Pharmacology and Toxicology

Chapter 23 Pharmacology and Toxicology

Khoshal Latifzai, Thomas A. Brown, MD, Sonali J. Shah

Insider’s Guide to Pharmacology and Toxicology for the USMLE Step 1

We recognize that pharmacology and toxicology are not trivial boards subjects. Each section has its own extensive list of drugs to know, and after a while, it can become very overwhelming. We hope that the following list of tips will help you prepare for this subject with the minimum amount of stress:

Although there are no shortcuts for learning all the drugs that you are expected to know for boards, you do not necessarily need to know an extensive amount of information about each and every drug. If a drug pops up over and over again in First Aid and in your question bank software, you should learn more about it because it has a greater chance of showing up on your exam. For example, the USMLE is not likely to ask you about the adverse effects of an infrequently used drug such as bosentan, but you will be expected to know its use and basic mechanism of action. On the other hand, you should know the mechanism of action, uses, adverse effects, and toxicity treatment for a drug such as digitalis, which is commonly used in practice and shows up repeatedly within the context of boards questions.

Focus on unique aspects and properties of the drugs you learn. Boards are not as likely to ask you about whether a drug causes headache or gastrointestinal (GI) upset because these reactions are quite common. You will be tested on drugs that cause seizures, sexual dysfunction, reflex tachycardia, or pulmonary fibrosis however.

You should expect to have a few questions on the fundamental principles of pharmacology included in the Basic Concepts section of this chapter. The equations for pharmacology are particularly high-yield. It is a great idea to practice using these equations as much as possible. You may consider writing these on your marker board immediately before you begin your exam.

Do not try to cram pharmacology. The more you practice, the better you will get at classifying drugs by groups and acquiring a feel for the drug categories that are most important to know for Step 1. Five-star topics include drugs of the autonomic nervous system (ANS). In fact, you should expect to get three to five questions on your exam specifically about ANS drugs. Four-star topics include antibiotics, analgesics, and cardiovascular and neurologic/psychiatric drugs.

Basic Concepts

1 How does the route by which a drug is administered affect its metabolism?

Most drugs that are taken orally enter the bloodstream at the level of the portal circulation, and encounter the liver almost immediately. Here, they undergo first-pass metabolism, which renders them less efficacious than if they had reached their target organs first. First-pass metabolism can be circumvented by administering the medication parenterally (e.g., intravenously, intramuscularly, or subcutaneously). Because the drug is able to reach its target faster and relatively unaltered, its onset of action is more rapid. In comparison with the oral route, the advantage of parenteral administration is that the clinician is able to observe the effects of the drug almost instantaneously and manage dosing appropriately. Disadvantages include elicitation of undesired effects that accompany rapid delivery, and the need for frequent dosing in cases in which a sustained effect is desired.

Other routes of delivery include inhalation (rapid effect, targeted delivery); intrathecal (into the cerebrospinal fluid [CSF]); sublingual (rapid onset, avoids first-pass metabolism); rectal (half of the delivered drug will undergo first-pass metabolism); topical (for local effect); and transdermal (sustained delivery).

The concentration of a drug in the body is dependent on the route of administration because this influences the bioavailability (F) of the drug. A drug administered intravenously has 100% bioavailability (F = 1), but drugs administered orally have F < 1. You should know how to calculate the concentration of a drug based on dose administered, bioavailability, and volume of distribution (V_D), which is the volume of the compartment into which a drug is distributed. V_D is dependent on the molecular weight and hydrophilicity of the drug.

2 What does the Henderson-Hasselbalch equation mean?

A simple rule of pharmacology is that for a drug to move as freely as possible across various membranes in the body, it must be uncharged. Most drugs are either weak acids (i.e., uncharged while they still have their proton), or weak bases (i.e., uncharged in their conjugate acid form). How much of a medication ends up being uncharged in solution depends on the drug (specifically, the pK_a of the drug) and the pH of the solution. If given a list of drugs that are weak acids and asked which will readily cross the blood-brain barrier, simply subtract the pK_a of the drug from the pH of the solution. For whichever choice this number is most negative, that is the drug that will primarily end up being uncharged at that pH. If given a list of weak bases and asked the same question, again subtract the pK_a from the pH. This time, however, the more positive this number, the more of that drug is in the uncharged form. This simplification is derived from the Henderson-Hasselbalch equation:

For acids (the acid itself is uncharged):

For bases (the conjugate acid is uncharged):

Look at these equations and convince yourself of the reason that the preceding simplification holds true.

