Drugs of abuse

1. Drugs of abuse Dr B.Vahabi

2. Drugs of abuse Learning outcomes • Differentiate between drug use and abuse • Identify different classes of drugs • Explain the mechanism of action by which different drugs mediate their effects

3. Is defined as self-administration of any drug in a manner that differs from approved use in that culture. A number of therapeutic drugs are abused because of their effects on the nervous system. The effects of many drugs of abuse are often complicated by the impurity Drug abuse

4. Risks associated with drug abuse • Acute toxicity • Behavioral impact (incapable of concentration, learning or clear thought) • Toxic effects of drug contaminants • Secondary medical problems such as psychiatric problems • Risk of dependency • Negative social, occupational, marital consequences.

5. Drug dependence/addiction • Describes the human condition in which drug taking becomes compulsive • State of physical as well as psychological dependence • Acute recreational drug use is generally positively reinforcing/rewarding • The biological/physiological basis for the reward system lies in the brain

6. The biological basis of dependence- the reward pathway Dependence is related to dopaminergic activity in mesolimbic system of the brain This system is involved in regulation of mood/ motivation and reward processes Mesolimbic system is activated by impulses arising from ventral tegmental area of the brain Impulses are relayed through the medial forebrain bundle via the nucleus accumbens to the prefrontal cortex Stimulation of postsynaptic D2 dopaminergic receptors activation of Gi (inhibitory) proteins reduction of cAMP levels in nucleus accumbens central to drug seeking behaviour

7. Chronic adaptations • Chronic exposure can cause common adaptations in dopamine function • Impaired dopamine system baseline levels of dopamine are reduced • Normal rewarding stimuli becomes less effective negative emotional symptoms observed between drug exposures or upon drug withdrawal • Chronic drug exposure seems to sensitize the dopamine system

8. Recreational drugs: Nicotine, Cannabis MDMA (Ecstasy) CNS stimulants: Cocaine, Caffeine Drugs of abuse Opiates: Heroin Opium • CNS • Depressants: • Alcohol • Benzodiazepines

9. CNS depressants • Display an inhibitory effect on brain activity • Major classes of CNS depressants: • Alcohol • Benzodiazepines • Barbiturates • Repeated use results in chronic tolerance, addiction and unpleasant withdrawal symptoms

10. Alcohol • Most frequently abused drug in our society • Refers to beverages containing ethyl alcohol or ethanol • Infinite solubility in water and slight charge of ethanol allows formation of an equilibrium in the water-rich areas of the body • Initial effects: depression of inhibitory neurons relaxation • Followed by: Progressive depression of all CNS functions • All effects are closely related to blood alcohol concentrations (BAC)

11. Mechanism of action of alcohol • The main effects are on the CNS • The main theories of ethanol action: • Enhancement of GABA (gamma-aminobutric acid)-mediated inhibition • Inhibition of Ca2+ entry through voltage-gated calcium channels • Inhibition of glutamate NMDA (N-methyl-D-asparate) receptor • Inhibition of adenosine transport • The common neurochemical mechanism of action is via GABAA receptors

12. GABAA receptors and alcohol Cl- Cl- Cl- Ethanol Cl- Cl- Hyperpolarization of the postsynaptic cell

13. Pyschological effects of alcohol • Depression of circulatory and respiratory processes • Human LD50 • 500 • Confused • Lack of comprehension • Possibility of passing out • 300 • Sensory/motor capabilities severely affected • Difficulty in focusing (double vision). • 200 BAC (mg/100ml) • Definite impairment to movement • Judgement and perception • Severely compromised • 150 • Slowed reaction time • Lack of muscle coordination • 70-90 • 30-40 • Low levels of alcohol can actually improve function on memory tasks. • Detectable increase in feeling of well-being and warmth • Light-headedness • Feeling of happiness • Slight exhilaration • 10-20

14. Chronic administration causes irreversible neurological effects May be due to ethanol itself or to metabolites such as acetaldehyde Heavy drinking causes irreversible dementia and motor impairment associated with thinning of cerebral cortex Degeneration in the cerebellum and other specific regions can also occur Alcohol withdrawal symptoms such as delirium tremens and withdrawal fits Pyschological effects of alcohol NADPH NADP Microsomal oxidase NAD+ NADH Ethanol Acetaldehyde Acetate Aldehyde dehydrogenase Cytoplasmic alcohol dehydrogenase NADH NAD+

15. Effect of alcohol on the mesolimbic reward pathway

16. Cardiovascular effects of alcohol • Modest intake (1 unit per day) may have beneficial effects • Higher intake has pressor effects: raise blood pressure. Increased risk of coronary artery disease and stroke • Cardiac arrhythmias (‘holiday heart’ syndrome) can occur following more chronic abuse

17. Hepatic effects of alcohol Hypoglycaemia occurs as a result of the metabolism of alcohol in the liver lactic acidosis Lactic acidosis facilitates synthesis of saturated fatty acids which accumulate in the liver hepataitis Malnutrition as a result of chronic alcohol abuse also results in liver damage The cellular toxicity of ethanol is the main factor promoting inflammatory changes in the liver and cirrhosis

