Pharmacology and Toxicology
PHARMACOKINETICS
Overview
Pharmacokinetics is the description of a drug’s journey through a patient’s body. This involves four main processes: (1) absorption, (2) distribution, (3) metabolism, and (4) excretion. Imagine this sequence logically: the patient takes a drug, absorbs it; then the drug distributes throughout the body, is metabolized by the body, and finally is excreted.
(1) Absorption is simply how the patient’s body takes in (absorbs) the drug in question.
Enteral, meaning absorbed through the intestines: oral and rectal.
Parenteral, meaning absorbed without the intestines: intravenous (IV), intramuscular (IM), subcutaneous (SQ), inhaled, topical, or transdermal.
The term bioavailability describes how much of what is ingested makes it into the systemic bloodstream. Oral drugs often have a lower bioavailability because (1) not everything is absorbed (incomplete tablet breakdown, barriers to absorption across the gut mucosa, gastric acid or enzymatic destruction), and (2) after absorption through the intestines into the portal vein, the drug first passes through the liver, where some of the drug is metabolized before reaching the systemic bloodstream—termed first-pass metabolism (Fig. 7-1).
Figure 7-1 First-pass metabolism. Any substance absorbed through the intestinal mucosa (except at the very end of the rectum) will drain into the portal system and be processed by the liver before reaching the systemic circulation. (From Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.)
IV administration always has 100% bioavailability because it goes directly into the bloodstream; all parenteral routes bypass first-pass metabolism, and rectal administration typically bypasses about half of first-pass metabolism (because some drug is absorbed through the portal system into the liver, and some into the caval system [meaning through the vena cava] back to the heart).
(2) Distribution is where the drug goes after it is absorbed and is usually discussed as the volume of distribution (Vd). The volume of distribution is defined as:
Conceptually, the volume of distribution is a way to indicate how much of a drug stays in the patient’s bloodstream and is unbound to protein. If the volume of distribution is high, it indicates that the drug is somehow not in the free state in the bloodstream—either it is bound to protein in the bloodstream or has left the bloodstream, such as lipid-soluble drugs going into fat. The average adult has about 5 L of blood, and therefore a Vd of about 5 indicates that it distributes only in blood—higher volumes of distribution indicate that it distributes further, likely into tissues or fat.
(3) Metabolism is one of the two ways that the body can decrease the concentration of active drug in the bloodstream (the other being excretion, described later). The liver is the primary site for metabolism of drugs; this is the reason that first-pass metabolism exists—if people in the Stone Age ate something poisonous, the liver would have a chance to detoxify it before it killed them! Unfortunately, the body also sees the drugs we prescribe as potential toxins and attempts to metabolize them through a process called biotransformation. There are two phases of biotransformation: phase I biotransformation (oxidation) and phase II biotransformation (conjugation).
Phase I biotransformation: Mediated by the microsomal cytochrome P-450 (CYP) monooxygenase system, with CYP3A4 being the most common subtype for these reactions. In general, these reactions are oxidations (by far the most common), reductions, or hydrolysis—the exact reactions are not important, but the goal is to make the drug more polar (more water soluble) so that it can be excreted by the kidney. The bioavailability of drugs is reduced by this step, but some drugs retain their activity after this process. In fact, some drugs (called prodrugs) are actually made active, rather than inactive, by this process—but this is the exception rather than the rule. Older adults have decreased phase I biotransformation ability, and this is one of the reasons that older adults often need smaller doses of medications for the same effect.
Phase II biotransformation: in these reactions, a molecule is “strapped on” (conjugated) to the drug, such as an acetyl group, sulfide, or glucuronide. Again, the reactions are not important, but this reaction almost always makes the drug inactive.
Metabolism has many important clinical implications. For instance, the opioid analgesic codeine is metabolized into the more active morphine by CYP2D6—10% of whites have decreased CYP2D6 activity and will not get adequate pain relief with codeine administration. In addition, CYP2C19 activates the antiplatelet agent clopidogrel into the active form. Therefore, those with poor CYP2C19 activity will not have therapeutic levels of the drug in their body, and this may have catastrophic consequences. Both drugs mentioned here are made active by the CYP enzymes in the liver—for review, is this a phase I or phase II reaction? Because the drugs are made active by this process, what are they called? If you did not get these answers immediately, revisit the previous paragraphs.
Another commonly tested and clinically relevant aspect of metabolism is that many drugs, herbs, and even foods can either inhibit or induce the CYP family of enzymes. Grapefruit juice inhibits CYP3A4 (recall this is the most common CYP for metabolizing drugs), and therefore patients may have higher drug levels if they take their medication with it. St. John’s wort, an herbal treatment for depression, induces CYP3A4 and can “rev up” metabolism of drugs so that the level of active drug in the body will decrease.
Finally, the drug must be (4) excreted from the body, typically by the kidneys in the urine (but also through feces by biliary excretion). For renal excretion, the previous metabolism steps helped make the drug more polar to be water soluble to stay in the urine, and now the kidneys must excrete the drug. There are a few things to keep in mind when looking at renal excretion:
Glomerular filtration: The drug must be delivered to the glomerulus if it is to be filtered. Therefore, patients with a decreased glomerular filtration rate (GFR; i.e., renal disease) or those taking a drug that is bound to proteins (so it cannot be delivered to the glomerulus free and unbound) will have decreased renal clearance of the drug.
Active tubular secretion: The kidney has channels called organic cation transporters and organic anion transporters for the active secretion of charged ions into the nephron. These can be blocked by medications such as probenecid, used in the treatment of gout.
Passive tubular reabsorption: Uncharged, lipid-soluble molecules can be more readily absorbed through renal tubular cell membranes. The metabolic steps in phase I and phase II biotransformation reactions help keep the molecules water soluble and charged, facilitating excretion. Many drugs are weak acids or weak bases, and the pH of the soon-to-be-urine can determine how much of the acid or base stays inside the nephron to be excreted in the urine and how much will be reabsorbed. Therefore, if the drug is a weak acid, then alkalization of the urine will increase excretion by making more of the drug in the charged A− form rather than the uncharged HA form—this is referred to as ion trapping (Fig. 7-2) because the charged ions are “trapped” inside the lumen of the nephron. Conversely, if the drug is a weak base, then acidification of the urine to make more of the drug in the charged HB+ form will facilitate excretion.
