of Addiction Experiments in monkeys - dopamine neurons in the VTA are most efficiently
activated by a reward - Few drops of fruit juice – not anticipated- 1st - only juice- 2nd - juice + sound- 3rd – only sound
Accuracy of this hypothesis??
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TOLERANCE Reduction in response to the drug after
repeated administrations
Innate tolerance
genetically defined sensitivity to a drug that is observed the first time that the drug administered
Acquired tolerance
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Acquired tolerance Pharmacokinetic tolerance Changes in the distribution or metabolism of a drug
after repeated administrations such that a given drug produces a lower blood concentration than the same dose did on initial exposure
Pharmacodynamic tolerance Adaptive changes that have taken place within systems
affected by the drug so that response to a given concentration of the drug is reduced
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Acquired tolerance Learned tolerance
- Reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences
1) Behavioral tolerance- Skills that can be developed through repeated experiences with
attempting to function despite mild to moderate intoxication
2) Conditioned tolerance- This develops when environmental cues such as sight or smell
consistently paired with the administration of drug
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Acquired tolerance Acute tolerance- Rapid tolerance developing with repeated
use on a single occasion such as in a “binge”
Reverse tolerance= Sensitization
- Increase in response with repetition of the same dose of the drug
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Acquired tolerance Cross tolerance- When repeated use of a drug in a given category
confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category
Barbiturates BDZs Amphetamine Cocaine.
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Physical dependence A state that develops as a result of the
adaptation produced by a resetting of homeostatic mechanisms in response to repeated use of drug
Indicates new balance in presence of drug Need of continuous presence of drug
Withdrawal syndrome is the actual evidence of physical dependence
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Withdrawal Syndrome Abrupt termination of drug in a physically dependent person
Appearance of various signs and symptoms – characteristic of the category of the drug
Two origins
- Removal of the drug of dependence
- CNS hyperarousal owing to readaptation to the absence of the drug of dependence
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Psychological dependence
Motivational component: great subjective need, compulsion, drive to get the drug
Will take drug periodically
Although physical dependence for a drug may not occur, “drug-seeking behavior” is present
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Classification of drugs of abuse Drugs that activate GPCR
Drugs that bind to ionotrophic receptor and ion channels
Drugs that bind to transporter of biogenic amines
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Drugs that activate GPCR
drugs Molecular target
Action Effect on DA neurons
Opiods μ- OR agonist disinhibition
Cannabinoids CB1R agonist disinhibition
Gamma- hydroxybutyric acid(GHB)
GABAbR Weak agonist disinhibition
LSD,
mescaline
5-HT2AR Partial agonist
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Drugs that bind to ionotrophic receptor and ion channels
drugs Molecular target
Action Effect on DA neurons
Nicotine nAChR Agonist Excitement,
disinhibition?
Alcohol GABAA,5-HT3, nACh, NMDA
Excitement,
disinhibition?
Benzodiazepines GABAA Positive modulator
disinhibition
Phencyclidine,
ketamine
NMDA antagonists -
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Drugs that bind to transporter of biogenic amines
drugs Molecular target
Action Effect on DA neurons
Cocaine DAT,SERT,
NET
Inhibitor Blocks DA uptake
Amphetamine DAT,SERT,
NET,VMAT
Reverses transport
Blocks DA uptake
Ecstasy SERT>DAT,
NET
Reverses transport
Blocks DA uptake
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Drugs that Activate Gio-Coupled Receptors
- Opioids- Cannabis- LSD
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Opioids – God's own medicine Among the remedies which it
has
pleased Almighty Godto give to man to relieve his
sufferings, none isso universal and so efficacious
as
opium.“
Thomas Sydenham
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Heroin- most commonly abused opiate Widely available in black market
Iv use , highly lipid soluble, quick action
Effects starts within a minute “high” , “kick” euphoria Intense pleasure = sexual orgasm warmth - all these remain for several minutes
period of sedation and tranquility upto 1 hr
Total duration 3-5 hrs
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Features of opioid action- Analgesia- Altered mood- Euphoria- Dysphoria- Miosis- Sedation- Nausea , vomiting- Respiratory depression- Constipation
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Tolerance – opioids High degree of tolerance - Euphoria- Sedation- Nausea , vomiting- Mental clouding