3 What is the difference between zero-order kinetics and first-order kinetics?

After a certain period of time in the body, most drugs are inactivated in the liver. Enzymes carry out this biotransformation in one of two ways: first-order kinetics or zero-order kinetics. If a drug is metabolized according to zero-order kinetics, this means that a constant amount of drug is metabolized in a given period of time regardless of the initial dose or half-life of the drug. In other words, enzymes metabolize the same amount of drug per unit time and do not respond to increased workload by increasing their rate of work. The only drugs that you should know are metabolized by zero-order kinetics are ethanol, phenytoin, and aspirin in high doses.

In first-order kinetics, a constant fraction of a drug dose is metabolized per unit time. If the concentration of the drug is steadily increased, metabolic enzymes increase the rate at which they work in order to abide by the rule of metabolizing a certain fraction per unit time. First-order kinetics takes half-life into account (see question 4).

4 What is half-life?

The half-life (t_½) of a drug refers to the amount of time required for half of a drug dose to be metabolized. Half-life can be calculated according to the following formula:

where Cl = the clearance of a drug. Clearance refers to the volume of blood from which a drug is removed per unit time.

After one half-life, 50% of a drug will disappear. After two half-lives, another 50% of the remaining drug dose will disappear (75% of the original dose). After four half-lives, 94% of the original drug dose will have been metabolized. For boards, you should know that steady state is reached after four to five half-lives.

6 What is therapeutic index?

Therapeutic index is used as a tool to measure the safety and efficacy of a drug. Therapeutic index is calculated using the formula:

The higher the therapeutic index, the safer the drug. Drugs with low therapeutic indices include phenobarbital, theophyline, digoxin, and warfarin (Coumadin). These drugs must therefore be monitored closely in patients who receive them.

Therapeutic window refers to the difference between the median lethal dose and the median effective dose of a drug.

7 What are the differences between competitive and noncompetitive inhibitors?

Competitive inhibitors bind to the same active site of an enzyme as the substrate of interest. In competitive inhibition, the enzyme is bound to either the substrate or the inhibitor at any given point. This is because the inhibitor closely resembles the substrate. Competitive inhibition can be overcome by overwhelming the system with increasing concentrations of substrate, which compete with the inhibitor for the active site of the catalytic enzyme. On the other hand, noncompetitive inhibitors bind to alternate sites of the enzyme than the substrate itself. They do not resemble the substrate, but binding of the noncompetitive inhibitor to the enzyme of interest distorts the enzyme such that it can no longer bind to the substrate. Noncompetitive inhibition is often irreversible and cannot be overcome by saturating the system with increasing concentrations of substrate.

Summary Box: Basic Concepts

Drugs administered orally are susceptible to first-pass metabolism, whereas the parenteral route largely bypasses this mechanism.

The Henderson-Hasselbalch equation can be used to determine the proportion of a drug that ends up being uncharged after being dissolved in solution. This is important because it is the uncharged form of a medication that is able to cross lipid barriers in the body.

When you hear first-order kinetics, think fractions; when you hear zero-order kinetics, think constant amounts.

Half-life refers to the time required to metabolize half the amount of drug. A drug reaches steady state after four to five half-lives.

Volume of distribution refers to the volume of the compartment into which a drug is distributed. Clearance refers to the volume of blood from which a drug is completely removed per unit time.

You should know the formulas listed in the preceding questions.

Case 23-1

A 2-year-old girl is evaluated for a 2-day history of fever, vomiting, and diarrhea. Since being given over-the-counter medications this morning she has become increasingly sleepy. Examination is significant for fever, tachycardia, tachypnea, hypotension, somnolence, and decorticate posturing. Urgent workup reveals normal electrolytes, normal head computed tomography (CT) scan, stool positive for rotavirus antigen, and markedly elevated liver enzymes.

