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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=Gonzalo Romero
|QuestionAuthor=Gonzalo Romero (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|MainCategory=Behavioral Science/Psychiatry, Pharmacology
|MainCategory=Pharmacology
|SubCategory=Neurology
|SubCategory=Neurology
|Prompt=A 75-year-old diabetic woman complains of worsening pain in her feet.  The pain started almost 7 months ago and has been increasing in severity lately.  The pain is localized in both feet, non-radiating and burning in nature. The patient admits that she has not been compliance with her diabetes medication.  Her vitals are blood pressure of 125/80 mmHg, heart rate of 70 beats/minute, temperature of 37 C and respiratory rate of 16 per minute. On physical exam, the patient has decreased sensation in the right and left legs below the knees and decreased Achilles tendon reflexes bilaterally. Laboratory tests reveal an HbA1c level of 15 mg/dL. The patient is educated about the important of adherence to diabetes medication and lifestyle changes to herald the progression of the different complications of diabetes.  The physician also considers the prescription of duloxetine to relieve the patient’s symptoms of pain in the feet. Which of the following is the mechanism of action of this drug?
|Prompt=A 79-year-old diabetic woman complains of worsening pain and burning sensation in both feet for the past 7 months. The patient admits that she has not been compliant with her diabetes medication.  Her blood pressure is 125/80 mmHg, heart rate is 70/minute, and temperature is 37 °C (98.6 °F). Neurological examination of the lower extremities reveals a 5/5 motor strength bilaterally, decreased pinprick sensation in both legs below the knees, with 1/4 Achilles tendon reflexes bilaterally. Laboratory tests reveal an HbA1c level of 10.8%. Following education on lifestyle changes and compliance to medications, the physician also prescribes duloxetine to relieve the patient’s symptoms. Which of the following is the mechanism of action of this drug?
|Explanation=This patient is presenting with peripheral diabetic neuropathy for which she is prescribed [[duloxetine]][[Duloxetine]] is a serotonin–norepinephrine reuptake inhibitor (SNRI). It inhibits [[norepinephrine]] and 5-HT reuptake. Its side effects are [[hypertension]], [[sedation]], [[nausea]] and stimulant effects.
|Explanation=Diabetic neuropathy is a symmetrical polyneuropathy that usually include the peripheral nerves, but may also be autonomic, proximal, or focal. It affects patients with long-standing and uncontrolled diabetes mellitus, usually manifesting as symmetrical painful and burning sensation in the lower extremities, starting in the feet. As the disease advances, diabetic neuropathy ascends proximally; and patients may eventually lose pain sensation due to advanced nerve injury. Motor, sensory, and autonomic nervous systems may all be affected; thus physical examination may be remarkable only for decreased sensation or a combination of findings. Of note, a 1/4 Achilles tendon reflexes is not a reliable finding in elderly patients because hyporeflexia of the Achilles tendon reflexes may be normal with aging.
 
   
'''Wiki-Mnemonics''': 
Duloxetine is a balanced selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI), which may be prescribed for patients with major depression, generalized anxiety disorder, panic disorder, peripheral neuropathy, and some cases of chronic pain. Duloxetine has central pain inhibitory activity by increasing the availability of both NE and 5-HT in the CNS. Both neurotransmitters are believed to act in synergy to decrease the pain signals transmitted from the PNS to the CNS. Notably, duloxetine has no effect on other receptors, such as histamine or opioid receptors. Duloxetine undergoes significant hepatic metabolism to inactive compounds by the cytochrome P-450 isoenzymes. It is subsequently eliminated in the urine (70-80%) and in the feces (20-30%).
# Duloxetine and velafaxine are '''DOBLE HITTERS''' = inhibit both NE and serotonin reuptake
# '''DUAL'''xetine = dual mechanism of action (inhibit both [[norepinephrine]] and [[serotonin]] reuptake)
|AnswerA=Serotonin reuptake inhibitor
|AnswerA=Serotonin reuptake inhibitor
|AnswerAExp=Selective serotonin reuptake inhibitors ([[SSRIs]]) inhibit 5-HT reuptake.  Examples of [[SSRI]] are [[paroxetine]], [[sertraline]], [[citalopram]] and [[sertraline]].  They are used for [[depression]], [[general anxiety disorder]], [[bulimia bulimia]], [[social phobias]], [[OCD]] and [[PTSD]]. Their side effects include [[sexual dysfunction]] and gastrointestinal distress.  When taken in excess, [[SSRI]] can cause [[serotonin syndrome]] if used in combination with other drugs that increase [[serotonin]].
|AnswerAExp=Selective serotonin reuptake inhibitors ([[SSRIs]]) inhibit [[5-HT]] reuptake.  Examples of [[SSRI]] are [[paroxetine]], [[sertraline]], [[citalopram]], and [[sertraline]].  They are prescribed for with [[depression]], [[generalized anxiety disorder]], [[bulimia nervosa]], [[social phobia]], [[OCD]], and [[PTSD]]. Their side effects include [[delayed ejaculation]] and gastrointestinal distress.  [[SSRI]] can cause [[serotonin syndrome]] if used in excess or in combination with other drugs that increase [[serotonin]] availability.