Minimal tolerance – miosis, constipation
Cross tolerance between opiods – not complete
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Physical dependence and withdrawal syndrome - opioids
symptoms signsRestlessness Mydriasis
Irritability Sweating
Insomnia Gooseflesh
Anxiety Tachycardia
Dysphoric mood, craving for drug
Yawning ,fever
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Rx of withdrawal syndrome Methadone therapy – 20-30mg Clonidine , Lofexidine
Activation of endogenous opioid system
acupuncture
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Rx of opioid addiction Methadone substitution therapy- Inpatient treatment
Partial agonist maintenance - Buprenorphine- Buprenorphine + naloxone
Antagonist treatment - naltrexone
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CANNABINOIDS
ganja- marijuana-hashish- charas
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CANNABINOIDS The most famous users of cannabis were
the ancient Hindus of India and Nepal
The herb was called
ganjika in Sanskrit
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CANNABINOIDS –ganja- marijuana-hashish- charas
Delta 9-tetrahydrocannabinol (THC)
CB1 receptor action
presynaptic inhibition of GABA neurons in the VTA
Disinhibition of DA neurons
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Common Routes- CANNABINOIDS
Smoking
Oral ingestion
Cannabis tea
Cannabis+alcohol = green dragon
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actions - cannabis Euphoria Feeling of well-being Relaxation Grandiosity
Long term effects- Panic, Anxiety- Frank psychosis- Depression
- Amotivational syndrome
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Tolerance ,depenadence, withdrawal
Tolerance develops rapidly Withdrawal syndrome – mild
Restlessness
Irritability
Agitation
Insomnia
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Rx of cannabis addiction No specific treatment
CB-1 receptor blocker - Rimonabant
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GAMMA-HYDROXYBUTYRIC ACID (GHB) 1st introduced as a general anesthetic
Endogenous - during GABA metabolism
Pharmacology – complex
Binding site – GABAB receptor
Available in salt form
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GHB – liquid ecstasy - club drug
Euphoria
Feeling of wellbeing
a feeling of social closeness
Amnesia - date rape drug
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LSD, MESCALINE & PSILOCYBIN Molecular target- 5-HT2AR – Gq receptor
Hallucinogens
- Altered sensory perception- Shape and color distortion- Distorted time perceptions
somatic symptoms- nausea, blurred vision, dizziness
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LSD, MESCALINE & PSILOCYBIN No dependence No addiction Tachyphylaxis
Animal studies - no rewarding properties
- no DA increase Ritanserin - 5-HT2R antagonist – in animal studies
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Drugs that Mediate Their Effects Via Ionotropic Receptors
- nicotine - alcohol - benzodiazepines - PCP,ketamine
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NICOTINE- Most dangerous
dependence producing
drug
- 2nd after alcohol
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nicotine Nicotiana tabacum
nAchR – selective agonist
nAchR – expressed in VTA Nicotine causes release of DA in NA and PFC
ά4β2- containing channels important for reward
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nicotine Most common route – smoking Oral ingestion
action some degree of euphoria and arousal improves attention, learning, problem solving, and
reaction time Toxic dose - respiratory paralysis and severe
hypotension
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Tolerance ,dependence, withdrawal -nicotine Some evidence for tolerance Best feeling after a day of abstinence Strong dependence
Mild withdrawal symptoms- Irritability- Anxiety- Restlessness- Impatience
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Rx of nicotine addiction Nicotine substitution
- Gum
- Transdermal patch
- Nasal spray
All these do not achieve peak nicotine level – but suppress the withdrawal
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Rx of nicotine addiction SR preparation of bupropion
Rimonabant
Varenicline – partial agonist of ά4β2 nAchR
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Alcohol – ethanol- Most commonly abused drug- 90% US adults have
experienced alcohol
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ethanol Complex pharmacology
Action on many receptors
- GABAA,5-HT3, nACh, NMDA- Inhibition of ENT1 Available in various concentration
Mainly act as CNS depressant
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William Shakespeare and action of ethanol in MACBETH
Porter said that-
Drink provoke
- noise painting
- sleep
- urine
- Desire but takes away performance
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Chronic alcohol abuse = alcoholismLIVER - Alcoholic fatty liver - Alcoholic hepatitis- Cirrhosis - Liver failure
Neurotoxicity- depression- Peripheral neuropathy- Gait disturbance- Wernicke-Korsakoff syndrome
