Drug Dependence

Presenter: Dr. Shrikrishna Shende

Dept. of Pharmacology,JR-2

DYPMC, Pune01-02-2016

Outline

Definitions Mechanism Of Dependence Variables Affecting Drug Dependence Classification Of Drugs Causing Dependence Individual Drugs

Definitions Drug dependence: (ICD-10)

A cluster of physiological, behavioral, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviors that once had greater value

Addiction It is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences.

AbuseSelf administration of any drug in a culturally disapproved manner (illegal) that causes adverse consequences

Tolerance A state of decreased responsiveness to the pharmacologic effect of a drug as a result of prior exposure to that drug

Cross toleranceWhen exposure to drug A produces tolerance to it and also to drug B

Withdrawal When drug administration in a physically dependent person is terminated abruptly.

Reinforcement The capacity of drugs to produce effects that make the user wish to take them again

DetoxificationInvolves giving gradually decreasing doses of the drug to prevent withdrawal symptoms, thereby weaning the patient from the drug of dependence.

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Facts & Figures

World: 10 thousand million people are regular alcohol users and about 13.5 million people use opioids

India: 75 million people are alcohol users and 3 million are opioid users

In a survey in India, 6.88% people fulfilled ICD 10 criteria for drug dependence

Drug abuse is mainly the disease of youth. 29.9% used cannabis. 4.3% used cocaine and less than 4% used other drugs

Majority had health related complications (86%) followed by family problems (77%) due to drug dependence

Types Of Dependence

Physiological or physical dependenceThe physiological state of neuroadaptation produced by repeated administration of drug necessitating continued administration to prevent the appearance of withdrawal syndrome

Psychological or psychic dependence A behavioral pattern of drug abuse characterized by overwhelming involvement with the use of a drug, the securing of its supply and a high tendency to relapse after its discontinuation

Mechanism Of Dependence Complex and chronic disease

process occurring in brain which is modulated by genetic, developmental and environmental factors

Most consistent and reproducible finding is activation of mesolimbic dopaminergic system

Mesolimbic system consists of dopaminergic neurons in ventral tegmental area and their axonal projections to nucleus accumbens (NAc) and the prefrontal cortex

Variables Affecting Drug Dependence

AGENT

ENVIRONMENT HOST

Classification Of Drugs Causing Dependence

Depend ing on the i r ab i l i t y to p roduce psycho log i ca l o r phys i ca l dependence

Depending on thei r character ist ic effects

Depending on thei r mechanism of act ion

Depending On Their Ability To Produce Psychological Or Physical Dependence

Drugs that cause severe

psychic as well as physical

dependence:Opiate or morphine type : Morphine, Heroin, Methadone, Diphenoxylate.

Alcohol-barbiturate type: Ethanol, barbiturates, BZDs.

Nicotine.

Drugs that cause definite psychic but

mild/no physical dependence :

Opiate antagonist type : Nalorphine.

Amphetamine type : Amphetamine, Methamphetamine.

Drugs that cause only psychic dependence :

Cocaine, LSD, Mescaline, Cannabis.

Depending On Their Chracteristic Effects

CNS Stimulants: Amphetamine, Cocaine

CNS Depressants: Alcohol, Barbiturates, BZDs

Narcotics: Heroin, Morphine, Codeine

Psychomimetic: LSD, Mescaline, Phencyclidine

Volatile Inhalants: Chloroform, Petrol, Kerosene

Depending On Their Mechanism Of Action

Drugs that activate G-

protein coupled receptors :

• OPIODS• CANNABINIODS• LSD• MESCALINE

Drugs that bind to

ionotropic receptors and ion channels :• ALCOHOL• BENZODIAZEPINES• PHENCYCLIDINE

Drugs that bind to the

transporters of biogenic amines :

• COCAINE• AMPHETAMINES• MDMA

Opioid Derived from the juice of opium poppy, Papaver somniferum Act on GPCR: the µ, κ and δ opioid receptors Serturner isolated the active principle, Morphine (named

after the Greek God of dreams – Morpheus), in 1806

Classification:1. Natural opium alkaloids: Morphine, Codeine2. Semisynthetic opiates: Diacetylmorphine (Heroin),

Pholcodeine.3. Synthetic opioids: Pethidine (Meperidine), Fentanyl,

Methadone, Tramadol.

