Module 30 Flashcards
List the symptoms of organophosphate poisoning. This will provide a good idea of the functions of the parasympathetic nervous system. What are the agents used to treat organophosphate poisoning and how do they work?
- Organophosphates phosphorylate cholinesterase leading to its inactivation and a buildup of acetylcholine. Acetylcholine is the neurotransmitter at 3 different types of neurons: muscarinic, nicotinic, and in the CNS.
- At low concentrations the major effects are muscarinic, and these include sweating, constricted pupils, increased secretions in the mouth, lungs, and eyes, bronchoconstriction, cramps and diarrhea, bradycardia, blurred vision, and urinary incontinence.
- The nicotinic effects acetylcholine include muscle fasciculations and cramps, with paralysis at high concentrations. In contrast to the muscarinic effects, the nicotinic effect of acetylcholine can cause tachycardia.
- The CNS effects include anxiety, ataxia, and convulsions. Death is usually from respiratory failure due to bronchoconstriction, paralyzed muscles of respiration or convulsions, and increased secretions. Acute treatment is an anticholinergic agent, usually atropine, and 2-PAM as described below.
Organophosphates are toxic because they are electrophilic and lead to phosphorylation of the serine of cholinesterase. Why is malathion (a organophosphate insecticide) much more toxic to insects than to humans while the nerve gas, sarin, is obviously also toxic to humans (as little as 0.01 mg/kg can be fatal in humans)?
- Malathion is not active because it is not sufficiently electrophilic. It must be metabolized so that the =S on the phosphorus is replaced by the more electronegative oxygen. This is the major pathway in insects.
- In contrast, the major metabolic pathway in mammals is hydrolysis of the ester groups, which leads to rapid elimination of the organophosphate.
- However, sarin is very electrophilic because in not only has oxygens on the phosphorous instead of sulfur, it also has a very electronegative fluorine, and it also readily penetrates the skin. Sarin also “ages” rapidly – no need to go into the details - but after binding to cholinesterase, it further hydrolyzes so that binding to the enzyme becomes irreversible, and the cholinesterase enzyme cannot be reactivated.
Pralidoxime or 2-PAM was probably the first drug that was designed based on what was known about the structure of a receptor. What are the key structural features of 2-PAM, and how do they contribute to its activity?
- Apart from blocking the acute effects of acetylcholine, another goal is to reactivate the cholinesterase enzyme so that acetylcholine can be broken down again. 2-PAM is designed to have a structure similar to acetylcholine and bind to cholinesterase through the quaternary amine.
○ Then the oxime (CH=NOH), which is a very good nucleophile, is designed to kick out the phosphate that came from the organophosphate and is inhibiting the enzyme. The distance between the quaternary amine and the oxime is the same as the distance between the quaternary amine and ester group in acetylcholine so that the oxime is in the right position to reactivate the enzyme.
○ In addition, the ring makes the structure of 2-PAM rigid thereby decreasing the degrees of freedom and making the oxime more likely to be close to the phosphate, i.e. it decreases the entropy of the reactivation reaction.
A major goal of drug companies is to find drugs that are useful in the prevention or treatment of Alzheimer’s disease. It appears that Alzheimer’s disease is due to the destruction of certain parts of the brain in which the neurotransmitter is acetylcholine. Based on this hypothesis how would you go about searching for a drug that might be useful for the treatment of the symptoms associated with Alzheimer’s disease? Use the treatment of Parkinson’s disease as a model
- The major neurotransmitter involved in neurons affected by Parkinson’s disease is dopamine, and agents that increase the levels of dopamine such as L-dopa significantly improve the symptoms of Parkinson’s disease.
- The major neurotransmitter involved in the areas of the brain affected by Alzheimer’s disease is acetylcholine. Therefore, agents that increase the level of acetylcholine such as the cholinesterase inhibitor donepezil are used to treat Alzheimer’s disease.
- However, in contrast to the agents used to increase dopamine in Parkinson’s disease, the effectiveness of cholinesterase inhibitors in treating Alzheimer’s disease is really marginal at best. On the other hand, many patients with Alzheimer’s disease are treated with drugs that have anticholinergic effects.
Why is ipratropium bromide used to treat asthma rather than atropine? Why is atropine used to treat organophosphate poisoning rather than ipratropium bromide?
- Ipratropium bromide is a quaternary amine, which means that it is 100% ionized and cannot get into the brain. Therefore, it is effective locally when inhaled for the treatment of asthma, but without CNS side-effects. A major site of toxicity of organophosphates is the brain, and therefore atropine, which is a tertiary amine, and although mostly ionized, does get into the brain is the drug of choice to treat organophosphate poisoning.
A common weed, Jimson weed or thornapple, is often used as an ornamental. However, it has anticholinergic effects and is often used as a drug of abuse. What are the main active constituents of Jimson weed? What symptoms would be expected in a person under the influence of Jimson weed
- This is a relatively common ornamental plant. It contains a large quantity of anticholinergic compounds such as scopolamine. It is sometimes used by teenagers because it causes hallucinations, although it is also an amnestic agent so they probably don’t remember what happened. The mnemonic for remembering the effects of anticholinergic agents “hot as a hare, dry as a bone, and mad as a hatter” applies. I remember several teenagers who presented to the ER after ingesting parts of the Jimson weed. They were naked “hot as a hare”, they certainly had a dry mouth etc “dry as a bone” and they were completely out of it “mad as a hatter”. Unfortunately, the reaction to Jimson weed can be fatal.
List some drugs that are associated with significant anticholinergic side-effects. What are the structural features that these drugs have in common? What are the major effects that you would warn patients about, and which patients are most likely to be affected by these side-effects
- Drugs include scopolamine used to treat motion sickness; diphenhydramine, dimenhydrinate, and doxylamine, which are antihistamines; dicyclomine used to treat irritable bowel syndrome, tolterodine, darifenacin, mebeverine, and osybutynin used to treat urinary incontinence; trihexyphenidyl/benzhexol, procyclidine, and benzatropine used to treat Parkinson’s disease; and tricyclic antidepressants. No need to remember the names of the drugs, but it is useful to know the uses of drugs that cause these side-effects.
- Of course drugs such as ipratroprium bromide used to treat asthma are also anticholinergic drugs, but they do not have the same systemic and CNS side-effects because they are not significantly absorbed.
- All of these drugs have a basic nitrogen that is mostly charged. In males with a large prostate it can also lead to acute urinary retention. The cumulative use of anticholinergic drugs is also associated with an increased incidence of dementia
What serious adverse reaction can tolterodine and other anticholinergic drugs used to treat urinary incontinence have on vision?
These drugs can cause an acute onset of closed-angle glaucoma leading to blindness