A similar concept is found in the use of lactulose for patients with hepatic encephalopathy. Patients with liver failure have decreased urea cycle activity because the liver is the main site where the urea cycle takes place, and therefore toxic ammonia-containing compounds build up and can cause changes in mental status. Lactulose taken orally is broken up by the bacteria in the colon to make lactic acid and acetic acid, acidifying the colonic contents and changing the absorbable weak base ammonia NH3 derived from dietary proteins into the charged, unabsorbable 
ammonium ion. This ion-trapping mechanism is the same as in the kidney—the charged is not absorbed and is instead excreted.
Another form of excretion is through the bile to eventually be excreted in the stool. Many drugs that underwent conjugation (recall that this is a phase II biotransformation) with glucuronate can be excreted in this fashion. In fact, bilirubin (a byproduct of red blood cell breakdown) is excreted in this way through a phase II reaction with UDP-glucuronosyltransferase (which is deficient in patients with Gilbert disease and those with Crigler-Najjar disease). Now when you look at a patient’s lab values for “unconjugated” and “conjugated” bilirubin (referred to as indirect and direct, respectively, in the lab values) you will understand what is occurring. However, because the intestines have so much surface area and absorptive capacity, as well as bacteria that can deconjugate the molecule, the drug has a “second chance” to be absorbed into the bloodstream yet again—termed enterohepatic cycling. If this occurs, the entire process of being absorbed and excreted in bile repeats.
Calculations and Kinetics
A basic understanding of the calculations in pharmacokinetics is important for both the USMLE Step 1 and also for clinical practice. First, it is important to talk about elimination of drugs in terms of zero-order kinetics versus first-order kinetics.
Zero-order kinetics: A constant amount of drug is eliminated per unit of time, so the rate of elimination is constant regardless of concentration of drug. Examples include phenytoin, ethanol, and aspirin (PEA)—use the mnemonic: a PEA is round, just like the 0 of zero-order kinetics. The zero-order kinetics of ethanol is where the idea that the body can only metabolize one alcoholic drink (such as a beer) per hour comes from. Regardless of how many beers are consumed, the body can only metabolize one beer per hour. Therefore, it exhibits zero-order kinetics because a constant amount of beer is removed from the body. Drinking more alcohol won’t make the body remove alcohol from your body any faster—drink one beer, and your body will metabolize one beer per hour; drink 10 beers (don’t test this, just take our word for it!), and your body will metabolize one beer per hour! The reason is that the elimination pathway becomes saturated, and there are only enough enzymes to clear one beer per hour.
First-order kinetics: A constant fraction of drug is eliminated per unit time, so the rate of elimination is proportional to the drug concentration—this is a much more common method in which drugs are metabolized. Except for the drugs in the PEA mnemonic mentioned earlier, almost all drugs are eliminated by first-order kinetics. For example, if the body can eliminate half of a given drug per hour, and a patient has a blood concentration of 100 mg/mL of that drug, the concentration will halve each hour from 100 to 50 to 25 to 12.5, and so on. Note that a progressively smaller absolute amount of drug is being removed each hour (50 in the first hour, 25 in the second hour, and so on), whereas in zero-order kinetics, a constant amount is removed each hour.
Another important concept to learn is the half-life of a drug, which is the time it takes for half the drug to be metabolized. Recall in the zero-order kinetics model that a constant amount of drug is eliminated per unit time, so the half-life of zero-order kinetics will change with the concentration of the drug. For instance, if you drank 10 beers, it would take 5 hours at the rate of one beer per hour to metabolize half the beer (half-life of 5 hours). However, if you instead drank two beers, it would only take an hour to metabolize half the beer because after 1 hour, you would have one beer left in your body (half-life of 1 hour). On the other hand, because in first-order kinetics, a constant proportion is metabolized, the half-life is constant for a specific drug.
For a first-order kinetics drug, the half-life can be given by the equation:
where Vd is the volume of distribution. This equation basically says that a higher volume of distribution will increase the half-life (because it is redistributing into fat or other body compartments and will not be available to be metabolized readily), and a faster clearance will cause a decreased half-life (which is intuitive because if the body gets rid of the drug faster, it will decrease the concentration of the drug faster). After a patient has taken a drug for a period of time (typically 4 to 5 times the half-life of the drug), it reaches a steady state (Table 7-1 and Fig. 7-3), where the amount of drug taken equals the amount of drug leaving the body.
The concept of steady state also applies to clinical practice. For instance, in hypothyroidism, levothyroxine is given as replacement T4 thyroid hormone and has a half-life of about 1 week. Therefore, when a patient is started on this daily medication, it will take about 5 half-lives to come to a new steady state. This is the rationale for checking thyroid-stimulating hormone (TSH) 6 weeks after starting a patient on levothyroxine for hypothyroidism; any sooner and the drug would not have reached steady state, and the TSH would not be an accurate reflection of whether or not the dose was therapeutic. (Refer to Chapter 9 for details on thyroid hormone physiology.)
The last calculations that you are expected to know are the loading dose and maintenance dose for a medication. These calculations build on the information already presented in this chapter.
where Cp is the target plasma concentration, Vd is the volume of distribution, and F is the bioavailability of the drug (remember this is always 1.0 [100%] for intravenous drugs). The loading dose is a larger one-time dose to get the patient up to the desired plasma concentration without having to wait for 5 half-lives because waiting isn’t always feasible. For a large volume of distribution, a much larger loading dose may need to be given because such a small amount of the drug will stay inside the plasma—instead, those drugs may be redistributing into fat or other tissues outside of the bloodstream.
where Cp is the target plasma concentration and F is the bioavailability of the drug. It represents the dose at which the net concentration of that drug in the bloodstream is unchanging. Therefore, the elimination of the drug equals the rate of administration of the drug. Think of this as a leaking bucket—the water leaking out is the metabolism of the drug, and the water being poured into the bucket is the administration of the drug. The goal here is to equalize these two things so that the level of water in the bucket (the amount of drug in the patient) remains unchanged.
PHARMACODYNAMICS
Overview
Pharmacodynamics is the study of how a given drug causes its effect. Pharmacodynamics includes, for example, the understanding of receptor activity, signal transduction pathways, and physiologic effects of a given drug. This section will highlight the fundamental concepts and some prototypical drugs that are instrumental to understanding this concept.
Fundamentally, drugs will interact with some form of receptor. When a drug interacts with a receptor, it can do so in many ways. Some drugs activate the receptor; these are called agonists. Some drugs block the receptor; these are called antagonists. Some drugs activate the receptors, but are unable to do so fully; they are called partial agonists because they can only elicit a submaximal (partial) response.
