Pharmacology

Question 1

This woman most likely overdosed on what medication?

Answer 1

Acetaminophen accounts for more overdose deaths in the United States than any other drug. Anticonvulsant medications can increase the toxicity of acetaminophen (phenytoin and carbamazepine both induce the isoenzyme CYP2E1, which metabolizes acetaminophen into hepatotoxic metabolites).

Question 2

What is the pathogenesis for Acetaminophen overdose?

Answer 2

At therapeutic doses, a small quantity of acetaminophen is metabolized by hepatic cytochrome P450 into a hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI) (see Figure 4-1A). Glutathione rapidly conjugates with NAPQI to form nontoxic compounds. At toxic doses, glutathione storage is depleted and hepatic damage ensues (see Figure 4-1B).

Question 3

What is the mechanism of action of the antidote for Acetaminophen overdose?

Answer 3

N-acetylcysteine (NAC), the antidote, works via several pathways. NAC enhances the conjugation of NAPQI into nontoxic compound, in part by increasing glutathione.

Question 4

Given the patient’s presentation, approximately how long ago was the overdose?

Answer 4

Question 5

What histologic regions of the liver would be most affected in an Acetaminophen overdose?

Answer 5

The centrilobular zone (zone III—the area surrounding the central hepatic venule of a lobule, furthest from the branch of the hepatic vein; see Figure 4-2) is most involved because it has the highest concentration of CYP4502E1. Histologic recovery takes approximately 3 months.

Question 6

What is the most likely diagnosis, given the findings in Figure 4-3?

Answer 6

Figure 4-3 shows the characteristic whitish plaques of oral candidiasis (thrush) on the buccal mucosa. The lymphoreticular disorders in this patient suggest agranulocytosis. Nystatin “swish and swallow” is used to treat thrush.

Question 7

Given her presentation, what medication is the patient likely to be taking?

Answer 7

This patient is acutely psychotic and suffering from agranulocytosis (lack of granulocytes [neutrophils, eosinophils, and basophils]). Clozapine, an antipsychotic, causes agranulocytosis in 1%–2% of patients and will usually do so in the initial months of treatment.

Question 8

What is the appropriate management for this patient?

Answer 8

First, the medication causing neutropenia should be discontinued immediately, which should cause neutropenia to resolve within 1–3 weeks. Treatment may include granulocyte colony–stimulating factor, which has been shown to restore immune function in some neutropenic patients with serious infections.

Question 9

What are the main differentials for white plaques in the oral cavity?

Answer 9

Although thrush is the most common cause, oral leukoplakia and oral hairy leukoplakia (OHL) should also be considered. Oral leukoplakia is a precancerous lesion representing hyperplasia of squamous epithelium. OHL (which is not considered to be premalignant) is seen in HIV patients and is caused by the Epstein-Barr virus. It usually occurs on the lateral part of the tongue and, unlike thrush, cannot be scraped off.

Question 10

What is the most likely diagnosis?

Answer 10

The first step in reaching a diagnosis in this case is determining whether the patient’s presentation is due to substance abuse/withdrawal or to a psychiatric condition such as schizophrenia. The constellation of physical symptoms here suggests a sympathomimetic toxidrome. The specific sensation of feeling bugs crawling over him, called formication, is highly suggestive of alcohol withdrawal.

Question 11

What is the appropriate treatment for Alcohol withdrawal?

Answer 11

Alcohol withdrawal is treated with benzodiazepines, usually chlordiazepoxide, diazepam, or lorazepam.

Question 12

Indications for Benzodiazepines other than alcohol withdrawal?

Answer 12

Benzodiazepines have many indications, including anxiety, status epilepticus, night terrors, and somnambulism. Benzodiazepines act by increasing the frequency of the γ-aminobutyric acid (GABA)A chloride channel opening. GABAA is a ligand-gated chloride channel; GABAB is linked via G-proteins to potassium channels.

Question 13

How do benzodiazepines differ from barbiturates?

Answer 13

Barbiturates increase GABAA (see Figure 4-4) signaling by increasing the duration of chloride channel opening, which causes hyperpolarization. Barbiturates are contraindicated in porphyria and are used primarily for their sedative effects. Importantly, barbiturates have a greater risk of coma and respiratory depression than benzodiazepines. In clinical practice, benzodiazepines have largely replaced barbiturates.

