Sedatives and Hypnotics

1. Sedatives and Hypnotics John A. Harvey, Ph.D. Department of Pharmacology and Physiology

2. Sleep Disorders Occur in About 33% of thePopulation at Any Given Time • 30-35% due to psychiatric illness • 15-20% due to primary causes • 10-15% due to alcohol and other drugs • 10-15% due to limb movement disorders • 5-10% due to sleep apnea • 5-10% due to medical illness

3. EEG Sleep Stages • Awake – Highly Frequency – Low Amplitude • Stage 1 – Relaxed Awake -Alpha Frequency – Low Amplitude • Stage 2 – Non REM Sleep - Lower Frequency – Higher Amplitude • Stage 3&4 – Slow Wave Sleep – Very Low Frequency and High Amplitude • REM Sleep – As in Stage 1 State – But Not Awake – Dreaming occurs

4. REM Sleep • Occurs 1-Hour or More After Onset of Sleep • Sensitive to Sedative Hypnotics • State of Dreaming • Rapid Eye Movements (REM) • Ponto-Geniculo-Occipital Spikes • Muscular Relaxation • Drooling • Immediate Onset in Narcolepsy

5. REM Awake Stage 1 Stage 2 Stage 3 and 4 0 1 2 3 4 5 6 7 8 Time (hours)

6. Benzodiazepines and drugs that act at the benzodiazepine modulatory site on the GABAA receptor-chloride channel molecular complex

7. Some barbiturates used for sedation

8. Summary • Benzodiazepines and Zolpidem act at the benzodiazepine site of the GABAA complex to increase the frequency of chloride channel openings and thus increase inhibition. • Barbiturates act at the barbiturate site of the • GABAA complex to increase the duration of chloride channel openings and thus increase inhibition as well as blocking the AMPA receptor thus decreasing glutamate induced excitation.

9. Principles of Drug Abuse John A. Harvey, Ph.D. Department of Pharmacology and Physiology Drexel University College of Medicine Philadelphia, PA

10. (A) (B) (B/A) % Ever % % Risk of DrugUsedAddictionAddiction Tobacco Alcohol Illicit Drugs Cannabis Cocaine Stimulants Anxiolytics Analgesics Psychedelics Heroin Inhalants 75.6 24.4 31.9 91.5 14.1 15.4 51.0 7.5 14.7 46.3 4.2 9.1 16.2 2.7 16.7 15.3 1.7 11.2 12.7 1.2 9.2 9.7 0.7 7.5 10.6 0.5 4.9 1.5 0.4 23.1 6.8 0.3 3.7

11. Pharmacological Variables • A. Tolerance • Tolerance is the decreased effect of a drug with repeated use. • Tolerance can be 200 fold: e.g. 1.5 g of methamphetamine daily. • Tolerance is surmountable. • Tolerance is typically lost in 10 to 14 days. • Tolerance does not develop to a drug, but to the effects of the drug. • Cross tolerance occurs to members of the same drug class. • Tolerance to CNS depressants can affect the Therapeutic Index.

12. Types of Tolerance • Pharmacokinetic tolerance. Microsomal enzymes. Produces a limited amount of tolerance – 2 to 3 fold. • 2) Pharmacodynamic tolerance – cellular changes. Up and Down regulation of receptors and other consequences of altered gene expression. Responsible for large amounts of tolerance, up to 200 fold. • Behavioral tolerance – learned and conditioned. • Cross tolerance – occurs within a drug class. • 5) Inverse tolerance: sensitization – can persist for years.

13. Physical Dependence • Physical dependence: inferred from occurrence of abstinence syndrome upon abrupt drug withdrawal. • 2. Due to cellular tolerance. Neuronal homeostatic mechanisms produce adaptations that work to overcome drug effects. Thus signs of drug withdrawal are opposite to those of inltoxication. • 3. Lost in 2 to 3 weeks but other bodily adaptations may take a year or more to return to normal. • 4. Type of withdrawal syndrome depends on drug category. Cross dependence is the basis for some drug therapies. e.g. methadone. • 5. Conditioned drug dependence inferred from withdrawal symptoms to environmental stimuli in the absence of physical dependence. It is characterized by intense craving.

14. Terminology of Drug Abuse A. Non-medical or non-accepted recreational use of a drug. B. Terms used include compulsive drug use, drug addiction substance dependence. 1) Use of these terms does not imply the existence of tolerance or physical dependence. 2) Tolerance and physical dependence do not imply addiction. C. Tolerance and physical dependence are biological phenomenon resulting from frequent drug use and can occur in an individual who is not addicted to the drug.

15. CRAVING NOT ADDICTED ADDICT PATIENT DRUG WITHDRAWAL

16. Drugs are Abused Because of Their Rewarding Effects • Reward is mediated by activation of the DA mesolimbic system. • Reward involves DA release in the nucleus accumbens leading to reward/euphoria. • 3. This is a biologically determined event shared by all animals.

