WBR0093

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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