12.10.2016
Treatment of neurodegenerative disorders
Antimanic drugs
PharmDr. Jana Rudá, Ph.D.
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)
1 12.10.2016
Causes
• Idiopathic disease
• Genetic cause • In approximately 5 % of PD patients • gen for α-synuclein (SNCA), parkin (PRKN) or leucin-rich repeat kinase 2 (LRRK2 or dardarin)
• Environmental influences • Pesticides • MPTP (1-metyl-4-fenyl-1,2,3,6-tetrahydropyridin) – toxic for DA neurons
Braak ´s hypothesis
Protective and risk factors
• Cigarette smoking • Job in teaching • Coffee • Job in healthcare • NSAIDs • Job in agriculture • hyperuricemia
2 12.10.2016
MPTP
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
Non -motor symptoms
• „mask“ face • Speech and writing problems • Anosmia • Vegetative dysbalance (e.g. constipation) • Blood pressure changes • High sebum production, especially in face • Psychiatric comorbidities (depression, dementia) • …
3 12.10.2016
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
• Rehabilitation
• Symptomatic pharmacotherapy A. Dopaminergic drugs 1) DA precursor 2) Inhibitors of DA degradation enzymes 3) DA agonists B. Anticholinergic drugs
A. Dopaminergic drugs
1) DA precursor - Levodopa (L-dopa)
2) Indirect dopaminergic drugs - MAO inhibitors - DA re-uptake inhibitors
3) Direct DA agonists
4 12.10.2016
DA metabolism
1) DA precursor: levodopa (L -dopa)
• First choice since 1969 • L-dopa crosses BBB (unlike DA) and decarboxylases to DA • Only around 1-3 % gets to CNS due to peripheral decarboxylation (COMT) – poor bioavailability (9 %)
antagonists of L -dopa peripheral breakdow n
• 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
5 12.10.2016
Adverse effects of L -dopa and its combinations • Dyskinesia https://www.youtube.com/watch?v=CaJymwziF-M 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
Michael J. Fox
• MJ Fox then and now: https://www.youtube.com/watch?v=koL0PWCJ4lo
• Michael J Fox Foundation https://www.michaeljfox.org/
6 12.10.2016
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
• In development • Gastric formulation with extended release (DM-1992) • Oral formulations with extended release
Dyskinesia's management
• amantadine via NMDA antagonisms, see later
• dipraglurant – selective antagonist of mGluR5, in clinical development (phase II) • piclozotan – selective 5HT1A agonist, D3 agonist, in pre-clinical development, potentially neuroprotective
2) Indirect dopaminergic drugs
• MAO-B inhibitors • Reversible • Irreversible • DA re-uptake inhibitor (amantadine) • New: safinamide
7 12.10.2016
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
8 12.10.2016
New: safinamide
• highly selective reversible MAO-B inhibitor → DA agonistic effect • inhibits DA reuptake • blocks calcium channels type N → GLU antagonism (lowers GLU release) • reduces L-dopa induced dyskinesia • monotherapy or L-dopa combination • Tablets (Xadago®)
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)
9 12.10.2016
Adverse effects of DA agonists
• dyskinesias similar to l-dopa • hallucinations, fuzziness, somnolence • Nausea, vomiting, constipation, activation of ulcers • postural hypotension, vasospasms (ergot alcaloids) • arrhytmias – warrant treatment discontinuation • impulsivity control problems (gambling, shopping, hyper sexuality, compulsive overeating)
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
10 12.10.2016
„PD, coffee and cigarettes“
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: • istradephyline , registered in Japan, FDA rejected the application in the 2008 for lack of data
Nicotine and PD
• Smokers have approximately 60% lower probalility 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
11 12.10.2016
Alzheimer's disease (AD)
• Neurodegeneration of unknown etiology • 60-70% of dementia cases • Loss of synapses in cortex (ACh), atrophy • Accumulation of beta- amyloid, tau protein, amyloid plaques
Causes
• Idiopathic disease • Genetic causes • Heritability of 50-80%, there is a familiar form (autosomal dominant, approx. 0.1% f cases, early start, before 65. year) • Amyloid hypothesis • Overproduction of amyloid based on genetic causes or spread as prion disease (!) • http://www.nature.com/news/alzheimer-s-research-takes-a-leaf-from-the-prion-notebook-1.17654#/ref-link-2 • https://www.youtube.com/watch?v=UuMNN2_mEVQ
Symptoms
• http://www.alz.org/alzheimers_disease_10_signs _of_alzheimers.asp#signs
12 12.10.2016
AD treatment
• Symptomatic pharmacotherapy A. Cognitive drugs 1) Acetylcholinesterase inhibitors - donepezil - rivastigmine - galantamine 2) NMDA antagonists - memantine B. Nootropic drugs C. Other drugs
A. Cognitive drugs 1) Acetylcholinesterase inhibitors
• All drugs are mainly active in the CNS!
