Introduction to Psychopharmacology Neurotransmitter Systems Pharmacology of dopamine in the CNS Antipsychotics Antiparkinsonics Prokinetics Jan Juřica Neuron Types of neuronal synapses Types of synapses Types of mediators within CNS Example Molecular target Main function Classical NT NA, DA, 5-HT, Glu, GABA Ion channel, G-PCR fast and slow neurotransmission, neuromodulation Neuropeptides substance P, neuropeptid Y, endorphins, enkephalins, CRH… G-PCR neuromodulation Lipidic mediators PG, AEA, 2-AG (endocannabinoids) G-PCR neuromodulation NO guanylyl- cyclase neuromodulation Neurotrofins, cytokines NGF, BDNF, IL-1 rcp coupled with kinase neuronal growth, sprouting, survival and plasticity Steroids androgens, estrogens, neurosteroids nuclear and membrane receptors functional plasticity Neurotransmitters • Synthesized presynaptically • Released after stimulation with action potential • Postsynaptic membrane receptors • Synapse stimulation triggers the AP • Blocking interrupts synaptic signaling Classification of neurotransmitters Classical" - small molecules a) amines- monoamines catecholamines (dopamine, noradrenaline) indolamines (serotonin, melatonin) quaternary amines acetylcholine b) Amino acids (glutamate, glycine, GABA) Peptides -"neurohormones" - these are not true neurotransmitters - are carried by blood (vasopressin, somatostatin, neurotensin) Dopamine ↑ anxiety, aggression anxiety, aggression ↓ attenuation, depression, apathy Synthesis - TYR (tetrahydrobiopterin, folate) Storage - in ATP / loose vesicles Release - depolarization (tonic GABA inhibition) Effect on rcp. - D1-D5 Degradation - reuptake !, MAOA + MAOB Pharmacology - agonists, antagonists Dopamine Dopamine • 1957 Kathleen Montagu († 1966) ↑agresivity ↓apathy • „reward, arousal“ • Parkinson disease, psychoses (schizophrenia) • depression, anxiety (GAD) Dopamine Controls within CNS: motoric function (nigrostriatal) behavior, psychological integration, reward – addiction (mesolimbic, mesocortical) Endocrine (tuberoinfundibular) Peripheral controls: GIT motility, blood pressure, vomiting (medulla + peripheral rcp) Serotonin – 5HT Vittorio Erspamer (1909-1999) 1935-“Enteramin“ (enterochromafinnic cells.) 1947 „Sero-tonin“ (serum) Serotonin – 5HT ↑ anxiety, aggression ↓ shock, depression Synthesis form TRP (tetrahydrobiopterin, folate) Storage - in ATP / loose vesicles Relaxation – depolarization Effect on rcp. - 5HT1-5HT7 Degradation - reuptake !, MAOA Pharmacology - agonists, antagonists Serotonin – 5HT Noradrenaline Noradrenaline regulator of activity of other projection systems, NA pathways modulate the excitatory function of glutamate, as well as the inhibitory function of GABA. „arousal“, vigility, alertness, regulation of BP Afective disorders (depression) α1 - postsynaptic neurons, mediates the excitatory effect of NA (α1A, α1B, α1C) α2-usually presynaptic, inhibitory effects. - presynaptic inhibition of NA release (α2A, α2B, α2C) β1-neuronal excitatory receptor, cortex, striatum, hippocampus β2-glial cells, cerebellum, integration of the nervous and immune system; β3 - probably not in the CNS Glutamate • main excitatory neurotransmitter in CNS, 50% CNS synapses • ubiquitous, discrete centers and their projections can not be defined • synaptic plasticity, memory retention, and the learning process Glutamate • main excitatory neurotransmitter in CNS, 50% CNS synapses • ubiquitous, discrete centers and their projections can not be defined • synaptic plasticity, memory retention, and the learning process • Rcp: ionotropic: AMPA, NMDA, kainate metabotropic : mGluR1-8 GABA • the most important inhibitory NT (spinal cord, brain stem: Gly) • 20% of the neurons in the CNS are GABA-ergic, 30% of the synapses - NT GABA • Synthesis - GLU, storage – vesicles • Degradation - reuptake, transamination • Transporters GAT1 and GAT3 (tiagabin-iGAT) • GABA transaminase (inhibition: vigabatrin) • Effect on rcp. - GABAA, GABAB, GABAC (GABAA-rho) • Pharmacology - allosteric modulation, i. GAT, transamination Glycine • ionotropic rcp. coupled with Cl channel (membrane hyperpolarization). • in the gray matter of the spinal cord • main neurotransmitter of inhibitory interneurons • allosteric modulator of NMDA rcp. • excitability in terms of facilitating the activity of the glutamatergic system. Acetylcholine Arousal, learning and memory (cognitive fctions), reward, motoric functions M1-M4 receptors Dementia, Parkinson's disease, modulation of pain transduction Endocannabinoids Anandamide, 2-arachidonoylglycerol, Noladin ether Virodhamine, N-arachidonoyl dopamine..