DRUG OF ABUSEBy: Dr.Israa Omar

DRUG DEPENDANCE

• It refers to the state of affairs when administration of drug is sought compulsively, leading to disturbed behavior if necessary to secure its supply.

• It comprises physical dependence, which there is distinct symptoms of withdrawal, and psychological dependence, which is craving for the drug .

PHYSICAL DEPENDANCE

• (tolerance and withdrawal syndrome) • Tolerance: The decrease in a pharmacological effect

on repeated administration of the drug

• Withdrawal symptoms: may be experienced upon discontinuation. Some of these symptoms are generally the opposite of the drug's direct effect on the body.

PHYSICAL DEPENDANCE

•Withdrawal symptoms( abstinence syndrome) can vary significantly among individuals and among drugs, but there are some commonalities. It is often characterized by depression, anxiety and dysphoria

PHYSICAL DEPENDANCE

• In general, the longer the half-life of the drug, the longer the acute abstinence syndrome is likely to last. However, with drugs with a longer half-life, the acute abstinence syndrome will be much milder than that of those with shorter half-lives.

DRUG ADDICTION

• It is not clearly defined but generally it refers to the state of severe psychological dependence that outlasts the physical withdrawal syndrome.

• Drug abuse and substance abuse are more general terms, meaning recurrent use of illicit substances

REWARD PATHWAYS• virtually all dependence-inducing drugs so far tested,

activate the REWARD PATHWAY - mesolimbic dopaminergic pathway, which runs from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens and limbic region positive reinforcing effect.

• addictive drugs increase the release of dopamine in the nucleus accumbens even though primary sites of action are generally elsewhere in the brain

• the hedonic effect of dependence-producing drugs results from activation of this pathway, rather than from a subjective appreciation of the diverse other effects (e.g. alertness or stimulation)

• Importance for drug-seeking behaviour

• MAJOR GROUPS OF DRUGS THAT ARE SUBJECT TO ABUSE:

1. Opioids analgesics: Morphine and Heroin2. General CNS depressant: Ethanol,

Barbiturates , Anesthetics and solvents3. Anxiolytics drugs: Benzodiazepines4. Psychomotor stimulant : Amphetamines,

Cocaine, Caffeine and Nicotine 5. Psychotomimetic: LSD, Cannabis, Mescaline

and Phencyclidine

NICOTINE AND TOBACCO• It appear to be the only pharmacologically active

substancesin tobacco smoke• One cigarette contain about 9-17mg of nicotine,

of which 10% is normally absorbed • In the brain it causes neuronal excitation that can

be blocked by mecamyline• In the spine it inhibits spinal reflex and thus

causing muscle relaxation • In the peripheral tissues, nicotine stimulates the

receptors at the ganglion and causes tachycardia, hypertension and reduced GI motility

MAIN HEALTH RISKS

• Cancer: lung mouth, throat, esophagus pancreas and kidney

• Coronary heart disease and peripheral vascular disease

• Chronic bronchitis • Deleterious effects in pregnancy: growth

retardation, low birth weight, increased abortion rate and perinatal mortality

ADVERSE EFFECTS• Tolerance: to peripheral (not central)

ganglionic stimulation, perhaps due to desensitization of receptors

• Physical dependence craving : increased irritability, anxiety, impaired performance of psychomotor tasks, aggressiveness and sleep disturbances, headache increased appetite lasts for 2-3 weeks :

• Psychological dependence and addiction

TREATMENT OF NICOTINE DEPENDENCE

• Nicotine replacement therapy–Nicotine in patches (controlled release),

chewing gums, nasal sprays several times daily (short effect)

• Adjunct therapy–Bupropion, TCAs and MAOI –Clonidine – rarely used due to the side-effects

(hypotension, drowsiness…)–Mecamylamine–Counselling the patients is very important

ETHANOL

• Most commonly taken substance leading to physical dependence (it is legal for adults!)

• Rapid absorption after oral administration (measurable concentration after 5 min), immediately from the stomach

• Wide distribution to the whole body fluids• More than 90% of ethanol is metabolised,

less than 5-10% excreted unchanged in expired air and in urine

• Saturation character of metabolism

METABOLISM OF ETHANOL

• Main metabolism via 2 subsequent oxidations:a) cytoplasmic alcoholdehydrogenase

→acetaldehyde b) aldehydedehydrogenase →acetic acid this enzyme can be inhibited by various substances →‘disulfiram effect’ (disulfiram but also chlorpropamide, nitrofurantoin etc.) Symptoms: nauzea, flushing, tachycardia, hyperventilation, panic

Limiting factor for ethanol metabolismis a NAD+ availability

PHARMACOLOGICAL EFFECTS OF ETHANOL

1. CNS EFFECTS- mainly depressant action at the cellular levelsymptoms of acute intake:- slurred speech, euphoria, motor incoordination, increased self-confidence, decreased concentration and learning ability.- higher plasma levels lead to mood lability, later ataxia, stupor and coma, death from respiratory failure2. effect on peripheral systems

-cutaneous vasodilatation ‘warm feeling’ and tachycardia,↑salivary and gastric secretion,↑ hydrocortisone, oxytocin secretion and ADH

TOLERANCE AND DEPENDENCE• Tolerance – it develops over 1-3 weeks of continuing

administration = 2-fold decrease in alcohol potency. There is a cross-tolerance with many anaesthetics .

