-Centrally acting drugs alter steps of neurotransmission

CNS is different from the PNS in some important ways

-CNS is more complex, with far more synapses than the PNS. The CNS also has a slew of inhibitory neurons to modulate transmission, and uses fore more kinds of neurotransmitters.

Important Physiology Side Notes

-EPSP’s are generated from Ach and Glutamate

-IPSP’s are generated from GABA and Glycine

List of neurodegenerative diseases

-Parkinson’s Disease

-Alzheimer’s Disease

-Multiple Sclerosis

-Amyotrophic Lateral Sclerosis

Parkinson’s Disease (PD) or Parkinsonism

-Progressive neurological disorder of muscle movement

-Tremors, Rigidity, Bradykinesia and Postural/Gait abnormalities

-Typically develops after age 65

-Correlates with loss of dopaminergic neurons in the substantia nigra causing reduced dopamine actions in the striatum (neuronal cluster responsible for movement)

-Secondary Parkinsonism is when drugs block dopamine signaling in the brain, causing pseudo-Parkinson’s symptoms. All antipsychotics have some risk of causing secondary Parkinson’s

-Treatment is only palliative, working to restore dopaminergic signaling and ensure the Ach/Dopamine balance in the brain. They also antagonize the effect of excitatory cholinergic neurons.

1. Drugs/Treatment

   1. Levodopa and Carbidopa

      1. These are precursors of dopamine that enhance dopamine generation in the remaining, living neurons in the substantia nigra to restore the above balance. Therapeutic response is usually consistent.

      2. Relief is symptomatic, while the drug is in the body, and needs at least 20% of the dopaminergic neurons left in the brain. This means the effect wears off in late stages of Parkinson’s Disease.

      3. Levodopa and Carbidopa need to be taken together. Levodopa is the dopamine precursor, but Carbidopa stops the former from being converted into dopamine in the periphery, leading to adverse side effects.

      4. First line of PD treatment, effective in 65% of patients. Drops off in effectiveness between the 3rd and 5th year of treatment, and drug discontinuation needs to be gradual.

      5. Pharmacokinetics: Rapidly absorbed, with a very short half life of 1-2 hours. Causes an “on-off” effect. Food, especially protein, interferes with absorption.

      6. Adverse Reactions: Can induce psychosis and hallucinations centrally. Causes mydriasis peripherally. Administration with a MAOI can cause a hypertensive crisis.

   2. Monoamine Oxidase Type B Inhibitors (MAOI’s) (Selegiline and rasagiline)

      1. These block the enzyme that metabolizes dopamine, leaving more available for neurotransmitter use. This mechanism lowers the chance of hypertensive crisis

      2. This can make Levodopa more potent

      3. Rasagiline is 5 times more potent than the others, and is irreversible

      4. Pharmacokinetics: Causes insomnia (Selegiline) because the metabolites function like methamphetamine and amphetamine

      5. Adverse Effects: Nausea, headaches, confusion. Contraindicated with SSRI’s and MAOI’S (NONSELECTIVE) because it can cause serotonin syndrome

   3. COMT Inhibitors (Entacapone)

      1. As Carbidopa increases Levodopa uptake, the blood serum levels of 3-O methyldopa. This competes with Levodopa for uptake into the CNS. COMT inhibitors reduce the blood levels of methyldopa, leading to better uptake of Levodopa into the CNS. This reduces the “on-off” effect.

      2. Pharmacokinetics: Readily absorbed, binds to blood and doesn’t distribute much. Tolcapone lasts a lot longer, and both are eliminated in feces and urine. Dose adjustments for liver impairment

      3. Adverse Effects: Diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders.

         1. Tolcapone can cause liver necrosis, and so is replaced with Entacapone

   4. Dopamine Receptor Agonists (Bromocriptine, ropinirole, pramipexole)

      1. Activate dopamine receptors to restore brain balance with Ach. These are longer acting than Levodopa, and are meant to work against the fluctuations that can be present with the first line of therapy.

      2. They potentiate levodopa, but do not replace it, and don’t work at all for patients who aren’t responsive to levodopa. Often used in conjunction with Levodopa treatment

      3. Pharmacokinetics: Levodopa with a longer duration

      4. Adverse Reactions: Nausea, vomiting, somnolence, and postural hypotension. Can cause a loss of impulse control. These are severe enough to limit application.

      5. BROMOCRIPTINE

         1. Levodopa, but with more adverse reactions in exchange for less dyskinesia

         2. Can worsen psychiatric illness

         3. Pulmonary and retroperitoneal fibrosis

      6. PRAMIPEXOLE and ROPINIROLE

         1. May delay the need for use of Levodopa in early PD and decrease needed dose in late PD.

         2. Less adverse effects than Bromocriptine, but have less effect.

         3. Pharmacokinetics: Orally active. Pramipexole is renally eliminated.

   5. Amantadine

      1. Discovered by accident; this is actually an antiviral medication. Less effective than Levodopa, and tolerance develops quicker, but less adverse effects altogether.

      2. Stimulates dopamine release, blocks cholinergic action, and and inhibits NMDA receptors.

      3. Adverse effects profile includes restlessness, hypotension, etc.

   6. Antimuscarinic Agents (benztropine and trihexyphenidyl)

      1. Blocks cholinergic activity in the neostriatum. This helps restore the balance in the brain, but isn’t all that effective, and is only used in adjuvant PD therapy

      2. Adverse Effects Profile is antimuscarinic activity.

Alzheimer’s Disease (AD)

-Accumulation of senile plaques, formations of neurofibrillary tangles, and loss of cortical neurons (especially cholinergic neurons)

-Less Ach leads to AD

-The antidote for any of these is atropine

-Our goal is to restore cholinergic transmissions.

-Treatment is only palliative.

1. Drugs/Treatment

   1. AchE inhibitors (Doneprezil and rivastigmine)

      1. Preserves Ach in the CNS to improve cognitive function.

      2. Rivastigmine is the only one approved with dementia associated with PD. It has little drug interactions, and is the only drug of its type available in a transdermal formulation.

      3. Adverse Reactions are cholinergic activity throughout the body.

   2. NMDA Receptor Antagonist (Memantine)

      1. Blocks glutamate signaling. This blocks calcium influx, which may cause cell death and toxic effects to the neurons. This gives Memantine a neuroprotective effect

      2. Supplements AchE therapy, and is well tolerated.

Multiple Sclerosis

-A demyelinating disease of the CNS. Very variable in it’s effects.

-To fix this, we manipulate the immune response to stop the demyelination of the neurons.

-Remember Teriflunomide; it reduces the lymphocytes count in the CNS. Avoid in pregnancy, can cause elevated liver enzymes

-Remember Interferons; they reduce inflammation

-Glatiramer acts as a decoy for T cell attack to save the myelin

-Fingolimod reduces lymphocyte migration into the CNS.

Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig Disease)

-Destruction of motor neurons, resulting in no movement

-Drug to remember is Riluzole. It’s a glutamate modulator. Blocks sodium channels and inhibits glutamate release. Edaravone is a free radical scavanger that MIGHT slow ALS.