17. Drugs of AbuseMost powerful effects on brain functionProvide clues to endogenous ligands and their receptors

18. Psychomotor Stimulants The actions of the amphetamines and cocaine provided clues to the receptors involved in schizophrenia and the therapeutic actions of antipsychotic drugs.

19. Psychomotor Stimulant Actions and Dopamine Pathways • Clues to Schizophrenia • Neostriatal pathway to caudate/putamen produces motor stimulation, at higher doses leading to stereotyped behavior and convulsions • Mesolimbic pathway to nucleus accumbens produces elevation of mood, euphoria and reward • 3. Mesocortical pathway to limbic cortex produces enhanced attention, alertness and associative processing. At higher doses produce .paranoid psychotic reactions.

20. Therapeutic uses of cocaine • Nasopharyngeal surgery – hemostatic effect plus local anesthesia

21. Cocaine • Pharmacology. Blocks DA uptake in CNS and NE uptake in PNS. • Duration of action short (half life 10-30 min) and this leads to binging. • Tolerance to euphoric effects but also sensitization. Evidence for changes in the DAT upon chronic use. • Toxic effects due to cardiovascular effects, cerebral ischemic effects and seizures. • Fetal effects can be direct including CNS lesions or indirect due to premature birth. Growing evidence of cocaine syndrome in offspring due to abnormal development of CNS. • Clinical issues. Withdrawal leads to dysphoria, depression, fatigue and craving. No drugs available for reliable treatment. Best treatment is a 12 step program.

22. Therapeutic uses of amphetamines In ADHD • Methylphenidate (Ritalin) a DAT blocker to increase extra-cellular dopamine. • Racemic mixtures of amphetamines to release dopamine from extra-vesicular stores. For weight loss. • Amphetamine or its substituted analogs.

23. Amphetamine and its Substituted Analogs • Pharmacology. Releases DA in CNS and NE in PNS. • Same CNS, PNS and withdrawal effects as seen with cocaine. High doses produce paranoid psychotic reactions and auditory hallucinations. • High doses Tolerance to euphoric effects but also sensitization. • CNS toxicity to dopamine neurons at high doses are seen in experimental animals due to increased levels of DA. • Extreme tolerance is observed with users able to consume as much as 1.6 grams of methamphetamine per day. • Methamphetamine, phenmetrazine, methylphenidate and diethylproprion produce similar effects. • Use as diet pills (amphetamine, phenylpropanolamine) is not associated with significant abuse potential. Used for ADHD.

24. Hallucinogens, Psychotomimetics and Psychodelics • Studies of LSD led to an understanding of the role of serotonin 5-HT2A receptors in schizophrenia. • This led to the development of atypical antipsychotic drugs that are more potent antagonists at the 5-HT2A receptor.

25. Psychodelic Drugs & Serotonin: Further Clues to Schizophrenia

26. Hallucinogens, Psychotomimetics and Psychedelics Produce perceptual distortions (Hallucinogenic) and/or thought disturbances (Psychotomimetic) and/or feelings of enhanced insight and self knowledge often of a spiritual nature (Psychedelic). Psychedelics such as LSD and LSD-Like drugs all act as partial agonists at the 5-HT2A receptors located throughout brain (Cortex, hippocampus, caudate, brain stem, cerebellum, spinal cord and motor nuclei). 1. Hallucinogens: Indoleamines: LSD, DMT, Psilocybin (Psylocin). 2. Hallucinogens: Phenethylamines: Mescaline, DOM, MDA, MDMA (Ecstasy). Produce greater sympathomimetic effects through an amp;phetamine-like action.

27. Dissociative Anesthetics • Provided clues to the role of glutamate in schizophrenia and in chronic pain syndrome. • Ketamine induced psychosis thought to provide a model for development of antipsychotic drugs. • Ketamine used for chronic pain.

28. B. Dissociative anesthetics: PCP (Phencyclidine) and PCP-Like Drugs 1. PCP, ketamine, dizocilpine. 2. Act as noncompetitive blockers of the NMDA associated calcium channel. 3. All three drugs produce neurotoxicity in cortex and hippocampus. 4. Effects include emotional withdrawal, concrete thinking, and bizarre responses to projective tests, catatonic posturing, hallucinations and hostile or assaultive behaviors. 5. Withdrawal symptoms include an agitated psychotic state that can be treated with diazepam and haloperidol. 6. Thought to provide a model for psychotic behavior

30. C. Marijuana • 1. Major active ingredient is 9-Tetrahydrocannabinol (9-THC). • Two major classes of G-protein coupled receptors whose activation • leads to an inhibition of cAMP. • a) CB1 Receptor: Occurs only in brain including cerebral cortex, • hippocampus, caudate nucleus, hypothalamus, mesencephalon, • and cerebellum. • b) CB2 Receptor: Occurs only in periphery including testes, spleen, • leukocytes, lymphocytes. • c) Endogenous ligand is anandamide (Arachidonylethanolamide) an • N-amide derivative of arachidonic acid.

