Clinical Pharmacology/Clinical Oncology Flashcards

1
Q

Which one of the following medications will not cause serotonin syndrome if given along with selective serotonin re-uptake inhibitors (SSRIs)?

A. Tryptophan.
B. Amitriptyline.
C. Moclobemide.
D. Chlorpromazine.
E. Lithium.

A

D. Chlorpromazine

Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. It is seen with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning.

The clinical features of serotonin syndrome include:

  • Cognitive features: confusion, agitation, hypomania, hyperactivity, restlessness
  • Autonomic features: hyperthermia, sweating, tachycardia, hypertension, mydriasis, flushing, shivering
  • Neuromuscular features: clonus (spontaneous/inducible/ocular), hyperreflexia, hypertonia, ataxia, tremor

See photo below.

Chlorpromazine is a HT2 receptor antagonist used for treatment of serotonin syndrome. It is does not contribute to development of serotonin syndrome.

TOPIC REVIEW

Management of serotonin syndrome

Meticulous supportive care is the mainstay of therapy:

  • All serotonergic drugs should be stopped at once and care should be taken that no other precipitant be inadvertently administered.
  • Those with moderate to severe serotonergic symptoms should be admitted to the hospital. Those with hyperthermia require admission to the ICU.
  • Intravenous hydration to establish a reassuring urine output
  • If the patient is hyperthermic, the temperature should aggressively be lowered using cool water sprays, ice packs, and even paralysis and ventilation
  • Benzodiazepines may be used to control seizures and muscle hyperactivity
  • Specific treatment of hypertension is usually not required

Specific therapy

The serotonin antagonist cyproheptadine is the first-line medication for treatment of moderate to severe serotonin syndrome: an initial does of 4-8mg is given orally. This can be repeated in 2 hours if needed.

Cyproheptadine should be discontinued if there is no response after a total dose of 16mg. If there is a response, it may be continued in divided doses up to 32 mg/day (e.g. up to 8 mg, 6-hourly)

Other suggested medications are chlorpromazine and propranolol, but these drugs are associated with more adverse effects. If sedation is desired, chlorpromazine may be more appropriate to use rather than other routine sedative agents. Since it can cause hypotension, patients must receive sufficient volume loading.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

A 68-year old woman presents with migratory superficial thrombophlebitis and recurrent deep vein thrombosis (DVT) of his lower extremities. Which one of the following malignancies is most likely to be the cause?

A. Ovarian cancer.
B. Endometrial cancer.
C. Gastric cancer.
D. Pancreatic cancer.
E. Lung cancer.

A

D. Pancreatic cancer

Trousseau’s syndrome is a variant of venous thrombosis characterized by recurrent and migratory pattern of superficial thrombophlebitis, frequently in unusual sites such as the arm or chest. Patients Trousseau’s syndrome usually have an occult tumor (usually adenocarcinoma) which is not always detectable at the time of presentation, and might be present months to years before the malignancy is clinically evident.

The most common cancers associated with Trousseau syndrome and the prevalence of the sydnrome in each are as follows:

  • Pancreatic cancer – 24%
  • Lung cancer – 20%
  • Prostatic cancer – 13%
  • Gastric cancer – 12%
  • Acute leukemia – 9%
  • Colon cancer – 5%

Of the given options, pancreatic cancer has the highest association with Trousseau sign.

Trousseau syndrome is extremely rare in ovarian and endometrial cancer; however, these cancers can result in hypercoagulable states and recurrent episodes of DVT.

References:

  • Medscape - What are the signs and symptoms of migratory thrombophlebitis
  • PubMed - Thrombophlebitis migrans in a man with pancreatic adenocarcinoma: a case report
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

A 56-year-old man is admitted to the hospital for treatment of methicillin resistant staphylococcus aureus (MRSA) pneumonia. He is a known case of hypertension and on amilodipine and hydrochlorothiazide. You decide to start him on vancomycin. Twenty minutes after intravenous infusion of vancomycin is started, he develops a generalized erythematous rash all over his body. There is no respiratory symptom and the vitals are within the normal range. Which one of the following is the most likely cause of this presentation?

A. Idiosyncratic drug reaction.
B. Toxic shock syndrome.
C. Stevens-Johnson syndrome.
D. Anaphylaxis.
E. Fixed drug eruption.

A

A. Idiosyncratic drug reaction

Vancomycin can cause various hypersensitivity reactions, with Red man syndrome (RMS) being the most commonly reported. RMS is not a true allergy but an idiosyncratic reaction that can occur even during the first administration of vancomycin. It is characterized by flushing, erythema (redness), and itching, often affecting the upper body, neck, and face more than the lower body. Additionally, RMS may include chest and back pain, muscle spasms, difficulty breathing, and low blood pressure. While RMS is usually not life-threatening, severe cases can lead to serious cardiovascular issues, including cardiac arrest.

Key points about vancomycin reactions:
- Red Man Syndrome (RMS): Flushing, redness, and itching, primarily in the upper body. Can include chest pain and muscle spasms. Rarely life-threatening but severe cases can be serious.
- Anaphylaxis: Rare, IgE-mediated reaction requiring previous exposure. Symptoms can overlap with severe RMS but often includes wheezing and respiratory distress.
- Other reactions: Maculopapular eruptions, drug-induced fever, nephrotoxicity (especially with other nephrotoxic drugs), and rare hematologic issues like neutropenia and thrombocytopenia.

Drug Interactions: Caution with drugs like opiates and contrast media, which can increase vancomycin’s adverse effects. Dihydropyridine calcium channel blockers like nifedipine may also interact.

Monitoring: Regular monitoring for adverse effects, including kidney function and blood counts, especially during prolonged use.

Understanding these reactions helps in prompt recognition and management of vancomycin-related adverse events.

Vancomycin can cause several different types of hypersensitivity reactions, ranging from localized skin reactions to generalized cardiovascular collapse. Red man syndrome (RMS) is the most reported adverse reaction. This patient’s presentation is more consistent with Red man syndrome (RMS).

RMS, also called “red neck syndrome” is an idiosyncratic rate-dependent infusion reaction, not a true allergic reaction. The etiology is unknown (idiopathic) but it is not thought to involve drug-specific antibodies and, in contrast to allergic reactions, may develop with first time administration of vancomycin.

RMS is characterized by flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body. Pains and muscle spasms in the back and chest, dyspnea, and hypotension may also occur. RMS is rarely life-threatening; however, severe cardiovascular toxicity and even cardiac arrest can occur.

IgE-mediated anaphylaxis can present with symptoms similar to those of severe RMS. Unlike RMS, an IgE-mediated reaction to vancomycin does not occur with initial administration. Such reaction requires previous sensitization. Severe RMS and anaphylaxis can present with similar signs and symptoms but wheezing and respiratory distress are more common in anaphylaxis. On the other hand, chest pain is more common in RMS than anaphylaxis.

NOTE: Since it may not be possible to distinguish anaphylaxis from severe RMS based upon clinical presentation, the patient should be assumed to have anaphylaxis and treated promptly if in doubt.

Concomitant use of some drugs that are capable of inducing histamine release may increase the risk of adverse drug reaction associated with vancomycin. Opiates and contrast media are the most implicated medications. Some studies suggest that the dihydropyridine calcium channel blockers nifedipine may increase the risk of vancomycin-related adverse drug interaction. No significant interaction with amilodipine has been reported thus far.

Other possible adverse reactions associated with vancomycin include:

  • Maculopapular eruptions
  • Vancomycin-related linear IgA bullous dermartosis
  • Leukocytosis, eosinophilia, neutropenia, and immune thrombocytopenia - neutropenia tends to occur with longer courses of therapy. Weekly monitoring of the white blood cell count and differential leukocyte counts during prolonged administration is indicated
  • Drug-induced fever - uncommonly, vancomycin been implicated as a cause of drug-induced fever
  • Nephrotoxicity, especially in patients receiving nephrotoxic drugs (e.g. aminoglycosides), or who have renal insufficiency or altered hemodynamics. Interstitial nephritis is seen at occasions.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC270616/

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

During hospital stay of a 62-year-old woman, she develops pneumonia. Since methicillin resistant staphylococcus aureus (MRSA) is highly suspected, intravenous vancomycin is started. After 20 minutes of infusion, the patient develops a generalized pruritic erythematous rash all over her face, torso and arms. She also complains of chest tightness. The infusion is stopped immediately, and within few minutes the rash resolves. A quick drug history reveals that he is on aspirin and amilodipine for treatment of her hypertension. Which one of the following is correct regarding continuation of vancomycin?

A. Change the concentration of vancomycin.
B. Restart the infusion at a slower rate.
C. Switch to another antibiotic.
D. Never give her vancomycin again.
E. Give vancomycin along with prednisolone.

A

B. Restart the infusion at a slower rate.

Vancomycin can cause several different types of hypersensitivity reactions, ranging from localized skin reactions to generalized cardiovascular collapse. Red man syndrome (RMS) is the most reported adverse reaction.

RMS, also called “red neck syndrome” is a rate-dependent infusion reaction, not a true allergic reaction. The etiology is unknown but it does not involve drug-specific antibodies and, in contrast to allergic reactions, may develop with the first administration of vancomycin.

RMS is characterized by flushing, erythema, and pruritus, usually affecting the upper body, neck, and face more than the lower body. Pains and muscle spasms in the back and chest, dyspnea, and hypotension may also occur. Chest pain and chest tightness are other reprted clinical features. RMS is rarely life-threatening; however, severe cardiovascular toxicity and even cardiac arrest can occur.

IgE-mediated anaphylaxis can present with symptoms similar those of severe RMS. Unlike RMS, an IgE-mediated reaction to vancomycin does not occur with first administration. However, there may be some characteristics distinguishing features. While wheezing, respiratory, and angioedema are more common in anaphylaxis, chest pain or a sense of chest tightness is seen more frequently in RMS.

Since it may not be possible to distinguish anaphylaxis from severe RMS based on clinical presentation, the patient should be assumed to have anaphylaxis and treated promptly if in doubt.

Concomitant use of some drugs associated with histamine release may increase the risk of vancomycin adverse reactions. Opiates and contrast media are the most implicated medications. Some studies suggest that the dihydropyridine calcium channel blockers – nifedipine may increase the risk of vancomycin-related adverse drug interaction.

Management of RMS is as follows:
For mild to moderate reactions, in which the patient is uncomfortable due to flushing or pruritus, but without hemodynamic instability, chest pain or muscle spasms, the infusion should be interrupted and patient be treated with diphenhydramine (50 mg orally or intravenously) and ranitidine (50 mg intravenously). Symptoms usually subside promptly. The infusion can then be restarted at one-half of the initial rate or
10 mg/min, whichever is slower.

For severe reactions associated with muscle spasms, chest pain, or hypotension, the infusion should be interrupted and the patient be treated with diphenhydramine (50 mg intravenously) and ranitidine (50 mg intravenously), and intravenous fluids if there is hypotension. Once symptoms have resolved, the infusion can be restarted, and given over 4 or more hours. For future administration in such patients, premedication with antihistamines before each dose and infusion over 4 hours is recommended.

If the reaction to vancomycin is anaphylaxis type, immediate treatment would be intramuscular adrenaline. Vancomycin should never be given again, unless desensitization is performed. Hives, laryngeal edema, and wheezing are suggestive of anaphylaxis.

This patient has typical presentation of RMS . Since chest tightness is present, the management would be restarting the infusion at a slower rate (over 4 hours) as well as premedication with histamine (and ranitidine).

Unlike antihistamines, addition of prednisolone to vancomycin has not shown to decrease the risk of recurrence of RMS.