|AnswerB=Serotonin and norepinephrine reuptake inhibitor
|AnswerB=Serotonin and norepinephrine reuptake inhibitor
|AnswerBExp=[[Venlafaxine]] is a serotonin and norepinephrine reuptake inhibitor and is used for [[general anxiety disorder]] and [[panic disorders]].
|AnswerBExp=[[Duloxetine]] is a serotonin and norepinephrine reuptake inhibitor and may be prescribed for patients with major depression, peripheral neuropathy, [[generalized anxiety disorder]], [[panic disorders]], and some cases of chronic pain.
|AnswerC=Serotonin, norepinephrine and dopamine metabolism inhibitor
|AnswerC=Serotonin, norepinephrine, and dopamine metabolism inhibitor
|AnswerCExp=[[Monoamine oxidase inhibitors]] (MOI) increase the levels of [[norepinephrine]], 5-HT and [[dopamine]]. MOI include [[phenelzine]], isocarboxacid and [[selegiline]] which is a selective MAO-B inhibitor. They are prescribed mainly for [[atypical depression]]. The major side effects of MOI are hypertensive crisis when combined with [[tyramine]], a compound found in cheese and wine.
|AnswerCExp=Although duloxetine increases the availability of serotonin, norepinephrine, and possibly dopamine, it acts by inhibiting the reuptake of these neurotransmitters rather than reducing their rate of metabolism. On the other hand, [[monoamine oxidase inhibitors]] (MAOi) increase the levels of [[norepinephrine]], [[5-HT]], and [[dopamine]]. MAOi include [[phenelzine]], [[isocarboxazid]], and [[selegiline]] which is a selective MAO-B inhibitor. They may be prescribed for patients with [[atypical depression]], which includes hypersomnia, weight gain, and emotional lability. A classical side effect of MAOi is hypertensive crisis when combined with [[tyramine]], a compound found in cheese and wine. Duloxetine and MAOi should not be co-administered because both drugs increase the availability of 5-HT.
|AnswerD=Alpha-2 receptor antagonist
|AnswerD=Alpha-2 receptor antagonist
|AnswerDExp=[[Mirtazapine]] is an alpha-2 receptor antagonist. It is an atypical antidepressant which causes increase in appetite and weight gain, thus useful in the elderly and anorexic patients.
|AnswerDExp=[[Mirtazapine]] is an alpha-2 receptor antagonist. It is an atypical antidepressant which causes increase in appetite and weight gain. It may be useful among the elderly and anorexic patients.
|AnswerE=Alpha-2 receptor agonist
|AnswerE=Alpha-2 receptor agonist
|AnswerEExp=[[Methyldopa]] and [[clonidine]] are selective α2-adrenergic agonists. Methyldopa is used to treat [[hypertension]], especially in pregnant women. [[Clonidine]] can be used for [[hypertension]], [[anxiety]], [[panic disorder]], and certain pain conditions.
|AnswerEExp=[[Methyldopa]] and [[clonidine]] are selective alpha-2 adrenergic agonists. Methyldopa is used to treat [[hypertension]], especially among pregnant women. [[Clonidine]] can be prescribed for patients with [[hypertension]], [[anxiety]], [[panic disorder]], and certain pain conditions.
|EducationalObjectives=# Duloxetine is an atypical antidepressant, which can be used for peripheral diabetic neuropathy. It inhibits both NE and 5-HT reuptake, having a dual mechanism of action.
|EducationalObjectives=Duloxetine is an atypical antidepressant, which can be used for peripheral diabetic neuropathy. It has a dual mechanism of action because it inhibits both [[norepinephrine]] and [[5-HT]] reuptake.
# Venlaxafine has the same mechanism of action as duloxetine.
|References=Smith T, Nicholson RA. Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vasc Health Risk Manag. 2007;3(6):833-44.
|References=First Aid 2013 page 472-476
First Aid 2014 page 519
|RightAnswer=B
|RightAnswer=B
|WBRKeyword=diabetic neuropathy, elderly, peripheral, burning, sensation, uncontrolled, duloxetine, SNRI, serotonin, norepinephrine, 5-HT, NE,  endocrinology, Pharmacology, Diabetes mellitus, diabetes,
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:19, 27 October 2020

 
Author [[PageAuthor::Gonzalo Romero (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Pharmacology
Sub Category SubCategory::Neurology
Prompt [[Prompt::A 79-year-old diabetic woman complains of worsening pain and burning sensation in both feet for the past 7 months. The patient admits that she has not been compliant with her diabetes medication. Her blood pressure is 125/80 mmHg, heart rate is 70/minute, and temperature is 37 °C (98.6 °F). Neurological examination of the lower extremities reveals a 5/5 motor strength bilaterally, decreased pinprick sensation in both legs below the knees, with 1/4 Achilles tendon reflexes bilaterally. Laboratory tests reveal an HbA1c level of 10.8%. Following education on lifestyle changes and compliance to medications, the physician also prescribes duloxetine to relieve the patient’s symptoms. Which of the following is the mechanism of action of this drug?]]
