Chapter 29 Quiz — The Peptide Drugs Already in Your Pharmacy

Twenty-two items. Mixed format: multiple choice, true/false with justification, and short answer. The answer key is collapsed at the bottom; work through the whole set before opening it.

1. Teriparatide is:

  • (a) full-length human parathyroid hormone
  • (b) the first 34 amino acids of human parathyroid hormone
  • (c) a synthetic analog of calcitonin
  • (d) a monoclonal antibody against a bone resorption target

2. Chronically elevated parathyroid hormone has what net effect on bone?

  • (a) it increases bone mineral density
  • (b) it has no measurable effect
  • (c) it removes bone
  • (d) it increases density in the spine and decreases it in the hip

3. True or false, with one sentence of justification: teriparatide works because it delivers more parathyroid hormone signal than the body produces on its own.

4. Teriparatide belongs to which class of osteoporosis agent, and what is the other main class?

5. The teriparatide boxed warning regarding osteosarcoma was:

  • (a) added on the basis of human trial data and never removed
  • (b) added on the basis of rodent data and later removed after human surveillance data accumulated
  • (c) added after post-marketing reports of human osteosarcoma
  • (d) never present; the concern was raised but not reflected in labeling

6. Desmopressin was engineered from vasopressin to favor which receptor subtype, and what effect does that subtype mediate?

7. Which of the following is not an approved indication for desmopressin?

  • (a) central diabetes insipidus
  • (b) primary nocturnal enuresis in children
  • (c) certain bleeding disorders
  • (d) vasodilatory shock

8. Desmopressin's role in bleeding disorders depends on V2 receptor stimulation causing which event?

9. The principal safety risk associated with desmopressin is:

  • (a) hyperkalemia
  • (b) hyponatremia
  • (c) rebound hypertension
  • (d) hepatic injury

10. Salmon calcitonin rather than human calcitonin is used therapeutically because:

  • (a) human calcitonin cannot be synthesized economically
  • (b) salmon calcitonin is more potent at the human calcitonin receptor
  • (c) human calcitonin is degraded too rapidly to formulate
  • (d) salmon calcitonin has fewer immunogenic epitopes

11. In the PROOF trial, the pattern that undermined confidence in the result was:

  • (a) the trial was stopped early for benefit
  • (b) the effect appeared in one dose arm but not consistently across higher doses
  • (c) the placebo arm outperformed the active arms
  • (d) the primary endpoint was changed after unblinding

12. True or false, with one sentence of justification: calcitonin lost its broad osteoporosis role because a scandal revealed suppressed safety data.

13. Vasopressin's use as a vasopressor in vasodilatory shock depends on which receptor subtype, and why is that pathway clinically useful alongside norepinephrine?

14. Terlipressin's most notable modern indication is:

  • (a) septic shock
  • (b) hepatorenal syndrome
  • (c) central diabetes insipidus
  • (d) hypercalcemia of malignancy

15. Glucagon is how many amino acids long, and from which precursor protein is it cut?

16. The key modern advance in emergency glucagon was:

  • (a) a more potent analog
  • (b) improved receptor selectivity
  • (c) nasal and stable ready-to-use liquid formulations that eliminate reconstitution
  • (d) extension of the half-life

17. In the glucagon story, the binding constraint on delivery was:

  • (a) proteolysis in the gut
  • (b) renal clearance
  • (c) the blood-brain barrier
  • (d) the untrained, frightened person who has to administer it

18. Cosyntropin is a synthetic fragment of which hormone, and what is it used to assess?

19. Secretin is notable in the history of endocrinology because:

  • (a) it was the first peptide to be chemically synthesized
  • (b) it was the first hormone ever identified
  • (c) it was the first peptide drug approved by a modern regulator
  • (d) it was the first hormone shown to act on an intracellular receptor

20. Cyclosporine is orally bioavailable in large part because of which combination of features?

  • (a) small size, high polarity, and rapid absorption
  • (b) cyclization, D-amino acid content, and N-methylation
  • (c) attached sugar groups and a lipid tail
  • (d) an absorption-enhancing excipient co-formulated with the drug

21. Linaclotide is taken orally and designed not to be absorbed. Explain in two sentences why that is a design goal rather than a failure, naming its receptor and where that receptor sits.

22. Short answer. State the §29.10 argument in three sentences: what are the five populated functional categories of approved peptide drugs, what is the sixth, and what does the sixth category's emptiness license you to conclude?