Vancomycin can cause Red Man Syndrome (RMS), a type of infusion reaction that is not an allergic response but rather a rate-dependent reaction. Here’s a simplified explanation:

  • Characteristics: RMS presents with flushing, redness (erythema), and itching (pruritus), typically affecting the upper body, neck, and face more than the lower body. It can also involve chest pain, muscle spasms, dyspnea (difficulty breathing), and low blood pressure (hypotension).
  • Severity: While RMS is usually not life-threatening, severe cases can lead to serious cardiovascular issues, including cardiac arrest.
  • Differentiation from Anaphylaxis: RMS can mimic anaphylaxis but is distinct because it can occur with the first dose of vancomycin and does not involve allergic antibodies (IgE). Anaphylaxis, in contrast, typically involves more respiratory symptoms like wheezing and angioedema (swelling).
  • Management: For mild to moderate RMS, treatment involves stopping the vancomycin infusion, administering diphenhydramine and ranitidine to relieve symptoms, and restarting the infusion at a slower rate. Severe cases may require intravenous fluids and cautious reintroduction of vancomycin over a longer period.
  • Prevention: Patients who experience severe RMS may benefit from premedication with antihistamines before future doses of vancomycin.

Understanding these points helps in managing and differentiating RMS from other adverse reactions to vancomycin effectively.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Catherine, 76 years old, is rushed to the Emergency Department of the local hospital you work at after she was found drowsy. She has end- stage ovarian cancer and is on methadone, codeine, paracetamol, naproxen, and diazepam for pain control. On her way to the hospital, she was given naloxone 0.4 mg intravenously because she has pinpoint pupils. On examination, you notice that her pupils are still pin-point sized, but she is less drowsy and able to communicate. The first thing she says to you is that she is still in severe pain. Which one of the following would be the most appropriate next step in management?

A. Give her naproxen.
B. Give her another dose of naloxone.
C. Give her diazepam.
D. Give her more methadone for adequate pain control.
E. Give her morphine, intravenously.

A

B. Give her another dose of naloxone.

With methadone and codeine on her drug list, opiate overdose is the cause of her drowsiness and pin-point pupils until proven otherwise. She has been given naloxone by paramedics in the ambulance, but her pupils are still pin-point, and she is still drowsy. These are pointers towards the fact that opiate toxicity is not still fully reversed. In such situations, repeated doses of naloxone are required as the most appropriate next step in management.

(Option A) It is unlikely that naproxen helps with pain control in a patient who has taken opiates in excess doses. Furthermore, reversal of opiate overdose is the main and most important objective for now. Efficient pain control may be carefully and judiciously planned for this patient once she is out of this emergency.

(Option C) Diazepam can lead to more CNS depression and drowsiness; moreover, it may suppress the respiratory drive in a patient who is already at increased risk of respiratory suppression and apnea due to opiate overdose.

(Options D and E) Giving a patient overdosed with opioids, more doses of opiates of any kind is not an appropriate option, as this deteriorates the patient’s condition.

Ref: Medscape - Opioid Toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

A 16-year-old girl, who is a known case of epilepsy for 5 years, has been started on sodium valproate and lamotrigine 4 weeks ago after her previous medications failed to control her seizures. She also has the history of recurrent urinary tract infections (UTI) with last episode
6 weeks ago for which she received amoxicillin. Today, she has presented with a maculopapular rash and a fever of 38°C. Which one of the following is the most likely cause of her presentation?

A. Adverse drug reaction to sodium valproate.
B. Adverse drug reaction to lamotrigine.
C. Adverse drug reaction to amoxicillin.
D. Septicemia.
E. Drug interaction between lamotrigine and sodium valproate.

A

B. Adverse drug reaction to lamotrigine.

Lamotrigine is a medication commonly used for epilepsy and bipolar disorder. It can cause rashes, ranging from mild to severe, potentially leading to life-threatening conditions.

  1. Timing: Rash usually appears between 5 days and 8 weeks after starting lamotrigine.
  2. Mild Rash:
    • Maculopapular (red spots or bumps)
    • Non-coalescing (do not merge together)
    • Non-tender, possibly itchy
    • No systemic symptoms (e.g., fever, malaise)
  3. Severe Rash:
    • Morbilliform rash (measles-like, red and blotchy)
    • Can progress to widespread, infiltrated erythema (redness)
    • May be tender, with follicular accentuation (hair follicles raised)
    • Associated with serious conditions like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or DRESS (drug reaction with eosinophilia and systemic symptoms)
  • Immediate Action: Stop lamotrigine at the first sign of a rash.
  • Evaluation: Assess for systemic symptoms and complications.
  • Sodium Valproate: Rarely causes rashes.
  • Amoxicillin: Common cause of allergic reactions, but unlikely if the medication has already been discontinued.
  • Septicaemia: Would likely present with higher fever and systemic illness.
  • Drug Interaction: Rash from lamotrigine can be exacerbated by sodium valproate but is primarily due to lamotrigine itself.
  • Characteristics:
    • Long latency (2-8 weeks post-exposure)
    • Persistent and relapsing course despite stopping the drug
    • Often linked with reactivation of latent herpes viruses
  • Common Culprits:
    • Anticonvulsants: Carbamazepine, Lamotrigine, Phenytoin, Phenobarbital
    • Others: Allopurinol, Sulfonamides (e.g., sulfasalazine), Dapsone, Minocycline, Vancomycin
  • Symptoms:
    • Fever (38-40°C)
    • Malaise
    • Lymphadenopathy (swollen, tender lymph nodes)
    • Internal organ involvement (e.g., liver, kidneys, lungs, heart, GI tract, pancreas, thyroid, brain, muscles, peripheral nerves, eyes)
  • Liver (60-80%)
  • Kidneys (10-30%)
  • Lungs
  • Heart (eosinophilic myocarditis, pericarditis)
  • Gastrointestinal Tract (diarrhea, mucosal erosions, bleeding)
  • Pancreas (pancreatitis)
  • Thyroid (autoimmune thyroiditis)
  • Brain (encephalitis, meningitis)
  • Muscles (myositis)
  • Peripheral Nerves (polyneuritis)
  • Eyes (uveitis)
  • Adverse reaction to lamotrigine: Rash typically appears within 5 days to 8 weeks of starting the drug. Severe cases can lead to life-threatening conditions like SJS, TEN, or DRESS.
  • Management: Stop the drug immediately and evaluate for systemic involvement.
  • DRESS Syndrome: Look for fever, malaise, lymphadenopathy, and involvement of internal organs. Commonly caused by anticonvulsants and other specific drugs.

To date, medications have been the most common cause of adverse allergic reactions. Allergic reactions can vary from immediate- to late- onset ,and from a not-clinically-significant rash to potentially life-threatening complications and systemic involvement. Lamotrigine, on the other hand, is well known for causing rash as a less frequent adverse effect. Simultaneous use of lamotrigine and sodium valproate has been associated with the higher chances of rash development.

Rash as an adverse effect of lamotrigine occurs between 5 days and 8 weeks (2 months) of taking lamotrigine. The rash might be maculopapular that often do not coalesce. Lesions are not tender on palpation but may be pruritic. The rash is not significant if there are no associated systemic symptoms such as fever, malaise, etc either before the appearance of the rash or contemporaneously.

There is also a more serious, but rarer form of rash that starts as a morbiliform rash progressing more or less rapidly to a diffuse confluent, and infiltrated erythema with follicular accentuation (hair follicles are raised and bumpy). This rash of lamotrigine is often associated with complications such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS).

On the sight of any rash while the patient is on lamotrigine, the drug should be immediately stopped, and careful evaluation performed.

(Option A) Sodium valproate has many potential adverse effects, but rash has been a very rare finding as an adverse reaction associated with this drug. Direct association of the rash and sodium valproate, although not impossible, seems very unlikely. There have been only few reports about such association.

(Option C) Amoxicillin and other penicillins are among the most common causes of allergic drug reactions while the patient is taking them. This patient has completed a course of amoxicillin for her UTI. She is not on the medication now; hence amoxicillin is not likely to be the cause of her presentation.

(Option D) There is no clue in history suggesting septicaemia as a cause to the rash; furthermore, with septicaemia a higher fever would be expected.

(Option E) Rash is not the result of interaction between lamotrigine and sodium valproate. It is more attributable to lamotrigine with enhancement by concomitant use of sodium valproate.

TOPIC REVIEW

DRESS is a rare, potentially life-threatening, drug-induced hypersensitivity reaction that includes rash, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and internal organ involvement (liver, kidney, lung, etc). DRESS is characterized by a long latency (2 to 8 weeks) between drug exposure and disease onset, a prolonged course with frequent relapses despite the discontinuation of the culprit drug, and frequent association with the reactivation of a latent human herpes virus infection.

The following medications are the most common causes of DRESS:

  • Carbamazepine
  • Lamotrigine
  • Phenytoin
  • Phenobarbital
  • Allopurinol
  • Other drugs less commonly associate with DRESS are sulfonamides (particularly sulfasalazine), dapsone, minocycline and vancomycin.

Systemic symptoms of DRESS are:

  • Fever (38-40°C)
  • Malaise
  • Lymphadenopathy (30-60% of patients) – slightly enlarged (1-2 cm) and tender nodes at several sites
  • Symptoms related to visceral involvement

At least one internal organ is involved in 90% of patients with DRESS.

Organs that can become involved in DRESS are:

  • Liver (60-80%)
  • Kidneys (10-30%)
  • Lungs
  • Heart (eosinophilic myocarditis, pericarditis)
  • Gastrointestinal tract (diarrhea, mucosal erosions, bleeding)
  • Pancreas (pancreatitis)
  • Thyroid (autoimmune thyroiditis, appearing often late, as a sequel of DRESS)
  • Brain (encephalitis, meningitis)
  • Muscle (myositis, increase in creatine kinase)
  • Peripheral nerves (polyneuritis)
  • Eye (uveitis)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Which one of the following medications can cause tachycardia?

A. Propranolol.
B. Verapamil.
C. Diltiazem.
D. Nifedipine.
E. Metoprolol.

A

D. Nifedipine.

Option A and E: Propranolol and metoprolol are beta blockers. Beta blockers, by inhibition of cardiac conductive system, result in bradycardia.

Option B and C: Verapamil and diltiazem are non-dihydropyridine calcium channel blockers (CCBs). Non-dihydropyridine CCBs has less effect on peripheral arteries and more on cardiac conductive system. They can cause myocardial depression and bradycardia.

Nifedipine is a dihydropyridine CCB. This group of CCBs has no clinically significant effect on the heart (i.e. myocardial depression and bradycardia), but significant effect on vessel wall and vasodilation. Vasodilation results in hypotension (the therapeutic effect). Excess vasodilation and hypotension, seen in overdose with dihydropyridine CCBs, can be followed by compensatory tachycardia.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

A 54-year-old man presents to your GP clinic with complaints of light-headedness and palpitation for 3 days. He is hypertensive and has been on nifedipine and hydrochlorothiazide for the past 5 years. Recently, he was diagnosed with generalized anxiety disorder and started on fluoxetine. On examination, he has a blood pressure of 90/60 mmHg, heart rate of 110 bpm, respiratory rate of 14 breaths per minute, and temperature of 37.5°C. The rest of the exam is inconclusive. An ECG is obtained, which shows sinus tachycardia with no other arrhythmias. Which one of the following is the most appropriate next step in management?

A. Stop nifedipine.
B. Stop fluoxetine.
C. Stop both.
D. Reduce fluoxetine.
E. Reduce nifedipine.

A

E. Reduce nifedipine.

The exam findings are hypotension and tachycardia which can be justified by increased plasma levels of nifedipine. Nifedipine is dihydropyridine calcium channel blocker (CCB)f. Dihydropyridine CCBs reduce the peripheral vascular resistance and by this decrease blood pressure. These drugs generally do not have clinically significant cardiac effects such as suppression of myocardium or cardiac conductive system.

SSRIs, such as fluoxetibe, can inhibit hepatic metabolism of CCBs and result in increased plasma levels of nifedipine leading to hypotension and compensatory tachycardia as seen in this patient.