+ endocannabinoid-like compounds • CB1 receptors in high density in the CNS, • CB2 receptors especially on PNS neurons, hematopoietic and immunocompetent cells. - antinociception and immune response modulation CVS – AMI, obesity, dislipidemia CNS – MS, addiction, psychoses, parkinsonism Immune system Pain Respir. System- Asthma bronchiale Eye - Glaucoma, ARMD Neurohormons/neuropeptides • Neuron-secreted • Diffuse into the bloodstream • Blood transport • Effect on the target cell • oxytocine, vasopressine, FSH, CRH, ACTH Ways of modulating neurotransmission Influence on • synthesis of NT • storage NT • release of NT • NT on postsynaptic rcp autoreceptors heteroreceptors • presynaptic modulation - inhibition - disinhibition • up-regulation • down-regulation Possibilities of therapeutic-driven influence on receptor systems • stimulation of release (amphetamines, cocaine) • inhibition of reuptake (SSRI, NDRI, SNRI) • inhibition of degradation (i-MAO) • stimulation of synthesis (precursors – TYR, TRP ) • agonism on rcp. (SARI- 5HT1A) • blockade of release • suppression of synthesis (fake substrate -methyldopa) • Storage inhibition (reserpin) • partial agonism / antagonism at rcp. (SARI, NASSA, fluoxetine - 5HT2C, + - Up-regulation • Long-term reduction of NT - cells synthesize more Rcp and expose them to their membrane → increase receptor density. Down-regulation • Long-term increased supply of NT - internalize receptors (decrease in number) - inactivate intracellular cascade (loss of function) Intracellular signaling of the membrane receptor Signal from activated membrane rcp. → intracellular signaling pathways. This may further: Amplify signal - successively switching to multiple signaling molecules, several hormone / NT molecules can cause significant change of function, signal amplification Diverge the signal to several target locations, 1 activated receptor may affect several functions of the target cell Converge signals - 2 insufficiently strong signals can cause a change in the concentration of a signal molecule sufficient to produce a specific effect Signal transduction "First messengers" - monoamines - binding to pre / postsynaptic receptors signal propagation through postsynaptic structures into the cell nucleus Intra-cellular processes: "Second messengers" - cAMP, IP3 "Third messengers" - early genes, modification of gene expression of cellular proteins – cyclic AMP response-element binding protein – CREB protein - regulation of gene transcription - influencing expression of genes for brain-derived neurotrophic factor BDNF - neuronal development and differentiation (neurogenesis) BDNF DA-neuron 5HT rcp heteroreceptor homoreceptor autoreceptor Postsynaptic receptor Lehmann classification of psychotropic substances Affectivity ↑ antidepressants, anxiolytics ↓ dysforics/antimanics Vigility ↑ psychostimulants/nootropics ↓ hypnotics/sedatives Psychic integrity/intergration ↑ neuroleptics ↓ halucinogens/psychodysleptics/delirogens memory and cognitive functions ↑ kognitive enhancers/ nootropics ↓ anticholinergics, dementogens, neurotoxins, amnestics ATC Classification N: NERVOUS SYSTEM N01: ANESTHETICS N02: ANALGESICS N03: ANTIEPILEPTICS N04: ANTI-PARKINSON DRUGS N05: PSYCHOLEPTICS N05A: ANTIPSYCHOTICS N05B: ANXIOLYTICS N05C: HYPNOTICS AND SEDATIVES N06: PSYCHOANALEPTICS N06A: ANTIDEPRESSANTS N06B: PSYCHOSTIMULANTS, AGENTS USED FOR ADHD AND NOOTROPICS N06C: PSYCHOLEPTICS AND PSYCHOANALEPTICS IN COMBINATION N06D: ANTI-DEMENTIA DRUGS N07: OTHER NERVOUS SYSTEM DRUGS 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) • Phone app ! https://www.ecnp.eu/~/media/Files/ecnp/Projects%20and%20initiatives/No menclature/140214%20Nomenclature%20list.pdf 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 Schizofrenia • 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 Symptoms of schizofrenia "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 Substances capable of causing psychosis • levodopa (DA) • CNS stimulants (NA, DA, 5HT) – cocain – amphetamins – khat, kathinon, methkathinon, mezkalin • halucinogens • cannabis • apomorphine (D2) • bupropion (NDRI) • phencyclidin, ketamine (NMDA antag.) Biological correlates 1. Genetic factors 2. Neurodevelopmental abnormalities 3. Environmental influences (stressors) Structural and functional changes 1. Enlarged brain ventricles 2. Atrophy in some areas of the cortex 3. Reduced volume of basal ganglia Mesolimbic. Mesocortical Tuberoinfundibular Nigrostriatal Hyperactivity: positive symptoms Blockade: EPS, akathisia, dyskinesis, dystonia… Hypoactivity: negative and cognitive symptoms Block: hyperprolaktinaemia Dopaminergic pathways in the human brain DA-ergic pathways Nigrostriatal pathway → DA supressess activity of Ach → inhibition of NS pathway → EPS Tuberoinfundibular pathway → inhibition of TI → hyperprolactinaemia PatofyziologieDopamine 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 PatofyziologieDopamine hypothesis of schizophrenia PatofyziologieDopamine hypothesis of schizophrenia • post-mortem increased DA density in pat. with schizophrenia. • changes in HVA levels in plasma, urine, cerebrospinal fluid. Neuromodulators of schizophrenia • Dopaminergic system Hyperactivity in the milsolimbic pathway - positive symptoms Hypoactivity in the prefrontal cortex - negative symptoms • Glutamatergic system Exciting aminoacid - probably a dopamine release modulator. In patients with schizophrenia, the amount of NMDA receptors is reduced. • Serotonergic system Associated with glutamate and dopamine Increase in the number of serotonin receptors in the prefrontal cortex • GABA system An increased number of receptors, lower levels of enzymes necessary for GABA synthesis, dopamine 2nd. Generation 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 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, peptides? Classification of antipsychotics 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 Antipsychotic binding profile Classical (Typical) antipsychotics -basal Chlorpromazine D2 antag. , one of the first APs, effective on posit. symptoms; doses up to 800 mg/day AE: EPS (tardive dyskinesia), ↑ weight, prolactin Overdose: EPS, respir. depression, coma (with alcohol) Thioridazine D2 antag. , considered in ther. failure of 1st line treatment AE: sedation, EPS, ↑ weight, ↑ QTc mtb: CYP2D6 overdose: confusion, respir. depression, hypotension, seizures, coma generally: risk ˃benefit 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 Classical (Typical) antipsychotics - incisive 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. , since the 1960s, highly potent, better than phenothiazines, long T1/2, less sedation, influencing BP better tolerability (blood count, liver injury) Comparison of basal and incisive AP 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 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 span between antipsychotic effects and EPS • selective extrastriatal (mesolimbic) blockade of dopamine D1, D2 receptors • risperidone, ziprasidone, olanzapine, quetiapine ... Atypical antipsychotics • selective D2/D3 receptor antagonists sulpiride, amisulpride • selective serotonin and dopamine receptor antagonists (SDAs) risperidone, ziprasidone, iloperidone, sertindole • multi-receptor antagonists (MARTA: D, 5-HT, α, H1, M) clozapine, olanzapine, quetiapine and zotepine • DSSS (D2) stabilizer aripiprazole Relative receptor profile AP2G Sumiyoshi, Expert Rev Clin Pharmacol. 2008;1:791-802 . Atypical antipsychotics - MARTA olanzapine antag. D2, antag. 5HT2A (↑ disinhibition DA) 5HT2C - improving cognitive symptoms better efficiency Available depot injectable DDF No/low risk of agranulocytosis AE: sedation, weight gain, tachycardia, rarely TD 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 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 = Paliperidon I: schizophrenia, mania, bipolar disorder, behavioral disorders in children, ADHD, resistant OCD AE: weight gain, dyslipidemia, hyperprolactinemia Atypical antipsychotics - DSSS 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, Pharmacokinetics • Most of APs are rapidly, but incompletely absorbed • significant 1st pass effect • F = 25-65% • Most lipophilic • Most are significantly bound to proteins (92-98 %). • Large Vd (> 7 L / Kg). • Slow elimination Tremor Rigidity Bradykinesia/ Akinesia Dystonia Dyskinesias Dysforia Anhedonia Depression Somatic Psychic Akathisia "Traditional" drug side effects of typical APs Adverse effects Blockade of D2 receptors in NS pathway EPS - early (acute) - late (tardive) Severity does not correlate with dose ! 