Drug of abuse

Drug of abuse Drug of abuse is usually taken to mean the use of an illicit drugs or the excessive or nonmedical use of a licit drug. A primary motivation for drug abuse appear to be the anticipated feeling of pleasure derived from the CNS effects of the drug.

High-yield terms to learn Abstinence syndrome: term used to describe the signs and symptoms that occur on withdrawal of a drug in a dependent person Addiction: compulsive drug using behavior in which the person uses the drug for personal satisfaction, often in the face of known risks to health; formerly termed psychological dependence.

High-yield terms to learn Dependence: a state characterized by signs and symptoms, frequently the opposite of those caused by a drug, when it is withdrawn from the chronic use or when the dose is abruptly lowered; formerly termed physical or physiologic dependence

High-yield terms to learn Tolerance: decrease response to drug, necessitating larger doses to achieve the same effect. Withdrawal symptoms: may be experienced upon discontinuation. Some of these symptoms are generally the opposite of the drug's direct effect on the body.

Major groups of drugs that are subject to abuse Opioids analgesics: Morphine and Heroin Sedative/hypnotics. Stimulants. Hallucinogens Marjuana Inhalants Steroids

1. Opioid analgesics The most commonly abused drug in this group are heroin, morphine, codeine, oxycodone and among health professionals, meperidine and fentanyl. The effect of IV heroin are described by abusers as a rush or orgasmic feeling followed by euphoria and then sedation IV administration is associated with rapid development of tolerance , dependence and addiction.

2. Sedative- hypnotics The group include ethanol, barbiturates, and benzodiazepines. Sedative-hypnotics reduce inhibitions, suppress anxiety, and produce relaxation. All of these action are thought to encourage repetitive use.

Sedative- hypnotics (effects) Flunitrazepam, a potent rapid onset benzodiazepines with marked amnestic properties, has been used in (date rape). Added to alcoholic beverages, chloral hydrate or ϒ-hydroxybutrate (GABA agonist) also render the victim incapable of resisting rape.

Withdrawal The most important signs of withdrawal derive from excessive CNS stimulation and include anxiety, tremor, nausea and vomiting, delirium and hallucination. Seizures are not uncommon and may be life threating.

Treatment of withdrawal Treatment of withdrawal involves administration of long acting sedative-hypnotics (chlordiazepoxide or diazepam) to suppress the acute withdrawal syndrome, followed by gradual dose reduction. The opioid receptor antagonist naltrexone reduces alcohol-induced reward (unclear mechanism) Disulfiram – blockade of ALDH lead to accumulation of acetaldehyde - nausea, flushing, tachycardia, hyperventilation, panic… Aim: to make alcohol consumption unpleasant and intolerable

3. Stimulants A. Methylxansines Natural alkaloids occurring in various beverages, namely tea, coffee, cocoa and cola-flavored drinks Substances: caffeine, theophylline, theobromine Pharmacological effects: CNS stimulation tremor, insomnia, and nervousness Diuresis (vasodilatation of the afferent glomerular arteriole) Stimulation of cardiac muscle Relaxation of smooth muscle, especially bronchial.

B. Nicotine It appear to be the only pharmacologically active substances in tobacco smoke Effects : 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

Nicotine 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 Severe toxicity has been described in children who ingest nicotine gum or patches

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 Mecamylamine Varenicline : nicotinic receptor partial agonist which occlude the rewarding effect of nicotine Rimonabant:  inverse agonist for the cannabinoid receptor CB1, is also used in smoking cessation

C. Amphetamines Substances: Amphetamine, dextrometamphetamine and methamphetamine 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 behavior, resistance to fatigue, decreased appetite, anorexia

Amphetamines 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’)

Amphetamines Amphetamine psychosis: Schizophrenic like attack Chronic abuse can cause necrotizing arteritis leading to cerebral hemorrhage and renal failure. Therapeutic use: minimal e.g. narcolepsy

D. Cocaine The most expensive drug illegally sold It act by Inhibiting catecholamine Re-uptake Pharmacological effects are very similar to those of amphetamines but with less psychotic effects Metabolized in liver and 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)

4. Hallucinogens 1. Phencyclidine (PCP) Antagonist at NMDA receptors. The most dangerous of the hallucinogenic agents. Chemically related to ketamine (anesthetic drug) and originally also developed as a drug with this indication Not so frequent among abusers, unpleasant vegetative effects Can cause severe delusions and/or hallucination which may turned into the violent behavior Overdose can cause nystagmus, marked hypertension, and seizures, which can be fatal.

2. LSD (lysergic acid diethylamide) Exact mechanism is unknown but it is thought ↑firing of 5-HT neurons Interestingly it dose not cause dependence. Sympathomimetinc effect Adverse effects: persistent mental disorder, schizophrenia, injury due to violent behavior

5. Marijuana 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

Mechanism of action Through cannabinoid receptors (GPCR type) CB1- brain; Mostly localized presynaptically, their activation inhibits neurotransmitter release. Their paucity in the brain stem → lack of serious respiratory and cardiovascular toxicity. Endogenous agonist: anandamide CB2- periphery - immune system (immunosuppressive effects?!)

Pharmacological effect 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 judgment. Feeling of time passing slowly, depersonalization; increased appetite Analgesia, antiemetic action In high doses: hallucination, paranoia, anxiety

Pharmacological effect Peripheral effects: vasodilatation (obvious on conjunctive vessels) tachycardia Bronchodilation (but opposite may appear during smoking) reduction of intraocular pressure 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

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

6. Inhalants Certain gases or volatile liquids are abused because they provide a feeling of euphoria or disinhibition. This group include: A. Anesthetics Nitrous oxide, chloroform, and diethylether. Such agents are hazardous because they affect judgment and include loss of consciousness

B. Industrial solvents Found in gasoline, paint thinners, glues and shoe polish. Because their ready availability, they are most frequently abused by children in early adolescence. Are toxic to liver, kidneys, lungs, bone marrow, and peripheral nerves and cause brain damage.

C. Organic Nitrites Amyl nitrite, isobutyl nitrate, and other organic nitrates are referred to as poppers and are mainly used as sexual intercourse enhancer . Causes dizziness, tachycardia , hypotension and flushing. With the exception methaemoglobinaemia the adverse effect are usually mild .

7. Steroids Effect sought by the abusers are increases in muscle mass and strength rather than euphoria . Adverse effects: Behavioral manifestation include increase libido and aggression(roid rage) Severe acne and masculinization in female Hepatic dysfunction has been reported , Increase risk of myocardial infarction A withdrawal syndrome has been described with fatigue and depression of mood.

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