To have an effect, the drug must bind to the receptor in question—it can either do this reversibly (noncovalent bonding, such as hydrogen bonding) or irreversibly (covalent bonding, such as with aspirin). Drugs will “like” to attach to different receptors more or less depending on their particular shape and size, referred to as the affinity of the drug for its receptor. We express this chemically by looking at the following equilibrium:
If the drug has a high affinity for the receptor, most of the above equilibrium will lie to the right as the drug–receptor complex. Only a small amount of the drug will be required to achieve the intended effect because it sticks to the receptor so well—this is called high potency. Potency is measured as the half maximal effective concentration (EC50), which is the concentration of the drug needed to elicit 50% of the maximal effect: if you need a lot of the drug to achieve that, the drug is a low potency drug. For instance, benzathine penicillin, a long-acting antibiotic used in the treatment of syphilis, has a dose of 2.4 million units. Because a high dose of the drug is required to have the intended effect, it is a low-potency drug.
As an aside, because pharmacologists love to confuse medical students, sometimes the drug–receptor interaction will be described in terms of a KD, or dissociation constant. This is tricky because a high dissociation constant (a high KD) means that the drug–receptor complex wants to dissociate and come apart, and therefore it would have a low affinity. Conversely, a low KD means the drug doesn’t want to dissociate, and it would have a high affinity—don’t get tricked by this.
The efficacy of a drug is the maximum response achievable from a drug—regardless of the amount of drug needed. Note that a drug can have great efficacy but not be potent if a drug has a high maximal response but requires a lot of the drug to do so. If an analgesic can take away 100% of a patient’s pain, but requires 1,000,000 mg to do so, this would have a high efficacy but low potency. Conversely, a drug can have high potency (small amount of drug required to get 50% of the maximal response) but have low efficacy if the drug cannot ever achieve a maximal response regardless of dose given (i.e., a very potent partial agonist). Do not be confused by this concept. Remember, potency and efficacy are independent of each other. Refer to graphs A to C later in Figure 7-5 to illustrate this concept.
Antagonists block receptor sites and try to prevent activation of that receptor. They can be either competitive (meaning they compete for the same active site as the normal agonist for that receptor) or noncompetitive (meaning they bind to a different site separate from that of the normal agonist for that receptor) (Fig. 7-4). This difference is important because if there are high levels of an agonist present, the competitive antagonist can be outcompeted, being “drowned out” by all the agonists competing for the same site. On the other hand, because noncompetitive antagonists and agonists do not compete for the same site, the noncompetitive antagonist cannot be outcompeted by high concentrations of agonists.
Figure 7-4 A, A competitive antagonist, binding at the same active site as the normal agonist for that receptor. B, A noncompetitive antagonist, with the antagonist binding at a separate site from the normal agonist for that receptor.
Take some time to familiarize yourself with Figure 7-5.
Figure 7-5 A dose-response curve and the modifications with a competitive agonist (A), an irreversible antagonist or noncompetitive antagonist (B), and a partial agonist (C) added.
A The addition of a competitive antagonist does not decrease the efficacy (ability to achieve a maximal effect) of the agonist because adding more of the agonist overwhelms the competitive antagonist; however, because more drug is required to achieve 50% of the maximal effect, the agonist is less potent.
B The addition of an irreversible antagonist causes decreased efficacy because regardless of how much of the agonist is added, it cannot outcompete the antagonist—it is irreversible and will not unbind. A noncompetitive antagonist would have the same effect because it does not bind to the same site as the agonist, so the high concentration of agonist cannot displace it.
C A partial agonist, as mentioned earlier, is something that cannot have a maximal effect (less than 100% efficacy). Of note, in this particular case, the partial agonist is more potent than the full agonist because the EC50 is at a lower dose than the full agonist. Again, this demonstrates the idea that efficacy and potency are independent of each other.
Lastly, familiarize yourself with the idea of the therapeutic index (TI), a measurement of the margin of safety of a drug. It is calculated as
If the drug has a TI of 100, then the median toxic dose is 100 times greater than the median effective dose—a very safe medication. However, if the TI was 1.001, for example, the median toxic dose would be barely greater than the median effective dose, and toxic effects would be much more likely (i.e., chemotherapeutics).
AUTONOMIC NERVOUS SYSTEM AND SIGNAL TRANSDUCTION
Overview
The nervous system is broken down into the central (brain and spinal cord) and peripheral (everything else) nervous systems; the peripheral nervous system includes the somatic (voluntary) and autonomic (involuntary) nervous systems. The autonomic nervous system is further divided into the sympathetic and parasympathetic nervous systems (Fig. 7-6A). In this chapter, the autonomic nervous system is described because understanding the sympathetic and parasympathetic nervous systems is critically important to understanding their pharmacology.
Figure 7-6 A, A breakdown of the nervous system and its components. B, A schematic of the actions of the parasympathetic nervous system and sympathetic nervous system on various organs in the body. (B, from Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.)
The autonomic nervous system is automatic (involuntary)—it involuntarily regulates the body’s activities, such as the activity of the intestines, tone of blood vessels, heart rate, secretions, and more. Recall that the sympathetic and parasympathetic divisions make up the autonomic nervous system; the actions of each of them are mostly opposing. The sympathetic nervous system regulates the four Fs of life: fight, flight, fright, and sex. The goal of the sympathetic nervous system is to keep you alive in a dangerous situation or one that requires a lot of activity. The parasympathetic nervous system (Fig. 7-6B) mediates the “rest-and-digest” response when it is safe to be more sedentary, and promotes gastrointestinal (GI) motility, defecation, and urination—you wouldn’t want to have to use the bathroom when running from an attacker!
SYMPATHETIC NERVOUS SYSTEM
The sympathetic nerves leave from the thoracolumbar (thoracic and lumbar) spinal cord. The primary neurotransmitter of the sympathetic nervous system is norepinephrine, but epinephrine is indirectly a key player because the adrenal medulla releases epinephrine into the bloodstream to further activate the sympathetic response. The sympathetic nervous system exerts its effect through alpha (α) and beta (β) receptors.
α1 Receptors act as smooth muscle constrictors, meaning that they tighten sphincters (again, don’t want to use the bathroom when running from a tiger) and also contract the smooth muscles of arterioles in the circulatory system (vasoconstriction), increasing systemic vascular resistance and raising blood pressure. The goal of this vasoconstriction is to decrease blood flow to nonvital areas and redirect it to skeletal muscle to support activity. Those parts of the body that are less vital to be perfused during activity will have more of these receptors, causing more vasoconstriction in these areas. In addition, the pupillary dilator muscle in the eye has α1 receptors, which cause dilation of the pupil to allow more light in during the fight-or-flight response. Phenylephrine is a pure α1 agonist that clamps down blood vessels, often used to raise blood pressure in hypotensive patients in the operating room and also used to stop runny noses (constricting vessels in the nose to stop vascular congestion)!
