Psychoactive drugs. Jan Juřica, PharmD, Ph.D.

Transcription

1 Psychoactive drugs Jan Juřica, PharmD, Ph.D.

2 Psychoactive drugs DEFINITION: Any medication which has the capability to alter mood, anxiety, behavior or cognitive processes; usually denotes drugs used in the treatment of mental illness

3 Classification according to influence on the basic psychic function I. VIGILITY + - Psychostimulants Hypnosedatives, General anaesthetics II. AFFECTIVITY + - Antidepressants Anxiolytics Antimanic drugs Dysphoric drugs (depressants) III. PSYCH. INTEGRATION IV. MEMORY (and cognitive fctions) Antipsychotics (Major tranqulizers) (neuroleptics) Hallucinogens, Dellirogens nootropics, cognitive enhancers Anticholinergic drugs

4 Classification according to the MAIN THERAPEUTIC effect ont the basic psychic disorders Examples: Drugs of affective diorders (antidepressants, thymoporphylactics) Drugs of anxiety disorders (anxiolytics) Drugs of sleeping disorders (hypnotics, sedatives, hypnosedatives) Drugs of movement disorders etc.

5 A n x i e t y In anxiety states the fear response to threatening stimuli occur in an anticipatory manner independently of external events. Among other the fear response includes defensive behaviours, autonomic reflexes, arousal and alertness, corticoid secretion and negative emotions. An effective anxiolytic agent should reduce anxiety and exert a calming effect - sedation - with little or no effect on motor and mental function.

6 Anxiolytic and hypnotic drugs Anxiety disorders include: - generalised anxiety disorder (an ongoing state of excessive anxiety lacking any clear reason ) - panic disorder (attacks of overwhelming fear occuring in association with somatic symptoms (sweating, tachycardia, chest pain) - phobias (strong fears of specific things or situation (snakes, flying) - postraumatic stress disorder (anxiety triggered by insistent recall of past stressful experiences

7 ANXIOLYTICS Syn. minor tranqulizers, ataractics, antiphobic drugs, antineurotics/ Drugs mostly depressant effe. on CNS (not allways sedative effect) Influencing subcortical structures in the brain, limbic system, F.R.

8 ANXIOLYTICS - benzodiazepines - risk of psychic + somatic dependence

9 Effects of BZDs 1) hypnosedative flunitrazepam 2) anxiolytic alprazolam, bromazepam, oxazepam 3) anticonvulsive diazepam, klonazepam 4) myorelaxant klonazepam (5) amnestic most of BZD

10 Action Profiles of Benzodiazepines Relief of anxiety Anticonvulsant action Sedation Induction of sleep Muscle relaxation Ansseau, M., Doumont, A., Diricq, S.: Methodology required to show clinical differences between benzodiazepines. Curr Med Res Opin 8, Suppl. 4, (1984). (Except <Dormicum> and <Dalmadorm>)

11 Anxiolytic and hypnotic drugs benzodiazepines (BZ) Pharmacological effects and uses: The main effects: reduction of anxiety and agression sedation and induction of sleep reduction of muscle tone and coordination anticonvulsant effects anterograde amnesia

12 Anxiolytic and hypnotic drugs benzodiazepines (BZ) reduction of muscle tone and coordination: increased muscle tone is a common feature of anxiety states and may contribute to pains (headache). Influence on manual skills (!) anticonvulsant effects (GABA A receptors) clonazepam to treat epilepsy diazepam (i.v.) status epilepticus to control lifethreatening seizures anterograde amnesia - BZDs obliterate memory of events experienced while under their influence

13 BZD Indications: Anxiety Sleeplessness Withdrawal Symptoms Epilepsy (emergency in status epilepticus) Convulsions Panic States (Alprazolam, Bromazepam, Clonazepam in High Doses) Extrapyramidal Undesirable Side Effects of Antipsychotics Premedication in Anaestesiology Post-traumatic stress disorder Depressive States (short term)

