Special Chapters from Neurologic Pharmacotherapy Department of Pharmacology Overview of pharmacotherapy of: • Parkinson‘s disease and parkinsonism • choreatic dyskinesias • spastic disorders • myasthenia gravis • Ménière‘s disease Parkinson‘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) Pharmacotherapy of PD • 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 Pharmacotherapy of PD • 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 Pharmacotherapy of PD 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 Drug-induced Extrapyramidal Reactions • 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 Drug-induced Extrapyramidal Reactions 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 Choreatic Dyskinesia = 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 Spastic Disorders 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! Local Therapy 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! Systemic Therapy • 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 Systemic Therapy 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 ! Myasthenia gravis • 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+ Symptomatic Therapy of MG • 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 Causal Therapy of MG • 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 Ménière‘s Disease • 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… Prophylactic Pharmacotherapy 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 Prophylactic Pharmacotherapy 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 Antivertigo Drugs • 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