α2 Receptors act as negative feedback to keep the sympathetic response regulated. Clonidine is an α2 agonist and therefore through negative feedback has the net effect of decreasing sympathetic outflow, which is beneficial in the treatment of hypertension but more commonly used to manage the sympathetic nervous system activation surges that often accompany opiate withdrawal in patients attempting to quit their addiction.
β1 Receptors are found mostly on the heart and act as cardiac stimulants. They mainly increase the rate (chronotropy) and contractility (inotropy) of the heart, allowing for increased cardiac output and delivery of blood to tissues to support their increased activity during one of those four Fs. Beta blockers work by preventing activation of this receptor, which ensures that the heart doesn’t work too hard (require more oxygen) in patients with heart disease. In patients with heart failure, prolonged sympathetic activation actually causes long-term remodeling and changes in the heart that are maladaptive—beta blockade also helps prevent this neurohumoral remodeling.
β2 Receptors act as smooth muscle relaxers, which seems counterintuitive when contrasted with α1 receptors. However, it is the location of these receptors that is important—to increase blood flow to skeletal muscle, more β2 receptors instead of α1 receptors are found on arterioles feeding skeletal muscles. In addition, β2 receptors are found on the bronchioles of the lung, and activation of these receptors relaxes smooth muscle in this area, allowing for better airflow during breathing—which is why the β2 agonist albuterol is so effective in treating asthma. You have 1 heart (β1 works on the heart), and you have 2 lungs (β2 works on the lungs).
Signal Transduction Pathways
All of the aforementioned receptors (and all receptors) need to trigger some sort of signal transduction pathway to relay the message and start the cascade that eventually causes the intended effect of the receptor. The most common pathway for this is through G-protein-coupled receptors (GPCRs), which are also known as seven-transmembrane domain receptors because they cross the cell membrane seven times. There are many subtypes of GPCRs, each of which has a different downstream pathway—it is important to understand the Gq, Gs, and Gi pathways (only three!). Now that you understand what each receptor of the sympathetic nervous system does, it is time to move on to how it does it, through these GPCRs.
GPCRs have α, β, and γ subunits and are active when a signal molecule (e.g., a neurotransmitter or drug) attaches to the receptor and causes the α subunit to exchange its bound inactive guanosine diphosphate (GDP) for an active guanosine triphosphate (GTP)—this activates the α subunit to in turn activate the βγ complex, which will then go on to activate whatever downstream pathway is involved, depending on whether or not it goes through the Gq, Gs, or Gi pathway. The α subunit has a GTPase, which will eventually hydrolyze one of the phosphates off of GTP to change it back to inactive GDP, to ensure that the signal doesn’t continue going on forever. (Note: these α and β are subunits of the GPCR—different from the α and β sympathetic nervous system receptors discussed previously!)
Gq: The Gq pathway has the end result of increasing calcium levels in the targeted cells; in the case of the α1 receptors on the arterioles of blood vessels, the calcium surge causes contraction of those muscles and therefore causes vasoconstriction. The exact mechanism of how calcium release allows muscular contraction is covered in Chapter 12 in detail. Refer to the graphic that depicts the Gq pathway: the active βγ complex activates phospholipase C, cleaving the PIP2 molecule into IP3 and diacylglycerol (DAG). The IP3 binds to a special channel on the sarcoplasmic reticulum (an organelle in smooth muscle cells that holds calcium to be ready for contraction) and releases that calcium. DAG, on the other hand, can be made into prostaglandins, which regulate pain and inflammatory responses, and also activates protein kinase C (PKC), which can phosphorylate other molecules and exert other effects (Fig. 7-7A).
Gs: The Gs pathway has the end result of activating protein kinase A (PKA), which phosphorylates various proteins to modify their activity (kinases phosphorylate things, dephosphorylases remove phosphates from things). The active βγ complex activates adenylyl cyclase, causing cyclic adenosine monophosphate (cAMP) production, which activates PKA. Both β1 and β2 receptors work through this pathway—each phosphorylating proteins that in turn cause their intended effects (Fig. 7-7B).
Gi: Luckily this one is easy—it inhibits adenylyl cyclase, preventing cAMP production and PKA activation. Gs stimulates cAMP production; Gi inhibits.
PARASYMPATHETIC NERVOUS SYSTEM
The parasympathetic nervous system has nerves that exit from the cervicosacral spinal cord; neurons that have parasympathetic activity are also found in some of the cranial nerves (specifically cranial nerves III, VII, IX, X, discussed in Chapter 13 in detail). The parasympathetic nervous system mediates the rest-and-digest response; when you are relaxed and sedentary, your body slows the heart rate, increases blood flow to the intestines and promotes digestion, and promotes urination and defecation—all of the “bodily maintenance” activities that the body previously put on hold while you were running from that tiger. In contrast to the sympathetic nervous system, which uses catecholamines such as norepinephrine and epinephrine, the parasympathetic nervous system uses acetylcholine to exert most of its effects on the body through muscarinic receptors.
M1, M3, and M5 (odd) receptors: Use the Gq pathway described previously. M3 receptors cause smooth muscle contractions at smooth muscles that aren’t sphincters (because if your sphincters were tight, it would make urinating and defecating difficult!)—an example of this contraction is the detrusor muscle, the smooth muscle of the urinary bladder, promoting urination. The M3 receptor also increases glandular secretions, important in the parasympathetic-mediated digestion response as well as in bronchial secretions, in which blocking this receptor is helpful to patients with asthma or chronic obstructive pulmonary disease (COPD). Again, the Gq pathway causes a calcium surge, leading to smooth muscle contraction through calcium release from the sarcoplasmic reticulum, but the receptors are in locations different from the sympathetic α1 receptors that also mediate smooth muscle contraction. In general, the odd-numbered muscarinic receptors are excitatory (whereas the even-numbered muscarinic receptors are inhibitory). A way to remember this is it’s odd to be excited about muscarinic receptors. (The M1 and M5 receptors are much less clinically important.)
M2 and M4 (even) receptors: As you may guess from above, M2 and M4 receptors are inhibitory and therefore act through the Gi pathway. The most important inhibitory muscarinic receptor is the M2 receptor found on the atria of the heart—the inhibitory actions on the sinus node (the pacemaker of the heart) cause a decreased heart rate as well as decreased contractility of the atria only. The ventricles do not have a high density of these receptors, and ventricular contractility is unaffected.