Question 14

Is there an antidote for benzodiazepine overdose or for barbiturate overdose?

Answer 14

Benzodiazepine overdose can be reversed with flumazenil, a competitive antagonist at the GABA receptor. However, flumazenil is used only in a controlled setting due to the risk of unmasking seizures in benzodiazepine-naïve patients. Barbiturate overdose is more dangerous because there is no reversal agent. Therefore, symptomatic management and ventilator support are the only treatments for barbiturate overdose.

Question 15

What is the time course of events that can occur in alcohol withdrawal?

Answer 15

Symptoms of alcohol withdrawal often start 4–10 hours after alcohol cessation (when the blood alcohol concentration drops < 100 mg/dL) and can include symptoms of autonomic hyperactivity (increased respiratory rate, temperature, pulse, sweating), headache, tremors, agitation, and hallucinations. Severity of symptoms usually peak at day 2–3. The most concerning event of alcohol withdrawal is delirium tremens (DT), which is defined by hallucinations, disorientation, hypertension, tachycardia, and fever in the setting of alcohol withdrawal. DT is usually seen 2–4 days after the last drink and can cause life-threatening seizures.

Question 16

What class of drug has the patient recently started?

Answer 16

The signs described by the wife indicate atypical depression. Monoamine oxidase inhibitors (MAOIs) are frequently used to treat patients with atypical depression (but not those with typical depression), especially after other medications have failed.

Question 17

What is the mechanism of action of Monoamine oxidase inhibitors (MAOIs)?

Answer 17

MAOIs (phenelzine, tranylcypromine, selegiline) increase the availability of monoamines such as epinephrine, norepinephrine, and dopamine (MAOA affects all of these, whereas MAOB affects only dopamine). They do so by inhibiting MAO, which breaks down such compounds.

Question 18

What caused this patient’s symptoms?

Answer 18

Symptoms of dizziness and lightheadedness have a wide differential, but given this patient’s blood pressure and MAOI use, they are likely due to hypotension. Orthostatic hypotension is a common side effect of MAOIs, although the mechanism is not completely understood.

Question 19

The drugs that could be used to increase this patient’s blood pressure act on what receptors?

Answer 19

For a hypotensive patient, activity should be increased on the α1-receptor. The α1-receptor is a G(Gq) protein–coupled receptor that vasoconstricts the arteries. Conversely, activity on the α2-receptor (also a G protein–coupled receptor, but Gi) leads to vasodilation. For this reason, midodrine is preferred to phenylephrine or epinephrine, as it is most selective for α1. In practice, the most commonly used first-line medication for chronic hypotension is fludrocortisone, which acts by increasing sensitivity of blood vessels to catecholamines and increasing norepinephrine release.

Question 20

What other precautions should a patient be given when starting Monoamine oxidase inhibitors (MAOIs)?

Answer 20

In addition to the risk of hypotension, paradoxically, various factors can cause a hypertensive crisis in patients taking MAOIs, including coadministration of a sympathomimetic (including over-the-counter drugs such as ephedrine) and ingestion of foods rich in tyramine, such as certain cheeses. In the latter case, when MAO is inhibited, excess tyramine is taken up by adrenergic neurons, which must then release norepinephrine, leading to acute hypertension.

Question 21

What type of drug was likely given? In what other locations can this subset of receptors be found?

Answer 21

Short-acting β2-adrenergic receptor agonists (β2-agonists) such as albuterol are a mainstay in treating acute asthma. β2-agonists such as albuterol cause bronchodilation. Other β2-agonists include terbutaline, metaproterenol, and ritodrine.

Question 22

Stimulation of adrenergic receptors activates what second-messenger system?

Answer 22

Question 23

What is the mechanism of action of the S subclass of G receptors?

Answer 23

The Gs protein activates adenyl cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate, which in turn activates protein kinase A (PKA). In uterine myometrial cells, the activated PKA phosphorylates other proteins; this reduces intracellular calcium concentration, decreases activity of myosin light-chain kinase, and diminishes contractility of the uterine muscle cells.

Question 24

What other classes of receptors are linked to the S subclass of G receptors?

Answer 24

Other receptors linked to Gs include β1, D1, H2, and V2 receptors. Activation of any of these receptors leads to activation of Gs and adenyl cyclase.

