Mechanisms of Drugs Affecting the Parasympathetic and Sympathetic Nervous System

Our second week of physiology lecture ended with a laundry list of drugs whose mechanism of action we had to memorize (thankfully not too long). I feel grateful that I've seen some of these used in practice so have some context for their use. I also learned a fair bit about some of these drugs in tech school. Still, it gets tiresome having list after list of things to memorize (I know, welcome to vet school).

For anyone who cares to follow along here is a quick cheat sheet;
Nicotinic receptors are found at ganglia in the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) as well as at the neuromuscular junction. They are ionotropic channels.
Muscarinic receptors are found at the neuroeffector junction in the PNS and at the neuroeffector junction of sweat glands in the sympathetic nervous system (except in the horse, which has adrenergic receptors). They are metabotropic, or G-protein coupled receptors. There are five types of muscarinic receptors but their significance was not emphasized to us.
Adrenergic receptors are found at the neuroeffector junction in the SNS. They are also metabotropic receptors and come in several flavors, or subtypes.
α1: generally excitatory, contractile on postsynaptic membrane
α2: mostly on presynaptic membrane, part of negative feedback mechanism
β1: mostly found on heart
β2: blood vessels, bronchioles, liver (smooth muscle and metabolic)
β3: adipocytes

Cholinergics:

Atropine: Muscarinic antagonist. Competitive inhibitor at parasympathetic neuroeffector junctions. Can block nicotinic sites only at very high concentrations.
Heart: Tachycardia, but the degree depends on the species' vagal tone, which is high in horses and dogs, producing marked effects in those species.
Blood vessels: Very little effect. Will block vasodilation induced by choline esters.
GI and Urinary Tracts: Reduce tone, motility, secretions
Respiratory: Increase luminal diameter, decrease secretions of bronchioles
Eye: Mydriasis, cyclopegia, increase intraocular pressure
Sweating: Impaired (horse is an exception)
Salivation: Reduced (dry mouth)
CNS: Moderate doses stimulate medullary and higher centers, eventually death by medullary paralysis

Bethanecol: Muscarinic agonist. Parasympathomimetic. More resistant to hydrolysis by cholinesterases than acetylcholine, so it has a longer duration of action that Ach. Never heard of this drug and not sure why someone would use it.

Edrophonium: Anticholinesterase (inhibits enzyme that breaks down acetylcholine, the neurotransmitter at the muscarinic junction). Shortest acting anticholinesterase. Used to diagnose myasthenia gravis (an immune disease where the muscarinic receptors are attacked and subsequently decreased in number).

Neostigmine: Anticholinesterase. Lasts for a few hours. Can be used to treat myasthenia gravis.

Pilocarpine: Muscarinic agonist. Parasympathomimetic. Treatment for glaucoma, lowers intraocular pressure.

Adrenergics:

Albuterol: Selective β2 agonist. Bronchodilate while minimizing stiumlation of the heart. I saw terbutaline used more often to treat asthmatics than albuterol, not sure why from this class. (Maybe later, as a first year there is always later!)

Epinephrine: Directly acting adrenergic agonist. Non-selective for α or β receptors.

Phenylephrine: Directly acting adrenergic agonist. "Pure" α-receptor agonist. Not sure why I've never seen this used in practice, instead always saw use of epinephrine.

Isoproterenol: Directly acting adrenergic agonist. Non-selective for β-recptors.

Phenoxybenzamine: α-adrenergic antagonist. Irreversible non-competitive antagonist that covalently attaches to receptors. I saw this used in the treatment of UO (obstructed cats) with a urinary catheter in place. I always thought it decreased spasms in the urethra. Now I know it blocks the contraction of the urinary sphincters.

Phentolamine: α-adrenergic antagonist. Competitive antagonist. Not sure when this is used.

Propanolol: Non-selective β-adrenergic antagonist. Primarily used to decrease blood pressure, excitability and work of the heart (decrease in heart rate, force of contraction, and cardiac output). Since it blocks β2-receptors in addition to β1-receptors it also blocks bronchodilation and can cause hypoglycemia. Therefor it should not be used in asthmatics or in the case of allergic reaction. It is also contraindicated in diabetes with insulin treatment. Interestingly, this drug is now being used to treat stage fright in people since it prevents the racing heart without affecting the mood.

Metoprolol: Cardioselective β1 antagonist. More potent for cardiac effects. Avoids the side effects of blocking bronchodilation and potentially causing hypoglycemia associated with propanolol. Never heard of this or seen it used either but sounds useful in certain cases.

Pain Receptors And Chili Peppers, Garlic, Wasabi And Menthol Mints

We had an interesting lecture this week titled "Molecular basis of nociception." Hot chili peppers (specifically the chemical capsaicin) induce pain by binding to transient receptor potential vanilloid-1 (TRPV1), an ion channel of non-selective cation permeability that transduces specific noxious stimuli (in this case capsaicin) into electrical impulses. What's interesting is that the TRPV1 channel is also activated by temperatures higher than 43 degrees Celsius and acidic extracellular pH. My notes explain, "Because capsaicin activates TRPV1 as effectively or more effectively than noxious heat, it evokes a similar hot and burning sensation like hot temperature does."