PHARMACOLOGY
Adrenergic Pharmacology
Adrenergic pharmacology will address how drugs manipulate catecholamines such as norepinephrine and epinephrine and their G-protein-linked α1, α2, β1, and β2 receptors. Drugs modifying this system have a wide clinical application, from treating anaphylactic shock (the most severe allergic response) with epinephrine, to helping people with benign prostate hyperplasia (BPH) urinate. Just as with the cholinomimetics, the sympathomimetics can act either directly through receptor agonists or indirectly. The indirect sympathomimetics work either by preventing reuptake of catecholamines or by increasing release of them. Catecholamines are synthesized from tyrosine and undergo various modification steps subsequently (Fig. 7-8B).
Figure 7-8 A, Neurotransmission at a sympathetic nervous system neuron synapse. B, Synthesis of catecholamines from tyrosine. (A, from Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.)
Figure 7-8A depicts an adrenergic synapse. The presynaptic neuron is stimulated to release acetylcholine into the synaptic cleft, the space between the presynaptic neuron and postsynaptic receptors, which may be located either on another neuron to carry the signal downstream or on the end organ to be affected. The acetylcholine binds to those receptors and activates them. Drugs act to potentiate or block this system.
Direct sympathomimetics act directly as agonists at an adrenergic receptor. The main direct sympathomimetics are epinephrine, norepinephrine, isoproterenol, dopamine, dobutamine, and phenylephrine. Epinephrine, norepinephrine, and dopamine are referred to as endogenous catecholamines because they are naturally found inside the body. The synthesis of these endogenous catecholamines begins with the amino acid tyrosine and then progress to the active catecholamines dopamine, norepinephrine, and epinephrine, in that order.
Epinephrine: Affinity for α1 = α2 and affinity for β1 = β2, with preference at low doses for β1. Therefore, because of the α1 and β1 agonist activity, epinephrine acts to vasoconstrict (increasing blood pressure) and increase cardiac output, respectively. The β2 agonist activity causes bronchodilation and increases blood flow to skeletal muscles. All of these should be intuitive: these are all things that you might need to happen when you are fighting an attacker. Clinically, this is used in anaphylaxis when an allergic reaction has caused histamine release with subsequent bronchospasm as well as widespread hypotension due to vasodilation; the epinephrine can help reverse these changes and save the patient’s life. This drug is so important clinically that patients with a history of anaphylaxis carry an intramuscular epinephrine injector with them in case another anaphylactic reaction occurs. This drug is also used in severe asthma exacerbations to allow for bronchodilation and ease of breathing.
Norepinephrine: Affinity for both α receptors is greater than for the β1 receptor, no significant β2 activity. Therefore, norepinephrine is primarily an excellent vasoconstrictor. It is used as a vasopressor (a drug that constricts blood vessels) in septic shock.
Dopamine: The immediate precursor to norepinephrine in the synthetic pathway, dopamine at low doses causes renal vasodilation through D1 and D2 dopamine receptors; at medium doses, it causes β1 stimulation and increases cardiac output; at high doses, it causes α1 activation and vasoconstriction. This is also used in treating the low blood pressure in septic shock.
Isoproterenol: A pure β agonist, β1 = β2. Therefore, the drug will cause increased cardiac output from β1 activation as well as vasodilation and decreased blood pressure from β2 activation. This is rarely used clinically.
Phenylephrine: A pure α1 agonist, phenylephrine is a potent vasoconstrictor that is used in various forms to decrease nasal congestion (nasal spray), increase blood pressure (IV), and even dilate pupils (eye drops) for eye exams by activating the pupillary dilator muscle.
Albuterol: A β2 agonist, albuterol is inhaled and relaxes smooth muscles in the airways, helping asthmatic patients breathe better. Salmeterol is another agent frequently used; it is longer acting.
Terbutaline: A β2 agonist, terbutaline relaxes smooth muscles and has found its use in the treatment of premature labor as a tocolytic (something that decreases uterine contractions). It can also be used in asthma exacerbations as a bronchodilator.
Indirect sympathomimetics work by either increasing release of catecholamines (such as amphetamine or ephedrine) or by preventing their reuptake into the presynaptic neuron (such as cocaine). These will generally increase sympathetic outflow, causing increased activity at all four adrenergic receptors, α1, α2, β1, and β2.
Amphetamine is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity; it causes increased release of endogenous catecholamines. This is similar to ephedrine, which can be used as a decongestant.
Cocaine blocks reuptake of catecholamines and leaves them in the synaptic cleft to continue to stimulate receptors.
In addition, there are many drugs that act to block these receptors or to reduce sympathetic outflow in general. These are called sympathoplegics or sympatholytics.
α2 Agonists such as clonidine and methyldopa decrease sympathetic outflow because the α2 receptor acts as negative feedback. Clonidine is used for the sympathetic surges that accompany opioid withdrawal, and methyldopa is used to treat hypertension in pregnancy because other blood pressure medications often have deleterious effects on the fetus.
α1 Antagonists block the smooth muscle–constricting effects of the α1 receptor.
Phenoxybenzamine: An irreversible nonselective α antagonist (unlike phentolamine, which is reversible), which is used in the treatment of pheochromocytoma (a catecholamine-secreting tumor). The fact that it is irreversible is important because the high levels of catecholamines secreted by this tumor would displace reversible antagonists. By blocking vasoconstriction at the arterioles, hypotension is a common side effect.
Prazosin, terazosin, doxazosin: These are α1 antagonists that are primarily used for their prevention of smooth muscle constriction in the urinary tract to treat benign prostate hyperplasia. The enlarged prostate causes increased resistance to urinary flow out of the bladder; this medication helps relax the smooth muscle and aid in urination. Of course, the side effect is that it also would block vasoconstriction and has the potential to cause hypotension; tamsulosin is a newer medication that is specific for the subtype of receptors in the urinary system.
β Antagonists (“beta blockers”) are used frequently in patients with high blood pressure, myocardial infarction, supraventricular tachycardia, and heart failure. Recall that β1 stimulation causes the heart to increase in rate (positive chronotrope) and contractility (positive inotrope); beta blockade prevents these responses, causing a decreased oxygen demand for the heart, as well as slowing it in patients with fast heart rates. These drugs typically end in -lol (e.g., propranolol, atenolol, metoprolol) and can either be β1 selective (atenolol, metoprolol) or nonselective for the β receptor (propranolol).
Cholinergic Pharmacology
Cholinergic pharmacology addresses how drugs manipulate acetylcholine and their G-protein-linked muscarinic receptors to have their intended effects on the body (Fig. 7-9). Before this is discussed, a concept that has not been introduced yet must be briefly mentioned—the somatic nervous system. The somatic nervous system is used for voluntary movement and also uses acetylcholine as a neurotransmitter to cause muscle contraction through nicotinic receptors that are linked to ion channels. Therefore, drugs that act directly on muscarinic receptors will not affect the somatic nervous system, but drugs that increase the activity of acetylcholine will because they share the same neurotransmitter type. A description of exactly how nicotinic receptor activation leads to muscular contraction is covered in Chapter 12.
