A 20-year-old college student presents to the emergency room complaining of insomnia for the past 48 hours. He explains that although his body feels tired, he is "full of energy and focus" after taking a certain drug an hour ago. He now wants to sleep because he is having hallucinations. His vital signs are T 100.0 F, HR 110 bpm, and BP of 150/120 mmHg. The patient states that he was recently diagnosed with "inattentiveness." Which of the following is the mechanism of action of the most likely drug causing the intoxication?

Increases presynaptic dopamine and norepinephrine release from vesicles

Displaces norepinephrine from secretory vesicles leading to norepinephrine depletion

A 44-year-old man presents to the clinic worried about his risk for bladder cancer. His best friend who worked with him as a painter for the past 20-years died recently after being diagnosed with transitional cell carcinoma. He is worried that their long and heavy cigarette smoking history might have contributed to his death. He also reports that he has been feeling down since his friend's death 2 months ago and has not been eating or sleeping as usual. He took time off from work but now is running past due on some of his bills. He feels like he is moving a lot slower than usual. He would like to stop smoking but feels like it's impossible with just his willpower. What side-effect is most likely if this patient were started on his appropriate pharmacotherapy?

Can treat overdose with sodium bicarbonate

Can cause restlessness at initiation or termination

Can cause sedation and weight gain

Can worsen uncontrolled hypertension

A 48-year-old woman presents to her primary care physician for a wellness visit. She states she is generally healthy and currently has no complaints. She drinks 1 alcoholic beverage daily and is currently sexually active. Her last menstrual period was 1 week ago and it is regular. She smokes 1 pack of cigarettes per day and would like to quit. She describes her mood as being a bit down in the winter months but otherwise feels well. Her family history is notable for diabetes in all of her uncles and colon cancer in her mother and father at age 72 and 81, respectively. She has been trying to lose weight and requests help with this as well. Her diet consists of mostly packaged foods. Her temperature is 98.0°F (36.7°C), blood pressure is 122/82 mmHg, pulse is 80/min, respirations are 12/min, and oxygen saturation is 98% on room air. Her BMI is 23 kg/m^2. Physical exam reveals a healthy woman with no abnormal findings. Which of the following is the most appropriate initial intervention for this patient?

Weight loss, exercise, and nutrition consultation

A 35-year-old man presents to his primary care physician for a routine visit. He is in good health but has a 15 pack-year smoking history. He has tried to quit multiple times and expresses frustration in his inability to do so. He states that he has a 6-year-old son that was recently diagnosed with asthma and that he is ready to quit smoking. What is the most effective method of smoking cessation?

Bupropion in conjunction with nicotine replacement therapy and cognitive behavioral therapy

Nicotine replacement therapy alone

Participating in a smoking-cessation support group

A researcher is currently working on developing new cholinergic receptor agonist drugs. He has formulated 2 new drugs: drug A, which is a selective muscarinic receptor agonist and has equal affinity for M1, M2, M3, M4, and M5 muscarinic receptors, and drug B, which is a selective nicotinic receptor agonist and has equal affinity for NN and NM receptors. The chemical structure and mechanisms of action of both drugs mimic acetylcholine. However, drug A does not have any nicotinic receptor activity and drug B does not have any muscarinic receptor activity. Which of the following statements is most likely correct regarding these new drugs?

Drug B acts by stimulating a receptor which is composed of 5 subunits

Drug B may produce some of its effects by activating the IP3-DAG (inositol triphosphate-diacylglycerol) cascade

Drug A acts by causing conformational changes in ligand-gated ion channels

Drug A acts on receptors located at the neuromuscular junctions of skeletal muscle

Drug A acts by stimulating a receptor which is composed of 6 segments

A 62-year-old man is referred to a gastroenterologist because of difficulty swallowing for the past 5 months. He has difficulty swallowing both solid and liquid foods, but there is no associated pain. He denies any shortness of breath or swelling in his legs. He immigrated from South America 10 years ago. He is a non-smoker and does not drink alcohol. His physical examination is unremarkable. A barium swallow study was ordered and the result is given below. Esophageal manometry confirms the diagnosis. What is the most likely underlying cause of this patient’s condition?

Pharyngoesophageal diverticulum

Gastroesophageal reflux disease

Squamous cell carcinoma of the esophagus

Tobacco use disorder — USMLE Lesson

Pathophysiology - The Nicotine Hijack

Primary Target: Nicotine is a potent agonist at nicotinic acetylcholine receptors (nAChRs) in the central nervous system.
Reward Pathway Activation:
- Binds to α4β2 nAChRs in the Ventral Tegmental Area (VTA).
- Triggers dopamine release in the Nucleus Accumbens (NAc) and prefrontal cortex.
- This activation of the mesolimbic reward system produces pleasure and powerfully reinforces tobacco use.
Neuroadaptation & Withdrawal:
- Chronic use upregulates nAChRs, leading to tolerance.
- Abrupt cessation causes a hypo-dopaminergic state, resulting in withdrawal symptoms like irritability, craving, and anxiety.

Nicotine’s Effect on Dopaminergic Neuron Signaling

⭐ Varenicline (Chantix) works as a partial agonist at the α4β2 nAChR, reducing cravings and blunting the rewarding effects of nicotine if the patient relapses.

Clinical Features - Smoke & Mirrors

Core Features (DSM-5):
- Using larger amounts or for longer than intended.
- Persistent desire or unsuccessful efforts to cut down.
- Significant time spent obtaining, using, or recovering from tobacco.
- Craving: A powerful, compulsive urge to use.
- Continued use despite physical or psychological problems (e.g., COPD, anxiety).
Physical Signs:
- "Smoker's cough," dyspnea, wheezing.
- Yellow/brown stains on teeth and fingers.
- Premature skin wrinkling.
Withdrawal Syndrome:
- Onset within 24 hours of cessation; peaks at 1-3 days.
- 📌 CRAVED: Craving, Restlessness, Anxiety/Anger, Vexation, Eating more (weight gain), Depressed mood/Difficulty concentrating.

⭐ The number of cigarettes smoked per day and the time to the first cigarette after waking are key indicators of nicotine dependence severity.

Management - The Quitting Blueprint

Counseling & Behavioral Support (The 5 A's)
- Ask: Systematically identify all tobacco users at every visit.
- Advise: Strongly urge all tobacco users to quit.
- Assess: Determine willingness to make a quit attempt.
- Assist: Aid the patient in quitting (pharmacotherapy, counseling).
- Arrange: Schedule follow-up.
Pharmacotherapy: First-Line Options
- Varenicline: Partial nicotinic receptor agonist. Most effective single agent.
- Bupropion: Antidepressant (NDRI). CI: Seizure d/o, eating disorders.
- Nicotine Replacement Therapy (NRT):
  - Long-acting: Patch
  - Short-acting: Gum, lozenge, inhaler, nasal spray.
  - Combination (patch + short-acting) is superior to monotherapy.

⭐ Varenicline's partial agonism reduces withdrawal cravings while simultaneously blocking nicotine from binding, which blunts the rewarding effect of smoking.

Quitting Algorithm

Nicotine withdrawal is characterized by irritability, anxiety, and intense cravings, peaking within 1-2 days.

First-line treatments include varenicline (a partial nicotinic agonist) and bupropion (an NDRI antidepressant).

Varenicline can increase the risk of cardiovascular events in susceptible individuals.

Bupropion is contraindicated in patients with seizure or eating disorders (e.g., bulimia).

Combining behavioral counseling with pharmacotherapy is the most effective treatment approach.

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