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 Û BDZs Amphetamine Û 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 Molecular target

Action Effect on DA neurons

Opiods μ- OR agonist disinhibition

Cannabinoids CB1R agonist disinhibitionGamma- hydroxybutyric acid(GHB)

GABAbR Weak agonist disinhibition

LSD,mescaline

5-HT2AR Partial agonist

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 -

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

• Drugs that Activate Gio-Coupled 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 signsRestlessness Mydriasis

Irritability Sweating

Insomnia Gooseflesh

Anxiety Tachycardia

Dysphoric mood, craving for drug

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- marijuana-hashish- 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- marijuana-hashish- 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

• ά4β2- 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 ά4β2 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 that- Drink 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

CVSCardiomyopathy and Heart FailureArrhythmias HypertensionCoronary 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,arrhythmiaThiamine 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 agitationInsomniaDizzinessParesthesiaMuscle 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 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

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, panic

attacks

- Long term - neurotoxicity

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

The Addiction EndsHere…!