18. Sexual function and alcohol abuse Sexual desire is often increased by alcohol but the ability to sustain penile erection is reduced Direct damage to Leydig cells of the testis Reduced testostrone levels Infertility Loss of the male distribution of body hair Gynaecomastia

19. Carcinogenesis and teratogenesis Cancer of the mouth, oesophagus and liver are more common with heavy alcohol use Risk of colon and breast cancer may also be increased Fetal alcohol syndrome (FAS): Abnormal facial development Reduced cranial circumference Retarded growth Mental retardation FAS affects about 30% of children born to alcoholic mothers

20. Benzodiazepines (BDZs) • The most important group of anxiolytic and hypnotic drugs • The first BDZ, chlorodiazepoxide, was synthesized by accident in 1961 • By mid 1980s there were 17 commercially available BDZs including: • Oxazepam • Nitrazepam • Flurazepam • Diazepam

22. Mechanism of action of BDZs • BDZs act selectively on GABAA receptors • They increase the affinity of GABAA receptors for GABA • Their effect is limited by the amount of neurotransmitter available in the local microenvironment • Only effective when GABA-ergic neurons are active Benzodiazepines

24. Mechanism of action of BDZs The sensitivity to BDZs requires both a & b subunits Mutations affecting a-subunit may eliminate BDZ action Experiments on transgenic animals have provided an insight into the role of different a-subunits Mutations affecting a2-subunit mostly affects anxiolytic action Mutations affecting a1-subunit mostly affects hypnotic actions

25. Pharmacological effects of BDZs • The main effects of BDZs are: • Reduction of anxiety and aggression • Sedation and induction of sleep • Reduction of muscle tone and coordination • Anticonvulsant effect

26. What is anxiety? • In Western world diagnosis of anxiety disorders comprise around 5-10% of psychiatrically diagnosed diseases

27. Unwanted effects of BDZs • Divided to: • Toxic effects from acute overdose • Unwanted side effects during normal therapeutic dose • Tolerance and dependence

28. Acute toxicity • Less dangerous than other anxiolytic/hypnotic drugs • Overdose causes prolonged sleep without serious depression of respiration or cardiovascular function • However, in the presence of other CNS depressants (e.g. alcohol) can cause life threatening respiratory depression • Availability of an effective antagonist, flumazenil, allows for the acute overdose to be counteracted

29. Side effects during therapeutic use • The main side effects are: • Drowsiness • Confusion • Amnesia • Impaired coordination • BDZs enhance the depressant effect of other drugs such as alcohol

30. Tolerance and dependency • Tolerance occurs with BDZs • Dependence also occurs with all BDZs • Addiction is not a major problem • Stopping BDZs after weeks/months causes an increase in symptoms of anxiety • Withdrawl symptoms include: • Tremor • Dizziness • Nervousness • Loss of appetite • Convulsions

31. Barbiturates • Are far more depressant than BZDs • Produce effects similar to inhalation of anaesthetics • The first barbiturate , barbituric acid was synthesized in 1846 • Only a few barbiturates are now used for clinical purposes due to adverse side effects

32. Mechanism of action of barbiturates • Directly open GABAA receptor Cl- channel in the absence of endogenous neurotransmitters • They stabilise the membrane at its resting potential rendering it unresponsive to physiological or electrical stimuli

33. Pharmacological/clinical effects of barbiturates • Low doses have euphoric/stimulant effect • Higher doses have hypnotic/anxiolytic effect Adverse effects • Overdosage can cause respiratory slowing and death • Dangerous effects if taken with other drugs such as alcohol

34. Recreational drugs: Nicotine, Cannabis MDMA (Ecstasy) CNS stimulants: Cocaine, Caffeine Drugs of abuse Opiates: Heroin Opium • CNS • Depressants: • Alcohol • Benzodiazepines

35. Key references • Parrott, A et al (2007) Drugs and behaviour. John Wiley & Sons Ltd. • Rang, H.P., Dale, M.M. (2007) Pharmacology. 6th ed. Churchill Livingstone. • Waller, D.G. et al (2007) Medical pharmacology and therapeutics. 2nd ed. Elsevier Saunders. • Nestler, E.J. (2005) Is there a common molecular pathway for addiction. Nature Neurosience. 8:1445-1449 • Kreek, M.J. & Koob, G.F. ( 1998) Drug dependence: stress and dysregualtion of brain reward pathways. Drug & Alcohol dependence. 51: 23-47 • Pierce, R.C. & Kumaresan, V. (2006) The mesolimbic dopamine system: The final common pathway for reinforcing effect of drug abuse. Neuroscience & Biobehavioral Reviews. 30: 215-238 • Thomas, J.D & Riley, E.P. (1998) Fetal alcohol syndrome. Does alcohol withdrawal play a role? Alcohol Health and Research World. 22:47-53