•Overview of pharmacotherapy of: • •Parkinson‘s disease and parkinsonism •choreatic dyskinesias •spastic disorders •myasthenia gravis •Ménière‘s disease •Degenerative disease of CNS: dying of dopaminergic neurons = dopamine deficit • •Non-specific symptoms: fatigue, depression •Specific symptoms: •Resting tremor, stiffness (rigidity) and increased muscle tone, postural impairments •Extent of movements is limited, ability to move is slown down •Impairment of the movement initiation, akinesia (sudden inability to move) •Typical changes in walking, graphomotor skills and facial mimics • •Psychiatric symptoms: cognitive impairment •Late-onset dyskinesia (night akinesia, morning stiffness, cramps) •https://www.youtube.com/watch?v=j86omOwx0Hk •Dopamine (DA) deficit → DA precursor: LEVODOPA •Metabolised by DOPA decarboxylase to DA in CNS •Used orally several times a day •AE: • a) Metabolism to DA in periphery = vomiting, diarrhea, gastric ulcers, hypertension, tachycardia… • b) DA excess = hallucinations, agression, psychosis (rarely) • •+ COMT inhibitors (catechol-O-methyl transferase) •entacapone, tolcapone •+ Peripheral DOPA decarboxylase inhibitors •carbidopa, benserazide • •Wearing-off effect – quick subsiding of the effect •Dopamine (DA) deficit → D receptors agonists •Used orally or by TTS •AE: drowsiness, irresistible falling asleep („sleep attacks“) • •a) Ergoline derivatives – bromocriptine, pergolide, dihydroergocriptine •Ergot alkaloids derivatives •AE: fibrotic changes in lungs, heart valves + increased risk of psychiatric AE (psychotic symptoms) • •b) Non-ergoline drugs – ropinirole, pramipexole, rotigotine •Lower risk of psychiatric AE, no fibrotic changes •Adjuvant therapy of Parkinson‘s disease: •Selegiline – MAO B inhibitor (DA degradation enzyme) • •Anticholinergics: •Relative excess of ACh → worsening of dyskinesia •Only for short-term use •Contraindication: elderly, patients with cognitive deficit •AE: anticholinergic effects – 3rd lecture •Amantadine – i.v. infusion in severe acute dyskinesia •Biperiden, procyclidine – used orally • • •Abnormal reaction of dopaminergic system •Imbalance between DA and ACh in CNS •Up-regulation of D receptors in basal ganglia •Dystonia, akathisia, facial choreatic movements •Tardive dyskinesia, parkinsonism • a)Typical (classical) antipsychotics – chlorpromazine, levopromazine, prochlorperazine, perfenazine, haloperidol… •Approx. 20% pacients ! • b)H1 antihistamines of 1st generation – thiethylperazine, prometazine c)Prokinetic agents – metoklopramid d)Older antihypertensive – reserpine, α-methyldopa e)Antivertigo agents – cinnarizine, flunarizine f)Antiepileptics – phenytoin, carbamazepine g)Antidepressants – tricyclic AD, trazodone h)Centrally active muscle relaxant baclofen • •Pharmacotherapy: •Switch to safer drug (safer antipsychotic etc.) • + •Dystonia, akathisia → i.v., p.o. anticholinergics •Tardive dyskinesia → sometimes i.m. botulinum toxin •Parkinsonism → antiparkinson agents • •Benzodiazepines p.o., i.v. – sedation, muscle relaxation •Enhace GABAergic transmission •= unintentional, involuntary, quick, irregular movements •Causes: •Huntington‘s chorea (hereditary neurodegenerative disease) •vascular chorea (ischemia in basal ganglia) •chorea minor (autoimmune disease) •Pharmacotherapy: •Antipsychotics – typical (haloperidol), or atypical (risperidone) •Risk of additional extrapyramidal reactions •Reserpine, tetrabenazine – ↓ levels of DA in CNS •Risk of additional extrapyramidal reactions, depression, hypotension •Benzodiazepines (clonazepam) •Amantadine • •Caused by damages of motor neurons: •a) peripheral motor neurons – ↓ muscle tone, strenght, progressive atrophy of skeletal muscles, long bones and skin •poliomyelitis anterior acuta •Charcot-Marie-Tooth disease •myasthenia gravis • •b) central motor neurons – ↑ muscle tone, muscle contractures, limited ability of joints to move, joint dislocations, muscle hypertrophy → atrophy, deformities of long bones •Cerebral palsy (CP) • •Pharmacotherapy is an adjuvant treatment – improves the results of physiotherapy, or enables it to be carried out! •Botulinum toxin A •Polypeptide from Clostridium botulinum •Injected i.m. into the spastic muscles •Causes irreversible inhibition of ACh release in NJs – peripherally active muscle relaxant (presynaptically acting) •Alleviate pain associated with spasms •Enables muscle growth – benefit for children with CP •Administered repeatedly, but sometimes 1 inj. can act even for 12 months •Reinnervation of muscles – new NJs are