Department of Pharmacology FM MU Introduction to Psychopharmacology Lehmann classification of psychotropic substances Affectivity ↑ antidepressants, anxiolytics ↓ dysforics/antimanics Vigility ↑ psychostimulants/nootropics ↓ hypnotics/sedatives Psychic integrity/integration ↑ neuroleptics ↓ halucinogens/psychodysleptics/delirogens memory and cognitive functions ↑ cognitive enhancers/ nootropics ↓ anticholinergics, dementogens, neurotoxins, amnestics [USEMAP] Adobe Systems SCHIZOPHRENIA PSYCHIC INTEGRATION psychotomimetics antipsychotics ANXIETY anxiolytics sedatives DEMENTIA nootropics antidepressants mood stabilizers halucinogens anticonvulsants antiepileptics ADHD MEMORY AND COGNITION INSOMNIA DEPRESSION EPILEPSY psychostimulants BIPOLAR DISORDER hypnotics cognitive enhancers [USEMAP] Classification of psychotropic drugs •a new classification of psychotropic drugs is created based on the main mechanisms of effects •(neuroscience based nomenclature - NbN) - ECNP (European College of Neuropsychopharmacology) • •Mobile phone app ! • •https://www.ecnp.eu/~/media/Files/ecnp/Projects%20and%20initiatives/Nomenclature/140214%20Nomencla ture%20list.pdf • • [USEMAP] Adobe Systems Antipsychotics •Drugs used predominantly in the therapy of psychoses but also other indications: • pharmacoresistant depression • psychotic depression • anxiety • Huntington's disease • Tourette's syndrome • anesthesia / neuroleptanalgesia • sleep disorders • nausea, vomitus • ̶ ̶ [USEMAP] http://casopis.vesmir.cz/clanek/schizofrenie Adobe Systems Schizophrenia ̶belong among psychoses with predominance of emotional disturbances, thinking, behavior, and personality disorder ̶ ̶the most striking symptoms are delusions and hallucinations ̶ ̶onset/Dg usually around 20th year of age ̶ ̶genetic predisposition - gender incidence - polygenic inheritance ̶ ̶affects about 1% of the population Dg. ICD 10: F20XX [USEMAP] http://casopis.vesmir.cz/clanek/schizofrenie Adobe Systems Symptoms of schizophrenia ̶ •"Positive" symptoms - hallucinations, delusions, disintegration of thinking, speaking, catatonia, agitation, paranoia ̶ •"Negative" - ​​absent, blunted or incongruous emotional responses, apathy, social withdrawal, anhedonia, lethargy, sexual dysfunction, impaired attention [USEMAP] Adobe Systems Substances capable of causing psychosis ̶levodopa (DA) ̶CNS stimulants (NA, DA, 5HT) ̶cocaine ̶amphetamines ̶khat, kathinon, methkathinon, mezkalin ̶hallucinogens – LSD (5HT2c agonist) ̶cannabis ̶apomorphine (agonism D2) ̶bupropion (NDRI) ̶phencyclidin, ketamine (NMDA antag.) • [USEMAP] http://casopis.vesmir.cz/clanek/schizofrenie Adobe Systems Dopamine hypothesis of schizophrenia •Antipsychotics reduce DA-activity on synapses • •Drugs increasing DA in the limbic system trigger psychosis • •Drugs that reduce DA-activity in the limbic system (DA antagonists on postsynaptic D receptors) reduce psychotic symptomatology • •Affinity of older "classical" APs to D2 rcp. correlates with their clinical effect [USEMAP] 2nd. generation („atypical“) less: EPS, tardive dyskinesias, prolactinemias, malignant neuroleptic. syndrome) MARTA (Multi-Acting Receptor Targeted Agents) SDA (Serotonin-Dopamine Antagonist) D2 / D3 antagonists DSSS (Dopamine-Serotonin System Stabilizers) 1st. generation „typical“ Classical (basic, sedative): doses up to hundreds of milligrams Incisive: doses in mg to tens of milligrams 3rd. Generation ? agonists of DA autoreceptors, partial agonists, glutamatergic, beta blockers? Classification of antipsychotics [USEMAP] Adobe Systems Classical (typical) antipsychotics •affects positive, less negative symptoms, can aggravate cognition. dysfunction •mechanism of action: reduction of dopaminergic neurotransmission (blockade of postsynaptic D2 receptors AE Extrapyramidal syndrome Early (parkinsonoid, acute dyskinesia, akathisia) Late (tardive dyskinesia and dystonia, tardive akathisia) Neuroleptic malignant syndrome, hyperprolactinemia, anticholinergic, antihistamine, adrenolytic and others q [USEMAP] Adobe Systems Classical (typical) antipsychotics - basal levomepromazine –D2 antag. + another