Clinical Pharmacology/Clinical Oncology Flashcards
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.
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.
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.
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
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. Idiosyncratic drug reaction
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/
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.
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.
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.
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
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.
B. Adverse drug reaction to lamotrigine.
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)
Which one of the following medications can cause tachycardia?
A. Propranolol.
B. Verapamil.
C. Diltiazem.
D. Nifedipine.
E. Metoprolol.
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.
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.
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.
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. 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.
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. 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.
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
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.
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.
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.
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.
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.
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. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
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:
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.
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:
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.
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.