Other adverse effects of CCBs such as headache, flushing, ankle edema, constipation, etc may be seen or worsen in this situation as well.

In such circumstances the dose of CCB should be reduced, or the drug temporarily stopped if the symptoms, particularly cardiovascular symptoms are profound.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

A 24-year-old woman has been started on an antipsychotic drug due to poorly-controlled schizophrenia 3 weeks ago. She has now presented with complaint of palpitations. Which one of the following drug is more likely to have been prescribed for her?

A. Clozapine.
B. Mirtazapine.
C. Olanzapine.
D. Quetiapine.
E. Venlafaxine.

A

A. Clozapine.

Clozapine is an effective antipsychotic for treatment of resistant schizophrenia, but is associated with serious adverse effects including sedation, postural hypotension, hypersalivation, severe constipation, dyslipidemia, myoclonus and epileptic seizures. Excessive weight gain and glucose intolerance may occur, precipitating type 2 diabetes.

The two serious adverse effects of neutropenia (2-3%), agranulocytosis (1%) are of significant concern as well. Tachycardia is another common side effect of clozapine, observed in 25% of patients. Arrhythmias may also occur. Moreover, a minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotic drugs, including ST segment depression and flattening or inversion of T-waves, which normalizes after discontinuation of clozapine.

NOTE - Of the given options, clozapine can be associated with tachycardia and palpitations as an adverse effect.

Myocarditis is a reported serious adverse effect of this drug which necessitates application of close monitoring protocols for patients on treatment with this drug.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Which one of the following is the most important diagnostic test to consider for a patient on clozapine who has developed palpitation?

A. Troponin.
B. Echocardiography.
C. Holter monitoring.
D. Full blood count.
E. Clozapine level.

A

A. Troponin.

Clozapine is an effective antipsychotic for treatment of resistant schizophrenia, but is associated with serious adverse effects including sedation, postural hypotension, hypersalivation, severe constipation, dyslipidemia, myoclonus and epileptic seizures. Excessive weight gain and glucose intolerance aand eventually type 2 diabetes mellitus can occur.

Neutropenia (2-3%) and agranulocytosis (1%) are other adverse effects. All patients taking clozapine should be registered in an approved clozapine monitoring service where ongoing monitoring primarily occurs for the detection of neutropenia and agranulocytosis

Tachycardia is another common side effect of clozapine, observed in 25% of patients. Arrhythmias may occur. Similar to other atypical antipsychotics, ST segment depression or T-wave flattening may be seen on ECG.

A range of cardiac disorders have also been associate with the use of clozapine, the most serious being myocarditis, cardiomyopathy and death. Myocarditis is most commonly observed early in treatment. Seriousness of such conditions requires engaging patients in a monitoring protocol devised for this purpose. The monitoring protocol recommends:

  • Obtaining baseline troponin I or T, CRP, ECG and echocardiography
  • Weekly monitoring of CRP and troponin for the first 4 weeks of treatment
  • During the first 4 weeks, vital signs must be measured and direct enquiry regarding symptoms performed at least every alternate day while the patient is an inpatient, and weekly if the patient has been transferred to an outpatient clinic
  • In the presence of relevant symptoms, an abnormally increased heart rate, or raised CRP (50 mg/L), it is recommended that troponin and CRP be measured daily
  • If troponin levels are only slightly raised (less than twice the upper limit of normal) and CRP remains less than 100 mg/L, clozapine may be continued
  • Discontinuation of clozapine and investigation by echocardiography is advised if either troponin is more than double the normal maximum, or CRP is more than 100 mg/L
  • Routine monitoring for myocarditis up to day 28 is recommended, in comparison to the previous guidelines which extended monitoring only to day 14.

With a high proportion of cases of myocarditis occurring during week 3, this recommendation as to active monitoring for myocarditis during the first 4 weeks proposes that this regime will have sufficient sensitivity to pick up all symptomatic cases of myocarditis developing between days 14 and 21.

In this patient with palpitations, troponin levels should be monitored along with CRP on a daily basis as the most appropriate next step in management.

(Option B) Echocardiography is used for baseline assessment (prior to commencement of clozapine) and if there are symptoms suggestive of heart failure.

(Option C) Holter monitoring is not routinely used for monitoring and assessment of clozapine-treated patients with tachycardia or other cardiac complications.

(Option D) Full blood count is performed on a regular basis to monitor development of neutropenia and agranulocytosis.

(Option E) Clozapine level measurement is not indicated for management of adverse effects as there is no reliable cut-off level.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

A 61-year-old man is brought to your clinic by his wife with complaint of sudden-onset tongue swelling. He is diabetic and is on treatment with metformin and chlorpropramide, has hypercholesterolemia for which he takes simvastatin, and also suffers from hypertension that
is controlled with ramipril. Four weeks ago, he presented to his GP with complaints of fever and productive cough, diagnosed as acute bronchitis, and was prescribed amoxicillin. On examination, his tongue is swollen. He has difficulty speaking and points to his tongue as the cause of his inability to speak. On lung auscultation, wheezes are heard. No rash is noted. Which one of the following drugs can be the cause of this presentation?

A. Metformin.
B. Simvastatin.
C. Amoxicillin.
D. Ramipril.
E. Chlorpropamide

A

D. Ramipril.

The clinical presentation of tongue swelling and respiratory tract involvement, in the absence of rash, is highly suggestive of angioedema caused by other reasons than anaphylaxis.

Angiotensin converting enzyme (ACE) inhibitors are the leading cause of drug-induced angioedema. The reason is that this drug group is widely prescribed. ACE inhibitor-induced angioedema most commonly affects the lips, tongue, face, and upper airway. Angioedema of the pharynx, larynx, and subglottic area have also been reported. Early signs of laryngeal edema include hoarseness and inspiratory stridor, which may progress to airway obstruction in up to 10% of cases. Rarely, fatalities due to massive tongue swelling and asphyxiation have been reported.

Less often, intestines can be involved, presenting as acute abdominal pain with diarrhea or other gastrointestinal symptoms.

ACE inhibitor-related angioedema occurs most commonly in the first years of treatment but can occur after years of use. Patients may have multiple episodes before the condition is recognized. Initial mild episodes may progress to severe life-threatening ones.

NOTE - Presence of rash and/or itching excludes the diagnosis of ACE inhibitor-induced angioedema. If present, other etiologies than ACE inhibitors should be considered.

After an episode of ACE inhibitor-related angioedema, the patient must not take this class of drug again. The common practice is switching to an angiotensin receptor blocker (ARB). ARBs can also induce angioedema but at a much lower rate and less severity than ACE inhibitors.

Of the current drugs the patient is on, ramipril is an ACE inhibitor and the most likely cause of this presentation.

(Option A) Metformin is not associated with such presentation, nor is chlorpropramide (a sulfonylurea).

(Option B) Statins (e.g. simvastatin) has not been shown to be associated with angioedema.

(Option C) Amoxicillin can cause a hypersensitivity reaction type I (anaphylaxis) presenting with angioedema, rash (wheels) and itching; however, absence of rash and itch makes amoxicillin a less likely cause of this presentation.

(Option E) Chlorpropamide is a sulfonylurea used for treatment of diabetes. Sulfonylureas have been reported as rare cause of angioedema.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

A 60-year-old woman is prescribed sertraline for management of depression. Her medical history includes hypertension that is well-controlled on nifedipine and atenolol. On review after 2 months, she feels better but her signs and symptoms of depression have not resolved completely; therefore, the dose of sertraline is increased. After 10 days, she presents again complaining of palpitations. On examination, she has a blood pressure of 100/78mmHg and heart rate of 110bpm. The rest of the examination is inconclusive. Which one of the following is most likely to have led to this presentation?

A. Sertraline.
B. Nifedipine.
C. Interaction between sertraline and nifedipine.
D. Increased metabolism of nifedipine.
E. A new rhythm disturbance irrelevant to her current medications.

A

C. Interaction between sertraline and nifedipine.

Nifedipine is a dihydropyridine calcium channel blocker (CCB). Dihydropyridine CCBs reduce the peripheral resistance and by this reduce the blood pressure. These drugs generally do not have clinically significant cardiac effects. Although nifedipine can cause compensatory tachycardia, the patient has been asymptomatic before the dose of sertraline was increased.

Tachycardia and palpitation are not expected adverse effects of SSRIs; However, SSRIs can inhibit hepatic metabolism of CCBs, and result in increased plasma levels of nifedipine leading to hypotension and compensatory tachycardia as seen in this patient. Therefore, the most likely explanation to the patient’s tachycardia and palpitation is an interaction between the two drugs.

(Option A) Sertraline alone does not cause tachycardia.

(Option B) Since tachycardia has been developed after increasing the dose of sertraline, it is unlikely that nifedipine alone has led to tachycardia.

(Option D) As mentioned earlier, SSRIs result in decreased metabolism of nifedipine, and by this, increase of the plasam level and effects of nifedipine.

(Option E) It is unlikely that a new rhythm disturbance is the underlying cause of tachycardia, while a known drug interaction exists and explains the symptoms.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

In which one of the following conditions nitrates are contraindicated?

A. Chronic left ventricular failure.
B. Unstable angina pectoris.
C. Acute left ventricular failure.
D. Myocardial infarction.
E. Hypotension.

A

E. Hypotension.

The following are the contraindications to nitrate use:

  • Pulse rate less than 50 bpm.
  • Pulse rate over 100 bpm.
  • Systolic blood pressure less than 90mmHg or more than 30 mmHg under the baseline
  • Right ventricular infarction.
  • Severe aortic stenosis.
  • Hypertrophic cardiomyopathy.
  • The patient has taken sildenafil in the past 24 hours or tadalafil in the past 5 days.

Of the given options, only hypotension is a contraindication to nitrate use. Other options are in fact indications for nitrates.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

A 25-year-old woman comes to your clinic concerned about a breast lump in her left breast. She says that the lump is mobile and tender to palpation. You find out that the lump is benign and is due to hormonal changes. She is concerned about her risk of having breast cancer. Her mother died of breast cancer at 45 years of age, and one of her aunts died of ovarian cancer. Which one of the following is not a risk indicator of familial breast-ovarian cancer in her?

A. Onset of the cancer > 50 years old.
B. Two first-degree or second-degree relatives on one side of family with ovarian or breast cancer.
C. Individuals with ovarian cancer.
D. Breast cancer in a male relative.
E. Bilateral or multifocal breast cancer.

A

A. Onset of the cancer > 50 years old.

Hereditary breast-ovarian cancer (HBOC) syndrome is mainly caused by a pathogenic mutation in either BRCA1 or BRCA2 genes. There result of this mutation is strong predisposition for breast, ovarian cancer, prostatic cancer and pancreatic cancer.

The lifetime risk for these cancers in individuals with a pathogenic variant in BRCA1 or BRCA2 is:

  • 40%-80% for breast cancer (~ 50%)
  • 11%-40% for ovarian cancer
  • 1%-10% for male breast cancer
  • Up to 39% for prostate cancer
  • 1%-7% for pancreatic cancer

The following features in history, if present, are suggestive of an increased risk of familial breast -ovarian cancer syndrome:

  • Two first-degree or second-degree relatives on one side of the family with ovarian or breast cancer
  • Breast cancer occurring in an affected relative younger than 50 years
  • One or more relatives with two cancers (breast and ovarian cancer or two independent breast cancers)
  • Individuals with bilateral or multifocal breast cancer
  • Individuals with ovarian cancer (especially if <50 years)
  • Breast cancer in a male relative
  • Ashkenazi Jewish descent (doubled risk)

of the options, cancer after the age of 50 in not a risk indicator for HBOC syndrome.

There are other less common hereditary syndroms associated with increased risk of breast/ovarian cancer:

Ataxia-telangiectasia - an autosomal recessive disorder characterized by progressive cerebellar degeneration (ataxia), dilated blood vessels in the eyes and skin (telangiectasia), immunodeficiency, chromosomal instability, increased sensitivity to ionizing radiation, and a predisposition to cancer, in particular lymphoma and leukemia. Solid tumors associated with AT include cancers of the breast, stomach, ovary, and melanoma.

