DRUG OF ABUSE

1. DRUG OF ABUSE By: Dr.Israa Omar

2. DRUG DEPENDANCE • It refers to the state of affairs when administration of drug is sought compulsively, leading to disturbed behavior becomenecessary to secure its supply. • It comprises physical dependence, where there is distinct symptoms of withdrawal, • and psychological dependence, which is craving for the drug .

3. 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.

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

5. 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.

6. 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

7. MAJOR GROUPS OF DRUGS THAT ARE SUBJECT TO ABUSE: • Opioids analgesics: Morphine and Heroin • General CNS depressant: Ethanol, Barbiturates , Anesthetics and solvents • Anxiolytics drugs: Benzodiazepines • Psychomotor stimulant : Amphetamines, Cocaine, Caffeine and Nicotine • Psychotomimetic: LSD, Cannabis, Mescaline and Phencyclidine

8. Nicotine and tobacco • Nicotine isthe only pharmacologically active substances in 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Limiting factor for ethanol metabolism is a NAD+availability

15. PHARMACOLOGICAL EFFECTS OF ETHANOL 1. CNS EFFECTS - mainly depressant action at the cellular level symptoms 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(a condition near un-consciousness )and coma, death from respiratory failure 2. effect on peripheral systems -cutaneous vasodilatation ‘warm feeling’ and tachycardia,↑salivary and gastric secretion,↑ hydrocortisone,  oxytocin secretion and ADH

16. 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

17. TREATMENT OF ALCOHOLISM • Disulfiram – blockade of aldehydedehydrogenase acummulationof acetaldehyde - nausea, flushing, tachycardia, hyperventilation, panic(fear of death within a few days) 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).

18. CANNABIS AND CANNABINOIDS • Extracts of the hemp plant;originallyfrom 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

19. PHARMACOLOGICAL EFFECT OF CANNABIS 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(personality disorder as well as mental illness), anxiety

20. PHARMACOLOGICAL EFFECT OF CANNABIS peripheral effects: • vasodilatation (obvious on conjunctive{at place of union OR Join} vessels) • tachycardia • Bronchodilation (but opposite may appear during smoking) • reduction of intraocular pressure

21. 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 release Their paucity(few,less) in the brain stem  lack of serious respiratory and cardiovascular toxicity. • Endogenous agonist: anandamide • CB2- periphery - immune system (immunosuppressive effects?!)

22. 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

23. 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

24. 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

25. 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

26. PSYCHOTOMIMETIC DRUGS (HALLUCINOGENS) • They 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(the ability to understand the thoughts & emotions of another person).

27. HALLUCINOGENS • Major groups/drugs (different classification in literature) • LSD and related compounds • MDMA (MethylenDioxyMethAmphetamine) and related compounds • Phencyclidine and ketamine

28. LSD (LYSERGIC ACID DIETHYLAMIDE) 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-HT2Aautoreceptors in CNS   firing of 5-HT neurons in Raphe N • Somatic effects: sympathomimetic (↑blood pand HR,neurological (tremor, ataxia) • Tolerance: develops quickly (on CNS effects) • Adverse effects and dangers: persistent mental disorder, schizophrenia, injury due to violent behaviour

29. OTHER HALLUCINOGENS • MDMA (MethylenDioxyMethAmphetamine, 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(growing) effects • Some delusions and/or hallucination may turned into the violent behaviour

30. PSYCHOMOTORSTIMULANTS 1)AMPHETAMINES ANDRELATED DRUGS 2)COCAINE 3)METHYLXANTINES (CAFFEINE )

31. 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(fixed & hard) behaviour, resistance to fatigue, decreased appetite, anorexia • Peripheral effects: tachycardia and palpitations, ↑blood pressure, ↓GIT motility

32. 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(personality disorder as well as mental illness), aggression. • Therapeutic use: minimal e.g.,narcolepsia(tendency of sleep) ,hyperkintic syndrome and treatment of obesity)

33. 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 transmission indirect „sympathomimetic“ agent Pharmacological 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

34. COCAINE • Tolerance: in most abusers is to euphoria • Intoxication (overdose): tremor, hypertension, tachycardia, arhythmias, cardiac pain, hyperpyrexia, convulsions and shock even with fatal consequences Long 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)

35. 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 50-100mg of caffeine Pharmacological effects: • CNS stimulation • diuresis (vasodilatation of the afferent glomerular arteriole) • stimulation of cardiac muscle • relaxation of smooth muscle, especially bronchial. MECHANISMS: • inhibition of phosphodiesterase, responsible for intracellular metabolism of cAMP • antagonism on both A1 and A2 adenosine receptors tolerance and habituation develop to a small extent and withdrawal effects are very slight (headache, fatigue)

36. THANK YOU Reference: RANG AND DALE PHARMACOLOGY