• Mechanism: not well explained, changes in CNS neurons – down-regulation of GABAA-receptors, up-regulation of voltage-gated Ca channels and NMDA receptors?

• Physical abstinence syndrome ( in 24-36h): tremor, nausea, sweating, fever, occasionally hallucinations and epilepsy-like seizures!

• ‘delirium tremens’ over few following days: confusion, agitation, aggression, unpleasant hallucinations

TREATMENT OF ALCOHOLISM• Disulfiram – blockade of aldehydedehydrogenase

cummulation of acetaldehyde - nausea, flushing, tachycardia, hyperventilation, panic…Aim: to make alcohol consumption unpleasant and intolerable

• Naloxone and naltroxone – reduces alcohol-induced reward (unclear mechanism)

• The drugs used to alleviate the acute abstinence syndrome: benzodiazepines, clonidine (inhibits exaggerated neurotransmitter release) and propranolol (blocks excessive sympathetic activity).

CANNABIS AND CANNABINOIDS• Extracts of the hemp plant;originally from

Himalaya and Kashmir• Marijuana - dried leaves and flower heads• Hashish - extracted resin• Active substances: cannabinoids (lipophilic non-

alkaloid natural compounds)• Routes of administration: mainly inhaled in

cigarette smoke

PHARMACOLOGICAL EFFECT OF CANNABIS

On CNS: combination of psychotomimetic, depressant effect– a feeling of relaxation, well-being and euphoria -

without accompanying aggression– Uncontrolled laughing without reason– a feeling sharpened sensory awareness– impairment of motor coordination (driving), short-

term memory and judgement. Feeling of time passing slowly, depersonalisation; increased appetite

– Analgesia, antiemetic action– In high doses: hallucination, paranoia, anxiety

PHARMACOLOGICAL EFFECT OF CANNABIS

peripheral effects:– vasodilatation (obvious on conjunctive

vessels)– tachycardia–Bronchodilation (but opposite may appear

during smoking)– reduction of intraocular pressure

MECHANISM OF ACTION• Through cannabinoid receptors (GPCR type)– CB1- brain – highly abundant in: hippocampus

(memory), cerebellum (loss of coordination), and substantia nigra (motor disturbances), hypothalamus (appetite) and mesolimbic dopaminergic pathway (reward) and cortex.

– Mostly localised presynaptically – their activation inhibits neurotransmitter releaseTheir paucity in the brain stem lack of serious respiratory and cardiovascular toxicity.• Endogenous agonist: anandamide

– CB2- periphery - immune system (immunosuppressive effects?!)

PHARMACOKINETICS

- lipophilic compound - well absorbed, highly bound to plasma proteins, widely distributed and partially sequestrated in body fat → excretion lasts for days (can still be detected in urine) - liver metabolism to mostly inactive metabolites

HARMFUL EFFECT

- Relatively safe from the viewpoint of acute drug overdose - Problems are rather with chronic use: -Somatic effects: decreased testosterone and sperm count -Long-term psychological changes: apathy, impaired memory and decision ability, may promote schizophrenia in pre-disposed patients

TOLERANCE AND DRUG DEPENDENCE

• Tolerance and physical dependence occur only to a minor degree in heavy users

• Withdrawal syndrome: weak and usually mild irritability, restlessness, confusion, sweating tremor and sleep disturbances

THERAPEUTIC USE OF CANNABINOIDS?

• Synthetic analogues– Nabilone and dronabilone

• Potential indications– Antiemetic therapy in cancer chemotherapy– Analgesia– Glaucoma– Multiple sclerosis

• Therapeutic values and utility?• Legal limitations

PSYCHOTOMIMETIC DRUGS (HALLUCINOGENS)

• affect thought, perception and mood without causing psychomotor stimulation or depression

• Effects: thoughts and perceptions tend to become distorted and dream-like, colours and sounds are more sharp. Induction of euphoria and happiness.

• Different kind of hallucination (visual, auditory, tactile and olfactory appear). Thought process tend to be illogical and disconnected but subject mostly retain insight that these effects are drug-induced. Increased sense of empathy.

