CASE STUDY 1

A 70-year-old man is seen in follow-up at your office after he has been hospitalized for a myocardial infarction (MI). He underwent successful angioplasty and is currently asymptomatic. Prior to his MI, he was not on medications. He is not a smoker and is not diabetic. During his hospitalization, he was noted to have persistently elevated blood pressure readings. He had asthma as a child, but has not had any recent wheezing episodes. While in the hospital, he was started on oral metoprolol. Metoprolol is selective for which adrenoceptor? What effects do agents such as metoprolol have on the cardiovascular system? In which organ is metoprolol primarily metabolized? Why must b-adrenergic antagonists be used with caution in asthmatics?

Summary: A 70-year-old hypertensive man with a childhood history of asthma had a recent myocardial infarction and is prescribed metoprolol. Adrenoceptor selectively antagonized by metoprolol: 1. Effect of b-adrenoceptor antagonists on the cardiovascular system: Reduction of sympathetic-stimulated increases in heart rate, contractility, and cardiac output; lower blood pressure as a result of effects on the heart, reninangiotensin system, and CNS; increased atrioventricular (AV) conduction time and refractoriness. Organ in which metoprolol is metabolized: Liver. Reason for caution in use in asthmatics: Blockade of 2-adrenoceptor in bronchial smooth muscle may cause increased airway resistance and bronchospasm. CLINICAL CORRELATION -Adrenergic receptor antagonists are widely used in medicine, primarily for their beneficial effects on the cardiovascular system and for lowering intraocular pressure in patients with glaucoma. Both the nonselective -adrenoreceptor antagonists and the relatively 1-adrenoceptor selective antagonists are used to treat hypertension. The mechanism of their action is multifactorial, probably including reduction in cardiac output, reduction in renin release, and some CNS effect. They are also beneficial for treating coronary artery disease and postmyocardial infarction patients as they reduce sympathetic-stimulated increases

in heart rate and contractility. This helps to reduce myocardial oxygen demand, providing prophylaxis for angina. b-Adrenoceptor antagonists have a proven benefit in prolonging survival after heart attacks. They lengthen AV conduction time and refractoriness and suppress automaticity. This helps to prevent both supraventricular and ventricular arrhythmias. Caution must be used when giving -blockers to patients with asthma, COPD, and diabetes. All adrenoceptor blockers, including those that are 1-adrenoceptor selective, have some 2-adrenoceptor antagonist activity and may cause bronchospasm by their effects on bronchial smooth muscle. They can also mask the symptoms of hypoglycemia in a diabetic by blocking the adrenergic stimulated symptoms of tremor, tachycardia, and nervousness that would normally occur.

CASE STUDY 2:
Following his third episode of gouty arthritis, a 50-year-old man sees you in the clinic. Each case was successfully treated acutely; however, your patient is interested in trying to prevent future episodes. He is not on regular medications and has a normal physical examination today. Blood work reveals an elevated serum uric acid level and otherwise normal renal function and electrolytes. A 24-hour urine collection for uric acid reveals that he is underexcreting uric acid. Suspecting that this is the cause of his recurrent gout, you place him onprobenecid. What is the mechanism of action of probenecid? Which drugs could have their excretion inhibited by probenecid?

Summary: A 50-year-old man with recurrent gout is prescribed probenecid. Mechanism of action of probenecid: Inhibits secretion of organic acids and decreases reabsorption of uric acid, causing a net increase in secretion. Other drugs whose secretion could be inhibited: Penicillin, indomethacin, and methotrexate. CLINICAL CORRELATION Gout is a disease in which uric acid crystals deposit in joints, causing an extremely painful acute inflammatory arthritis. Persons with recurrent gout often have chronically elevated levels of uric acid in their blood. This hyperuricemia is frequently caused by either overproduction of uric acid or underexcretion of uric acid by the kidneys. Probenecid (and other uricosuric drugs) promotes the excretion of uric acid. It works by inhibiting the secretion of organic acids from the plasma into the tubular lumen and blocking the reuptake of uric acid. The net result of this is an increase in the secretion of uric acid. The benefit of this is the prevention of recurrent gout attacks in chronic underexcreters of uric acid. In those individuals who overproduce uric acid, allopurinol is used. This inhibits xanthine oxidase, a key enzyme in the production of uric acid.

CASE STUDY 3
A healthy 25-year-old man is undergoing a brief surgical procedure requiring general anesthesia. He underwent an unremarkable intubation and induction of anesthesia using IV succinylcholine and inhaled halothane. During the surgery the patient develops muscle rigidity and tachycardia, and his temperature rapidly rises. What is the mechanism of action of succinylcholine? What reaction is occurring in the patient? What drug should immediately be given to the patient, and what is its mechanism of action?