Cowden syndrome - (also known as multiple hamartoma syndrome) is an autosomal dominant condition characterized by multiple hamartomatous tumors, mucocutaneous findings, and an increased risk of early onset breast, uterine, and non-medullary thyroid cancer. Up to 75% of women with Cowden syndrome have benign breast conditions such as ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic changes, and breast cancer develops in 25% to 50% percent of female carriers. Most breast cancers are diagnosed premenopausally.

Peutz-Jeghers syndrome (PJS) – is an autosomal dominant condition characterised by hamartomatous polyps in the gastrointestinal tract and mucocutaneous melanin deposits in the buccal mucosa, lips, fingers, and toes. Affected patients are at increased risk for both gastrointestinal (small bowel, stomach, colorectal, and pancreas) and extraintestinal cancers, including cancers of the lung, breast, uterus, and ovary.

Inherited CDH1 mutations and Hereditary Diffuse Gastric Cancer Syndrome (HDGC) - HDGC is an inherited form of diffuse type gastric cancer, a highly invasive tumor that is characterized by late presentation and a poor prognosis. The syndrome is highly penetrant, with the lifetime risk of gastric cancer exceeding 80%. It is also associated
with development of lobular breast cancer in women, with a cumulative lifetime risk estimated to be as high as 60% for some families, and possibly colon cancer.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) - HNPCC, also called Lynch Syndrome, is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, MSH2, MLH1, MSH6, PMS1, and PMS2. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. Although information is limited, some studies have suggested that breast cancer is a part of the spectrum of HNPCC-associated tumors.

Mutations in PALB2 gene -Mutations in a gene known as partner and localizer of BRCA2 (PALB2) are associated with an increased risk of pancreatic cancer and also appear to be associated with a 2- to 4-fold increased risk of breast cancer in women (roughly a 18 to 35 percent lifetime risk). Risks of male breast cancer are also elevated.

Here’s a simplified explanation of these genetic conditions:

  • Genetics: Autosomal recessive (both parents must carry the gene).
  • Symptoms:
    • Progressive loss of coordination (ataxia).
    • Dilated blood vessels, especially in the eyes and skin (telangiectasia).
    • Weakened immune system (immunodeficiency).
    • High sensitivity to radiation.
    • Increased cancer risk, especially for lymphomas and leukemias.
    • Also associated with some solid tumors like breast, stomach, ovarian cancers, and melanoma.
  • Genetics: Autosomal dominant (one parent can pass on the gene).
  • Symptoms:
    • Multiple benign tumors (hamartomas) and skin/mucous membrane findings.
    • High risk of early-onset cancers, particularly in the breast, uterus, and thyroid.
    • Many women develop benign breast conditions, but up to 50% may develop breast cancer, often before menopause.
  • Genetics: Autosomal dominant.
  • Symptoms:
    • Hamartomatous polyps in the gastrointestinal tract.
    • Dark spots on the lips, mouth, fingers, and toes.
    • Increased risk of cancers, including those in the gastrointestinal tract (like small bowel, stomach, and pancreas) and other organs like the lung, breast, uterus, and ovaries.
  • Genetics: Inherited mutations in the CDH1 gene.
  • Symptoms:
    • High risk of diffuse type gastric cancer (an aggressive form of stomach cancer) with over 80% lifetime risk.
    • Also linked to a high risk of lobular breast cancer in women, and possibly colon cancer.
  • Genetics: Caused by mutations in mismatch repair genes like MSH2, MLH1, MSH6, PMS1, PMS2.
  • Symptoms:
    • Increased risk of colorectal cancer and endometrial (uterine) cancer.
    • Less common risks include cancers of the ovaries, stomach, small bowel, liver, kidneys, and brain.
    • There is some evidence that breast cancer may also be part of the spectrum of cancers in HNPCC.
  • Genetics: Mutations in the PALB2 gene.
  • Symptoms:
    • Increased risk of breast cancer in women (2- to 4-fold higher risk, or about 18-35% lifetime risk).
    • Higher risk for pancreatic cancer.
    • Elevated risk of male breast cancer.

These explanations summarize each condition in terms of their genetic inheritance, key symptoms, and associated cancer risks.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Lithium is commonly used in treatment of bipolar disorder. Which one of the following is the least common side effect of lithium?

A. Renal impairment.
B. Hypothyroidism.
C. Hyperparathyroidism.
D. Weight gain.
E. Teratogenicity.

A

E. Teratogenicity.

Lithium can potentially cause many acute and chronic adverse effects even if the plasma levels are within therapeutic range.

The most common acute adverse effects of lithium include:

  • Nausea
  • Tremor
  • Polyuria (related to nephrogenic diabetes insipidus) and thirst
  • Weight gain
  • Loose stools
  • Cognitive impairment (including apathy, decreased creativity, and changes in verbal learning, memory, and concentration)

Chronic (long-term) adverse effects include:

  • Renal involvement - Renal function is adversely affected by lithium. Lithium initially reduces the ability of the kidney to concentrate urine, leading to dilute urine and polyuria (nephrogenic diabetes insipidus). In the long run, interstitial nephritis or even fibrosis can follow. This process can lead to increased serum creatinine and, rarely, to progressive renal failure.
  • Thyroid involvement - the most common adverse effect of lithium on thyroid gland is hypothyroidism, but goiter and chronic autoimmune thyroiditis have been reported as well. Hyperthyroidism is also possible. However, pre-existing hypothyroidism or hypothyroidism caused by lithium is not a contraindication to lithium use. TSH should be monitored regularly. Once elevated, treatment with T4 should be started, while lithium is continued.

NOTE - Renal and thyroid problems are the most common log-term adverse effects of lithium.

  • Parathyroid gland involvement - lithium can result in hyperparathyroidism and hypercalcemia. Elevated serum calcium level should be followed by serum PTH measurement, and an endocrine consultant involved if elevated.
  • Cardiac involvement - rarely, lithium may cause cardiac arrhythmias in patients without pre-existing cardiac disease. Moreover, lithium may lead to ECG abnormalities such as abnormalities of T wave or ST segment, findings consistent with sick sinus syndrome, or an unmasked Brugada pattern.
  • Although lithium is generally considered as a teratogenic medication due to increased risk cardiac anomalies in a fetus (1:1000-2000 compared to 1:20000 in general population, the absolute risk is low (0.05%). Of the options, teratogenicity is the least common adverse effect.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Which one of the following is not a contraindication to ACE inhibitor use?

A. Bilateral renal artery stenosis.
B. Pregnancy.
C. Cough.
D. Angioedema.
E. Previous allergic reaction to ACE inhibitors.

A

C. Cough.

The following are absolute contraindications to ACE inhibitors:

  • History of angioedema regardless of cause (even if not due to ACE inhibitor) Pregnancy (due to harm to fetus)
  • Bilateral renal artery stenosis.
  • Previous allergic reaction to ACE inhibitors

Relative contraindications are:

  • Aortic stenosis
  • Hypertrophic cardiomyopathy
  • A dry cough is a common adverse effect of ACE inhibitors and a main cause of non-compliance and abandonment of treatment; however, neither pre-existing cough nor ACE inhibitor-induced cough is not a contraindication to their use.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Janet, 32 years old, has been prescribed sertraline for treatment of her major depression. She comes to you for follow-up, and admits to taking ecstasy at occasions. She says that she take the pill because she wants to enjoy more from time to time. Which one of the following is a correct advice to give her in this regard?

A. Sertraline and ecstasy are synergistic.
B. Ecstasy is contraindicated in patients on sertraline.
C. The combination can lead to irreversible psychosis.
D. Ecstasy decreases the therapeutic effect of sertraline. E. Ecstasy and sertraline have no interactions.

A

A. Sertraline and ecstasy are synergistic.

Selective serotonin reuptake inhibitors (SSRIs) such as sertraline are first-line medications for treatment of depression. Serotonin toxicity occurs when the amount of the serotonin rises beyond the therapeutic range. Concomitant use of certain drugs is associated with increased risk of serotonin toxicity. These drugs often lead to a synergistic effect on serotonin, and increase the risk of serotonin toxicity.

Certain illicit drugs such as ecstasy, amphetamine, and methamphetamine are examples of the drugs that can result in increased concentration of serotonin in the body.

3,4- methylenedioxy-N-methamphetamine (MDMA), also known as ecstasy, is a unique psychedelic amphetamine with stimulant, euphoriant and empahtogenic/entactogenic effect. The effect on serotonin is larger than amphetamine or methamphetamine. MDMA causes increased release of serotonin in the body and has a synergistic effect on SSRIs.

Although this synergistic effect associated with simultaneous use of ecstasy and SSRIs increases the risk of serotonin toxicity, ecstasy is not contraindicated to SSRIs use, and vice versa. However, advice should be given against the concomitant use. Of antidepressants, only monoamine oxidase inhibitors (MAO inhibitors) is a contraindication to ecstasy use.

Other contraindications to ecstasy use are use of drugs metabolized through the same liver enzyme as MDMA (i.e.CYP2D6) such as ritonivar (protease inhibitor), codeine and other opiates and dextromethorphan (DXM) which is found in over-the counter cough medications.
Studies have shown that combining ecstasy with SSRIs may reduce the effects of both ecstasy and the SSRI, making the treatment with SSRIs less effective and prevents from desired effects of ecstasy to occur.

18
Q

A 67-year-old man presents to your office complaining of a painful swollen right thigh. He has diabetes well controlled on metformin 500mg 12-hourly and hypertension for which he is taking losartan 25mg 12-hourly. He is also on simvastatin 20 mg/daily hypercholesterolemia. His recent medical history is significant for atrial fibrillation (AF) under treatment with warfarin. One week ago, he was started on amiodarone after he was diagnosed with ventricular tachycardia (VT). On physical examination, he has a blood pressure of 140/95mmHg, pulse rate of 98bpm and a temperature of 37.3°C. The right thigh is painful, swollen and slightly tender but not warm or red, and has a circumference 4 cm greater than that of the left thigh. Which one of the following could be the most likely cause of this presentation?

A. Deep vein thrombosis (DVT).
B. Drug reaction.
C. Cellulitis.
D. A thigh hematoma.
E. Rhabdomyolysis.

A

D. A thigh hematoma.

A painful swollen thigh can be caused by a number of different conditions such as DVT, cellulitis and hematoma. This patient is on warfarin for treatment of AF. Although not impossible, it is less likely that he develops DVT (which is treated with warfarin as well). This makes DVT (option A)
a less likely yet possible diagnosis.

Interaction between warfarin and amiodarone is well-known. Amiodarone results in decreased metabolization of warfarin through hepatic pathways and leads to increased bleeding tendency. Considering that the patient has been recently started on amiodarone while on warfarin, a hematoma can also be possibility and in fact the most likely one. Hematomas are a frequent result of increased bleeding tendency occurring in over-anticoagulated patients.

Drug reaction (option B) is different from drug interaction. Drug reaction means an adverse reaction caused by a single drug while in drug interaction the effect of one drug leads to unwanted or exaggerated response to another. While this scenario is very likely to have been caused by the interaction between amiodarone and warfarin, resulting in increased untoward effects of warfarin, none of the drugs in the medications he is taking are not likely to result in such presentation.

Cellulitis (option C) presents with a warm and red areas of swollen skin. Fever is often present. This patient has no fever and the thigh swelling is not warm and red. This makes cellulitis a less likely diagnosis compared to hematoma.

