Drug abuse and addiction

14-times Olympic gold medal winner Michael Phelps caught with cannabis pipe

Confusion in definition !!!

Various terms like

- Drug addiction - Drug abuse - Drug dependence

- Drug habituation

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

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.

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

THE MESOLIMBIC DOPAMINERGIC REWARD PATHWAY

Animal models

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

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??

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

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

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

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

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.

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

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

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

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

Drugs that activate GPCR

drugs
Opiods Cannabinoids
Gammahydroxybutyric acid(GHB)

Molecular target
- OR CB1R GABAbR

Action
agonist agonist

Effect on DA neurons
disinhibition disinhibition

Weak agonist disinhibition

LSD, mescaline

5-HT2AR

Partial agonist

Drugs that bind to ionotrophic receptor and ion channels

drugs
Nicotine Alcohol

Molecular target
nAChR GABAA,5-HT3, nACh, NMDA GABAA NMDA

Action
Agonist

Effect on DA neurons
Excitement, disinhibition? Excitement, disinhibition?

Benzodiazepines Phencyclidine, ketamine

Positive modulator antagonists

disinhibition

Drugs that bind to transporter of biogenic amines

drugs
Cocaine

Molecular target
DAT,SERT, NET DAT,SERT, NET,VMAT

Action
Inhibitor

Effect on DA neurons
Blocks DA uptake Blocks DA uptake

Amphetamine

Reverses transport

Ecstasy

SERT>DAT, NET

Reverses transport

Blocks DA uptake

 Drugs that Activate GioCoupled Receptors - Opioids - Cannabis - LSD

Opioids God's own medicine

Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as

opium.

Thomas Sydenham

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

 Features of opioid action - Analgesia

Altered mood Euphoria Dysphoria Miosis Sedation Nausea , vomiting Respiratory depression Constipation

Tolerance opioids
High degree of tolerance - Euphoria - Sedation - Nausea , vomiting - Mental clouding
Minimal tolerance miosis, constipation Cross tolerance between opiods not complete

Physical dependence and withdrawal syndrome - opioids

symptoms
Restlessness Irritability Insomnia

signs
Mydriasis Sweating Gooseflesh

Anxiety
Dysphoric mood, craving for drug

Tachycardia
Yawning ,fever

Rx of withdrawal syndrome
Methadone therapy 20-30mg Clonidine , Lofexidine

Activation of endogenous opioid system acupuncture

Rx of opioid addiction
Methadone substitution therapy - Inpatient treatment Partial agonist maintenance - Buprenorphine - Buprenorphine + naloxone

Antagonist treatment - naltrexone

CANNABINOIDS
ganja- marijuanahashish- charas

CANNABINOIDS
The most famous users of cannabis were the ancient Hindus of India and Nepal The herb was called ganjika in Sanskrit

CANNABINOIDS ganja- marijuanahashish- charas

Delta 9-tetrahydrocannabinol (THC) CB1 receptor action

presynaptic inhibition of GABA neurons in the VTA

Disinhibition of DA neurons

Common Routes- CANNABINOIDS

Smoking Oral ingestion Cannabis tea Cannabis+alcohol = green dragon

actions - cannabis
Euphoria Feeling of well-being Relaxation Grandiosity Long term effects Panic, Anxiety Frank psychosis Depression

- Amotivational syndrome

Tolerance ,depenadence, withdrawal

Tolerance develops rapidly Withdrawal syndrome mild Restlessness Irritability Agitation Insomnia

Rx of cannabis addiction
No specific treatment CB-1 receptor blocker - Rimonabant

GAMMA-HYDROXYBUTYRIC ACID (GHB)

1st introduced as a general anesthetic Endogenous - during GABA metabolism Pharmacology complex Binding site GABAB receptor

Available in salt form

GHB liquid ecstasy - club drug

Euphoria Feeling of wellbeing a feeling of social closeness Amnesia - date rape drug

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

LSD, MESCALINE & PSILOCYBIN

No dependence No addiction Tachyphylaxis Animal studies - no rewarding properties - no DA increase Ritanserin - 5-HT2R antagonist in animal studies

 Drugs that Mediate Their Effects Via Ionotropic Receptors

- nicotine

- alcohol - benzodiazepines - PCP,ketamine

NICOTINE
- Most dangerous dependence producing drug - 2nd after alcohol

nicotine
Nicotiana tabacum nAchR selective agonist nAchR expressed in VTA Nicotine causes release of DA in NA and PFC

