Pharmacology Section 13. Treatment of motor disorders Treatment of Alzheimer’s disease

1. PharmacologySection 13.Treatment of motor disordersTreatment of Alzheimer’s disease Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz martia1@tlen.pl

2. Parkinson's Disease • PD belongs to a group of conditions called motor system disorders • progressive neurologic disorder that affects neurons in the part of the brain controlling muscle movement. • 1-2% of population suffer from this condition normal, AD, PD, PD+dementia

3. Symptoms of PD Primary symptoms of PD: • Tremor • Muscle rigidity(stiffness or inflexibility) • Bradykinesia (slowing of voluntary movement ) • Postural and gait abnormalities

4. Causes of PD • DA-ergic neurons in substantia nigra and corpus striatum (nigrostriatal DA-ergic tract) are destroyed • nigrostriatal DA-ergic tract - part of the extrapyramidal system, responsible for motor control • 80% of DA-eric neurons are damaged, the symptoms of Parkinson disease appear.

5. The striatum, is also rich in excitatory cholinergic neurons that counteract the action of dopamine. This is the dopamine-acetylocholine balance the dopaminergic system inhibits the acetylocholinergic system. Causes of PD DA ACh

6. In Parkinson`s disease dopaminergic neurons degenerate in nigro-striatal dopaminergic tract and the inhibitory influence of dopamine on the striatum is diminished, resulting in increased activityof excitatorycholinergic neurons.

7. Causes of PD • Parkinson's disease may result from a combination of genetic and environmental factors. • Certain toxins, diseases (viral encephalitis, small vascular lesions) and drugs may also cause symptoms similar to those of PD. - haloperidol (Haldol) - chlorpromazine (Thorazine) - metoclopramide (Reglan) - prochlorperazine (Compazine) - valproate (Depacon)

8. Risk factors • Age- PD usually affects people over the age of 50 • Genetic factors/Heredity • Sex-Men are more likely to develop Parkinson's disease than women are. • Exposure to pesticides and herbicides • Reduced estrogen levels • Reduced folate levels

9. There is no cure for PD, but a variety of medications provide dramatic relief from the symptoms! The strategy of treatment of PD rests on: dopamine levels in nigro-striatal dopaminergic tract restoring the correct dopamine-acetylocholine balance (through antagonizing the excitatory effect of cholinergic neurons) Treatment of PD

10. Drugs used in PD • Drugs, which restore the dopamine levels in nigro-striatal dopaminergic tract: • Levodopa (L-dopa) and carbidopa • COMT inhibitors • Dopamine agonists • Amantadine • Selegiline • Drugs, which restore the dopamine-acetylocholine balance: • Anticholinergics

11. Levodopa • the most effective medication for Parkinson`s disease.  • 70-80% of treated Parkinson`s patients are on levodopa therapy.  • Standard release preparations: - levodopa/carbidopa (Sinemet or Atamet) - levodopa/benserazide (Madopar) • Prolonged release preparations: - levodopa/carbiopa (Sinemet CR) - levodopa/benserazide (Madopar HBS)

12. Levodopa • Mechanism of actions: dopamine doesn't cross the BBB! Levodopa – metabolic precursor of DA easily penetrate the BBB into the CNS. DOPA-decarboxylase Levodopa Dopamine

13. DOPA decarboxylase inhibitors • Levodopa combined with DOPA decarboxylase inhibitors represent a significant improvement in the treatment of PD. • Carbidopa • Benserazide • a smaller dose of levodopa is needed to treat symptoms • nausea and vomiting often associated with levodopa treatment are greatly reduced by the presence of DOPA decrboxylase inhibitors. 

14. Levodopa • Actions: Levodopa reduces akinesia and rigidity, in smallest degree decreases tremor. • Pharmacokinetics: • well absorbedupon oral administration. • should be taken on empty stomach, 45 minutes before a meal. Foods inhibit the absorption from the gut of levodopa and it`s transport into the CNS. • Interactions: • Vit. B6 • MAOIs • Antidepressants • Neuroleptics • Hypotensive drugs Levodopa loses therapeutic efficacy after a long time of treatment. This means that the length of time that each dose is effective begins to decrease, leading to more frequent doses.