Rhabdomyolysis (option E) is a serious condition caused by muscle fibers breakdown and release of muscle cell contents such as myoglobin and potassium. Myoglobinuria results in deposition of myoglobin in kidneys and renal failure. Release of excess potassium from damaged muscle cells leads to hyperkalemia and serious complications such as cardiac arrhythmias. Statins such as atorvastatin and simvastatin in particular are metabolized by cytochrome P450-3A4 (CYP3A4), and amiodarone is a potent inhibitor of this cytochrome. Concomitant use of amiodarone and statins can result in increased activity of statins and rises the likelihood of statin-related adverse effects such as muscular pain, myopathy and rarely rhabdomyolysis. However, in the event of statin-induced rhabdomyolysis, a systemic presentation is expected. Rhabdomyolysis never causes focal signs mentioned in the scenario.

19
Q

A 52-year-old man presents to the emergency department with complaint of a swollen tongue after he had seafood 2 hours ago. His medical history is remarkable for diabetes mellitus for which he is taking metformin 500md 8-hourly, hypertension controlled on ramipril and indapamide, and hypercholesterolemia treated with atorvastatin 20mg daily. He mentions no itching. On examination, he has stable vital signs with no respiratory or abdominal symptoms. Which one of the following could be the most likely cause of this presentation?

A. Anaphylaxis.
B. C1 esterase inhibitor deficiency.
C. Ramipril.
D. Atorvastatin.
E. Metformin.

A

C. Ramipril.

The scenario represents a case of angioedema manifested as a tongue swelling and no other symptoms pointing towards allergy or anaphylaxis.

Angioedema is localized deep dermis, subcutaneous, or submucosal swelling which is self-limiting and results from extravasation of fluid into interstitial tissue (blood vessel leakage). Depending on the underlying cause, angioedema can occur in isolation, accompanied by urticarial, or as a component of anaphylaxis.

Angioedema typically affects the gravity-independent areas with loose connective tissue such as the face, lips, tongues, throat, uvula, larynx, extremities and genitalia.it also may affect bowel wall (most commonly the jejunum) with the clinical picture of colicky abdominal pain, obstruction, or ascites. Angioedema of the bowel wall often presents as a diagnostic dilemma.

Angioedema can be clinically differentiated from other forms of edema by the following characteristic features:

  • Onset is in minutes to hours and resolution occurs spontaneously in hours to days. Asymmetric distribution.
  • Tendency not to involve gravitationally-dependent areas of the body.
  • Involvement of the face, lips, larynx, and bowels.
  • Association of some forms of angioedema with other clinical features of allergic reaction or anaphylaxis.

Based on the pathophysiology, there are three main types of angioedema:

Mast cell-related angioedema – in mast cell-related angioedema, seen in allergic reactions to food or insect stings, there are often (not always) other clinical features of mast cell-mediator release including urticarial, flushing, pruritus (generalized), bronchospasms, throat tightness or obstruction, and/or hypotension. Mast cell-mediated angioedema often begins within minutes of exposure to the allergen, build up over a few hours and resolve within 24-48 hours.

Histamine-related angioedema – angioedema might be histamine- dependent without clear evidence of mast cell degranulation. This is often the cause in cases of idiopathic (spontaneous) angioedema. In this type, angioedema may occur in isolation or with urticaria, but is not associated with respiratory or circulatory symptoms.

Bradykinin- induced angioedema – this type of angioedema is not associated with other manifestations of the other two groups such, i.e. signs and symptoms of an allergic reaction such as urticaria, respiratory and/or circulatory symptoms, pruritus, etc. There is a more prolonged time course. The sign and symptoms usually develop over 24-36 hours and resolve within 2 to 4 days. In this type of angioedema, there is no definite relationship between the trigger and the onset of symptoms.

This man has presented with a swollen tongue as the sole manifestation of angioedema and the most likely diagnosis for him is bradykinin- induced angioedema. Angiotensin converting enzyme inhibitors (ACIs) such as captopril, ramipril, lisinopril, enalapril, and perindopril are the most common triggering factors for bradykinin-induced angioedema; therefore, the most likely cause to this presentation would be the ACEI ramipril. Angiotensin receptor blockers (ARBs) such a losartan and valsartan are also capable of inducing such presentation, but the association is not as strong.

(Option A) Although anaphylaxis can have angioedema as a manifestation, the absences of urticaria, circulatory/respiratory symptoms and pruritus makes this diagnosis makes anaphylaxis (e.g. brought up by the seafood) a remote possibility.

(Option B) acquired C1esterase inhibitor (C1-INH) deficiency, also called acquired angioedema (AAE), is a rare syndrome presenting with recurrent episodes of angioedema without urticaria. This syndrome is sometimes associated with B cell lymphoproliferative disorders. Like ACEI-induced angioedema, manifestations include swelling of the face, tongue, upper respiratory tract, or bowel walls. C1-INH deficiency presents similar to hereditary angioedema (HAA); however, unlike patients with HAA who are often young, patients with this disease are often older than 40 years. Although C1-INH deficiency can be a diagnosis in this man, its rarity makes it a less likely possibility.

Statins such as atorvastatin (option D) and metformin (option E) are not associated with angioedema, especially the bradykinin-induced type.

20
Q

A 62-year-old man presents to your practice complaint of recent-onset shortness of breath which is brought up by physical activity. He is diabetic and takes metformin and rosiglitazone for treatment and also has hypertension controlled on enalapril and metoprolol. Recently, he has been started on amiodarone due to episodes of sustained ventricular tachycardia. Which one of the following medications is more likely have caused this clinical picture?

A. Rosiglitazone.
B. Metformin.
C. Enalapril.
D. Metoprolol.
E. Amiodarone.

A

A. Rosiglitazone.

Of the options, rosiglitazone is more likely to have caused this clinical picture.

Rosiglitazone (Avandia®) is a thiazolidinedione and is prescribed as an oral antidiabetic agent and is used in management of type 2 diabetes mellitus. The primary mechanism of action has been hypothesized to be through increasing insulin sensitivity.

Fluid retention may occur in patients on rosiglitazone. This may lead to or exacerbate heart failure in such patients, who often already have risk factors in the setting of diabetes. Diuretic therapy may be necessary for treatment of fluid retention. Weight gain, probably due to fluid overload has been observed during therapy.

It is estimated that 1-10% of patients on rosiglitazone develop adverse effects such as:

  • Edema
  • Hypertension
  • Heart failure
  • Myocardial ischemia
  • Diarrhea
  • Upper respiratory tract infection

Increased total cholesterol, LDH and HDL are other findings seen in >10% of patients on this medication.

While on rosiglitazone, patients should be monitored for signs and symptoms of fluid retention and heart failure, including rapid weight gain, edema and dyspnea, and the drug should be discontinued if any deterioration is cardiac status occurs.

(Option B) Metformin is an anti-hyperglycemic agent with adverse effects including hypoglycemia and lactic acidosis, abdominal pain, decreased appetite, muscle pain and cramps, somnolence, etc. Dyspnea is not a known adverse effect of this medication.

(Option C) Enalapril is an angiotensin converting enzyme inhibitor (ACEI). ACEI adverse effects include dry cough, hyperkalemia, fatigue, dizziness, headache, and loss of taste. Dyspnea is not an adverse effect.

(Option D) Beta blockers such as metoprolol can exacerbate an existing heart failure and result in sign and symptoms such as dyspnea, fluid retention and edema. This patient does not have heart failure and metoprolol is not likely to have resulted in this presentation.

(Option E) Amiodarone use is also associated with several adverse effects including pulmonary toxicity that can lead to dyspnea as a presenting symptom. However, months to even years of use is required before the cumulative dose of amiodarone reaches toxic levels and results in pulmonary toxicity. This patient has just recently been started on amiodarone and his dyspnea is unlikely to have been caused by it.

There are several different types of pulmonary toxicity caused by amiodarone. Interstitial pneumonitis is the most common; others include organizing pneumonia, acute respiratory distress syndrome, and a solitary lung mass. A non-productive cough and dyspnea are often present in 50% to 75% of patients with amiodarone-induced pulmonary toxicity. Pleuritic chest pain, weight loss, fever and malaise can also occur.

21
Q

Joan is 60-year old woman who is suffering migraine. The pain has been crushing and disabling despite medical therapy with maximum dose of paracetamol. Seven hours ago, in a desperate attempt she took 20 500mg paracetamol tablets to make the pain go away. She is now in the Emergency Department of the tertiary hospital you work in with complaints of right upper quadrant abdominal pain, nausea, and vomiting. She weighs 65 kilograms. Which one of the following is the next best step in management?

A. Give her intravenous N-acetyl cysteine immediately.
B. Obtain a serum paracetamol level and give her N-acetyl cysteine.
C. Do immediate gastric lavage and give her activated charcoal.
D. Check liver function tests prior to decision making on giving N-acetyl cysteine. E. Refer the patient to toxicology registrar.

A

B. Obtain a serum paracetamol level and give her N-acetyl cysteine.

Before making a decision as to treatment of potential paracetamol poisoning, it should be determined whether the ingested dose can be toxic. The following table from the Medical Journal of Australia summarizes the doses associated with hepatic toxicity: (see photo)

Joan has ingested at least 10 g (500mgX20) paracetamol in less than 8 hours that puts her in a significant risk of toxicity and liver damage. Management of potential paracetamol toxicity depends on the time of presentation and is summarized in the following table (from Medical Journal of Australia):

Since the presentation is within 8 hours, the next best step is obtaining a blood sample for serum paracetamol level and starting N-acetyl cysteine (NAC) immediately because it is unlikely that Joan’s serum paracetamol levels is available within 8 hours. NAC can be safely stopped if the paracetamol level is within the safe range and continued if in the toxic range.

(Option A) Administration of NAC should not be delayed more than 8 hours of ingestion. Ingestion has occurred 7 hours ago and it is very unlikely that the results of the serum paracetamol level is available within 1 hour. Therefore, NAC should be started but taking blood samples for paracetamol level should be obtained first.

(Option C) Gastric lavage is indicated if the presentation is within the first hour of toxic ingestion. Active charcoal is indicated if the presentation is within the first 2 hours of ingestion.

(Option D) Although assessing the potential damage to the liver demands liver function testing, this step is not of priority at this stage and can be considered once other appropriate measures are taken.

(Option E) Referring the patient to toxicology registrar is incorrect. Action should be taken immediately now. Seeking expert advice can come later in the course of treatment.

22
Q

A 72-year-old man is brought to the emergency department after he collapsed while walking back home from shopping. After administration of oxygen, an ECG strip is obtained emergently which is shown in the following photograph. He lost her wife 12 months ago and is currently on sertraline 100 mg/day due to depression as a result of complicated grief. One week ago, he was prescribed azithromycin for treatment of atypical pneumonia. His other medications include aspirin 80 mg/day for treatment of ischemic heart disease (IHD), atorvastatin 20 mg/day for hyperlipidemia and multivitamin. Which one of the following is most likely to have lead in such presentation?

A. Interaction between aspirin and azithromycin.
B. Sertraline.
C. Azithromycin and sertraline.
D. Azithromycin.
E. Ischemic heart disease.

A

C. Azithromycin and sertraline.

The ECG is characteristic of Torsades de pointes (TdP). TdP is a specific form of polymorphic ventricular tachycardia (PVT) occurring in the context of QT prolongation. It has a characteristic morphology in which the QRS complexes “twist” around the isoelectric line. For TdP to be the diagnosis, the patient has to have evidence of both PVT and QT prolongation.

QT interval prolongation (QTc>500 ms) is the essential predisposing factors for TdP. QT interval prolongation is cause by a variety of conditions including:

  • Electrolyte Disturbances, in particular hypokalemia, hypomagnesemia and more rarely hypocalcemia
  • Concomitant use of more than one drug that prolongs the QT interval
  • Congenital Long QT Syndrome
  • Cardiac Disease such as congestive heart failure, ventricular hypertrophy, recent conversion from AF
  • Thyroid Disease - more common with hypothyroidism and usually normalizes with treatment
  • Drugs

Female gender and age 65 or older are risk factors for QT interval prolongation.

