Anesthetics: Questions Still Abound

Anesthetics were the drugs that intrigued me the most during my pharmacology classes in pharmacy school. One reason may have been their longevity: we learned that anesthetics were used in ancient times by the Egyptians and early Greeks. Now, more than 50 years after graduation, I have experienced anesthesia for the first time during dental surgery and a colonoscopy. This direct exposure has rekindled my interest as it relates to the following questions: What is it about these drugs that bring on such a rapid response, namely, analgesia and amnesia? What is the mechanism of action-how do they work? Is it true that exposure to general anesthesia increases the risk of dementia or other side effects? This article attempts to answer these questions while providing an abbreviated history of anesthesia. The references listed are a starting point for discovering even more information about this most important branch of medicine.

History

Throughout history, people have sought ways to relieve physical pain. Many substances that control pain were found serendipitously or adopted after trial and error. As early as 4200 BC, people discovered plants and plant roots that could cause unconsciousness and used them to relieve pain.¹ Important drugs used in antiquity included hashish, mandrake and opium. All were employed into the Middle Ages and beyond.² But it was not until the first half of the 19^th century that anesthetics began to be used safely and effectively in surgery. Until then, there were only mild, habit-forming analgesics that were not suitable for surgery, and surgery was traumatic, barbaric and often fatal.

Nitrous oxide (N₂O), or laughing gas, was used in 1844 in a demonstration by an American dentist, Horace Wells, before a skeptical audience of doctors. Unfortunately, the patient was unusually resistant and laughter, not anesthesia, ensued. Prior to Wells' dental application, nitrous oxide was used mainly in traveling medicine shows and carnivals.³ Nitrous oxide remains useful as a general anesthetic, but in light of its low potency, it is administered in combination with other drugs.⁴

The first true anesthetic experiment occurred on 16 October 1846 when John Collins Warren, MD, performed a surgical procedure using ether to prevent pain. The drug was administered using an inhaler apparatus designed by William Morton who, like Wells, was a dentist. Morton participated in the surgery, which proved that ether, when inhaled in the proper dose, provided safe and effective anesthesia. The operation was concluded by Warren with the words: "Gentlemen, this is no humbug."⁵ Henry Bigelow, MD, described the surgery in a report that same year.⁶ It became, in the opinion of today's New England Journal of Medicine editors, the most important article published in their journalover the last two centuries. Bigelow wrote, "It has long been an important problem in medical science to devise some method of mitigating the pain of surgical operations. A patient has been rendered completely insensible during an amputation of the thigh, regaining consciousness after a short interval." Shortly thereafter, physician and poet Oliver Wendell Holmes, Sr., coined the term "anesthesia" to describe the drug-induced insensibility to sensation.^7,8

James Young Simpson, MD, (1811-1870) was a Scottish obstetrician and gynecologist whose search for a better anesthetic than ether led him to introduce chloroform, which was previously just an organic solvent. According to tradition, he and his assistants had been testing a series of chemicals when late one evening somebody knocked over a bottle of chloroform. When Simpson's wife brought dinner to the laboratory that evening she found the entire staff sleeping peacefully in strange positions. The breakthrough for chloroform came in 1853 when it was used by John Snow, MD, to deliver Queen Victoria's son, Prince Leopold.⁹ (Snow was perhaps more famous for his seminal epidemiological work in preventing the spread of cholera in London in 1854.¹⁰) Because of its high toxicity, chloroform is no longer used as an anesthetic.

Today, halogenated ethers have replaced most other compounds for use as inhalation anesthetics. Examples include isoflurane, enflurane, desflurane and sevoflurane. Halogenated ethers have the advantages of being nonflammable and less toxic than earlier general anesthetics.¹¹

Anesthetic Techniques

This article is focused on general anesthesia, in which a state of unconsciousness is achieved using anesthetic vapors, and the patient's breathing may be controlled by a ventilator, which requires the insertion of an oral airway tube. Regional anesthesia uses nerve blocks with a local anesthetic to numb an area of the body. Regional anesthetics allow patients to control their own breathing. For example, epidural blocks allow women to give birth without pain. Local anesthesia is used by surgeons to remove small skin lesions, biopsy superficial tissues or suture small wounds.¹² Also, other drugs that may include pain relievers, sedatives and muscle relaxants are used in surgical procedures.

Mechanism of Action and Effects

Many modern anesthetics share the structural and clinical effects of ether. However, delivery of anesthesia has evolved into a sophisticated art form in light of the complex equipment used, including gas monitors, vaporizers, ventilators, breathing circuits and oximeters. Today's general anesthetics are the most potent depressors of the brain and spinal cord used in medicine, so extreme skill and care are needed.