HALLUCINOGENS

• Major groups/drugs (different classification in literature)–LSD and related compounds–MDMA and related compounds–Phencyclidine and ketamine

LSD (LYSERGIC ACID DIETHYLAMIDE)

Originally produced as a drug candidate in Sandoz Labs in 1938 by Albert Hoffman It is among the most potent drugs known so far Mechanism of action: acting on different 5-HT receptors in CNS• mainly as agonist on 5-HT2A autoreceptors in

CNS firing of 5-HT neurons in Raphe N• Somatic effects: sympathomimetic (↑blood p

and HR, neurological (tremor, ataxia)• Tolerance: develops quickly (on CNS effects)• Adverse effects and dangers: persistent mental

disorder, schizophrenia, injury due to violent behaviour

OTHER HALLUCINOGENS• MDMA (MethylenDioxyMethAmphetaminem, ecstasy)– Dance-floor drug– Stimulant and hallucinogenic effects (related to

amphetamines)– Danger in acute overdose: exhaustions, dehydratation,

hyperpyrexia, arrhythmias

• Phencycline („angel dust“, PCP)– Chemically related to ketamine (anaesthetic drug) and

originally also developed as a drug with this indication– Not so frequent among abusers, unpleasant vegetative

effects – Some delusions and/or hallucination may turned into

the violent behaviour

PSYCHOMOTOR STIMULANTS

1)AMPHETAMINES AND RELATED DRUGS

2)COCAINE

3)METHYLXANTINES (CAFFEINE )

AMPHETAMINES AND RELATED COMPOUNDS

• substances: amphetamine, methamphetamine and other drugs like ephedrine, phentermine, methylphenidate and MDMA.

• Routes of administration: oral, nasal, inhalation and parenteral

• Mechanism of action: indirect CNS „sympathomimetic“ effect – release of monoamines (noradrenaline, dopamine, or 5-HT) from nerve terminals in the brain

• Main effects on CNS: locomotor stimulation, euphoria and excitement, increased self-confidence,

stereotyped behaviour, resistance to fatigue, decreased appetite, anorexia

• Peripheral effects: tachycardia and palpitations, ↑blood pressure, ↓GIT motility

AMPHETAMINES AND RELATED STIMULANTS

• Tolerance develops rapidly to the peripheral sympathomimetic and anorexic effects, but more slowly to the central effects

• no clear-cut physical withdrawal syndrome → dependence seems to be a consequence of the unpleasant after-effects (i.e. fatigue, lethargy, anxiety, depression, hunger) and the effort to avoid them

• full-blown dependence occurs in 5% of users – characterized by strong craving, increased doses, and common uncontrolled ‘runs’)

• Amphetamine psychosis – closely resembles the Schizophrenic attack – incoherent thought, hallucinations, paranoia, aggression.

• Therapeutic use: minimal e.g., narcolepsia ,hyperkintic syndrome and treatment of obesity)

COCAINE• the most expensive drug illegally sold• Routes of administration: salt - nasal or i.v. , free base:

smoking-inhalation • MECHANISM OF ACTION:

inhibition of catecholamine Re-uptake increase noradrenaline and dopamine transmissionindirect „sympathomimetic“ agentPharmacological effects: very similar to those of amphetamines yet less prone to cause stereotyped behaviour, paranoia, delusions

• Duration of effect is much more shorter (30 min, i.v.) than in amphetamines, rapid metabolism – liver and plasma esterase (hair deposit of metabolites).

• no clear-cut physical dependence syndrome but depression, tiredness and dysphoria coupled with very intensive craving for the drug (strong psychological dependence

COCAINE • Tolerance: in most abusers is to euphoria• Intoxication (overdose): tremor, hypertension,

tachycardia, arhythmias, cardiac pain, hyperpyrexia, convulsions and shock even with fatal consequencesLong term abuse

• Characteristic behavioural changes: paranoia, anxiety, aggression, loss of social contacts

• Increased risk of coronary and cerebral thrombosis• slowly developing damage to myocardium leading to

heart failure may appear• Therapeutic use: rarely as a local anaesthetic drug in

ophthalmology (event. nose/throat surgery)

METHYLXANTHINES• natural alkaloids occurring in various beverages, namely tea,

coffee, cocoa and cola-flavored drinks• substances: caffeine, theophylline, theobromine• a cup of coffee or strong tea contains 50-100 mg of caffeine Pharmacological effects:• CNS stimulation • diuresis (vasodilatation of the afferent glomerular arteriole)• stimulation of cardiac muscle• relaxation of smooth muscle, especially bronchial.MECHANISMS:1) inhibition of phosphodiesterase, responsible for intracellular

metabolism of cAMP2) antagonism on both A1 and A2 adenosine receptorstolerance and habituation develop to a small extent and withdrawal

effects are very slight (headache, fatigue)

THANK YOU Reference:RANG AND DALE PHARMACOLOGY