antag. (NA, 5HT, H, Ach) more pronounced sedation, less EPS, adjuvant with analgesics antiemetic, antihistaminic, anti-adrenergic and anticholinergic effects AE: Orthostatic collapse, QTc prolongation, torsades chlorprotixen 5HT2, D1, D2, D3, H1, M and alpha 1 receptor antagonist In low dose for insomnia (up to 50 mg) q Adobe Systems •melperone •Low affinity D2 antagonism •5HT2A, alpha1 antagonist, without affinity for H1, M •low risk of dyskinesia + EPS •Confusion, anxiety restlessness, especially in the elderly and alcoholics (deliria) (low doses) •tiaprid •D2, D3 antagonism •lacks affinity for H1, α1, α2, 5HTR •I: Behavioral disorders, confusion, agitation, especially in the elderly and alcoholics (deliria) (low doses Classical (typical) antipsychotics -basal Adobe Systems Classical (typical) antipsychotics -incisive fluphenazine D2 antag., Highly effective (Dmax 40 mg) AE: EPS, TD, priapism, galactorea flupentixol - D2 antag, not so sedative, more EPS AE: EPS - initiation of therapy, TD, insomnia, tachycardia, ↑ weight, dyslipidemia, rarely NMS i.m.- noncompliance haloperidol - D2 antag. ,highly potent, better than phenothiazines, long T1/2, less sedation, influencing BP better tolerability (blood count, liver injury) q Pokud pacienti na Haloperidol odpovídají při níizkých dávkách, tak na pozit. I negat. příznaky Adobe Systems Comparison of basal and incisive AP q Basal AP - Low potency (high doses – hundreds of milligrams) - Sedation to hypnosis - D2 receptor blockade - slower PK - Frequent anticholinergic and antihistaminic adverse effects - ↓ EPS Incisive AP - High potency (lower doses) - Little sedation - Block D2 receptor - faster PK - Causes ↑ EPS [USEMAP] Adobe Systems Atypical antipsychotics •higher efficacy, better tolerability •affect positive and negative symptoms, cognition •D2 receptor occupancy <80%, binding to multiple neurotransmitter systems •affect not only transport of dopamine but also other neuromediators (serotonin) •wide range between antipsychotic effects and EPS •selective extrastriatal (mesolimbic) blockade of dopamine D1, D2 receptors •risperidone, ziprasidone, olanzapine, quetiapine ... [USEMAP] Adobe Systems Atypical antipsychotics ̶selective D2/D3 receptor antagonists sulpiride, amisulpride ̶selective serotonin and dopamine receptor antagonists (SDAs) • risperidone, ziprasidone, lurasidone, iloperidone, sertindole ̶multi-receptor antagonists (MARTA: D, 5-HT, α, H1, M) • clozapine, olanzapine, quetiapine and zotepine ̶DSSS (D2) stabilizer • aripiprazole, cariprazine [USEMAP] ecp584586 Relative receptor profile AP2G Sumiyoshi, Expert Rev Clin Pharmacol. 2008;1:791-802 . [USEMAP] Adobe Systems Atypical antipsychotics - MARTA clozapine antag. D2 , antag. 5HT2A (↑ release DA) 5HT1A, 5HT2C, (cognitive, affective symptoms) minimal impact on the nigrostriatal system Effect on alpha, 5HT2 rcp Useful in: Pharmacoresistant psychoses - responds about 1/3 risk of suicidium, aggressive patients, EPS AE: sedation, weight gain, agranulocytosis - genetic test q multi acting receptor targeted agents Adobe Systems Atypical antipsychotics - MARTA olanzapine antag. D2, antag. 5HT2A 5HT2C - improving cognitive symptoms better efficiency available depot injectable DDF No/low risk of agranulocytosis AE: sedation, weight gain, tachycardia, rarely TD q Adobe Systems Atypical antipsychotics - SDA risperidone antag. D2 , antag. 5HT2A (↑ release DA) , α1, 5HT7 (antidepresive action) p.o. i.m. depot inj. active metabolite 9-OH risperidon = Paliperidone I: schizophrenia, mania, bipolar disorder, behavioral disorders in children, ADHD, resistant OCD AE: weight gain, dyslipidemia, hyperprolactinemia paliperidone antag. D2 , antag. 5HT2A, α1, less affinity 5HT7 p.o. and depot inj. q Adobe Systems Atypical antipsychotics- SDA lurasidone •Risk of EPS: modest •Relat. safe, well tolerated AP – (lacks AE: weight gain, metabolic AE, anticholinergic, sedtion, ortostatic hypotension, low risk of QTc prolongation) cariprazine •D2, D3, 5HT2B, 5HT1A partial agonist •5HT2A, 5HT2C alpha1B antagonist • • • • q Adobe Systems Atypical antipsychotics - DSS aripiprazole – partial agonist D2 + 5HT1A, antag. 