Drugs For Parkinson’s Disease

Drugs for Parkinson’s disease History  1817 – English physician, James Parkinson’s.  Late 1800s – French neurologist, Charcot. Epidemiology  The most common movement disorder affecting 1 – 2% of the general population over the age of 65 years.  The second most common neurodegenerative disorder after AD. Risk     factors Age is the most important risk factor. Positive family history. Gender: male > female. Environmental exposure: herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills, and steel alloy industries.  Life experiences: trauma, emotional stress, personality traits (e.g. shyness and depressiveness). Clinical features  Resting tremor.  Bradykinesia (generalised slowness of movements).  Muscle rigidity. Physiology  The substantia nigra is the major origin of the dopaminergic innervation of the striatum.  Dopamine synthesis: o The precursor to dopamine is DOPA (from tyrosine).  One major function of the striatum is the regulation of posture and muscle tone. Pathology  Eosinophilic, round intracytoplasmic inclusion called Lewy bodies and Lewy neurites. o Lewy bodies first described by Friedrich Lewy in 1912.  Lewy bodies affect the cell by disturbing intracellular activities, particularly reducing the efficiency of axonal transport of dopamine vesicles to the synapse.    Confined largely to neurons; glial cells only rarely affected. Consists of aggregates of α-synuclein. Inclusions particularly numerous in the substantia nigra pars compacta.  Other areas involved include: o Locus coeruleus. o Motor nucleus of the vagus nerve. o Hypothalamus. o Nucleus basalis of Meynert. o Cerebral cortex. o Olfactory bulb. o Autonomic nervous system. PD symptoms manifest when about 50 – 60% of the DA-containing neurons in the substantia nigra and 70 – 80% of striatum are lost. o To determine extent of DA-containing neurons left, use antibodies stained with fluorescence.  Possible drug targets Possible drug targets Synthesising more dopamine  Levodopa (L-Dopa) is the cornerstone of PD treatment.  Reason why it’s used: o Dopamine cannot cross the blood brain barrier because it is charged (its amino group is protonated). o Thus, its precursor, L-Dopa is used. It is able to pass the blood brain barrier because its structure is closely related to tyrosine. This allows it to travel through an amino acid transporter and into the neuron.  Also used to treat encephalitis lethargica. o Disease characterised by high fever, headache, double vision, delayed physical and mental response, and lethargy. o Acute cases, patients may enter coma. o The disease shows depletion of dopaminergic neurons. o L-Dopa produces dramatic responses.  Limitations: o Efficacy tends to decrease as the disease progresses. o Chronic treatment associated with adverse events (motor fluctuations, dyskinesias and neuropsychiatric problems). o Does not prevent the continuous degeneration of nerve cells in the substantia nigra; treatment is only symptomatic. Inhibiting dopamine production until CNS  DOPA decarboxylase inhibitor (DDC inhibitor). o L-Dopa is converted into dopamine via DOPA decarboxylase. o If this occurs too early, dopamine will not enter the brain (because it can’t pass through blood brain barrier). o CardiDOPA (e.g. Lodosyn) is an add-on drug which inhibits peripheral metabolism of L-Dopa by inhibiting DOPA decarboxylase. o It cannot cross the blood brain barrier, and so it only inhibits peripheral DOPA decarboxylase, increasing the amount which reaches the brain. o Once in the brain, L-Dopa is converted into dopamine to elicit its effects.  Catechol-O-methyl transferase inhibitor (COMT inhibitor). o L-Dopa is converted into 3-OMD via catechol-O-methyl transferase. o Thus, to increase the amount of L-Dopa reaching the CNS, and hence dopamine formed within, COMT inhibitors (e.g. entacapone) are used. Other treatments  DA receptor agonists: o Bromocriptine. o Pergolide. o Pramipexole. o Ropinirole. o Cabergoline.  Monoamino-oxidase (MAO) inhibitors. o Prevent degradation of dopamine. o Longer lasting effect on synapses.  Surgical techniques, including inserting of “brain pacemakers”. Summary  1 – 2% of the general population >65 years old has PD.  Lewy bodies and Lewy neurites, particularly in the substantia nigra pars compacta dopaminergic neurons projecting to the striatum  dopamine levels severely reduced in striatum.  Clinical features include resting tremor, bradykinesia and muscle rigidity.  L-Dopa and other drugs work to help alleviate symptoms.  No treatment which would prevent the continuous degeneration of nerve cells in the substantia nigra and resulting striatal dopamine loss.