Figure 7-9 Neurotransmission at a parasympathetic nervous system neuron synapse. (From Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.)
There are two ways to increase muscarinic cholinergic transmission: either directly through muscarinic receptor agonists, or indirectly by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine by splitting it into choline and acetate for recycling into the neuron. Both of these would be called cholinomimetic agents because they mimic acetylcholine’s activity.
The most commonly used example of a direct cholinomimetic is pilocarpine, given as eye drops (Fig. 7-10). Pilocarpine works on the M3 muscarinic receptor on the pupillary sphincter muscle, causing contraction and miosis (constriction of the pupil). Study Figure 7-10; the circular muscles of the iris sphincter will get smaller when contracted, causing pupillary constriction, whereas the dilator muscle under α-receptor control will stretch back the iris and cause mydriasis (myDriasis = pupillary Dilation). This drug is important in the treatment of angle-closure glaucoma, in which the aqueous humor of the eye builds to high pressures owing to blockage of the canal of Schlemm. Angle-closure glaucoma is often precipitated in susceptible individuals by dilation of the pupil, which increases the contact between the iris and the lens as the iris becomes “scrunched up” by compacting and thickening during dilation. Pilocarpine will constrict the pupil, helping restore normal flow of aqueous humor.
Figure 7-10 The eye and its pupillary dilator muscle (α receptor, sympathetic) and pupillary constrictor muscle (M receptor, parasympathetic).
There are also indirect cholinomimetics that function by blocking the breakdown of acetylcholine into acetate and choline. This prolongs the action of acetylcholine in the synapse. The indirect cholinomimetics include the reversible acetylcholinesterase inhibitors (edrophonium, pyridostigmine, and physostigmine) as well as pesticides, which are commonly irreversible acetylcholinesterase inhibitors. Edrophonium is a commonly tested medication owing to it previously being a test for diagnosing myasthenia gravis, an autoimmune disease in which the body blocks and destroys the nicotinic receptors that the somatic nervous system uses for movement, leaving fewer functional nicotinic receptors and causing weakness. Edrophonium is a short-acting reversible acetylcholinesterase inhibitor, allowing more acetylcholine to attach to the nicotinic receptors that are still functioning, restoring strength. If the patient improved after administration, it was suggestive of the disease. Because the half-life of edrophonium is so short, treatment of myasthenia gravis is with pyridostigmine, which is longer acting. Pyridostigmine does not cross the blood–brain barrier and therefore does not affect the brain. Physostigmine crosses the blood–brain barrier and is therefore less commonly used, except in overdoses of anticholinergics that cross the blood–brain barrier.
Too much activation of the parasympathetic nervous system due to cholinomimetics can lead to SLUDGE syndrome, a mnemonic toxidrome characterized by Salivation, Lacrimation, Urination, Defecation, Gastrointestinal upset, and Emesis—this is covered more in depth later in the section “Toxicology,” but by now each of these symptoms should make sense given the activity of the cholinergic system. The parasympathetic nervous system through muscarinic receptors mediates the rest-and-digest response; salivation, urination, and defecation, as well as increased GI motility (GI upset), are all direct parts of that response. Additionally, because of the pupillary sphincter muscle discussed previously, increased cholinergic tone will cause miosis. Pilocarpine does not have these systemic effects because it is administered as eye drops, which are not absorbed in large quantities into the systemic circulation.
There are also muscarinic antagonists that are used to prevent activity at these receptors.
Atropine is a common muscarinic antagonist that finds many uses—eye drops of atropine analogues cause mydriasis (because it blocks the iris constrictor muscle, blocking constriction). In addition, it is used in the treatment of symptomatic bradycardia because the M2 receptor inhibits the sinus node, which is the pacemaker of the heart; inhibiting the inhibitory receptor causes an increase in heart rate.
Oxybutynin is used to inhibit urination in individuals with urinary incontinence, allowing the patient to feel less urinary urgency and be more comfortable. This works because the parasympathetic nervous system promotes urination; oxybutynin blocks this response.
Ipratropium is an inhaled muscarinic antagonist often used in the treatment of asthma. It decreases bronchial secretions and also opens the bronchi by blocking muscarinic-mediated bronchoconstriction.
TOXICOLOGY
When people think of toxicology, they think of poisons. However, the drugs that we use can be poisonous too, usually at higher doses than intended. Toxins can also be environmental exposures such as pesticides or lead. Many of these have antidotes, and an understanding of why each antidote works the way it does is important in treating these patients.
Common Drugs and Toxicology
Acetaminophen (Tylenol) is a common analgesic. Recent guidelines recommend no more than 3 g of acetaminophen daily, for fear of liver damage. The reason that acetaminophen hurts the liver is that during its metabolism, a fraction of the drug is turned into a compound that can cross-link and damage proteins called N-acetyl-p-benzoquinone imine (NAPQI) through a phase I biotransformation. NAPQI is normally immediately made harmless by conjugation with glutathione. In individuals who either consume a lot of acetaminophen, or are alcoholic and have poor nutritional status, this pathway can be overwhelmed and cause liver failure. The treatment is N-acetylcysteine. This regenerates glutathione stores and allows detoxification of the NAPQI.
Aspirin (acetylsalicylic acid) and other salicylates in overdose can cause tinnitus (ringing in the ears), an anion gap metabolic acidosis (because it is an acid), and a respiratory alkalosis (because aspirin directly stimulates central chemoreceptors and stimulates respiration). Because the drug is an acid, alkalinization of the urine with sodium bicarbonate (NaHCO3) will cause ion trapping in the kidney and increase excretion. In children, any administration of aspirin is considered unsafe because it can cause Reye syndrome (liver failure and encephalopathy) that can be potentially fatal. (An exception to the “never give kids aspirin” rule is in patients with Kawasaki disease, for which the treatment includes aspirin and intravenous immunoglobulin.)
Beta-blocker overdose is characterized by hypotension, bradycardia, and first-degree atrioventricular block as well as possible altered mental status. Treatment is with glucagon, which is not intuitive—glucagon activates myocardial adenylyl cyclase independently of the β receptor and therefore provides an alternative pathway to stimulate the Gs pathway in the face of complete beta blockade.
