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Lecture Nine

Parkinsons Disease

QuestionAnswer
Parkinsons Disease is due to a loss of neurons. **Describe the nature of this loss of neurons Progressive and irreversible loss of neurons
**Parkinsons Disease involves a s____________ v______________ within neuronal populations. This means that there is a selective loss of neurons selective vulnerability.
**What are the Cardinal features of PD? (4 of them) 1) Bradykinesia (movement) 2) Muscle rigidity - can progress to Akinetic (not being able to move at all) 3) Tremor at rest 4) Impaired balance/gait.
Parkinsons Disease is **primarily a movement disorder** but also involves sensory, cognitive and behavioural changes. so **primarily a movement disorder**
**Describe the Characteristic pathology (what happens in the brain) of PD, in two ways.. 1) 70-80% loss of DA neurons in substantia nigra. 2) Lewy Bodies appear so makes plaques in tissue
**Describe the Aetiology of PD. (3/4 parts to it) The majority of cases idiopathic (we don't know the cause). The minority of cases are familial (genetic, identified mutations in genes in family). A subset of cases are linked to encephalitis lethargica epidemic in early 20th century.
**Describe the Aetiology of PD. (4th part to it) "Parkinsonian" movement disorders can also be drug-induced.
In 1982, 6 people appeared in California clinics displaying mysterious symptoms: their bodies were so stiff that they appeared frozen. All of them had used MPPP (an illicit opioid analgesic) which was contaminated by MPTP (a neurotoxin).What does this do? MPTP selectively destroys DA neurons in substantia nigra.
**Why do we care about MPTP? We still use it intentionally in labs. Its used as a standard **"Parkinsonian model"** in mice/rats to study PD to selectively destroy neurons in the substantia nigra.
**If all we need to do is restore/increase DA, then why don't we just administer dopamine? **Because DA doesn't cross the BBB.
**Describe the synthesis of DA Tyrosine --> DOPA --> dopamine
**What is DA enzymatically degraded by? MOA (monoamine oxidase) and COMT enzyme
**Describe the DA receptors Classed D1 - D1, D5 which are metabotropic (Gs), Classed D2 - D2, D3, D4 which are metabotropic (Gi).
**Describe the clearance of DA There is a pre-synaptic transporter (DAT) and MAO-B (monoamine oxidase) and COMT enzymes break it down.
**What are the three things to NOTE about DA diagram?** Theres a D2 (Gi) autoreceptor and a DAT and that the MAO-B enzyme is DA specific.
**Synthesis is one of the 4 key pharmacological manipulations. What drug is used for PD that targets the synthesis?** L-Dopa. Which is a pro-drug and helps the synthesis (creation) of DA (synthesis is Tyrosine --> L-DOPA --> dopamine). So as long as you have this L-Dopa enzyme, you can make more DA.
**What is the major shortcoming of targeting the synthesis of DA by using the pro-drug L-Dopa? You have this L-Dopa enzyme everywhere in your body (in the periphery) so DA starts to be made before it gets into the brain.
**What happens when L-dopa is administered? 99% of L-dopa is converted into DA in the PERIPHERY --> so minimal L-Dopa gets into the brain!!. And high peripheral DA has side effects!!
**What are the side effects from having high (99%) L-Dopa in the peripheral? hypertension, arrhythmias, nausea and vomiting.
**How/What allows ALL of L-Dopa to be available to go into the brain? Carbidopa as it inhibits PERIPHERAL AA decarboxylase AND Tolcapon inhibits PERIPHERAL COMT
**So what drugs can you take to increase the amount of L-Dopa that enters the CNS? And what does this increased L-Dopa do?** A combination of L-Dopa with Carbidopa or a combination of L-Dopa with Tolcapone
**While L-Dopa continues to be the standard therapy for PD, what is a shortcoming of it? It has an "on/off phenomenon" or a "wearing off".
**So in early phases of L-Dopa treatment, the medication works great. Then in later phases the medication provides only ?-? hours mobility and then....? 1-2 hours mobility, wears off
**So in early phases of L-Dopa treatment, the medication works great. Then in later phases the medication provides only 1-2 hours mobility and then wears off. Unfortunately increasing the dose/frequency does not work because it causes? dyskinesias and psychoses.
**What is the name of the neurologist who strongly supported the idea of exploiting the synthesis of the DA (using L-Dope)? What was his main finding that made him support this idea? Oliver Sacks, he found that patients in the end-stage of catatonia and PD could be 'awakened' with L-Dopa.
**Recall the shortcomings of the use of L-Dopa treatment for PD? On/Off patterning, tolerance (wears off) and psychoses (if you increase dose/frequency).