M/c abused morphine, heroin, codeine (Meperidine is most common among health professionals.)

Opioid withdrawal syndrome: very severe (except codeine)Intense dysphoria, muscle aches, lacrimation, nausea, mydriasis, rhinorrhea, yawning, fever etc. Recreational purpose Highly addictive.

First approach Change the patient from a short- acting

opioid (heroin) to long – acting one (Methadone)

Second approach Use of oral Clonidine

Third approachActivation of the

endogeneous opioid system without

medication

Cannabis (Marijuana) Cannabis sativa/indica (Hemp plant) Tetrahydrocannabinol (Δ9 THC) – Psychoactive component

(1964) Endocannabinoids – Anandamide , 2-arachadonyl glycerol

(2AG)

Cannabis Effects start in < 1 minutes, last for 2-3 hours Tolerance, Cross tolerance. Withdrawal Syndrome–1. Restlessness2. Irritability3. Insomnia 4. Nausea, Cramping Dependence – Psychic (mild to severe) Rx- No specific treatment

Cannabis Uses

APPROVED – Cancer Chemotherapy and Vomiting (Nabilone, Dronabinol), Appetite stimulant (in HIV and Cancer)

POTENTIAL – Agonists: Neuropathic pain.Antagonists: Obesity

CB1 antagonist – Rimonabant (anti obesity) depression, neurological side effects not used now.

LSD- Lysergic Acid Diethylamide

Synthesis: Hoffmann in SANDOZ laboratory, Switzerland in 1938.

Ergot derivative. 5HT agonist –

5HT1: acts on inhibitory autoreceptor in Raphe cell bodies.

5HT2: disrupts thalamic gating sensory overload of cortex – hallucinations. Agonist at central DA receptors. But, does not

stimulate DA release no addiction.

Mescaline And Psilocybin

MescalineIsolated in 1846.Mexican ‘Payote Cactus’ Lophophora williamasii.By Aldous Huxley in The Doors of Perception.Used by tribals. Hallucinations. Lasts for 12 hours after a single dose.

PsilocybinMexican mushroom/Magic mushroom. 5HT related compoundUsed by red Indians in rituals

Nicotine (Tobacco)

Nicotiana tabacum Effects on autonomic ganglia -

Langley and Dickinson in 1828 Stimulates sympathetic and

parasympathetic ganglia at low doses

At high doses, causes persistent depolarization and ganglion blockade.

Causes release of Ach, NE, DA, 5HT.

Nicotine Withdrawal Irritability, anxiety, restlessness, impaired

concentration, headache, increased appetite, weight gain, craving, depression.

Dependence Physical dependence: severe Psychological dependence: craving Treatment of dependence1. Substitution2. Other drugs3. Vaccine

Nicotine (Tobacco)SUBSTITUTION – to reduce withdrawal symptoms, to reduce cravingTRANSDERMAL • Once daily• Reduces withdrawal

symptoms and craving• >20 cig/day – start with

30cm2 patch. Gradually reduce (max 12 weeks)

CHEWING GUM • >20cig/day –

start with 4mg, reduce.

• Not >15gums/day

NASAL SPRAY / INHALER

S/E – headache, dyspepsia, abdominal cramps, loose stools, insomnia, nightmares, flu like symptoms, local irritation.C/I – IHD, arrhythmias

Nicotine (Tobacco)

Partial agonist at α4β2 nicotinic receptorInhibits reward, reduces craving, withdrawal symptoms

S/E – mood changes, irrational behaviour,

appetite disturbance, agitation, impairs ability

to driveSuicidal ideations

t1/2 14 to 24 hoursDose – 0.5mg BD to

1mg BD (max 12 weeks)

VARENICLINE

Nicotine (Tobacco)

Inhibits NE and DA reuptake – augments rewardSR tablet for smoking cessationEfficacy = replacement

S/E – insomnia, agitation, dry mouth,

nauseaLowers seizure threshold

C/I- eating disorder, bipolar illness, liver and

kidney disease.