1 Given the preceding clinical picture, what is the most likely explanation for this patient’s presentation?

This patient appears to have started out with a viral gastroenteritis that was then compounded with an over-the-counter medication, which is now causing confusion, somnolence, and fulminant hepatitis. Given this presentation, the most likely culprit is acetylsalicylic acid (Aspirin) exposure, which led to Reye syndrome (fulminant hepatitis and cerebral edema). Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) that is contraindicated in children for this exact reason. To treat this patient, one needs to alkalinize the urine (bicarbonate is commonly used) to facilitate aspirin excretion from the body. Consider the pharmacologic principles by which this process occurs: Ionized species can be trapped in urine and eventually excreted, but neutral substances are reabsorbed into the bloodstream. Aspirin is a weak acid and is thus ionized in an alkaline environment from RCOOH ↔ RCOO⁻ + H⁺. This ionized form is then excreted in the urine. In the instance that a patient consumes large quantities of a weak base (e.g., amphetamines), the base can be ionized using an acid.

2 What are the pharmacotherapeutic actions of aspirin and other nonsteroidal anti-inflammatory drugs?

Aspirin and other NSAIDs have anti-inflammatory, antipyretic, and analgesic actions. Because of its potency as an anti-inflammatory, aspirin is the NSAID to which all other NSAIDs are typically compared. These other NSAIDs include ibuprofen, indomethacin (drug of choice for a gouty flare or for closing a patent ductus arteriosus), ketorolac, and naproxen.

3 What is the mechanism of action of NSAIDs?

Injurious stimuli induce involved cells to release arachidonic acid. The two general pathways by which arachidonic acid is broken down in the body are referred to as the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. NSAIDs play a role in inhibiting the COX pathway, thus reducing prostaglandin production. Prostaglandins are local hormones that are proinflammatory, heighten sensitivity to painful stimuli, and alter the hypothalamic temperature setting so as to promote fever.

4 What are some side effects of NSAIDs, and what alternative medications exist that circumvent these side effects?

The COX pathway is run by one of two isozymes, depending on where in the body the reaction is taking place. COX-1 is the isozyme involved almost anywhere in the body, whereas COX-2 is typically active at the site of inflammation. Ideally, selective inhibition of the latter would achieve the goal of decreasing inflammation. NSAIDs in general are not selective for COX-2 and thus cause effects in other tissues as well. These other sites include platelets (where inhibition of thromboxane A₂ leads to inability of these cells to aggregate into a clot), and gastric mucosa (where reduction of prostaglandins PGE₂, PGF₂, and PGI₂ compromises the protective lining of the stomach and increases acid secretion, thus predisposing to ulcers).

Selective COX-2 inhibitors (e.g., celecoxib) do exist that purportedly have less renal and intestinal toxicity. Alternatively, acetaminophen may be given to patients with a coagulopathy or a history of gastric ulcers.

5 If given the choice of aspirin or acetaminophen, which would you administer to a child with a fever

Aspirin given to a child during a viral infection can lead Reye syndrome, which can be fatal. To avoid this possibility, always pick acetaminophen over aspirin for children. The exception to this rule is Kawasaki disease. Children suffering from this condition should be treated with high-dose aspirin to prevent coronary aneurysm.

Summary Box: Nonsteroidal Anti-Inflammatory Drugs and Reye Syndrome

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used therapeutically for their anti-inflammatory, antipyretic, and analgesic actions.

They produce their effects by inhibiting the cyclooxygenase (COX) pathway, thus reducing prostaglandin production. Prostaglandins are involved in pain, inflammation, and fever.

There are two versions of the COX pathway, and because NSAIDs are not selective in which of these they inhibit, side effects involving the gastrointestinal (GI) system and coagulability are not uncommon.

Aspirin is an NSAID that is contraindicated in children because it causes Reye syndrome, which is marked by fulminant hepatitis and cerebral edema. Acetaminophen is a better alternative in this patient population.