My notes continue, "TRPA1 is an ion channel frequently co-expressed with TRPV1 in heat sensitive sensory neurons. TRPA1 is activated by pungent chemicals, including allicin from garlics and mustard oil from Japanese Wasabi roots." TRPA1 is also activated by THC (the active ingredient in Marijuana) and some pungent anesthetics like isoflurane, desflurane and propofol. Interestingly, "because TRPA1 positive neurons usually contain TRPV1, allicin and mustard oil evokes hot burning pain similar to how chili peppers do."

Finally, another channel in the TRP family, TRPM8, is "considered to be the molecular cold sensor for thermal sensation." It is activated by temperatures lower than 30 degrees Celsius. It is also activated by menthol, which explains the cool sensation associated with menthol mints.

Fugu (Puffer fish/Blowfish) Sushi, Black Widow Spider Venom And Other Interesting Toxins

Yesterday we had a lecture titled "Neuromuscular Pharmacology" which touched on some interesting toxins:

Fugu sushi is known for its potentially lethal toxicity if it is not prepared correctly. The toxin involved is called tetrodotoxin and is found mainly in the gonads of the fish, although it is also elsewhere in the body. Tetrodotoxin works by blocking voltage-gated sodium channels from the extracellular side. Supposedly fugu sushi gives you a little buzz when you eat it (I don't quite get this-- how does one get a buzz from a toxin that blocks action potentials?)

Saxitoxin is another toxin that works by the same mechanism-- blocking voltage-gated sodium channels. It is found in the single cell algae responsible for the red tide. During red tide, shellfish concentrate this toxin, which can lead to "shellfish paralysis" if the shellfish are consumed.

Latrotoxin is found in black widow spider venom and mediates fusion and release of vesicles containing acetylcholine at the motor neuron terminal even in the absence of calcium-- an impressive phenomenon whose mechanism remains a mystery. After this massive release of acetylcholine there is subsequent decreased synthesis and release of acetylcholine.

No, I don't expect to be treating domestic species for these toxins (with the possible exception of black widow spider bites), they are just illustrations of how toxins work at the neuromuscular junction, which I find pretty cool.

Equine Nigropallidal Encephalomalacia

I'm done with neuroanatomy (yay), at least for now, but this is one interesting disease that we learned about that I didn't write about at the time. Here's what my notes say:

Damage to the basal ganglia in humans causes debilitating motor and cognitive deficits [not surprising as they are involved in the cognitive aspects of motor coordination and planning] as demonstrated by Parkinson's disease (degeneration of the substantia nigra) and Huntington's disease (degeneration of caudate nucleus and putamen). In domestic animals, disease processes are rarely as restricted and specific as in these human diseases. One exception to this is Equine Nigropallidal Encephomalacia, which can be seen in horses that have eaten Yellow Star Thistle or Russian Knapweed (both found in the Western US). These horses develop motor dysfunction associated predominantly with their facial muscles and die of starvation because they cannot prehend food. Lesions can be identified in the substantia nigra and globus pallidus.

I know from living in California tha there is lots of Yellow Star Thistle around (at least in the Bay area) so I imagine this is of concern to horse owners, although I had never heard of the disease prior to this class. Interesting stuff.

On a related note, the Corticospinal (Pyramidal) pathway is the major pathway for voluntary control of motor movements in primates, particularly for fine motor movements of the digits. It is not nearly as developed in domestic animals, with the possible exception of raccoons who use their fingers extensively to almost "see" by feeling. However, in horses the related corticobulbar tract [note corticobulbar means going from cortex to brainstem rather than cortex to spinal cord as in the corticospinal] is the major pathway that innervates the muscles that control the lips. I remember my professor saying something like, "as horse people know, horses can do all kinds of amazing things with their lips." In a way, horse lips are akin to human fingers! Just in case you are wondering, the major pathway for voluntary movement in domestic animals is the Cortico-rubrospinal tract. But I won't get into that.

Sunny Springtime Day In Ithaca, New Camera Photos

I think this canal downtown is very picturesque. Simon was happy to have a few sunny days in a row. He could be found predictably in the first spot to get sun in the mornings in the far bedroom.

It's so nice to be able to take photos without smudges. Thanks, Dad for the new camera!

Round Three/Neuroanatomy: I Advance!!!

I got my grade for neuroanatomy this afternoon and was very pleased. I had worried quite a bit about the possibility of failing the course, but I was far from failing.

I also got my grade for ruminant anatomy, which I considered miraculous. I had been certain that I flunked the course coming out of the final exam, but I did just fine.

Distributions were the hardest semester of vet school so far. I felt discombobulated, overwhelmed and it didn't help that I live someplace fairly isolated and also that there was a lot of snow which made driving difficult.

I'm hoping that things won't be quite so hard this spring. So far block IIIa, function and dysfunction, aka physiology, doesn't seem any easier than last term, but I'm told it is a fairly manageable workload overall.

Things To Look Forward To

1. The Ithaca farmer's market re-opens Saturday morning. I know it might sound silly, but I have been looking forward to this all week. The farmer's market has been part of my weekend routine for years now and not going feels strange, almost sacrilegious.
2. Getting back my neuroanatomy exam. I'm one week into block 3a and I still don't know for sure if I passed my required neuroanatomy course. I don't know when we will get our exams back but it will be nice to know how I did instead of being left to wonder...
   
3. Summer vacation. Less than two months away. I'm going to get out of Ithaca for part of it and head back to California. I might also make stops in a few other states depending on what my friends and family are up to.
   
4. The Campbell farmer's market in California. One thing Ithaca does not have is fresh fish. Every Sunday I would buy sand dabs and squid. Delicious. I can't wait for that.