31. C. Marijuana (Cont) • 3. Both antagonists and agonists have been synthesized that are specific • for the two receptor subtypes. • 4. Activation of the CB1 receptor is correlated with analgesia, hypothermia, • catalepsy, decreased locomotor activity and memory disturbances. • 5. Withdrawal symptoms include restlessness, irritability, mild agitation, • insomnia, nausea-cramping and sleep disturbances. • 6. Therapeutic use has been suggested for treatment of anorexia in aids • patients, as an antiemetic during chemotherapy, analgesic in chronic • pain, in movement disorders and glaucoma. • 1) Dronabinol (Marinol), an agonist, has been developed as an • antinausea and antiemetic drug. • 2. Levonantradol has been developed for possible use as an • analgesic and antispasmodic.

32. Central Nervous System Depressants • Ethanol • 2. Benzodiazepines • 3. Barbiturates

33. ETHANOL 1 Drink = shot of liquor, glass of beer, glass of wine

34. A. Ethanol • Pharmacology. Reduces excitation by inhibition of receptor and enhances • inhibition by actions at modulatory site on GABA-A supramolecular • complex, and at 5-HT3 receptors located on GABA neurons. • Tolerance results in a decrease in the therapeutic index since tolerance • to the depression of respiratory neurons occurs more slowly than to • sedation. Cross-tolerance to other sedative-hypnotic drugs such as • benzodiazepines and barbiturates. • Cellular tolerance involves up-regulation of the NMDA receptor and • down regulation of GABA receptor and thus withdrawal can be • accompanied by grand mal convulsions.

35. A. Ethanol (cont) 4. Toxicity includes liver disease, cardiovascular disease, endocrine and gastrointestinal effects, malnutrition and CNS conditions such as severe depression (often leading to suicide) and alcoholic Korsakoff’s syndrome consisting of a loss of short-term memory and an inability to acquire new skills. 5. Since ethanol crosses the placental barrier it also produces fetal toxicity – the fetal alcohol syndrome, a major cause of mental retardation. 6. Withdrawal symptoms can be treated with short acting benzodiazepines (e.g., oxazepam). 7. Treatment for addiction is best accomplished by behavioral approaches, e.g., a 12 step program. Pharmacological treatments with disulfiram, naltrexone, lithium and SSRIs have not been successful.

36. Alcohol dehydrogenase or MEOS • (1) Ethanol Acetaldehyde • Aldehyde dehydrogenase • Blocked by Disulfiram • Acetaldehyde Acetate • Large Increases in Acetaldehyde Produces Facial Flushing, • Nausea, Vomiting, Dizziness and Headache

37. Benzodiazepines • 1. Actions are at the modulatory site on the GABA-A complex. • 2. Tolerance and physical dependence are slow in developing (several months), • and occur to the sedative effects with little evidence of tolerance to the • anti-anxiety effects or to the effects on memory. • 3. Both licit and illicit use over extended periods produces physical • dependence. Withdrawal symptoms can be difficult to differentiate from • re-emergence of the anxiety symptoms for which the drug may have been • prescribed.

38. B. Benzodiazepines (cont) 4. Intentional abuse is rare. It may occur for production of a “high” but also may involve use to heighten the effects of other drugs (e.g., methadone) or to reduce unwanted side effects (e.g., cocaine). 5. Addiction can lead to enormous escalation of dose, e.g., while 5-20 mg of diazepam per day is typical for anti-anxiety, abusers may take over 1000 mg/day and not appear grossly sedated. 5. Withdrawal symptoms from low doses are usually mild, but symptoms of withdrawal from high doses include grand mal seizures and delirium. Anticonvulsant medication can be used (e.g., carbamazepine and phenobarbital).

39. Barbiturates • Pharmacology: Block excitatory (glutamate) and enhance inhibitory • (GABA) neurons. • 2. Tolerance results in a decreased therapeutic index. • 3. Physical dependence involves an upregulation of MDA receptors and • down regulation of GABA receptors. • 4. Withdrawal symptoms resemble those seen with benzodiazepines • including seizures. Treatment as for benzodiazepines.

40. D. OPIOIDS 1. Pharmacology. Analgesia and euphoria are mediated by actions at the -opioid receptor. 2. Tolerance can lead to 100 fold increases in dose. Tolerance occurs to respiratory depressant, sedative and emetic effects. 3. Duration of action about 4 hours so dosing occurs 2-4 times/day. 4. Treatment of addiction based on cross tolerance (e.g., methadone or clonidine).

41. Summary of abused drugs and their receptor targets Alcohol and barbiturates: depress excitatory (glutamate) actions at the NMDA Receptor and enhance inhibitory (GABA) actions at the GABA-A complex. Benzodiazepines: enhance inhibitory (GABA) actions at the benzodiazepine Modulatory site of the GABA-A complex. Opioids: act at the -opioid receptor. Cocaine: blocks the DA transporter in cns. Amphetamines: presynaptic release of DA in CNS. LSD and LSD-like hallucinogens (LSD, DMT, MDMA, etc): agonists at the 5-HT2A receptor. Phencyclidine (PCP): noncompetitive NMDA calcium channel blocker. Marijuana: agonist at cannabinoid CB1 and CB2 receptors.