Answer A AnswerA::Serotonin reuptake inhibitor
Answer A Explanation [[AnswerAExp::Selective serotonin reuptake inhibitors (SSRIs) inhibit 5-HT reuptake. Examples of SSRI are paroxetine, sertraline, citalopram, and sertraline. They are prescribed for with depression, generalized anxiety disorder, bulimia nervosa, social phobia, OCD, and PTSD. Their side effects include delayed ejaculation and gastrointestinal distress. SSRI can cause serotonin syndrome if used in excess or in combination with other drugs that increase serotonin availability.]]
Answer B AnswerB::Serotonin and norepinephrine reuptake inhibitor
Answer B Explanation [[AnswerBExp::Duloxetine is a serotonin and norepinephrine reuptake inhibitor and may be prescribed for patients with major depression, peripheral neuropathy, generalized anxiety disorder, panic disorders, and some cases of chronic pain.]]
Answer C AnswerC::Serotonin, norepinephrine, and dopamine metabolism inhibitor
Answer C Explanation [[AnswerCExp::Although duloxetine increases the availability of serotonin, norepinephrine, and possibly dopamine, it acts by inhibiting the reuptake of these neurotransmitters rather than reducing their rate of metabolism. On the other hand, monoamine oxidase inhibitors (MAOi) increase the levels of norepinephrine, 5-HT, and dopamine. MAOi include phenelzine, isocarboxazid, and selegiline which is a selective MAO-B inhibitor. They may be prescribed for patients with atypical depression, which includes hypersomnia, weight gain, and emotional lability. A classical side effect of MAOi is hypertensive crisis when combined with tyramine, a compound found in cheese and wine. Duloxetine and MAOi should not be co-administered because both drugs increase the availability of 5-HT.]]
Answer D AnswerD::Alpha-2 receptor antagonist
Answer D Explanation [[AnswerDExp::Mirtazapine is an alpha-2 receptor antagonist. It is an atypical antidepressant which causes increase in appetite and weight gain. It may be useful among the elderly and anorexic patients.]]
Answer E AnswerE::Alpha-2 receptor agonist
Answer E Explanation [[AnswerEExp::Methyldopa and clonidine are selective alpha-2 adrenergic agonists. Methyldopa is used to treat hypertension, especially among pregnant women. Clonidine can be prescribed for patients with hypertension, anxiety, panic disorder, and certain pain conditions.]]
Right Answer RightAnswer::B
Explanation [[Explanation::Diabetic neuropathy is a symmetrical polyneuropathy that usually include the peripheral nerves, but may also be autonomic, proximal, or focal. It affects patients with long-standing and uncontrolled diabetes mellitus, usually manifesting as symmetrical painful and burning sensation in the lower extremities, starting in the feet. As the disease advances, diabetic neuropathy ascends proximally; and patients may eventually lose pain sensation due to advanced nerve injury. Motor, sensory, and autonomic nervous systems may all be affected; thus physical examination may be remarkable only for decreased sensation or a combination of findings. Of note, a 1/4 Achilles tendon reflexes is not a reliable finding in elderly patients because hyporeflexia of the Achilles tendon reflexes may be normal with aging.

Duloxetine is a balanced selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI), which may be prescribed for patients with major depression, generalized anxiety disorder, panic disorder, peripheral neuropathy, and some cases of chronic pain. Duloxetine has central pain inhibitory activity by increasing the availability of both NE and 5-HT in the CNS. Both neurotransmitters are believed to act in synergy to decrease the pain signals transmitted from the PNS to the CNS. Notably, duloxetine has no effect on other receptors, such as histamine or opioid receptors. Duloxetine undergoes significant hepatic metabolism to inactive compounds by the cytochrome P-450 isoenzymes. It is subsequently eliminated in the urine (70-80%) and in the feces (20-30%).
Educational Objective: Duloxetine is an atypical antidepressant, which can be used for peripheral diabetic neuropathy. It has a dual mechanism of action because it inhibits both norepinephrine and 5-HT reuptake.
References: Smith T, Nicholson RA. Review of duloxetine in the management of diabetic peripheral neuropathic pain. Vasc Health Risk Manag. 2007;3(6):833-44. First Aid 2014 page 519]]

Approved Approved::Yes
Keyword WBRKeyword::diabetic neuropathy, WBRKeyword::elderly, WBRKeyword::peripheral, WBRKeyword::burning, WBRKeyword::sensation, WBRKeyword::uncontrolled, WBRKeyword::duloxetine, WBRKeyword::SNRI, WBRKeyword::serotonin, WBRKeyword::norepinephrine, WBRKeyword::5-HT, WBRKeyword::NE, WBRKeyword::endocrinology, WBRKeyword::Pharmacology, WBRKeyword::Diabetes mellitus, WBRKeyword::diabetes
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