42- containing channels important for reward

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

Tolerance ,dependence, withdrawal -nicotine

Some evidence for tolerance Best feeling after a day of abstinence Strong dependence Mild withdrawal symptoms Irritability Anxiety Restlessness Impatience

Rx of nicotine addiction
Nicotine substitution - Gum - Transdermal patch - Nasal spray

All these do not achieve peak nicotine level but suppress the withdrawal

Rx of nicotine addiction
SR preparation of bupropion Rimonabant Varenicline partial agonist of 42 nAchR

Alcohol ethanol
- Most commonly abused drug - 90% US adults have experienced alcohol

ethanol
Complex pharmacology Action on many receptors

- GABAA,5-HT3, nACh, NMDA - Inhibition of ENT1

Available in various concentration

Mainly act as CNS depressant

William Shakespeare and action of ethanol in MACBETH

Porter said thatDrink provoke - noise painting - sleep - urine - Desire but takes away performance

Chronic alcohol abuse = alcoholism

LIVER - Alcoholic fatty liver - Alcoholic hepatitis - Cirrhosis - Liver failure Neurotoxicity - depression - Peripheral neuropathy - Gait disturbance - Wernicke-Korsakoff syndrome

alcoholism
CVS
Cardiomyopathy and Heart Failure Arrhythmias Hypertension Coronary Heart Disease

FETAL ALCOHOL SYNDROME

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

Alcohol withdrawal syndrome

Craving Tremor Sweating Nausea and vomiting Tachycardia Hypertension Seizures Visual hallucination

Delirium tremens

Rx of withdrawal syndrome alcoholism

Objective is to prevent - seizure,delirium,arrhythmia Thiamine therapy Electrolyte balance BZDs commonly used drugs detoxification - Long acting BZDs

Rx of alcoholism
Behavioral & psychosocial therapy Naltrexone 50 mg OD Nalmefene Acamprosate 333mg tid Disulfiram -125-500mg/day Topiramite Ondensatrone

BENZODIAZEPINES(BZDs)
Action on GABAA receptors Increase frequency of single channel opening Disinhibition DA neurons reward Short acting BZDs more commonly abused

BZDs
Mild euphoric effect Street lore diazepam + methadone With cocaine Tolerance develops after months of use - sedative effect

Benzodiazepine withdrawal
Anxiety agitation Insomnia Dizziness Paresthesia Muscle cramps Seizure

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

KETAMINE & PHENCYCLIDINE (PCP)

Club drugs Angel dust Special K Blockade of NMDA receptor vivid dreams hallucinations

KETAMINE & PHENCYCLIDINE (PCP)

Powder forms snorted ,smoked, ingested Reinforcing in monkeys Dependence not seen Chronic exposure schizophrenia like state

Drugs that Bind to Transporters of Biogenic Amines

- Cocaine - Amphetamine - Ecstasy

cocaine
alkaloid found in the leaves of Erythroxylon coca Local anesthetic recreational drug

Common form crack cocaine

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

Effects of cocaine
Psychostimulation - 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

Speedball
Cocaine + heroin
- Improved euphoria - Heroin reduces irritability in cocaine users - Faster onset

Tolerance ,dependence, withdrawal - cocaine

Sensitization common in animal studies In human tolerance is seen Withdrawal or cocaine crash Depression Dysphoria Craving Sleepiness Bradycardia

Rx of cocaine addiction
Withdrawal symptoms no treatment Enhancing GABAergic inhibition prevents relapse of cocaine use seen in animal studies - Topiramite - Baclofen - Modafinil

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

AMPHETAMINE
intravenous administration , pill, smoked Increase arousal Bruxism Skin flushing Reduce sleep Euphoria Hallucination Hypertensive crisis, stroke

Neurotoxic on long term use

MDMA = ecstasy
Party drug or club drug preferential affinity for the serotonin transporter (SERT) marked intracellular depletion for 24 hours after a single dose

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, attacks

panic

- Long term - neurotoxicity

references
Goodman & Gillman's the pharmacological basis of therapeutics- 11th edition Katzung basic and clinical pharmacology 10th edition Lippincotts illustrated reviews pharmacology 4th edition en.wikipedia.org Various internet sites

The Addiction Ends Here!