14 MECHANISM OF ACTION OF BZD - specific (via receptors) - selectively binding to the specific binding site ( benzodiazepine receptor ) of GABA A subunit (coupled with Cl - channel) - increase affinity of binding site for GABA (positive allosteric modulation)

15 MECHANISM OF ACTION OF BZD increase in frequency of opening Cl - channel Hyperpolarization of neuron membrane inhibition of signal transduction

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17 tolerance, dependence Tolerance (gradual escalation of dose needed to produce the required effect) occurs with all BZs. T.appears to represent a change at the receptor level. Dependence In human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness. rebound phenomenon!! Anxiolytic and hypnotic drugs benzodiazepines (BZ) unwanted effects occuring during therapeutic use ---Influence on manual skills (such as driving performance) due to drowsiness, confusion, amnesia and impaired coordination --- enhance of depressant action of other drugs (in a more than additive way) --- breath center depression

18 Anxiolytic and hypnotic drugs benzodiazepines (BZ) The withdrawal syndrome: short acting BZs cause more abrupt withdrawal effects Addiction (-craving -severe psychological dependence) is not a major problem. Note: BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam)

19 Anxiolytic and hypnotic drugs benzodiazepines (BZ) Unwanted effects acute overdosage effects occuring during normal therapeutic use tolerance and dependence acute overdosage (BZs are relatively safe in overdose) BZs produce prolonged sleep, without serious depression of respiration or cardiovascular function Severe even life-threatening respiratory depression may appear in BZD combination with other CNS depressants, particularly alcohol. Acute overdosage can be counteracted with flumazenil

20 BZD contraindications Pregnancy, lactation myasthenia gravis Ethylism, hypnotics comedication Sleep apnoe Any addiction suspected

21 Pharmacokinetics of BZD: - absorption: well absorbed if given orally, Cmax reached in about 1 h - binding: strongly bound to plasma proteins - distribution: large Vd: accumulation in body fat (high lipid solubility) - metabolism: hydroxylation conjugation with glucuronic acid short-, medium- and long-acting BZ the role of N-desmethyldiazepam

22 Anxiolytic and hypnotic drugs - benzodiazepines (BZ)

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24 Remember: advancing age affects the rate of oxidative reactions more than that of conjugation. the effect of long-acting BZs tends to increase with age (drowsiness and confusion) (BEERS criteria)

25 Anxiolytics (Benzodiazepine Derivates) Generic Name diazepam chlordiazepoxide oxazepam alprazolam bromazepam medazepam Trade Mark DIAZEPAM SLOVAKOFARMA APO-DIAZEPAM APAURIN, SEDUXEN DIAZEPAM DESITIN DIAZEPAM DESITIN SUPP. DEFOBIN, ELENIUM RAPEDUR OXAZEPAM LÉČIVA NEUROL XANAX FRONTIN, HELEX LEXAURIN ANSILAN, RUDOTEL tbl. 2.5; 10 mg inj. 10 mg supp. 5 mg tbl. a drg. 10 mg Form Mean Doses (mg) tbl. 10 mg tbl mg ; 1 mg tbl. 0.25; 0.5; 1; 2 mg 1-10 tbl. 1; 5; 3 mg 3-36 tbl. 10 mg tofisopam GRANDAXIN K+ clorazepate TRANXENE lorazepam clobazam prazepam clonazepam TAVOR FRISIUM DEMETRIN RIVOTRIL ANTELEPSIN tbl. 50 mg tbl. 5; 10; 50 mg inj. 20; 50; 100 mg tbl. 1; 2,5 mg 2 tbl. 10 mg tbl. 10 mg tbl. 0.5 ; 2 mg gttae mg/ml inj. 1 mg tbl. 0.25; 1 mg 1-4