Summary: A 25-year-old man develops muscle rigidity, tachycardia, and high fever during surgery . Mechanism of action of succinylcholine: Nicotinic receptor agonist at the motor endplate of the neuromuscular junction, which causes persistent stimulation and depolarization of muscle cells. Reaction that is occurring: Malignant hyperthermia. Drug given for treatment and its mechanism of action: Dantrolene, which acts by interfering with calcium release from the sarcoplasmic reticulum. CLINICAL CORRELATION Succinylcholine is the only depolarizing neuromuscular agent in wide clinical use. It is used for the rapid induction of a brief flaccid paralysis. It works as an agonist of the nicotinic receptor at the motor endplate of the neuromuscular junction. This causes a persistent stimulation and depolarization of the muscle, preventing stimulation of contraction by ACh. It has a rapid onset and short duration of action because it is quickly hydrolyzed by plasma and liver cholinesterase. Malignant hyperthermia, a rare but significant cause of anesthetic morbidity and mortality, is an inherited autosomal dominant disorder that results in tachycardia, muscle rigidity, and high body temperatures in response to the use of certain inhaled anesthetics in combination with muscle relaxants, usually succinylcholine. It is caused by a release of calcium ions from the sarcoplasmic reticulum in muscle cells. Dantrolene interferes with this release and is therefore the treatment of choice for this condition.

CASE STUDY 4
A 61-year-old man is noted to have increased intraocular pressure on a routine eye examination. The visual acuity is normal in both eyes. The dilated eye examination reveals no evidence of optic nerve damage. Visual field testing shows mild loss of peripheral vision. He is diagnosed with primary open-angle glaucoma and is started on pilocarpine ophthalmic drops. What is the action of pilocarpine on the muscles of the iris and cilia? What receptor mediates this action? Is pilocarpine the appropriate first-line drug for treatment of primary open-angle glaucoma? Summary: A 61-year-old man with open-angle glaucoma is prescribed pilocarpine ophthalmic drops. Action of pilocarpine on muscles of the iris and cilia: Constriction of the muscles Receptor that mediates this action: Muscarinic cholinoreceptor First-line drugs to treat primary open-angle glaucoma: Prostaglandin analogs CLINICAL CORRELATION Open-angle glaucoma is a disease caused by obstruction of the outflow of aqueous humor into the canal of Schlemm, causing an increase in intraocular pressure. The use of a direct-acting muscarinic agonist, such as pilocarpine, causes contraction of the muscles of the cilia and iris. Because these are circular muscles, the pupil is constricted, which helps to relieve the outflow obstruction and lower the intraocular pressure. Although not common with the use of topical ophthalmic drops, bronchospasm and pulmonary edema has been noted with the use of pilocarpine drops. More commonly, blurred vision and myopia (nearsightedness) occur as a result of the\ impairment of accommodation caused by the contraction of the iris and ciliary muscles. The use of a direct-acting muscarinic agonist such as pilocarpine to treat open-angle glaucoma is now not common due to its numerous side effects, the need to administer it up to four times per day, and the availability of other agents. Prostaglandin analogs such as latanoprost are now considered firstline therapy for this condition followed by -adrenoceptor agonists.

CASE STUDY 5
A 12-year-old girl presents to your office with a sore throat and fever. You diagnose her with pharyngitis caused by group A -hemolytic Streptococcus. She is given an IM injection of penicillin. Approximately 5 minutes later, she is found to be in respiratory distress and audibly wheezing. Her skin is mottled and cool, she is tachycardic (rapid heart rate), and her blood pressure has fallen to 70/20 mm Hg. You immediately diagnose her as having an anaphylactic reaction to the penicillin and give an SC injection of epinephrine. What effect will epinephrine have on this patients vascular system? Which adrenoceptor primarily mediates the vascular response? What effect will epinephrine have on her respiratory system? Which adrenoceptor primarily mediates the respiratory system response? Summary: A 12-year-old girl with strep throat is given an injection of penicillin and develops an acute anaphylactic reaction. Effect of epinephrine on vascular system: Vasoconstriction. Adrenoceptor which primarily mediates the vascular response: Alpha-1 (1). Effect of epinephrine on the pulmonary system: Bronchial muscle relaxation. Adrenoceptor which primarily mediates the pulmonary response: Beta-2 (2). CLINICAL CORRELATION Anaphylaxis is an acute, immune-mediated response to an allergen characterized by bronchospasm, wheezing, tachycardia, and hypotension. Epinephrine is the drug of choice used to treat this condition because it appears, through the activation of alpha ()- and beta ()-adrenoceptors, to counteract the pathophysiologic processes underlying anaphylaxis. As with all emergencies, the ABCs (airway, breathing, circulation) should be addressed first. Occasionally, the anaphylaxis causes laryngeal edema to the extent that the airway is compromised, and intubation (placement of a tube in the trachea) is impossible. In these circumstances, an emergency airway, is required.