Digoxin is used as a positive inotrope, improving symptoms in congestive heart failure (although it unfortunately does not improve mortality rates). Digoxin works by blocking the Na+/K+-ATPase pump, leading to increased myocardial intracellular sodium concentration and therefore preventing use of a sodium–calcium exchanger that normally pumps calcium out of the cell; this inhibition of calcium efflux causes increased calcium concentration in the cell (Fig. 7-11). This increased calcium is now available to aid in contraction, increasing inotropy. Digoxin has a specific antidote: fragmented antibodies that bind to digoxin, called digoxin-specific Fab antibody fragments. Because digoxin competes for potassium at the Na+/K+-ATPase site, hypokalemia causes more digoxin to bind (less K+ competing for binding site) and can promote toxicity.
Figure 7-11 A cardiac myocyte showing digoxin blocking the potassium site of the Na+/K+-ATPase pump, with subsequent decreased function of the Na+/Ca+ exchanger and increased cytosolic calcium. (From Costanzo L. Physiology. 4th ed. New York: Elsevier; 2009.)
Opioid pain medications and heroin are commonly abused and can lead to overdose. Clinical clues are history, presence of track marks on the arms at prior injection sites, miosis (“pinpoint pupils”), and respiratory depression because the μ-opioid receptor that most opioids use for analgesic effects also can cause significant respiratory depression. Treatment is straightforward: use an opioid antagonist such as naloxone.
Benzodiazepines (alprazolam, lorazepam) are used in the treatment of anxiety, insomnia, seizures, and alcohol withdrawal. They are γ-aminobutyric acid (GABA) agonists; the GABA receptor is found in the central nervous system and, when activated, causes chloride influx into the cell, which hyperpolarizes it and therefore decreases neuronal excitability and causes sedation and anxiolysis. The treatment is also intuitive: flumazenil, a GABA antagonist. Caution in treatment of benzodiazepine overdose is warranted because blocking the inhibitory GABA receptors can lead to overexcitation and seizures in some patients.
Tricyclic antidepressants (TCAs) (amitriptyline, nortriptyline) are now rarely used as an antidepressant; they have been supplanted by selective serotonin reuptake inhibitors (SSRIs) but now find use in treating chronic pain as well as other diseases. Toxicity is characterized by the three Cs: cardiotoxicity, convulsions, and coma. TCAs have actions on many receptors, including antihistamine (causing sedation), α1 antagonism (hypotension), inhibition of catecholamine reuptake (accounting for its antidepressant efficacy), and sodium channel blockade (important in cardiotoxicity). The treatment is sodium bicarbonate (NaHCO3) for two reasons: (1) it allows for ion trapping of the medication and increased renal excretion, and (2) it helps correct the sodium channel blockade of the TCA, preventing cardiac arrhythmias.
Heparin is an anticoagulant that is commonly used for patients with deep venous thrombosis (a clot in the deep veins of the leg) or pulmonary embolism (clot in the pulmonary arterial tree) because it prevents new blood clots from forming. It can also be used to prevent clot formation in patients who are at risk. Heparin activates antithrombin, which, in turn, inactivates thrombin (factor IIa) and factor Xa. Supratherapeutic doses of heparin can lead to uncontrolled bleeding; protamine sulfate binds to heparin and is the antidote.
Warfarin is an oral anticoagulant that blocks vitamin K epoxide reductase to prevent the liver’s synthesis of the vitamin K–dependent clotting factors II, VII, IX, X, C, and S. Because warfarin prevents synthesis of clotting factors, rather than blocking existing ones, the onset of action is delayed, and this is one reason that patients started on warfarin need to be “bridged” by being started on heparin first to give immediate anticoagulation (there is also a transient phase of warfarin that makes patients hypercoagulable, which is discussed in Chapter 11). Although giving vitamin K would treat an overdose, it would take hours to days to replenish all of the clotting factors by synthesizing new ones, so fresh frozen plasma (FFP) which has donor clotting factors is given for immediate reversal.
Tissue plasminogen activator (tPA), a thrombolytic, is used for active breakdown of blood clots (unlike warfarin and heparin, which prevent formation of new clot). It does this by turning the body’s inactive plasminogen into active plasmin, which is the body’s own natural pathway for breaking down clots. This is used acutely in ischemic stroke, myocardial infarction, and massive pulmonary embolism. In contrast, aminocaproic acid binds competitively to plasminogen, preventing transformation into active plasmin, and is therefore the antidote.
Heavy Metal Toxicity
Iron is widely available as a supplement for individuals with iron deficiency anemia; most of the overdoses occur in children accidentally taking someone else’s iron because the pills are often colorful and sugar coated. Iron, although important in the synthesis of hemoglobin and other enzymes, also is a potent catalyst for free radical formation. Overdose can cause high amounts of free radical formation in the intestines where the iron is passing through and cause damage to the intestines, leading to mucosal ulceration, GI bleeding, diarrhea, and vomiting. Normally, when the body has surplus iron, intestinal absorption of iron is inhibited—when the intestines become damaged, iron can enter in the bloodstream unimpeded and can cause mitochondrial damage and subsequent lactic acidosis, as well as liver damage from the high amounts of iron entering the liver through the portal vein. The treatment of iron overdose is deferoxamine, an iron-chelating agent. Mnemonic: treat Fe (iron) overdose with deFEroxamine.
Lead is a heavy metal that used to cause numerous cases of lead poisoning due to lead-based paint (patient history will usually describe an “old” house, built before 1974 when lead paint use was stopped). The mechanism of lead toxicity is complex, but in general it interferes with a multitude of enzymes, especially δ-aminolevulinic acid dehydratase (leading to a buildup of aminolevulinic acid) and ferrochelatase, which both are important in heme synthesis, leading to a microcytic anemia. The buildup of aminolevulinic acid leads to increased vessel permeability, cerebral edema, and encephalopathy. Interference with ribonuclease leads to persistent ribosomes in the red blood cells that are made, leading to basophilic stippling (Fig. 7-12) on a peripheral blood smear. There are many treatments for lead poisoning, including dimercaprol (previously known as British anti-Lewisite, or BAL), CaEDTA, succimer, and penicillamine. A common mnemonic is: when kids succ on lead paint chips, they need succimer. Dimercaprol and succimer are also effective in treating mercury, arsenic, and gold toxicity; a way to remember this is a British (BAL, dimercaprol) reading a MAGazine (Mercury, Arsenic, Gold) that succs (succimer).
Figure 7-12 Basophilic stippling, seen in lead poisoning due to denaturing of ribonuclease. Without ribonuclease, the ribosomes in the red blood cell are not degraded and cause the basophilic inclusion. (From Naeim F. Atlas of Bone Marrow and Blood Pathology. Philadelphia: Saunders; 2001:27.)