15. Levodopa • The adverse side effects: CNS: - visual and auditory hallucinations, - mood changes (depression, excitation). With increased dosing and prolonged use of levodopa, patients experience: -dyskinesias (spontaneous, involuntary movements) and "on-off" periods when the medication will suddenly and unpredictably start or stop working. - insomnia and anxiety. Peripheral: - nausea, vomiting - low blood pressure.

16. COMT inhibitors • represent a new class of Parkinson's medications • they must be taken as an adjunct with levodopa/carbidopa! Entacapone (Comtan) Tolcapone (Tasmar)

17. Side effects: diarrhea, postural hypotension, dyskinesias, insomnia, nausea, hallucinations, anorexia, constipation . Tolcapone is hepatotoxic Interaction: MAOIs Indication: Tolcapone- reduces the frequency of the “on-off”periods (motor fluctuations) Entacapone- secondary medication; delays wearing off by prolonging effectiveness of levodopa (Stalevo) COMT inhibitors

18. Agonists available in the United States include: bromocriptine (Parlodel) pergolide (Permax) New drugs: pramipexole (Mirapex) ropinirole (Requip) They mimic the effects of dopamine in the brain The older used in combination with levodopa The side effects: similar to those of levodopa, although they are less likely to cause involuntary movements (dyskinesia)and more likely to cause hallucinations, confusion, nausea or orthostatic hypotension. Dopamine agonists The newer used alone, as the first-line; side effects similar to bromocriptine but they are milder.

19. antiviral drug Mechanism of actions: enhences the syntesis and release of DA andimprove Dopaminergicneurotransmission. Actions: less efficacious than levodopa but it has fewer side effects has little effect on tremor but is more effective than the anticholinergics against rigitidy and bradykinesia Side effects: difficulty in concentrating confusion, insomnia nightmares, agitation hallucinations  leg swelling mottled skin Amantadine- Symmetrel for people in the latter stages of Parkinson's disease, if they have problems with dyskinesia induced by levodopa

20. selective IMAO-B an adjunct to levodopa therapy, prevent the break down of both naturally occurring DA and DA formed from levodopa, resulting in dopamine levels in the brain Side effects: heartburn, nausea, dry mouth, dizziness risk for severe hypertension (only at high doses of drug) Selegiline- Deprenyl - Eldepryl - Atapryl - Carbex has a mild antidepressanteffect. 

21. the main treatment for Parkinson's disease before the introduction of levodopa. Mechanism of actions: the activity of Ach Actions: - used as secondary- adjuvant medications. - they help control tremors in the early stages of the disease.  Adverse effects: blurred vision, drymouth, urinaryretention) mental problems: memory loss, confusion hallucinations. They are not used long-term due to their side effects. Anticholinergics Biperiden HCL (Akineton), Benztropine mesylate (Cogentin)Procyclidine (Kemadrin), Trihexyphenidyl (Artane)

22. Over the counter medications • Free radicals or reactive oxygen species may be harmful to cells and lead to their death. • Antioxidants protect nerve cells from oxidative damage. • Neuroprotective treatments may be most helpful at an early stage of PD.

23. PharmacologySection 13.Treatment of Alzheimer’s disease Marta Jóźwiak-Bębenista Department of Pharmacology Medical University of Lodz martia1@tlen.pl

24. Alzheimer’s disease • ADit is one of the dementing disorders, which are a group of brain diseases that result in the loss of mental and physical functions. • AD is a progressive disease of the brain that is characterized by impairment of memory and a disturbance in at least one other thinking function (for example, language or perception of reality).

25. Symptoms of AD • Cognitive symptoms: - memory loss - disorientation - confusion - difficulty with reasoned thought - loss of language skills. • Behavioral symptoms: - agitation/anxiety - delusions/hallucinations - depression - insomnia - wandering The severity of the symptoms increases over time. The onset of AD is usually very slow and gradual.