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alcoholism
CVSCardiomyopathy and Heart FailureArrhythmias HypertensionCoronary Heart Disease
FETAL ALCOHOL SYNDROME
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Tolerance , dependence, withdrawal - alcohol abuse Acute tolerance soon after administration of
alcohol
Chronic tolerance due to altered metabolism
Cross tolerance with BZDs
Withdrawal syndrome is common and sometimes severe
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Alcohol withdrawal syndrome Craving Tremor
Sweating Nausea and vomiting
Tachycardia Hypertension
Seizures Visual hallucination
Delirium tremens
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Rx of withdrawal syndrome - alcoholism Objective is to prevent- seizure,delirium,arrhythmia
Thiamine therapy
Electrolyte balance
BZDs – commonly used drugs – detoxification - Long acting BZDs
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Rx of alcoholism Behavioral & psychosocial therapy
Naltrexone – 50 mg OD Nalmefene Acamprosate – 333mg tid Disulfiram -125-500mg/day
Topiramite Ondensatrone
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BENZODIAZEPINES(BZDs) Action on GABAA receptors
Increase frequency of single channel opening
Disinhibition DA neurons –reward
Short acting BZDs – more commonly abused
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BZDs Mild euphoric effect Street lore – diazepam + methadone With cocaine
Tolerance develops after months of use
- sedative effect
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Benzodiazepine withdrawal
Anxiety agitation
Insomnia
Dizziness
Paresthesia
Muscle cramps
Seizure
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Rx of BZDs addiction Gradual reduction of dose Long acting BZD can be used for substitution Carbamazepine phenobarbitone
Withdrawal symptoms Rx by phenobarbitone
Specific antagonist – flumazenil
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KETAMINE & PHENCYCLIDINE (PCP) Club drugs Angel dust Special K
Blockade of NMDA receptor
vivid dreams hallucinations
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KETAMINE & PHENCYCLIDINE (PCP)
Powder forms – snorted ,smoked, ingested
Reinforcing in monkeys
Dependence not seen
Chronic exposure – schizophrenia like state
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Drugs that Bind to Transporters of Biogenic Amines
- Cocaine- Amphetamine- Ecstasy
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cocaine alkaloid found in the leaves of Erythroxylon
coca Local anesthetic
recreational drug
Common form – crack cocaine
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cocaine Iv use , inhalation – instant rush
blocks the uptake of dopamine, noradrenaline and serotonin through their respective transporters
block of the dopamine transporter (DAT) – reinforcing property
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Effects of cocainePsychostimulation- Increase arousal- Improved performance- Sense of self confidence- Alertness- Euphoria after higher dose
Chronic abuse – involuntary motor activity - irritability - risk of violence - Megnan's symptom
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Speedball
Cocaine + heroin- Improved euphoria- Heroin reduces irritability in cocaine users- Faster onset
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Tolerance ,dependence, withdrawal- cocaine Sensitization common in animal studies
In human – tolerance is seen
Withdrawal or cocaine crash
- Depression - Dysphoria- Craving- Sleepiness- Bradycardia
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Rx of cocaine addiction Withdrawal symptoms – no treatment
Enhancing GABAergic inhibition – prevents relapse of cocaine use – seen in animal studies
- Topiramite- Baclofen- Modafinil
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AMPHETAMINE indirect-acting sympathomimetic
reversing the action of biogenic amine transporters at the plasma membrane
interfere with the vesicular monoamine transporter (VMAT)
One of the CLUB DRUGS
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AMPHETAMINE intravenous administration , pill, smoked Increase arousal Bruxism Skin flushing Reduce sleep Euphoria Hallucination Hypertensive crisis, stroke
Neurotoxic on long term use
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MDMA = ecstasy Party drug or club drug
preferential affinity for the serotonin transporter (SERT)
marked intracellular depletion for 24 hours after a single dose
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MDMA = ecstasy Available in tablet forms – 100mg
Acute effect- Feeling of energy- Altered sense of time- Enhanced perception- Tachycardia- Dry mouth- Higher dose – visual hallucinations, hyperthermia,
panic attacks
- Long term - neurotoxicity
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referencesGoodman & Gillman's – the pharmacological basis of therapeutics-
11th edition
Katzung – basic and clinical pharmacology 10th edition
Lippincott‘s illustrated reviews pharmacology – 4th edition
en.wikipedia.org
Various internet sites
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The Addiction EndsHere…!