26 Flumazenil Specific antagonist of BZD receptors USE: in benzodiazepine overdose dg. coma of unknown aetiology

27 Barbiturates similar mech. Of action as BZD, obsolete for more than 15 yrs) as anxiolytics - dependance - high risk of serious advers effects - high interaction potential

28 Other anxiolytics I. partial agonists of 5 - HT 1A rec. buspiron Influencing serotonergic system II. Low dose of antidepress. fluvoxamine, fluoxetine (SSRI), venlafaxin, amitriptylin, dosulepine, III. low doses of neuroleptics (levomepromazine, thioridazin, ) IV. H 1 - antihis.: hydroxyzin V. beta-blockers: metipranolol, metoprolol, VI. Derrivatives of propan: guaifenesin (+myorelaxant+expectorant action), (meprobamat, mephenoxolon)

29 Anxiolytics Generic Name Trade Mark Form Mean Doses (mg) Propandiol Derivates guaiphenesine Mephenoxalone meprobamate Piperazin Derivates hydroxyzine Azapiron Derivates buspirone GUAJACURAN DORSIFLEX, DIMEXOL MEPROBAMAT LÉČIVA ATARAX ANXIRON, BUSPIRON-EGIS drg. 200,400mg inj. 1 g tbl. 200 mg tbl. 400 mg tbl. 10, 25 mg inj. 100 mg sir tbl. 5, 10 mg 15-30

30 A sedative-hypnotic drug (terminology) Sedation can be defined as a supression of responsiveness to a constant level of stimulation, with decreased spontaneous activity and ideation.

31 A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural state of sleep. Hypnotic effects involve more pronounced depression of the CNS than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.

32 INDICATION HYPNOTICS: are used for treating sleep disturbances and disorders insomnia SEDATIVES in anxiety, ammeliorrate hyperactivity, aggresivity No clear cut-off between HYPNOTICS and SEDATIVES HYPNOSEDATIVES

33 Insomnia : temporary= less than weeek short term = less than month chronic = more than month

34 A Physiological and Behavioral Description Stages of Sleep Measured by EEG Alpha activity: A smooth electrical activity of 8 12 Hz recorded from the brain; generally associated with a state of relaxation or meditation. Beta activity: Irregular electrical activity of Hz recorded from the brain; generally associated with a state of arousal.

35 A Physiological and Behavioral Description Stages of Sleep Theta activity: EEG activity of Hz that occurs intermittently during early stages of slow wave sleep and REM sleep. Delta activity: Regular, synchronous electrical activity of less than 4 Hz recorded from the brain; occurs during the deepest stages of slow-wave wave sleep.

36 Copyright 2004 Allyn and Bacon

37 A Physiological and Behavioral Description Stages of Sleep REM sleep: A period of desynchronized EEG activity during sleep, at which time dreaming, rapid eye movements, and muscular paralysis occur. Decreased blood flow to inferior frontal lobe associated with distortions of time. Non-REM sleep: All stages of sleep except REM sleep.

38 REM sleep ( rapid eye movement) artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced!

39 INDICATIONS Sleep disorders in case of: No causative treatment available * Causative treatment still not effective * Short term treatment * Severe sleep disorder

40 IDEAL HYPNOTIC drug To mimick physiological structure of sleep cycles Broad ther. range optimal halflife of elimination Rapidly absorbed after p.o. admin. terap. levels in blood 5-7 h, no active metabolites No ADE, interactions No risk of addiction

41 HYPNOTICS I. generation III. generation II. generation prolong 2 NREM, shorten 3 and 4 NREM and REM prolong 2 NREM, just slightly supress 3 and 4 NREM, do not supress REM Prolong 2 NREM, shorten 3 and 4 NREM, just slightly supress REM