5HT2A (localy increases DA –improves cognitive fctions, affectivity) blocks 5HT2C, 5HT7 –antidepresive action ¨ lacks sedation, weight gain p.o. + depot inj. Other Indications: augmentation of antidepressants, q Adobe Systems Adverse effects •Blockade of D2 receptors in nigrostriatal pathway • •EPS - early (acute) • - late (tardive) •Severity does not correlate with dose ! •https://www.youtube.com/watch?v=FUr8ltXh1Pc&t=8s •Acute dystonia ̶involuntary contraction of individual muscles or muscle groups of prolonged duration, causing abnormal movements or positioning of different body parts. ̶occurs in up to 25-33% of all patients treated with typical AP •https://www.youtube.com/watch?v=2krwEbm5hBo • • [USEMAP] Adobe Systems •Blockade of D2 receptors in nigrostriatal pathway • •EPS • Akathisia • - intense mental discomfort, compulsive movements restlessness • •https://www.youtube.com/watch?v=W_iiy8ISvdY • Adverse effects Při vzniku akutní dystonie je nutné ihned podat jednorázově i. v. anticholinergikum [biperiden (Akineton) v dávce 2,5–5 mg]. Podání biperidenu může přinést dramaticky příznivý efekt již po 10–20 sekundách a slouží i jako diagnostický test akutní dystonie – pokud se efekt nedostaví do 15 minut, nejedná se s největší pravděpodobností o akutní dystonii. http://zdravi.e15.cz/clanek/postgradualni-medicina/postneurolepticke-extrapyramidove-syndromy-15410 0 Adobe Systems •Blockade of D2 receptors in nigrostriatal pathway • •EPS • Parkinson's syndrome (PS) •combination of bradykinesia (movement retardation) •akinesia (inability to start movement) •hypokinesia (reduction of motion range) •stiffness/rigidity (increased muscle tone) •shaking •Typical APs : about 30-50%. https://www.youtube.com/watch?v=6HKMusvSfeI • Adverse effects Adobe Systems 1.AP treatment in the previous 7 days (in depot inj. In previous 2-4 weeks) 2.Hypertermia > 38 st. C 3.Muscle rigidity 4.5symptoms of: -Changes in mental state -Tachycardia -Hypertension or hypotension -Tachypnoea or hypoxia -Sweating or salivation -Tremor -Incontinence -Increased creatine phosphokinase or myoglobinuria -Leukocytosis -Metabolic acidosis •Excluding other neuropsychiatric or somatic disease Neuroleptic malignant syndrome [USEMAP] Adobe Systems Anxiolytic and hypnosedative drugs [USEMAP] Adobe Systems Anxiety disorder •A chronic condition characterized by an excessive and persistent sense of apprehension, with physical symptoms such as sweating, palpitations, and feelings of stress • •Anxiety disorders recognised clinically include the following: •generalised anxiety disorder (GAD) •obsessive–compulsive disorder (OCD) •post-traumatic stress disorder (PTSD) •social anxiety disorder, phobias etc. Adobe Systems Anxiolytics • ̶First line: non-benzodiazepine (SSRI + others, see the AD materials) ̶ ̶Second line: benzodiazepines (BZ, adjuvant therapy) ̶ ̶ ̶drugs mostly acting like CNS depressants (not always sedative) ̶ ̶affecting receptors in limbic system, hypothalamus, cerebellum and corpus striatum • [USEMAP] Adobe Systems Mechanism of action (BZD) -specific (via receptors) - •- selectively binding to the benzodiazepine binding site of GABAA subunit (coupled with Cl- channel) •- increase affinity of binding site for GABA (positive allosteric modulation) •- increase in frequency of opening of Cl- channel •- hyperpolarization of neuron membrane • • • inhibition of signal transduction • •Inhibition of neural activity is leading to anxiolytic effect • in higher doses to sedation and sleep •overdose can be lethal (specially if combined with ethanol) • • GABA [USEMAP] Adobe Systems GABAA subunit effect α1 sedative, anterograde amnesia, partially anticonvulsive; addictive α2 anxiolytic, myorelaxant α3 α5 contributing to myorelaxant effects α1 α5 modulating temporal and spatial memory [USEMAP] Adobe Systems Indications ̶adjuvant therapy in psychiatry (for transient period) ̶acute intervention of panic attack ̶ treatment of acute alcohol withdrawal ̶ diagnostic/therapeutic procedures (gastroscopy, colonoscopy) ̶ commonly used together with an