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 https://www.youtube.com/watch?v=9WH3HPTChkQ Adverse effects Blockade of D2 receptors in nigrostriatal pathway EPS Akathisia - intense mental discomfort, compulsive movement restlessness https://www.youtube.com/watch?v=W_iiy8ISvdY Adverse effects 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 • rare, severe AE • may be lethal • may occur at any time during treatment • no association with – age – duration of treatment – dose – specific drug Neuroleptic malignant syndrome 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 Seifertová, 2008 Neuroleptic malignant syndrome Discontinue all antipsychotics Hospitalization, monitoring Symptomatic and supportive therapy Dantrolen 1-10 mg/kg Dopamine agonists ECT Combination Seifertová, 2008 Treatment of NMS block ACh rcp. dry mouth blurred vision urine retention constipation clozapine chlorpromazine tioridazine Adverse effects Adverse effects Blockade α-adrenergic rcp. Orthostatic hypotension chlorpromazine tioridazine Blockade of H1 – rcp sedation, weight gain risperidone haloperidol Adverse effects Blockade of D rcp. on basal ganglia • Catalepsy (muscular rigidity and fixity of posture regardless, decreased sensitivity to pain) Blockade of D2 rcp. In lactotrophic cells of hypophysis increase in prolactin, galactorhoea risperidone Concerns in the past Current concerns Urological AE EPS+TD Body weight QTc CVS - diseases Hyper- lipidaemia Hyper- glycaemia Body weight QTc CVS - diseases DM Hyper- Glycaemia EPSInsulin resistance Insulin resistance Hyper- lipidaemia Lieberman, 2006 Side effects earlier and now Causes of relapse • Insufficient efficacy of antipsychotics • Non-compliance • Abuse of addictive substances • Psychosocial Stressors Hoeschl 2009, Weiden et al., 1995 Restriction of non-adherence / therapeutic failure • AP with better tolerance and better efficiency • Depot forms – Injection (once every 14 -21 days) – Implants • ITAREPS - https://www.itareps.com/cs/?c=cz • Information Technology Aided Relaps Prevention in Schizophrenia Neurodegenerative disorders Parkinson's disease Alzheimer's disease Huntington's disease Parkinson's disease (PD) • Degeneration of dopaminergic (DA) neurons in substantia nigra (basal ganglia) Motor symptoms • Resting tremor https://www.youtube.com/watch?v=7uhT2ipQpKs • Muscle rigidity https://www.youtube.com/watch?v=kDOi0m5N7Lw • Bradykinesia, akinesia https://www.youtube.com/watch?v=5ZzIk-jC7RA • Gait problems https://www.youtube.com/watch?v=j86omOwx0Hk Non-motor symptoms • „mask“ face • Speech and writing problems • Anosmia • Vegetative imbalance (e.g. constipation) • Blood pressure changes • High sebum production, especially in face • Psychiatric comorbidities (depression, dementia) • … Parkinsonian syndrome (secondary) • Symptoms resemble PD but have different etiology – Viral encephalitis – Iatrogenic – by DA blockade (typical antipsychotics, antihistaminics of 1st gen., antiemetics, etc.) Therapy of PD • Symptomatic pharmacotherapy A. Dopaminergic drugs 1) DA precursor 2) Inhibitors of DA degradation enzymes 3) DA agonists B. Anticholinergic drugs • Rehabilitation A. Dopaminergic drugs 1) DA precursor - Levodopa (L-dopa) 2) Indirect dopaminergic drugs - MAO inhibitors - DA re-uptake inhibitors 3) Direct DA agonists 1) DA precursor: levodopa (L-dopa) • First choice since 1969 • L-dopa crosses BBB (unlike DA) and DA decarboxylase converts it to DA • Only around 1-3 % gets to CNS due to peripheral decarboxylation (COMT) – poor bioavailability (9 %) antagonists of L-dopa peripheral breakdown • carbidopa • benserazide – Peripheral inhibitors of DOPA-decarboxylase (do not cross BBB) – In fixed combinations with L-dopa 4:1 (L-dopa : inhibitor) • tolcapone, entacapone – COMT inhibitors (entacapone acts on periphery only) – Fixed combinations: L-dopa + carbidopa + entacapone Adverse effects of L-dopa and its combinations • Dyskinesia, on-off syndrome https://www.youtube.com/watch?v=AaOWRYqMQc0 https://www.youtube.com/watch?v=qvENE02Kiwo (animal model) Adverse effects of L-dopa and its combinations • on-off syndrome • chorea, dystonia, extrapyramidal and motor disorders • hallucinations, fuzziness, vertigo, night