Question 25

What is the most likely diagnosis?

Answer 25

Organophosphate ingestion. Organophosphates are cholinesterase suicide inhibitors, which cause an excess of acetylcholine (ACh) in the synapse. Organophosphates are commonly found in insecticides and can be ingested, inhaled, or cutaneously absorbed. Organophosphorus nerve agents are a known deadly chemical weapon and have been used to this end in the past—most notably in the 1995 attack on the Tokyo subway system by a religious cult using sarin.

Question 26

What symptoms can be expected in parasympathetic excess?

Answer 26

Symptoms resulting from parasympathetic excess can be summarized by the mnemonic DUMBBELSS: Diarrhea, Urinary incontinence, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscle and central nervous system, Lacrimation, Sweating, and Salivation. Central nervous system effects, such as confusion or slurred speech, are common.

Question 27

What are two treatments for Organophosphate ingestion and their mechanisms of action?

Answer 27

Atropine and pralidoxime (2-PAM) can reverse organophosphate poisoning. Atropine works by inhibiting muscarinic receptors (it has little effect at nicotinic receptors), thereby decreasing the effect of acetylcholine. 2-PAM works by inhibiting the binding of organophosphates to acetylcholinesterase. A schematic of neuromuscular blockade is shown in Figure 4-5.

Question 28

What adverse events are associated with Atropine treatment?

Answer 28

Atropine poisoning can lead to sympathomimetic adverse effects, including pupillary dilation, decreased gastrointestinal motility, increased body temperature, rapid heart rate, dry mouth, dry skin, constipation, and disorientation.

Question 29

What is the most likely diagnosis? What other medications can cause a similar presentation?

Answer 29

Rash, arthralgias, and antihistone antibodies suggest drug-induced systemic lupus erythematosus (SLE). Hydralazine is the causative drug in this case. Positive ANA is nonspecific, as there are many conditions, mostly infectious and autoimmune, that show positive ANA. However, the sensitivity of ANA for drug- induced SLE is 100%, so if ANA is negative, drug-induced SLE can be ruled out. Drugs known to induce SLE include procainamide, chlorpromazine, isoniazid, methyldopa, minocycline, penicillamine, and diltiazem.

Question 30

How do spontaneous forms of SLE differ from drug-induced forms?

Answer 30

Whereas hematologic abnormalities (anemias) are common in spontaneous SLE, they are unusual in drug- induced SLE. Also, rash is common in spontaneous SLE but is not frequent in drug-induced SLE.

Question 31

In which phase of testing is this drug?

Answer 31

The drug is in phase 2 of clinical testing, which entails the enrollment of a small group of patients, usually 100–300, into a trial. The trial, usually single-blinded, compares the new product to placebo as well as to an older drug that has already been proven effective.

Question 32

What characterizes the phase of testing that the drug has already been through?

Answer 32

The first step of clinical testing, phase 1, involves nonblinded testing on a small group (20–30) of healthy volunteers (see Figure 4-6). The goals in this phase are to determine if the response of humans to the drug is significantly different from the response of animals (before reaching clinical trials, a drug is extensively tested on animals for toxicity, carcinogenicity, etc.) and whether the effects of the drug are a function of dose (Figure 4-7).

Question 33

What happens in Phase 3 of drug testing?

Answer 33

Phase 3 testing involves evaluating the drug in a trial of a large group of patients (hundreds to thousands). The trial is usually double-blinded and evaluates the overall benefit-risk relationship to provide an adequate basis for physician labeling. If phase 3 testing is successful, the company will submit a New Drug Application to the Food and Drug Administration (FDA), which will include preclinical and clinical data. The FDA will then review this material and if the drug is approved for market, phase 4 testing starts. Phase 4 entails monitoring the drug as it is used in real conditions with large numbers of patients. This phase is important for discovering low-incidence toxicities that would not be uncovered in clinical trials. Phase 4 is the last phase of testing and continues indefinitely.

Question 34

What is a double-blinded study and why is it the most powerful type of research study?

Answer 34

In a double-blinded study, neither the subjects nor researchers know who is receiving the experimental drug and who is receiving placebo. Masking this information eliminates both observer and subject bias, which is why it is considered to be the best format for obtaining objective data.

Question 35

If this drug passes all phases of testing, when will a generic form become available?