Answer key **1.** (b) — teriparatide is PTH(1–34), the N-terminal fragment carrying full receptor-activating capability at roughly 40% of the mass of full-length PTH. **2.** (c) — chronic elevation removes bone; this is what hyperparathyroidism does, and it has been understood for the better part of a century. **3.** **False.** Teriparatide does not work by delivering more signal. It works by delivering the signal in a different *temporal pattern* — once-daily pulses that rise and clear, rather than the sustained exposure that dissolves bone. The variable that changed is the shape of the exposure over time, not the amount in any simple sense. **4.** Teriparatide is an **anabolic** agent — it stimulates new bone formation. The other main class is **antiresorptive** (bisphosphonates, and the antibody denosumab), which slows removal of existing bone. Antiresorptives dominate prescribing; teriparatide is positioned for severe disease or very high fracture risk. **5.** (b) — rats developed osteosarcoma at high lifetime exposures, driving a boxed warning at approval; roughly two decades of human post-marketing surveillance did not show the expected excess, and the warning was subsequently removed with duration-of-use language relaxed. **6.** **V2**, which mediates water reabsorption in the renal collecting duct — the antidiuretic effect. Desmopressin was engineered to favor V2 over V1 (vasoconstriction) and to last longer than native vasopressin. **7.** (d) — vasodilatory shock is an indication for **vasopressin**, which acts through V1. That is the receptor desmopressin was specifically engineered away from. **8.** V2 stimulation triggers vascular endothelial cells to release stored **von Willebrand factor and factor VIII**. In mild hemophilia A or type 1 von Willebrand disease, mobilizing those endogenous stores can raise circulating levels enough to support hemostasis. **9.** (b) hyponatremia — a drug whose job is free water retention can dilute blood sodium, which is why fluid intake is a genuine clinical issue and why sodium monitoring is part of how the drug is used. **10.** (b) — salmon calcitonin is substantially more potent at the human calcitonin receptor than human calcitonin is, a genuinely odd piece of comparative endocrinology. **11.** (b) — the middle dose separated from placebo while the highest dose tested did not, or did so less clearly. A real effect usually shows a dose-response relationship; a scattered pattern is a reason to want replication, which never came at the necessary scale. PROOF also had considerable attrition, which was widely discussed. **12.** **False.** Nothing was hidden and nobody was punished. Better-evidenced competitors arrived, the fracture evidence never became strong, and regulatory reviews concluded the benefit-risk balance did not support the osteoporosis indication. It is the book's clearest example of a class contracting because the evidence improved. **13.** **V1** receptors on vascular smooth muscle. The pathway is useful because it is non-adrenergic: it adds vascular tone in parallel with catecholamines, allowing reduced norepinephrine requirements. Endogenous vasopressin is also often inappropriately low in prolonged vasodilatory shock. Trials including VASST and VANISH support an adjunct role; a general mortality benefit has not been convincingly demonstrated. **14.** (b) hepatorenal syndrome — kidney failure in advanced liver disease driven substantially by splanchnic vasodilation, which terlipressin counteracts by constricting the splanchnic circulation. **15.** **29 amino acids**, cut from the **proglucagon** precursor — the same precursor that yields GLP-1 in a different tissue with different processing enzymes (Chapter 7). **16.** (c) — the molecule did not change; the number of ways to fail did. **17.** (d) — this is the point of §29.6. Every problem in Chapter 4 is a contest between a peptide and a body. This one was a contest between a product and a panicking bystander, and it was solved by formulation and industrial design rather than by chemistry. **18.** Cosyntropin (tetracosactide) is **ACTH(1–24)**, a synthetic 24-residue fragment of adrenocorticotropic hormone. It is used to assess whether the adrenal cortex can respond — the standard test for adrenal insufficiency. **19.** (b) — secretin was the messenger Bayliss and Starling identified in 1902, the discovery that produced the concept of a hormone. It is now a workaday diagnostic agent for pancreatic exocrine function. **20.** (b) — cyclization defeats exopeptidases; a D-amino acid defeats protease recognition; N-methylation defeats protease recognition *and* removes backbone hydrogen-bond donors, which is what makes the molecule far more membrane-permeable than its size predicts. **21.** Linaclotide's target is the **guanylate cyclase-C receptor on the luminal surface of intestinal epithelial cells** — it faces the inside of the gut. The drug therefore needs to reach the gut lumen and nothing else; systemic absorption would add off-target exposure without adding therapeutic effect, so its confinement to the gut is the specification being met rather than a barrier being overcome. **22.** The five populated categories are: replace a missing or insufficient signal; suppress or block an overactive one; act locally within a defined compartment; kill a pathogen; and ask a diagnostic question. The sixth — broadly support, optimize, enhance, or modulate a healthy system — is empty. That emptiness does not prove any specific claim false, but it establishes an extremely strong prior: a claim of that type has never once succeeded in obtaining approval, despite fifty years of development, enormous commercial incentive, and more than eighty approved drugs in the class.