Parkinson s Disease Degenerative Disease loss of dopamine containing neurons in substantia nigra located in basal ganglia in brain Characterized by onset of tremor muscle rigidity and difficulty in initiating movement Usually occurs in elderly patients but impurities in street drugs have caused Parkinson s in young addicts as well In unaffected people acetylcholine and dopamine in caudate are balance but as dopamine cells are lost acetylcholine effects tend to dominate Two approaches to therapy o Increases dopamine effects o Decrease acetylcholine effects Dopamine and Ach Balance Increase dopamine effects Muscarinic Antagonists in Parkinson s Disease Anticholinergic Agents Muscarinic antagonists decrease the effects of excess acetylcholine but have all the side effects Drugs o Atropine or scopolamine not used for this anymore o Benztropine prototype drug o Trihexyphenidyl o Also other drug classes with anti muscarinic side effects diphenhydramine are also used Side Effects o Anti SPLUDD effects o Constipation dry skin and mouth o Difficulty in urine o Dilated pupil o Sedation and drowsiness Less frequent o Postural hypotension o Numbness o Tachycardia Adverse Reaction confusion glaucoma attack Overdose same as side effects more severe tachycardia seizures Drug Interactions enhances sedation effects of alcohol and CNS hallucinations flushed red skin depressants Ways to Increase Dopamine Effects Increase synthesis o L DOPA o L DOPA carbidopa prototype Increase release o Amantadine antiviral with unknown action Directly stimulate dopamine receptors o Pramipexole dopamine agonist o Ropinirole restless leg syndrome Decrease degradation o MAO B Inhibitor selegiline rasagiline o COMT Inhibitor tolcapone L DOPA Treatment of Parkinson s Disease L DOPA o Crosses blood brain barrier and is converted to dopamine in remaining cells in substantia nigra Side Effects and ADR o Chloroform movements o Difficulty in urination o Mood change psychosis o Aggressiveness o Dysrhythmias hypotension o Nausea and vomiting o On off phenomena Drug Interactions with L DOPA Drug interactions MAO inhibitors antipsychotics vitamin B6 pyridoxine Carbidopa and L DOPA L dopa and carbidopa Sinemet o 99 of L dopa is metabolized in periphery o 95 by dopa decarboxylase o Carbidopa blocks peripheral dopa decarboxylase increasing amount of L dopa that gets into CNS o L dopa crosses blood brain barrier carbidopa does not Side Effects ADRs o Generally the same with L dopa alone but allows lower L DOPA doses and reduces the incidence and severity of side effects and drug interactions Physical Therapy Considerations for Treating Parkinson s Exercise and rehabilitation is more useful if timed for periods when the patient is more mobile Most individuals with mild to moderate Parkinson s show improved movement within 1 1 5 hours of dopamine replacement therapy L DOPA or dopamine agonist Research is ongoing whether exercise changes the pharmacokinetics of L DOPA therapy Myasthenia Gravis Autoimmune Disease body produces antibodies against nicotinic receptors on muscle cells that respond to Ach paralyze the muscle Progressive and incurable Symptoms are muscle weakness drooping eyelids that is worse for repetitive tasks Diagnosis short term improvement seen with short acting anticholinesterase edrophonium Myasthenia Gravis Treatment Thymectomy plasmapheresis remove antibodies corticosteroids inhibit immune system response Primary treatment is anticholinterases Rationale by blocking breakdown of Ach more is available to activate the remaining muscle nicotinic receptors Anticholinesterases and Effects on Myasthenia and Curariform Drugs Drugs for Treating Myasthenia Gravis Drugs o Edrophonium prototype drug diagnoses only o Ambenonium o Neostigime prototype drug for treatment o Pyridostigmine Side Effects o SPLUDD effects o Sweating vomiting o Diarrhea drooling o Urge to urinate constricted pupils tears Treatment of Side Effects o Atropine or other antimuscarinics Caution asthma or pregnancy Cholinergic Crisis in Myasthenia Too much anticholinesterase can lead to muscle paralysis just like succinylcholine by over activating the nicotinic receptors Myasthenics with too much anticholinesterase are in cholinergic crisis and resemble the disease Alzheimer s Disease Incurable progressive mental impairment in elderly o Characterized by plaques and tangles in brain o Posthumous diagnosis Symptoms o Memory loss o Loss of logical thinking o Disorientation leading to wandering behavior Theories o Loss of cholinergic neurons in brain o Genetic abnormality 10 o Autoimmune disease o Abnormality in protein processing amyloid Drugs for Alzheimer s Disease Rivastigmine prototype Exelon centrally acting anticholinesterase Used to increase Ach in brain Common adverse effects nausea and vomiting anorexia weight loss Use caution with asthma COPD can cause bradycardia incontinence Give on an empty stomach to maximize absorption but if severe GI upset Interacts with other cholinergic drugs occurs can be taken with food Riluzole for ALS riluzole treats it Not explicitly known what causes amyotrophic lateral sclerosis or how ALS is a progressive loss of motor neurons leading to death by suffocation Riluzole delays the need for tracheotomy Riluzole decreases glutamate effects in the CNS Monitor liver function as riluzole can damage liver Glatiramer for Multiple Sclerosis MS patients mount an autoimmune attack on the myelin that insulates their ABC treatment Aconex betaseron copaxone Glatiramer Copazonr is synthetic similar to basic myelin protein that acts as an immune modulator Can cause hives rash chest pain and breathing difficulties Contraindicated by allergy to mannitol use caution in immune compromised nerves patients Muscle Spasm and Spasticity Spams are sudden involuntary muscle contractions while spasticity involves muscle that are continually contracted Centrally acting muscle relaxants used for spasms o Cyclobenaprine Centrally acting spasmolytics used for spasticity Peripherally acting spasmolytics o Baclofen o Dantrolene Cyclobenzaprine Acts in the CNS to block muscle spams Causes sedation warn patients about driving and operating dangerous machine Sudden withdrawal can cause anxiety hallucinations seizures psychosis Can interact with CNS depressants or alcohol Anticholinergic Side Effects dry mouth and skin difficulty urinating or defecating Anti SPLUDD effects avoid for glaucoma patients Centrally Acting Spasmolytics Baclofen Used to treat