Answer 35

A drug patent is typically issued for 20 years, after which time generic forms become available. However, the evaluation of the application by the FDA may take several years. Up to 5 years of the review time may be added back to the patent.

Question 36

What is the most likely diagnosis?

Answer 36

This could be either methanol or ethylene glycol poisoning, as both are found in antifreeze. However, the most likely diagnosis is ethylene glycol poisoning because methanol poisoning leads to ophthalmologic abnormalities such as afferent papillary defect and mydriasis. Ethylene glycol has a mildly sweet taste, which allows unintentional consumption by both children and adults, often in large quantities. Although ethylene glycol and methanol themselves are mostly nontoxic, accumulation of the metabolites (see Figure 4-8) is toxic.

Question 37

Without treatment, what symptoms would likely occur in methanol or ethylene glycol poisoning?

Answer 37

Ethylene glycol poisoning typically follows three stages. Stage 1 is pure intoxication with dizziness and slurred speech. Stage 2 comprises metabolic acidosis, tachycardia, and hypertension due to the toxic metabolite oxalic acid that is formed by metabolism of ethylene glycol by alcohol dehydrogenase. Stage 3 is often kidney failure.

Question 38

Why might kidney failure occur if a patient with Ethylene glycol poisoning is not treated?

Answer 38

Alcohol dehydrogenase is an endogenous enzyme that can metabolize ethanol, methanol, and ethylene glycol to eventually produce acetate, formaldehyde, and oxalate, respectively. The calcium in the kidney can combine with the oxalate to produce calcium oxalate crystals in the kidney, which causes renal failure.

Question 39

What is the treatment for toxic alcohol poisoning?

Answer 39

There are three possible treatments: 1. Fomepizole (Figure 4-9) is a competitive inhibitor of alcohol dehydrogenase. It blocks metabolism of ethylene glycol (or methanol), allowing it to be excreted in a harmless premetabolic stage. 2. An intravenous infusion of alcohol can be administered if fomepizole is not available. 3. Hemodialysis may be needed in patients that present with ethylene glycol toxicity late enough that their kidneys are severely affected. Of note, gastric lavage and emesis are no longer recommended methods of decontamination for any ingestion.

Question 40

What is the most likely diagnosis?

Answer 40

Subacute lead poisoning. In terms of presentation, abdominal colic is one of the hallmark symptoms of lead poisoning and can be followed by bloody diarrhea.

Question 41

If a blood smear of a patient with lead posioning were examined microscopically, what signs would help confirm the diagnosis?

Answer 41

Basophilic stippling of erythrocytes (see Figure 4-10) is commonly seen with lead poisoning. In addition, lead poisoning may present in the form of sideroblastic anemia. Sideroblastic anemias impair heme synthesis in developing RBCs, leading to impaired hemoglobin production and the formation of hypochromic and microcytic cells. In addition to lead poisoning, sideroblastic anemia can also be seen in alcoholism, prescription drug use (isoniazid, chloramphenicol), copper deficiency, refractory anemia, and some rare congenital diseases.

Question 42

What neurologic complications can occur in lead posioning?

Answer 42

Lead poisoning may present with a range of neurological symptoms, including hearing loss, developmental delay, and neuropathies. Two neuropathies often seen are wrist and foot drop, reflecting radial and common peroneal neuropathies, respectively. Lead poisoning may also cause encephalopathy.

Question 43

What radiographic findings might be present in chronic forms of paediatric lead poisoning?

Answer 43

In chronic pediatric lead poisoning, lead deposits can form in the epiphyses of long bones.

Question 44

How does treatment differ between children and adults with lead posioning?

Answer 44

In both children and adults, further prevention of lead exposure is the most important treatment. Succimer is a water-soluble analog of dimercaprol and can be used to treat children with lead poisoning as it increases the excretion of lead. For adults, the first-line treatment is ethylenediaminetetraacetic acid (EDTA) and dimercaprol.

Question 45

Which drug, A or D, has a higher efficacy?

Answer 45

Efficacy refers to the maximal response a drug elicits. Thus, drug A has a higher efficacy, since it produces a higher maximal response (Figure 4-11).

Question 46

Which drug is more potent?