Dose – 150-300mg/day for 7

days prior to cessation of smoking

followed by 300mg/day for 6-12

weeks

BUPROPION

Nicotine (Tobacco)

VACCINES UNDER TRIAL

1. NicVAX - Pseudomonas aeruginosa exoprotein- failed in Phase III (not better than placebo)2. Nicotine-Qbeta - Escherichia coli - Phase II completed3. TA-NIC Inactivated cholera toxin - Phase II completed

Ethanol (Alcohol) National Institute on Alcohol Abuse and Alcoholism

(NIAAA) defines ‘at risk’ drinking as1. >14/week or >4/occasion – for men2. >7/week or >3/occasion – for women A drink is any beverage containing 12g of Alcohol. Neurological affliction – Wernicke’s encephalopathy,

Korsakoff’s psychosis, seizures Organ damage – Liver cirrhosis, cardiomyopathy Malignancies – Hepatic, oropharyngeal Tolerance – subjective and behavioural effects

Alcohol Withdrawal Syndrome

TREATMENT-Maintain nutrition, electrolyte balance. Glucose IV Delirium – Diazepam IVTo prevent seizures – CarbamezapineAutonomic hyperactivity – ClonidineReplacement – BZD (oxazepam, lorazepam), Carbamezapine

Alcohol craving, tremor, irritability, nausea, sleep disturbance, hypertension, visual hallucinations, delirium tremans

Alcohol Dependence Physical, psychological Treatment of Dependence1. Detoxification2. Rehabilitation Drugs used1. Aversion drugs – Disulfiram2. Opioid antagonists – Naltrexone3. DA antagonists – Tiapride (experimental)4. NMDA receptor antagonist – Acamprosate5. Supporting drugs – Lithium, Ondansetron, Topiramate.

Treatment Of Dependence

DISULFIRAM (ANTABUSE)• Irreversible alcohol dehydrogenase inhibitor• Acetaldehyde accumulation• Distressing symptoms like flushing, burning,

throbbing headache, perspiration, uneasiness, tightness in chest, dizziness, vomiting, visual disturbances, mental confusion, postural fainting, circulatory collapse: 1-4 hours

• Dose dependent hepatotoxicity• No alcohol for 12hrs before administration• 500mg/d for 1 week 250mg daily for 1 year.

Treatment Of Dependence NALTREXONE• Blocks alcohol induced DA

release in N. accumbens• Used only after

detoxification• Reduces urge, craving• 50mg OD• Max 12-16 weeks• Dose dependent

hepatotoxicity• Once a month depot

preparation - VIVITRIOL

ACAMPROSATE• GABA analogue,

agonist at GABAA• Weak NMDA

antagonist• Reduces voluntary

consumption, craving

• As effective as Naltrexone, combined

• Given soon after withdrawal

• 666mg 2-3 times a day

Benzodiazepines GABA receptor – Chloride Channel Complex. Ventral Tegmental Area – GABAA receptors

disinhibition of DA neurons. Tolerance – sedative, anti-convulsant Cross tolerance – Other CNS depressants Withdrawal symptoms:

Anxiety, agitation ↑ sensitivity to light & sound Muscle cramps Myoclonic jerks, sleep disturbances

Treatment-Overdose – Flumazenil.Dependence: physical, psychological – mild.

Barbiturates

Use has declined after the introduction of benzodiazepines.

Acts on GABA receptor – Chloride Channel complex. Tolerance: disappears after 1-2 weeks of abstinence. Cross tolerance – other CNS depressants. Dependence: 1. Physical, Psychological. 2. Treatment – symptomatic.3. Slow withdrawal over 1-3 weeks4. Replacement, if required, Chlordiazepoxide 50mg or

Diazepam 10mg

Phencyclidine Angel dust. Date rape drug 1950, Phencyclidine – anaesthetic –

post-op delirium and hallucinations – abandoned.

