Module 33 Flashcards
Atracurium has been suggested to display many of the characteristics of an ideal neuromuscular blocking agent. These properties are largely related to the structure and stability of the drug, and have implications, not only in the duration of activity and relative absence of side-effects of the drug, but also in the formulation and storage of the dosage form (injection solution). Atracurium is formulated as the besylate (benzenesulphonic acid) salt. The pH of this product is adjusted to pH 3.25-3.65 using benzenesulphonic acid, and the product is directed to be stored under refrigeration and protected from freezing. Under these conditions decomposition is about 6% per annum. At 25°C, the decomposition is reported to be about 5% per month.
What is the nature of the decomposition products that you would expect on storage in this acid medium? At a more neutral pH and at 37°C, 50% decomposition occurs in 75 minutes at pH 7.1 and in 30 minutes at pH 7.6. What is the nature of the decomposition products you predict to be formed at this pH? Would you expect this type of chemical reaction (decomposition) to occur in vivo, and if so, would you predict that the products would have any neuromuscular blocking activity?
- During storage in the acidic formulation, the major reaction would be hydrolysis of the ester linkages. Under neutral pH conditions the drug undergoes a Hofmann elimination as shown below, and the products are inactive (It takes two positively charged groups on the same molecule to cause neuromuscular blockade.) This is spontaneous, i.e. it does not require an enzyme, and it occurs in the body as well. The Hofmann elimination depends on the fact that the hydrogen next to the carbonyl group is slightly acidic, and once the hydrogen leaves as a proton, the electrons move toward the positive charge leading to breaking the carbon-nitrogen bond.
Myasthenia Gravis is an autoimmune disease in which antibodies block the binding of acetylcholine at motor neurons leading to paralysis. What is the rationale for the use of the combination of pyridostigmine and atropine for the treatment of Myasthenia Gravis? Specifically, why doesn’t the atropine inhibit the therapeutic effects of pyridostigmine?
Pyridostigmine inhibits cholinesterase leading to an increase in the levels of acetylcholine in most of the body. The increase in acetylcholine at motor neurons helps to overcome the paralysis, but this increase in acetylcholine also causes side effects by stimulating the parasympathetic neurons (It does not have CNS effects because it is a quaternary amine, and therefore it cannot get into the brain.) Atropine specifically blocks binding of acetylcholine at muscarinic (parasympathetic) receptors; it has no effects on the motor neurons
What impurity of a “designer” drug led to a good model of Parkinson’s disease? What is the mechanism of this toxicity?
In the attempts to make MPPP, a synthetic opiate very similar to meperidine (demerol), the reaction mixture was allowed to overheat.
- This led to elimination of propionic acid and the formation of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) as shown below. This agent is metabolized by MAO-B in the brain to MPP+, which is very toxic to the dopaminergic neurons of the substantia nigra, and it produces a rapid onset of permanent symptoms of Parkinson’s disease.
What is the basis for the selective toxicity of MPTP? When MPP+ is given to animals, why does it not cause a Parkinsonian syndrome? Is there evidence that metabolites of other drugs or xenobiotics may also cause Parkinson’s disease?
- The MPP+ is actually formed by MAO in glial cells, not the dopaminergic cells. However, MPP+ is a substrate for the dopamine transporter in the dopaminergic cells and that is why it is most toxic to these cells. It is further concentrated in mitochondria because of its charge, and it undergoes redox cycling to produce large amounts of superoxide similar to the herbicide paraquat. This leads to the death of the dopaminergic cells.
If MPP+ is given to animals it is not toxic because it is a quaternary amine and cannot pass the blood brain barrier. There has been speculation that other drugs such as haloperidol or natural components of food can form similar toxic metabolites and cause Parkinson’s disease. However, to date, there is not good evidence to substantiate this hypothesis.
Why is L-dopa given to patients with Parkinson’s disease rather than dopamine?
- Because there is a transporter that does not allow significant amounts of dopamine to cross the blood/brain barrier.
This prevents neurotransmitters derived from the diet from interfering with brain function. L-dopa enters the brain with the help of an amino acid transporter and is converted to dopamine.
Why are dopa decarboxylase inhibitors such as carbidopa used in combination with L-dopa and why don’t they prevent the conversion of L-dopa to dopamine in the brain?
- Peripheral conversion of L-dopa to dopamine results in side-effects, especially nausea, and this is decreased by carbidopa, which inhibits aromatic-L-amino acid decarboxylase. Carbidopa does not significantly affect conversion of L-dopa to dopamine in the brain because it also does not get past the blood/brain barrier.
Inhibition of what other metabolic pathway is used to increase dopamine levels in the brain?
Catechol-o-methyltransferase. Example: entacapone. Inhibition of monoamine oxidase (MAO)-B, e.g. selegiline, has also been used to treat Parkinson’s disease but this is less common