Answer 46

Drug D is more potent (Figure 4-11). Potency is the amount of drug required for a specified response. Typically, potency is measured by the ED50, or the dose that gives 50% of the maximal response. The lower the ED50, the more potent the drug.

Question 47

What type of antagonist is drug B?

Answer 47

Drug B is a competitive antagonist—that is, it binds to the same site on the receptor as does drug A (Figure 4-12A). It does not affect the maximal response the agonist can elicit, but it does increase the ED50, requiring more agonist to achieve the same response, thus decreasing potency.

Question 48

What type of antagonist is drug C?

Answer 48

Drug C is a noncompetitive antagonist (Figure 4-12B). These drugs act by binding irreversibly to a site on the receptor distinct from the site of agonist binding. Noncompetitive antagonists do not affect the ED50 but do affect the maximal response (decrease efficacy) that the agonist can elicit.

Question 49

How can the effect of drug B be overcome?

Answer 49

Since competitive antagonists bind at the same site as the agonist, their action can be overcome by increasing agonist dose. If enough agonist is present, the same efficacy can be reached that the agonist had in the absence of an antagonist.

Question 50

Is this substance being metabolized by first-order or zero-order kinetics?

Answer 50

The shape of the graph shows that the drug is being eliminated by first-order kinetics (see Figure 4-14A), meaning that a constant fraction of the substance is eliminated per unit of time. As a result, the rate of elimination is proportional to the concentration of the drug. By contrast, zero-order kinetics (see Figure 4-14B) results in a constant amount of the substance being cleared per unit of time; the elimination rate is constant regardless of the plasma concentration (Cp), and the plot of Cp vs. time is a straight line.

Question 51

Which drugs follow zero-order kinetics?

Answer 51

Nearly all medications follow first-order kinetics. Three notable exceptions are aspirin, phenytoin, and alcohol.

Question 52

Which drugs follow zero-order kinetics?

Answer 52

Nearly all medications follow first-order kinetics. Three notable exceptions are aspirin, phenytoin, and alcohol.

Question 53

Why does the volume of distribution affect the half-life of a drug?

Answer 53

Question 54

Why does the volume of distribution affect the half-life of a drug?

Answer 54

Question 55

What is the half-life of this substance, and how does the half-life change if a dosage of 100 mg is administered?

Answer 55

Half-life (t1/2) is the time necessary to decrease the Cp of the drug by 50%. As shown in Figure 4-13, at 5 hours the Cp of the drug is half of the initial concentration, and thus t1/2 is 5 hours. Half-life does not depend on the size of the dose being eliminated.

Question 56

How would the therapeutic index of this drug be determined, and why is this important?

Answer 56

Question 57

In what clinical settings are NMBDs used?

Answer 57

The NMBDs are used for muscle paralysis during surgery or mechanical ventilation.

Question 58

What are some examples of neuromuscular blocking (NMBD) drugs?

Answer 58

Examples of these agents include succinylcholine, tubocurarine, and most drugs that end in “–curium” (eg, atracurium) or “–curonium” (eg, rocuronium).

Question 59

For what type of receptors is neuromuscular blocking drugs selective for?

Answer 59

Neuromuscular agents are specific for the motor nicotinic acetylcholine receptors present at the neuromuscular junction.

Question 60

What are the two types of neuromuscular blocking drugs?

Answer 60

There are depolarizing and nondepolarizing (of which succinylcholine is the only one commonly used) blocking agents.

Question 61

What is the mechanism of action of depolarizing blocking agents?

Answer 61

Depolarizing agents such as succinylcholine act in two phases. Phase I consists of active depolarization of sodium channels, which can be potentiated by cholinesterase inhibitors. Phase II keeps sodium channels stuck in their depolarized state. Phase II can be reversed with cholinesterase inhibitors.

Question 62

What is the mechanism of action of nondepolarizing blocking agents?

Answer 62

These drugs are mostly close relatives of tubocurarine. They act by competing with acetylcholine for nicotinic motor receptors. These drugs can be reversed using cholinesterase inhibitors.

Question 63

What is an important potential risk of using succinylcholine?

Answer 63

The combination of inhalational anesthetics and succinylcholine may result in malignant hyperthermia (sympathetic hyperactivity, muscular rigidity, acidosis) due to the prevention of calcium release from the sarcoplasmic reticulum of skeletal muscle. This condition can be treated with dantrolene.