26. Causes of AD • Neuropathologic causes: - beta-amyloid protein (amyloid plaques) - degeneration of cholinergic neurons - atrophy of NA,DA,5-HTergic neurons - Large amount patologic proteins: apolipoprotein E, presenilins - Inflammation. - traumatic head injuries earlier in life.

27. Causes of AD • Age (10 % of people over age 65 and 50 % of those over 85 have AD) • Geneticfactors • Abnormalities in the brain's neurotransmitters, • ACh is a critical neurotransmitter in the process of forming memories. • ACh is abundant in the nerve cells of the hippocampus and cerebral cortex, the regions that are devastated by AD.

28. There is no treatment that will stop or reverse the symptoms of AD. The used drugs attempt to slow the progression of the disease. These drugs work to maintain levels of neurotransmitters in the brain! To increase the activity of cholinergic system we use: 1. acetylocholine precursors (lecithin, choline) 2. ACh-esterase inhibitors (acetylcholinesterase, an enzyme responsible for the destruction of acetylcholine) Tacrine (Cognex), Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne, Reminyl) Treatment of AD

29. Side effects of tacrine: abdominal cramps nausea polyuria diarrhea hepatotoxic The newer anticholinesterase inhibitors: donepezil, rivastigmine, galantamine are better tolerated. The main side effects are nausea, vomitimg, diarrhea. The newer anticholinesterase inhibitors have proved beneficial in improving memory, and have fewer side effects. Treatment of AD The newer drugs are not effective for everyone, and their effectiveness is limited to the early and middle stages of AD.

30. Treatment of AD Memantine (Namenda) • approved to treat moderate to severe AD, • It`s effects are independent of acetylcholine and acetylcholinesterase. • by blocking the NMDA receptors and the effects of glutamate, memantine may protect nerve cells from excess stimulation by glutamate.

31. It is possible to reduce some of the common emotional and behavioral symptoms associated with AD. Tranquilizers- reduce agitation, anxiety, unpredictable behavior. Benzodiazepines- improve sleeping patterns Antidepressants - treat depression. Other drugs: selegiline antioxidants (vit. E, koenzym Q10) anti-inflammatory drugs: indometacin (NSAIDs) Treatment of AD

32. Huntington`s disease

33. Huntington's disease (HD) = Huntington disease = Huntington's chorea = chorea maior • movement disorder associated with defects in the basal ganglia • inherited neurological disorder • appears during adult life • one out of every 10,000 Americans has HD

34. Pathophysiology of HD Imbalance of dopamine, acetylcholine, GABA and perhaps other neurotransmitter in the basal ganglia. • overactivity in dopaminergic nigrostriatal pathways • increased responsiveness of postsynaptic dopamine receptors • deficiency of a neurotransmitter that normally antagonizes dopamine.

35. Pathophysiology of HD • GABA and glutamic acid decarboxylase are reduced in the basal ganglia of patients with HD. • Ach and choline acetyltransferase are reduced in the basal ganglia of patients with HD. Theses deficiencies reduce the inhibitory influence on the nigrostriatal dopaminergic neurons and lead to the dopamainergic hyperactivity associated with Huntington`s disease

36. The symptoms of HD are suppressed by drugs that block dopaminergic receptors and worsened by drugs that increase basal ganglia dopaminergic activity.

37. Drugs that deplete central dopamine stores by blocking entry into the neuronal storage vesicles: reserpine(small doses of 0.25 mg daily; no longer used in the UK) tetrabenazine The adverse effects: hypotension, depression, sedation, gastrointestinal disturbances. Drugs that block the dopaminergic receptors: phenothiazines (e.g. Perphenazine) butyrophenones (e.g. Haloperidol) The adverse effects: restlessness, parkinsonism. Treatment of HD Reduction basal ganglia dopaminergic activity

38. Treatment of HD • enhance central GABA or Ach activity no consistently beneficial response