When acetylcholine (ACh) binds to its nicotinic or muscarinic receptor on a postsynaptic cell, the ligand-gated sodium ion channel opens allowing an influx of sodium into the cell. This influx of Na+ reduces the membrane potential, called an excitatory postsynaptic potential (EPSP). If depolarization of the postsynaptic membrane reaches threshold, an action potential is generated inside the cell (e.g. contraction in skeletal muscle).

Note: ACh can produce various effects depending on the cell and receptor. At some sites, ACh receptors are coupled to g-proteins that regulate adenylate cyclase and cyclic AMP production. Not all cells have cAMP as the second messenger (eg, muscle). At these cells ACh can cause sodium channels to open so that depolarization (excitation) occurs.

Inhibitory pathways are simply defined as movement of ions that result in hyperpolarization of the post-synaptic membrane, therefore decreasing the chance that a future action potential will occur as it moves further away from the firing thresold. An inhibitory post-synaptic potential (IPSP) is generated when inhibitory neurons release neurotransmitter molecules, such as GABA or glycine, which bind to their respective receptors, increasing permeability of potassium (K+) and chloride (Cl-) ions.

Excitatory pathways are the opposite, defined as temporary depolarization of post-synaptic membrane potential caused by a flow of positive ions (i.e. Na+) through ligand-gated ion channels into the post-synaptic cell, causing it to either come close to or to reach the firing threshold. Excitatory pathways are caused when excitatory neurons release neurotransmitter molecules , such as glutamate or acetylcholine, which bind to their respective receptors, causing the opening in the sodium channels.

A dopamine infusion would not benefit a PD patient because dopamine does not cross the blood-brain barrier, which is where dopamine is made and utilized. Dopamine's precursor, Levodopa, can cross the blood-brain barrier and is often used in treatment of PD to increase dopamine production.

TYR and L-DOPA cross BBB, DA does not. If you give TYR, TYR will not be converted to L-DOPA in CNS because the enzyme tyrosine hydroxylase is rate limiting. If you administer L-DOPA, all the L-DOPA that enters nerve cells may be converted to DA because this enzyme (dopa decarboxylase) is not rate limiting.

L-DOPA crosses the blood brain barrier whereas dopamine itself cannot; therefore, L-DOPA is used to increase dopamine concentrations in the treatment of PD because once the L-DOPA enters the CNS, it is converted into dopamine by the enzyme DOPA decarboxylase.

The active transport enzymes that transport amino acids across the BBB are able to transport L-DOPA (which is an amino acid) but not able to transport DA (which is not an amino acid). - JM

The effects of levodopa on the CNS can be greatly enhanced by co-administering carbidopa because it diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues. This results in increased availability of levodopa to the CNS. The addition of carbidopa also lowers the dose of levodopa needed by four to five fold; therefore, decreases the severity of the side effects from peripherally formed dopamine.

Carbidopa inhibits the enzyme DOPA decarboxylase which converts L-DOPA to DA. This does two things: (1) allows L-DOPA dose to be reduced; and, (2) reduces the peripheral DA levels and therefore reduces DA side-effects (nausea, vomitting, orthostatic hypotension, and arrhythmias)

MAO-A metabolizes norepinephrine, epinephrine, and serotonin where MAO-B metabolizes dopamine and phenylethylamine.

At very high doses MAOb inhibitors will also inhibit MAOa.

Selegiline is a selective inhibitor of MAO-B. Selegiline exhibits little therapeutic benefit when used independently, but enhances and prolongs the anti-parkinson effects of levodopa by decreasing the metabolism of dopamine and increasing the dopamine levels in the brain resulting in the enhancement of the actions of levodopa when administered with levodopa.

Selegiline will not work as monotherapy. Must be given with L-DOPA to be effective. CNS DA levels will be higher if you make more DA (by increasing L-DOPA levels) or if you break down less DA (by inhibiting MAO and COMT). Selegiline causes CNS DA levels to be higher by inhibiting MAOb.

Entacapone and tolcapone inhibit catechol-O-methyltransterase (COMT), which is used in metabolism of levodopa. If we decrease the metabolism of levodopa, it will therefore increase central uptake of levodopa which in turn increases concentration of dopamine in the brain. Both drugs are eliminated in feces and urine.

Differences in each drug as listed:

Entacapone- does not cross blood brain barrier, has largely replaced tolcapone because it is not associated with hepatic necrosis.

Tolcapone- crosses blood brain barrier, long duration of action, associated with hepatic necrosis requiring close hepatic function monitoring, therefore is a last resort drug.