** Describe the "on/off phenomenon" from using L-Dopa "On" states become shorter as the L-Dopa wears off quicker (tolerance) and "off"states occur when person is stiff and cannot move for a few minutes
**Another treatment strategy for treating PD is by targeting the Release of DA. **What drugs could you use to prompt vesicular DA release? Discuss if this is a good idea Amphetamines, Methylphenidate (Ritalin). Mechanistically this would work to change the DAergic tone but we do not want to be prescribing amphetamines etc due to their abuse potential.**
**A 3rd target for the treatment of PD is by targeting the Post-synaptic receptor(D1,D2 excitatory)or(D2,D3,D4 inhibitory)by using DA Receptor Agonist.What are the 2 Advant. of this approach (using Receptor Agonists).Why is the 1st advantage so important? (1)Doesn't require functional neurons to convert L-dopa to DA(2) Acts for longer (the half-life is 12-14 hours so only have to take 1-2 times a day). First advant. is so import. cos PD patients are losing Substantia Nigra so don't have enzymes to convert
**What DA receptors are excitatory? D1, D2 (classed D1)
**What DA receptors are inhibitory? D2, D3, D4 (classed D2)
**What are the 2 major disadvantages of using DA receptor agonists? (targeting the post-synaptic receptor) (these side effects occur because DA receptor agonists effect other DA pathways relating to decision making, impulsive shopping for example) 1) Older agents are only marginally effective - do not work that well, not much efficacy. 2)Side effects : **hallucinations, psychoses, nausea, excess fatigue, hypotension and impulsivity**
**What is the fourth and final approach/target for treating PD? Clearance (targeting DAT and MAO + COMT enzymes)
**What drugs could be used to reduce clearance of DA? Cocaine, Methylphenidate (Ritalin) would mechanistically work to inhibit clearance enzymes but would not want to give to PD patients due to high abuse potential.
Although Cocaine and Ritalin would mechanistically work to inhibit clearance of DA, they cannot be used due to abuse potential. **What drug can be used (doesn't have abuse potential) and can mechanistically be used?How does this drug work/what does it do? Selegiline which selectively inhibits MAO B enzyme (specific clearance enzyme for DA)
With Selegiline, which selectively inhibits MAO-B clearance enzyme. With this, the metabolic intermediates include amphetamine. **Would this be a good or bad thing? Ask Natu!
**Recall the three Primary pharmacotherapeutic strategies: 1) L-Dopa combined with Carbidopa or with Talcapone. 2) Dopamine Receptor Agonists e.g.Mirpex 3) Selegiline
**Explain the L-Dopa combined with Carbidopa or Talcapone strategy** ...
**Explain the Dopamine Receptor Agonist strategy** ...
**Explain the Selegiline strategy** ...
Pharmacoloy has significantly increased the quality of life for patients with Parkinson's Disease, but still doesn't cure the disease. **How could PD be cured? **Is there a current treatment approach that does this? You would have to restore the substantia nigra neurons by stopping their deaths & making new ones. Currently Stem Cell transplants of substantia nigra neurons are being done BUT the new neurons still die again so prolongs treatment but doesnt' cure yet!
ALZHEIMERS DISEASE
**Alzheimers Disease is primarily a ______________ disorder but also involves ______________ and ______________ changes cognitive, personality, behavioural.
**Describe the key clinical features of Alzheimers. Impairments in short term memory, executive functions, circadian rhythm, behavioural/personality changes, language
**Why do AD rates seem to be increasing in the 21st Century? Because people are living longer - into our 60s, 70s, 80s, so prevelance of AD is increasing.
**Name the 4 Characteristic pathology's for Alzheimers Disease. (1) Cortical atrophy (folds in cortex shrink) (2) Beta - amyloid plaques 3) Neurofibrillary tangles, 4) Significant loss of ACh (Acetylcholine) .
**The 4th characteristic pathology of Alzheimers relates to what hypothesis? The "Cholinergic Deficiency Hypothesis" (Perry, 1986)
**Alzheimer's cannot be definitely diagnosed until....? diagnosis in post-mortems
**How do we diagnose Alzheimers prior to post-mortem when patient is still alive? (ante-mortem) By exclusion - ruling out all other possibilities
**What four things must we rule out before diagnosing Alzheimers? Delirium, Clinical Depression, Mild Cognitive Impairment, Dementia
**What is Delirium? An ACUTE reduction in mental function
**What is Mild Cognitive Impairment (MCI)? "old age". People have varying degrees of MCI seen in normal ageing - we all forget things
** What are the key points to remember about Dementia to know whether to exclude it? That it is a SIGNIFICANT, PERSISTANT, PROGRESSIVE, loss in cognitive capacities. NOT PART of normal ageing.
**Although the cause of Alzheimers is also not know, what are the current treatment approaches ? **And of what nature are they? They are symptomatic. 1) They have low levels of ACh in AD so the goal is to increase cholinergic tone 2) They have cell loss due to excitotoxicity so the goal is to decrease excitatory tone.