SSRI to provide symptomatic relief for the first few weeks before the effects of the SSRI kick in ̶ phobias (strong fears of specific things or situation (snakes, flying) ̶ psychosomatic disorders ̶ post-traumatic stress disorder (anxiety triggered by insistent recall of past stressful experiences ̶ OCD ̶ [USEMAP] Effects of benzodiazepines •1) hypnosedative • midazolam •2) anxiolytic • alprazolam, bromazepam, oxazepam •3) anticonvulsant • diazepam, clonazepam •4) myorelaxant • clonazepam •5) amnestic (anterograde amnesia) • most of benzodiazepines, historically typical for flunitrazepam [USEMAP] Adobe Systems Pharmacokinetics of benzodiazepines ̶ABSORPTION: ̶well absorbed if given orally , Cmax reached in about 1 h ̶intramuscular injection – absorption time is mostly unpredictable ̶possible IV and per rectum application (used for pediatric febrile seizures) ̶ ̶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 Adobe Systems obr Adobe Systems Specific antagonist of benzodiazepine receptors flumazenil Use: in benzodiazepine overdose, antagonising the central sedative effects of benzodiazepines in anaesthesiology •the onset of action is rapid and usually effects are seen within one to three minutes • •its action lasts for only about 1 hour, so drowsiness tends to return - repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off • •can cause acute withdrawal syndrome in benzodiazepine dependent patient [USEMAP] Adobe Systems Unwanted effects ̶drowsiness, confusion, amnesia, impaired coordination ̶paradoxical reactions (aggression, violence; see Beers list) ̶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) ̶cognitive deficits (memory loss, slower psychomotor deficits) ̶breath center depression ̶muscle relaxation ̶tolerance (gradual escalation of dose needed to produce the required effect and occurs with all BZs. Appears to represent a change at the receptor level) ̶“rebound“ phenomenon ̶may cause „floppy baby syndrome“ or neonatal abstinence syndrome when used during third trimester of gravidity (tremor, tachypnea, convulsions) ̶ Adobe Systems Beers list ̶guidelines for healthcare professionals to help improve the safety of prescribing medications for older adults [USEMAP] https://www.dcri.org/beers-criteria-medication-list/ http://www.medscape.com/viewarticle/846136#vp_2 Adobe Systems Adobe Systems Contraindications ̶pregnancy and lactation ̶ ̶myasthenia gravis ̶ ̶ethylism, co-medication with other hypnotics ̶ ̶respiratory insufficiency, sleep apnoe ̶ ̶any other comorbid addiction ̶ ̶patients using benzodiazepines should not donate blood or drive vehicles Adobe Systems Benzodiazepine withdrawal syndrome ̶the cluster of symptoms that emerge when patient undergoes abrupt discontinuation of use ̶more frequent with: short-acting benzodiazepines (alprazolam), higher doses, serious concurrent psychopathology ̶more expressed in women and patients abusing alcohol ̶25-50 % patients are capable of consecutive discontinuation of BZ use during 6-21 months. First half of dose is discontinued easier then the other half, therefore rapid discontinuation of first half is recommended, followed by 10-20 % reduction during 3-5 days ̶„plateau“ stage is recommended during discontinuation, when the dose is not reduced ̶usually the morning dose is reduced in the first place, then the afternoon’s one a the evening dose is the last reduced ̶long-acting benzodiazepines cause delayed withdrawal syndrome (2-4 weeks later) [USEMAP] Adobe Systems Non-benzodiazepine drugs with anxiolytic effect ̶SSRI: sertraline, fluvoxamine, fluoxetine (see AD materials) ̶ ̶other AD: mirtazapine, trazodone, amitriptyline, dosulepin, venlafaxine ̶ ̶antiepileptics: gabapentin, pregabalin (generalised anxiety disorder), tiagabine, valproic acid ̶ ̶antipsychotics: quetiapine, olanzapine [USEMAP] Adobe Systems Non-benzodiazepine drugs with anxiolytic effect ̶partial agonist at 5-HT1A receptors: buspirone - used to treat generalised anxiety disorders and as adjuvant therapy in depression, less effective in controlling panic attacks or severe anxiety states ̶H1 antihistamins: hydroxyzine ̶guaifenesin (+ myorelaxant+expectorant action) ̶beta-blockers: metipranolol, metoprolol ̶ ̶medicinal herbs: Valerian, Hop, Saffron, Passionflower, St. Johns Wort, Rhodiola, Lavender [USEMAP] Adobe Systems Hypnosedatives •Sedation •can be defined as a suppression of responsiveness to a constant •level of stimulation, with decreased spontaneous activity and •ideation. • •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. • • [USEMAP] Adobe Systems •INDICATION • ̶HYPNOTICS: are used for treating sleep disturbances and disorders • – insomnia • ̶SEDATIVES – in anxiety, ammeliorrate hyperactivity, aggressivity ̶ ̶No clear cut-off between HYPNOTICS and SEDATIVES „HYPNOSEDATIVES“ • • Adobe Systems Výsledek obrázku pro insomnia depression anxiety https://commons.wikimedia.org/wiki/File:Complications_of_insomnia.svg Adobe Systems Insomnia: ̶ temporary = less than week ̶ ̶ short term= less than month • ̶ chronic = more than month (according to International Classification of Sleep Disorders 3 months with a frequency of 3 times a week) Adobe Systems Indications •Sleep disorders in case of: ̶no causative treatment available ̶causative treatment still not effective ̶short term treatment ̶severe sleep disorder (debilitating for patient, causing sick leave) •Recommended just for short courses of treatment of insomnia- from few days to 2 weeks (max. of 4 weeks in a row) [USEMAP] Adobe Systems „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 [USEMAP] Adobe Systems First generation hypnotics • • •clomethiazole •acts as a positive allosteric modulator at the barbiturate/picrotoxin site of the GABAA receptor •Indications: insomnia in geriatric patients, acute alcohol withdrawal syndrome, delirium tremens •Contraindicated in case of sleep apnoe and chronic respiratory insufficiency • •barbiturates ̶obsolete, death from respiratory and cardiovascular depression if given in large dose – flumazenil not effective ̶mainly used in anaesthesia (thiopental) and as a treatment of epilepsy (phenobarbital) • • • [USEMAP] Adobe Systems Second generation hypnotics •Benzodiazepines ̶midazolam – also for premedication in anaesthesiology ̶diazepam ̶cinolazepam ̶clobazam ̶medazepam •unwanted effect: dependence, drowsiness, disturbed sleep cycle Third generation hypnotics •Selective agonists at benzodiazepine site containing α1 subunit • - selective hypnotic effect, lacking moyrelaxant, anxiolytic and anticonvulsive effect • - non-benzodiazepine structure •can cause dependence, not causing morning „hangover“, causing confusion, hallucinations, somnambulism and delusions in sensitive and geriatric patients • •zopiclone • •zolpidem • •zaleplon • [USEMAP] Adobe Systems Antidepressive drugs in treating insomnia ̶trazodone ̶agomelatine ̶mirtazapine – see AD materials [USEMAP] Adobe Systems New trends in hypnosedatives Drugs influencing circadian rhytms melatonin •just weak hypnotic • •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 • • • [USEMAP] Adobe Systems New trends in hypnosedatives •Dual orexin receptor antagonist • ̶suvorexant ̶produces similar reinforcing effects to those of zolpidem and thus may have a similar abuse liability ̶unwanted effects: sleep terror, drowsiness ̶contraindicated in pregnancy ̶ [USEMAP] Adobe Systems Risks associated with using hypnotics ̶dependence, cognitive disorders ̶higher mortality (respiratory center depression caused by overdose) ̶higher infection rate (weak respiratory infections, pneumonia) ̶higher risk of cancer ̶depression and suicide ̶higher risk of dementia, fractures and injuries ̶ ̶ [USEMAP] 84% higher of Alzheimer disease for those who took the drug for 6 months or longer Adobe Systems Other drugs with hypnosedative effect ̶antipsychotics: quetiapine ̶ ̶chlorprothixen, levomepromazine ̶ ̶H1 antihistamins (1. generation): hydroxyzine, promethazine, moxastine, bisulepine ̶ ̶medicinal herbs ̶ [USEMAP] Adobe Systems Medicinal herbs as hypnosedatives ̶Melissa off. (Lemon balm) ̶ ̶Valeriana off. (Valerian) ̶ ̶Humulus lupulus (Hop) ̶ ̶Passiflora incarnata (maypop, purple Passionflower) ̶ ̶Hypericum perforatum (St. Johns Wort)