Many drugs -human beings consume -they choose to, and not because they are advised by doctors.

Society in general disapproves, Because there is a social cost Use is banned in many countries. 3 most commonly used non-therapeutic

drugs are caffeine, nicotine and ethanol-legally and freely available.

Many other drugs are widely used Others -'sport' drugs

Psychotropic drugs-Those affect brain

Used by Physician-Psychiatric diseases-can be misused or abused

Non-prescription psychotropic drugs- legal or illegal

Psychopharmacology explains how these drugs affect brain when misused or abused

They dominates the lifestyle of the individual and damages his or her quality of life

Habit itself causes actual harm to the individual or the community. [HIV, Criminal behaviour]

Addiction[Substance abuse]= Physiologic+ Psychologic dependence Psychologic =Compulsive drug

seeking, craving Physiologic = symptoms and signs

opposite to drug Tolerance-PK, PD DIAGNOSTIC and STATISTICAL MANUAL

OF MENTAL DISEASES- DSM IV

Reinforcement:Tendency of a pleasure-producing drug to lead to repeated self administration

Withdrawal-Drug is suddenly stopped— develop a withdrawal syndrome characterized by craving, dysphoria, signs of sympathetic overactivity.

Rebound -Drug (usually for a medically sanctioned use)- suddenly stopped— their symptoms come back in an exaggerated fashion.

Eg. BZDP for panic attacks suddenly stop panic attack[Rebound panic attack].

Detoxification: Tapering of a drug that has caused dependence and would cause withdrawal if stopped suddenly.

Detoxification accomplished slowly withdrawing the drug itself or by substitution of a cross-dependent drug that has a similar pharmacological mechanism of action.

Prevents withdrawal symptoms. Tapered discontinuation.

[Glucocorticoids, Anti HTN]

Mesolimbic Dopamine Pathway and the Psychopharmacologyof Reward[Reinforcement]

Natural High•Intellectual accomplishments •Athletic accomplishments •Enjoying a symphony •Experiencing an orgasm•Less intense•Brain’s own!!!

•Pleasure center •Pleasure Neurotransmitter. [DA]

Drug induced highNatural High

•Brain’s own!!!•Endorphins[Morphine!]•Marijuana (anandamide),•Nicotine•(acetylcholine)•Cocaine and• amphetamine (dopamine itself)

•Alcohol, opiates,•Stimulants,•Marijuana,•Benzodiazepines,•Hallucinogens•‘HIGH ON’ DEMAND!•Unfortunately at aPRICE

Drug-induced reward Feeding of dopamine to

postsynaptic limbic (D2) sites -furiously crave more drug to replenish dopamine

Drug stopped Individual becomes preoccupied

with finding more drug and thus beginning a vicious circle.

Few receptors Low initial response to a drug

High initial response Many receptors

High risk for ultimate abuse

Aversion to drug

Stimulants: Cocaine and Amphetamine

Cocaine•Cocaine powerful inhibitor -dopamine transporter.

•Blocking this transporter acutely causes dopamine to accumulate, •Produces euphoria,•Reduces fatigue,

•Cocaine has similar but less important actions at the NE and 5HT transporters.

Local anestheticFreud and tongue Ca

•Repeated intoxication with cocaine• Sensitization or

"reversetolerance.“ •Cocaine releases more and more dopamine.

•Doses of cocaine that previously only induced euphoria

•Now create an acute paranoid psychosis virtually indistinguishable from paranoid schizophrenia.

•The clinical effects of amphetamine Derivatives are similar to thoseof cocaine•Euphoria - less intense•Last longer than that due to cocaine

The hallucinogens are a group of agents that produce intoxication, sometimes called

a "trip,“ With changes in sensory experiences,

including visual illusions and hallucinations,

Enhanced awareness of external stimuli Enhanced awareness of internal

thoughts and stimuli.

These hallucinations are produced with a clear level of consciousness and a lack of confusion

Psychedelic is the term for the subjective experience, due to

Heightened sensory awareness, that one's mind is being expanded or

that one is in unison with mankind or the universe and having some sort of a religious experience.

Psychotomimetic means that the experience mimics a state of psychosis

•Hallucinogens such as Lysergic acid diethylamide (LSD),Mescaline, Psyloscibin, and 3,4-methylenedioxymethamphetamine (MDMA) •Partial agonists at 5HT2A receptors.

Phenylcyclidine (PCP) developed as an anesthetic Not used- psychotomimetic hallucinatory

experience. Its structurally related and mechanism-related

analogue Ketamine –Used Phenylcyclidine causes intense Analgesia, amnesia, delirium, stimulant as well as

depressant effects, Staggering gait, slurred speech, and a unique

form of nystagmus (i.e., vertical nystagmus). Catatonia (excitement alternating with stupor and catalepsy),

Hallucinations, delusions, paranoia, disorientation, and lack of judgment

Neuroprotective

Cannabis preparations are smoked THC delta-9-tetrahydrocannabinol (THC) Interact with brain's cannabinoid

receptors Triggers dopamine release from the

mesolimbic reward system Cannabinoid receptors, CB1 - brain CB2 - immune system Anandamide –endo genous cannabinoids Receptor antagonists and

analogues-?????