1970, abuse. Non competitive NMDA receptor

antagonist Inhibits reuptake of DA, 5HT, NE Tolerance, dependence, withdrawal

may be seen

KETAMINE• Dissociative

anaesthesia• Anterograde

amnesia• Date rape

drug

Cocaine Erythroxylon coca Isolated – Albert Neimann, 1860 Psychostimulant properties – Sigmund Freud, 1884 Ocular anaesthetic – Carl Koller, 1886

Available as1. Cocaine hydrochloride – IV, Intranasally2. Crack Cocaine – Inhaled, Smoked.3. Leaves – chewed 4. Speed ball – Cocaine + Heroin

Cocaine

• Blocks reuptake of DA

• Activates dopaminergic system

• Inhibits 5HT and tryptophan reuptake –enhancement of excitatory effect of DA

• Onset: rapid• Lasts – smoked: 20mins,

intranasal: 1 to 1.5 hours

• With alcohol - COCAETHYLENE – longer and more toxic.

• Dependence – psychological, little physical

• Reverse tolerance

Cocaine Euphoria, excitement, mental confusion, restlessness,

tremors, muscle twitching, convulsions, unconsciousness, respiratory depression, death – in a dose dependent manner.

Increases the power of endurance. COCAINE BUGS Stimulates Vagal centre, VMC, vomiting centre,

temperature regulating centre. Withdrawal:1. Lasts 1-3 weeks2. Bradycardia, fatigue, sleepiness, dysphoria,

anhedonia.3. Treatment: Supportive.

Drugs Under Trials

Disulfiram – inhibits DA β- carboxylase, thus counteracting effect of cocaine.

VACCINE• Attempts began in

1992.• A recent approach

was the TA-CD -Inactivated cholera toxin vaccine (Phase 3 complete).

• No significant difference in its efficacy as compared to a placebo.

• Thus till date there are no FDA approved anti-cocaine vaccines.

1. Topiramate

2. Lamotrigine

3. GHB4. Modafinil

Amphetamines & related agents

Superman drugs, Billy Whizz, Speed Non catecholamine sympathomimetic amine Potent CNS stimulant with weak peripheral

cardiovascular actions. Isomers 1. Dexamphetamine2. Methamphetamine (more central action, abused)

Amphetamine Toxicity

Euphoria, restlessness, insomnia, panic, aggression, excitement leading to confusion, delirium, hallucinations, acute psychotic state (Amphetamine psychosis).

Hypertension, palpitation, arrhythmias, vomiting, abdominal cramps, vascular collapse, convulsions, coma, death.

Treatment:1. Sedation 2. Acidification of urine3. Chlorpromazine4. Haloperidol may be used.

Amphetamine Withdrawal Syndrome

Chronic fatigue Mental depression Asthenia, tremors GI disturbances Drowsiness Lethargy, intense craving.

Ecstasy (MDMA) Methylene Dioxy MethAmphetamine Raves Synthesis, release and inhibition of reuptake of 5HT

(psychomimetic effect) Release of DA and NE (initial euphoria followed by

dysphoria) 5HT > DA/NE Chronic: psychosis, OCDs, cognitive impairment.

Ecstasy (MDMA) Mid week blues – depression, irritability,

aggression. Toxicity – hyperthermia, metabolic acidosis,

dehydration excessive water intake water intoxication: hyponatremia, cerebral oedema, seizures, death.

Also, diuresis (by secondary inhibition of ADH). Treatment- Supportive. Withdrawal – mood offset, depression – 1 week.

Inhalants Recreational exposure to chemical vapors such as

nitrates, ketones and aliphatic and aromatic hydrocarbons

Sniffing Prevalent in children Leads to euphoria, excitement, dizziness, slurred

speech, apathy, impaired judgement, coma, death is due to respiratory depression, arrhythmias or asphyxia

No specific treatment

De-addiction Centres in Pune

Muktangan Rehabilitation Centre, Yerwada, Pune. Chaitanya Mental Health Care & Rehab Centre, Warje,

Pune Kripa Foundation, Pune Aasra Foundation, Pune Anandvan De-addiction Centre, Kharadi, Pune Truecare Trust, Pune. deaddictioncentres.in/city/pune

Recent advances DRUG USE For De-addiction Dronabinol Marijuana AddictionDynorphin Opiate Related Disorders

Piracetam Cocaine Related Disorders

Modafinil Methamphetamine Addiction

Ondansetron Alcohol AbuseBaclofen Alcohol AbuseTopiramate Alcohol AbuseZonisamide Alcohol AbuseLevetiracetam Alcohol Abuse

THANK YOU…