1. Indicate if the following drug actions will result in an INCREASE or REDUCTION of the level of chemical neurotransmission at the affected synapse.

DRUG ACTION	EFFECT ON CNT
Neurotransmitter receptor blockade	Reduction
Inhibition of neurotransmitter precursor uptake	Reduction
Inhibition of neurotransmitter bioinactivating enzyme	Increase
Prevention of neurotransmitter storage following biosynthesis	Reduce
Inhibition of presynaptic neuronal Ca2+ influx	Reduce

2. Name two chemical neurotransmitters that are inhibitory amino acids.

a. Glycine

b. GABA (gamma-aminobutyric acid)

3. Answer the following questions about the drug structure below.

FCH₂-O-CHCl–CHF₂

a. Potential therapeutic use: General Anesthetic

b. Show the reaction of this drug with alkali involving the elimination of the elements of HCl.

c. One of the metabolites of this drug is difluoroacetic acid. Show the metabolic reactions leading to this metabolite.

d. Assuming that difluoroacetic acid generated by this drug is not particularly toxic, are there any other toxic metabolites formed during its metabolism?

Yes, further metabolism of difluoroacetic acid to oxalic acid would result in the generation of 2F^- as follows:

The F^- generated by this metabolism has nephrotoxic potential.

4. The generally accepted mechanism of action of a general anesthetic is:

Dissolution in the lipid bilayer of the neuronal membrane which promotes a disorganization in the membrane structure which can negatively affect the function of membrane protein channels involved in ion flux - the basis of impulse conductance.

5. The generally accepted mechanism of action of a local anesthetic is that it retards neuronal conductance by blocking ION CHANNELS (e.g. Na⁺, K⁺) channels in neuronal membranes.

6. Answer the following questions about the following drug structure.

a. Structural classification: ANILIDE/AMIDE

b. Acid-base character: BASIC

c. Draw the structures of this drug involved in the chemical equilibrium established at physiologic pH.

d. Which of the species above (question 6c.) penetrates to the site of pharmacologic action?
the unionized, base species

e. A derivative of this drug where R₂ = (CH₃)₂ has a pKa of 7.6 whereas a derivative where R2 = (C₃H₇)₂ has a pKa of 8.0.

1) Which derivative will have the most rapid onset of action. Why?

The unionized form of the less basic local anesthetic, R2=(CH3)2, will exist in higher concentrations at the neuronal membrane than for the more basic LA. Therefore, the former drug will penetrate to the intramembrane channel site of action more rapidly which accounts, at least in part, for its more rapid onset of action.

2) Show the metabolite of the derivative where R₂ = (CH₃)₂ resulting from a 2-step oxidative N-dealkylation.

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