Nicotine-Cigarette smoking is a nicotine delivery system

•Nicotine acts directly on nicotinic cholinergicreceptors,• which are located in part on mesolimbic dopamine neurons

Reinforcing actions of nicotine similar cocaine andAmphetamine-But SUBTLE

Nicotine shuts down receptor shortly after binding to it

Neither it nor Ach can stimulate for a while[longer and much more intense euphoria with cocaine]

Pleasure of nicotine is a desirable butsmall boost in the sensation of pleasure ("minirush"), → decline untilthe smoker takes the next puff or smokesthe next cigarette.

Somewhat self-regulating –Behavioral effects less severe thancocaine

Over time, up-regulationOf receptors

Nicotine and DA release

No Nicotine and No DA releaseCRAVING

Cigarette smoking is a pulsatile nicotine delivery system

withdrawal from nicotine is characterizedby craving and agitation,

Nicotine →nAChRs- α4β2

Produces inhibitory and excitatory effects

Shows reinforcing properties

Peripheral effects → Ganglionic stimulation: tachycardia,↑ BP,and ↓GI motility.

Tolerance develops rapidly

Metabolised, mainly in the liver, within 1-2 hours.

The inactive metabolite, cotinine, has a long plasma half-life -used as a measure of smoking habits

Tolerance, physical dependence and psychological dependence (craving), and is highly addictive.

Long-term cessation succeed -20% of cases

The life expectancy of smokers is shorter than that of non-smokers

Cancer, particularly of the lung and upper respiratory tract but also of the oesophagus, pancreas and bladder

CAD and other forms of PVD Chronic bronchitis Harmful effects in pregnancy-Birth wt.,

physical and mental development↓[7yrs]

Parkinson's disease is approximately twice as common in non-smokers as in smokers

Motivation Psychological help Transdermal patch Nicotine gum Bupropion

Opiate drugs act on a variety of receptors,

“Brain's own morphine-like molecules."

Pain relievers, -Codeine or Morphine,

Drugs of abuse, -Heroin,

Euphoria, -reinforcing property.

Withdrawal syndrome Dysphoria, craving for

another dose of opiate, irritability, and signs of autonomic hyperactivity, such as tachycardia, tremor, sweating.

Piloerection ("goose bumps") associated with opiate withdrawal,

Symptoms subjectively so horrible

Opiate abuser will often stop at nothing in order to obtain another dose of opiate to relieve symptoms of withdrawal.

What may have begun as a

Quest for euphoria may End up as a Quest to avoid

withdrawal.

Alcohol acts by enhancing inhibitoryneurotransmission at GABA-A receptors Reducing excitatory neurotransmission

at the (NMDA) subtype of glutamate receptors

So alcohol enhances inhibition and reduces

excitation,

Alcohol

Decreases the actions of theexcitatory NMDA receptor complex—that is, it diminishes excitation.

•Enhancie GABA inhibition•Reduces glutamate excitation, •Enhances euphoric effects•by releasing•Opiates and endocannabinoids,•Thereby mediating its "high."

Naltrexone Blocks opiate receptors Decreases craving -increases

abstinence rates. If one drinks when taking

Naltrexone, the opiates released do not lead to pleasure, so why bother drinking?

Some patients may also say, why bother taking Naltrexone?

•Acamprosate, a derivative of the amino acid taurine, •Interacts with the NMDA receptor•Substitute s for this effect of alcohol during abstinence •Thus, when alcohol is withdrawn and the mesolimbic D2 receptors are whining for dopamine because of too much glutamate, •Alcamprosate substitution reduces neuronal hyperexcitability of alcohol withdrawal,Reduced withdrawal distress and craving.Treatment alcohol abuse and

dependence 12-step programs

Benzodiazepine

Modulators of GABA-A

•Benzodiazepine -drug-naive patient,•Acute benzodiazepine effect,•Opening the Cl- channel maximally-Enhancing inhibitory neurotransmissionAnxiolytic actions.Psychopharmacological mechanism of euphoria,Drug reinforcement

•Chronic administration of a benzodiazepine•Tolerance and dependence•Cl- channel to open less than before•But still enough to give an anxiolytic Euphoric and drug-reinforcing effect.•Less than before•Brain gets used to too much benzodiazepine at its receptors

BZDP-ACUTE ADMN.BZDP-SUDDEN WITHDRAWAL[REVERSE OF BENZODIAZEPINE INTOXICATION]

Euphoria Tranquility and lack of

anxiety Sedation and sleep Muscle relaxation Anticonvulsant effects.

Dysphoria and depression Anxiety and agitation Insomnia Muscle tension Seizures

•These actions continue until benzodiazepine is replaced•Alternatively BZDP can be tapered•So that the receptors have time to readaptwithdrawal symptoms are prevented.

Has the clinical condition benefitted? If ‘Yes” is he stable? Has the pt. limited the use within

prescribed limits? BZDP tapering programme