Of the above list, drugs play an important role in a marked number of patients. There is a long list of drugs with potential capability of prolongation of the QT interval as the underlying cause for TdP. Some examples are:

Antibiotics:

  • Macrolides (azithromycin, clarithromycin, erythromycin)
  • Moxifloxacin.
  • Ketoconazole.
  • Fluconazole.

Antidepressants:

  • SSRIs (e.g. citalopram, escitalopram, sertraline)
  • TCAs (e.g. amitriptyline, imipramine, clomipramine, doxepin)
  • First-generation anti-psychotics (e.g. haloperidol, chlorpromazine)
  • Atypical antipsychotics (e.g. risperidone, pimozide, quetiapine, clozapine)

Anti-arrhythmics:

  • Sotalol
  • Quinidine
  • Flecainide
  • Amiodarone

Anti-emetics

  • Ondansetron
  • Domperidone

Other:

  • Methadone
  • Protein kinase inhibitors e.g. sunitinib
  • Lofepramine
  • Some antimalarials
  • Some antiretrovirals
  • Telaprevir
  • Boceprevir

NOTE - Often a combination of two or more of these drugs are necessary for QT interval prolongation.

Both sertraline (an SSRI) and azithromycin (a macrolide) can cause QT interval prolongation and TdP. This patient, however, has been on sertraline for months without any complication and just has become problematic after azithromycin was added. This makes the concomitant use and accumulative effect of sertraline and azithromycin the most likely cause for this presentation.

Theoretically, azithromycin can result in QT interval prolongation, but as mentioned earlier often more than one drug with such effect in required for this. Therefore, azithromycin alone is less likely to have caused this problem. This holds through about sertraline (option B). Moreover, this patient has been on sertraline for a rather long time with no complaints.

QT interval prolongation is not a known effect of aspirin and aspirin does not increase the effect of azithromycin on QT interval prolongation (option A).

Although heart disease such as IHD (option E) can be a cause of QT interval prolongation and TdP, the presence of concomitant use of a macrolide and an SSRI in the history, makes IHD a less likely trigger for this presentation than the drug combination.

23
Q

A 69-year-old man presents to the emergency department with a painful swollen left thigh. His current medications include metformin 500 mg 8-hourly for diabetes, valsartan 80 mg daily for hypertension, atorvastatin 10mg daily for hypercholesterolemia, and warfarin 5mg daily for chronic atrial fibrillation. One week earlier, he was started on amiodarone after he was diagnosed with ventricular tachycardia (VT). On physical examination, he has a blood pressure of 138/87mmHg, pulse rate of 82 pm and a temperature of 36.6°C. The left thigh is painful, swollen and slightly tender but not warm or red. The affected leg circumference is 5 cm greater than the unaffected one. Which one of the following options is the most appropriate next step in management?

A. Duplex Doppler ultrasound of the left leg.
B. Blood culture.
C. INR.
D. Commencement of antibiotics.
E. Decrease the dose of warfarin.

A

C. INR.

A painful swollen thigh can be caused by a number of different conditions such as deep vein thrombosis (DVT), cellulitis and hematoma. This patient is on warfarin for treatment of AF.

Interaction between warfarin and amiodarone is well-known. Amiodarone results in decreased metabolization of warfarin through hepatic pathways and leads to increased bleeding tendency. Considering that the patient has been recently started on amiodarone while on warfarin, a hematoma is the most likely diagnosis. Given the normal temperature, cellulitis is a less likely diagnosis and while the patient is on warfarin it is less likely but not impossible to develop DVT.

With hematoma being on the top of the differential diagnoses, measurement of INR would be the most appropriate initial step to take in management of this patient. An increased INR beyond the therapeutic range of 2-3 makes the diagnosis more certain; however, it is not uncommon that bleeding develops in the presence of therapeutic or even subtherapeuthic INR ranges.

(Option A) Duplex Doppler ultrasound for assessment of possible DVT may be considered after hematoma, as the most likely diagnosis, is excluded, or even for assessment of hematoma.

(Options B and D) Blood culture and antibiotics are measures for suspected cellulitis. Absence of fever, warmth and erythema make cellulitis a far less likely diagnosis and these measures not appropriate steps at least for now.

(Option E) Dose reduction or cessation of warfarin may be considered if the INR is found to be above the therapeutic range.

24
Q

The laboratory test results of a 55-year-old man on polypharmacy shows a total cholesterol level of 4.5mmol/L and HDL of 0.8mmol/L. Which one of the following medications can be the cause of this lipid profile?

A. Allopurinol.
B. Aspirin.
C. Hydrochlorothiazide.
D. NSAIDs.
E. Calcium channel blockers.

A

C. Hydrochlorothiazide.

This patient has an elevated total cholesterol level of 4.5 mmol/L (normal: < 4mmol/L) and a decreased HDL level of 0.8mmol/L (normal: men:1-1.3mmol/L, women: 1.3-1.5mmol/L). Of the options, only hydrochlorothiazide in doses greater than 25mg/day or prolonged use is capable of producing such lipid profile.

Hydrochlorothiazide has not shown to adversely affect lipid profile in doses of 6.25-12mg/day. In dose of 25mg/day, it increases TG levels but not total cholesterol or HDL levels. With doses more than 25mg/day, hydrochlorothiazide is associated with an increase in total cholesterol and TG levels, and decreased HDL levels especially in diabetic patients.

(Option A) Allopurinol is a uric acid-lowering agent. Studies suggest that allopurinol is associated with an increase in TG, total cholesterol and LDL and HDL levels. HDL level was shown to increase later on after 3 months of therapy. With decreased HDL in this patient, allopurinol would be a less likely cause to this lipid profile.

(Options B and D) Salicylates such as aspirin or NSAIDs have not shown to have an adverse effect on lipid profile.

(Option E) Calcium channel blockers appear to have no effect on lipid profile.

TOPIC REVIEW

Effects of some cardiovascular drugs on lipid profile:

25
Q

Which one of the following is the most common pathologic ECG abnormality in intoxication with amitriptyline?

A. Ventricular tachycardia.
B. Widening of QRS complexes.
C. Prolongation of QT interval.
D. Prolongation of PR interval.
E. Premature ventricular contractions.

A

B. Widening of QRS complexes.

Widening of QRS complexes is probably the most prominent pathological ECG abnormality in patients intoxicated with tricyclic antidepressants. If untreated, this can lead to ventricular tachycardia (VT) and ventricular fibrillation (VF). Other possible abnormalities include:

Prolongation of QT (option C) and/or PR intervals (option D). The latter can cause first-degree AV block if PR>200 milliseconds. VT (option A) and VF are seen in approximately 4% of patients and are the most common cause of death in TCA intoxication. Sinus tachycardia due to anticholinergic effect of TCAs (probably the most common benign ECG finding in TCA intoxication).

NOTE - QRS prolongation >100ms is associated with a 30% chance of seizure. With QRS>160ms, there is a 50% risk of serious arrhythmias.

Premature ventricular contractions (option E) are the most common ECG abnormality seen in patients with digoxin intoxication.

26
Q

Which one of the following malignancies is most likely to have hypokalemia as an associated feature?

A. Colon cancer.
B. Breast cancer.
C. Lung cancer.
D. Renal cell carcinoma.
E. Cancer of the pancreas.

A

C. Lung cancer.

Paraneoplastic syndromes are rare disorders that are triggered by an altered immune system response to a neoplasm and are defined as clinical syndromes involving non-metastatic systemic effects that accompany malignant disease.

These syndromes are collections of symptoms that result from substances produce remote from the tumor itself.

Manifestations of symptoms can be related to either of the following:

  • Endocrine
  • Renal
  • Neuromuscular
  • Musculoskeletal
  • Cutaneous
  • Hematologic
  • Gastrointestinal
  • Miscellaneous in nature

Paraneoplastic syndromes may be the first or most prominent manifestation of a cancer. When a patient without a known cancer presents with a paraneoplastic syndrome, cancer should be considered and promptly investigated.

Hypokalemic nephropathy, which is characterized by urinary potassium leakage of more than 20 mEq per 24 hours, may develop in patients with tumors that secrete adrenocorticotropic hormone (ACTH) or ACTH-like substances. It occurs in 50% of individuals with ACTH-secreting tumors of the lung (i.e. small cell cancer).

Cushing syndrome is another paraneoplastic syndrome (endocrine syndrome) that may be caused by ACTH or ACTH-like substances produced by small cell carcinoma of the lung.

27
Q

A 73-year-old woman presents to the Emergency Department with vomiting, abdominal pain, and abdominal distention. She has congestive heart failure (CHF) in the setting of long-standing hypertension. She had been taking carvedilol, ramipril, and atorvastatin until 10 days ago when she had digoxin and hydrochlorothiazide added to her medications for a tighter control of her rather poorly controlled hypertension and CHF. On examination, she has a blood pressure of 130/85 mmHg, an irregular pulse of 110 bpm in rate, respiratory rate of 22 breaths per minute, and temperature of 37.5°C. Her abdomen is distended but not tender. There is also no guarding or rigidity. Bowel sounds are absent. Which one of the following is the most likely cause of her abdominal distention?

A. Hypokalemia.
B. Digoxin toxicity.
C. Hypocalcemia.
D. Mesenteric ischemia.
E. Hyperkalemia.

A

A. Hypokalemia.

  • Paralysis of the colon: Causes symptoms like bowel obstruction without an actual physical blockage.
  • Hypokalemia (low potassium): Can be caused by certain medications.
  • Hydrochlorothiazide: A thiazide diuretic known for causing hypokalemia.
    • Other effects: Hyponatremia (low sodium), high blood sugar, increased uric acid, hypercalcemia (high calcium).
  • Digoxin: Used for heart conditions, but low potassium from thiazide diuretics can increase risk of digoxin toxicity.
  • Loss of appetite, nausea, vomiting, constipation, abdominal pain
  • Increased thirst, frequent urination
  • Fatigue, weakness, muscle pain
  • Confusion, disorientation, headaches, depression
  • Note: Hypercalcemia does not typically cause bowel obstruction.
  • Digoxin toxicity: Symptoms include anorexia, nausea, vomiting, abdominal pain, diarrhea. Does not cause abdominal distention or bowel obstruction.
  • Hypocalcemia: Symptoms include muscle spasms, numbness, tingling, and severe CNS issues like hallucinations. Not likely here.
  • Mesenteric ischemia: Associated with atrial fibrillation. Symptoms include severe abdominal pain and bloody diarrhea. Abdominal distention is not typical.
  • Carvedilol: A beta blocker, does not cause hypokalemia. It tends to cause hyperkalemia.
  • This patient’s symptoms are most likely due to hypokalemia caused by thiazide diuretics, leading to paralytic ileus.

This patient has the clinical picture of paralytic ileus. As the name implies, the condition is associated with paralysis of colon wall leading the clinical picture of bowel obstruction in the absence of a mechanical blockage. Hypokalemia is one the causes of paralytic ileus and can be the most likely explanation for this clinical scenario. The problem has started after introduction of hydrochlorothiazide and digoxin to her medications. Thiazide diuretics are notorious for causing hypokalemia. Other metabolic derangements induced by thiazide diuretics are hyponatremia, increased blood glucose, increase uric acid, and hypercalcemia.

Hypercalcemia often presents with symptoms such as loss of appetite, nausea and vomiting, constipation and abdominal pain, increased thirst and frequent urination, fatigue, weakness, muscular pain, confusion and disorientation, headaches, and depression. Although both hypokalemia and hypercalcemia share constipation as a feature, hypercalcemia does not cause a clinical picture consistent with bowel obstruction.

Thiazide-induced hypokalemia in this patient may predispose her to digoxin toxicity (option B) and digoxin toxicity results in hyperkalemia (option E); however, gastrointestinal manifestations of digoxin toxicity are anorexia, nausea, vomiting, abdominal pain, and diarrhea. Abdominal distention is not a feature of digoxin toxicity or the consequent hyperkalemia.