42 HYPNOTICS I. generation barbiturates obsolete Non-bartbiturates (obsolete or less freq. used) e.g. clomethiazol

43 Disadvantage of use: if given in a large dose death from respiratory and cardiovascular depression (flumazenil not effective) a high degree of tolerance: BA strongly induce the synthesis and activity of hepatic CYP450 and conjugating enzymes thus increasing the rate of metabolic degradation of many other drugs --- drug-drug interactions dependence barbiturates are no longer used as anxiolytic and hypnotic drugs

44 Barbiturates in clinical use use as sedative and hypnotic agents is no longer recommended BAs are mainly used: in anaesthesia - thiopental (i.v.) treatment of epilepsy - phenobarbital

45 HYPNOTICS II. generation benzodiazepines midazolam flunitrazepam diazepam nitrazepam

46 HYPNOTICS III. generation selective agonists of Ω 1 benzodiazepine receptors (Ω 1 rec.=bzd 1 rec.) - Selective hypnotic effect, lacking myorelaxant effect, lacking anxiolytic + anticonvulsive effect. non-benzodiazepine structure

47 HYPNOTICS III. generace generation selective agonists of Ω 1 benzodiazepine receptors (Ω 1 rec.=bzd 1 rec.) newer hypnotics Zolpidem, zopiclon, zaleplon

48 Anxiolytic and hypnotic drugs zoplidem, zaleplon Zolpidem pharmacodynamics binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition like the BZs, the actions of zolpidem are antagonised by f l u m a z e n i l minimal muscle relaxing and anticonvulsant effects the risk of development of tolerance and dependence with extended use is less than with the use of hypnotic BZs pharmacokinetics rapidly metabolized to inactive metabolites by the liver, T1/ h. Dosage reduction in hepatic dysfuction, elderly.

49 Anxiolytic and hypnotic drugs zoplidem, zaleplon Ind- short-term treatment of insomnia Zaleplon resembles zolpidem, t 1/2 = 1h Rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep.

50 Hypnotics 1 st Generation 2 nd Generation 3 rd Generation Other Drugs with Hypnotic Efficacy Generic Name barbiturates chloralhydrate glutethimide nitrazepam flunitrazepam triazolam midazolam clonazepam zolpidem zopiclone zaleplone Trade Mark Form Mean Doses (mg) CHLORALOURAT NOXYRON NITRAZEPAM SLOVAKOFARMA FORTE ROHYPNOL, SOMNUBENE tbl. 250 mg tbl. 5; 10 mg 5-20 tbl. 1 a 2 mg inj. 2 mg HALCION tbl mg DORMICUM tbl. 7.5 a 15 mg inj. 5 mg GERODORM STILNOX, HYPNOGEN, EANOX tbl. 40 mg tbl. 10 mg IMOVANE tbl. 7.5 mg SONATA Antihistaminics (promethazine PROTHAZIN) Antidepressants (mirtazapine, trazodone) Antipsychotics Melatonins tbl. 10 mg 5 10

51 Medicinal herbs as hypnosedatives - Melissa off. (Lemon balm) - Valeriana off. (Valerian) - Humulus lupulus (Hop) - Crataegus monogyna (single-seeded hawthorn) - Passiflora incarnata (maypop, purple passionflower - Hypericum perforatum (St. Johns Wort)

52 NEW trends in hypnosedatives Drugs influencing circadiann rhytms melatonin (just WEAK hypnotic!!) syntetic drugs acting on melatonin receptors

53 Melatonin Universal signal molecule which gives estimate about light/dark cycle to the brain Is synthetised in epiphysis, retina, GIT Sleep do not affect synthesis, peak levels between 11PM and 3AM In GIT = ROS scavenger

54 Where Melatonin Binds Works by binding 3 receptors MT1 = Found in the SCN of hypothalamus, pituitary gland, cardiac blood vessels MT2 = Retina and hippocampus MT3 = Kidney, brain, other organs

55 Melatonin hypnotics melatonin (CIRCADIN) agomelatin (THYMANAX, VALDOXAN - antidepressant) ramelteon, tasimelteon