DRUGS FOR NEURODEGENERATIVE DISEASES

JOSEPH DE SOTO MD, PHD, FAIC

OVERVIEW

Most of our medications that we use for the central act by altering a step in the neurotransmission process. Hence, drugs may alter the production, storage, release and termination of action of neurotransmitters.

The central nervous system is much more complex than the peripheral nervous system due to many more synapses.

Here we will look at Parkinson’s disease, Alzheimer’s disease and multiple sclerosis.

SYNAPTIC POTENTIALS

IN the central nervous system are coupled to ion channels. Thus binding of neurotransmitters to the post synaptic receptor will cause a rapid and transient change in the opening of channels.

Neurotransmitters can be classified as either excitatory if they increase the influx of sodium across the post synaptic membrane into the cell. Neurotransmitters are classified as inhibitory if they increase the amount of chloride going into the cell or the amount of potassium going outside the cell.

Some excitatory neurotransmitters are acetylcholine and glutamate.

Inhibitory neurotransmitters include γ-aminobutyric acid (GABA), and glycine.

PARKINSON’S DISEASE

Parkinson's disease (PD) is a degenerative disorder of the central nervous system mainly affecting the motor system. The symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, of the midbrain.

The disease can be either primary or secondary. Primary Parkinson's disease is referred to as idiopathic though some atypical cases have a genetic origin. Secondary parkinsonism is due to known causes like toxins like pesticides and heavy metals. Interestingly, there is a decreased risk in tobacco smokers and those who drink coffee.

Clinical symptoms do not occur until almost 80% of the neurons in the substantia nigra have died.

PARKINSON’S DISEASE - SYMPTOMS

There are generally four motor symptoms in Parkinson’s 1) tremor, 2) rigidity, 3) slowness of movement, and 4) postural instability.

Cognitive disturbances can occur in the initial stages of the disease and sometimes prior to diagnosis, and increases in prevalence with duration of the disease.

Fluctuations in attention and slowed cognitive speed are among other cognitive difficulties. Memory is affected, specifically in recalling learned information.

LEVODOPA & CARBIDOPA

Levodopa is a metabolic precursor to dopamine. This restores the dopaminergic neurotransmission of the neostratium by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra.

As more cells die there are less and less cells that convert levodopa to dopamine and changes in motor function begin to occur. Levodopa only provides symptomatic relief. The effects of levodopa only treat the clinical symptoms and some evidence suggest that it may accelerate the disease.

LEVODOPA & CARBIDOPA

Levodopa: dopamine does not cross the blood brain barrier , levodopa on the other hand is actively transported into the CNS and converted to dopamine. Levodopa must be given with carbidopa the drug is degraded in the periphery resulting in nausea, vomiting, cardia arrhythmias, and hypotension.

Carbidopa: is a dopamine decarboxylase inhibitor and inhibits the metabolism of levodopa in the periphery increasing the amount of levodopa needed and decreases the toxicity.

In about 3 to 5 years after therapy patients start to experience a decline in response.

LEVODOPA & CARBIDOPA

Peripheral effects: Anorexia, nausea, and vomiting occur may occur. Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Mydriases and hypotensiion may occur. Saliva and urine may become brownish due to elevated catecholamine oxidation.

CNS effects: Visual and auditory hallucinations and dyskinesias may occur. Mood changes can occur with psychosis.

COMT INHIBITORSCOMT inhibitors: Levodopa is metabolized by catechol-O-methyltransferase (COMT) to 3-methyldopa. Entacapone and Tolcapone selectively and reversibly inhibit COMT.

This in turn increases peripheral levels of levodopa allowing more of it to enter into the neurons. Tolcapone has a half life of 2-3 hours while Entacapone has a half life of 30 minutes.

Side effects are due to increasing levels of levodopa and include hallucinations, dyskinesias, anorexia, hypotension and nausea.

Tolcapone alone in rare cases may cause fulmating hepatic necrosis and liver monitoring is necessary when a patient is on this medication.

MAO-B INHIBITORSMAOB inhibitors: such as Selegline selectively inhibits MAO B type enzymes at low to moderate doses. At higher doses it will begin to inhibit MAO B.

This drug decreases the metabolism of dopamine thereby increasing the levels of dopamine in the brain. This drug is frequently given with Levodopa and increase the clinical effect of it.

Selegine is metabolized to methampetamine and amphetamine and which may produce insomnia.

Rasagiline is an irreversible and selective inhibitor of MAO B and is not metabolized to the amphetamines.

DOPAMINE AGONISTS

Bromocriptine: is a dopamine agonist that is used in the treatment of Parkinson's disease (PD), hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes. A rare event - pulmonary fibrosis may occur when bromocriptine is used in high doses for the treatment of Parkinson's disease. Side effects: nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre. Half- Life 12-14 hours

Prampipexole: is a dopamine agonist of the non-ergoline class indicated for treating Parkinson's disease (PD)and restless legs syndrome. Odd side effects may occur such with this drug ropinirole including compulsive gambling, punding, hypersexuality, and overeating. Half Life 8-12 hours.