Case 23-2

A 14-year-old obtunded boy is brought to the emergency department by his friends, who subsequently leave without providing a history. Vital signs reveal a heart rate of 45 beats/min, respiratory rate (RR) of 8 breaths/min, and oxygen saturation of 90% on room air. Examination is significant for pinpoint pupils. There is no sign of trauma. He does not smell of alcohol, no needle track marks are evident, and there is no indication of an irritated or perforated nasal septum. The patient has several chewed-up pieces of plastic in his possession that resemble pharmacologic dermal patches.

1 On the basis of the preceding information, what can be the cause of this patient’s presentation?

The patient is likely intoxicated on a substance that is depressing his mental status and his cardiorespiratory status, and inducing pinpoint pupils. The substance was likely introduced into his bloodstream sublingually given the chewed-up dermal patches that were recovered. Given this presentation, the culprit is likely to be an opioid that is available in a transdermal form (e.g., fentanyl).

2 What is the mechanism of action of opioids?

There are four types of opioid receptors: μ, κ, σ, and δ. The μ-receptors in particular are concentrated in central and peripheral pain pathways and account for the analgesic effects of opioids. When opioids bind these receptors, the cell becomes hyperpolarized, and it becomes difficult to reach the firing threshold. As a result, release of neurotransmitters that are associated with the perception of pain (e.g., substance P) is hindered, and the painful stimulus is not conducted through the nervous system.

In addition to their analgesic effects, opioids also have anxiolytic effects. It is this ability to relieve anxiety and induce a state of euphoria that has led to the illicit use of opioids. Among the family of opioids, heroin ranks toward the top in terms of being able to cross the blood-brain barrier, possibly explaining its use as an illicit agent.

3 List a few members of the opioid family

See Table 23-1.

Table 23-1 Opioids

Agent	Description
Morphine	A natural substance
Codeine	A natural substance A fraction of the potency of morphine (less potential for abuse) Can be taken orally (a common ingredient in cough syrup for its antitussive properties)
Heroin	A derivative of morphine, but altered to increase potency threefold Eventually gets converted back to morphine while in the body Because heroin is lipid-soluble, it crosses the blood-brain barrier faster than morphine
Methadone	Synthetic
Meperidine	Synthetic
Fentanyl	Synthetic 80 times more potent than morphine

4 What are some signs/symptoms of opioid intoxication? Is it life-threatening?

See Table 23-2.

Table 23-2 Opioid Intoxication

Structure/System Affected	Manifestations
Eyes	Miosis (“pinpoint pupils”) due to stimulation of the parasympathetic outflow to the eye
Central nervous system	Confusion, obtundation, euphoria
Lungs	Central respiratory depression resulting in hypercapnic respiratory failure, which can be life-threatening
Intestines	Constipation

5 How can an opioid overdose be reversed?

Because opioid intoxication is life-threatening, cases of overdose need to be rapidly treated. To this end, naloxone is a competitive antagonist that quickly (in seconds to minutes) displaces opioids already bound to receptors. Note that the administration of naloxone may cause intense pain in opiate-dependent patients.

6 What is the difference between naloxone and naltrexone?

Naltrexone has a longer duration of action and is therefore better suited for long-term management of opioid dependence (rather than acute cases of intoxication, for which naloxone would be a better option). Because the euphoria associated with alcohol dependence is also related to stimulation of opioid receptors, naltrexone can be used to manage alcohol depen dence as well.

7 What role can methadone play in treating opioid dependence?

Methadone is a long-acting opioid that reduces the patient’s pain to a tolerable level so that he or she can function relatively normally. However, methadone does not cause the euphoric symptoms that drew the patient to opioids in the first place. The patient is then weaned off methadone slowly. Because the withdrawal symptoms of methadone are not as severe and take longer to develop compared with other opioids, the process is more tolerable.

8 What are signs/symptoms of opioid withdrawal?

Gooseflesh skin, abdominal pain, and diarrhea can all occur. Withdrawal is not life-threatening.