mares, sleepiness, fatigue, insomnia, depression, euphoria, dementia, abnormal dreams • palpitations, arrhythmias, orthostatic hypotension • anorexia, nausea, vomiting, dry mouth, bitter taste in mouth • Levodopa + dopaminergic drugs: impulsivity disorders, compulsive behavior, gambling, hypersexuality, compulsive overeating, shopping • punding – repetitive compulsive behavior New drug dosage forms of L-dopa • To reduce the on-off phenomenon • Intestinal gel L-dopa/carbidopa (orphan status) – Nasogastric administration or by endoscopic gastrostomy (pump) – Quick absorption, stable levels – Allows better symptom control 2) Indirect dopaminergic drugs • MAO-B inhibitors – Reversible – Irreversible • DA re-uptake inhibitor (amantadine) • New: safinamide (inhibits MAO-B and re- uptake) MAO-B inhibitors Irreversible inhibitors • selegiline • rasagiline (neuroprotective?) – Prevent MPTP damage Reversible inhibitors • caroxazone – antidepressant (RIMA) – discontinued, 5x more selective to MAO-B • safinamide (new) IMAO-B adverse events • vertigo, headache, sleep disturbances, mood changes, nausea, dry mouth, bradycardia, supraventricular tachycardia • In combination with levodopa may increase its AE (dyskinesia) • non-selective drugs at higher doses also inhibit MAO-A, leading to hypertension crisis (tyramine reaction) DA re-uptake inhibitor • amantadine – Inhibits DA re-uptake, increases DA release – Antiviral drug (flu), NMDA antagonist, used for L-dopa induced dyskinesia – Antiparkinsonian effects wear off after approx. 6 months – AE: similar as in other drugs, mild safinamide • highly selective reversible MAO-B inhibitor + inhibits DA reuptake → DA agonistic effect • blocks calcium channels type N → GLU antagonism (lowers GLU release) • reduces L-dopa induced dyskinesia • monotherapy or L-dopa combination 3) Direct DA agonists • Ergot alkaloid derivatives: – bromokriptine (also to suppress lactation) – cabergoline, lisuride, pergolide 3) Direct DA agonists • Non-ergot drugs: – pramipexole – agonist of D2, D3 a D4, oral – ropinirole – mostly D2 agonists, oral – rotigotine – agonist of D3, D2 a D1, transdermal – apomorphine – D1 and D2 agonist, injection, mostly used as a quick relieve in patients with variable response to DA drugs • Initial therapy, postponing L-dopa treatment • Add-on to L-dopa treatment (reduction of L-dopa doses) B. Anticholinergic drugs • Against relative prevalence of cholinergic system in striatum and normalization of increased gland secretion, tremor and partially also rigidity and bradykinesia • Drugs with good CNS penetration – biperiden – mostly M1 antagonist – orphenadrin - M, H1, NMDA antagonist (central myorelaxant, combined with diclofenac) • AE: typical for PSL, pro-dementive effect! • In case patient does not respond, we can try a different drug. B. Anticholinergic drugs • Other drugs with central cholinergic effects: – H1 antihistaminics – 1st generation – tricyclic antidepressants „PD, coffee and cigarettes“ nicotine caffeine Caffeine and PD • Regular intake of caffeine is associated with lower tendency to PD development • Caffeine is adenosine A2A receptor antagonist • First drug with this mechanism: – istradefylline, registered in Japan, FDA rejected the application in the 2008 for lack of data Nicotine and PD • Smokers have approximately 60% lower probability to develop PD than non-smokers • Nicotine effects: – Neuroprotective for DA neurons – Reducing L-dopa induced dyskinesia – Improving cognitive faculties • Unclear issues – Clinical relevance – Route of administration D2 receptor antagonists: – metoclopramide – itopride – domperidone • (alizapride, cisapride) – sulpiride • acts centrally on the CTZ and also has a peripheral action on the GIT itself – increasing the motility of the oesophagus, stomach and intestine • metoclopramide crosses BBB (unwanted effects including disorders of movement, fatigue, motor restlessness, prolactin release Prokinetics References: Rang & Dale's Pharmacology H.P. Rang:, J. M. Ritter, R. J. Flower, G. Henderson 8th. Ed. CNS forum (www.cnsforum.com) Seifertová D., Praško J., Horáček J., Höschl C.: Postupy v léčbě psychických poruch. Algoritmy České neuropsychofarmakologické společnosti. Academia Medica Pragensis, ČNPS, Medical Tribune; Praha, 2008, Multimediální skripta 3LF UK (http://fblt.cz/skripta/ ) Lectures: prof. Šulcová, Mohr, Höschl, Votava, J. Rudá