Hypocalcemia (option C) presents with muscle spasms, numbness and tingling in the hands, feet, and face, and in more severe case, central nervous system problems such as hallucinations. There are no clues in the history suggestive of hypocalcemia as the cause, nor is there an identifiable etiology for that.

(Option D) The rapid irregular pulse in this patient indicated atrial fibrillation (AF). AF predisposes to mesenteric ischemia; however, acute mesenteric ischemia presents with abdominal pain and bloody diarrhea, especially after meals. Chronic mesenteric ischemia has postprandial periumbilical and/or epigastric pain, fear of eating, and weight loss as typical symptoms. Less common features include nausea, vomiting, diarrhea, constipation, and flatulence. Although some of this patient’s symptoms are seen in chronic mesenteric ischemia as well, abdominal distention goes against this diagnosis.

NOTE Carvedilol is a beta blocker. Beta blockers do not commonly cause hypokalemia. In fact, they more tend to cause hyperkalemia by impairing potassium transport into the cells.

28
Q

A 72-year-old woman presents to the Emergency Department complaining of nausea and vomiting. Apparently, she visited the on-call GP a few days earlier and was prescribed clarithromycin for a respiratory tract infection. Past medical history of significance includes chronic obstructive pulmonary disease (COPD) for which she takes high-dose oral corticosteroid, tiotropium and oral theophylline, ischemic heart disease for which she takes ramipril, amlodipine and indapamide, and chronic kidney disease. On examination, she has a blood pressure of 135/70 mmHg and heart rate of 105 bpm that is irregularly irregular. There is also bilateral basal lung crackles consistent with mild left ventricular failure.

Her laboratory results are as follows:

  • Hemoglobin: 11.4 mg/dl (11.5-16.5)
  • WBC: 7 x 109/L (4x109 – 11x109)
  • Platelet: 197 x 109/L(150x109 – 400x109)
  • Serum sodium: 128 mmol/L (135 - 46)
  • Serum potassium: 4.0 mmol/L (3.5 – 5)
  • Creatinine: 178 μmol/L (79 – 118 μmol/L)

Which one of the following medication is most likely to have resulted in her presentation?

A. Amlodipine.
B. Indapamide.
C. Ramipril.
D. Theophylline.
E. Tiotropium.

A

B. Indapamide. (Thiazide-like diuretic)

Multiple medications, especially in a fragile elderly, is a common problem in general practice. Adverse effects and/or drug interactions can leave the patient with problems that in fact can outweigh the benefits of medications.

This woman has some abnormal laboratory findings. One is an elevated serum creatinine level which can be justified by the chronic kidney disease. Another is hyponatremia. Although both uremia in chronic kidney disease and hyponatremia can cause nausea and vomiting, considering the level of creatinine and the fact that she has chronic kidney disease, hyponatremia is more likely to have resulted in such presentation.

Hyponatremia is decrease in serum sodium concentration. Common causes of hyponatremia are:

  • Diuretic use
  • Diarrhea
  • Heart failure
  • Liver disease
  • Renal disease
  • Syndrome of inappropriate ADH secretion (SIADH)

Signs and symptoms of hyponatremia include nausea and vomiting, headache, short-term memory loss, confusion, lethargy, fatigue, loss of appetite, irritability, muscle weakness, spasms or cramps, seizures, and decreased consciousness or coma.

This patient has congestive heart failure, kidney disease. These can result in hyponatremia in isolation but none are an option. COPD can cause SIADH, but it is less likely to be the underlying cause compared to more probable scenarios.

This woman is also taking amlodipine (option A), indapamide, ramipril (option C), and also theophylline all of which can result in hyponatremia.

Amlodipine is a calcium channel blocker. Even low doses of this drug class can cause a marked increase in urinary sodium by up to four fold. Another mechanism of hyponatremia may be via direct action on the renal tubule with resultant increased sodium excretion and inhibition of renal sodium reabsorption.

Ramipril is an angiotensin converting enzyme inhibitor. Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatremia has been observed in some patients treated with ramipril. It is recommended that serum sodium levels be monitored regularly in the elderly who are taking this drug class.

Theophylline has sometime been associated with hyponatremia. A thiazide-like action of the drug on the stimulation of SIADH could be the underlying mechanism.

Indapamide is a thiazide-like diuretic. The mechanism of action is excretion of sodium and water via the loop of Henle.

Of these medications, however, indapamide is very well-known for hyponatremia and more likely to have caused hyponatremia among others. A mentioned before, diuretic use is a very common cause of hyponatremia.

For this patient, it is very important to stop indapamide and monitor the response very closely. Gentle fluid restriction and daily weighing is also recommended.

Tiotropium (Spiriva) (option E) is a member of the drug class anticholinergic bronchodilators which is used in inhalation form mostly in patients with COPD. Inhaled tiotropium is not a known cause of hyponatremia.

29
Q

Which one of the following is the most common adverse effect of aripiprazole?

A. Light-headedness.
B. Dizziness.
C. Bloating.
D. Sleepiness.
E. Tiredness.

A

A. Light-headedness.

Aripiprazole is an atypical antipsychotic used in treatment of schizophrenia, bipolar disorder, and depression with psychotic features. Reported adverse effects of aripiprazole in order of prevalence include:

> 10%

  • Weight gain (8-30%)
  • Headache (27%)
  • Agitation (19%)
  • Insomnia (18%)
  • Anxiety (17%)
  • Nausea and vomiting (11-15%)
  • Akathisia (10-13%)
  • Lightheadedness (11%)
  • Constipation (10-11%)

1-10%

  • Dizziness (10%)
  • Dyspepsia (9%)
  • Somnolence (5-8%)
  • Fatigue (6%)
  • Restlessness (6%)
  • Tremor (6%)
  • Dry mouth/xerostomia (5%)
  • Extrapyramidal disorder (5%)
  • Orthostatic hypotension (1-5%)
  • Musculoskeletal stiffness (4%)
  • Abdominal discomfort (3%)
  • Blurred vision (3%)
  • Cough (3%)
  • Pain (3%)
  • Myalgia (2%)
  • Rash
  • Rhinitis

< 1%

  • Altered mental status
  • Autonomic instability
  • Dysphagia
  • Hyperpyrexia
  • Muscle rigidity
  • Neuroleptic malignant syndrome (NMS)
  • Seizure
  • Tardive dyskinesia

Of the options, light-headedness is the most prevalence one (11%) followed by dizziness (10%) . Light-headedness is defined as a pre-faint state while dizziness is used by patients to imply or describe a sense of movement or even vertigo which is absent in light- headedness.

NOTE - Aripiprazole is a non-sedative antipsychotic. Insomnia is commonly reported adverse effect (18%), sleepiness (somnolence) has a prevalence of 5-8%.

30
Q

Janet, 55 years of age, has presented to your GP clinic with complaint of recent-onset hair loss for the past few weeks. The hair loss is generalized and not local to a specific area. She has bipolar disorder and had been on lithium for a long time until recently when her psychiatrist increased the dose and added carbamazepine because she had an acute manic attack despite being on lithium. She also has migraine for which she takes sumatriptan. Her other medications are aspirin for coronary artery disease and prophylactic dose of enoxaparin after she had a deep vein thrombosis of her left lower leg. Which one of the following medications is more likely to have caused the hair loss?

A. Aspirin.
B. Lithium.
C. Carbamazepine.
D. Enoxaparin.
E. Sumatriptan.

A

B. Lithium.

Hair loss and alopecia from medications is characteristically a diffuse nonscarring hair loss that occurs within days to weeks of starting a new medication or changing the dose. The development and severity of the hair loss depends on the medication and individual predisposition of the patient. While some medication cause hair loss in almost all patients (e.g., chemotherapy agents), others may affect only some patients.

There are two types of drug-induced hair loss:

Anagen effluvium – the shedding of actively growing hairs which is usually caused by chemotherapy drugs, or rarely with gold, colchicine, or poisoning with arsenic, bismuth, thaliumm or boric acid.

Telogen effluvium – the shedding of resting, or bulb hairs.

Telogen effluvium is the mechanism of virtually all other medication-induced hair loss. The list of possible drug causes is very long and includes:

  • Anti-coagulants: heparin, warfarin and possibly newer anticoagulants such as rivaroxaban, dabigatran and apixaban
  • Anti-hypertensives: beta-blockers, ACE inhibitors
  • hormones : oral contraceptives pills (during/after/changing), hormone replacement therapy, androgens
  • Anticonvulsants — valproic acid 12–28% (dose-dependent), carbamazepine up to 6%, phenytoin
  • Mood stabilizers and antidepressants — most, such as lithium 12–19%
  • Others — cimetidine, retinoids (acitretin > isotretinoin), antithyroid drugs, cholesterol-lowering drugs, interferons, anti-infective agents, amphetamines, nonsteroidal anti-inflammatory drugs (NSAIDs), bromocriptine, levodopa, some antipsychotics and anti-anxiety drugs, rarely tricyclic antidepressants such as amitriptyline.

Of the given options, lithium with the highest association of 12-19% among other options is the most likely cause for the hair loss. The second most likely cause could be carbamazepine (option C) (1.6-6%). Although the patient has been on lithium for a long time, the increased dose of lithium is still more likely to have resulted in the hair loss than carbamazepine.

Enoxaparin-induced hair loss is rather rare, and enoxaparin (option D) is less likely, yet not impossible, to have caused the issue. Aspirin (option A) and triptans e.g., sumatriptan (option E) are not associated with any clinically meaningful correlation with hair loss to date.

31
Q

A 70-year-old man presents to the Emergency Department for an ongoing central chest pain that started about 1 hour ago. He has the history of recurrent chest pains that are brought on with exertion and relieved with rest, and type II diabetes mellitus. Further assessment establishes the diagnosis of unstable angina. You start him on aspirin, clopidogrel, heparin, and glyceryl trinitrate. The on-call cardiologist advises that you start him on tirofiban as well if it is not contraindicated. Which one of the following is not a contraindication for tirofiban?

A. Non-ST elevation myocardial infarction (NSTEMI).
B. Acute pericarditis.
C. Vasculitis.
D. Aortic dissection.
E. History of intracranial neoplasm.

A

A. Non-ST elevation myocardial infarction (NSTEMI).

Tirofiban and abciximab are glycoprotein IIb/IIIa inhibitors. Their mechanism of action is preventing fibrin from binding to platelets by occupying the glycoprotein IIIa/IIb receptors. They may be indicated in management of unstable angina, or NSTEMI, particularly if early cardiac catheterization is planned.

Contraindications to their use include:

  • History of stroke within 30 days or any history of hemorrhagic stroke
  • Known history of intracranial disease (e.g., neoplasm, arteriovenous malformation, aneurysm)
  • Active or recent (within the previous 30 days) clinically relevant bleeding (e.g., gastrointestinal bleeding)
  • Malignant hypertension
  • Trauma or major surgical intervention within the past 6 weeks
  • Thrombocytopenia (platelet count < 100,000/mm3); disorders of platelet function
  • Clotting disturbances (e.g. prothrombin time >1.3 times normal or INR >1.5)
  • Severe liver failure

Tirofiban is not recommended in the following situations:

  • Traumatic or protracted cardiopulmonary resuscitation, organ biopsy or lithotripsy within the past 2 weeks
  • Severe trauma or major surgery > 6 weeks but < 3 months
  • Active peptic ulcer within past 3 months
  • Uncontrolled hypertension (>180/110 mm Hg)
  • Acute pericarditis
  • Active or a known history of vasculitis
  • Suspected aortic dissection
  • Hemorrhagic retinopathy
  • Occult blood in the stool or hematuria
  • Thrombolytic therapy
  • Concurrent use of drugs that increase the risk of bleeding
32
Q

A 45-year-old man is diagnosed with a primary lymphoma of the small bowel. In check for predisposing factors, which one of the following risk factors is most likely to be present?

