• Ach binds to either nicotinic or muscarinic receptors on a postsynaptic cell.
• Ligand gated sodium channels open --> influx of sodium into cell
• Influx of sodium decreases the membrane potential (excitatory postsynaptic potential --> EPSP)
• If depolarization occurs of the postsynaptic membrane (reaching threshold) action potential is generated --> muscle contraction

What is the difference between:

• inhibitory pathways
• excitatory pathways

Inhibitory pathways: movement of ions that cause hyperpolarization of the postsynaptic membrane moving it farther away from threshold for an AP.

1. AN inhibitory postsynaptic potential (IPSP) is generated when inhibitory neurons release neurotransmitter molecules (GABA or glycine) --> increasing permeability to potassium ions.

Excitatory pathways: temporary depolarization of postsynaptic membrane potential caused by a flow of sodium ions via ligan gated channels reaching or nearly reaching AP threshold.

1. Excitatory neurons release neurotransmitter molecules (glutamate or Ach) --> opening sodium gated channels

1. Tyrosine and L-DOPA both cross the BBB (dopamine does not)

2. If you give Tyrosine it will not be converted to L-DOPA in the CNS b/c the enzyme tyrosine hydroxylase is rate limiting

3. If you administer L-DOPA, all the L-DOPA will enter nerve cells --> converted to dopamine b/c the enzyme dopa decarboxylase if not rate limiting

1. Dopamine does not cross the BBB

2. L-DOPA crosses the BBB causing an increase in dopamine levels in the CNS

3.L-DOPA is converted to dopamine by the enzyme dopa decarboxylase after entering the CNS

Carbidopa inhibits the enzyme DOPA decarboxylase which converts L-DOPA to dopamine (peripherally) allowing for:

1. reduction of dose of L-DOPA
2. decreases the conversion of L-DOPA to dopamine in the periphery thereby decreasing the dopamine side effects of:

• nausea, vomiting
• orthostatic hypotension
• arrhythmias

What is the difference between:

• MAO-A
• MAO-B

1. MAO-A: metabolizes Nepi/serotonin (5HT)

2. MAO-B: metabolizes DA/phenylethylamine

Selegiline causes CNS dopamine levels to be increased by inhibiting MAO-B.

CNS dopamine levels will be higher if you:

1. make more dopamine (by increasing L-DOPA)
2. break down less  dopamine (by inhibiting MAO and COMT)

1. Would a patient with parkinson's disease benefit from an IV dopamine infusion?

2. Why or why not?

(In this case, we are interested in the CNS effects of dopamine and not the cardiovascular effects.)

NO, because dopamine in the IV infusion form does not cross the BBB, which is where parkinson's disease patients need the dopamine, not peripherally.

Dopamine's precursor L-DOPA does cross the BBB and is often used to treat PD patients to increase dopamine levels in the CNS.

Entacapone and tolcapone inhibit COMT from metabolizing L-DOPA to dopa --> if there is a decrease in the metabolism of L-DOPA (levodopa) there is more available to cross the BBB --> increasing central uptake --> increasing concentration of dopamine in the brain.

Differences:

Entacapone: does not cross the BBB, has largely replaced tolcapone b/c it does not cause liver necrosis

Tolcapone: crosses the BBB, associated with hepatic necrosis --> last resort drug

1. Both cross BBB by active transport process
2. Tyrosine concentration is not the rate-limiting part of dopamine production (tyrosine hydroxylase is)
3. The regulatory enzyme TYR hydroxylase does not convert all available TYR to L-DOPA
4. This is unlike DOPA decarboxylase which does quickly convert all available L-DOPA to DA

Memantine, PCP and ketamine are all NMDA receptor antagonists.

PCP and ketamine are much more effective at blocking these receptoros than memantine.

Amantadine is not a dopmaine agonist, it enhances the release of endogenous dopamine.

Readily absorbed and crosses the BBB.

1. What is the rationale behind using AchE inhibitors and NMDA antagonists for the treatment of patients with Alzheimer's?

2. What are the most common toxic effects noted by patients being treated with AchE inhibitors?

1. AchE inhibitors delay/prevent worsening of symptoms and/or help control behavioral symptoms by preventing the breakdown of Ach (important for memory and thinking)

2. NMDA antagonists delays progression of some symptoms by regulating glutamate allowing ADL's to be maintained.

3. Toxic effects:

• Hepatotoxicity
• PNS effects (bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, decreased IOP)

Semi-synthetic ergot alkaloid, ergoline derivative. Acts as a dopaminergic agonist and is used in the treatment of:

• Pituitary tumors
• Parkinson's disease (based on the dopaminergic effects)
  
• hyperprolactinemia
• neuroleptic malignant syndrome

NMDA is a type of glutamate receptor. NMDA binds to and regulates the NMDA receptor and has not effect on other glutamate receptors.

Glutamate is one of 20 amino acids and function as a neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells. They are important for neural communication, memory formation, learning and regulation.

Glutamate stimulates NMDA receptors, NMDA stimulates those glutamate receptors that are NMDA receptors but not other glutamate receptors.

Fill in the blanks:

There are two classes of drugs for treatment of Alzheimer's Disease:____________(donepezil, galatamine, rivastigmine) and _________(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. Bromocriptine
2. apomorphine
3. dopamine (but NOT L-DOPA or amantadine)

Question 8.1 from book:

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

LEVODOPA, CARBIDOPA, 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 which competes with DOPA for the active transport process into the CNS. By administering entacapone (COMT inhibitor) the competing product is not formed and more dopa enters the brain.

Question 8.2 from book:

Peripheral adverse effects of levodopa (including nausea, hypotension and cardiac arrhythmias) can be diminished by including which of the following drugs in the therapy?

CARBIDOPA

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

Question 8.3 from book:

Which of the following antiparkinson drugs may cause peripheral vasospasm?

BROMOCRIPTINE

Bromocriptine is a dopamine receptor agonist that may cause vasospasm, it is contraindicated in patients with peripheral vascular disease.

Question 8.4 from book:

Modest improvement in memory of patients with Alzheimer's disease may occur with drugs that increase transmission at which of the following receptors?

CHOLINERGIC

AchE inhibitors such as rivastigmine increase cholinergic transmission in the CNS and may cause a modest delay in the progression of Alzheimer's disease