Pharmacology Flashcards
This woman most likely overdosed on what medication?
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).
What is the pathogenesis for Acetaminophen overdose?
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).
What is the mechanism of action of the antidote for Acetaminophen overdose?
N-acetylcysteine (NAC), the antidote, works via several pathways. NAC enhances the conjugation of NAPQI into nontoxic compound, in part by increasing glutathione.
Given the patient’s presentation, approximately how long ago was the overdose?
What histologic regions of the liver would be most affected in an Acetaminophen overdose?
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.
What is the most likely diagnosis, given the findings in Figure 4-3?
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.
Given her presentation, what medication is the patient likely to be taking?
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.
What is the appropriate management for this patient?
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.
What are the main differentials for white plaques in the oral cavity?
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.
What is the most likely diagnosis?
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.
What is the appropriate treatment for Alcohol withdrawal?
Alcohol withdrawal is treated with benzodiazepines, usually chlordiazepoxide, diazepam, or lorazepam.
Indications for Benzodiazepines other than alcohol withdrawal?
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.
How do benzodiazepines differ from barbiturates?
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.
Is there an antidote for benzodiazepine overdose or for barbiturate overdose?
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.
What is the time course of events that can occur in alcohol withdrawal?
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.
What class of drug has the patient recently started?
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.
What is the mechanism of action of Monoamine oxidase inhibitors (MAOIs)?
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.
What caused this patient’s symptoms?
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.
The drugs that could be used to increase this patient’s blood pressure act on what receptors?
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.
What other precautions should a patient be given when starting Monoamine oxidase inhibitors (MAOIs)?
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.
What type of drug was likely given? In what other locations can this subset of receptors be found?
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.
Stimulation of adrenergic receptors activates what second-messenger system?
What is the mechanism of action of the S subclass of G receptors?
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.
What other classes of receptors are linked to the S subclass of G receptors?
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.
What is the most likely diagnosis?
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.
What are two treatments for Organophosphate ingestion and their mechanisms of action?
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.
What is the most likely diagnosis? What other medications can cause a similar presentation?
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.
In which phase of testing is this drug?
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.
What characterizes the phase of testing that the drug has already been through?
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).
What is the most likely diagnosis?
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.
What is the most likely diagnosis?
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.
If a blood smear of a patient with lead posioning were examined microscopically, what signs would help confirm the diagnosis?
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.
Which drug, A or D, has a higher efficacy?
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).
Which drug is more potent?
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.
What type of antagonist is drug B?
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.
What type of antagonist is drug C?
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.
How can the effect of drug B be overcome?
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.
Is this substance being metabolized by first-order or zero-order kinetics?
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.
Why does the volume of distribution affect the half-life of a drug?
Why does the volume of distribution affect the half-life of a drug?
What is the half-life of this substance, and how does the half-life change if a dosage of 100 mg is administered?
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.
How would the therapeutic index of this drug be determined, and why is this important?
In what clinical settings are NMBDs used?
The NMBDs are used for muscle paralysis during surgery or mechanical ventilation.