A. Crohn disease.
B. Peutz-Jeghers syndrome.
C. Celiac disease.
D. Familial adenomatous polyposis.
E. Previous gastrectomy.

A

C. Celiac disease.

Approximately, 50% of small bowl malignancies are adenocarcinomas. The rest include carcinoid tumor, lymphoma, gastrointestinal stromal tumors, and metastatic deposits.

Of the given options, the most important risk factor for small bowl lymphoma is celiac disease. Other options are potential risk factors for development of small bowel adenocarcinoma (not lymphoma).

(Option A) Crohn disease is associated with a 100-fold increase in risk of small bowel adenocarcinoma in the affected areas, especially the distal ileum.

(Option B) Peutz – Jeghers syndrome, characterized by development of hamartomas which may undergo malignant changes, increases the risk of adenocarcinoma.

(Option D) Although patients with familial adenomatous polyposis are at significantly increased risk of colorectal cancer, duodenal and small bowel adenocarcinoma can also occur.

(Option E) Patients who have undergone gastrectomy more than 25 years ago are at increased risk of developing adenocarcinoma in the gastric stump.

33
Q

Which one of the following statements is correct about adenosine?

A. It blocks impulse transmission through atrioventricular (AV) node.
B. It has a short half-life of 10-15 minutes.
C. It is not contraindicated in asthmatic patients.
D. It is the first-line therapy for ventricular tachycardias.
E. It does not reduce heart rate.

A

A. It blocks impulse transmission through atrioventricular (AV) node.

Adenosine is the treatment of choice for narrow-complex supraventricular tachycardias (SVTs). The mechanism of action is by transient blockage of impulse transmission through AV node. It has no or little effect on myocytes or other parts of the cardiac conductive system. The half-life is short and 10-15 seconds. Adenosine is given as bolus, followed by saline flush.

It efficiently reduces the heart rate and improves cardiac output once the heart rate slowed down.

The following conditions are contraindications to adenosine administration:

  • Second- or third-degree AV block (except patients with a functioning artificial pacemaker)
  • Sinus node disease, such as sick sinus syndrome, or symptomatic sinus bradycardia (except in patients with a functioning artificial pacemaker)
  • Known or suspected bronchoconstrictive or bronchospastic disease such as asthma or COPD
  • Known hypersensitivity to adenosine
34
Q

Which one of the following malignancies is least treatable?

A. Hodgkin lymphoma (HL).
B. Non-Hodgkin lymphoma (NHL).
C. Breast cancer.
D. Testicular cancer.
E. Choriocarcinoma.

A

B. Non-Hodgkin lymphoma (NHL).

Of the options, NHL, with a 5-year survival of 66%, is the least treatable malignancy. Some malignancies and their 5-year survival rates are summarized in the following table:

35
Q

Which one of the following is not an ECG finding associated with digoxin use?

A. Prolonged QT interval.
B. Prolonged PR interval.
C. Inverted T waves.
D. Ventricular bigeminy.
E. ST depression.

A

A. Prolonged QT interval.

`There are 4 benign ECG changes associated with therapeutic levels of digoxin, including:

  1. T-wave changes such as flattening or inversion
  2. QT interval shortening
  3. “Scooped” appearance of ST segment with ST segment depression
  4. Increased amplitude of U-wave`

ECG changes in toxic levels include:

  • Frequent PVCs, especially in a sick heart – the most common arrhythmia
  • Supraventricular tachyarrhythmias
  • AV block (including PR interval lengthening in 1st degree AV block)
  • Junctional escape rhythms
  • Prolongation of PR interval
  • Bidirectional ventricular tachycardia with an alternating axis of the QRS complex is rare but the most specific ECG finding of digoxin toxicity.

Prolongation of QT interval is not an ECG feature of digoxin use or toxicity.

36
Q

Which one of the following is the most common cancer in Australia?

A. Lung cancer.
B. Skin cancer.
C. Breast cancer.
D. Prostate cancer.
E. Colorectal cancer.

A

B. Skin cancer.

Non-melanoma skin cancers (basal cell carcinoma and cutaneous squamous cell carcinoma) are the most common cancers in Australia.

Excluding non-melanoma skin cancers, the top five concerns in the Australian population in the order of prevalence are as follows:

  1. Prostate cancer
  2. Breast cancer (in females)
  3. Melanoma of the skin
  4. Colorectal cancer
  5. Lung cancer

However, once non-melanoma skin cancers (e.g., squamous and basal cell carcinoma) are included, skin cancer remains the most prevalent in Australia.

37
Q

A mother brings her 5-year-old boy to your practice for consultation. He has recently been started on FLixotide® (fluticasone propionate) inhaler, 4-hourly, after he was diagnosed with asthma. She wants to know about the adverse effects of this drug. Which one of the following is not an adverse effect of this medication?

A. Linear growth retardation.
B. Candidiasis.
C. Osteoporosis.
D. Weight gain.
E. Osteomalacia.

A

E. Osteomalacia.

Long-term inhaled corticosteroid use in asthmatic patients is associated with a number of complications. These complications can be local or systemic.

Local effects- local effects are the most common adverse effects of inhaled corticosteroids, and include:

  • Oropharyngeal Candidiasis
  • Dysphonia (hoarseness)

These adverse effects can be easily managed by rinsing the mouth and gargling with water after use.

Systemic effects- systemic adverse effects are far less common and may be seen in those on long-term high-dose inhaled corticosteroids:

  • Adrenal suppression
  • Bone loss (osteopenia and osteoporosis)
  • Skin thinning
  • Increased rate of cataract formation
  • Weight gain
  • Metabolic changes (alteration of glucose and lipid metabolism) Decreased linear growth in children
  • Psychiatric effects

Osteomalacia is not an adverse effect of inhaled corticosteroids.

38
Q

Which one of the following malignancies is associated with poorest prognosis?

A. Hodgkin lymphoma.
B. Non-Hodgkin lymphoma.
C. Testicular cancer.
D. Metastatic breast cancer.
E. Melanoma.

A

D. Metastatic breast cancer.

Hodgkin lymphoma has a 5-year survival of 86%, which is higher than that of non-Hodgkin lymphoma, 69%.

Testicular cancers often have an excellent prognosis and a 5-year-survival rate of approximately 98%. 5-year survival rate of melanoma is 86%.

Of the given options, metastatic breast cancer has the poorest prognosis. Unlike non-metastatic breast cancers that are associated with good prognosis, stage IV breast cancer or metastatic breast cancer is associated with a 5-year survival rate of 22% which is the lowest among other options.

An estimate of 5-year survival rates for different cancers is summarized in the following table:

39
Q

During a routine visit, a 50-year-old woman with a 10-year history of type 2 diabetes mellitus is found to have a blood pressure of 145/90 mmHg. Further assessment reveals microalbuminuria. The patient is planned to be started on ACE inhibitors. Which one of the following would be an absolute contraindication to use of an ACE inhibitor in this patient?

A. A previous history of angioneurotic edema.
B. Renal insufficiency.
C. Asthma.
D. A history of recent myocardial infarction.
E. A cardiac ejection fraction of <25%.

A

A. A previous history of angioneurotic edema.

Angiotensin converting enzyme (ACE) inhibitors are drugs of choice in diabetic patients who develop hypertension. Even in normotensive diabetics who develop microalbuminuria, ACE inhibitors or angiotensin receptor blockers (ARBs) are strongly recommended. ACE inhibitors, by inhibiting the angiotensin converting enzyme, result in dilation and consequently decreased hydrostatic pressure of the glomerular capillaries. The decreased hydrostatic pressure of the glomerular space leads to less protein extravasation into glomerulae and slowing down of the rate at which diabetic nephropathy develops.

`The only absolute contraindications to use of this drug class are:

  • Pregnancy
  • Previous angioedema following use of ACE inhibitors
  • Hypersensitivity to a specific ACE inhibitor.`

(Option B) Although ACE inhibitors are associated with decreased GFR, the benefit of delayed progression to renal failure outweighs the transient reduction in GFR in the long run. However, with significant reduction in GFR, either pre-existing or as a result of ACE inhibitor use, is a relative contraindication to using this drug class.

(Option C) Asthma is not a contraindication to use of ACE inhibitors.

(Options D and E) Myocardial infarction and heart failure (diastolic or systolic) are among main indications for ACE inhibitors.

40
Q

A 78-year-old man with advanced prostate cancer is found dead in his house. Which one of the following could be the most likely primary cause of his death?

A. Multi-organ failure.
B. Chronic renal failure.
C. Urinary tract infection.
D. Sepsis.
E. Heart attack.

A

A. Multi-organ failure.

Studies show that off all deaths in patients with metastatic (advanced) prostate cancer, almost 77.8% are directly related to the prostatic cancer, 5.5% from other cancers and, 16.7% from non-cancer causes.

This case represents a sudden death in a patient with advanced (terminal cancer) which is defined as an incident in which a patient who had been ambulatory, suddenly experiences a change in condition and dies within a day. Of the options, multiorgan failure seems to be the most common cause of such cancer-related sudden deaths.

Urinary tract infection (option C) can result in sepsis (option D) especially in the elderly with comorbid conditions. Additionally, sepsis is prevalent in patients with prostate cancer and the prevalence increases with time. However, this is multiorgan failure, as the end-result of the sepsis, that leads to death.

Cardiovascular disease, cerebrovascular disease, and lung diseases such as COPD and pulmonary embolism are the most common causes of non-cancer deaths in patients with advanced prostate cancer. An acute condition such as heart attack or pulmonary embolism might as well be the cause of this sudden death. Although there is a good chance that this patient has died of an acute coronary event i.e., heart attack (option E) or pulmonary embolism as well, the question asks about the most likely cause of primary cause of the death rather than conditions not directly related to the disease process (secondary causes).

While acute renal failure (either in isolation or as a part of multiorgan failure) could cause sudden death, chronic renal failure is less likely to have caused sudden death in this patient.

NOTE - the primary cause of death is the disease, situation, or event that started the chain of events resulting in death. Consequences or complication of this are usually considered secondary causes of death.

41
Q

A 65-year-old man, who is on selegiline for treatment of Parkinson disease, recently has been started on sertraline after he was diagnosed with major depression. Today, he is brought to the Emergency Department with abdominal pain, diarrhea, and confusion. Which one of the following would be the most appropriate next step in management?

A. Reduce sertraline.
B. Reduce selegiline.
C. Stop sertraline.
D. Stop selegiline.
E. Stop both sertraline and selegiline.

A

E. Stop both sertraline and selegiline.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) and selegiline is a monoamine oxidase inhibitor (MAOI) type B. The combination of the two is notorious as the most common cause of serotonin syndrome.

Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. Serotonin syndrome can occur with therapeutic medication use, inadvertent interactions between drugs, and intentional self-poisoning.

The clinical features of serotonin syndrome include:

  • Cognitive features: confusion, agitation, hypomania, hyperactivity, restlessness
  • Autonomic features: hyperthermia, sweating, tachycardia, hypertension, mydriasis, flushing, shivering
  • Neuromuscular features: clonus (spontaneous/inducible/ocular), hyperreflexia, hypertonia, ataxia, tremor

NOTE - Hypertonia and clonus are always symmetrical and are often much more dramatic in the lower limbs

The drugs implicated to cause serotonin syndrome and their mechanism of action are shown in the following table: -See photo below.-

Meticulous supportive care is the mainstay of therapy. Once serotonin syndrome is suspected, the most important initial management is to stop all serotonergic drugs at once and care be taken that no other precipitant be inadvertently administered.

In the presence of abdominal pain, diarrhea and confusion, serotonin is very likely; hence, both sertraline and selegiline should be stopped as the most important initial management.

If medical treatment is required, the serotonin antagonist cyproheptadine (antagonist of HT2) would be the first-line medication for treatment of moderate to severe serotonin syndrome.