The primary site of action for inhalation anesthetics is the central nervous system, where they inhibit nerve transmission by a mechanism distinct from that of local anesthetics. Local anesthetics block nerve transmission to pain centers in the central nervous system. General anesthetics cause a reduction in nerve transmission at synapses, the sites at which neurotransmitters are released and exert their initial action in the body.¹³ Research indicates that anesthetics induce amnesia and immobility by affecting distinct molecular targets. GABA_A  (ɤ-aminobutyric acid type A) receptors are most likely involved in the actions of many general anesthetics. Some general anesthetics may act by inhibiting excitatory ion channels such as neuronal nicotinic and glutamate receptors. The subtly different clinical actions of inhaled anesthetics are probably due to distinct, specific actions on a small number of critical molecular targets. There is growing evidence that anesthetics affect neuronal ion channels by binding to protein sites. Different ion channels display strikingly unique sensitivities to various inhaled anesthetics, suggesting different channels are involved in distinct behavioral effects and that several pathways may converge to produce similar anesthetic states.¹⁴

After administration of the anesthetic, the patient loses awareness but his vital physiologic functions, such as breathing and maintenance of blood pressure, continue to function. There is general insensibility to pain. Onset of action is remarkably fast-about 10 to 20 seconds of anesthesia induction produces an unconscious state. Recovery is greatly dependent upon the type of surgery. It may take up to a few hours for the anesthesia to wear off. To prevent complications, patients are expected to sit on the edge of the bed or walk as soon as they are able. Common side effects include coughing, constipation, nausea, diarrhea or difficulty in urinating.

At different concentrations, inhaled anesthetics induce a variety of reversible, clinically important effects. Low concentrations can induce amnesia, euphoria, analgesia, hypnosis, excitation and hyperreflexia. Higher concentrations cause deep sedation, muscle relaxation and diminished motor and autonomic responses to noxious stimuli.¹⁵

Dementia and Other Risks

According to a recent report, exposure to general anesthesia increases the risk of dementia in the elderly by 35%.¹⁶ Postoperative cognitive dysfunction (POCD) could be associated with dementia several years after major surgery. It has been proposed that the association is due to a common pathological mechanism through the amyloid β peptide. Studies suggest that some anesthetics could promote inflammation of neural tissues leading to POCD and/or Alzheimer's disease precursors, including β amyloid plaques and neurofibillary tangles.¹⁷ On the other hand, a comprehensive study published in Mayo Clinic Proceedings found no significant association between exposure to procedures requiring general anesthesia after age 45 and incident dementia.¹⁸ More work needs to done and longer-term follow-up is ongoing.

Pediatric use of general anesthetics may be a different story. Results in children under age three reported from a large Australian study indicated that this cohort had a higher relative risk of language and abstract reasoning deficits at age 10 than children not exposed to anesthesia.¹⁹

Final Thoughts

Although a great deal of research has been done to discover physiologic effects and macroscopic sites of action, scientists still do not know the exact molecular mechanisms of action for general anesthetics. One reason is that volatile anesthetics, unlike most of the drugs used in medicine, bind only weakly to their sites of action. Another is that volatile anesthetics partition into lipids and exert their primary effects on synaptic neurotransmission by interacting with proteins in a lipid environment. It remains unclear whether anesthetics exert their primary effects by direct interaction with these proteins or indirectly via interaction with the lipids surrounding them.²⁰ Moreover, there is still controversy over the association between dementia and anesthesia. Thus, I must continue to wait for answers to the questions posed at the beginning of this article. I hope I am fully conscious when that day arrives.

References

1. Caruana CM. Anesthesia - chemistry in the operating room. Chem Matters. February 2010:8-9.
2. Blatner A. Lecture 4: The Discovery and Invention of Anesthesia. http://www.blatner.com/adam/consctransf/historyofmedicine/4-anesthesia/hxanesthes.html. Published 16 February 2009. Accessed 10 June 2013
3. Haeger K. The Illustrated History of Surgery. New York, NY: Bell Publishing Co; 1988.
4. Op cit. 1
5. Op cit. 3
6. Bigelow HJ. Insensibility during surgical operations produced by inhalation. Boston Med and Surg Journal. 1846; XXXV(16):309-317.
7. Perkins B. How does anesthesia work? Scientific American. 7 February 2005. http://www.scientificamerican.com/article.cfm?id=how-does-anesthesia-work&print=true. Accessed 27 October 2010.
8. Holmes was perhaps more famous for writing that "Science is a first rate piece of furniture for a man's upper chamber, if he has common sense on the ground floor."
9. Op cit. 2
10. Johnson S. The Ghost Map. New York, NY: Riverhead Books; 2006
11. Op cit 1.
12. Anesthetic Techniques. Rhode Island Society of Anesthesiologists website. http://rianesthesia.org/anesthetic_techniques.html. Accessed 10 June 2013
13. Op cit 7.
14. Campagna JA et al. Mechanisms of actions of inhaled anesthetics. New Eng J Med. 2003;348(21):2110-24.
15. Ibid.
16. Science Daily. Exposure to general anesthesia could increase the risk of dementia in Elderly by 35 percent (http://www.sciencedaily.com/releases/2013/06/130601133925.htm ).Accessed 3 June 2013.
17. Sprung J et al. Anesthesia and incident dementia: a population-based, nested, case-control study. Mayo Clinic Proceedings. 2013;88(6):552-61.
18. Ibid.
19. Ing C et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012; 130(3):e476-85
20. Op cit 7.