Summary Box: Opioids

Opioids bind μ-receptors that are located on the neuronal cell surface. This hyperpolarizes the cell and blunts its ability to conduct painful stimuli. In addition to their analgesic effects, opioids are also anxiolytics.

Some common opioids are morphine, codeine, heroin, methadone, meperidine, and fentanyl.

Signs and symptoms of opioid intoxication include miosis, obtundation, euphoria, respiratory depression, and constipation.

Opioid intoxication can be reversed with naloxone in an acute setting, whereas opioid dependence can be addressed with naltrexone and methadone.

Opioid intoxication is life-threatening, whereas withdrawal is not.

Case 23-3

A 22-year-old man with no prior medical history is brought to the emergency department after he had a seizure on the floor of his office nearly an hour ago. His coworkers describe him as a very energetic individual who regularly forgoes sleep in order to excel at his job. He is not taking any medications, and there is no recent history of head trauma. Examination reveals a diaphoretic and confused young man with a heart rate of 140 beats/min, dilated but reactive pupils, and an eroded nasal septum. No focal neurologic deficits or needle-track marks can be appreciated.

1 Given this clinical picture, what is the most likely explanation for this patient’s presentation?

This is a young man brought in because he had a seizure recently. His tachycardia, hyperthermia, dilated pupils (mydriasis), and perforated nasal septum suggest cocaine intoxication, likely by inhalation.

2 What is the mechanism of action of cocaine?

Cocaine acts both centrally and peripherally to block the reuptake of norepinephrine, serotonin, and dopamine. When this occurs centrally, the result is an increase in mental awareness, hallucinations, delusions, and paranoia. At high-enough doses, tremors, convulsions, and even death can result from these effects. When reuptake of these neurotransmitters is blocked peripherally, sympathomimetic effects (tachycardia, hypertension [HTN], and pupillary dilation) can occur as a result.

3 The net effects of cocaine on the body can mimic those of which other illicit drug?

It should be apparent that cocaine is a stimulant, similar to amphetamines.

4 What is the explanation for development of tolerance to cocaine use?

The euphoric effects of cocaine are due to prolongation of dopaminergic effects. Over the long term, however, dopamine levels become depleted, and the person craves more cocaine to achieve the same degree of euphoria (this phenomenon is called tolerance). Put another way, dopamine levels become depleted but the threshold at which dopamine causes euphoria remains the same. To reach that same threshold, more cocaine is needed to elicit dopamine release.

5 Aside from tolerance and dependence, what are some other adverse effects of cocaine?

Cocaine can cause cardiac arrhythmias (manage with propranolol) and seizures (manage with diazepam). As with use of other stimulants, cocaine use is followed by post-use “crash” in which the person is physically and emotionally depressed.

Amphetamines

6 How does the mechanism of action of amphetamines differ from that of cocaine?

As mentioned, amphetamines are stimulants, similar to cocaine. Unlike cocaine, however, instead of inhibiting reuptake of neurotransmitters, amphetamines induce release of catecholamines. Think of the two drugs as being analogous to filling a kitchen sink: the amount of water in the sink (i.e., the amount of the neurotransmitter in the synaptic cleft) can be increased in one of two ways: the drain can be plugged (similar to what cocaine does), or the faucet can be turned on high (what amphetamines do).

When amphetamines act centrally, the result is a release of dopamine. Dopamine increases mental awareness, while decreasing fatigue, appetite, and the need for sleep. Because of these effects, amphetamines can be used therapeutically to treat depression, an abnormally high appetite, and narcolepsy. Paradoxically, they can also be used to treat hyperactivity (attention-deficit/hyperactivity disorder [ADHD]) in children. When amphetamines act peripherally, the result is a release of norepinephrine that causes tachycardia, HTN, and pupillary dilation.

7 What are some adverse effects of amphetamines?

Through their effects on the central nervous system (CNS), amphetamines can cause insomnia, irritability, tremor, and panic. Long-term use can lead to development of psychosis (i.e., hallucinations, delusions, loose thought process) that resembles schizophrenia.

Through their peripheral effects, amphetamines can cause cardiac arrhythmias, HTN, headache, diaphoresis, anorexia, and diarrhea.