created in the muscle → spasms reoccur •Improves physiotherapy effects! •Spasticity of larger areas → centrally acting muscle relaxants •BACLOFEN •GABAB agonist – enhances GABAergic transmission = inhibits release of excitatory AA (glutamate, aspartate) •AE: drowsiness, confusion, hypotension, muscle weakness •Progressive tolerance – need for higher doses •Intrathecal administration – s.c. pump with catheter inserted into subarachnoideal space = lower doses • •α2 RECEPTOR AGONISTS •Activation lead to decrease of neurotransmitter levels in CNS – in spinal cord activation inhibits release of excitatory AA •AE: sedation, xerostomia, bradycardia, hypotension •tizanidine, clonidine • •BENZODIAZEPINES – clonazepam, tetrazepam, diazepam •Other drugs used in spastic disorders: •dantrolene •gabapentin, lamotrigine – antiepileptics (GABAergic MoA) •riluzole – amyotrophic lateral sclerosis •Cannabinoids •Mixture of THC and cannabidiol (oral spray) •Agonists of CB1 and CB2 receptors, decrease releasing of excitatory AA •Good therapeutical outcome in 30‒40% patients •AE: psychiatric (mood changes, depression, cognitive impairment, appetite changes etc.), GIT AE, off-balance, drowsiness etc. •Young patients – increased risk of schizophrenia or psychosis development ! •Autoimmune disease – autoantibodies aganist NM receptors of NJs (women > men) •Fluctuating muscle weakness, patient get tired easily, worsening in afternoon and evening and after muscle strain •1st symptoms: ocular muscles, ptosis •Progression: facial muscles (facial weakness), head and neck muscles (difficulties with chewing, swallowing, speaking etc.) •Severe progression: myasthenic crisis – respiratory muscles • •Drugs inducing MG: interferon α •Drugs worsening MG: aminoglycosides, quinidine, quinine, chloroquine, i.v. Mg2+ • •Cholinomimetics – acetylcholine esterase inhibitors = ↑ levels of ACh v synaptic clefts and NJs •pyridostigmine – p.o. several times a day •neostigmine – short-term acting, before muscle strain •ambedonium – N+, no central effect • •AE: activation of ACh receptors = cholinergic effects: •a) muscarinic (salivation, sweating, streaming eyes, miosis, blurred vision, nausea, diarrhea, abdominal cramps, bronchospasmus, confusion, restlessness…) • •b) nicotinic (fasciculations) • •c) accumulation → cholinergic crisis = depolarization blockade of ANS ganglia and NJs •muscle weakness, potentially life-threatening •therapy: mechanical ventilation + i.v. atropine •The cause is autoimmunity → immunosuppressives •Decrease number of B-cells, which produce antibodies •AE: non-specific effect = suppression of overall immune reactions – ↑ infections, risk of sepsis, risk of cancer • •Glucocorticoids (prednisone, prednisolone, methylprednisolone) •Titration dose, the lowest efficient dose is used •Long-term oral therapy with typical AE (stomach, adipose tissue, diabetes, bone structure…) •Azathioprine – stops proliferation of lymphocytes •Combination with corticoids – enables lower doses • •Other immunosupressives: cyclosporin, mycophenolate, methotrexate, tacrolimus • •Disease of the inner ear – endolymphatic hydrops •Accumulation of endolymph + distended endolymphatic space •Acute attack: microrupture of vestibular membrane between endolymphatic and perilymphatic space •Dizziness (vertigo), nystagmus, tinnitus, hearing loss… • •BETAHISTINE •H3 receptor antagonist •CNS, receptors of negative feedback •Regulate histaminergic transmission •Antagonism = ↑ release of histamine •Vasodilation in the inner ear – better microcirculation •Long-term use (lifelong), orally • •CINNARIZINE •H1 receptor antagonist + T-type Ca2+ channel blockator •Antivertigo and prophylactic effect •Used orally • •Cerebral vasodilators and hemorheologics •Improve circulation in CNS •Increase erythrocytes deformability, reduce blood viscosity •Mild antitrombotic, antiinflammatory and antioxidative effect •Used orally, i.v. in acute cases •Standardized extract from Ginkgo biloba •Vinpocetine •Pentoxifylline • • •Other drugs used for prophylaxis •Glucocorticoids, diuretics – antiedema effects • •Acute attack of Ménière‘s disease – nausea, vomiting, dizziness, hearing loss, tinnitus, feeling of the pressure in the ear… • •Antiemetic/antivertigo drugs: •H1 antihistamines of 1st generation •cross BBB, central effects •used also for the treatment of motion sickness •embramine, moxastine, dimenhydrinate… •AE: drowsiness, attention (vigilance) deficit •thiethylperazine – D2 receptor antagonist (suppositories) •cinnarizine + H1 antihistamines •