Copper is only rarely ingested as an overdose, but those with Wilson disease (also known as hepatolenticular degeneration, for the damage it does to the liver and the lenticular nucleus of the brain) have an inability to excrete copper. The treatment is penicillamine, which chelates copper.
Environmental Exposures
Carbon monoxide (CO) is a colorless and odorless gas, a byproduct of combustion; and toxicity is either intentional (e.g., a suicide attempt by leaving a running car in a closed garage) or unintentional (e.g., using combustion as a means of heating a cold house in winter, thinking it’s a good idea to barbeque indoors). CO has an affinity for hemoglobin more than 200 times greater than that of oxygen, causing CO to take up spots on hemoglobin that should be taken up by oxygen, leading in turn to hypoxia and relative anemia (not that there is too little hemoglobin, it’s just occupied by CO). History is usually suggestive, and symptoms include headache, vomiting, and confusion. Treatment is to outcompete the CO with as much oxygen as possible, either 100% oxygen or hyperbaric oxygen.
Cyanide (CN−), in addition to being a means of murder in movies, is also released when synthetic materials are burned, and therefore a house fire could cause not only CO poisoning but also cyanide poisoning. The antihypertensive medication nitroprusside has cyanide as part of its molecular structure and can cause cyanide poisoning as well. Cyanide binds highly to cytochrome oxidase in the mitochondria, halting the electron transport chain and stopping adenosine triphosphate (ATP) production. Anxiety, palpitations, dyspnea, and headache are common symptoms. Treatment is two step: (1) Administer nitrites (such as amyl nitrite inhaled or sodium nitrite IV) to oxidize the hemoglobin (Fe2 +) to methemoglobin (Fe3 +), which avidly binds cyanide, helping steer it away from the mitochondria where it is poisonous. (2) Administer sodium thiosulfate, which changes cyanide to thiocyanate, a less toxic substance that is excreted by the kidneys. An alternative therapy is giving a form of vitamin B12, hydroxycobalamin, because the cobalt can bind cyanide.
Methemoglobinemia occurs when the Fe2 + in hemoglobin is oxidized to Fe3 + by oxidizing agents; this form cannot carry and deliver oxygen to the peripheral tissues. Common precipitating agents include sulfa drugs, local anesthetics such as benzocaine, and of course nitrates, as described earlier for the treatment of cyanide poisoning. METHemoglobinemia can be treated with METHylene blue. Methylene blue is a potent reducing agent that changes the Fe3 + back into Fe2 +.
Organophosphate poisoning is common in farm areas; the pesticide can be an acetylcholinesterase inhibitor and with exposure can cause symptoms of excessive cholinergic activation called SLUDGE syndrome, a mnemonic toxidrome characterized by Salivation, Lacrimation, Urination, Defecation, Gastrointestinal upset, and Emesis. The organophosphates phosphorylate acetylcholinesterase, leading to irreversible inhibition of the enzyme. However, there is a window period during which a medication called pralidoxime can be given, which can detach the organophosphate from the receptor—however, this is time dependent, and after hours have passed, the pralidoxime will no longer be able to unbind the organophosphate because a process called “aging” has occurred and the bond is unbreakable. Because the problem is overactive cholinergic signaling, the supportive treatment is an antagonist—atropine is a muscarinic antagonist that reverses the symptoms of overactive cholinergic drive. It does not, however, do anything to prevent the overactive acetylcholine at nicotinic receptors of the somatic nervous system, so it cannot treat the muscle weakness.
Atropine, described earlier, is a muscarinic antagonist; too much atropine (or other anticholinergics) will cause symptoms consistent with shutting down the effects of acetylcholine at muscarinic receptors. The common way to remember these is hot as a hare (no sweating), dry as a bone (no sweating, no salivation, no urination), red as a beet (cutaneous vasodilation), blind as a bat (mydriasis), mad as a hatter (disorientation). Treatment is the opposite of above: administer an acetylcholinesterase inhibitor that is reversible, such as physostigmine.
Ethanol, Methanol, and Ethylene Glycol
Ethanol, methanol, and ethylene glycol are all metabolized by the same enzymatic pathway, but with different substrates at each step, causing different clinical symptoms (Fig. 7-13).
Figure 7-13 Metabolic pathway for ethanol (top) and methanol (bottom). Note that aldehyde dehydrogenase is commonly referred to as acetaldehyde dehydrogenase (as it dehydrogenates acetaldehyde), but it can also dehydrogenate other aldehydes (such as formaldehyde). (From Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Elsevier; 2009.)
Ethanol is the most common ingestion of the three; it is metabolized by alcohol dehydrogenase into acetaldehyde and then by acetaldehyde dehydrogenase to acetate. Disulfiram, a medication created to prevent alcohol abuse, blocks acetaldehyde dehydrogenase to cause a buildup of acetaldehyde when drinking; this leads to unpleasant side effects such as flushed skin, tachycardia, and nausea and vomiting. Some antibiotics such as metronidazole are said to have a “disulfiram-like” reaction because drinking alcohol while taking these antibiotics leads to similar symptoms as taking disulfiram. Also, the red flushing that some individuals (especially of Asian descent) experience while drinking alcohol is due to decreased acetaldehyde dehydrogenase activity.
Methanol, found in windshield washer fluid and photocopying fluid, is highly toxic when ingested because of formaldehyde generation (the same stuff used to embalm your cadavers in anatomy lab) by alcohol dehydrogenase enzyme activity and formic acid generation from aldehyde dehydrogenase activity. Formic acid binds to cytochrome oxidase and blocks the electron transport chain, leading to lactic acidosis; formic acid also causes optic nerve damage and retinal damage, leading to permanent blindness. Because disulfiram only inhibits acetaldehyde dehydrogenase, it would be ineffective in treatment—an antagonist such as fomepizole at the alcohol dehydrogenase enzyme must be used. Before fomepizole, physicians administered ethanol to compete for the alcohol dehydrogenase enzyme.
Ethylene glycol is found in antifreeze and tastes sweet, making it appealing to children to drink. Again, like with methanol, the metabolism of the substance results in damaging byproducts. Oxalic acid is produced by alcohol dehydrogenase. Oxalic acid avidly binds calcium, leading to hypocalcemia and precipitation of calcium oxalate crystals in the urine and kidneys, leading to stone formation and renal damage, respectively. The classic findings are metabolic acidosis (as with methanol poisoning), altered mental status, and renal failure from calcium precipitation. Treatment is similar to methanol poisoning in that fomepizole is used because toxic products are formed by alcohol dehydrogenase, which fomepizole inhibits.