Amantadine is used in the treatment of Parkinson’s disease and has also been used in treatment of Influenza A in the past. It is believed to release brain dopamine from nerve endings making it more available to activate dopaminergic receptors. It is readily absorbed and passes the blood-brain barrier.

Amantadine is not a DA agonist. It enhances release of endogenous DA.

What is the rationale behind using acetylcholinesterase inhibitors and NMDA antagonists for the treatment of patients with Alzheimer's Disease?

What are the most common toxic effects noted by patients being treated with AChE inhibitors?

Acetlycholinesterase (AChE) inhibitors are prescribed for mild to moderate Alzheimer’s disease to help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. AChE inhibitors work by preventing breakdown of acetylcholine which is important for memory and thinking.

NMDA antagonists are prescribed for severe Alzheimer’s disease. The main effect is to delay progression of some symptoms allowing the patient to maintain some activities of daily living. NMDA works by regulating glutamate.

A toxic effect of AChE inhibitor is hepatotoxicity. Other side effects caused by the parasympathetic nervous system are bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, and decreased intraocular pressure. 

Bromocriptine is a semi-synthetic ergot-alkaloid, ergoline derivative. It acts as a dopaminergic agonist and is used in the treatment of pituitary tumors, Parkinson’s disease, hyperprolactinemia, and neuroleptic malignant syndrome. The effect on Parkinson’s disease is based on the dopaminergic effect.

The effect on all these conditions is based on the dopaminergic effect. The pituitary tumor = prolactinoma, which may cause hyperprolactinemia. DA stimulation decreases prolactin production, improves symptoms of PD, and since NMS is caused by DA antagonists, DA agonists may be used to treat NMS.

Glutamate receptors are synaptic receptors and can be found on neuronal cells. Glutamate is one of the 20 amino acids and it functions as a neurotransmitter. The glutamate receptors are responsible for the glutamate-mediated post-synaptic excitation of neural cells. They are important for neural communication, memory formation, learning and regulation. Glutamate receptors are implicated in the pathologies of a number of neurodegenerative diseases due to their influence throughout the CNS.

NMDA receptors are a type of glutamate receptor. Glutamate stimulates NMDA receptors, NMDA stimulates those glutamate receptors that are NMDA receptors but not other glutamate receptors.

Memantine, an NMDA receptor antagonist used for treatment of Alzheimer's Disease, as well as a drugs such as phencyclidine (PCP) and ketamine block NMDA receptor-associated ion channels. This inhibits sodium and to a greater extent calcium from entering neurons via these ion channels. These drugs differ in the number of NMDA receptors that are blocked. Memantine blocks only a fraction of ion channels. This allows a sufficient amount of Calcium to enter the neuron through unblocked channels to preserve vital processes that depend on calcium influx. PCP, on the other hand, blocks nearly all of these channels. Memantine, PCP, and Ketamine all cross the blood-brain barrier.

Know that all three of these drugs are NMDA-antagonists. PCP and ketamine are much more effective at blocking these receptors than memantine.

Fill in the blanks: There are two classes of drugs for treatment of Alzheimer's Disease (AD): ______(eg. donepezil, galatamine, rivastigmine) and _______

(eg. memantine).

In AD there are decreased cholinergic neural projections. ______ receptor activity is low while _______ receptor activity is too high (especially NMDA activity).

Overstimulation of _______ receptors leads to neuronal death. NMDA receptor _______ are neuroprotective.

1. Acetylcholinesterase inhibitors, NMDA receptor antagonists.

2. Cholinergic, Glutamate. 

3.  NMDA, antagonists.

Which one of the following combinations of antiparkinson drugs is an appropriate therapy?

A. Amantadine, Carbidopa, and Entacapone.

B. Levodopa, Carbidopa, and Entacapone.

C. Pramipexole, Carbidopa, and Entacapone.

D. Ropinirole, Selegiline, and Entacapone.

E. Ropinirole, Carbidopa, and Selegiline.  

Levodopa, Carbidopa, and Entacapone.

To reduce the dose of levodopa and its peripheral side effects, the peripheral decarboxylase inhibitor, carbidopa, is coadministered. As a result of this combination, more levodopa is available for metabolism by COMT to 3-methyldopa, which competes with dopa for the active transport processes in the CNS. By administering entacapone (inhibitor of COMT), the competing product is not formed, and more dopa enters the brain.  

Carbidopa-it inhibits the peripheral decarboxylation of levodopa to dopamine, thereby diminishing the GI and CV side effects of levodopa.

Bromocriptine, because it is a dopamine-receptor agonist, it is contraindicated in patients with peripheral vascular disease.

Acetylcholinesterase Inhibitors, such as rivastigmine, increase cholinergic transmission in the CNS and may cause a modest delay in the progression of Alzheimer's disease.