• donepezil – reversible noncompetitive IACHE, oral • rivastigmine – reversible IACHE, oral, transdermal • galantamine – reversible IACHE, increases ACh activity on nicotinic rc, oral
AE of IACHE
• nausea, vomiting (aesophagus ruptures were described!), vertigo, diarrhea, headache, sleep disturbances, mood changes, fuzziness • Relatively less in donepezil • In the PD patients, the PD symptoms may worsen
13 12.10.2016
2) NMDA antagonist • memantine – noncompetitive NMDA antagonist with low affinity, oral • Blocks primarily activated receptors (open channels) • limits glutamate excitotoxicity
3) New - bexarotene • retinoid, selective agonist of the retinoid X receptors (RXR) • Induces cell proliferation, differentiation and apoptosis • AD is characteristic by abnormal accumulation of cholesterol • Bexarotene enhances cholesterol efflux
14 12.10.2016
• Dg. 12/2010 • Bexarotene: 10/2012
B. Nootropic drugs
• Help in attention and memory deficits , e.g. After injuries • Some of them are psychostimulant • Increase oxygen and glucose turnover in CNS without vasodilation, improve blood rheology • Mechanism is not fully understood • Efficacy in the AD is not fully confirmed
• I: stroke, intoxications, memory loss, dementia, vertigo, etc.
Main drugs
• Piracetam and its derivatives • pramiracetam • oxiracetam • aniracetam • (levetiracetam – antiepileptic)
• Pyritinol • vitamine B6 derivative
15 12.10.2016
Other drugs
• Vasodilators of brain vessels • cinnarizine • flunarizine • pentoxiphyline • naftidrofuryl
• Ginkgo biloba extracts • 40-120 mg of standardized extract registered as a drug in several preparations
Huntingtons disease (HD)
• Genetic disorder (huntingtine) • Movement disorder (chorea), dementia • Degeneration of Ach and GABAergic neurons in basal ganglia → increase of DA in striatum → hyperkine c syndrome
HD treatment
• Pharmacotherapy is based in suppression of DA signaling • Dealing with psychiatric comorbidities and AE of the main treatment
16 12.10.2016
Terapie HD
• Symptomatic pharmacotherapy A. Antidopaminergic drugs 1) Tetrabenazine 2) Antipsychotics B. Antiepileptics (levetiracetam, valproát, klonazepam) C. Other drugs 1) Antidepressants (SSRI) 2) Mood stabilizers (antimanic drugs) 3) Neuroprotective drugs
A. Antidopaminergic drugs 1. Tetrabenazine • Blocks uptake of DA to vesicles in the presynaptic neuron by a short reverzible bound • Acts as DA antagonist
• Earlier used drug: reserpine
Tetrabenazine
Binds reversibly vesicular monoamine transporter in peripheral nerves
DA competitive antagonism
17 12.10.2016
2. Antipsychotics
1st generation - haloperidol
2nd generation - risperidone
18 12.10.2016
Antimanic drugs – Mood stabilizers – Thymoprophylactic drugs
• Bipolar afective disorder
Antimanic drugs
• Stabilize the mood, suppress both manic and depressive episodes
• lithium • Antiepileptic drugs • carbamazepine • valproate • lamotrigine • gabapentine
lithium
• Commonly used salt is lithium carbonate • Lithium is a cation which passes the voltage gated ion channels to neurons and accumulates there (not excreted by ATPase) • Other effects are not well understood • Effect comes after approx. 10 days, at the beginning antipsychotics can be added • Narrow therapeutic window, TDM
19 12.10.2016
lithium
• Toxicity: • Tremor (propranolol) • Fuzziness • Hypothyreosis (reversible, monitoring) • Polydipsia, polyuria, renal dysfunction
• Overdose: peritoneal or hemodialysis
antiepileptic drugs
• Besides their main mechanisms they also improve mood (probably by a different mechanism) • In the manic phase can be combined with atypical antipsychotics • olanzapine • quetiapine • risperidone • aripiprazole
20