**List the FIRST strategy for increasing Cholinergic Tone (the first approach due to low levels of ACh) 1)Since u need more of Choline & Acetyl CoA, you should give Choline so that body makes more ACh (can buy in store).BUT you only have so much CHAT enzyme that turns Choline and Acetyl CoA into ACh and it can only work so fast,so this strategy has downfall
**List the SECOND and THIRD strategy for increasing Cholinergic Tone (the first approach due to low levels of ACh)? 2) Giving nicotine will increase Cholinergic tone. 3) Inhibit enzyme AChE (clearance for ACh) to increase ACh.
**Recall the third strategy for increasing Cholinergic Tone (the first approach due to low levels of ACh)? **What are the 3 issues with AChE inhibitors (in drug form) for AD? 1) The half life is short so patient has to take frequently which is not ideal as they are forgetful. 2)ROA is oral to also difficult for patients to remember to take and some may be resistant to taking a pill 3) Side effects are insomnia
**Recall the second approach for Alzheimers disease and list the first 2 strategies to do this Decreasing Glutamatergic Tone. 1)Synthesis: we get Glutamate from diet so deprive self from Glutamate by starvation. 2)Release: nothing 3) Post-synaptic Receptors: want to an antagonist for post-synaptic receptors, specifically NMDA receptor
**Recall the second approach for Alzheimers disease and list the third strategies to do this Decreasing Glutamatergic Tone. 4) Clearance: promote transporter of Glutamate but no current drug for this.
**Recall the second approach for Alzheimers disease and name only strategy that we know how to to atm The 2 strategy : Post-synaptic receptors: want to an antagonist for post-synaptic receptors, specifically NMDA receptor
**What is the name of the drug that is an NMDA receptor antagonist used for the approach of decreasing Glutamatergic Tone and strategy of having an antagonist for a post-synaptic receptor. Memantine
Most drugs used to treat AD are aimed at **________ the rate at which symptoms become worse. The benefit from these drugs is often small and patients and their families may not always notice much of a **_____________ slower, change
INTRO TO DRUG DESIGN
There is intense pharmaceutical interest and competition in finding new drugs for neurodegenerative disorders, particularly in finding THE **____ drug and the **__ BIOMARKER AD, AD
**What are the 3 steps to drug discovery? (1) Research (Pre-clinical research and Pre-clinical testing. (2) Clinical Trials (Phase 1, Phase 2, Phase 3). (3) Approval (Federal Approval).
**Which phase and step of drug discovery is in a petri dish? Research step : Pre-Clinical Research.
**In the lab, during Research step (Pre-clinical research with petri dish), finding chemicals that bind receptors would determine..? Selectivity
**In the lab,during Research step (Pre-clinical research with petri dish) determining which chemical exerts an effect when bound to a receptor determines....? Efficacy
**In the lab, during Research step (Pre-clinical research with petri dish), determining which chemicals bind the best (fits well) to receptors determines....? Affinity
What is the name of the example DA receptor agonist used in the second strategy for treating PD? Bromocriptine
**In the lab during Research step (Pre-clinical research with petri dish) what determines Selectivity? Finding chemicals that bind to the receptor
**In the lab during Research step (Pre-clinical research with petri dish) what determines Efficacy? Determining which chemical exerts an effect when bound to receptor
**In the lab during Research step (Pre-clinical research with petri dish) what determines Affinity? Determining which chemical binds the best (fits well)
**Which phase and step of drug discovery uses animals? Researchs step: Pre-clinical testing
**In the lab, during Research step (Pre-Clinical Testing), testing the candidate drugs in animals determines what...? Pharmacokinetics/toxicity
**In the lab, during Research step (Pre-Clinical Testing), testing the candidate drugs in animal models determines what....? Efficacy (whether it is useful)
**In the lab during Research step (Pre-clinical Testing) what determines Pharmacokinetics/Toxicity? Testing the candidate drugs in animals
**In the lab during Research step (Pre-clinical Testing) what determines effectiveness (whether it is useful)? Testing the candidate drug in animal models.
In the Clinic, Phase 1 trials use only 15-30 volunteers. **What does Phase 1 determine? Dosage, and side effects
In the Clinic, Phase 2 trials use less than 100 PATIENTS. **What does Phase 2 determine? Effectiveness and side effects
In the Clinic, Phase 3 trials use 100s-1000s PATIENTS. **What does Phase 3 determine? Significant effectiveness
**What are the key comparisons in Phase 3? Comparing experimental drug with placebo and comparing a drug already available for that illness (if not better than new drug then no point going forward)
Once a drug has passed Phase 3 trials, you can apply for FDA approval. **But what two things do you also need to do after this point? Run regulatory studies (should include longitudinal studies) and charter patent law to get patent approved and maintained.
Created by: alice476