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DOPAMINE AGONISTS

Amantadine: is used both as an antiviral, multiple sclerosis and an parkinsons disease. Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. This makes it a weak therapy for Parkinson's disease.

Adverse effects: include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia.

Half-Life: 10 -31 hours

ANTIMUSCARINIC AGENTS

Benztropine, trihexylphenidyls, and biperiden: these are much less effective than the dopamine agonists. Blockage of cholinergic transmission is similar to augmenting dopaminergic transmission.

Side effects: xerostomia, constipation, and visual changes. Should not be used in glaucoma or prostate hypertrophy.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS), is an inflammatory disease autoimmune disease in which the myelin sheath of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to communicate effectively, resulting in a wide range of signs and symptoms, including physical, mental, and occasional psychiatric problems.

MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing) or building up over time (progressive). Between attacks, symptoms may disappear completely; however, permanent neurological problems often occur, especially as the disease advances.

MULTIPLE SCLEROSIS

MS is more common in people who live farther from the equator, and is most common in those of Northern European ancestry. The Hygiene hypothesis and the infection hypothesis are used to explain the risks for multiple sclerosis.

Symptoms: specific symptoms may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, very pronounced reflexes, muscle spasms, or difficulty in moving; ataxia; problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others.

Difficulties thinking and emotional problems such as depression or unstable mood are also common

MULTIPLE SCLEROSIS

Currently though is no cure for multiple sclerosis though there are drugs to reduce the symptom and the number of acute attacks.

Interferon β1a and β1b: balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood brain barrier. Overall, therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also increases the production of nerve growth factor enhancing neuronal survival.

Side effects: depression, flu-like symptoms, hepatic enzyme increase

MULTIPLE SCLEROSIS

Glatiramer: this is a synthetic polypeptide is a random polymer of four amino acids found in myelin basic protein, glutamic acid, lysine, alanine, and tyrosine and is administered sub-Q.

Side effects: flushing, chest pain, anxiety, and itching.

Fingolamod: is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction.

Side effects: Macular edema and bradycardia. electrocardiogram monitoring before treatment and then continuously for the first six hours after the first dose, and measurement of blood pressure and heart rate every hour.

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MULTIPLE SCLEROSIS

Natalizumab: This is a second line drug and is used after treatment failure of first line drugs. Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin.

This limits the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier. Natalizumab is used in the treatment of multiple sclerosis and Crohn's disease.

Adverse effects: Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus, and that only occurs in patients who are immunocompromised.

MULTIPLE SCLEROSIS

Mitoxantrone: a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells, by intercalation between the DNA bases. This drug is used to suppress the immune system.

Side effects: Neutropenia, nausea, vomiting, hair loss, heart damage, nausea, vomiting, hair loss, heart damage, and immunosuppression

Dalfampridine: is an oral potassium channel blocker, Fampridine has been used clinically in Lambert-Eaton myasthenic syndrome and multiple sclerosis. Use to help patients walk.

Side effects: paresthesias, seizures,and atrial fibrillation

ALZHEIMER’S

Alzheimer’s disease: has three characteristics: 1) accumulation of senile plaques of β- amyloid, 2) formation of neurofibrillary tangles, and 3) loss of cortical cholinergic neurons.

Current therapy tries to improve cholinergic transmission in the CNS and to prevent over excitation of the NMDA receptors.

The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include: problems with language, disorientation mood swings, loss of motivation, not managing self care, and behavioral issues, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years.

ALZHEIMER’S DISEASENMDA receptor: The N-methyl-D-aspartate receptor , is a glutamate receptor and ion channel protein found in nerve cells. It is activated when glutamate (or D-serine) bind to it, and when activated

It allows positively charged ions to flow through the cell membrane. The NMDA receptor is very important for controlling synaptic plasticity and memory function

ALZHEIMER’S DISEASE

Acetylcholinesterase inhibitors: Reversible cholinesterase inhibitors are used to treat Alzheimer’s disease. Among them are: donezepil, galantamine, and rivastigmine. These drugs improve clinical symptoms but DO NOT change the rate of progression of the disease.

Rivastigmine, is also approved for the treatment of Parkinson’s based dementia.

Side effects:

ALZHEIMER’S DISEASE

NMDA receptor antagonist: the stimulation of glutamate receptors in the CNS is important for forming certain memories. Overstimulation of glutamate receptors especially the NMDA receptors may cause over excitation and neuronal death.

Memantadine is an NMDA receptor antagonist indicated for moderate to severe Alzheimer’s disorder.

Side effects include: confusion, agitation, and restlessness indistinguishable from Alzheimer’s disease.