Lysergic Acid Diethylamide (LSD)

8 What is the mechanism of action of LSD and its effects on the body?

Lysergic acid diethylamide (LSD) is a serotonin agonist. It stimulates the sympathetic nervous system and causes tachycardia, HTN, pupillary dilation, and other similar effects. It also causes visual hallucinations of bright colors (in contrast with opioids, for which tactile hallucinations predominate). These hallucinations can be treated with antipsychotics (e.g., haloperidol).

Phencyclidine (PCP)

9 What is the mechanism of action of phencyclidine and its resultant effects on the body?

Phencyclidine (PCP) inhibits the reuptake of dopamine, serotonin, and norepinephrine. The result is a feeling of numbness, staggering gait, slurred speech, rigidity, and hostile behavior.

PCP derivatives have some clinical value. An example is ketamine, which is used to produce anesthesia without loss of consciousness. A major side effect of ketamine is hallucinations and bad dreams (after all, it is still a PCP derivative). Its use is not recommended in children.

Tetrahydrocannabinol (THC)

10 What is the mechanism of action of tetrahydrocannabinol and its resultant effects on the body?

Tetrahydrocannabinol (THC) is an ingredient in marijuana. Although its mechanism of action is unknown, it does cause a feeling of euphoria, drowsiness, xerostomia, visual hallucinations, conjunctival injection (red eyes), impaired judgment, and increase in appetite.

Summary Box: Cocaine, Amphetamines, and Other Illicit Drugs

Cocaine blocks the reuptake of norepinephrine, serotonin, and dopamine. This results in an increase in mental awareness, hallucinations, delusions, paranoia, tremors, convulsions, and even risk of death (typically from myocardial infarction or fatal cardiac dysrhythmia).

The effect of cocaine on the body is very similar to that of amphetamines. Instead of blocking reuptake, however, amphetamines induce the release of catecholamines.

Lysergic acid diethylamide (LSD) is a serotonin agonist that stimulates the sympathetic nervous system to cause tachycardia, hypertension, mydriasis, and visual hallucinations.

Phencyclidine (PCP) inhibits reuptake of serotonin and catecholamines, thus causing numbness, ataxia, slurred speech, and hostile behavior.

Tetrahydrocannabinol (THC) is a component of marijuana and is responsible for inducing euphoria, drowsiness, xerostomia, visual hallucinations, conjunctival injection, and increase in appetite.

Case 23-4

A 26-year-old woman with an unremarkable medical history is evaluated for a several-hour history of confusion, dizziness, blurred vision, dyspnea, and nausea/vomiting. These symptoms started this morning after she drank herbal tea that was prepared using leaves from a foxglove plant. Examination is significant for an irregular heart rate of 52 beats/min, confusion, and normally reactive pupils. An electrocardiogram (ECG) shows what is termed paroxysmal atrial tachycardia with a 2:1 atrioventricular (AV) heart block. Blood work shows a moderately elevated potassium level of 5.7 mEq/L.

1 Based on this presentation, what is the likely culprit?

This patient became acutely symptomatic after ingesting extracts from a foxglove plant. A reader who is familiar with the pharmaceutical uses of this plant can quickly infer that this is a case of digitalis toxicity. Even if the reader is unfamiliar with this use, physical examination of this patient nonetheless points to cardiac manifestations (bradyarrhythmia, heart block) and (hyperkalemia, both of which suggest digitalis toxicity).

Digitalis belongs to a class of drugs called cardiac glycosides. Because most members of this class are derived from the Digitalis lanata plant (foxglove), the class as a whole is sometimes referred to as digitalis glycosides. Included in this group are digitoxin and digoxin. In terms of their action, glycosides are considered ionotropes, which are drugs that increase cardiac contractility by increasing intracellular calcium.

Note: Because there is no sign of hemodynamic instability, and because the associated arrhythmia will likely resolve with supportive measures, there is no need to administer antiarrhythmics (e.g., lidocaine, atropine) at this point.

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Apr 7, 2017 | Posted by admin in NURSING | Comments Off

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